Note: Descriptions are shown in the official language in which they were submitted.
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
CONTENANT LES PAGES 1 A 353
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
THIS IS VOLUME 1 OF 2
CONTAINING PAGES 1 TO 353
NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
TRACELESS LINKERS AND PROTEIN-CONJUGATES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of United States Provisional
Application No.
62/872,229, filed July 9, 2019; United States Provisional Application No.
62/937,721, filed
November 19, 2019; PCT Patent Application No. PCT/U52019/012786, titled
Steroids and
Antibody Conjugates Thereof, which was filed January 8, 2019; and US Patent
Application No.
16/243,020, titled Steroids and Antibody Conjugates Thereof, which was also
filed January 8, 2019.
The contents of each priority patent application are incorporated herein by
reference in their
entireties for all purposes.
FIELD
[0002] Provided herein are novel traceless linkers, and protein conjugates
thereof, and methods
for treating a variety of diseases, disorders, and conditions including
administering compounds or
payloads via traceless linker-payloads, and protein conjugates thereof
BACKGROUND
[0003] Antibody-drug conjugates (ADCs) are antibodies that are covalently
linked to
biologically active small molecule drugs, often referred to as payloads, thus
combining the targeting
specificity of antibodies with the mode-of-action and potency of small
molecule drugs. The
therapeutic utility of ADC(s) has been validated in cancer treatment and is a
major ongoing focus
of study. ADCETRIS (bentruximab vedotin) and KADCYLA (ado-trastuzumab
emtansine) are
ADCs approved for the treatment of certain cancer types, and several other
ADCs are currently in
clinical development.
[0004] Glucocorticoids (GCs) are small molecule steroids that bind to
glucocorticoid receptors
(GRs) and are utilized in anti-inflammatory and immunosuppressive therapies.
However, due to the
ubiquitous expression of glucocorticoid receptors in many cell types,
glucocorticoid treatments are
compromised by toxicities to most organ systems. Thus, there is need for both
novel glucocorticoids
as well as novel therapies that minimize the side effects arising from
glucocorticoid administration,
particularly those arising from activating glucocorticoid receptors in non-
target cells. The instant
disclosure provides solutions to the aforementioned needs as well as other
unmet needs in the field
to which the instant disclosure pertains. Included in the instant disclosure
are antibody-drug
conjugates comprising glucocorticoid payloads.
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[0005] Liver X Receptor (LXR) includes LXRa and LXR13 which are ligand-
dependent
transcription factors that control the expression of genes involved in
cholesterol, lipid and glucose
homeostasis, inflammation, and innate immunity. LXRa is highly expressed in
liver, intestine,
adipose tissue, and differentiated macrophages; and LXR13 is ubiquitously
expressed. LXRs have
various biological functions including (i) stimulating the expression of
cholesterol transporters, for
example, ABCA1 and ABCG1, both of which mediate cellular cholesterol efflux;
and (ii) negatively
regulating macrophage inflammatory gene expression via repression of NF-kB
activation. LXRs
have also been implicated in atherosclerosis, proliferative disorders,
neurodegeneratiye disorders,
and inflammation. The development of ADCs comprising LXR modulators would
allow for target-
specific modulation of LXR, thereby avoiding side-effects caused by off-target
modulation of LXR.
Furthermore, such ADCs would provide improved modulation of biological
targets, improved
bioavailability, and improved therapeutic window. Therefore, there is a
continuing need for
effective treatments of, for example, metabolic diseases using small molecule
ADCs of LXR
modulators.
[0006] Linkers covalently link the payload portion, e.g., small molecule
therapeutic agent of an
ADC to its antibody. A significant challenge in linker design is in finding
moieities that keep the
payload stably attached to the antibody during storage, formulation,
administration, and plasma
circulation in the patient, yet allow efficient release upon the antibody
binding its target, that allow
facile conjugation to the payload under synthesis conditions, and that allow
release of the intended
payload without alteration in structure. There is a continuing need for
linkers that possess these and
other attributes.
SUMMARY
[0007] Provided herein are novel traceless linkers, and protein conjugates
thereof, and methods
for treating a variety of diseases, disorders, and conditions including
administering compounds or
payloads via traceless linker-payloads, and protein conjugates thereof
Included herein are linkers
that bond with a hydroxyl group of a payload and allow release of the payload
under appropriate
conditions with its hydroxyl group intact.
[0008] Provided herein are compounds, compositions, and methods useful for
treating, for
example, inflammatory diseases and autoimmune disorders, or managing symptoms
of any diseases,
disorders, or conditions associated with the glucocorticoid receptor,
glucocorticoid binding, and/or
2
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
glucocorticoid receptor signalling; and/or dyslipidemia, a metabolic disease,
inflammation, or a
neurodegenerative disease, in a subject.
[0009] In one embodiment, provided are compounds having the structure of
Formula I:
ir ORla Rib
R2 i43
-n
or a pharmaceutically acceptable salt thereof, wherein Rla and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein
when RI-a is alkylene or heteroalkylene, the alkylene or heteroalkylene is
further bonded to 123 to
form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl; R2 is hydrogen,
alkylene, heteroalkylene, or
an amino acid side chain, wherein when R2 is alkylene or heteroalkylene, the
alkylene or
heteroalkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; R3 is hydrogen,
alkyl, alkylene, or heteroalkylene, wherein when R3 is alkylene or
heteroalkylene, the alkylene or
heteroalkylene is further bonded to Rla or R2 to form the 3-, 4-, 5-, 6-, 7-,
or 8 membered
heterocyclyl; R4 is hydrogen or alkyl; R5 is oxygen, NR6, or sulfur; R6 is
hydrogen or alkyl; D* is
acyl, or a residue of a biologically active compound comprising hydroxyl,
amino, or thiol; and n is
zero, one, two, three, four, five, or six.
[0010] In one embodiment, provided are compounds having the structure of
Formula I:
ir ORla Rib
R2 i43
-n
(I)
or a pharmaceutically acceptable salt thereof, wherein Rla and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein
when RI-a is alkylene or heteroalkylene, the alkylene or heteroalkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or an amino
acid side chain, wherein when R2 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is
hydrogen, alkyl, alkylene,
or heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
3
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
further bonded to Rla or R2 to form the 4-, 5-, or 6-membered heterocyclyl; R4
is hydrogen or alkyl;
R5 is oxygen, NR6, or sulfur; R6 is hydrogen or alkyl; D* is acyl, or a
residue of a biologically active
compound comprising hydroxyl, amino, or thiol; and n is zero, one, two, three,
four, or five.
[0011] In another embodiment, provided are linker-payload compounds having
the structure of
Formula II:
- -
R4 0 Ria Rib
I
N
L'' YL N R5¨D*
R2 R3
- -n
or a pharmaceutically acceptable salt thereof, wherein L is a linker
comprising a moiety reactive
with an antibody or an antigen binding fragment thereof; R" and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein
when R" is alkylene or heteroalkylene, the alkylene or hetereoalkylene is
further bonded to 123 to
form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl; R2 is hydrogen,
alkylene, heteroalkylene, or
an amino acid side chain, wherein when R2 is alkylene or heteroalkylene, the
alkylene or
heteroalkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; R3 is hydrogen,
alkyl, alkylene, or heteroalkylene, wherein when R3 is alkylene or
heteroalkylene, the alkylene or
heteroalkylene is further bonded to Rla or R2 to form the 3-, 4-, 5-, 6-, 7-,
or 8-membered
heterocyclyl; R4 is hydrogen or alkyl; R5 is oxygen, NR6, or sulfur; R6 is
hydrogen or alkyl; D* is
acyl, or a residue of a biologically active compound comprising hydroxyl,
amino, or thiol; and n is
zero, one, two, three, four, five, or six.
[0012] In another embodiment, provided are linker-payloads having the
structure of Formula II:
- -
R4 0 Ria Rib
I
N
L'' YLN R5¨D*
R2 R3
- -n
(II)
or a pharmaceutically acceptable salt thereof, wherein L is a linker
comprising a moiety reactive
with an antibody or an antigen binding fragment thereof; R" and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein
when R" is alkylene or heteroalkylene, the alkylene or hetereoalkylene is
further bonded to R3 to
4
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or an amino
acid side chain, wherein when R2 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is
hydrogen, alkyl, alkylene,
or heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R" or R2 to form the 4-, 5-, or 6-membered heterocyclyl; R4
is hydrogen or alkyl;
R5 is oxygen, NR6, or sulfur; R6 is hydrogen or alkyl; D* is acyl, or a
residue of a biologically active
compound comprising hydroxyl, amino, or thiol; and n is zero, one, two, three,
four, five, or six.
[0013] In another embodiment, provided are compounds having the structure
of Formula III:
¨ ¨
R4 0 Ria Rib
I
N
BA¨L"- YLN )( R5 ¨D*
R2 R3
- -n
¨ ¨k
wherein L is a linker; BA is a binding agent; Rla and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein when RI-a
is alkylene or heteroalkylene, the alkylene or heteroalkylene is further
bonded to R3 to form a 3-, 4-
5-, 6-, 7-, or 8-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or an amino acid
side chain, wherein when R2 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is hydrogen,
alkyl, alkylene, or
heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is
further bonded to RI-a or R2 to form the 3-, 4-, 5-, 6-, 7-, or 8-membered
heterocyclyl; R4 is hydrogen
or alkyl; R5 is oxygen, NR6, or sulfur; R6 is hydrogen or alkyl; D* is a
residue of a biologically
active compound comprising hydroxyl, amino, or thiol; n is zero, one, two,
three, four, five, or six;
and k is an integer from one to thirty.
[0014] In another embodiment, provided are compounds having the structure
of Formula III:
¨ ¨
R4 0 Ria Rib
I
N
BA¨L"- ))'( N )( R5 ¨D*
R2 R3
- -n
¨ ¨k
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
wherein L is a linker; BA is a binding agent; Rla and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein when Ria
is alkylene or heteroalkylene, the alkylene or heteroalkylene is further
bonded to R3 to form a 3-, 4-
5-, 6-, 7-, or 8-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or an amino acid
side chain, wherein when R2 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is hydrogen,
alkyl, alkylene, or
heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is
further bonded to Ria or R2 to form the 3-, 4-, 5-, 6-, 7-, or 8-membered
heterocyclyl; R4 is hydrogen
or alkyl; R5 is oxygen, NR6, or sulfur; R6 is hydrogen or alkyl; D* is a
residue of an anti-
inflammatory biologically active compound comprising hydroxyl, amino, or
thiol; n is zero, one,
two, three, four, five, or six; and k is an integer from one to thirty.
[0015] In another embodiment, provided are compounds having the structure
of Formula III:
¨ ¨
R4 0 Rla Rib
I
N
BA-L'' ))LN )R5¨D*
R2 R3
- -n
¨ ¨k
wherein L is a linker comprising PAB or PABC; BA is a binding agent; Rla and
Rib are,
independently, hydrogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,
heteroaryl, alkylene, or
heteroalkylene, wherein when Ria is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R3 to form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl;
R2 is hydrogen,
alkylene, heteroalkylene, or an amino acid side chain, wherein when R2 is
alkylene or
heteroalkylene, the alkylene or heteroalkylene is further bonded to R3 to form
a 4-, 5-, or 6-
membered heterocyclyl; R3 is hydrogen, alkyl, alkylene, or heteroalkylene,
wherein when R3 is
alkylene or heteroalkylene, the alkylene or heteroalkylene is further bonded
to Rla or R2 to form the
3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl; R4 is hydrogen or alkyl; R5 is
oxygen, NR6, or sulfur;
R6 is hydrogen or alkyl; D* is a residue of a biologically active compound
comprising hydroxyl,
amino, or thiol; n is zero, one, two, three, four, five, or six; and k is an
integer from one to thirty.
[0016] In another embodiment, provided are compunds having the structure of
Formula III:
6
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R4 0 Ria Rib
BA_LNNR5_D*
R2 R3
¨ n
¨k
wherein L is a linker; BA is a binding agent; Rla and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein when 12"
is alkylene or heteroalkylene, the alkylene or heteroalkylene is further
bonded to R3 to form a 3-, 4-
5-, 6-, 7-, or 8-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or an amino acid
side chain, wherein when R2 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is hydrogen,
alkyl, alkylene, or
heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is
further bonded to R" or R2 to form the 3-, 4-, 5-, 6-, 7-, or 8-membered
heterocyclyl; R4 is hydrogen
or alkyl; R5 is oxygen, NR6, or sulfur; R6 is hydrogen or alkyl; D* is a
residue of a biologically
active compound comprising hydroxyl, amino, or thiol; n is zero, one, two,
three, four, five, or six;
wherein conjugation of L to BA is selected from the group consisting of a
click chemistry residue,
an amide residue, and a residue comprising two cysteine residues of a single
BA that are chemically
bonded to L; and k is an integer from one to thirty.
[0017] In another embodiment, provided are compounds having the structure
of Formula III:
R4 0 Ria Rib
BA_LNR5_D*5¨D*
R2 R3
-n
¨k
(III)
wherein L is a linker; BA is a binding agent; Rla and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein when 12"
is alkylene or heteroalkylene, the alkylene or heteroalkylene is further
bonded to R3 to form a 4-, 5-
or 6-membered heterocyclyl; R2 is hydrogen, alkylene, heteroalkylene, or an
amino acid side chain,
wherein when R2 is alkylene or heteroalkylene, the alkylene or heteroalkylene
is further bonded to
R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is hydrogen, alkyl,
alkylene, or heteroalkylene,
7
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
wherein when R3 is alkylene or heteroalkylene, the alkylene or heteroalkylene
is further bonded to
Rla or R2 to form the 4-, 5-, or 6-membered heterocyclyl; R4 is hydrogen or
alkyl; 125 is oxygen,
NR6, or sulfur; R6 is hydrogen or alkyl; D* is a residue of a biologically
active compound
comprising hydroxyl, amino, or thiol; n is zero, one, two, three, four, five,
or six; and k is an integer
from one to thirty.
[0018] In another embodiment, provided are methods for treating a disease,
disorder, or
condition associated with glucocorticoid receptor signaling in a subject
comprising administering to
the subject an effective amount of a compound, linker-payload, antibody-drug
conjugate,
pharmaceutical composition, and/or combinations thereof, as described herein.
[0019] In another embodiment, provided are methods for treating
dyslipidemia, a metabolic
disease, inflammation, or a neurodegenerative disease in a subject comprising
administering to the
subject an effective amount of a compound, linker-payload, antibody-drug
conjugate,
pharmaceutical composition, and/or combinations thereof, as described herein.
[0020] In another embodiment, provided are methods for treating
dyslipidemia in a subject
comprising administering to the subject an effective amount of a compound,
linker-payload,
antibody-drug conjugate, pharmaceutical composition, and/or combinations
thereof, as described
herein.
[0021] In another embodiment, provided are methods for treating a metabolic
disease in a
subject comprising administering to the subject an effective amount of a
compound, linker-payload,
antibody-drug conjugate, pharmaceutical composition, and/or combinations
thereof, as described
herein.
[0022] In another embodiment, provided are methods for treating
inflammation in a subject
comprising administering to the subject an effective amount of a compound,
linker-payload,
antibody-drug conjugate, pharmaceutical composition, and/or combinations
thereof, as described
herein.
[0023] In another embodiment, provided are methods for treating a
neurodegenerative disease
in a subject comprising administering to the subject an effective amount of a
compound, linker-
payload, antibody-drug conjugate, pharmaceutical composition, and/or
combinations thereof, as
described herein.
8
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
BRIEF DESCRIPTIONS OF THE DRAWING
[0024] FIGS. 1-9 show synthetic chemistry schemes for payloads, prodrugs,
traceless linkers,
traceless linker-payloads, and protein conjugates thereof
DESCRIPTION OF EXEMPLARY EMBODIMENTS
Definitions
[0025] When referring to the compounds provided herein, the following terms
have the
following meanings unless indicated otherwise. Unless defined otherwise, all
technical and
scientific terms used herein have the same meaning as is commonly understood
by one of ordinary
skill in the art. In the event that there is a plurality of definitions for a
term provided herein, these
Definitions prevail unless stated otherwise.
[0026] As used herein, "alkyl" refers to a monovalent and saturated
hydrocarbon radical moiety.
Alkyl is optionally substituted and can be linear, branched, or cyclic, (i.e.,
cycloalkyl). Alkyl
includes, but is not limited to, those radicals having 1-20 carbon atoms,
i.e., C1-20 alkyl;
1-12 carbon atoms, i.e., C1-12 alkyl; 1-8 carbon atoms, i.e., C1-8 alkyl; 1-6
carbon atoms, i.e.,
C1-6 alkyl; and 1-3 carbon atoms, i.e., C1_3 alkyl. Examples of alkyl moieties
include, but are not
limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-
butyl, a pentyl moiety, a hexyl
moiety, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A pentyl moiety
includes, but is not
limited to, n-pentyl and i-pentyl. A hexyl moiety includes, but is not limited
to, n-hexyl.
[0027] As used herein, "alkylene" refers to a divalent alkyl group. Unless
specified otherwise,
alkylene includes, but is not limited to, 1-20 carbon atoms. The alkylene
group is optionally
substituted as described herein for alkyl. In some embodiments, alkylene is
unsubstituted. Examples
of alkylene moieties include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and
the like.
[0028] As used herein, "heteroalkylene" refers to a divalent alkyl group
wherein one or more
carbon atoms is replaced with a heteroatom. Unless specified otherwise,
heteroalkylene includes,
but is not limited to, 1-20 total atoms (i.e., carbons and heteroatoms). The
heteroalkylene group is
optionally substituted as described herein for alkyl. In some embodiments,
heteroalkylene is
unsubstituted. In some embodiments, heteroatoms contemplated within
heteroalkylene moieties
include oxygen, nitrogen, sulfur (i.e., including sulfoxide, sulphite,
sulfate, and sulfone), silicon,
and phosphorous (i.e., including phosphite and phosphate), and/or combinations
thereof.
Nonlimiting exemplary embodiments of heteroalkylene moieties include -CH20-, -
CH2OCH2-,
9
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
-CH2OCH2CH2-, -CH2CH2CH2OCH2-, and the like; -CH2NR-, -CH2NRCH2-,
-CH2NRCH2CH2-, -CH2CH2CH2NRCH2-, and the like; and -CH2S-, -CH2SCH2-,
-CH2SCH2CH2-, -CH2CH2CH2SCH2-, and the like.
[0029] Designation of an amino acid or amino acid residue without
specifying its
stereochemistry is intended to encompass the L- form of the amino acid, the D-
form of the amino
acid, or a racemic mixture thereof
[0030] As used herein, "haloalkyl" refers to alkyl, as defined above,
wherein the alkyl includes
at least one substituent selected from a halogen, for example, fluorine (F),
chlorine (Cl), bromine
(Br), or iodine (I). Examples of haloalkyl include, but are not limited to,
¨CF3,
¨CH2CF3, ¨CC12F, ¨CHF2, and ¨CC13.
[0031] As used herein, "alkenyl" refers to a monovalent hydrocarbon radical
moiety containing
at least two carbon atoms and one or more non-aromatic carbon-carbon double
bonds. Alkenyl is
optionally substituted and can be linear, branched, or cyclic. Alkenyl
includes, but is not limited to,
those radicals having 2-20 carbon atoms, i.e., C2-20 alkenyl; 2-12 carbon
atoms, i.e., C2-12 alkenyl;
2-8 carbon atoms, i.e., C2_8 alkenyl; 2-6 carbon atoms, i.e., C2-6 alkenyl;
and 2-4 carbon atoms, i.e.,
C2-4 alkenyl. Examples of alkenyl moieties include, but are not limited to,
vinyl, propenyl, butenyl,
and cyclohexenyl.
[0032] As used herein, "alkynyl" refers to a monovalent hydrocarbon radical
moiety containing
at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl
is optionally
substituted and can be linear, branched, or cyclic. Alkynyl includes, but is
not limited to, those
radicals having 2-20 carbon atoms, i.e., C2_20 alkynyl; 2-12 carbon atoms,
i.e., C2-12 alkynyl; 2-8
carbon atoms, i.e., C2-8 alkynyl; 2-6 carbon atoms, i.e., C2-6 alkynyl; and 2-
4 carbon atoms, i.e., C2-
4 alkynyl. Examples of alkynyl moieties include, but are not limited to
ethynyl, propynyl, and
butynyl.
[0033] As used herein, "alkoxy" refers to a monovalent and saturated
hydrocarbon radical
moiety wherein the hydrocarbon includes a single bond to an oxygen atom and
wherein the radical
is localized on the oxygen atom, e.g., CH3CH2-0 = for ethoxy. Alkoxy
substituents bond to the
compound which they substitute through this oxygen atom of the alkoxy
substituent. Alkoxy is
optionally substituted and can be linear, branched, or cyclic, i.e.,
cycloalkoxy. Alkoxy includes, but
is not limited to, those having 1-20 carbon atoms, i.e., C1_20 alkoxy; 1-12
carbon atoms, i.e., C1_12
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkoxy; 1-8 carbon atoms, i.e., C1_8 alkoxy; 1-6 carbon atoms, i.e., C1_6
alkoxy; and 1-3 carbon atoms,
i.e., C1-3 alkoxy. Examples of alkoxy moieties include, but are not limited
to, methoxy, ethoxy, n-
propoxy, , i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, a pentoxy
moiety, a hexoxy moiety,
cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.
[0034] As
used herein, "haloalkoxy" refers to alkoxy, as defined above, wherein the
alkoxy
includes at least one substituent selected from a halogen, e.g., F, Cl, Br, or
I.
[0035] As
used herein, "aryl" refers to a monovalent moiety that is a radical of an
aromatic
compound wherein the ring atoms are carbon atoms. Aryl is optionally
substituted and can be
monocyclic or polycyclic, e.g., bicyclic or tricyclic. Examples of aryl
moieties include, but are not
limited to, those having 6 to 20 ring carbon atoms, i.e., C6-20 aryl; 6 to 15
ring carbon atoms, i.e., C6-
15 aryl, and 6 to 10 ring carbon atoms, i.e., C6_10 aryl. Examples of aryl
moieties include, but are
limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and
pyrenyl.
[0036] As
used herein, "arylalkyl" refers to a monovalent moiety that is a radical of an
alkyl
compound, wherein the alkyl compound is substituted with an aromatic
substituent, i.e., the aromatic
compound includes a single bond to an alkyl group and wherein the radical is
localized on the alkyl
group. An arylalkyl group bonds to the illustrated chemical structure via the
alkyl group. An
arylalkyl can be represented by the structure, e.g., B ,
B 6F12 , Or
, wherein B is an aromatic moiety, e.g., aryl or phenyl. Arylalkyl is
optionally
substituted, i.e., the aryl group and/or the alkyl group, can be substituted
as disclosed
herein. Examples of arylalkyl include, but are not limited to, benzyl.
[0037] As
used herein, "alkylaryl" refers to a monovalent moiety that is a radical of an
aryl
compound, wherein the aryl compound is substituted with an alkyl substituent,
i.e., the aryl
compound includes a single bond to an alkyl group and wherein the radical is
localized on the aryl
group. An alkylaryl group bonds to the illustrated chemical structure via the
aryl group. An
=
alkylaryl can be represented by the structure, e.g., 6, or B
, wherein B is an aromatic moiety, e.g., phenyl. Alkylaryl is optionally
substituted, i.e., the aryl
group and/or the alkyl group, can be substituted as disclosed herein. Examples
of alkylaryl include,
but are not limited to, toluyl.
11
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[0038] As
used herein, "aryloxy" refers to a monovalent moiety that is a radical of an
aromatic
compound wherein the ring atoms are carbon atoms and wherein the ring is
substituted with an
oxygen radical, i.e., the aromatic compound includes a single bond to an
oxygen atom and wherein
6
the radical is localized on the oxygen atom, e.g.,01
for phenoxy. Aryloxy substituents bond
to the compound which they substitute through this oxygen atom. Aryloxy is
optionally substituted.
Aryloxy includes, but is not limited to, those radicals having 6 to 20 ring
carbon atoms, i.e., C6-20
aryloxy; 6 to 15 ring carbon atoms, i.e., C6-15 aryloxy, and 6 to 10 ring
carbon atoms, i.e., C6-10
aryloxy. Examples of aryloxy moieties include, but are not limited to phenoxy,
naphthoxy, and
anthroxy.
[0039] As
used herein, "arylene" refers to a divalent moiety of an aromatic compound
wherein
the ring atoms are only carbon atoms. Arylene is optionally substituted and
can be monocyclic or
polycyclic, e.g., bicyclic or tricyclic. Examples of arylene moieties include,
but are not limited to
those having 6 to 20 ring carbon atoms, i.e., C6-20 arylene; 6 to 15 ring
carbon atoms, i.e., C6-15
arylene, and 6 to 10 ring carbon atoms, i.e., C6-10 arylene.
[0040] As
used herein, "heteroalkyl" refers to an alkyl in which one or more carbon
atoms are
replaced by heteroatoms. As used herein, "heteroalkenyl" refers to an alkenyl
in which one or more
carbon atoms are replaced by heteroatoms. As used herein, "heteroalkynyl"
refers to an alkynyl in
which one or more carbon atoms are replaced by heteroatoms. Suitable
heteroatoms include, but
are not limited to, nitrogen, oxygen, and sulfur atoms. Heteroalkyl,
heteroalkenyl, and heteroalkynyl
are optionally substituted. Examples of heteroalkyl moieties include, but are
not limited to,
aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moieties
also include, but
are not limited to, methylamino, methylsulfonyl, and methylsulfinyl.
[0041] As
used herein, "heteroaryl" refers to a monovalent moiety that is a radical of
an aromatic
compound wherein the ring atoms contain carbon atoms and at least one oxygen,
sulfur, nitrogen,
or phosphorus atom. Examples of heteroaryl moieties include, but are not
limited to those having 5
to 20 ring atoms; 5 to 15 ring atoms; and 5 to 10 ring atoms. Heteroaryl is
optionally substituted.
[0042] As
used herein, "heteroarylene" refers to a divalent heteroaryl in which one or
more ring
atoms of the aromatic ring are replaced with an oxygen, sulfur, nitrogen, or
phosphorus atom.
Heteroarylene is optionally substituted.
12
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[0043] As
used herein, "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl in
which one
or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms
include, but are not limited
to, nitrogen, oxygen, and sulfur atoms (i.e., including sulfoxide and
sulfone). Heterocycloalkyl or
heterocyclyl is optionally substituted. Examples of heterocycloalkyl and
heterocyclyl moieties
include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl,
pyrrolidinyl, aziridnyl,
imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl,
or thianyl.
[0044] As
used herein, "Lewis acid" refers to a molecule or ion that accepts an electron
lone
pair. The Lewis acids used in the methods described herein are those other
than protons. Lewis
acids include, but are not limited to, non-metal acids, metal acids, hard
Lewis acids, and soft Lewis
acids. Lewis acids include, but are not limited to, Lewis acids of aluminum,
boron, iron, tin,
titanium, magnesium, copper, antimony, phosphorus, silver, ytterbium,
scandium, nickel, and
zinc. Illustrative Lewis acids include, but are not limited to, AlBr3, A1C13,
BC13, boron trichloride
methyl sulfide, BF3, boron trifluoride methyl etherate, boron trifluoride
methyl sulfide, boron
trifluoride tetrahydrofuran, dicyclohexylboron trifluoromethanesulfonate, iron
(III) bromide, iron
(III) chloride, tin (IV) chloride, titanium (IV) chloride, titanium (IV)
isopropoxide, Cu(OT02,
CuC12, CuBr2, zinc chloride, alkylaluminum halides (R,A1X3, wherein R is
hydrocarbyl), Zn(OT02, ZnC12, Yb(OT03, Sc(OT03, MgBr2, NiC12, Sn(OT02,
Ni(OT02, and
Mg(0T02.
[0045] As
used herein, "N-containing heterocycloalkyl," refers to a cycloalkyl in which
one or
more carbon atoms are replaced by heteroatoms and wherein at least one
replacing heteroatom is a
nitrogen atom. Suitable heteroatoms in addition to nitrogen, include, but are
not limited to, oxygen
and sulfur atoms. N-containing heterocycloalkyl is optionally substituted.
Examples of N-
containing heterocycloalkyl moieties include, but are not limited to,
morpholinyl, piperidinyl,
pyrrolidinyl, imidazolidinyl, oxazolidinyl, or thiazolidinyl.
[0046] As
used herein, "optionally substituted," when used to describe a radical moiety,
for
example, optionally substituted alkyl, means that such moiety is optionally
bonded to one or more
substituents. Examples of such substituents include, but are not limited to,
halo, cyano, nitro,
amino, hydroxyl, optionally substituted haloalkyl, aminoalkyl, hydroxyalkyl,
azido, epoxy,
1-ORA 1-SRA
optionally substituted heteroaryl, optionally substituted heterocycloalkyl,
,
13
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0 0 0 0 NH
4-NRARB, IL
AIL - NRR ORA II A B
+NRci-LRA II NRARB
ARA
NH RA
N 0
+NRc¨U¨NRARB -Fs(0)-RA _-S(0)2-RA .-g, ,,Xv S
ii
" , "
, or " , wherein RA, RB, and RC are,
independently at each occurrence, a hydrogen atom, alkyl, alkenyl, alkynyl,
aryl, alkylaryl,
arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or RA and RB together
with the atoms to
which they are bonded, form a saturated or unsaturated carbocyclic ring,
wherein the ring is
optionally substituted, and wherein one or more ring atoms is optionally
replaced with a heteroatom.
In certain embodiments, when a radical moiety is optionally substituted with
an optionally
substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally
substituted saturated or
unsaturated carbocyclic ring, the substituents on the optionally substituted
heteroaryl, optionally
substituted heterocycloalkyl, or optionally substituted saturated or
unsaturated carbocyclic ring, if
they are substituted, are not substituted with substituents which are further
optionally substituted
with additional substituents. In some embodiments, when a group described
herein is optionally
substituted, the substituent bonded to the group is unsubstituted unless
otherwise specified.
[0047] As
used herein, "binding agent" refers to any molecule, e.g., protein, antibody,
or
fragment thereof, capable of binding with specificity to a given binding
partner, e.g., antigen.
[0048] As
used herein, "linker" refers to a divalent, trivalent, or multivalent moiety
that
covalently links, or is capable of covalently linking (e.g., via a reactive
group), the binding agent to
one or more compounds described herein, for instance, payload compounds and
enhancement
agents.
[0049] As
used herein, "amide synthesis conditions" refers to reaction conditions
suitable to
effect the formation of an amide, e.g., by the reaction of a carboxylic acid,
activated carboxylic acid,
or acyl halide with an amine. In some examples, amide synthesis conditions
refers to reaction
conditions suitable to effect the formation of an amide bond between a
carboxylic acid and an amine.
In some of these examples, the carboxylic acid is first converted to an
activated carboxylic acid
before the activated carboxylic acid reacts with an amine to form an amide.
Suitable conditions to
effect the formation of an amide include, but are not limited to, those
utilizing reagents to effect the
reaction between a carboxylic acid and an amine, including, but not limited
to,
dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide
(DIC), (b enz otriaz ol-1-
14
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
(BOP), (b enz otri az ol-1-
yl ox y)trip yrro lidinopho sphonium hexafluorophosphate
(P yB OP), (7-az ab enz otriaz ol-1-
yl ox y)trip yrro li dinopho sphonium hexafluorophosphate
(PyA0P),
bromotripyrrolidinophosphonium hexafluorophosphate
(PyBrOP), 0-(b enzotriaz ol-1 -y1)-
N,N,N' ,N'-tetramethyluronium hexafluorophosphate (HBTU), 0-(benzotriazol-1 -
y1)-N,N,N' ,N'-
tetramethyluronium tetrafluorob orate
(TBTU),
1- [Bis(dimethylamino)methylene] -1H-1 ,2,3 -triazo lo [4,5-b]pyridinium 3-
oxide
hexafluorophosphate (HATU), N- ethoxyc arb ony1-2- ethox y-1,2-dihydro quino
line (EEDQ),
N-ethyl-N'-(3 -dimethyl aminoprop yl)c arb o diimi de
(EDC),
2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate
(CIP),
2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and carbonyldiimidazole (CDI).
In some
examples, a carboxylic acid is first converted to an activated carboxylic
ester before treating the
activated carboxylic ester with an amine to form an amide bond. In certain
embodiments, the
carboxylic acid is treated with a reagent. The reagent activates the
carboxylic acid by deprotonating
the carboxylic acid and then forming a product complex with the deprotonated
carboxylic acid as a
result of nucleophilic attack by the deprotonated carboxylic acid onto the
protonated reagent. The
activated carboxylic esters for certain carboxylic acids are subsequently more
susceptible to
nucleophilic attack by an amine than the carboxylic acid is before it is
activated. This results in
amide bond formation. As such, the carboxylic acid is described as activated.
Exemplary reagents
include DCC and DIC.
[0050] As
used herein, "regioisomer," "regioisomers," or "mixture of regioisomers"
refers to
the product(s) of 1,3-cycloadditions or strain-promoted alkyne-azide
cycloadditions (SPAACs)
otherwise known as click reactions ________________________________________
that derive from suitable azides (e.g., ¨N3, or ¨PEG-N3
derivitized antibodies) treated with suitable alkynes. In certain embodiments,
for example,
regioisomers and mixtures of regioisomers are characterized by the click
reaction products shown
below:
Ne
Y
R'
N---N
#
N-N 6
N
A R R R
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
In certain embodiments, more than one suitable azide and more than one
suitable alkyne can be
utilized within a synthetic scheme en route to a product, where each pair of
azide-alkyne can
participate in one or more independent click reactions to generate a mixture
of regioisomeric click
reaction products. For example, a person of skill will recognize that a first
suitable azide may
independently react with a first suitable alkyne, and a second suitable azide
may independently react
with a second suitable alkyne, en route to a product, resulting in the
generation of four possible click
reaction regioisomers or a mixture of the four possible click reaction
regioisomers.
[0051] As used herein, the term "residue" refers to the chemical moiety
within a compound that
remains after a chemical reaction. For example, the term "amino acid residue"
or "N-alkyl amino
acid residue" refers to the product of an amide coupling or peptide coupling
of an amino acid or a
N-alkyl amino acid to a suitable coupling partner; wherein, for example, a
water molecule is expelled
after the amide or peptide coupling of the amino acid or the N-alkylamino
acid, resulting in the
product having the amino acid residue or N-alkyl amino acid residue
incorporated therein.
[0052] As used herein, "therapeutically effective amount" refers to an
amount (e.g., of a
compound) that is sufficient to provide a therapeutic benefit to a patient in
the treatment or
management of a disease or disorder, or to delay or minimize one or more
symptoms associated
with the disease or disorder.
[0053] As used herein, "constitutional isomers" refers to compounds that
have the same
molecular formula, but different chemical structures resulting from the way
the atoms are arranged.
Exemplary constitutional isomers include n-propyl and isopropyl; n-butyl, sec-
butyl, and tert-butyl;
and n-pentyl, isopentyl, and neopentyl, and the like.
[0054] Certain groups, moieties, substituents, and atoms are depicted with
a wiggly line that
intersects a bond or bonds to indicate the atom through which the groups,
moieties, substituents,
atoms are bonded. For example, a phenyl group that is substituted with a
propyl group depicted as:
4(
CH3 1_(CH3
CH3 or CH3
has the following structure:
16
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
. CH3
CH-4 .
As used herein, illustrations showing substituents bonded to a cyclic group
(e.g.,
aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl
or heterocycloalkyl)
through a bond between ring atoms are meant to indicate, unless specified
otherwise, that the cyclic
group may be substituted with that substituent at any ring position in the
cyclic group or on any ring
in the fused ring group, according to techniques set forth herein or which are
known in the field to
R1)
(R1)q ( q
which the instant disclosure pertains. For example, the group, or
c' , wherein
subscript q is an integer from 0 to 4 and in which the positions of
substituent R1 are described
generically, i.e., not directly attached to any vertex of the bond line
structure, i.e., specific ring
carbon atom, includes the following, non-limiting examples of groups in which
the substituent R1
R1
R1 R1 R1
RI
is bonded to a specific ring carbon atom: , , ,
R1 RI RI RI RI
RI
..õ4.,
RI RI RI RI 110. RI
RI
RI RI
RI
RI RI RI RI
RI
RI RI RI RI RI RI
RI RI
RI RI
RI RI -Fr'ri
RI RI RI ilfr RI
RI RI
RI RI RI RI RI
RI RI RI RI
RI RI RI RI RI , and R1 R1 .
,
17
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[0055] As
used herein, the phrase "reactive linker," or the abbreviation "RL" refers to
a
monovalent group that includes a reactive group ("RG") and spacer group
("SP"), depicted for
RG-SP-1
example as ,
wherein RG is the reactive group and SP is the spacer group. As described
herein, a reactive linker may include more than one reactive group and more
than one spacer group.
The spacer group is any divalent moiety that bridges the reactive group to
another group, such as a
payload (e.g., a biologically active compound). The reactive linkers (RLs),
together with the
payloads to which they are bonded, provide intermediates ("linker-payloads" or
LPs) useful as
synthetic precursors for the preparation of the antibody conjugates described
herein. The reactive
linker includes a reactive group, which is a functional group or moiety that
is capable of reacting
with a reactive portion of another group, for instance, an antibody, modified
antibody, or antigen
binding fragment thereof, or an enhancement group. The moiety resulting from
the reaction of the
reactive group with the antibody, modified antibody, or antigen binding
fragment thereof, together
with the linking group, include the "binding agent linker" ("BL") portion of
the conjugate, described
herein. In certain embodiments, the "reactive group" is a functional group or
moiety (e.g.,
maleimide or N-hydroxysuccinimide (NHS) ester) that reacts with a cysteine or
lysine residue of an
antibody or antigen-binding fragment thereof In certain embodiments, the
"reactive group" is a
functional group or moiety that is capable of undergoing a click chemistry
reaction (see, e.g., click
chemistry, Huisgen Proc. Chem. Soc. 1961, Wang et al. I Am. Chem. Soc. 2003,
and Agard et al.
Am. Chem. Soc. 2004). In some embodiments of said click chemistry reaction,
the reactive group
is an alkyne that is capable of undergoing a 1,3-cycloaddition reaction with
an azide. Such suitable
reactive groups include, but are not limited to, strained alkynes, e.g., those
suitable for strain-
promoted alkyne-azide cycloadditions (SPAAC), cycloalkynes, e.g.,
cyclooctynes, benzannulated
alkynes, and alkynes capable of undergoing 1,3-cycloaddition reactions with
alkynes in the absence
of copper catalysts. Suitable alkynes also include, but are not limited to,
S (TMTH);
O In
0 / \
0
\/-0 0,\Z
0 (COMBO); (PYRROC);
cyclooctyne
18
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
OTBS
/
3.5.0 \) MeO". __ N
(OCT); 0 (SNO-OCTs); azacyclooctyne
cOo
(DIMAC); dibenzoazacyclooctyne or 0
(DIBAC), dibenzocyclooctyne or
OR (DIBO), biarylazacyclooctynone or 0 R
(BARAC),
0
F
of
mono fluorinated cyclooctyne
(M0F0); difluorinated cyclooctyne or
F
F ¨ F COOH ¨ F
HOOC COOH
\--0 , Or , Or
(DIFO), substituted, e.g.,
OR
fluorinated alkynes, aza-cycloalkynes, bicycle[6.1.0]nonyne or
(BCN, where R
is alkyl, alkoxy, or acyl), and derivatives thereof
Particularly useful alkynes include
=0
I I
and .
Linker-payloads including such reactive groups
are useful for conjugating antibodies that have been functionalized with azido
groups. Such
functionalized antibodies include antibodies functionalized with azido-
polyethylene glycol groups.
In certain embodiments, such a functionalized antibody is derived by treating
an antibody having at
least one glutamine residue, e.g., heavy chain Gln295, with a compound bearing
an an amino agroup
and an azide group, in the presence of the enzyme transglutaminase.
19
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[0056] In some examples, the reactive group is an alkyne, e.g., ,
which can react
via click chemistry with an azide, e.g., N=N=, to form a click chemistry
product, e.g.,
NA
,
Or .
In some examples, the group reacts with an azide on a modified
antibody or antigen binding fragment thereof In some examples, the reactive
group is an alkyne,
e.g., ,
which can react via click chemistry with an azide, e.g., N=N=N)L to form a
\N-P)L
click chemistry product, e.g., .
In some examples, the reactive group is an alkyne,
e.g., CH
, which can react via click chemistry with an azide, e.g., N=N= NA. , to form
a click
chemistry product, e.g., Or
N\Pr . In some examples, the reactive group is a
0
rt
functional group, e.g., 0
,which reacts with a cysteine residue on an antibody or antigen-
Ab¨s
0
binding fragment thereof, to form a carbon-sulfur bond thereto, e.g., 0
, wherein Ab
refers to an antibody or antigen-binding fragment thereof and S refers to the
S atom on a cysteine
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
residue through which the functional group bonds to the Ab. In some examples,
the reactive group
0
0
is a functional group, e.g., 0
,which reacts with a lysine residue on an antibody or
0
Ab¨ki
antigen-binding fragment thereof, to form an amide bond thereto, e.g., sr
, wherein Ab
refers to an antibody or antigen-binding fragment thereof and NH refers to the
NH atom on a lysine
side chain residue through which the functional group bonds to the Ab.
[0057] As
used herein, the phrase "biodegradable moiety" refers to a moiety that
degrades in
vivo to non-toxic, biocompatible components which can be cleared from the body
by ordinary
biological processes. In some embodiments, a biodegradable moiety completely
or substantially
degrades in vivo over the course of about 90 days or less, about 60 days or
less, or about 30 days or
less, where the extent of degradation is based on percent mass loss of the
biodegradable moiety, and
wherein complete degradation corresponds to 100% mass loss. Exemplary
biodegradable moieties
include, without limitation, aliphatic polyesters such as poly(c-caprolactone)
(PCL), poly(3-
hydroxybutyrate) (PHB), poly(glycolic acid) (PGA), poly(lactic acid) (PLA) and
its copolymers
with glycolic acid (i.e., poly(D,L-lactide-coglycolide) (PLGA) (Vert M,
Schwach G, Engel R and
Coudane J (1998) J Control Release 53(1-3):85-92; Jain R A (2000) Biomaterials
21(23):2475-
2490; Uhrich K E, Cannizzaro S M, Langer R S and Shakesheff K M (1999)
Chemical Reviews
99(11): 3181-3198; and Park T G (1995) Biomaterials 16(15):1123-1130, each of
which are
incorporated herein by reference in their entirety).
[0058] As
used herein, the phrase "binding agent linker," or "BL" refers to any
divalent,
trivalent, or multi-valent group or moiety that links, connects, or bonds a
binding agent (e.g., an
antibody or an antigen-binding fragment thereof) with a payload compound set
forth herein (e.g.,
tubulysins) and, optionally, with one or more side chain compounds. Generally,
suitable binding
agent linkers for the antibody conjugates described herein are those that are
sufficiently stable to
exploit the circulating half-life of the antibody conjugates and, at the same
time, capable of releasing
its payload after antigen-mediated internalization of the conjugate. Linkers
can be cleavable or non-
cleavable. Cleavable linkers are linkers that are cleaved by intracellular
metabolism following
internalization, e.g., cleavage via hydrolysis, reduction, or enzymatic
reaction. Non-cleavable
21
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
linkers are linkers that release an attached payload via lysosomal degradation
of the antibody
following internalization. Suitable linkers include, but are not limited to,
acid-labile linkers,
hydrolytically-labile linkers, enzymatically cleavable linkers, reduction
labile linkers,
self-immolative linkers, and non-cleavable linkers. Suitable linkers also
include, but are not limited
to, those that are or comprise peptides, glucuronides, succinimide-thioethers,
polyethylene glycol
(PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citruline
units, and para-
aminobenzyloxycarbonyl (PABC), para-aminobenzyl (PAB) units. In some
embodiments, the
binding agent linker (BL) includes a moiety that is formed by the reaction of
the reactive group
(RG) of a reactive linker (RL) and reactive portion of the binding agent,
e.g., antibody, modified
antibody, or antigen binding fragment thereof
N A
1 \
'-z,--N
[0059] In some examples, the BL includes the following moiety: ' N%N
Or
N A
N \
tt
N¨N
1
1 ,
wherein 1 is the bond to the binding agent. In some examples, the BL includes
li<NOL
1 \ 1
the following moiety: ,
wherein 1 is the bond to the binding agent. In some
1
Niir-1
3<f=I N¨N
IV ----->-1 -rrsj\ 1 1
examples, the BL includes the following moiety: Or , wherein is
the bond
"1
.._..1)
sos
to the binding agent. In some examples, the BL includes the following moiety:
0 , wherein
1
1 is the bond to the cysteine of the antibody or antigen-binding fragment
thereof In some
22
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
1
examples, the BL includes the following moiety: ,
wherein 1 is the bond to the lysine of
the antibody or antigen-binding fragment thereof
[0060]
As used herein, "amino acid side chain" refers to the additional chemical
moiety on the
same carbon that bears a primary or secondary amine and a carboxylic acid of
an amino acid. As
would be appreciated by a person of skill in the art, there are twenty-one
"standard" amino acids.
Exemplary "standard" amino acids include, without limitation, alanine, serine,
proline, arginine, and
aspartic acid. Other amino acids include, cysteine, selenocysteine, and
glycine (e.g., wherein the
additional chemical moiety on the same carbon that bears the primary amine and
carboxylic acid of
glycine is hydrogen). Exemplary amino acid side chains include, without
limitation, methyl (i.e.,
alanine), sec-buytl (i.e., isoleucine), iso-butyl (i.e.,
leucine),
N H
¨C H2 C H2 S CH3 (i.e., methionine), ¨CH2Ph (i.e., phenyl al anine),
(i.e., tryptophan),
'S OH (i.e., tyrosine), iso-propyl (i.e., valine), hydroxymethyl (i.e.,
serine),
¨CH(OH)CH3 (i.e., threonine), ¨CH2C(0)NH2 (i.e., asparagine), ¨CH2CH2C(0)NH2
(i.e.,
glutamine), ¨CH2SH (i.e., cysteine), ¨CH2SeH (i.e., selenocysteine), ¨CH2NH2
(i.e., glycine),
propylene or -CH2CH2CH2- (i.e., proline), ¨CH2CH2CH2NHC(=NH)NH2 (i.e.,
arginine),
\<y,
NH (i.e., histidine), ¨CH2CH2C H2 C H2NH2 (i.e., lysine), ¨CH2COOH (i.e.,
aspartic acid),
and ¨CH2CH2COOH (i.e., glutamic acid).
[0061]
As used herein, "biologically active compound" refers to a compound, prodrug,
or
payload that elicits a biological response when administered to a biological
entity. Exemplary
biological responses include, without limitation, increase or decrease in DNA
or protein synthesis,
up-regulation or down-regulation of signalling pathways, and increase or
decrease in cell
proliferation, and the like.
Compounds, Prodrugs, or Payloads
[0062]
Provided herein are compounds or payloads. Without being bound by any
particular
theory of operation, the compounds include anti-inflammatory biologically
active compounds,
23
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
steroids, steroid derivatives, and/or LXR modulators, and derivatives thereof,
for example, prodrugs
thereof The terms or phrases "compounds," "biologically active compounds,"
"prodrugs," and
"payloads" are used interchangeably throughout this disclosure. In certain
embodiments, the
biologically active compound (D*) or residue thereof includes hydroxyl
functionality (e.g., D*-0H
or D*-0¨R). In certain embodiments herein, for example and convenience, R5
represents the
hydroxyl, amino, and thiol functional groups within the biologically active
compounds described
herein, as would be appreciated by a person of skill, or a portion thereof
such as -0-, -N(R)-, or -S-
Alternatively stated, a person of skill would recognize that R5 may be part of
the biologically active
compounds described herein (e.g., D*), and may be used as a functional group
for conjugation
purposes. In one embodiment, the hydroxyl functionality is a primary hydroxyl
moiety (e.g.,
D*¨CH20H or D*¨CH20¨R; or D*¨C(0)CH20H or D*¨C(0)CH20¨R). In another
embodiment,
the hydroxyl functionality is a secondary hydroxyl moiety (e.g., D*¨CH(OH)R or
D*¨CH(O¨R)R;
or D*¨C(0)CH(R)(OH) or D*¨C(0)CH(R)(0¨R)). In another embodiment, the hydroxyl
functionality is a tertiary hydroxyl moiety (e.g., D*¨C(R1)(R2)(OH) or
D*¨C(R1)(R2)(0¨R); or
D*¨C(0)C(R1)(R2)(OH) or D*¨C(0)C(R1)(R2)(0¨R)). Those of skill will recognize
that each
functional group in the previous sentences can be part of the biologically
active compound D* and
simultaneously be depicted in the formula for clarity, convenience, and/or
emphasis. In another
embodiment, the D* including the hydroxyl functionality is an aryl hydroxyl or
phenolic hydroxyl
(e.g., D*¨Ar¨OH, D*¨Ar¨O¨R. In one embodiment, the biologically active
compound (D*)
including hydroxyl functionality (D*-0H) is dexamethasone, and the residue
including the
0
z 0
0 HO
hydroxyl functionality is OH
wherein / indicates attachment to a
prodrug moiety (as shown in Formulae Ia and/or lb), a linker, and/or binding
agent, as described
herein. In one embodiment, the biologically active compound (D*) including
hydroxyl functionality
is dexamethasone, and the residue including the hydroxyl functionality is
HO
0
0 HO
0
wherein / indicates attachment to a prodrug moiety (as shown in
Formulae Ia and/or Ib), a linker, and/or binding agent, as described herein.
In one embodiment, the
24
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
biologically active compound (D*) including hydroxyl functionality (D*-0H) is
budesonide, and
0
0 0
0 0
the residue including the hydroxyl functionality is OH
wherein /
indicates attachment to a prodrug moiety (as shown in Formulae Ia and/or lb),
a linker, and/or
binding agent, as described herein. In one embodiment, the biologically active
compound (D*)
including hydroxyl functionality is budesonide, and the residue including the
hydroxyl functionality
0
0 0
HO 0
/0
is
wherein / indicates attachment to a prodrug moiety (as shown
in Formulae Ia and/or Ib), a linker, and/or binding agent, as described
herein. In one embodiment,
the biologically active compound (D*) including hydroxyl functionality (D*-0H)
is 6,1 1-2F-
budesonide, and the residue including the
hydroxyl functionality is
0
iIi0 0
0 0
OH
wherein / indicates attachment to a prodrug moiety (as shown
in Formulae Ia and/or lb), a linker, and/or binding agent, as described
herein. In one embodiment,
the biologically active compound (D*) including hydroxyl functionality is 6,11-
2F-budesonide, and
0
0 0
HO 0
/0
the residue including the hydroxyl functionality is
wherein /
indicates attachment to a prodrug moiety (as shown in Formulae Ia and/or lb),
a linker, and/or
binding agent, as described herein. In one embodiment, the biologically active
compound (D*)
including hydroxyl functionality (D*-0H) is an LXR agonist, and the residue
including the
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0 0 0
.õH
`zz( N N OH
hydroxyl functionality is wherein
indicates attachment to a prodrug moiety (as shown in Formulae Ia and/or lb),
a linker, and/or
binding agent, as described herein. In one embodiment, the biologically active
compound (D*)
including hydroxyl functionality is an LXR agonist, and the residue including
the hydroxyl
0 rri 0 0
.õH
HOJ=LN
N
H
functionality is wherein
indicates
attachment to a prodrug moiety (as shown in Formulae Ia and/or Ib), a linker,
and/or binding agent,
as described herein. In certain embodiments, the biologically active compound
(D*) or residue
thereof includes amino functionality (e.g., D*¨NR2 or D*¨N(R)¨R). In one
embodiment, the amino
functionality is a primary amino moiety (e.g., D*¨CH2NR2 or D*¨CH2N(R)¨R; or
D*¨C(0)CH2NR2 or D*¨C(0)CH2N(R)¨R). In another embodiment, the amino
functionality is a
secondary amino moiety (e.g., D*¨CH(NR2)R or D*¨CH(NR¨R)R; or
D*¨C(0)CH(R)(NR2) or
D*¨C(0)CH(R)(NR¨R)). In another embodiment, the amino functionality is a
tertiary amino
moiety (e.g., D*¨C(R1)(R2)(NR2) or D*¨C(R1)(R2)(N(R)¨R); or
D*¨C(0)C(R1)(R2)(NR2) or
D*¨C(0)C(R1)(R2)(N(R)¨R)). In another embodiment, the D* including the amino
functionality is
an aryl amine (e.g., D*¨Ar¨NR2, D*¨Ar¨N(R)¨R. In certain embodiments, the
biologically active
compound (D*) or residue thereof includes thiol functionality (e.g., D*¨SH or
D*¨S¨R). In one
embodiment, the thiol functionality is a primary thiol moiety (e.g.,
D*¨CH2SH or D*¨CH2S¨R; or D*¨C(0)CH2SH or D*¨C(0)CH2S¨R). In another
embodiment,
the thiol functionality is a secondary thiol moiety (e.g., D*¨CH(SH)R or
D*¨CH(S¨R)R; or
D*¨C(0)CH(R)(SH) or D*¨C(0)CH(R)(S¨R)). In another embodiment, the thiol
functionality is a
tertiary thiol moiety (e.g., D*¨C(R1)(R2)(SH) or D*¨C(R1)(R2)(S¨R); or
D*¨C(0)C(R1)(R2)(SH) or D*¨C(0)C(R1)(R2)(S¨R)). In another embodiment, the D*
including
the thiol functionality is an aryl thiol or thiophenol (e.g., D*¨Ar¨SH,
D*¨Ar¨S¨R. In certain
embodiments, D* is a tetra- or penta-cyclic steroidal scaffold, as would be
appreciated by a person
of skill in the art. In certain embodiments, the compounds can be delivered to
cells as part of a
conjugate. In certain embodiments, the compounds are capable of carrying out
any activity of
26
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
steroids, steroid derivatives, LXR modulators, or derivatives thereof at or in
a target, for instance, a
target cell. Certain compounds can have one or more additional activities.
[0063] In certain embodiments, set forth herein is a compound having the
structure of Formula
Ia:
I 0 Ria Rib
H --N YLII)(0¨D*
R2 R3
- -n
(Ia)
or a pharmaceutically acceptable salt thereof, wherein Rla and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or alkylene,
wherein when Rla is alkylene,
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; R2 is hydrogen
or an amino acid side chain; R3 is hydrogen, alkyl, or alkylene, wherein when
R3 is alkylene, the
alkylene is further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is acyl, or a
residue of a biologically active compound comprising hydroxyl; and n is zero,
one, two, three, four,
or five.
[0064] In certain embodiments, set forth herein is a compound having a
structure of Formula
Iaa:
1 0 Ria Rib
H 11 fl¨D*
R2 R3 Rs
- -n
(Iaa)
or a pharmaceutically acceptable salt thereof, wherein Rla and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein
when R" is alkylene or heteroalkylene, the alkylene or heteroalkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or an amino
acid side chain, wherein when R2 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is
hydrogen, alkyl, alkylene,
or heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R" or R2 to form the 4-, 5-, or 6-membered heterocyclyl; R6
is hydrogen or alkyl;
27
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
D* is acyl, or a residue of a biologically active compound comprising amino;
and n is zero, one,
two, three, four, or five.
[0065] In certain embodiments, set forth herein is a compound having a
structure of Formula
Iaaa:
1 0 Rla Rib
H --N ))LN)(S-D*
R2 143
- -n
(Iaaa)
or a pharmaceutically acceptable salt thereof, wherein RI-a and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein
when R" is alkylene or heteroalkylene, the alkylene or heteroalkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or an amino
acid side chain, wherein when R2 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is
hydrogen, alkyl, alkylene,
or heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R" or R2 to form the 4-, 5-, or 6-membered heterocyclyl; D*
is acyl, or a residue
of a biologically active compound comprising thiol; and n is zero, one, two,
three, four, or five.
[0066] In certain embodiments, set forth herein is a compound having the
structure of Formula
lb:
- _
0 Ria Rib
HA J'LN )(0-D*
R2 R3
- -n
(Ib)
or a pharmaceutically acceptable salt thereof, wherein Rla and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or alkylene,
wherein when Rla is alkylene,
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; R2 is hydrogen
or an amino acid side chain; R3 is hydrogen, alkyl, or alkylene, wherein when
R3 is alkylene, the
alkylene is further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is acyl, or a
28
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
residue of a biologically active compound comprising hydroxyl; and n is zero,
one, two, three, four,
or five.
[0067] In certain embodiments, set forth herein is a compound having the
structure of Formula
Ibb:
0 Ria Rib
HEJJ*L- N)(N¨D*
z .
R2 R3 Rs
- -n
(Ibb)
or a pharmaceutically acceptable salt thereof, wherein Rla and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein
when R" is alkylene or heteroalkylene, the alkylene or heteroalkylene is
further bonded to 123 to
form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or an amino
acid side chain, wherein when R2 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is
hydrogen, alkyl, alkylene,
or heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R" or R2 to form the 4-, 5-, or 6-membered heterocyclyl; R6
is hydrogen or alkyl;
D* is acyl, or a residue of a biologically active compound comprising amino;
and n is zero, one,
two, three, four, or five.
[0068] In certain embodiments, set forth herein is a compound having the
structure of Formula
Ibbb:
- -
EJ 0 Ria Rib
HN(S¨D*
R2 R3
- -n
(Ibbb)
or a pharmaceutically acceptable salt thereof, wherein Rla and Rib are,
independently, hydrogen,
alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein
when R" is alkylene or heteroalkylene, the alkylene or heteroalkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or an amino
acid side chain, wherein when R2 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is
hydrogen, alkyl, alkylene,
29
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
or heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene
or heteroalkylene is
further bonded to 12" or R2 to form the 4-, 5-, or 6-membered heterocyclyl; D*
is acyl, or a residue
of a biologically active compound comprising thiol; and n is zero, one, two,
three, four, or five.
[0069] The following embodiments of Formula I and/or Formula Ib are
contemplated, where in
any one or more of the foregoing embodiments, the biologically active compound
includes
hydroxyl; or in a residue of a biologically active compound, D*, in certain
embodiments, is linked
to the rest of the molecule through a residue of the hydroxyl (i.e., a bond to
the oxygen). In one
embodiment, Ria is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is
hydrogen; D* is hydrogen;
and n is zero. In another embodiment, Ria is hydrogen and Rib is alkyl; R2 is
hydrogen; R3 is
hydrogen; D* is hydrogen; and n is zero. In another embodiment, Ria is
hydrogen and Rib is alkoxy;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is zero. In another
embodiment, Ria is
hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is zero. In
another embodiment, Ria is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is
hydrogen; and n is zero. In another embodiment, Ria is hydrogen and Rib is
aryl; R2 is hydrogen;
R3 is hydrogen; D* is hydrogen; and n is zero. In another embodiment, Ria is
hydrogen and Rib is
arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is zero. In
another embodiment,
Ria is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is
hydrogen; and n is
zero. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3
is hydrogen; D* is
hydrogen; and n is zero. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl;
R2 is hydrogen; R3 is
hydrogen; D* is hydrogen; and n is zero. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is zero. In another
embodiment, Ria is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is
zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is hydrogen; D*
is hydrogen; and n
is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is hydrogen; D* is
hydrogen; and n is zero. In another embodiment, Ria is alkylene, wherein the
alkylene is further
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is hydrogen; D* is hydrogen; and n is zero. In any of the embodiments in this
paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[0070] In another embodiment, RI-a is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is
hydrogen; R3 is hydrogen;
D* is hydrogen; and n is zero. In another embodiment, Rla is hydrogen and Rib
is hydrogen; R2 is
an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is zero. In
another embodiment,
Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3 is hydrogen;
D* is hydrogen; and
n is zero. In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an
amino acid side chain;
R3 is hydrogen; D* is hydrogen; and n is zero. In another embodiment, Rla is
hydrogen and Rib is
alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n
is zero. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is hydrogen; and n is zero. In another embodiment, Ria is hydrogen and Rib
is aryl; R2 is an
amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is zero. In
another embodiment, Rla
is hydrogen and Rib is arylalkyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is hydrogen;
and n is zero. In another embodiment, Rla is hydrogen and Rib is heteroaryl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is hydrogen; and n is zero. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is hydrogen; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is zero. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain;
R3 is hydrogen; D*
is hydrogen; and n is zero. In another embodiment, Rla is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is hydrogen; and n is zero. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3
is hydrogen; D* is
hydrogen; and n is zero. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is an amino acid side
chain; R3 is hydrogen; D* is hydrogen; and n is zero. In another embodiment,
Rla is alkylene,
31
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is zero. In any
of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this paragraph,
R4 is alkyl.
[0071] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain; R3
is hydrogen; D* is hydrogen; and n is zero. In another embodiment, Rla is
hydrogen and Rib is
hydrogen; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is zero. In
another embodiment, Rla
is hydrogen and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and
n is zero. In another
embodiment, Rla is hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is alkyl; D*
is hydrogen; and n
is zero. In another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is
hydrogen; R3 is alkyl; D*
is hydrogen; and n is zero. In another embodiment, Rla is hydrogen and Rib is
alkynyl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is zero. In another embodiment,
RI-a is hydrogen and
Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is zero. In
another embodiment, Rla
is hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen;
and n is zero. In
another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3
is alkyl; D* is
hydrogen; and n is zero. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is alkyl; D* is hydrogen; and n is zero. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is hydrogen; R3 is alkyl; D* is hydrogen; and n is zero. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is zero. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen;
and n is zero. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is alkyl;
D* is hydrogen; and
n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is alkyl; D* is
hydrogen; and n is zero. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
32
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is alkyl; D* is hydrogen; and n is zero. In another embodiment, RI-a is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is heteroaryl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is zero. In another embodiment,
Rla is hydrogen and
Rib is hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen;
and n is zero. In another
embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3
is alkyl; D* is
hydrogen; and n is zero. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[0072] In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an
amino acid side
chain; R3 is alkyl; D* is hydrogen; and n is zero. In another embodiment, Rla
is hydrogen and Rib
is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n
is zero. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is alkyl; D* is
hydrogen; and n is zero. In another embodiment, Rla is hydrogen and Rib is
aryl; R2 is an amino
acid side chain; R3 is alkyl; D* is hydrogen; and n is zero. In another
embodiment, Ria is hydrogen
and Rib is arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D* is
hydrogen; and n is zero. In
another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an amino acid
side chain; R3 is
alkyl; D* is hydrogen; and n is zero. In another embodiment, Rla is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is hydrogen; R2 is an
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is zero. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen;
and n is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3
is alkyl; D* is
hydrogen; and n is zero. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is alkyl; D* is hydrogen; and n is zero. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n
is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is
alkyl; D* is hydrogen;
and n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain;
33
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R3 is alkyl; D* is hydrogen; and n is zero. In another embodiment, RI-a is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n is zero. In
another embodiment,
Rla is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the
4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is zero. In any of
the embodiments in
this paragraph, R4 is hydrogen. In any of the embodiments in this paragraph,
R4 is alkyl.
[0073] In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is zero. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene
further bonded to
Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is
zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene
further bonded to RI-a to
form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is zero. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the
4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is zero. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is aryl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-
membered heterocyclyl; D* is hydrogen; and n is zero. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is zero. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is hydrogen; and n is zero. In another embodiment, Rla is alkylene, wherein
the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is an
amino acid side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-
, or 6-membered
heterocyclyl; D* is hydrogen; and n is zero. In another embodiment, Rla is
alkylene, wherein the
34
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is an amino acid side chain; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is zero. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is zero. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkenyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is zero. In any of the embodiments in this
paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[0074] In another embodiment, RI-a is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain; R3
is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain;
R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is zero. In another embodiment, Rla is hydrogen and Rib is hydrogen; R2
is hydrogen; R3 is
hydrogen; D* is acyl; and n is zero. In another embodiment, Rla is hydrogen
and Rib is alkyl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is zero. In another embodiment,
Rla is hydrogen and
Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is zero. In
another embodiment,
Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is
acyl; and n is zero. In
another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is
acyl; and n is zero. In another embodiment, Rla is hydrogen and Rib is aryl;
R2 is hydrogen; R3 is
hydrogen; D* is acyl; and n is zero. In another embodiment, Rla is hydrogen
and Rib is arylalkyl;
R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is zero. In another
embodiment, Rla is hydrogen
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
and Rib is heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is
zero. In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is hydrogen; D*
is acyl; and n is
zero. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is
hydrogen; D* is acyl;
and n is zero. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is
hydrogen; R3 is hydrogen;
D* is acyl; and n is zero. In another embodiment, R" is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is hydrogen; R3
is hydrogen; D* is acyl; and n is zero. In any of the embodiments in this
paragraph, R4 is hydrogen.
In any of the embodiments in this paragraph, R4 is alkyl.
[0075] In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen;
R3 is hydrogen; D*
is acyl; and n is zero. In another embodiment, Rla is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is
hydrogen; R3 is hydrogen;
D* is acyl; and n is zero. In another embodiment, R" is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is hydrogen; D* is acyl; and n is zero. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is heteroaryl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is zero. In another embodiment,
Rla is hydrogen and
Rib is hydrogen; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl;
and n is zero. In another
embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3
is hydrogen; D* is
acyl; and n is zero. In another embodiment, Rla is hydrogen and Rib is alkoxy;
R2 is an amino acid
side chain; R3 is hydrogen; D* is acyl; and n is zero. In another embodiment,
Rla is hydrogen and
Rib is alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl;
and n is zero. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is acyl; and n is zero. In another embodiment, Rla is hydrogen and Rib is
aryl; R2 is an amino
acid side chain; R3 is hydrogen; D* is acyl; and n is zero. In another
embodiment, Rla is hydrogen
and Rib is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
acyl; and n is zero. In
another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an amino acid
side chain; R3 is
hydrogen; D* is acyl; and n is zero. In another embodiment, Rla is alkylene,
wherein the alkylene
36
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is hydrogen; R2 is an
amino acid side chain; R3 is hydrogen; D* is acyl; and n is zero. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl;
and n is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3
is hydrogen; D* is
acyl; and n is zero. In another embodiment, Rla is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is
an amino acid side
chain; R3 is hydrogen; D* is acyl; and n is zero. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkynyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is zero. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is hydrogen;
D* is acyl; and n is
zero. In any of the embodiments in this paragraph, R4 is hydrogen. In any of
the embodiments in
this paragraph, R4 is alkyl.
[0076] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain; R3
is hydrogen; D* is acyl; In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
heteroaryl; R2 is an amino
acid side chain; R3 is hydrogen; D* is acyl; and n is zero. In another
embodiment, Rla is hydrogen
and Rib is hydrogen; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is zero.
In another embodiment,
Rla is hydrogen and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and
n is zero. In another
embodiment, Rla is hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is alkyl; D*
is acyl; and n is
zero. In another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is
hydrogen; R3 is alkyl; D* is
acyl; and n is zero. In another embodiment, Rla is hydrogen and Rib is
alkynyl; R2 is hydrogen; R3
is alkyl; D* is acyl; and n is zero. In another embodiment, Rla is hydrogen
and Rib is aryl; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is zero. In another embodiment, Rla
is hydrogen and Rib is
arylalkyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is zero. In another
embodiment, Rla is
hydrogen and Rib is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n
is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is alkyl; D* is
acyl; and n is zero.
37
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkyl;
D* is acyl; and n is
zero. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3
is alkyl; D* is acyl;
and n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is
hydrogen; R3 is alkyl; D* is
acyl; and n is zero. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is
hydrogen; R3 is alkyl;
D* is acyl; and n is zero. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is hydrogen; R3 is
alkyl; D* is acyl; and n is zero. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is zero. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is
heteroaryl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is zero. In another
embodiment, Rla is
hydrogen and Rib is hydrogen; R2 is an amino acid side chain; R3 is alkyl; D*
is acyl; and n is zero.
In another embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino acid side
chain; R3 is alkyl;
D* is acyl; and n is zero. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[0077] In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an
amino acid side
chain; R3 is alkyl; D* is acyl; and n is zero. In another embodiment, Rla is
hydrogen and Rib is
alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
zero. In another embodiment,
Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side chain; R3 is
alkyl; D* is acyl; and n is
zero. In another embodiment, Rla is hydrogen and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is acyl; and n is zero. In another embodiment, Rla is hydrogen and
Rib is arylalkyl; R2 is
an amino acid side chain; R3 is alkyl; D* is acyl; and n is zero. In another
embodiment, Rla is
hydrogen and Rib is heteroaryl; R2 is an amino acid side chain; R3 is alkyl;
D* is acyl; and n is zero.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side
chain; R3 is alkyl;
D* is acyl; and n is zero. In another embodiment, R" is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl;
R2 is an amino acid
38
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
side chain; R3 is alkyl; D* is acyl; and n is zero. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is zero. In
another embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl;
and n is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3
is alkyl; D* is acyl;
and n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is acyl; and n is zero. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an
amino acid side chain; R3 is alkyl; D* is acyl; and n is zero. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n
is zero. In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is alkylene
further bonded to Ria
to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is zero. In
any of the embodiments
in this paragraph, R4 is hydrogen. In any of the embodiments in this
paragraph, R4 is alkyl.
[0078] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene
further bonded to RI-a to
form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is zero. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the 4-
5-, or 6-membered heterocyclyl; D* is acyl; and n is zero. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-
, 5-, or 6-membered
heterocyclyl; D* is acyl; and n is zero. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is aryl; R2 is hydrogen;
39
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R3 is alkylene further bonded to 12" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is acyl; and
n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is
hydrogen; R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is zero. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is
alkylene further bonded
to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is
zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or
6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is
alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3
is alkylene further
bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side chain; R3
is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is zero. In any of
the embodiments in this paragraph, R4 is hydrogen. In any of the embodiments
in this paragraph,
R4 is alkyl.
[0079] In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
zero. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid
side chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is zero. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is zero. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is zero. In
another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is
hydrogen; D* is a
residue of a biologically active compound; and n is zero. In another
embodiment, Rla is hydrogen
and Rib is alkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is zero. In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is
hydrogen; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is zero. In
another embodiment,
Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is zero. In another embodiment, Rla is hydrogen and Rib
is alkynyl; R2 is
hydrogen; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is zero. In
another embodiment, Rla is hydrogen and Rib is aryl; R2 is hydrogen; R3 is
hydrogen; D* is a
residue of a biologically active compound; and n is zero. In another
embodiment, Rla is hydrogen
and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is zero. In another embodiment, Rla is hydrogen and Rib is
heteroaryl; R2 is
hydrogen; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is zero. In
another embodiment, Rla is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is
hydrogen; D* is a residue
of a biologically active compound; and n is zero. In another embodiment, Ria
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkyl;
R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is zero. In
any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[0080] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen;
R3 is hydrogen; D*
is a residue of a biologically active compound; and n is zero. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically
active compound; and
n is zero. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen;
R3 is hydrogen; D*
is a residue of a biologically active compound; and n is zero. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
41
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is aryl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically
active compound; and n is
zero. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3
is hydrogen; D* is a
residue of a biologically active compound; and n is zero. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is zero. In another embodiment, Ria is hydrogen and Rib is hydrogen; R2
is an amino acid
side chain; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is zero. In
another embodiment, Ria is hydrogen and Rib is alkyl; R2 is amino acid side
chain; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is zero. In another
embodiment, Ria is
hydrogen and Rib is alkoxy; R2 is an amino acid side chain; R3 is hydrogen; D*
is a residue of a
biologically active compound; and n is zero. In another embodiment, R" is
hydrogen and Rib is
alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is zero. In another embodiment, R" is hydrogen and Rib is
alkynyl; R2 is an amino
acid side chain; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is zero. In
another embodiment, Ria is hydrogen and Rib is aryl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is zero. In another
embodiment, Ria is
hydrogen and Rib is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen;
D* is a residue of a
biologically active compound; and n is zero. In another embodiment, R" is
hydrogen and Rib is
heteroaryl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of
a biologically active
compound; and n is zero. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of
the embodiments in this paragraph, R4 is alkyl.
[0081] In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is hydrogen; D* is a residue of a biologically active compound; and n is zero.
In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is a
residue of a biologically active compound; and n is zero. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of
a biologically active
compound; and n is zero. In another embodiment, Ria is alkylene, wherein the
alkylene is further
42
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is zero. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side
chain; R3 is hydrogen; D*
is a residue of a biologically active compound; and n is zero. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is aryl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is zero. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an amino acid
side chain; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is zero. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is zero. In another
embodiment, Ria is
hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is alkyl; D* is a residue of
a biologically active
compound; and n is zero. In another embodiment, Ria is hydrogen and Rib is
alkyl; R2 is hydrogen;
R3 is alkyl; D* is a residue of a biologically active compound; and n is zero.
In another embodiment,
Ria is hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is zero. In another embodiment, Ria is hydrogen and Rib
is alkenyl; R2 is
hydrogen; R3 is alkyl; D* is a residue of a biologically active compound; and
n is zero. In another
embodiment, Ria is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is zero. In another embodiment, R" is
hydrogen and Rib is
aryl; R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is zero.
In any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[0082] In another embodiment, Ria is hydrogen and Rib is arylalkyl; R2 is
hydrogen; R3 is alkyl;
D* is a residue of a biologically active compound; and n is zero. In another
embodiment, Ria is
hydrogen and Rib is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is a residue
of a biologically active
compound; and n is zero. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is alkyl; D* is a residue of a biologically active compound; and n is zero.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
43
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is a residue
of a biologically active
compound; and n is zero. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl;
R2 is hydrogen; R3
is alkyl; D* is a residue of a biologically active compound; and n is zero. In
another embodiment,
Ria is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is a residue
of a biologically active
compound; and n is zero. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3
is alkyl; D* is a residue of a biologically active compound; and n is zero. In
another embodiment,
Ria is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is a residue of
a biologically active
compound; and n is zero. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is alkyl; D* is a residue of a biologically active compound; and n is zero. In
another embodiment,
Ria is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is zero. In another embodiment, Ria is hydrogen and Rib
is hydrogen; R2
is an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
zero. In another embodiment, Ria is hydrogen and Rib is alkyl; R2 is amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is zero. In
another embodiment, Ria
is hydrogen and Rib is alkoxy; R2 is an amino acid side chain; R3 is alkyl; D*
is a residue of a
biologically active compound; and n is zero. In another embodiment, RI-a is
hydrogen and Rib is
alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is zero. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of
the embodiments in this paragraph, R4 is alkyl.
[0083] In another embodiment, Ria is hydrogen and Rib is alkynyl; R2 is an
amino acid side
chain; R3 is alkyl; D* is a residue of a biologically active compound; and n
is zero. In another
embodiment, Ria is hydrogen and Rib is aryl; R2 is an amino acid side chain;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is zero. In another
embodiment, Ria is hydrogen
and Rib is arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is zero. In another embodiment, Ria is hydrogen and Rib
is heteroaryl; R2
44
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
zero. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid
side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is zero. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is zero. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and
n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is zero. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is zero. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
zero. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is zero. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side chain; R3 is
alkyl; D* is a residue of a
biologically active compound; and n is zero. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is hydrogen;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is zero. In any of
the embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[0084] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is zero. In another embodiment, Rla is alkylene, wherein the
alkylene is further
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl;
R2 is hydrogen; R3
is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of
a biologically active compound; and n is zero. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkenyl;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is zero. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkynyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to
form the 4-, 5-, or 6-
membered heterocyclyl; D* is a residue of a biologically active compound; and
n is zero. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to
form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a biologically
active compound; and
n is zero. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is
hydrogen; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is zero. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is zero. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is hydrogen; R2 is an amino acid side chain; R3 is alkylene further
bonded to Rla to form
the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a biologically
active compound; and n is
zero. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino acid
side chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is zero. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of a biologically active compound; and n is
zero. In any of the
embodiments in this paragraph, R4 is hydrogen. In any of the embodiments in
this paragraph, R4 is
alkyl.
46
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[0085] In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl;
D* is a residue of a
biologically active compound; and n is zero. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkynyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to Ria to form
the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of a biologically active compound; and n is
zero. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is
alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is zero. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an amino acid
side chain; R3 is alkylene further bonded to Ria to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is a residue of a biologically active compound; and n is zero. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is an amino acid side chain; R3 is alkylene further bonded
to RI-a to form the 4-, 5-
or 6-membered heterocyclyl; D* is a residue of a biologically active compound;
and n is zero. In
any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[0086] In another embodiment, Ria is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
hydrogen; D* is hydrogen; and n is one. In another embodiment, Ria is hydrogen
and Rib is alkyl;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is one. In another
embodiment, Ria is
hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is one. In
another embodiment, Ria is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is
hydrogen; D* is
hydrogen; and n is one. In another embodiment, Ria is hydrogen and Rib is
alkynyl; R2 is hydrogen;
R3 is hydrogen; D* is hydrogen; and n is one. In another embodiment, Ria is
hydrogen and Rib is
aryl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is one. In another
embodiment, Ria is
hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is one. In
another embodiment, Ria is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3
is hydrogen; D* is
hydrogen; and n is one. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
47
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R3 is hydrogen; D* is hydrogen; and n is one. In another embodiment, RI-a is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is hydrogen; R3 is hydrogen; D* is hydrogen; and n is one. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is one. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is
hydrogen; and n is one. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is hydrogen;
and n is one. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen;
R3 is hydrogen; D*
is hydrogen; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is hydrogen; D* is hydrogen; and n is one. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is one. In another
embodiment, Ria is
hydrogen and Rib is hydrogen; R2 is an amino acid side chain; R3 is hydrogen;
D* is hydrogen; and
n is one. In another embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino
acid side chain; R3
is hydrogen; D* is hydrogen; and n is one. In another embodiment, Rla is
hydrogen and Rib is
alkoxy; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n
is one. In another
embodiment, Rla is hydrogen and Rib is alkenyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is hydrogen; and n is one. In another embodiment, Rla is hydrogen and Rib
is alkynyl; R2 is an
amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is one. In
another embodiment, Rla
is hydrogen and Rib is aryl; R2 is an amino acid side chain; R3 is hydrogen;
D* is hydrogen; and n
is one. In another embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is an
amino acid side chain;
R3 is hydrogen; D* is hydrogen; and n is one. In another embodiment, Rla is
hydrogen and Rib is
heteroaryl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is one. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3
is hydrogen; D* is
hydrogen; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl;
R2 is an amino acid
48
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
side chain; R3 is hydrogen; D* is hydrogen; and n is one. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[0087] In another embodiment, 12" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino
acid side chain; R3 is
hydrogen; D* is hydrogen; and n is one. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkenyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is one.
In another
embodiment, RI-a is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3
is hydrogen; D* is
hydrogen; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is an amino acid side
chain; R3 is hydrogen; D* is hydrogen; and n is one. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is one. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side chain;
R3 is hydrogen; D*
is hydrogen; and n is one. In another embodiment, Rla is hydrogen and Rib is
hydrogen; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is one. In another embodiment,
Rla is hydrogen and
Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is one. In
another embodiment, Rla
is hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is alkyl; D* is hydrogen;
and n is one. In another
embodiment, Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is alkyl;
D* is hydrogen; and
n is one. In another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is
hydrogen; R3 is alkyl;
D* is hydrogen; and n is one. In another embodiment, Rla is hydrogen and Rib
is aryl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is one. In another embodiment,
Rla is hydrogen and
Rib is arylalkyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is one.
In another embodiment,
Rla is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is
hydrogen; and n is one. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is alkyl;
D* is hydrogen; and
n is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen;
R3 is alkyl; D* is
hydrogen; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
49
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl;
R2 is hydrogen; R3
is alkyl; D* is hydrogen; and n is one. In another embodiment, Ria is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkenyl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is one. In another embodiment,
Ria is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is one. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[0088] In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is alkyl; D* is
hydrogen; and n is one. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is alkyl; D* is hydrogen; and n is one. In another embodiment, Ria is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is heteroaryl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is one. In another embodiment,
Ria is hydrogen and
Rib is hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen;
and n is one. In another
embodiment, Ria is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3
is alkyl; D* is
hydrogen; and n is one. In another embodiment, Ria is hydrogen and Rib is
alkoxy; R2 is an amino
acid side chain; R3 is alkyl; D* is hydrogen; and n is one. In another
embodiment, Ria is hydrogen
and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is
hydrogen; and n is one. In
another embodiment, Ria is hydrogen and Rib is alkynyl; R2 is an amino acid
side chain; R3 is alkyl;
D* is hydrogen; and n is one. In another embodiment, Ria is hydrogen and Rib
is aryl; R2 is an
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is one. In another
embodiment, Ria is
hydrogen and Rib is arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D*
is hydrogen; and n is
one. In another embodiment, Ria is hydrogen and Rib is heteroaryl; R2 is an
amino acid side chain;
R3 is alkyl; D* is hydrogen; and n is one. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is hydrogen;
R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n is one. In
another embodiment,
RI-a is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is alkyl;
D* is hydrogen; and n is
one. In another embodiment, Ria is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid
side chain; R3 is alkyl;
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
D* is hydrogen; and n is one. In another embodiment, R" is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is alkyl; D* is hydrogen; and n is one. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n
is one. In any of the
embodiments in this paragraph, R4 is hydrogen. In any of the embodiments in
this paragraph, R4 is
alkyl.
[0089] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is hydrogen; and n is one. In another embodiment, Rla is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is arylalkyl; R2 is an
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is one. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is alkyl; D* is
hydrogen; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is one. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is
hydrogen; R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is one. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is
alkylene, further bonded to
R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is
one. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene
further bonded to RI-a to
form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is one. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the
4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is one. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is aryl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-
51
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
membered heterocyclyl; D* is hydrogen; and n is one. In another embodiment,
12" is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is one. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is hydrogen; and n is one. In any of the embodiments in this paragraph, R4
is hydrogen. In any
of the embodiments in this paragraph, R4 is alkyl.
[0090] In another embodiment, RI-a is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is one. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain; R3
is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is one. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain;
52
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R3 is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is one. In another embodiment, R" is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
hydrogen; D* is acyl; and n is one. In another embodiment, Rla is hydrogen and
Rib is alkyl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is one. In another embodiment, Rla
is hydrogen and
Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is one. In
another embodiment, Rla
is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is acyl;
and n is one. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is acyl; and n
is one. In another embodiment, Rla is hydrogen and Rib is aryl; R2 is
hydrogen; R3 is hydrogen; D*
is acyl; and n is one. In another embodiment, Rla is hydrogen and Rib is
arylalkyl; R2 is hydrogen;
R3 is hydrogen; D* is acyl; and n is one. In another embodiment, Rla is
hydrogen and Rib is
heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is one. In any
of the embodiments in
this paragraph, R4 is hydrogen. In any of the embodiments in this paragraph,
R4 is alkyl.
[0091] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is
hydrogen; R3 is hydrogen;
D* is acyl; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl;
R2 is hydrogen; R3 is
hydrogen; D* is acyl; and n is one. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkoxyl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is one. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkenyl;
R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is one. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is one. In
another embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is aryl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is one. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is
acyl; and n is one. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is
hydrogen; D* is acyl; and
n is one. In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is an
amino acid side
chain; R3 is hydrogen; D* is acyl; and n is one. In another embodiment, Rla is
hydrogen and Rib is
53
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkyl; R2 is amino acid side chain; R3 is hydrogen; D* is acyl; and n is one.
In another embodiment,
RI-a is hydrogen and Rib is alkoxy; R2 is an amino acid side chain; R3 is
hydrogen; D* is acyl; and
n is one. In another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is an
amino acid side chain;
R3 is hydrogen; D* is acyl; and n is one. In another embodiment, Rla is
hydrogen and Rib is alkynyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is one. In
another embodiment,
Rla is hydrogen and Rib is aryl; R2 is an amino acid side chain; R3 is
hydrogen; D* is acyl; and n is
one. In another embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is an
amino acid side chain;
R3 is hydrogen; D* is acyl; and n is one. In another embodiment, Rla is
hydrogen and Rib is
heteroaryl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n
is one. In any of the
embodiments in this paragraph, R4 is hydrogen. In any of the embodiments in
this paragraph, R4 is
alkyl.
[0092] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is hydrogen; D* is acyl; and n is one. In another embodiment, Rla is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkyl; R2 is an
amino acid side chain; R3 is hydrogen; D* is acyl; and n is one. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain;
R3 is hydrogen; D* is
acyl; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is
an amino acid side
chain; R3 is hydrogen; D* is acyl; and n is one. In another embodiment, Rla is
alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkynyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is one. In
another embodiment,
Ria is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or
6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3
is hydrogen; D* is
acyl; and n is one. In another embodiment, Ria is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2
is an amino acid side
chain; R3 is hydrogen; D* is acyl; and n is one. In another embodiment, Rla is
alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is
heteroaryl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n
is one. In another
embodiment, Rla is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is alkyl;
D* is acyl; and n is
54
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
one. In another embodiment, RI-a is hydrogen and Rib is alkyl; R2 is hydrogen;
R3 is alkyl; D* is
acyl; and n is one. In another embodiment, Rla is hydrogen and Rib is alkoxy;
R2 is hydrogen; R3
is alkyl; D* is acyl; and n is one. In another embodiment, Rla is hydrogen and
Rib is alkenyl; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is one. In another embodiment, Rla is
hydrogen and Rib is
alkynyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is one. In another
embodiment, Rla is
hydrogen and Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is
one. In another
embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is alkyl;
D* is acyl; and n is
one. In another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is
hydrogen; R3 is alkyl; D*
is acyl; and n is one. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is
hydrogen; R3 is alkyl;
D* is acyl; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl;
R2 is hydrogen; R3 is
alkyl; D* is acyl; and n is one. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkoxyl; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is one. In any of the embodiments in
this paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[0093] In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen;
R3 is alkyl; D* is
acyl; and n is one. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is
hydrogen; R3 is alkyl;
D* is acyl; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is hydrogen; R3 is
alkyl; D* is acyl; and n is one. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is one. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is alkyl; D* is acyl; and n is one. In another embodiment,
Rla is hydrogen and
Rib is hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and
n is one. In another
embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3
is alkyl; D* is acyl;
and n is one. In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is
an amino acid side
chain; R3 is alkyl; D* is acyl; and n is one. In another embodiment, Rla is
hydrogen and Rib is
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
one. In another embodiment,
RI-a is hydrogen and Rib is alkynyl; R2 is an amino acid side chain; R3 is
alkyl; D* is acyl; and n is
one. In another embodiment, Rla is hydrogen and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is acyl; and n is one. In another embodiment, Rla is hydrogen and
Rib is arylalkyl; R2 is
an amino acid side chain; R3 is alkyl; D* is acyl; and n is one. In another
embodiment, Rla is
hydrogen and Rib is heteroaryl; R2 is an amino acid side chain; R3 is alkyl;
D* is acyl; and n is one.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side
chain; R3 is alkyl;
D* is acyl; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl;
R2 is an amino acid
side chain; R3 is alkyl; D* is acyl; and n is one. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is one. In
another embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl;
and n is one. In any of
the embodiments in this paragraph, R4 is hydrogen. In any of the embodiments
in this paragraph,
R4 is alkyl.
[0094] In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
alkyl; D* is acyl; and n is one. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
aryl; R2 is an amino
acid side chain; R3 is alkyl; D* is acyl; and n is one. In another embodiment,
Rla is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is
arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
one. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side chain;
R3 is alkyl; D* is
acyl; and n is one. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is
hydrogen; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
one. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is
alkylene further bonded
56
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is
one. In another
embodiment, RI-a is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene
further bonded to Rla to
form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is one. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the 4-
5-, or 6-membered heterocyclyl; D* is acyl; and n is one. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-
, 5-, or 6-membered
heterocyclyl; D* is acyl; and n is one. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is aryl; R2 is hydrogen;
R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is acyl; and
n is one. In any of the embodiments in this paragraph, R4 is hydrogen. In any
of the embodiments
in this paragraph, R4 is alkyl.
[0095] In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is
hydrogen; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is one. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is
alkylene further bonded
to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is
one. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or
6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is one. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is
alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is one. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3
is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is one. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side chain; R3
is alkylene further
57
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is one. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3
is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is one. In another
embodiment, 12" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is
alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is one. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side chain;
R3 is alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is one. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side chain;
R3 is alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is one. In another
embodiment, Ria is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is
hydrogen; D* is a residue
of a biologically active compound; and n is one. In another embodiment, R" is
hydrogen and Rib
is alkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically
active compound; and n
is one. In any of the embodiments in this paragraph, R4 is hydrogen. In any of
the embodiments in
this paragraph, R4 is alkyl.
[0096] In another embodiment, Ria is hydrogen and Rib is alkoxy; R2 is
hydrogen; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is one. In
another embodiment,
Ria is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is one. In another embodiment, R" is hydrogen and Rib
is alkynyl; R2 is
hydrogen; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is one. In another
embodiment, Ria is hydrogen and Rib is aryl; R2 is hydrogen; R3 is hydrogen;
D* is a residue of a
biologically active compound; and n is one. In another embodiment, R" is
hydrogen and Rib is
arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically
active compound; and n
is one. In another embodiment, Ria is hydrogen and Rib is heteroaryl; R2 is
hydrogen; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is one. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is one. In another embodiment, Ria is alkylene, wherein
the alkylene is
58
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkyl; R2 is hydrogen;
R3 is hydrogen; D* is a residue of a biologically active compound; and n is
one. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is hydrogen; D*
is a residue of a
biologically active compound; and n is one. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkenyl;
R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is one. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is a residue of
a biologically active compound; and n is one. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
hydrogen; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is one. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen;
D* is a residue of a
biologically active compound; and n is one. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is one. In
any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[0097] In another embodiment, Ria is hydrogen and Rib is hydrogen; R2 is an
amino acid side
chain; R3 is hydrogen; D* is a residue of a biologically active compound; and
n is one. In another
embodiment, Ria is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3
is hydrogen; D* is a
residue of a biologically active compound; and n is one. In another
embodiment, Ria is hydrogen
and Rib is alkoxy; R2 is an amino acid side chain; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is one. In another embodiment, RI-a is hydrogen and Rib
is alkenyl; R2 is
an amino acid side chain; R3 is hydrogen; D* is a residue of a biologically
active compound; and n
is one. In another embodiment, Ria is hydrogen and Rib is alkynyl; R2 is an
amino acid side chain;
R3 is hydrogen; D* is a residue of a biologically active compound; and n is
one. In another
embodiment, Ria is hydrogen and Rib is aryl; R2 is an amino acid side chain;
R3 is hydrogen; D* is
a residue of a biologically active compound; and n is one. In another
embodiment, Ria is hydrogen
and Rib is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is a
residue of a biologically
59
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
active compound; and n is one. In another embodiment, RI-a is hydrogen and Rib
is heteroaryl; R2
is an amino acid side chain; R3 is hydrogen; D* is a residue of a biologically
active compound; and
n is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is hydrogen; D* is a residue of a biologically active compound; and n is one.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is a residue of a
biologically active compound; and n is one. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is one. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an
amino acid side chain; R3
is hydrogen; D* is a residue of a biologically active compound; and n is one.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is a residue of
a biologically active compound; and n is one. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
an amino acid side chain; R3 is hydrogen; D* is a residue of a biologically
active compound; and n
is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino
acid side chain; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is one. In
any of the
embodiments in this paragraph, R4 is hydrogen. In any of the embodiments in
this paragraph, R4 is
alkyl.
[0098] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain; R3
is hydrogen; D* is a residue of a biologically active compound; and n is one.
In another embodiment,
Rla is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is one. In another embodiment, R" is hydrogen and Rib
is alkyl; R2 is
hydrogen; R3 is alkyl; D* is a residue of a biologically active compound; and
n is one. In another
embodiment, Rla is hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is alkyl; D*
is a residue of a
biologically active compound; and n is one. In another embodiment, R" is
hydrogen and Rib is
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkenyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is one.
In another embodiment, RI-a is hydrogen and Rib is alkynyl; R2 is hydrogen; R3
is alkyl; D* is a
residue of a biologically active compound; and n is one. In another
embodiment, Rla is hydrogen
and Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is a residue of a
biologically active compound; and
n is one. In another embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is
hydrogen; R3 is alkyl;
D* is a residue of a biologically active compound; and n is one. In another
embodiment, Rla is
hydrogen and Rib is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is a residue
of a biologically active
compound; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is alkyl; D* is a residue of a biologically active compound; and n is one.
In another embodiment,
Rla is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is a residue
of a biologically active
compound; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl;
R2 is hydrogen; R3
is alkyl; D* is a residue of a biologically active compound; and n is one. In
another embodiment,
Rla is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is a residue
of a biologically active
compound; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3
is alkyl; D* is a residue of a biologically active compound; and n is one. In
another embodiment,
Ria is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is a residue of
a biologically active
compound; and n is one. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[0099] In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is
hydrogen; R3 is alkyl; D* is
a residue of a biologically active compound; and n is one. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically
active compound; and n
is one. In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is an
amino acid side chain;
R3 is alkyl; D* is a residue of a biologically active compound; and n is one.
In another embodiment,
61
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3 is alkyl; D*
is a residue of a
biologically active compound; and n is one. In another embodiment, Rla is
hydrogen and Rib is
alkoxy; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is one. In another embodiment, Rla is hydrogen and Rib is
alkenyl; R2 is an amino
acid side chain; R3 is alkyl; D* is a residue of a biologically active
compound; and n is one. In
another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid
side chain; R3 is alkyl;
D* is a residue of a biologically active compound; and n is one. In another
embodiment, Rla is
hydrogen and Rib is aryl; R2 is an amino acid side chain; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is one. In another embodiment, Rla is hydrogen and Rib
is arylalkyl; R2 is
an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
one. In another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an
amino acid side chain;
R3 is alkyl; D* is a residue of a biologically active compound; and n is one.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3 is
alkyl; D* is a residue of a
biologically active compound; and n is one. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
one. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid
side chain; R3 is alkyl;
D* is a residue of a biologically active compound; and n is one. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is one. In another embodiment, Rla is alkylene, wherein
the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkynyl; R2 is an
amino acid side chain; R3 is alkyl; D* is a residue of a biologically active
compound; and n is one.
In any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[00100] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is one. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
62
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side chain; R3 is
alkyl; D* is a residue of a
biologically active compound; and n is one. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and
n is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is
hydrogen; R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is one. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is one. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to
form the 4-, 5-, or 6-
membered heterocyclyl; D* is a residue of a biologically active compound; and
n is one. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene
further bonded to Ria to
form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a biologically
active compound; and
n is one. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is hydrogen; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is a residue of a
biologically active compound; and n is one. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is arylalkyl;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is one. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is heteroaryl; R2 is hydrogen; R3 is alkylene further bonded to Rla to
form the 4-, 5-, or 6-
membered heterocyclyl; D* is a residue of a biologically active compound; and
n is one. In any of
63
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
the embodiments in this paragraph, R4 is hydrogen. In any of the embodiments
in this paragraph,
R4 is alkyl.
[00101] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of
a biologically active compound; and n is one. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is an amino acid side chain; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
heterocyclyl; D* is a residue of a biologically active compound; and n is one.
In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3
is alkylene further
bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is a residue of a biologically active compound; and n is one. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is an amino acid side chain; R3 is alkylene further bonded to
Rla to form the 4-, 5-, or
6-membered heterocyclyl; D* is a residue of a biologically active compound;
and n is one. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain;
R3 is alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is one. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an amino acid
side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is a residue of a biologically active compound; and n is one. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is an amino acid side chain; R3 is alkylene further bonded
to Rla to form the 4-, 5-
or 6-membered heterocyclyl; D* is a residue of a biologically active compound;
and n is one. In
any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
64
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00102] In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
hydrogen; D* is hydrogen; and n is two. In another embodiment, Rla is hydrogen
and Rib is alkyl;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is two. In another
embodiment, Ria is
hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is two. In
another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is
hydrogen; D* is
hydrogen; and n is two. In another embodiment, Rla is hydrogen and Rib is
alkynyl; R2 is hydrogen;
R3 is hydrogen; D* is hydrogen; and n is two. In another embodiment, Rla is
hydrogen and Rib is
aryl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is two. In another
embodiment, Rla is
hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is two. In
another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3
is hydrogen; D* is
hydrogen; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is hydrogen; D* is hydrogen; and n is two. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is hydrogen; R3 is hydrogen; D* is hydrogen; and n is two. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is two. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is
hydrogen; and n is two. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is hydrogen;
and n is two. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen;
R3 is hydrogen; D*
is hydrogen; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is hydrogen; D* is hydrogen; and n is two. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is two. In another
embodiment, Rla is
hydrogen and Rib is hydrogen; R2 is an amino acid side chain; R3 is hydrogen;
D* is hydrogen; and
n is two. In another embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino
acid side chain; R3
is hydrogen; D* is hydrogen; In another embodiment, Rla is hydrogen and Rib is
alkoxy; R2 is an
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is two. In any of
the embodiments in
this paragraph, R4 is hydrogen. In any of the embodiments in this paragraph,
R4 is alkyl.
[00103] In another embodiment, RI-a is hydrogen and Rib is alkenyl; R2 is an
amino acid side
chain; R3 is hydrogen; D* is hydrogen; and n is two. In another embodiment,
Rla is hydrogen and
Rib is alkynyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
hydrogen; and n is two. In
another embodiment, Rla is hydrogen and Rib is aryl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is hydrogen; and n is two. In another embodiment, Rla is hydrogen and Rib
is arylalkyl; R2 is
an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is two. In
another embodiment,
Rla is hydrogen and Rib is heteroaryl; R2 is an amino acid side chain; R3 is
hydrogen; D* is
hydrogen; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is an amino
acid side chain; R3 is hydrogen; D* is hydrogen; and n is two. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
hydrogen; and n is two. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side
chain; R3 is hydrogen; D*
is hydrogen; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is hydrogen; and n is two. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is two. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is
hydrogen; D* is
hydrogen; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an amino acid
side chain; R3 is hydrogen; D* is hydrogen; and n is two. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is two. In
another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is
alkyl; D* is
hydrogen; and n is two. In another embodiment, Rla is hydrogen and Rib is
alkyl; R2 is hydrogen;
R3 is alkyl; D* is hydrogen; and n is two. In another embodiment, Rla is
hydrogen and Rib is alkoxy;
66
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is two. In another
embodiment, R" is hydrogen
and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is two.
In another embodiment,
Ria is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is alkyl; D* is
hydrogen; and n is two. In
any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[00104] In another embodiment, Ria is hydrogen and Rib is aryl; R2 is
hydrogen; R3 is alkyl; D*
is hydrogen; and n is two. In another embodiment, Ria is hydrogen and Rib is
arylalkyl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is two. In another embodiment,
Ria is hydrogen and
Rib is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is two.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is alkyl; D* is
hydrogen; and n is two. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D*
is hydrogen; and n is
two. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3
is alkyl; D* is
hydrogen; and n is two. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is hydrogen; R3
is alkyl; D* is hydrogen; and n is two. In another embodiment, Ria is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkynyl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is two. In another embodiment,
Ria is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is aryl;
R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is two. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is two. In
another embodiment, Ria
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is
hydrogen; and n is two. In
another embodiment, Ria is hydrogen and Rib is hydrogen; R2 is an amino acid
side chain; R3 is
alkyl; D* is hydrogen; and n is two. In another embodiment, Ria is hydrogen
and Rib is alkyl; R2 is
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is two. In another
embodiment, Ria is
hydrogen and Rib is alkoxy; R2 is an amino acid side chain; R3 is alkyl; D* is
hydrogen; and n is
two. In another embodiment, Ria is hydrogen and Rib is alkenyl; R2 is an amino
acid side chain; R3
67
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is alkyl; D* is hydrogen; and n is two. In another embodiment, RI-a is
hydrogen and Rib is alkynyl;
R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n is two. In
another embodiment,
Rla is hydrogen and Rib is aryl; R2 is an amino acid side chain; R3 is alkyl;
D* is hydrogen; and n
is two. In any of the embodiments in this paragraph, R4 is hydrogen. In any of
the embodiments in
this paragraph, R4 is alkyl.
[00105] In another embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is an
amino acid side
chain; R3 is alkyl; D* is hydrogen; and n is two. In another embodiment, Rla
is hydrogen and Rib
is heteroaryl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen;
and n is two. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3
is alkyl; D* is
hydrogen; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl;
R2 is an amino acid
side chain; R3 is alkyl; D* is hydrogen; and n is two. In another embodiment,
Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n
is two. In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side chain; R3
is alkyl; D* is
hydrogen; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is an amino acid
side chain; R3 is alkyl; D* is hydrogen; and n is two. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is aryl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n is
two. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side chain;
R3 is alkyl; D* is
hydrogen; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
heteroaryl; R2 is an amino
acid side chain; R3 is alkyl; D* is hydrogen; and n is two. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is hydrogen; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is two. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
68
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is hydrogen; R3 is alkylene further bonded to R" to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is hydrogen; and n is two. In another embodiment, R" is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl;
R2 is hydrogen; R3
is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is two. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is
hydrogen; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is two.
In any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[00106] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is two. In
another embodiment, Rla is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is alkylene
further bonded to Rla
to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is two.
In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is alkylene
further bonded to Rla
to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is two.
In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is alkylene
further bonded to Rla
to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is two.
In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3
is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is two. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is two. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is two.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
69
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is two.
In another embodiment, Rla is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is two.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is two.
In any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[00107] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain; R3
is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is two. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain;
R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is two. In another embodiment, Rla is hydrogen and Rib is hydrogen; R2
is hydrogen; R3 is
hydrogen; D* is acyl; and n is two. In another embodiment, Rla is hydrogen and
Rib is alkyl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is two. In another embodiment, Rla
is hydrogen and
Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is two. In
another embodiment, Rla
is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is acyl;
and n is two. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is acyl; and n
is two. In another embodiment, Rla is hydrogen and Rib is aryl; R2 is
hydrogen; R3 is hydrogen; D*
is acyl; and n is two. In another embodiment, Rla is hydrogen and Rib is
arylalkyl; R2 is hydrogen;
R3 is hydrogen; D* is acyl; and n is two. In another embodiment, Rla is
hydrogen and Rib is
heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is two. In
another embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is hydrogen; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is two.
In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is hydrogen; D* is
acyl; and n is two.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is
hydrogen; D* is acyl; and
n is two. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen;
R3 is hydrogen; D*
is acyl; and n is two. In another embodiment, RI-a is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is
hydrogen; R3 is
hydrogen; D* is acyl; and n is two. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
aryl; R2 is hydrogen;
R3 is hydrogen; D* is acyl; and n is two. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is arylalkyl;
R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is two. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00108] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is
hydrogen; R3 is hydrogen;
D* is acyl; and n is two. In another embodiment, Ria is hydrogen and Rib is
hydrogen; R2 is an
amino acid side chain; R3 is hydrogen; D* is acyl; and n is two. In another
embodiment, Rla is
hydrogen and Rib is alkyl; R2 is amino acid side chain; R3 is hydrogen; D* is
acyl; and n is two. In
another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an amino acid
side chain; R3 is
hydrogen; D* is acyl; and n is two. In another embodiment, Rla is hydrogen and
Rib is alkenyl; R2
is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is two. In
another embodiment, Rla
is hydrogen and Rib is alkynyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is acyl; and n is
two. In another embodiment, Rla is hydrogen and Rib is aryl; R2 is an amino
acid side chain; R3 is
hydrogen; D* is acyl; and n is two. In another embodiment, Rla is hydrogen and
Rib is arylalkyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is two. In
another embodiment,
Rla is hydrogen and Rib is heteroaryl; R2 is an amino acid side chain; R3 is
hydrogen; D* is acyl;
and n is two. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an
amino acid side chain;
R3 is hydrogen; D* is acyl; and n is two. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is two. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is acyl; and n
71
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is two. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid
side chain; R3 is
hydrogen; D* is acyl; and n is two. In another embodiment, Ria is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkynyl; R2 is an
amino acid side chain; R3 is hydrogen; D* is acyl; and n is two. In another
embodiment, Ria is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is aryl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl;
and n is two. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side chain;
R3 is hydrogen; D* is
acyl; and n is two. In another embodiment, Ria is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2
is an amino acid side
chain; R3 is hydrogen; D* is acyl; and n is two. In any of the embodiments in
this paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00109] In another embodiment, Ria is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
alkyl; D* is acyl; and n is two. In another embodiment, Ria is hydrogen and
Rib is alkyl; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is two. In another embodiment, Ria is
hydrogen and Rib is
alkoxy; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is two. In another
embodiment, Ria is hydrogen
and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is two. In
another embodiment,
Ria is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is alkyl; D* is acyl;
and n is two. In another
embodiment, Ria is hydrogen and Rib is aryl; R2 is hydrogen; R3 is alkyl; D*
is acyl; and n is two.
In another embodiment, Ria is hydrogen and Rib is arylalkyl; R2 is hydrogen;
R3 is alkyl; D* is
acyl; and n is two. In another embodiment, RI-a is hydrogen and Rib is
heteroaryl; R2 is hydrogen;
R3 is alkyl; D* is acyl; and n is two. In another embodiment, Ria is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is hydrogen; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is two. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is hydrogen; R3 is alkyl; D* is acyl; and n is two. In another embodiment, Ria
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkoxyl;
R2 is hydrogen; R3 is alkyl; D* is acyl; and n is two. In another embodiment,
Ria is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkenyl;
R2 is hydrogen; R3 is alkyl; D* is acyl; and n is two. In another embodiment,
Ria is alkylene, wherein
72
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3 is alkyl; D* is acyl; and n is two. In another embodiment,
Rla is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is aryl;
R2 is hydrogen; R3 is alkyl; D* is acyl; and n is two. In another embodiment,
Rla is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is two. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is two.
In another embodiment,
Rla is hydrogen and Rib is hydrogen; R2 is an amino acid side chain; R3 is
alkyl; D* is acyl; and n
is two. In another embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino
acid side chain; R3 is
alkyl; D* is acyl; and n is two. In another embodiment, Rla is hydrogen and
Rib is alkoxy; R2 is an
amino acid side chain; R3 is alkyl; D* is acyl; and n is two. In another
embodiment, Rla is hydrogen
and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl;
and n is two. In any of
the embodiments in this paragraph, R4 is hydrogen. In any of the embodiments
in this paragraph,
R4 is alkyl.
[00110] In another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an
amino acid side
chain; R3 is alkyl; D* is acyl; and n is two. In another embodiment, Rla is
hydrogen and Rib is aryl;
R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is two. In
another embodiment, Rla is
hydrogen and Rib is arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D*
is acyl; and n is two.
In another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is acyl; and n is two. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is an
amino acid side chain; R3 is alkyl; D* is acyl; and n is two. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
two. In another embodiment,
Ria is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3 is alkyl;
D* is acyl; and n is
two. In another embodiment, Ria is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid
side chain; R3 is alkyl;
D* is acyl; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is an amino acid
73
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
side chain; R3 is alkyl; D* is acyl; and n is two. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is aryl;
R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is two. In
another embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl;
and n is two. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side chain;
R3 is alkyl; D* is
acyl; and n is two. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is
hydrogen; R3 is
alkylene further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
two. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is
alkylene further bonded
to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is
two. In any of the
embodiments in this paragraph, R4 is hydrogen. In any of the embodiments in
this paragraph, R4 is
alkyl.
[00111] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen;
R3 is alkylene further
bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is two. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene
further bonded to RI-a to
form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is two. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the
4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is two. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is aryl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-,
5-, or 6-membered
heterocyclyl; D* is acyl; and n is two. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is arylalkyl; R2 is
hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is acyl; and n is two. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2
is hydrogen; R3 is
74
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkylene further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
two. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid
side chain; R3 is
alkylene further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
two. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino acid
side chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is two. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is two. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is two. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is two. In
any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[00112] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
two. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
two. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
two. In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is two. In another
embodiment, Rla is
hydrogen and Rib is alkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of
a biologically active
compound; and n is two. In another embodiment, Rla is hydrogen and Rib is
alkoxy; R2 is hydrogen;
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
123 is hydrogen; D* is a residue of a biologically active compound; and n is
two. In another
embodiment, RI-a is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is
hydrogen; D* is a residue of
a biologically active compound; and n is two. In another embodiment, Rla is
hydrogen and Rib is
alkynyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically
active compound; and n
is two. In another embodiment, Rla is hydrogen and Rib is aryl; R2 is
hydrogen; R3 is hydrogen; D*
is a residue of a biologically active compound; and n is two. In another
embodiment, Rla is hydrogen
and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is two. In another embodiment, R" is hydrogen and Rib is
heteroaryl; R2 is
hydrogen; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is two. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is
hydrogen; D* is a residue
of a biologically active compound; and n is two. In another embodiment, R" is
alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkyl;
R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is two. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is
hydrogen; D* is a residue of
a biologically active compound; and n is two. In any of the embodiments in
this paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00113] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen;
R3 is hydrogen; D*
is a residue of a biologically active compound; and n is two. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically
active compound; and
n is two. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is hydrogen; D* is a
residue of a biologically active compound; and n is two. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active compound; and
n is two. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is
hydrogen; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is two. In another
embodiment, Rla is
76
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
hydrogen and Rib is hydrogen; R2 is an amino acid side chain; R3 is hydrogen;
D* is a residue of a
biologically active compound; and n is two. In another embodiment, Ria is
hydrogen and Rib is
alkyl; R2 is amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is two. In another embodiment, Ria is hydrogen and Rib is alkoxy; R2 is
an amino acid side
chain; R3 is hydrogen; D* is a residue of a biologically active compound; and
n is two. In another
embodiment, Ria is hydrogen and Rib is alkenyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is two. In another
embodiment, Ria is
hydrogen and Rib is alkynyl; R2 is an amino acid side chain; R3 is hydrogen;
D* is a residue of a
biologically active compound; and n is two. In another embodiment, R" is
hydrogen and Rib is
aryl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is two. In another embodiment, R" is hydrogen and Rib is
arylalkyl; R2 is an
amino acid side chain; R3 is hydrogen; D* is a residue of a biologically
active compound; and n is
two. In another embodiment, Ria is hydrogen and Rib is heteroaryl; R2 is an
amino acid side chain;
R3 is hydrogen; D* is a residue of a biologically active compound; and n is
two. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3
is hydrogen; D* is
a residue of a biologically active compound; and n is two. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00114] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino
acid side chain; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is two. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is a residue of
a biologically active compound; and n is two. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkenyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is two. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an
amino acid side chain; R3
is hydrogen; D* is a residue of a biologically active compound; and n is two.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is hydrogen;
D* is a residue of a
77
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
biologically active compound; and n is two. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is arylalkyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is two. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain;
R3 is hydrogen; D* is a residue of a biologically active compound; and n is
two. In another
embodiment, Ria is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is two. In another embodiment, R" is
hydrogen and Rib is
alkyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is two.
In another embodiment, Ria is hydrogen and Rib is alkoxy; R2 is hydrogen; R3
is alkyl; D* is a
residue of a biologically active compound; and n is two. In another
embodiment, Ria is hydrogen
and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a
biologically active compound;
and n is two. In another embodiment, Ria is hydrogen and Rib is alkynyl; R2 is
hydrogen; R3 is
alkyl; D* is a residue of a biologically active compound; and n is two. In
another embodiment, Ria
is hydrogen and Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is two. In another embodiment, Ria is hydrogen and Rib is
arylalkyl; R2 is
hydrogen; R3 is alkyl; D* is a residue of a biologically active compound; and
n is two. In another
embodiment, Ria is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3 is
alkyl; D* is a residue of
a biologically active compound; and n is two. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is hydrogen;
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is two. In any
of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this paragraph,
R4 is alkyl.
[00115] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is two. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
two. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3
is alkyl; D* is a residue
of a biologically active compound; and n is two. In another embodiment, R" is
alkylene, wherein
78
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is two. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is alkyl; D*
is a residue of a
biologically active compound; and n is two. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is arylalkyl;
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is two. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is
alkyl; D* is a residue of a
biologically active compound; and n is two. In another embodiment, Ria is
hydrogen and Rib is
hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is two. In another embodiment, Ria is hydrogen and Rib is
alkyl; R2 is amino acid
side chain; R3 is alkyl; D* is a residue of a biologically active compound;
and n is two. In another
embodiment, Ria is hydrogen and Rib is alkoxy; R2 is an amino acid side chain;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is two. In another
embodiment, Ria is hydrogen
and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is two. In another embodiment, R" is hydrogen and Rib
is alkynyl; R2 is
an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
two. In another embodiment, Ria is hydrogen and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is two. In
another embodiment, Ria
is hydrogen and Rib is arylalkyl; R2 is an amino acid side chain; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is two. In another embodiment, R" is
hydrogen and Rib is
heteroaryl; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is two. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[00116] In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is alkyl; D* is a residue of a biologically active compound; and n is two. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is two. In another embodiment, R" is
alkylene, wherein the
79
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and
n is two. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is two. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is two. In another embodiment, RI-a is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
two. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is two. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side chain; R3 is
alkyl; D* is a residue of a
biologically active compound; and n is two. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is hydrogen;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is two. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-
membered heterocyclyl; D* is a residue of a biologically active compound; and
n is two. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene
further bonded to Ria to
form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a biologically
active compound; and
n is two. In any of the embodiments in this paragraph, R4 is hydrogen. In any
of the embodiments
in this paragraph, R4 is alkyl.
[00117] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3
is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of
a biologically active compound; and n is two. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is a residue of a biologically active compound; and n is two. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
heterocyclyl; D* is a residue of a biologically active compound; and n is two.
In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is alkylene
further bonded to Rla
to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a
biologically active compound;
and n is two. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an
amino acid side chain;
R3 is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue
of a biologically active compound; and n is two. In another embodiment, Rla is
alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of a biologically active compound; and n is two.
In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3
is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is a residue of a biologically active compound; and n is two. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00118] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is a residue of a
biologically active compound; and n is two. In another embodiment, R" is
alkylene, wherein the
81
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
an amino acid side chain; R3 is alkylene further bonded to Rla to form the 4-,
5-, or 6-membered
heterocyclyl; D* is a residue of a biologically active compound; and n is two.
In another
embodiment, RI-a is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side chain;
R3 is alkylene further
bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is two. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
heteroaryl; R2 is an amino
acid side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is two. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00119] In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
hydrogen; D* is hydrogen; and n is three. In another embodiment, Ria is
hydrogen and Rib is alkyl;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is three. In another
embodiment, Rla is
hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is three. In
another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is
hydrogen; D* is
hydrogen; and n is three. In another embodiment, Rla is hydrogen and Rib is
alkynyl; R2 is
hydrogen; R3 is hydrogen; D* is hydrogen; and n is three. In another
embodiment, Rla is hydrogen
and Rib is aryl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is
three. In another
embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is
hydrogen; D* is hydrogen;
and n is three. In another embodiment, Rla is hydrogen and Rib is heteroaryl;
R2 is hydrogen; R3 is
hydrogen; D* is hydrogen; and n is three. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is hydrogen;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is three. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is
three. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is hydrogen; D*
is hydrogen; and n
is three. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen;
R3 is hydrogen; D*
is hydrogen; and n is three. In another embodiment, Rla is alkylene, wherein
the alkylene is further
82
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3
is hydrogen; D* is hydrogen; and n is three. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
hydrogen; R3 is hydrogen; D* is hydrogen; and n is three. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is three.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is
hydrogen; and n is three.
In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is an amino
acid side chain; R3 is
hydrogen; D* is hydrogen; and n is three. In another embodiment, Rla is
hydrogen and Rib is alkyl;
R2 is amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is three.
In another embodiment,
Rla is hydrogen and Rib is alkoxy; R2 is an amino acid side chain; R3 is
hydrogen; D* is hydrogen;
and n is three. In another embodiment, Rla is hydrogen and Rib is alkenyl; R2
is an amino acid side
chain; R3 is hydrogen; D* is hydrogen; and n is three. In another embodiment,
Rla is hydrogen and
Rib is alkynyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
hydrogen; and n is three. In
another embodiment, Ria is hydrogen and Rib is aryl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is hydrogen; and n is three. In another embodiment, Rla is hydrogen and Rib
is arylalkyl; R2 is
an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is three. In
another embodiment,
Rla is hydrogen and Rib is heteroaryl; R2 is an amino acid side chain; R3 is
hydrogen; D* is
hydrogen; and n is three. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is an amino
acid side chain; R3 is hydrogen; D* is hydrogen; and n is three. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
hydrogen; and n is three. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side
chain; R3 is hydrogen; D*
is hydrogen; and n is three. In another embodiment, Rla is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is hydrogen; and n is three. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
83
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00120] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
hydrogen; D* is hydrogen; and n is three. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is three. In
another embodiment,
RI-a is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or
6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side chain;
R3 is hydrogen; D*
is hydrogen; and n is three. In another embodiment, Rla is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
heteroaryl; R2 is an amino
acid side chain; R3 is hydrogen; D* is hydrogen; and n is three. In another
embodiment, Rla is
hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and
n is three. In another
embodiment, Rla is hydrogen and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D*
is hydrogen; and n
is three. In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is
hydrogen; R3 is alkyl; D*
is hydrogen; and n is three. In another embodiment, Rla is hydrogen and Rib is
alkenyl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is three. In another embodiment,
Rla is hydrogen and
Rib is alkynyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is three.
In another embodiment,
Rla is hydrogen and Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is hydrogen;
and n is three. In
another embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is hydrogen; R3
is alkyl; D* is
hydrogen; and n is three. In another embodiment, Rla is hydrogen and Rib is
heteroaryl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is three. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is hydrogen; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is three. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen;
and n is three. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkyl; D* is
hydrogen; and n is
three. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3
is alkyl; D* is hydrogen;
and n is three. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is
hydrogen; R3 is alkyl; D* is
84
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
hydrogen; and n is three. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[00121] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is alkyl; D* is
hydrogen; and n is three. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is alkyl; D* is hydrogen; and n is three. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is heteroaryl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is three. In another embodiment,
Rla is hydrogen and
Rib is hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen;
and n is three. In
another embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino acid side
chain; R3 is alkyl; D*
is hydrogen; and n is three. In another embodiment, Rla is hydrogen and Rib is
alkoxy; R2 is an
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is three. In another
embodiment, Rla is
hydrogen and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D*
is hydrogen; and n is
three. In another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an
amino acid side chain;
R3 is alkyl; D* is hydrogen; and n is three. In another embodiment, Rla is
hydrogen and Rib is aryl;
R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n is three.
In another embodiment,
Rla is hydrogen and Rib is arylalkyl; R2 is an amino acid side chain; R3 is
alkyl; D* is hydrogen;
and n is three. In another embodiment, Rla is hydrogen and Rib is heteroaryl;
R2 is an amino acid
side chain; R3 is alkyl; D* is hydrogen; and n is three. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and
n is three. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is
alkyl; D* is hydrogen;
and n is three. In another embodiment, Ria is alkylene, wherein the alkylene
is further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an
amino acid side chain; R3
is alkyl; D* is hydrogen; and n is three. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkenyl; R2 is an
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is three. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkynyl; R2 is an amino acid side chain; R3 is alkyl; D* is
hydrogen; and n is three. In
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
another embodiment, RI-a is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain;
R3 is alkyl; D* is
hydrogen; and n is three. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[00122] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain; R3
is alkyl; D* is hydrogen; and n is three. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is heteroaryl; R2 is an
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is three. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is hydrogen; R2 is hydrogen; R3 is alkylene further bonded to Rla to
form the 4-, 5-, or 6-
membered heterocyclyl; D* is hydrogen; and n is three. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-,
5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is three. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is hydrogen; and n is three. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkenyl; R2 is
hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is hydrogen; and n is three. In another embodiment, Rla is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3
is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is three. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen;
R3 is alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is three. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is
alkylene further bonded to
R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is
three. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or
6-membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is alkylene
further bonded to
86
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is
three. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or
6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is three. In
any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[00123] In another embodiment, 12" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is three. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is three. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is three. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is three. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is three. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain; R3
is alkylene further bonded to Ria to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is three. In another embodiment, RI-a is alkylene, wherein the alkylene
is further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain;
R3 is alkylene further bonded to Ria to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is three. In another embodiment, Ria is hydrogen and Rib is hydrogen; R2
is hydrogen; R3 is
hydrogen; D* is acyl; and n is three. In another embodiment, Ria is hydrogen
and Rib is alkyl; R2
is hydrogen; R3 is hydrogen; D* is acyl; and n is three. In another
embodiment, Ria is hydrogen and
Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is three. In
another embodiment,
87
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is
acyl; and n is three. In
another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is
acyl; and n is three. In another embodiment, Rla is hydrogen and Rib is aryl;
R2 is hydrogen; R3 is
hydrogen; D* is acyl; and n is three. In another embodiment, Rla is hydrogen
and Rib is arylalkyl;
R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is three. In another
embodiment, Rla is hydrogen
and Rib is heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is
three. In any of the
embodiments in this paragraph, R4 is hydrogen. In any of the embodiments in
this paragraph, R4 is
alkyl.
[00124] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is
hydrogen; R3 is hydrogen;
D* is acyl; and n is three. In another embodiment, R" is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl;
R2 is hydrogen; R3 is
hydrogen; D* is acyl; and n is three. In another embodiment, Ria is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkoxyl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is three. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is three. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is hydrogen; D* is acyl;
and n is three. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is hydrogen;
D* is acyl; and n is
three. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3
is hydrogen; D* is
acyl; and n is three. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2
is hydrogen; R3 is
hydrogen; D* is acyl; and n is three. In another embodiment, Rla is hydrogen
and Rib is hydrogen;
R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is three. In
another embodiment,
Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3 is hydrogen;
D* is acyl; and n is
three. In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an
amino acid side chain;
R3 is hydrogen; D* is acyl; and n is three. In another embodiment, Rla is
hydrogen and Rib is
alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is
three. In another
88
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
embodiment, RI-a is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is acyl; and n is three. In another embodiment, Rla is hydrogen and Rib is
aryl; R2 is an amino
acid side chain; R3 is hydrogen; D* is acyl; and n is three. In another
embodiment, Rla is hydrogen
and Rib is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
acyl; and n is three. In
another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an amino acid
side chain; R3 is
hydrogen; D* is acyl; and n is three. In another embodiment, Rla is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is hydrogen; R2 is an
amino acid side chain; R3 is hydrogen; D* is acyl; and n is three. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl;
and n is three. In any
of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this paragraph,
R4 is alkyl.
[00125] In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino
acid side chain; R3 is
hydrogen; D* is acyl; and n is three. In another embodiment, Rla is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkenyl; R2 is an
amino acid side chain; R3 is hydrogen; D* is acyl; and n is three. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkynyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
acyl; and n is three. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain;
R3 is hydrogen; D* is
acyl; and n is three. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2
is an amino acid side
chain; R3 is hydrogen; D* is acyl; and n is three. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is
heteroaryl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n
is three. In another
embodiment, Rla is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is alkyl;
D* is acyl; and n is
three. In another embodiment, Rla is hydrogen and Rib is alkyl; R2 is
hydrogen; R3 is alkyl; D* is
acyl; and n is three. In another embodiment, Rla is hydrogen and Rib is
alkoxy; R2 is hydrogen; R3
is alkyl; D* is acyl; and n is three. In another embodiment, Rla is hydrogen
and Rib is alkenyl; R2
is hydrogen; R3 is alkyl; D* is acyl; and n is three. In another embodiment,
Rla is hydrogen and Rib
89
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is alkynyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is three. In
another embodiment, R" is
hydrogen and Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is
three. In another
embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is alkyl;
D* is acyl; and n is
three. In another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is
hydrogen; R3 is alkyl;
D* is acyl; and n is three. In another embodiment, R" is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is alkyl; D* is acyl; and n is three. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkyl; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is three. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkoxyl;
R2 is hydrogen; R3 is alkyl; D* is acyl; and n is three. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkenyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is three. In any of
the embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00126] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen;
R3 is alkyl; D* is
acyl; and n is three. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is
hydrogen; R3 is alkyl; D*
is acyl; and n is three. In another embodiment, R" is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is alkyl; D* is acyl; and n is three. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
heteroaryl; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is three. In another embodiment, Rla
is hydrogen and Rib
is hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
three. In another
embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3
is alkyl; D* is acyl;
and n is three. In another embodiment, Rla is hydrogen and Rib is alkoxy; R2
is an amino acid side
chain; R3 is alkyl; D* is acyl; and n is three. In another embodiment, Rla is
hydrogen and Rib is
alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
three. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is alkyl; D* is
acyl; and n is three. In another embodiment, Rla is hydrogen and Rib is aryl;
R2 is an amino acid
side chain; R3 is alkyl; D* is acyl; and n is three. In another embodiment,
Rla is hydrogen and Rib
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n
is three. In another
embodiment, RI-a is hydrogen and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is alkyl; D*
is acyl; and n is three. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is an amino
acid side chain; R3 is alkyl; D* is acyl; and n is three. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
three. In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3 is alkyl;
D* is acyl; and n is
three. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid
side chain; R3 is alkyl;
D* is acyl; and n is three. In another embodiment, Rla is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is an amino acid
side chain; R3 is alkyl; D* is acyl; and n is three. In any of the embodiments
in this paragraph, R4
is hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00127] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is acyl; and n is three. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an
amino acid side chain; R3 is alkyl; D* is acyl; and n is three. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n
is three. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is alkylene
further bonded to Ria
to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is three. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkylene further bonded
to Rla to form the 4-,
5-, or 6-membered heterocyclyl; D* is acyl; and n is three. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-
, 5-, or 6-membered
heterocyclyl; D* is acyl; and n is three. In another embodiment, Rla is
alkylene, wherein the alkylene
91
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkenyl; R2 is
hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is acyl; and n is three. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3
is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is acyl; and n
is three. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is three. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is alkylene
further bonded to Rla
to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is three. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the
4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is three. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00128] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is acyl; and n
is three. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
three. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid
side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
three. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid
side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
three. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid
side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
three. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
92
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid
side chain; R3 is alkylene
further bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is three. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is three. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is three. In
another embodiment, Ria is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is
hydrogen; D* is a
residue of a biologically active compound; and n is three. In another
embodiment, Ria is hydrogen
and Rib is alkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is three. In another embodiment, Ria is hydrogen and Rib is alkoxy; R2
is hydrogen; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is three.
In another embodiment,
Ria is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is three. In another embodiment, Ria is hydrogen and
Rib is alkynyl; R2 is
hydrogen; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is three. In any
of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this paragraph,
R4 is alkyl.
[00129] In another embodiment, Ria is hydrogen and Rib is aryl; R2 is
hydrogen; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is three. In another
embodiment, Ria is
hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue
of a biologically
active compound; and n is three. In another embodiment, Ria is hydrogen and
Rib is heteroaryl; R2
is hydrogen; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is three. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is
hydrogen; D* is a residue
of a biologically active compound; and n is three. In another embodiment, R"
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkyl;
R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is three.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is
hydrogen; D* is a residue
of a biologically active compound; and n is three. In another embodiment, R"
is alkylene, wherein
93
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkenyl;
R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is three.
In another embodiment, Rla is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is a residue
of a biologically active compound; and n is three. In another embodiment, RI-a
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is aryl;
R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is three.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is
hydrogen; D* is a residue
of a biologically active compound; and n is three. In another embodiment, R"
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is
heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically
active compound; and
n is three. In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
an amino acid side
chain; R3 is hydrogen; D* is a residue of a biologically active compound; and
n is three. In another
embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3
is hydrogen; D* is a
residue of a biologically active compound; and n is three. In another
embodiment, Ria is hydrogen
and Rib is alkoxy; R2 is an amino acid side chain; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is three. In any of the embodiments in this paragraph,
R4 is hydrogen. In
any of the embodiments in this paragraph, R4 is alkyl.
[00130] In another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is an
amino acid side
chain; R3 is hydrogen; D* is a residue of a biologically active compound; and
n is three. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is three. In another
embodiment, Rla is
hydrogen and Rib is aryl; R2 is an amino acid side chain; R3 is hydrogen; D*
is a residue of a
biologically active compound; and n is three. In another embodiment, R" is
hydrogen and Rib is
arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of
a biologically active
compound; and n is three. In another embodiment, R" is hydrogen and Rib is
heteroaryl; R2 is an
amino acid side chain; R3 is hydrogen; D* is a residue of a biologically
active compound; and n is
three. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid
side chain; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is three.
In another embodiment,
94
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
12" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is a residue of a
biologically active compound; and n is three. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is three. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an
amino acid side chain; R3
is hydrogen; D* is a residue of a biologically active compound; and n is
three. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3
is hydrogen; D* is a
residue of a biologically active compound; and n is three. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is aryl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is three. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an amino acid
side chain; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is three. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is three. In any of
the embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00131] In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
alkyl; D* is a residue of a biologically active compound; and n is three. In
another embodiment, Rla
is hydrogen and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is a residue of
a biologically active
compound; and n is three. In another embodiment, R" is hydrogen and Rib is
alkoxy; R2 is
hydrogen; R3 is alkyl; D* is a residue of a biologically active compound; and
n is three. In another
embodiment, Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is three. In another embodiment, R" is
hydrogen and Rib is
alkynyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is
three. In another embodiment, Rla is hydrogen and Rib is aryl; R2 is hydrogen;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is three. In another
embodiment, Rla is hydrogen
and Rib is arylalkyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a
biologically active compound;
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
and n is three. In another embodiment, RI-a is hydrogen and Rib is heteroaryl;
R2 is hydrogen; R3 is
alkyl; D* is a residue of a biologically active compound; and n is three. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is three. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkyl; R2 is hydrogen;
R3 is alkyl; D* is a residue of a biologically active compound; and n is
three. In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkyl; D* is a residue
of a biologically active
compound; and n is three. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is hydrogen; R3
is alkyl; D* is a residue of a biologically active compound; and n is three.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is alkyl; D* is a residue
of a biologically active
compound; and n is three. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is hydrogen; R3 is
alkyl; D* is a residue of a biologically active compound; and n is three. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is three. In any of the embodiments in this paragraph,
R4 is hydrogen. In
any of the embodiments in this paragraph, R4 is alkyl.
[00132] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is
hydrogen; R3 is alkyl; D* is
a residue of a biologically active compound; and n is three. In another
embodiment, Rla is hydrogen
and Rib is hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is three. In another embodiment, R" is hydrogen and Rib
is alkyl; R2 is
amino acid side chain; R3 is alkyl; D* is a residue of a biologically active
compound; and n is three.
In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an amino acid
side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is three. In
another embodiment, Rla
is hydrogen and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is three. In another embodiment, R" is
hydrogen and Rib is
96
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkynyl; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is three. In another embodiment, R" is hydrogen and Rib is
aryl; R2 is an amino
acid side chain; R3 is alkyl; D* is a residue of a biologically active
compound; and n is three. In
another embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is an amino acid
side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is three. In
another embodiment, Rla
is hydrogen and Rib is heteroaryl; R2 is an amino acid side chain; R3 is
alkyl; D* is a residue of a
biologically active compound; and n is three. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is hydrogen;
R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and
n is three. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is three. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is three. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkenyl;
R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and
n is three. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is three. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is alkyl; D*
is a residue of a
biologically active compound; and n is three. In any of the embodiments in
this paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00133] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain; R3
is alkyl; D* is a residue of a biologically active compound; and n is three.
In another embodiment,
Rla is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side chain; R3 is
alkyl; D* is a residue of a
biologically active compound; and n is three. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is hydrogen;
97
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R2 is hydrogen; R3 is alkylene further bonded to R" to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is three. In another
embodiment, R" is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-
membered heterocyclyl; D* is a residue of a biologically active compound; and
n is three. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene
further bonded to Ria to
form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a biologically
active compound; and
n is three. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is three. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3
is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of
a biologically active compound; and n is three. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is a residue of a biologically active compound; and n is three. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is arylalkyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to
form the 4-, 5-, or 6-
membered heterocyclyl; D* is a residue of a biologically active compound; and
n is three. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is alkylene
further bonded to Rla
to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a
biologically active compound;
and n is three. In any of the embodiments in this paragraph, R4 is hydrogen.
In any of the
embodiments in this paragraph, R4 is alkyl.
[00134] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of
a biologically active compound; and n is three. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
98
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is an amino acid side chain; R3 is alkylene further bonded to 12" to form the
4-, 5-, or 6-membered
heterocyclyl; D* is a residue of a biologically active compound; and n is
three. In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3
is alkylene further
bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is three. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is a residue of a biologically active compound; and n is three. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkynyl; R2 is an amino acid side chain; R3 is alkylene further
bonded to Rla to form the
4-, 5-, or 6-membered heterocyclyl; D* is a residue of a biologically active
compound; and n is
three. In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid
side chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is three. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is arylalkyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to Rla to form
the 4-,
5-, or 6-membered heterocyclyl; D* is a residue of a biologically active
compound; and n is three.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid
side chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is three. In any of the embodiments in
this paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00135] In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
hydrogen; D* is hydrogen; and n is four. In another embodiment, Rla is
hydrogen and Rib is alkyl;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is four. In another
embodiment, Rla is
hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is four. In
another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is
hydrogen; D* is
hydrogen; and n is four. In another embodiment, Rla is hydrogen and Rib is
alkynyl; R2 is hydrogen;
R3 is hydrogen; D* is hydrogen; and n is four. In another embodiment, Rla is
hydrogen and Rib is
99
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
aryl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is four. In
another embodiment, Ria is
hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is four. In
another embodiment, Ria is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3
is hydrogen; D* is
hydrogen; and n is four. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is hydrogen; D* is hydrogen; and n is four. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is hydrogen; R3 is hydrogen; D* is hydrogen; and n is four. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is four. In
another embodiment,
Ria is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-
, or 6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is
hydrogen; and n is four. In
another embodiment, RI-a is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is hydrogen;
and n is four. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen;
R3 is hydrogen; D*
is hydrogen; and n is four. In another embodiment, Ria is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is hydrogen; D* is hydrogen; and n is four. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is four. In another
embodiment, Ria is
hydrogen and Rib is hydrogen; R2 is an amino acid side chain; R3 is hydrogen;
D* is hydrogen; and
n is four. In another embodiment, Ria is hydrogen and Rib is alkyl; R2 is
amino acid side chain; R3
is hydrogen; D* is hydrogen; and n is four. In another embodiment, Ria is
hydrogen and Rib is
alkoxy; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n
is four. In another
embodiment, Ria is hydrogen and Rib is alkenyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is hydrogen; and n is four. In another embodiment, Ria is hydrogen and Rib
is alkynyl; R2 is an
amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is four. In any
of the embodiments in
this paragraph, R4 is hydrogen. In any of the embodiments in this paragraph,
R4 is alkyl.
[00136] In another embodiment, Ria is hydrogen and Rib is aryl; R2 is an amino
acid side chain;
R3 is hydrogen; D* is hydrogen; In another embodiment, Ria is hydrogen and Rib
is arylalkyl; R2
100
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is four. In
another embodiment,
RI-a is hydrogen and Rib is heteroaryl; R2 is an amino acid side chain; R3 is
hydrogen; D* is
hydrogen; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is an amino
acid side chain; R3 is hydrogen; D* is hydrogen; and n is four. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
hydrogen; and n is four. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side
chain; R3 is hydrogen; D*
is hydrogen; and n is four. In another embodiment, Rla is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is hydrogen; and n is four. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is four. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is
hydrogen; D* is
hydrogen; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an amino acid
side chain; R3 is hydrogen; D* is hydrogen; and n is four. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is four. In
another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is
alkyl; D* is
hydrogen; and n is four. In another embodiment, Rla is hydrogen and Rib is
alkyl; R2 is hydrogen;
R3 is alkyl; D* is hydrogen; and n is four. In another embodiment, Rla is
hydrogen and Rib is
alkoxy; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is four. In another
embodiment, Rla is
hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and
n is four. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is alkyl;
D* is hydrogen; and
n is four. In another embodiment, Rla is hydrogen and Rib is aryl; R2 is
hydrogen; R3 is alkyl; D*
is hydrogen; and n is four. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of
the embodiments in this paragraph, R4 is alkyl.
101
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00137] In another embodiment, RI-a is hydrogen and Rib is arylalkyl; R2 is
hydrogen; R3 is alkyl;
D* is hydrogen; and n is four. In another embodiment, Rla is hydrogen and Rib
is heteroaryl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is four. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is hydrogen; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is four. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen;
and n is four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkyl; D* is
hydrogen; and n is
four. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3
is alkyl; D* is hydrogen;
and n is four. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is
hydrogen; R3 is alkyl; D* is
hydrogen; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is hydrogen; R3 is
alkyl; D* is hydrogen; and n is four. In another embodiment, Ria is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is arylalkyl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is four. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is four. In
another embodiment,
Rla is hydrogen and Rib is hydrogen; R2 is an amino acid side chain; R3 is
alkyl; D* is hydrogen;
and n is four. In another embodiment, Rla is hydrogen and Rib is alkyl; R2 is
amino acid side chain;
R3 is alkyl; D* is hydrogen; and n is four. In another embodiment, Rla is
hydrogen and Rib is
alkoxy; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n is
four. In another
embodiment, Rla is hydrogen and Rib is alkenyl; R2 is an amino acid side
chain; R3 is alkyl; D* is
hydrogen; and n is four. In another embodiment, Rla is hydrogen and Rib is
alkynyl; R2 is an amino
acid side chain; R3 is alkyl; D* is hydrogen; and n is four. In another
embodiment, Rla is hydrogen
and Rib is aryl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen;
and n is four. In another
embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is an amino acid side
chain; R3 is alkyl; D*
is hydrogen; and n is four. In another embodiment, Rla is hydrogen and Rib is
heteroaryl; R2 is an
102
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is four. In any of
the embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00138] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is alkyl; D* is hydrogen; and n is four. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkyl; R2 is an
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is four. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain;
R3 is alkyl; D* is
hydrogen; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is an amino acid
side chain; R3 is alkyl; D* is hydrogen; and n is four. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n
is four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is
alkyl; D* is hydrogen;
and n is four. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain;
R3 is alkyl; D* is hydrogen; and n is four. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n is four. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the
4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is four. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-
membered heterocyclyl; D* is hydrogen; and n is four. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-
, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is four. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkenyl;
103
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R2 is hydrogen; R3 is alkylene further bonded to R" to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is hydrogen; and n is four. In another embodiment, R" is alkylene, wherein
the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkynyl; R2 is
hydrogen; R3 is alkylene further bonded to R" to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is hydrogen; and n is four. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of
the embodiments in this paragraph, R4 is alkyl.
[00139] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is alkylene further
bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is four. In
another embodiment, RI-a is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is
alkylene further bonded to
Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is
four. In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is alkylene
further bonded to Rla
to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is four.
In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3
is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is four. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is four. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is four.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is four.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is four.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
104
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is four.
In another embodiment, Rla is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is four.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid
side chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
hydrogen; and n is four.
In any of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this
paragraph, R4 is alkyl.
[00140] In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
hydrogen; D* is acyl; and n is four. In another embodiment, Rla is hydrogen
and Rib is alkyl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is four. In another embodiment,
Ria is hydrogen and
Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is four. In
another embodiment,
Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is
acyl; and n is four. In
another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is
acyl; and n is four. In another embodiment, Rla is hydrogen and Rib is aryl;
R2 is hydrogen; R3 is
hydrogen; D* is acyl; and n is four. In another embodiment, Rla is hydrogen
and Rib is arylalkyl;
R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is four. In another
embodiment, Rla is hydrogen
and Rib is heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is
four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is hydrogen; D*
is acyl; and n is
four. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is
hydrogen; D* is acyl;
and n is four. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is
hydrogen; R3 is hydrogen;
D* is acyl; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is hydrogen; R3
is hydrogen; D* is acyl; and n is four. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkynyl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is four. In another embodiment,
Rla is alkylene, wherein
105
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is aryl;
R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is four. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is four. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is
acyl; and n is four. In
another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is an amino acid
side chain; R3 is
hydrogen; D* is acyl; and n is four. In another embodiment, Rla is hydrogen
and Rib is alkyl; R2 is
amino acid side chain; R3 is hydrogen; D* is acyl; and n is four. In any of
the embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00141] In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an
amino acid side
chain; R3 is hydrogen; D* is acyl; and n is four. In another embodiment, Rla
is hydrogen and Rib is
alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is
four. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is acyl; and n is four. In another embodiment, Rla is hydrogen and Rib is
aryl; R2 is an amino
acid side chain; R3 is hydrogen; D* is acyl; and n is four. In another
embodiment, Rla is hydrogen
and Rib is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
acyl; and n is four. In
another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an amino acid
side chain; R3 is
hydrogen; D* is acyl; and n is four. In another embodiment, Rla is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is hydrogen; R2 is an
amino acid side chain; R3 is hydrogen; D* is acyl; and n is four. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl;
and n is four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3
is hydrogen; D* is
acyl; and n is four. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is
an amino acid side
chain; R3 is hydrogen; D* is acyl; and n is four. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkynyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and n is four. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
106
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is hydrogen;
D* is acyl; and n is
four. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino
acid side chain; R3 is
hydrogen; D* is acyl; and n is four. In another embodiment, Rla is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is heteroaryl; R2 is an
amino acid side chain; R3 is hydrogen; D* is acyl; and n is four. In another
embodiment, Rla is
hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is alkyl; D* is acyl; and n
is four. In another
embodiment, Rla is hydrogen and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D*
is acyl; and n is four.
In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is hydrogen; R3
is alkyl; D* is acyl;
and n is four. In any of the embodiments in this paragraph, R4 is hydrogen. In
any of the
embodiments in this paragraph, R4 is alkyl.
[00142] In another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is
hydrogen; R3 is alkyl;
D* is acyl; and n is four. In another embodiment, RI-a is hydrogen and Rib is
alkynyl; R2 is hydrogen;
R3 is alkyl; D* is acyl; and n is four. In another embodiment, Rla is hydrogen
and Rib is aryl; R2 is
hydrogen; R3 is alkyl; D* is acyl; and n is four. In another embodiment, Rla
is hydrogen and Rib is
arylalkyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is four. In another
embodiment, Rla is
hydrogen and Rib is heteroaryl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n
is four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is alkyl; D* is
acyl; and n is four.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkyl;
D* is acyl; and n is
four. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3
is alkyl; D* is acyl;
and n is four. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is
hydrogen; R3 is alkyl; D* is
acyl; and n is four. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is
hydrogen; R3 is alkyl;
D* is acyl; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is hydrogen; R3 is
alkyl; D* is acyl; and n is four. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is
107
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
hydrogen; R3 is alkyl; D* is acyl; and n is four. In another embodiment, Ria
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is
heteroaryl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is four. In another
embodiment, Ria is
hydrogen and Rib is hydrogen; R2 is an amino acid side chain; R3 is alkyl; D*
is acyl; and n is four.
In another embodiment, Ria is hydrogen and Rib is alkyl; R2 is amino acid side
chain; R3 is alkyl;
D* is acyl; and n is four. In another embodiment, Ria is hydrogen and Rib is
alkoxy; R2 is an amino
acid side chain; R3 is alkyl; D* is acyl; and n is four. In another
embodiment, Ria is hydrogen and
Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n
is four. In another
embodiment, Ria is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is alkyl; D* is
acyl; and n is four. In another embodiment, Ria is hydrogen and Rib is aryl;
R2 is an amino acid
side chain; R3 is alkyl; D* is acyl; and n is four. In another embodiment, Ria
is hydrogen and Rib
is arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n
is four. In another
embodiment, Ria is hydrogen and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is alkyl; D*
is acyl; and n is four. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[00143] In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino
acid side chain; R3
is alkyl; D* is acyl; and n is four. In another embodiment, Ria is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkyl; R2 is an amino
acid side chain; R3 is alkyl; D* is acyl; and n is four. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
four. In another
embodiment, RI-a is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side chain; R3
is alkyl; D* is acyl;
and n is four. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an
amino acid side chain; R3
is alkyl; D* is acyl; and n is four. In another embodiment, Ria is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
aryl; R2 is an amino
acid side chain; R3 is alkyl; D* is acyl; and n is four. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n
is four. In another
108
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
embodiment, RI-a is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side chain;
R3 is alkyl; D* is
acyl; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is
hydrogen; R3 is
alkylene further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
four. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is
alkylene further bonded
to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is
four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene
further bonded to R" to
form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is four. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the 4-
5-, or 6-membered heterocyclyl; D* is acyl; and n is four. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00144] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen;
R3 is alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is alkylene further
bonded to R" to
form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is four. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is alkylene,
further bonded to
R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is four.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the
4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is four. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is hydrogen; R2 is an amino acid side chain; R3 is alkylene further
bonded to Rla to form
the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is four. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
109
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
and Rib is alkyl; R2 is an amino acid side chain; R3 is alkylene further
bonded to Rla to form the 4-
5-, or 6-membered heterocyclyl; D* is acyl; and n is four. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is an amino acid side chain; R3 is alkylene further bonded to
Rla to form the 4-, 5-, or
6-membered heterocyclyl; D* is acyl; and n is four. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkenyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-membered
heterocyclyl; D* is acyl; and n is four. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkynyl; R2 is an
amino acid side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-
, or 6-membered
heterocyclyl; D* is acyl; and n is four. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is aryl; R2 is an amino
acid side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is acyl; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an amino acid
side chain; R3 is alkylene further bonded to RI-a to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is acyl; and n is four. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[00145] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain; R3
is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is acyl; and n
is four. In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is four. In
another embodiment,
Rla is hydrogen and Rib is alkyl; R2 is hydrogen; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is four. In another embodiment, R" is hydrogen and Rib
is alkoxy; R2 is
hydrogen; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is four. In
another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is
hydrogen; D* is a
residue of a biologically active compound; and n is four. In another
embodiment, Rla is hydrogen
and Rib is alkynyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is four. In another embodiment, Rla is hydrogen and Rib is
aryl; R2 is hydrogen;
R3 is hydrogen; D* is a residue of a biologically active compound; and n is
four. In another
110
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
embodiment, Ria is hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is
hydrogen; D* is a residue
of a biologically active compound; and n is four. In another embodiment, R" is
hydrogen and Rib
is heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is four. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is
hydrogen; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is four. In another
embodiment, Ria is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is four. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is
hydrogen; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is four. In another
embodiment, Ria is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is four. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is hydrogen; R3
is hydrogen; D* is a residue of a biologically active compound; and n is four.
In any of the
embodiments in this paragraph, R4 is hydrogen. In any of the embodiments in
this paragraph, R4 is
alkyl.
[00146] In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is hydrogen; D* is a
residue of a biologically active compound; and n is four. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active compound; and
n is four. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is
hydrogen; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is four. In another
embodiment, Ria is
hydrogen and Rib is hydrogen; R2 is an amino acid side chain; R3 is hydrogen;
D* is a residue of a
biologically active compound; and n is four. In another embodiment, R" is
hydrogen and Rib is
alkyl; R2 is amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is four. In another embodiment, Ria is hydrogen and Rib is alkoxy; R2 is
an amino acid side
chain; R3 is hydrogen; D* is a residue of a biologically active compound; and
n is four. In another
111
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
embodiment, RI-a is hydrogen and Rib is alkenyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is four. In another
embodiment, Rla is
hydrogen and Rib is alkynyl; R2 is an amino acid side chain; R3 is hydrogen;
D* is a residue of a
biologically active compound; and n is four. In another embodiment, R" is
hydrogen and Rib is
aryl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is four. In another embodiment, R" is hydrogen and Rib is
arylalkyl; R2 is an
amino acid side chain; R3 is hydrogen; D* is a residue of a biologically
active compound; and n is
four. In another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an
amino acid side chain;
R3 is hydrogen; D* is a residue of a biologically active compound; and n is
four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3
is hydrogen; D* is
a residue of a biologically active compound; and n is four. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is four. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side
chain; R3 is hydrogen; D*
is a residue of a biologically active compound; and n is four. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00147] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is four. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is aryl; R2 is an amino acid side chain; R3 is hydrogen;
D* is a residue of a
biologically active compound; and n is four. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is arylalkyl;
R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is four. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain;
112
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
123 is hydrogen; D* is a residue of a biologically active compound; and n is
four. In another
embodiment, RI-a is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is four. In another embodiment, Rla is
hydrogen and Rib is
alkyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is four.
In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is hydrogen; R3
is alkyl; D* is a
residue of a biologically active compound; and n is four. In another
embodiment, Rla is hydrogen
and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a
biologically active compound;
and n is four. In another embodiment, Rla is hydrogen and Rib is alkynyl; R2
is hydrogen; R3 is
alkyl; D* is a residue of a biologically active compound; and n is four. In
another embodiment, Rla
is hydrogen and Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is four. In another embodiment, R" is hydrogen and Rib is
arylalkyl; R2 is
hydrogen; R3 is alkyl; D* is a residue of a biologically active compound; and
n is four. In another
embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3 is
alkyl; D* is a residue of
a biologically active compound; and n is four. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is hydrogen;
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is four. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D*
is a residue of a
biologically active compound; and n is four. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is four. In any
of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this paragraph,
R4 is alkyl.
[00148] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is four. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
four. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is
alkyl; D* is a residue of
a biologically active compound; and n is four. In another embodiment, Rla is
alkylene, wherein the
113
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is arylalkyl;
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is four. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is
alkyl; D* is a residue of a
biologically active compound; and n is four. In another embodiment, Ria is
hydrogen and Rib is
hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is four. In another embodiment, Ria is hydrogen and Rib is
alkyl; R2 is amino acid
side chain; R3 is alkyl; D* is a residue of a biologically active compound;
and n is four. In another
embodiment, Ria is hydrogen and Rib is alkoxy; R2 is an amino acid side chain;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is four. In another
embodiment, Ria is hydrogen
and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is four. In another embodiment, Ria is hydrogen and Rib
is alkynyl; R2 is
an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
four. In another embodiment, Ria is hydrogen and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is four. In
another embodiment, Ria
is hydrogen and Rib is arylalkyl; R2 is an amino acid side chain; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is four. In another embodiment, R" is
hydrogen and Rib is
heteroaryl; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is four. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is an amino
acid side chain; R3 is alkyl; D* is a residue of a biologically active
compound; and n is four. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is four. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00149] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is four. In
another embodiment, Ria
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side chain;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is four. In another
embodiment, Ria is alkylene,
114
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is an amino acid side
chain; R3 is alkyl; D* is a residue of a biologically active compound; and n
is four. In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side chain;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is four. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is heteroaryl; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of
a biologically active
compound; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue
of a biologically active compound; and n is four. In another embodiment, R" is
alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is alkyl;
R2 is hydrogen; R3 is alkylene, further bonded to RI-a to form the 4-, 5-, or
6-membered heterocyclyl;
D* is a residue of a biologically active compound; and n is four. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to
form the 4-, 5-, or 6-
membered heterocyclyl; D* is a residue of a biologically active compound; and
n is four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or
6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene
further bonded to Rla
to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a
biologically active compound;
and n is four. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is
hydrogen; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is four. In any of the embodiments in this
paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00150] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
115
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
compound; and n is four. In another embodiment, R" is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of
a biologically active compound; and n is four. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is four. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is hydrogen; R2 is an amino acid side chain; R3 is alkylene further
bonded to Rla to form
the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a biologically
active compound; and n is
four. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino acid
side chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is four. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to RI-a to form
the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue of a biologically active compound; and n is
four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or
6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side chain;
R3 is alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is an amino acid
side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is a residue of a biologically active compound; and n is four. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is aryl; R2 is an amino acid side chain; R3 is alkylene further bonded to Rla
to form the 4-, 5-, or 6-
membered heterocyclyl; D* is a residue of a biologically active compound; and
n is four. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side chain;
R3 is alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is four. In another embodiment, Rla is alkylene, wherein the
alkylene is further
116
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
heteroaryl; R2 is an amino
acid side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is four. In any of
the embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00151] In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
hydrogen; R3 is
hydrogen; D* is hydrogen; and n is five. In another embodiment, Rla is
hydrogen and Rib is alkyl;
R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is five. In another
embodiment, Rla is
hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is five. In
another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is
hydrogen; D* is
hydrogen; and n is five. In another embodiment, Rla is hydrogen and Rib is
alkynyl; R2 is hydrogen;
R3 is hydrogen; D* is hydrogen; and n is five. In another embodiment, Rla is
hydrogen and Rib is
aryl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is five. In
another embodiment, Rla is
hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen;
and n is five. In
another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3
is hydrogen; D* is
hydrogen; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is hydrogen; D* is hydrogen; and n is five. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is hydrogen; R3 is hydrogen; D* is hydrogen; and n is five. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is hydrogen; R3 is hydrogen; D* is hydrogen; and n is five. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is
hydrogen; and n is five. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is hydrogen;
and n is five. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen;
R3 is hydrogen; D*
is hydrogen; and n is five. In another embodiment, Rla is alkylene, wherein
the alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is hydrogen; D* is hydrogen; and n is five. In any of the embodiments in this
paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
117
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00152] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is
hydrogen; R3 is hydrogen;
D* is hydrogen; and n is five. In another embodiment, Rla is hydrogen and Rib
is hydrogen; R2 is
an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is five. In
another embodiment,
Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3 is hydrogen;
D* is hydrogen; and
n is five. In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an
amino acid side chain;
R3 is hydrogen; D* is hydrogen; and n is five. In another embodiment, Rla is
hydrogen and Rib is
alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen; and n
is five. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is hydrogen; and n is five. In another embodiment, Rla is hydrogen and Rib
is aryl; R2 is an
amino acid side chain; R3 is hydrogen; D* is hydrogen; and n is five. In
another embodiment, Rla
is hydrogen and Rib is arylalkyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is hydrogen;
and n is five. In another embodiment, Rla is hydrogen and Rib is heteroaryl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is hydrogen; and n is five. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is hydrogen; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is five. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkyl; R2 is an amino acid side chain; R3 is
hydrogen; D* is
hydrogen; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is hydrogen; and n is five. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is five. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3
is hydrogen; D* is
hydrogen; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is an amino acid side
chain; R3 is hydrogen; D* is hydrogen; and n is five. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is hydrogen;
and n is five. In any
118
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this paragraph,
R4 is alkyl.
[00153] In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain; R3
is hydrogen; D* is hydrogen; and n is five. In another embodiment, Ria is
hydrogen and Rib is
hydrogen; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is five. In
another embodiment, Ria is
hydrogen and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n
is five. In another
embodiment, Ria is hydrogen and Rib is alkoxy; R2 is hydrogen; R3 is alkyl; D*
is hydrogen; and n
is five. In another embodiment, Ria is hydrogen and Rib is alkenyl; R2 is
hydrogen; R3 is alkyl; D*
is hydrogen; and n is five. In another embodiment, Ria is hydrogen and Rib is
alkynyl; R2 is
hydrogen; R3 is alkyl; D* is hydrogen; and n is five. In another embodiment,
Ria is hydrogen and
Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is five. In
another embodiment, Ria
is hydrogen and Rib is arylalkyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen;
and n is five. In
another embodiment, Ria is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3
is alkyl; D* is
hydrogen; and n is five. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is hydrogen;
R3 is alkyl; D* is hydrogen; and n is five. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is hydrogen; R3 is alkyl; D* is hydrogen; and n is five. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkoxyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen; and n is five. In
another embodiment, Ria
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is hydrogen;
and n is five. In
another embodiment, RI-a is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is alkyl;
D* is hydrogen; and
n is five. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3
is alkyl; D* is
hydrogen; and n is five. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is alkyl; D* is hydrogen; and n is five. In another embodiment, Ria is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is heteroaryl; R2 is
119
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
hydrogen; R3 is alkyl; D* is hydrogen; and n is five. In any of the
embodiments in this paragraph,
R4 is hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00154] In another embodiment, Ria is hydrogen and Rib is hydrogen; R2 is an
amino acid side
chain; R3 is alkyl; D* is hydrogen; and n is five. In another embodiment, Ria
is hydrogen and Rib
is alkyl; R2 is amino acid side chain; R3 is alkyl; D* is hydrogen; and n is
five. In another
embodiment, Ria is hydrogen and Rib is alkoxy; R2 is an amino acid side chain;
R3 is alkyl; D* is
hydrogen; and n is five. In another embodiment, Ria is hydrogen and Rib is
alkenyl; R2 is an amino
acid side chain; R3 is alkyl; D* is hydrogen; and n is five. In another
embodiment, Ria is hydrogen
and Rib is alkynyl; R2 is an amino acid side chain; R3 is alkyl; D* is
hydrogen; and n is five. In
another embodiment, Ria is hydrogen and Rib is aryl; R2 is an amino acid side
chain; R3 is alkyl;
D* is hydrogen; and n is five. In another embodiment, Ria is hydrogen and Rib
is arylalkyl; R2 is
an amino acid side chain; R3 is alkyl; D* is hydrogen; and n is five. In
another embodiment, Ria is
hydrogen and Rib is heteroaryl; R2 is an amino acid side chain; R3 is alkyl;
D* is hydrogen; and n
is five. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid
side chain; R3 is
alkyl; D* is hydrogen; and n is five. In another embodiment, Ria is alkylene,
wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is alkyl; R2 is an
amino acid side chain; R3 is alkyl; D* is hydrogen; and n is five. In another
embodiment, Ria is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkoxyl; R2 is an amino acid side chain; R3 is alkyl; D* is
hydrogen; and n is five. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid side
chain; R3 is alkyl; D* is
hydrogen; and n is five. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is an amino acid
side chain; R3 is alkyl; D* is hydrogen; and n is five. In another embodiment,
Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is aryl; R2 is an amino acid side chain; R3 is alkyl; D* is hydrogen; and n is
five. In another
embodiment, RI-a is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side chain;
R3 is alkyl; D* is
hydrogen; and n is five. In another embodiment, Ria is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
heteroaryl; R2 is an amino
120
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
acid side chain; R3 is alkyl; D* is hydrogen; and n is five. In another
embodiment, RI-a is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is hydrogen; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is five. In any of the embodiments in this
paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00155] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen;
R3 is alkylene further
bonded to 12" to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen;
and n is five. In
another embodiment, Rla is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene
further bonded to
Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is
five. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene
further bonded to Ria to
form the 4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is five. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the
4-, 5-, or 6-membered heterocyclyl; D* is hydrogen; and n is five. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is aryl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-
membered heterocyclyl; D* is hydrogen; and n is five. In another embodiment,
Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is five. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is heteroaryl;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is hydrogen; and n is five. In another embodiment, Rla is alkylene, wherein
the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is an
amino acid side chain; R3 is alkylene further bonded to Rla to form the 4-, 5-
, or 6-membered
heterocyclyl; D* is hydrogen; and n is five. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is an amino acid side chain; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
121
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
heterocyclyl; D* is hydrogen; and n is five. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen; and n is five. In any of the embodiments in this
paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00156] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is five. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is five. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is hydrogen; and
n is five. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an
amino acid side chain; R3
is alkylene further bonded to R" to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is five. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain;
R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is hydrogen;
and n is five. In another embodiment, Rla is hydrogen and Rib is hydrogen; R2
is hydrogen; R3 is
hydrogen; D* is acyl; and n is five. In another embodiment, Rla is hydrogen
and Rib is alkyl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is five. In another embodiment,
Rla is hydrogen and
Rib is alkoxy; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is five. In
another embodiment,
Rla is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is
acyl; and n is five. In
another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is
acyl; and n is five. In another embodiment, Rla is hydrogen and Rib is aryl;
R2 is hydrogen; R3 is
hydrogen; D* is acyl; and n is five. In another embodiment, Rla is hydrogen
and Rib is arylalkyl;
R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is five. In another
embodiment, Rla is hydrogen
and Rib is heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is acyl; and n is
five. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
122
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
membered heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is hydrogen; D*
is acyl; and n is
five. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is
hydrogen; D* is acyl;
and n is five. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is
hydrogen; R3 is hydrogen;
D* is acyl; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl;
R2 is hydrogen; R3
is hydrogen; D* is acyl; and n is five. In any of the embodiments in this
paragraph, R4 is hydrogen.
In any of the embodiments in this paragraph, R4 is alkyl.
[00157] In another embodiment, R" is alkylene, wherein the alkylene is further
bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen;
R3 is hydrogen; D*
is acyl; and n is five. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is
hydrogen; R3 is hydrogen;
D* is acyl; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is hydrogen; R3
is hydrogen; D* is acyl; and n is five. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is heteroaryl; R2 is
hydrogen; R3 is hydrogen; D* is acyl; and n is five. In another embodiment,
Rla is hydrogen and
Rib is hydrogen; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl;
and n is five. In another
embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3
is hydrogen; D* is
acyl; and n is five. In another embodiment, Rla is hydrogen and Rib is alkoxy;
R2 is an amino acid
side chain; R3 is hydrogen; D* is acyl; and n is five. In another embodiment,
Rla is hydrogen and
Rib is alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl;
and n is five. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is acyl; and n is five. In another embodiment, Rla is hydrogen and Rib is
aryl; R2 is an amino
acid side chain; R3 is hydrogen; D* is acyl; and n is five. In another
embodiment, Rla is hydrogen
and Rib is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is
acyl; and n is five. In
another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an amino acid
side chain; R3 is
hydrogen; D* is acyl; and n is five. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is an
amino acid side chain; R3 is hydrogen; D* is acyl; and n is five. In another
embodiment, Rla is
123
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl;
and n is five. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side chain; R3
is hydrogen; D* is
acyl; and n is five. In another embodiment, Ria is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is
an amino acid side
chain; R3 is hydrogen; D* is acyl; and n is five. In any of the embodiments in
this paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00158] In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino
acid side chain; R3 is
hydrogen; D* is acyl; and n is five. In another embodiment, Ria is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
aryl; R2 is an amino
acid side chain; R3 is hydrogen; D* is acyl; and n is five. In another
embodiment, Ria is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is acyl; and
n is five. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side chain;
R3 is hydrogen; D*
is acyl; and n is five. In another embodiment, RI-a is hydrogen and Rib is
hydrogen; R2 is hydrogen;
R3 is alkyl; D* is acyl; and n is five. In another embodiment, Ria is hydrogen
and Rib is alkyl; R2
is hydrogen; R3 is alkyl; D* is acyl; and n is five. In another embodiment,
Ria is hydrogen and Rib
is alkoxy; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is five. In another
embodiment, Ria is
hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is
five. In another
embodiment, Ria is hydrogen and Rib is alkynyl; R2 is hydrogen; R3 is alkyl;
D* is acyl; and n is
five. In another embodiment, Ria is hydrogen and Rib is aryl; R2 is hydrogen;
R3 is alkyl; D* is
acyl; and n is five. In another embodiment, Ria is hydrogen and Rib is
arylalkyl; R2 is hydrogen; R3
is alkyl; D* is acyl; and n is five. In another embodiment, Ria is hydrogen
and Rib is heteroaryl; R2
is hydrogen; R3 is alkyl; D* is acyl; and n is five. In another embodiment,
Ria is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is
hydrogen; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is five. In another
embodiment, Ria is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and n is five. In
another embodiment, Ria
124
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkyl; D* is acyl; and
n is five. In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is
acyl; and n is five. In
another embodiment, RI-a is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is alkyl;
D* is acyl; and n is
five. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is
alkyl; D* is acyl; and n
is five. In any of the embodiments in this paragraph, R4 is hydrogen. In any
of the embodiments in
this paragraph, R4 is alkyl.
[00159] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is
hydrogen; R3 is alkyl; D* is
acyl; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2
is hydrogen; R3 is
alkyl; D* is acyl; and n is five. In another embodiment, Rla is hydrogen and
Rib is hydrogen; R2 is
an amino acid side chain; R3 is alkyl; D* is acyl; and n is five. In another
embodiment, Rla is
hydrogen and Rib is alkyl; R2 is amino acid side chain; R3 is alkyl; D* is
acyl; and n is five. In
another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an amino acid
side chain; R3 is alkyl;
D* is acyl; and n is five. In another embodiment, Rla is hydrogen and Rib is
alkenyl; R2 is an amino
acid side chain; R3 is alkyl; D* is acyl; and n is five. In another
embodiment, Rla is hydrogen and
Rib is alkynyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n
is five. In another
embodiment, Rla is hydrogen and Rib is aryl; R2 is an amino acid side chain;
R3 is alkyl; D* is acyl;
and n is five. In another embodiment, Rla is hydrogen and Rib is arylalkyl; R2
is an amino acid side
chain; R3 is alkyl; D* is acyl; and n is five. In another embodiment, Rla is
hydrogen and Rib is
heteroaryl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
five. In another
embodiment, Ria is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3
is alkyl; D* is acyl;
and n is five. In another embodiment, Ria is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino
acid side chain; R3 is
alkyl; D* is acyl; and n is five. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkoxyl; R2 is an
125
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
amino acid side chain; R3 is alkyl; D* is acyl; and n is five. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is acyl; and n is
five. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3
is alkyl; D* is acyl;
and n is five. In another embodiment, R" is alkylene, wherein the alkylene is
further bonded to R3
to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is acyl; and n is five. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
arylalkyl; R2 is an
amino acid side chain; R3 is alkyl; D* is acyl; and n is five. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00160] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an
amino acid side chain; R3
is alkyl; D* is acyl; and n is five. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
hydrogen; R2 is
hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl; D*
is acyl; and n is five. In another embodiment, R" is alkylene, wherein the
alkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is
hydrogen; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is five. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene
further bonded to
R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is five.
In another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene further
bonded to Rla to form the 4-
5-, or 6-membered heterocyclyl; D* is acyl; and n is five. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkynyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-
, 5-, or 6-membered
heterocyclyl; D* is acyl; and n is five. In another embodiment, Rla is
alkylene, wherein the alkylene
is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib
is aryl; R2 is hydrogen;
R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is acyl; and
n is five. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
126
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is
hydrogen; R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is five. In
another embodiment, Rla is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is
alkylene further bonded
to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and n is
five. In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3
is alkylene further
bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is acyl; and
n is five. In any of
the embodiments in this paragraph, R4 is hydrogen. In any of the embodiments
in this paragraph,
R4 is alkyl.
[00161] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
five. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid
side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
five. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkenyl; R2 is an amino acid
side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
five. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid
side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is acyl; and n is
five. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid
side chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is five. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is five. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is
acyl; and n is five. In
127
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
another embodiment, Ria is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is
hydrogen; D* is a
residue of a biologically active compound; and n is five. In another
embodiment, Ria is hydrogen
and Rib is alkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active compound;
and n is five. In another embodiment, Ria is hydrogen and Rib is alkoxy; R2 is
hydrogen; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is five. In
another embodiment,
Ria is hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is five. In another embodiment, Ria is hydrogen and Rib
is alkynyl; R2 is
hydrogen; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is five. In
another embodiment, Ria is hydrogen and Rib is aryl; R2 is hydrogen; R3 is
hydrogen; D* is a
residue of a biologically active compound; and n is five. In another
embodiment, Ria is hydrogen
and Rib is arylalkyl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a
biologically active
compound; and n is five. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[00162] In another embodiment, Ria is hydrogen and Rib is heteroaryl; R2 is
hydrogen; R3 is
hydrogen; D* is a residue of a biologically active compound; and n is five. In
another embodiment,
R" is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-,
or 6-membered
heterocyclyl; and Rib is hydrogen; R2 is hydrogen; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is five. In another embodiment, Ria is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkyl; R2 is hydrogen;
R3 is hydrogen; D* is a residue of a biologically active compound; and n is
five. In another
embodiment, R" is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkoxyl; R2 is hydrogen; R3 is hydrogen; D*
is a residue of a
biologically active compound; and n is five. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkenyl;
R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is five. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen; R3 is
hydrogen; D* is a residue of
a biologically active compound; and n is five. In another embodiment, Ria is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is aryl; R2 is
hydrogen; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is five. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
128
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
or 6-membered heterocyclyl; and Rib is arylalkyl; R2 is hydrogen; R3 is
hydrogen; D* is a residue
of a biologically active compound; and n is five. In another embodiment, Rla
is alkylene, wherein
the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib is
heteroaryl; R2 is hydrogen; R3 is hydrogen; D* is a residue of a biologically
active compound; and
n is five. In another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is
an amino acid side
chain; R3 is hydrogen; D* is a residue of a biologically active compound; and
n is five. In another
embodiment, Rla is hydrogen and Rib is alkyl; R2 is amino acid side chain; R3
is hydrogen; D* is a
residue of a biologically active compound; and n is five. In another
embodiment, Rla is hydrogen
and Rib is alkoxy; R2 is an amino acid side chain; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is five. In another embodiment, Ria is hydrogen and Rib
is alkenyl; R2 is
an amino acid side chain; R3 is hydrogen; D* is a residue of a biologically
active compound; and n
is five. In another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an
amino acid side chain;
R3 is hydrogen; D* is a residue of a biologically active compound; and n is
five. In another
embodiment, Rla is hydrogen and Rib is aryl; R2 is an amino acid side chain;
R3 is hydrogen; D* is
a residue of a biologically active compound; and n is five. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00163] In another embodiment, Rla is hydrogen and Rib is arylalkyl; R2 is an
amino acid side
chain; R3 is hydrogen; D* is a residue of a biologically active compound; and
n is five. In another
embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is hydrogen;
D* is a residue of a biologically active compound; and n is five. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is hydrogen; R2 is an amino acid side chain; R3 is hydrogen; D* is a
residue of a biologically
active compound; and n is five. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkyl; R2 is an amino
acid side chain; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is five. In
another embodiment, Ria is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid side
chain; R3 is hydrogen; D*
is a residue of a biologically active compound; and n is five. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is alkenyl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue of
a biologically active
compound; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
129
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl;
R2 is an amino acid
side chain; R3 is hydrogen; D* is a residue of a biologically active compound;
and n is five. In
another embodiment, Rla is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid side chain;
R3 is hydrogen; D* is
a residue of a biologically active compound; and n is five. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is an amino acid side chain; R3 is hydrogen; D* is a residue
of a biologically active
compound; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
heteroaryl; R2 is an amino
acid side chain; R3 is hydrogen; D* is a residue of a biologically active
compound; and n is five. In
another embodiment, Rla is hydrogen and Rib is hydrogen; R2 is hydrogen; R3 is
alkyl; D* is a
residue of a biologically active compound; and n is five. In another
embodiment, Rla is hydrogen
and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a
biologically active compound; and
n is five. In another embodiment, Rla is hydrogen and Rib is alkoxy; R2 is
hydrogen; R3 is alkyl;
D* is a residue of a biologically active compound; and n is five. In another
embodiment, Rla is
hydrogen and Rib is alkenyl; R2 is hydrogen; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is five. In any of the embodiments in this paragraph, R4 is
hydrogen. In any of the
embodiments in this paragraph, R4 is alkyl.
[00164] In another embodiment, Rla is hydrogen and Rib is alkynyl; R2 is
hydrogen; R3 is alkyl;
D* is a residue of a biologically active compound; and n is five. In another
embodiment, Rla is
hydrogen and Rib is aryl; R2 is hydrogen; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is five. In another embodiment, R" is hydrogen and Rib is
arylalkyl; R2 is
hydrogen; R3 is alkyl; D* is a residue of a biologically active compound; and
n is five. In another
embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is hydrogen; R3 is
alkyl; D* is a residue of
a biologically active compound; and n is five. In another embodiment, Rla is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is hydrogen;
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is five. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkyl; R2 is hydrogen; R3 is alkyl; D*
is a residue of a
biologically active compound; and n is five. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkoxyl;
130
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is five. In
another embodiment, RI-a is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkyl;
D* is a residue of a
biologically active compound; and n is five. In another embodiment, 12" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkynyl;
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is five. In
another embodiment, RI-a is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is aryl; R2 is hydrogen; R3 is alkyl; D*
is a residue of a
biologically active compound; and n is five. In another embodiment, RI-a is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is arylalkyl;
R2 is hydrogen; R3 is alkyl; D* is a residue of a biologically active
compound; and n is five. In
another embodiment, RI-a is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is hydrogen; R3 is
alkyl; D* is a residue of a
biologically active compound; and n is five. In another embodiment, R" is
hydrogen and Rib is
hydrogen; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of a
biologically active
compound; and n is five. In another embodiment, Ria is hydrogen and Rib is
alkyl; R2 is amino acid
side chain; R3 is alkyl; D* is a residue of a biologically active compound;
and n is five. In another
embodiment, Rla is hydrogen and Rib is alkoxy; R2 is an amino acid side chain;
R3 is alkyl; D* is a
residue of a biologically active compound; and n is five. In any of the
embodiments in this
paragraph, R4 is hydrogen. In any of the embodiments in this paragraph, R4 is
alkyl.
[00165] In another embodiment, Rla is hydrogen and Rib is alkenyl; R2 is an
amino acid side
chain; R3 is alkyl; D* is a residue of a biologically active compound; and n
is five. In another
embodiment, Rla is hydrogen and Rib is alkynyl; R2 is an amino acid side
chain; R3 is alkyl; D* is
a residue of a biologically active compound; and n is five. In another
embodiment, Rla is hydrogen
and Rib is aryl; R2 is an amino acid side chain; R3 is alkyl; D* is a residue
of a biologically active
compound; and n is five. In another embodiment, R" is hydrogen and Rib is
arylalkyl; R2 is an
amino acid side chain; R3 is alkyl; D* is a residue of a biologically active
compound; and n is five.
In another embodiment, Rla is hydrogen and Rib is heteroaryl; R2 is an amino
acid side chain; R3 is
alkyl; D* is a residue of a biologically active compound; and n is five. In
another embodiment, Rla
is alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or
6-membered
heterocyclyl; and Rib is hydrogen; R2 is an amino acid side chain; R3 is
alkyl; D* is a residue of a
131
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
biologically active compound; and n is five. In another embodiment, RI-a is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is an amino acid side chain; R3 is alkyl; D* is a residue of a biologically
active compound; and n is
five. In another embodiment, Rla is alkylene, wherein the alkylene is further
bonded to R3 to form
a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino acid
side chain; R3 is alkyl;
D* is a residue of a biologically active compound; and n is five. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkenyl; R2 is an amino acid side chain; R3 is alkyl; D* is a
residue of a biologically
active compound; and n is five. In another embodiment, Rla is alkylene,
wherein the alkylene is
further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
alkynyl; R2 is an
amino acid side chain; R3 is alkyl; D* is a residue of a biologically active
compound; and n is five.
In another embodiment, R" is alkylene, wherein the alkylene is further bonded
to R3 to form a 4-,
5-, or 6-membered heterocyclyl; and Rib is aryl; R2 is an amino acid side
chain; R3 is alkyl; D* is a
residue of a biologically active compound; and n is five. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is an amino acid side chain; R3 is alkyl; D* is a residue of
a biologically active
compound; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is
heteroaryl; R2 is an amino
acid side chain; R3 is alkyl; D* is a residue of a biologically active
compound; and n is five. In any
of the embodiments in this paragraph, R4 is hydrogen. In any of the
embodiments in this paragraph,
R4 is alkyl.
[00166] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is hydrogen; R2 is
hydrogen; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is five. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is five. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is alkoxyl; R2 is hydrogen; R3 is alkylene further bonded to Rla to
form the 4-, 5-, or 6-
membered heterocyclyl; D* is a residue of a biologically active compound; and
n is five. In another
132
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkenyl; R2 is hydrogen; R3 is alkylene
further bonded to R" to
form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue of a biologically
active compound; and
n is five. In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkynyl; R2 is hydrogen;
R3 is alkylene further
bonded to Ria to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is hydrogen; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is a residue of a
biologically active compound; and n is five. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is arylalkyl;
R2 is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is a residue of a biologically active compound; and n is five. In another
embodiment, Rla is
alkylene, wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
and Rib is heteroaryl; R2 is hydrogen; R3 is alkylene further bonded to Rla to
form the 4-, 5-, or
6-membered heterocyclyl; D* is a residue of a biologically active compound;
and n is five. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is hydrogen; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is five. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkyl; R2
is an amino acid side chain; R3 is alkylene further bonded to Rla to form the
4-, 5-, or 6-membered
heterocyclyl; D* is a residue of a biologically active compound; and n is
five. In any of the
embodiments in this paragraph, R4 is hydrogen. In any of the embodiments in
this paragraph, R4 is
alkyl.
[00167] In another embodiment, Rla is alkylene, wherein the alkylene is
further bonded to R3 to
form a 4-, 5-, or 6-membered heterocyclyl; and Rib is alkoxyl; R2 is an amino
acid side chain; R3 is
alkylene further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl;
D* is a residue of a
biologically active compound; and n is five. In another embodiment, R" is
alkylene, wherein the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
and Rib is alkenyl;
R2 is an amino acid side chain; R3 is alkylene further bonded to Rla to form
the 4-, 5-, or 6-membered
133
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
heterocyclyl; D* is a residue of a biologically active compound; and n is
five. In another
embodiment, Rla is alkylene, wherein the alkylene is further bonded to R3 to
form a 4-, 5-, or 6-
membered heterocyclyl; and Rib is alkynyl; R2 is an amino acid side chain; R3
is alkylene further
bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl; D* is a residue
of a biologically active
compound; and n is five. In another embodiment, Rla is alkylene, wherein the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; and Rib is aryl; R2
is an amino acid side
chain; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a
residue of a biologically active compound; and n is five. In another
embodiment, Rla is alkylene,
wherein the alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; and Rib
is arylalkyl; R2 is an amino acid side chain; R3 is alkylene further bonded to
Rla to form the 4-, 5-,
or 6-membered heterocyclyl; D* is a residue of a biologically active compound;
and n is five. In
another embodiment, R" is alkylene, wherein the alkylene is further bonded to
R3 to form a 4-, 5-,
or 6-membered heterocyclyl; and Rib is heteroaryl; R2 is an amino acid side
chain; R3 is alkylene
further bonded to R" to form the 4-, 5-, or 6-membered heterocyclyl; D* is a
residue of a
biologically active compound; and n is five. In any of the embodiments in this
paragraph, R4 is
hydrogen. In any of the embodiments in this paragraph, R4 is alkyl.
[00168] In certain embodiments of Formula I and/or lb, R" and Rib are each
hydrogen. In
another embodiment of Formula I and/or lb, n is two. In another embodiment of
Formula I and/or
lb, n is two and R2 is hydrogen or methyl. In another embodiment of Formula I
and/or lb, n is two,
R2 is hydrogen or methyl, R3 is hydrogen, and D* is a residue of a
biologically active compound
comprising hydroxyl. In another embodiment of Formula I and/or Ib, the
compound is selected from
the group consisting of:
0 ==µ` .:E1
----N.¨(
0 0
0 H
H2N ).(N0 0 OH
H 0
,
134
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
J-I
0
---\_¨(
0 0
. 0 j.,..,(H
N.,,-0 0
H2N.J.LN OH
: H 0
,and
f
H
0 0
0 H
H2N
N
H 6
; or a pharmaceutically acceptable salt thereof
In certain embodiments within this paragraph, all diastereomers are
contemplated. For example, in
one embodiment, the stereochemistry at the acetal is undefined or racemic. By
way of further
example, in one embodiment, the stereochemistry at the acetal is (R)-. By way
of further example,
in one embodiment, the stereochemistry at the acetal is (S)-. By way of
further example, in one
embodiment, the stereochemistry at the acetal is (R)- in excess of (S)-. By
way of further example,
in one embodiment, the stereochemistry at the acetal is (S)- in excess of
(R)-.
[00169] In certain embodiments of Formula I and/or lb, Ria and Rib are each
hydrogen. In
another embodiment of Formula I and/or lb, n is one. In another embodiment of
Formula I and/or
lb, R2 is hydrogen, methyl, or ¨CH2Ph. In another embodiment of Formula I
and/or Ib, R3 is
hydrogen. In another embodiment of Formula I and/or lb, D* is a residue of a
biologically active
compound comprising hydroxyl. In another embodiment of Formula I and/or lb,
the compound is
selected from the group consisting of:
H 0
0 oõ,
H2N N/\ 0 z
H OH OH
0 ,
135
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
----\---
O 0
H N.,...õ--n 0 OH
H2N'(
O ,
F
H --
0 =,"
--N-(
O 0
H
N.,..,70 0 OH
H2N'(
O ,
H
1-1
0
---\_¨
O 0
H ,
OH
H2N (s)
O ,
¨\\_<
H H
_
O 0 0 \ <0
0
H ri H
OH
H2N (s) N0 0
H2N 0 A
OH
0 0 ; and
,
OH
OW
11
µos. Fi
0 .1-IN 0
,sµh
H2N kl,o,AN =,,,, 0
H
0
; or a pharmaceutically acceptable salt
thereof In certain embodiments within this paragraph, all diastereomers are
contemplated. For
example, in one embodiment, the stereochemistry at the acetal is undefined or
racemic. By way of
further example, in one embodiment, the stereochemistry at the acetal is (R)-.
By way of further
example, in one embodiment, the stereochemistry at the acetal is (S)-. By way
of further example,
136
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
in one embodiment, the stereochemistry at the acetal is (R)- in excess of (S)-
. By way of further
example, in one embodiment, the stereochemistry at the acetal is (S)- in
excess of (R)-.
[00170] In certain embodiments of Formula I and/or lb, Ria and Rib are each
hydrogen. In
another embodiment of Formula I and/or lb, n is one. In another embodiment of
Formula I and/or
lb, R2 is hydrogen or methyl. In another embodiment of Formula I and/or Ib, R3
is alkyl. In another
embodiment of Formula I and/or Ib, D* is a residue of a biologically active
compound comprising
hydroxyl. In another embodiment of Formula I and/or lb, the compound is
selected from the group
consisting of
H 0 p H H 0 :
-----\_¨ ----\.¨
0 0 0 0
1 i
rt....1(N ..õ,/0 0 OH
H2Nyr H2N
0 and 0 ,
or a
pharmaceutically acceptable salt thereof In certain embodiments within this
paragraph, all
diastereomers are contemplated. For example, in one embodiment, the
stereochemistry at the acetal
is undefined or racemic. By way of further example, in one embodiment, the
stereochemistry at the
acetal is (R)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)-. By way of further example, in one embodiment, the stereochemistry at the
acetal is (R)- in
excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)- in excess of (R)-.
[00171] In certain embodiments of Formula I, RI-a is alkyl or arylalkyl, and
Rib is hydrogen. In
another embodiment of Formula I, n is one. In another embodiment of Formula I,
R2 is hydrogen.
In another embodiment of Formula I, R3 is hydrogen. In another embodiment of
Formula I, D* is a
residue of a biologically active compound comprising hydroxyl. In another
embodiment of Formula
I, the compound is selected from the group consisting of
137
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
ti
0
H -----\¨ ,
H
0 :
0 0 0 0 OH
H H2N7')IN
N 0
H2Nr 11 -st.,.... 0
0 and ; or a
pharmaceutically acceptable salt thereof In certain embodiments within this
paragraph, all
diastereomers are contemplated. For example, in one embodiment, the
stereochemistry at the
hemiaminal ether (or hemiaminal, or N-acyl-N,0-acetal, wherein each name for
this functional
group is used interchangeably throughout this disclosure) is undefined or
racemic. By way of further
example, in one embodiment, the stereochemistry at the hemiaminal ether is (R)-
. By way of further
example, in one embodiment, the stereochemistry at the hemiaminal ether is
(S)-. By way of further example, in one embodiment, the stereochemistry at the
hemiaminal ether is
(R)- in excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the
hemiaminal ether is (S)- in excess of (R)-. For example, in one embodiment,
the stereochemistry at
the acetal is undefined or racemic. By way of further example, in one
embodiment, the
stereochemistry at the acetal is (R)-. By way of further example, in one
embodiment, the
stereochemistry at the acetal is (S)-. By way of further example, in one
embodiment, the
stereochemistry at the acetal is (R)- in excess of (S)-. By way of further
example, in one embodiment,
the stereochemistry at the acetal is (S)- in excess of (R)-.
[00172] In certain embodiments of Formula I, R" is alkylene, where the
alkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; Rib is hydrogen;
and R3 is alkylene
further bonded to Rla to form the 4-, 5-, or 6-membered heterocyclyl. Useful 4-
membered
heterocyclyls include, without limitation, optionally substituted aziridine.
Useful 5-membered
heterocyclyls include, without limitation, optionally substutitued
pyrrolidine. In one exemplary
embodiment, optionally substituted pyrrolidine is indoline or indolinyl.
Useful 6-membered
heterocyclyls include, without limitation, optionally substituted piperidine.
In one exemplary
embodiment, optionally substituted piperidine is tetrahydroquinoline or
tetrahydroquinolinyl. In
another embodiment of Formula I, n is one. In another embodiment of Formula I,
R2 is hydrogen.
In another embodiment of Formula I, D* is a residue of a biologically active
compound comprising
hydroxyl. In another embodiment of Formula I, the compound is selected from
the group consisting
of
138
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
H
0 0
0 0 0
0 H2N
OH 0
0 0H
H2N
and
H
El
H2Nrs_j0 0 11010
HO14
0 ; or a pharmaceutically acceptable salt thereof In certain
embodiments within this paragraph, all diastereomers are contemplated. For
example, in one
embodiment, the stereochemistry at the hemiaminal ether (or hemiaminal, or N-
acyl-N,0-acetal,
wherein each name for this functional group is used interchangeably throughout
this disclosure) is
undefined or racemic. By way of further example, in one embodiment, the
stereochemistry at the
hemiaminal ether is (R)-. By way of further example, in one embodiment, the
stereochemistry at the
hemiaminal ether is (S)-. By way of further example, in one embodiment, the
stereochemistry at the
hemiaminal ether is (R)- in excess of (S)-. By way of further example, in one
embodiment, the
stereochemistry at the hemiaminal ether is (S)- in excess of (R)-. For
example, in one embodiment,
the stereochemistry at the acetal is undefined or racemic. By way of further
example, in one
embodiment, the stereochemistry at the acetal is (R)-. By way of further
example, in one
embodiment, the stereochemistry at the acetal is (S)-. By way of further
example, in one
embodiment, the stereochemistry at the acetal is (R)- in excess of (S)-. By
way of further example,
in one embodiment, the stereochemistry at the acetal is (S)- in excess of (R)-
.
[00173] In certain embodiments, other compounds, prodrugs, payloads, or
biologically active
compounds comprising hydroxyl are contemplated. Exemplary compounds, prodrugs,
or payloads
contemplated include, without limitation,
139
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
f H H . tl
tl H
0 0 :
0 0 0 0
H2N ..,,v0 0 OH . H2N ....,70 0 OH =
and
, ,
F
.:
H H 0
.õ, =:i
0 .
-F
--1--"\---L
HN N 0 O OH
0
I 0 .
In certain embodiments within this paragraph, all
diastereomers are contemplated. For example, in one embodiment, the
stereochemistry at the acetal
is undefined or racemic. By way of further example, in one embodiment, the
stereochemistry at the
acetal is (R)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)-. By way of further example, in one embodiment, the stereochemistry at the
acetal is (R)- in
excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)- in excess of (R)- .
[00174] In certain embodiments of Formula I and/or Ib, R" and Rib are each
hydrogen. In
another embodiment of Formula I and/or Ib, n is one. In another embodiment of
Formula I and/or
lb, R2 is alkylene, wherein the alkylene is further bonded to R3 to form a 6-
membered heterocyclyl;
and R3 is alkylene, wherein the alkylene is further bonded to R2 to form the 6-
membered
heterocyclyl. In another embodiment of Formula I and/or lb, D* is a residue of
a biologically active
compound comprising hydroxyl. In another embodiment of Formula I and/or lb,
the compound is
H
tl
0
---\_¨(
0 0
H2N
0 ;
or a pharmaceutically acceptable salt thereof In certain
embodiments within this paragraph, all diastereomers are contemplated. For
example, in one
embodiment, the stereochemistry at the acetal is undefined or racemic. By way
of further example,
in one embodiment, the stereochemistry at the acetal is (R)-. By way of
further example, in one
embodiment, the stereochemistry at the acetal is (S)-. By way of further
example, in one
embodiment, the stereochemistry at the acetal is (R)- in excess of (S)-. By
way of further example,
in one embodiment, the stereochemistry at the acetal is (S)- in excess of (R)-
.
140
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Binding agents
[00175] Suitable binding agents for any of the conjugates provided in the
instant disclosure
include, but are not limited to, antibodies, lymphokines (e.g., IL-2 or IL-3),
hormones (e.g., insulin
and glucocorticoids), growth factors (e.g., EGF, transferrin, and fibronectin
type III), viral receptors,
interleukins, or any other cell binding or peptide binding molecules or
substances. Binding agents
also include, but are not limited to, ankyrin repeat proteins and interferons.
[00176] In some embodiments, the binding agent is an antibody or an antigen-
binding fragment
thereof The antibody can be in any form known to those of skill in the art.
The term "antibody," as
used herein, refers to any antigen-binding molecule or molecular complex
comprising at least one
complementarity determining region (CDR) that specifically binds to or
interacts with a particular
antigen. The term "antibody" includes immunoglobulin molecules comprising four
polypeptide
chains, two heavy (H) chains and two light (L) chains inter-connected by
disulfide bonds, as well
as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain
variable region
(abbreviated herein as HCVR or VH) and a heavy chain constant region. The
heavy chain constant
region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a
light chain
variable region (abbreviated herein as LCVR or VL) and a light chain constant
region. The light
chain constant region comprises one domain (CL1). The VH and VL regions can be
further subdivided
into regions of hypervariability, termed complementarity determining regions
(CDRs), interspersed
with regions that are more conserved, termed framework regions (FR). Each VH
and VL is composed
of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus
in the following
order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of
disclosed herein,
the FRs of the antibodies (or antigen-binding portion thereof) suitable for
the compounds herein
may be identical to the human germline sequences, or may be naturally or
artificially modified. An
amino acid consensus sequence may be defined based on a side-by-side analysis
of two or more
CDRs. The term "antibody", as used herein, also includes antigen-binding
fragments of full
antibody molecules. The terms "antigen-binding portion" of an antibody,
"antigen-binding
fragment" of an antibody, and the like, as used herein, include any naturally
occurring,
enzymatically obtainable, synthetic, or genetically engineered polypeptide or
glycoprotein that
specifically binds an antigen to form a complex. Antigen-binding fragments of
an antibody may be
derived, e.g., from full antibody molecules using any suitable, standard
technique(s) such as
proteolytic digestion or recombinant genetic engineering technique(s)
involving the manipulation
141
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
and expression of DNA encoding antibody variable and optionally constant
domains. Such DNA is
known and/or is readily available from, e.g., commercial sources, DNA
libraries (including, e.g.,
phage-antibody libraries), or can be synthesized. The DNA may be sequenced and
manipulated
chemically or by using molecular biology techniques, for example, to arrange
one or more variable
and/or constant domains into a suitable configuration, or to introduce codons,
create cysteine
residues, modify, add or delete amino acids, etc. Non-limiting examples of
antigen-binding
fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd
fragments; (iv) Fv fragments;
(v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal
recognition units
consisting of the amino acid residues that mimic the hypervariable region of
an antibody (e.g., an
isolated CDR such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide.
Other
engineered molecules, such as domain-specific antibodies, single domain
antibodies, domain-
deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies,
triabodies, tetrabodies,
minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies,
etc.), small modular
immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also
encompassed within
the expression "antigen-binding fragment," as used herein. An antigen-binding
fragment of an
antibody will typically comprise at least one variable domain. The variable
domain may be of any
size or amino acid composition and will generally comprise at least one CDR
which is adjacent to
or in frame with one or more framework sequences. In antigen-binding fragments
having a VH
domain associated with a VL domain, the VH and VL domains may be situated
relative to one another
in any suitable arrangement. For example, the variable region may be dimeric
and contain VH-V11,
VH-VL, or VL-VL dimers. Alternatively, the antigen-binding fragment of an
antibody may contain
a monomeric VH or VL domain. In certain embodiments, an antigen-binding
fragment of an antibody
may contain at least one variable domain covalently linked to at least one
constant domain. Non-
limiting, exemplary configurations of variable and constant domains that may
be found within an
antigen-binding fragment of an antibody of the present invention include: (i)
VH-Cul; (ii) VH-CH2;
(iii) VH-CH3; (iv) VH-Cu1-Cu2; (v) VH-Cu1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-
CL; (viii) VL-Cul;
(ix) VL-CH2; (x) VL-CH3; (xi) VL-CH 1 -CH2; (xii) VL-Cu1-CH2-Cu3; (xiii) VL-
CH2-Cu3; and (xiv)
VL-CL. In any configuration of variable and constant domains, including any of
the exemplary
configurations listed above, the variable and constant domains may be either
directly linked to one
another or may be linked by a full or partial hinge or linker region. A hinge
region may consist of
at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a
flexible or semi-flexible
142
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
linkage between adjacent variable and/or constant domains in a single
polypeptide molecule. As
with full antibody molecules, antigen-binding fragments may be monospecific or
multispecific (e. g. ,
bispecific). A multispecific antigen-binding fragment of an antibody will
typically comprise at least
two different variable domains, wherein each variable domain is capable of
specifically binding to
a separate antigen or to a different epitope on the same antigen. Any
multispecific antibody format,
including the exemplary bispecific antibody formats disclosed herein, may be
adapted for use in the
context of an antigen-binding fragment of an antibody of the present
disclosure using routine
techniques available in the art. In certain embodiments described herein,
antibodies described herein
are human antibodies. The term "human antibody", as used herein, is intended
to include antibodies
having variable and constant regions derived from human germline
immunoglobulin sequences.
The human antibodies of the invention may include amino acid residues not
encoded by human
germline immunoglobulin sequences (e.g., mutations introduced by random or
site-specific
mutagenesis in vitro or by somatic mutation in vivo), for example, in the CDRs
and in particular
CDR3. However, the term "human antibody", as used herein, is not intended to
include antibodies
in which CDR sequences derived from the germline of another mammalian species,
such as a mouse,
have been grafted onto human framework sequences. The term "human antibody"
does not include
naturally occurring molecules that normally exist without modification or
human
intervention/manipulation, in a naturally occurring, unmodified living
organism. The antibodies of
the invention may, in some embodiments, be recombinant human antibodies. The
term
"recombinant human antibody", as used herein, is intended to include all human
antibodies that are
prepared, expressed, created, or isolated by recombinant means, such as
antibodies expressed using
a recombinant expression vector transfected into a host cell (described
further below), antibodies
isolated from a recombinant, combinatorial human antibody library (described
further below),
antibodies isolated from an animal (e.g., a mouse) that is transgenic for
human immunoglobulin
genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or
antibodies prepared,
expressed, created, or isolated by any other means that involves splicing of
human immunoglobulin
gene sequences to other DNA sequences. Such recombinant human antibodies have
variable and
constant regions derived from human germline immunoglobulin sequences. In
certain
embodiments, however, such recombinant human antibodies are subjected to in
vitro mutagenesis
(or, when an animal transgenic for human Ig sequences is used, in vivo somatic
mutagenesis) and
thus the amino acid sequences of the VH and VL regions of the recombinant
antibodies are sequences
143
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
that, while derived from and related to human germline VH and VL sequences,
may not naturally
exist within the human antibody germline repertoire in vivo. Human antibodies
can exist in two
forms that are associated with hinge heterogeneity. In one form, an
immunoglobulin molecule
comprises a stable four chain construct of approximately 150-160 kDa in which
the dimers are held
together by an interchain heavy chain disulfide bond. In a second form, the
dimers are not linked
via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed
composed of a
covalently coupled light and heavy chain (half-antibody). These forms have
been extremely
difficult to separate, even after affinity purification. The frequency of
appearance of the second
form in various intact IgG isotypes is due to, but not limited to, structural
differences associated
with the hinge region isotype of the antibody. A single amino acid
substitution in the hinge region
of the human IgG4 hinge can significantly reduce the appearance of the second
form (Angal et al.
(1993) Molecular Immunology 30:105) to levels typically observed using a human
IgG1 hinge. The
instant disclosure encompasses antibodies having one or more mutations in the
hinge, CH2, or CH3
region which may be desirable, for example, in production, to improve the
yield of the desired
antibody form. The antibodies described herein may be isolated antibodies. An
"isolated antibody,"
as used herein, refers to an antibody that has been identified and separated
and/or recovered from at
least one component of its natural environment. For example, an antibody that
has been separated
or removed from at least one component of an organism, or from a tissue or
cell in which the
antibody naturally exists or is naturally produced, is an "isolated antibody"
for purposes of the
instant disclosure. An isolated antibody also includes an antibody in situ
within a recombinant cell.
Isolated antibodies are antibodies that have been subjected to at least one
purification or isolation
step. According to certain embodiments, an isolated antibody may be
substantially free of other
cellular material and/or chemicals. The antibodies used herein can comprise
one or more amino
acid substitutions, insertions, and/or deletions in the framework and/or CDR
regions of the heavy
and light chain variable domains as compared to the corresponding germline
sequences from which
the antibodies were derived. Such mutations can be readily ascertained by
comparing the amino
acid sequences disclosed herein to germline sequences available from, for
example, public antibody
sequence databases. The present invention includes antibodies, and antigen-
binding fragments
thereof, which are derived from any of the amino acid sequences disclosed
herein, wherein one or
more amino acids within one or more framework and/or CDR regions are mutated
to the
corresponding residue(s) of the germline sequence from which the antibody was
derived, or to the
144
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
corresponding residue(s) of another human germline sequence, or to a
conservative amino acid
substitution of the corresponding germline residue(s) (such sequence changes
are referred to herein
collectively as "germline mutations"). A person of ordinary skill in the art,
starting with the heavy
and light chain variable region sequences disclosed herein, can easily produce
numerous antibodies
and antigen-binding fragments which comprise one or more individual germline
mutations or
combinations thereof In certain embodiments, all of the framework and/or CDR
residues within
the VH and/or VL domains are mutated back to the residues found in the
original germline sequence
from which the antibody was derived. In other embodiments, only certain
residues are mutated back
to the original germline sequence, e.g., only the mutated residues found
within the first 8 amino
acids of FR1 or within the last 8 amino acids of FR4, or only the mutated
residues found within
CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and/or
CDR
residue(s) are mutated to the corresponding residue(s) of a different germline
sequence (i.e., a
germline sequence that is different from the germline sequence from which the
antibody was
originally derived). Furthermore, the antibodies of the present disclosure may
contain any
combination of two or more germline mutations within the framework and/or CDR
regions, e.g.,
wherein certain individual residues are mutated to the corresponding residue
of a particular germline
sequence while certain other residues that differ from the original germline
sequence are maintained
or are mutated to the corresponding residue of a different germline sequence.
Once obtained,
antibodies and antigen-binding fragments that contain one or more germline
mutations can be easily
tested for one or more desired property such as, improved binding specificity,
increased binding
affinity, improved or enhanced antagonistic or agonistic biological properties
(as the case may be),
reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained
in this general
manner are encompassed within the present disclosure. Antibodies useful for
the compounds herein
also include antibodies comprising variants of any of the HCVR, LCVR, and/or
CDR amino acid
sequences disclosed herein having one or more conservative substitutions. The
term "epitope" refers
to an antigenic determinant that interacts with a specific antigen-binding
site in the variable region
of an antibody molecule known as a paratope. A single antigen may have more
than one epitope.
Thus, different antibodies may bind to different areas on an antigen and may
have different
biological effects. Epitopes may be either conformational or linear. A
conformational epitope is
produced by spatially juxtaposed amino acids from different segments of the
linear polypeptide
chain. A linear epitope is one produced by adjacent amino acid residues in a
polypeptide chain. In
145
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
certain circumstance, an epitope may include moieties of saccharides,
phosphoryl groups, or
sulfonyl groups on the antigen.
[00177] In certain embodiments, the antibody comprises a light chain. In
certain embodiments,
the light chain is a kappa light chain. In certain embodiments, the light
chain is a lambda light chain.
In certain embodiments, the antibody comprises a heavy chain. In some
embodiments, the heavy
chain is an IgA. In some embodiments, the heavy chain is an IgD. In some
embodiments, the heavy
chain is an IgE. In some embodiments, the heavy chain is an IgG. In some
embodiments, the heavy
chain is an IgM. In some embodiments, the heavy chain is an IgGl. In some
embodiments, the heavy
chain is an IgG2. In some embodiments, the heavy chain is an IgG3. In some
embodiments, the
heavy chain is an IgG4. In some embodiments, the heavy chain is an IgAl . In
some embodiments,
the heavy chain is an IgA2.
[00178] In some embodiments, the antibody is an antibody fragment. In some
embodiments, the
antibody fragment is an Fv fragment. In some embodiments, the antibody
fragment is a Fab
fragment. In some embodiments, the antibody fragment is a F(abr)2 fragment. In
some embodiments,
the antibody fragment is a Fab' fragment. In some embodiments, the antibody
fragment is an scFv
(sFv) fragment. In some embodiments, the antibody fragment is an scFv-Fc
fragment.
[00179] In some embodiments, the antibody is a monoclonal antibody. In some
embodiments,
the antibody is a polyclonal antibody. In some embodiments, the antibody is a
bispecific antibody
including a first antigen-binding domain (also referred to herein as "Dl"),
and a second antigen-
binding domain (also referred to herein as "D2").
[00180] As used herein, the expression "antigen-binding domain" means any
peptide,
polypeptide, nucleic acid molecule, scaffold-type molecule, peptide display
molecule, or
polypeptide-containing construct that is capable of specifically binding a
particular antigen of
interest (e.g., PRLR or STEAP2). The term "specifically binds" or the like, as
used herein, means
that the antigen-binding domain forms a complex with a particular antigen
characterized by a
dissociation constant (KD) of 1 IVI or less, and does not bind other
unrelated antigens under ordinary
test conditions. "Unrelated antigens" are proteins, peptides, or polypeptides
that have less than 95%
amino acid identity to one another.
[00181] Exemplary categories of antigen-binding domains that can be used in
the context of the
present disclosure include antibodies, antigen-binding portions of antibodies,
peptides that
146
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
specifically interact with a particular antigen (e.g., peptibodies), receptor
molecules that specifically
interact with a particular antigen, proteins comprising a ligand-binding
portion of a receptor that
specifically binds a particular antigen, antigen-binding scaffolds (e.g.,
DARPins, HEAT repeat
proteins, ARM repeat proteins, tetratricopeptide repeat proteins, and other
scaffolds based on
naturally occurring repeat proteins, etc., [see, e.g., Boersma and Pluckthun,
2011, Cum Opin.
Biotechnol. 22:849-857, and references cited therein]), and aptamers or
portions thereof
[00182] Methods for determining whether two molecules specifically bind one
another are well
known in the art and include, for example, equilibrium dialysis, surface
plasmon resonance, and the
like. For example, an antigen-binding domain, as used in the context of the
present disclosure,
includes polypeptides that bind a particular antigen (e.g., a target molecule
[T] or an internalizing
effector protein [E]) or a portion thereof with a KD of less than about 1 M,
less than about 500 nM,
less than about 250 nM, less than about 125 nM, less than about 60 nM, less
than about 30 nM, less
than about 10 nM, less than about 5 nM, less than about 2 nM, less than about
1 nM, less than about
500 pM, less than about 400 pM, less than about 300 pM, less than about 200
pM, less than about
100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM,
less than about 60
pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less
than about 20 pM,
less than about 10 pM, less than about 5 pM, less than about 4 pM, less than
about 2 pM, less than
about 1 pM, less than about 0.5 pM, less than about 0.2 pM, less than about
0.1 pM, or less than
about 0.05 pM, as measured in a surface plasmon resonance assay.
[00183] In some embodiments, the antibody is a chimeric antibody. In some
embodiments, the
antibody is a humanized antibody. In some embodiments, the antibody is a human
antibody.
[00184] In some embodiments, the antibody is an anti-PSMA, anti-PRLR, anti-
MUC16, anti-
HER2, or anti-EGFRvIII, or anti-STEAP2 antibody. In some embodiments, the
antibody is an anti-
PRLR or anti HER2 antibody. In some embodiments, the antibody, or antigen-
binding fragment
thereof, is anti-STEAP2. In some embodiments, the antibody, or antigen-binding
fragment thereof,
is anti-PRLR
[00185] The antibody can have binding specificity for any antigen deemed
suitable to those of
skill in the art. In certain embodiments, the antigen is a transmembrane
molecule (e.g., receptor). In
one embodiment, the antigen is expressed on a tumor. In some embodiments, the
binding agents
interact with or bind to tumor antigens, including antigens specific for a
type of tumor or antigens
147
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
that are shared, overexpressed, or modified on a particular type of tumor. In
one embodiment, the
antigen is expressed on solid tumors. Exemplary antigens include, but are not
limited to,
lipoproteins; alphal-antitrypsin; a cytotoxic T-lymphocyte associated antigen
(CTLA), such as
CTLA-4; vascular endothelial growth factor (VEGF); receptors for hormones or
growth factors;
protein A or D; fibroblast growth factor receptor 2 (FGFR2), EpCAM, GD3, FLT3,
PSMA, PS CA,
MUC1, MUC16, STEAP, STEAP2, CEA, TENB2, EphA receptors, EphB receptors, folate
receptor,
FOLRI, mesothelin, cripto, alphavbeta6, integrins, VEGF, VEGFR, EGFR,
transferrin receptor,
IRTA1, IRTA2, IRTA3, IRTA4, IRTA5; CD proteins such as CD2, CD3, CD4, CD5,
CD6, CD8,
CD11, CD14, CD19, CD20, CD21, CD22, CD25, CD26, CD28, CD30, CD33, CD36, CD37,
CD38,
CD40, CD44, CD52, CD55, CD56, CD59, CD70, CD79, CD80, CD81, CD103, CD105,
CD134,
CD137, CD138, CD152, or an antibody which binds to one or more tumor-
associated antigens or
cell-surface receptors disclosed in US Publication No. 2008/0171040 or US
Publication No.
2008/0305044 each incorporated in their entirety by reference; erythropoietin;
osteoinductive
factors; immunotoxins; a bone morphogenetic protein (BMP); T-cell receptors;
surface membrane
proteins; integrins, such as CD1 1 a, CD1 lb, CD1 1 c, CD18, an ICAM, VLA-4
and VCAM; a tumor
associated antigen such as AFP, ALK, B7H4, BAGE proteins, P-catenin, brc-abl,
BRCA1, BORIS,
CA9 (carbonic anhydrase IX), caspase-8, CD20, CD40, CD123, CDK4, CEA, CLEC12A,
c-kit,
cMET, CTLA4, cyclin-B1, CYP1B1, EGFR, EGFRvIII, endoglin, Epcam, EphA2,
ErbB2/Her2,
ErbB3/Her3, ErbB4/Her4, ETV6-AML, Fra-1, FOLR1, GAGE proteins, GD2, GD3,
GloboH,
glypican-3, GM3, gp100, Her2, HLA/B-raf, HLA/EBNA1, HLA/k-ras, HLA/MAGE-A3,
hTERT,
IGF1R, LGR5, LMP2, MAGE proteins, MART-1, mesothelin, ML-IAP, Mud, Muc16, CA-
125,
MUM1, NA17, NGEP, NY-BR1, NY-BR62, NY-BR85, NY-ES01, 0X40, p15, p53, PAP,
PAX3,
PAX5, PCTA-1, PDGFR-a, PDGFR-13, PDGF-A, PDGF-B, PDGF-C, PDGF-D, PLAC1, PRLR,
PRAME, PSCA, PSGR, PSMA (FOLH1), RAGE proteins, Ras, RGS5, Rho, SART-1, SART-
3,
Steap-1, Steap-2, STn, survivin, TAG-72, TGF-3, TMPRSS2, Tn, TNFRSF17, TRP-1,
TRP-2,
tyrosinase, and uroplakin-3, and fragments of any of the above-listed
polypeptides; cell-surface
expressed antigens; MUC16; c-MET; molecules such as class A scavenger
receptors including
scavenger receptor A (SR-A), and other membrane proteins such as B7 family-
related member
including V-set and Ig domain-containing 4 (VSIG4), Colony stimulating factor
1 receptor
(CSF1R), asialoglycoprotein receptor (ASGPR), and Amyloid beta precursor-like
protein 2 (APLP-
2); macrophage receptor with collagenous structure (MARCO), scavenger receptor
with C-type
148
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
lectin (SRCL), and scavenger receptor A-5 (SCARA5), COLEC12, class B
macrophage scavenger
receptors including CD36, LIMPII, SRBI, SRBII, class D scavenger receptor
CD68, and lysosomal
membrane glycoprotein (LAMP), class E scavenger receptor including lectin-like
oxidized low
density lipoprotein receptor 1 LOX-1 and Dectin-1, class F scavenger receptors
including scavenger
receptor expressed by endothelial cells-I (SREC-I) and SREC-II as well as
multiple epidermal
growth factor (EGF)-like domains (MEGF)10, class G scavenger receptor CXC
chemokine ligand
16 (CXCL16), class H scavenger receptors including Fasciclin, EGF-like, lamin
type EGF-like and
link domain-containing scavenger receptor-1 (FEEL-1) and -2 (FEEL-2), class I
scavenger receptor
CD163, and class J scavenger receptor receptor for advanced glycation end
products (RAGE), other
C-type lectin superfamily members including DEC205, CD206, Dectin-2, Mincle,
DC-SIGN, and
DNGR-1, and other membrane proteins such as B7 family-related member including
V-set and Ig
domain-containing 4 (VSIG4); AXL, BAFFRõ BCR-list components, BDCA2, BDCA4,
BTLA,
BTNL2, BTNL3, BTNL8, BTNL9, ClOorf54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7,
CCR9,
CCR10, CD168, CD177, CD209, CD209L, CD226, CD248, CD27, CD274, CD276, CD300A,
CD45, CD46, CD47, CD48, CD62E, CD68, CD69, CD74, CD79a, CD79b, CD86, CD90.2,
CD96,
CLEC12B, CLEC7A, CLEC9A, CR1, CR3, CRTAM, CXCR1/2, CXCR4, CXCR5, DDR1, DDR2,
DEC-205, DLL4, DR6, FAP, FCamR, FCMR, FcR's, Fire, GITR, HER2, HHLA2, HLA
class II,
HVEM, ICOSLG, IFNLR1, ILlOR1, IL1 OR2, IL12R, IL13RA1, IL13RA2, IL15R, IL17RA,
IL17RB, IL17RC, IL17RE, IL20R1, IL20R2, IL21R, IL22R1, IL22RA, IL23R, IL27R,
IL29R,
IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R, IL7R, IL9R, LAG3, LIFR,
MAG/Siglec-4,
MMR, MSR1, NCR3LG1, NKG2D, NKp30, NKp46, PDCD1, PROKR1, PVR, PVRIG, PVRL2,
PVRL3, RELT, SIGIRR, Siglec-1, Siglec-10, Siglec-5, Siglec-6, Siglec-7, Siglec-
8, Siglec-9,
SIRPA, TACI, TCR-list components/assoc, PTCRA, TCRb, CD3z, TEK, TGFBR1,
TGFBR2,
TGFBR3, TIGIT, TLR2, TLR4, TNF-a, TROY, TSLPR, TYRO, VLDLR, and VTCN1. In some
embodiments, the binding agent is adalimumab or infliximab. In some
embodiments, the binding
agent is alemtuzumab, muromonab, rituximab, tosituzumab, or agonistic
antibodies (where immune
stimulation might be part of the intended mechanism of action). In some
embodiments, the antigen
is PRLR or HER2. In some embodiments, the antigen is STEAP2. In some
embodiments the antigen
is human STEAP2. In some examples, the MAGE proteins are selected from MAGE-1,
-2, -3, -4,
-6, and -12. In some examples, the GAGE proteins are selected from GAGE-1 and
GAGE-2.
149
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00186] Exemplary antigens also include, but are not limited to, BCMA, SLAMF7,
GPNMB,
MSR1, and UPK3A. Exemplary antigens also include, but are not limited to,
MUC16, STEAP2,
and HER2.
[00187] In some embodiments, the antigens include MUC16. In some embodiments,
the antigens
include STEAP2. In some embodiments, the antigens include PSMA. In some
embodiments, the
antigens include MSR1. In some embodiments, the antigens include HER2. In some
embodiments,
the antigen is prolactin receptor (PRLR) or prostate-specific membrane antigen
(PSMA). In some
embodiments, the antigen is MUC16. In some embodiments, the antigens include
PSMA. In some
embodiments, the antigen is HER2. In some embodiments, the antigen is STEAP2.
In some
embodiments, the antigen is MSR1.
[00188] In certain embodiments, the antibody comprises a glutamine residue at
one or more
heavy chain positions numbered 295 in the EU numbering system. In the present
disclosure, this
position is referred to as glutamine 295, or as Gln295, or as Q295. Those of
skill will recognize that
this is a conserved glutamine residue in the wild type sequence of many
antibodies. In other useful
embodiments, the antibody can be engineered to comprise a glutamine residue.
In certain
embodiments, the antibody comprises one or more N297Q mutations. Techniques
for modifying an
antibody sequence to include a glutamine residue are within the skill of those
in the art (see, e.g.,
Ausubel et al. Current Protoc. Mol. Biol.).
[00189] In some embodiments, the antibody, or antigen-binding fragment
thereof, conjugated to
the linker-payload or payload can be an antibody that targets STEAP2. Sutiable
anti-STEAP
antibodies or antigen-binding fragments thereof include those, for example, in
International
Publication No. WO 2018/058001 Al, including those comprising amino acid
sequences disclosed
in Table 1, on page 75 therein. In some embodiments, an anti-STEAP2 antibody
is H1H7814N of
WO 2018/058001 Al, comprising the CDRs of H1M7814N in the same publication. In
some
embodiments, an anti-STEAP2 antibody comprises a heavy chain complementarity
determining
region (HCDR)-1 comprising SEQ ID NO: 2; an HCDR2 comprising SEQ ID NO: 3; an
HCDR3
comprising SEQ ID NO: 4; a light chain complementarity determining region
(LCDR)-1 comprising
SEQ ID NO: 6; an LCDR2 comprising SEQ ID NO: 7; and an LCDR3 comprising SEQ ID
NO: 8.
In some embodiments, an anti-STEAP2 antibody comprises a heavy chain variable
region (HCVR)
comprising SEQ ID NO: 1 and a light chain variable region (LCVR) comprising
SEQ ID NO: 5. In
any of the foregoing embodiments, the anti-STEAP2 antibody can be prepared by
site-directed
150
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
mutagenesis to insert a glutamine residue at a site without resulting in
disabled antibody function or
binding. For example, in any of the foregoing embodiments, the anti-STEAP2
antibody can
comprise an Asn297Gln (N297Q) mutation. Such antibodies having an N297Q
mutation can also
contain one or more additional naturally occurring glutamine residues in their
variable regions,
which can be accessible to transglutaminase and therefore capable of
conjugation to a payload or a
linker-payload (Table A). In certain embodiments, the antibody or antigen-
binding fragment thereof
comprises three heavy chain complementarity determining regions (HCDR1, HCDR2,
and HCDR3)
within a heavy chain variable region (HCVR) amino acid sequence of SEQ ID
NO:1; and three light
chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) within a
light chain
variable region (LCVR) amino acid sequence of SEQ ID NO:5. In certain
embodiments, the
antibody or antigen-binding fragment thereof comprises an HCVR amino acid
sequence of SEQ ID
NO:1; and an LCVR amino acid sequence of SEQ ID NO:5. International
Publication No.
WO 2018/058001 Al is hereby incorporated herein by reference in its entirety.
[00190] In some embodiments, the antibody, or antigen-binding fragment
thereof, conjugated to
the linker-payload or payload can be an antibody that targets human prolactin
receptor (PRLR).
Suitable anti-PRLR antibodies or antigen-binding fragments thereof include
those, for example, in
International Publication No. WO 2015/026907 Al, including those comprising
amino acid
sequences disclosed in Table 1, on page 36 therein. In some embodiments, an
anti-PRLR antibody
is H1H6958N2 of WO 2015/026907 Al, comprising the CDRs of H2M6958N2 in the
same
publication The expression "PRLR" includes both monomeric and multimeric PRLR
molecules,
such as those described in WO 2015/026907 In some embodiments, an anti-PRLR
antibody
comprises a heavy chain complementarity determining region (HCDR)-1 comprising
SEQ ID
NO: 10; an HCDR2 comprising SEQ ID NO: 11; an HCDR3 comprising SEQ ID NO: 12;
a light
chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 14; an
LCDR2
comprising SEQ ID NO: 15; and an LCDR3 comprising SEQ ID NO: 16. In some
embodiments, an
anti-PRLR antibody comprises a heavy chain variable region (HCVR) comprising
SEQ ID NO: 9
and a light chain variable region (LCVR) comprising SEQ ID NO: 13. In any of
the foregoing
embodiments, the anti-PRLR antibody can be prepared by site-directed
mutagenesis to insert a
glutamine residue at a site without resulting in disabled antibody function or
binding. For example,
in any of the foregoing embodiments, the anti-PRLR antibody can comprise an
Asn297Gln (N297Q)
mutation. Such antibodies having an N297Q mutation can also contain one or
more additional
151
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
naturally occurring glutamine residues in their variable regions, which can be
accessible to
transglutaminase and therefore capable of conjugation to a payload or a linker-
payload (Table A).
In certain embodiments, the antibody or antigen-binding fragment thereof
comprises three heavy
chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) within a
heavy chain
variable region (HCVR) amino acid sequence of SEQ ID NO:9; and three light
chain
complementarity determining regions (LCDR1, LCDR2, and LCDR3) within a light
chain variable
region (LCVR) amino acid sequence of SEQ ID NO:13. In certain embodiments, the
antibody or
antigen-binding fragment thereof comprises an HCVR amino acid sequence of SEQ
ID NO:9; and
an LCVR amino acid sequence of SEQ ID NO:13. International Publication No. WO
2015/026907
Al is hereby incorporated herein by reference in its entirety.
152
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Table A. Sequences of Exemplary Antibodies H1H7814N (anti-STEAP2)
and H1H6958N (anti-PRLR)
SEQ Molecule / Region Sequence
ID NO: Antibody
1 H1H7814N HCVR QVQLVESGGGVVQPGRSLRLSCVASGFTISSYGMN
WVRQAPGKGLEWVAVISYDGGNKYSVDSVKGRFT
ISRDNSKNTLYLQMNSLRAEDSAVYYCARGRYFDL
WGRGTLVTVSS
2 H1H7814N HCDR1 GFTISSYG
3 H1H7814N HCDR2 ISYDGGNK
4 H1H7814N HCDR3 ARGRYFDL
H1H7814N LCVR DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWY
QQKPGRAPNLLISKASSLKSGVPSRFSGSGSGTEFTL
TVS SLQPDDFATYYCQQYYSYSYTFGQGTKLEIK
6 H1H7814N LCDR1 QSISSW
7 H1H7814N LCDR2 KAS
8 H1H7814N LCDR3 QQYYSYSYT
153
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
SEQ Molecule / Region Sequence
ID NO: Antibody
9 H1H6958N2 HCVR QVQLVESGGGVVQPGRSLRLSCGASGFTFRNYGMQ
WVRQGPGKGLEWVTLISFDGNDKYYADSVKGRFTI
SRDNSKNTLFLQMNSLRTEDTAVYYCARGGDFDY
WGQGTLVTVSS
H1H6958N2 HCDR1 GFTFRNYG
11 H1H6958N2 HCDR2 ISFDGNDK
12 H1H6958N2 HCDR3 ARGGDFDY
13 H1H6958N2 LCVR DIQMTQSPSSLSASVGDRVTITCRASQDIRKDLGWY
QQKPGKAPKRLIYAASSLHSGVPSRFSGSGSGTEFTL
TISSLQPEDFATYYCLQHNSYPMYTFGQGTKLEIK
14 H1H6958N2 LCDR1 QDIRKD
H1H6958N2 LCDR2 AAS
16 H1H6958N2 LCDR3 LQHNSYPMYT
17 hPRLR ecto- MHRPRRRGTRPPPLALLAALLLAARGADAQLPPGK
MMH PEIFKCRSPNKETFTCWWRPGTDGGLPTNYSLTYHR
EGETLMHECPDYITGGPNSCHFGKQYTSMWRTYIM
MVNATNQMGS SF SDELYVDVTYIVQPDPPLELAVE
VKQPEDRKPYLWIKWSPPTLIDLKTGWFTLLYEIRL
KPEKAAEWEIHFAGQQTEFKILSLHPGQKYLVQVR
CKPDHGYWSAWSPATFIQIPSDFTMNDEQKLISEED
LGGEQKLISEEDLHHHHHH
154
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00191] This disclosure provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising an HCVR comprising an amino acid sequence
selected
from any of the HCVR amino acid sequences listed in Table A, or a
substantially similar sequence
thereof having at least 90%, at least 95%, at least 98% or at least 99%
sequence identity thereto.
[00192] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising an LCVR comprising an amino acid sequence
selected from
any of the LCVR amino acid sequences listed in Table A, or a substantially
similar sequence
thereof having at least 90%, at least 95%, at least 98% or at least 99%
sequence identity thereto.
[00193] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising an HCVR and an LCVR amino acid sequence
pair
(HCVR/LCVR) comprising any of the HCVR amino acid sequences listed in Table A
paired with
any of the LCVR amino acid sequences listed in Table A. According to certain
embodiments, this
disclosure provides antibodies, or antigen-binding fragments thereof,
comprising an HCVR/LCVR
amino acid sequence pair contained within any of the exemplary anti-STEAP2
antibodies listed in
Table A. In certain embodiments, the HCVR/LCVR amino acid sequence pair is
selected from the
group consisting of: 250/258; as described in International Publication No. WO
2018/058001 Al,
the contents of which are incorporated herein by reference in its entirety.
[00194] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising a heavy chain CDR1 (HCDR1 ) comprising an
amino acid
sequence selected from any of the HCDR1 amino acid sequences listed in Table A
or a
substantially similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least
99% sequence identity.
[00195] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising a heavy chain CDR2 (HCDR2) comprising an
amino acid
sequence selected from any of the HCDR2 amino acid sequences listed in Table A
or a
substantially similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least
99% sequence identity.
[00196] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising a heavy chain CDR3 (HCDR3) comprising an
amino acid
sequence selected from any of the HCDR3 amino acid sequences listed in Table A
or a
155
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
substantially similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least
99% sequence identity.
[00197] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising a light chain CDR1 (LCDR1 ) comprising an
amino acid
sequence selected from any of the LCDR1 amino acid sequences listed in Table A
or a substantially
similar sequence thereof having at least 90%, at least 95%, at least 98% or at
least 99% sequence
identity.
[00198] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising a light chain CDR2 (LCDR2) comprising an
amino acid
sequence selected from any of the LCDR2 amino acid sequences listed in Table A
or a substantially
similar sequence thereof having at least 90%, at least 95%, at least 98% or at
least 99% sequence
identity.
[00199] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising a light chain CDR3 (LCDR3) comprising an
amino acid
sequence selected from any of the LCDR3 amino acid sequences listed in Table A
or a substantially
similar sequence thereof having at least 90%, at least 95%, at least 98% or at
least 99% sequence
identity.
[00200] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising an HCDR3 and an LCDR3 amino acid sequence
pair
(HCDR3/LCDR3) comprising any of the HCDR3 amino acid sequences listed in Table
A paired
with any of the LCDR3 amino acid sequences listed in Table A. According to
certain
embodiments, this disclosure provides antibodies, or antigen-binding fragments
thereof,
comprising an HCDR3/LCDR3 amino acid sequence pair contained within any of the
exemplary
anti-STEAP2 antibodies listed in Table A. In certain embodiments, the
HCDR3/LCDR3 amino
acid sequence pair is selected from the group consisting of: 256/254; as
described in International
Publication No. WO 2018/058001 Al, the contents of which are incorporated
herein by reference
in its entirety.
[00201] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind STEAP2, comprising a set of six CDRs (i.e., HCDR1-HCDR2-
HCDR3-LCDR1-
LCDR2-LCDR3) contained within any of the exemplary anti-STEAP2 antibodies
listed in Table
156
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
A. In certain embodiments, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid
sequence set is selected from the group consisting of: 252-254-256-260-262-
264; as described in
International Publication No. WO 2018/058001 Al, the contents of which are
incorporated herein
by reference in its entirety.
[00202] In a related embodiment, this disclosure provides antibodies, or
antigen-binding
fragments thereof that specifically bind STEAP2, comprising a set of six CDRs
(i.e., HCDR1-
HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within an HCVR/LCVR amino acid
sequence pair as defined by any of the exemplary anti-STEAP2 antibodies listed
in Table A. For
example, this disclosure includes antibodies or antigen-binding fragments
thereof that specifically
bind STEAP2, comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid
sequence set contained within an HCVR/LCVR amino acid sequence pair selected
from the group
consisting of: 250/258; as described in International Publication No. WO
2018/058001 Al, the
contents of which are incorporated herein by reference in its entirety.
Methods and techniques for
identifying CDRs within HCVR and LCVR amino acid sequences are well known in
the art and
can be used to identify CDRs within the specified HCVR and/or LCVR amino acid
sequences
disclosed herein. Exemplary conventions that can be used to identify the
boundaries of CDRs
include, e.g., the Kabat definition, the Chothia definition, and the AbM
definition. In general terms,
the Kabat definition is based on sequence variability, the Chothia definition
is based on the location
of the structural loop regions, and the AbM definition is a compromise between
the Kabat and
Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological
Interest," National
Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol.
273:927-948 (1997);
and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public
databases are also
available for identifying CDR sequences within an antibody.
[00203] This disclosure provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising an HCVR comprising an amino acid sequence
selected from
any of the HCVR amino acid sequences listed in Table A, or a substantially
similar sequence
thereof having at least 90%, at least 95%, at least 98% or at least 99%
sequence identity thereto.
[00204] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising an LCVR comprising an amino acid sequence
selected from
157
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
any of the LCVR amino acid sequences listed in Table A, or a substantially
similar sequence
thereof having at least 90%, at least 95%, at least 98% or at least 99%
sequence identity thereto.
[00205] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising an HCVR and an LCVR amino acid sequence
pair
(HCVR/LCVR) comprising any of the HCVR amino acid sequences listed in Table A
paired with
any of the LCVR amino acid sequences listed in Table A. According to certain
embodiments, this
disclosure provides antibodies, or antigen-binding fragments thereof,
comprising an HCVR/LCVR
amino acid sequence pair contained within any of the exemplary anti-PRLR
antibodies listed in
Table A. In certain embodiments, the HCVR/LCVR amino acid sequence pair is
selected from the
group consisting of: 18/26; 66/74; 274/282; 290/298; and 370/378; as described
in International
Publication No. WO 2015/026907 Al, the contents of which are incorporated
herein by reference
in its entirety.
[00206] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising a heavy chain CDR1 (HCDR1 ) comprising an
amino acid
sequence selected from any of the HCDR1 amino acid sequences listed in Table A
or a
substantially similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least
99% sequence identity.
[00207] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising a heavy chain CDR2 (HCDR2) comprising an
amino acid
sequence selected from any of the HCDR2 amino acid sequences listed in Table A
or a
substantially similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least
99% sequence identity.
[00208] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising a heavy chain CDR3 (HCDR3) comprising an
amino acid
sequence selected from any of the HCDR3 amino acid sequences listed in Table A
or a
substantially similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least
99% sequence identity.
[00209] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising a light chain CDR1 (LCDR1 ) comprising an
amino acid
sequence selected from any of the LCDR1 amino acid sequences listed in Table A
or a substantially
158
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
similar sequence thereof having at least 90%, at least 95%, at least 98% or at
least 99% sequence
identity.
[00210] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising a light chain CDR2 (LCDR2) comprising an
amino acid
sequence selected from any of the LCDR2 amino acid sequences listed in Table A
or a substantially
similar sequence thereof having at least 90%, at least 95%, at least 98% or at
least 99% sequence
identity.
[00211] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising a light chain CDR3 (LCDR3) comprising an
amino acid
sequence selected from any of the LCDR3 amino acid sequences listed in Table A
or a substantially
similar sequence thereof having at least 90%, at least 95%, at least 98% or at
least 99% sequence
identity.
[00212] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising an HCDR3 and an LCDR3 amino acid sequence
pair
(HCDR3/LCDR3) comprising any of the HCDR3 amino acid sequences listed in Table
A paired
with any of the LCDR3 amino acid sequences listed in Table A. According to
certain
embodiments, this disclosure provides antibodies, or antigen-binding fragments
thereof,
comprising an HCDR3/LCDR3 amino acid sequence pair contained within any of the
exemplary
anti-PRLR antibodies listed in Table A. In certain embodiments, the
HCDR3/LCDR3 amino acid
sequence pair is selected from the group consisting of: 24/32; 72/80; 280/288;
296/304; and
376/384; as described in International Publication No. WO 2015/026907 Al, the
contents of which
are incorporated herein by reference in its entirety.
[00213] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind PRLR, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-
LCDR1-
LCDR2-LCDR3) contained within any of the exemplary anti-PRLR antibodies listed
in Table A.
In certain embodiments, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid
sequence set is selected from the group consisting of: 20-22-24-28-30-32; 68-
70-72-76- 78-80;
276-278-280-284-286-288; 292-294-296-300-302-304; and 372-374-376-380-382-384;
as
described in International Publication No. WO 2015/026907 Al, the contents of
which are
incorporated herein by reference in its entirety.
159
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00214] In a related embodiment, this disclosure provides antibodies, or
antigen-binding
fragments thereof that specifically bind PRLR, comprising a set of six CDRs
(i.e., HCDR1-
HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within an HCVR/LCVR amino acid
sequence pair as defined by any of the exemplary anti-PRLR antibodies listed
in Table A. For
example, this disclosure includes antibodies or antigen-binding fragments
thereof that specifically
bind PRLR, comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid
sequence set contained within an HCVR/LCVR amino acid sequence pair selected
from the group
consisting of: 18/26; 66/74; 274/282; 290/298; and 370/378; as described in
International
Publication No. WO 2015/026907 Al, the contents of which are incorporated
herein by reference
in its entirety. Methods and techniques for identifying CDRs within HCVR and
LCVR amino acid
sequences are well known in the art and can be used to identify CDRs within
the specified HCVR
and/or LCVR amino acid sequences disclosed herein. Exemplary conventions that
can be used to
identify the boundaries of CDRs include, e.g., the Kabat definition, the
Chothia definition , and
the AbM definition. In general terms, the Kabat definition is based on
sequence variability, the
Chothia definition is based on the location of the structural loop regions,
and the AbM definition
is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat,
"Sequences of
Proteins of Immunological Interest," National Institutes of Health, Bethesda,
Md. (1991); Al-
Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc.
Natl. Acad. Sci. USA
86:9268-9272 (1989). Public databases are also available for identifying CDR
sequences within
an antibody.
[00215] In any of the compound or conjugate embodiments provided, BA is an
antibody, or
antigen binding fragment thereof, that binds PRLR. In any of the compound or
conjugate
embodiments provided, BA is an antibody or antigen-binding fragment thereof,
and conjugation
is through at least one Q295 residue. In any of the compound or conjugate
embodiments provided,
BA is an antibody or antigen-binding fragment thereof, and conjugation is
through two Q295
residues. In any of the compound or conjugate embodiments provided, BA is a
N297Q antibody
or antigen-binding fragment thereof In any of the compound or conjugate
embodiments provided,
BA is a N297Q antibody or antigen-binding fragment thereof, and conjugation is
through at least
one Q295 and at least one Q297 residue. In any of the compound or conjugate
embodiments
provided, BA is a N297Q antibody or antigen-binding fragment thereof, and
conjugation is through
160
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
two Q295 residues and two Q297 residues. In particular embodiments, numbering
is according to
the EU numbering system.
[00216] In any of the embodiments above, BA is an anti-MSR1 antibody. In
certain
embodiments, BA is the anti-MSR1 antibody H1H21234N. In certain embodiments,
BA is the
anti-MSR1 antibody H1H21234N N297Q. In certain embodiments, BA is an anti-MSR1
antibody
comprising an HCVR according to SEQ ID NO:19 and an LCVR according to SEQ ID
NO: 27.
In certain embodiments, BA is an anti-MSR1 antibody comprising one, two,
three, four, five, or
six of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 according to SEQ ID NOS:
21,
23, 25, 29, 31, and 33, respectively. In certain embodiments, the HCVR is
encoded by SEQ ID
NO:18. In certain embodiments, the LCVR is encoded by SEQ ID NO: 26. In
certain embodiments,
one, two, three, four, five, or six of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and
LCDR3 are
encoded by the polynucleotide sequences SEQ ID NOS: 20, 22, 24, 28, 30, and
32, respectively.
N297Q indicates that one or more residues 297 are mutated from asparagine (N)
to glutamine (Q).
In certain embodiments, each residue 297 is mutated to Q. In preferred
embodiments, numbering
is according to the EU numbering system. In certain embodiments of this
paragraph, the
drug:antibody ratio (DAR) is from 1 to 4. In certain embodiments, DAR is 1, 2,
3, or 4. In certain
embodiments, DAR is 2. In certain embodiments, DAR is 4.
[00217] This disclosure provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising an HCVR comprising an amino acid sequence
selected from
any of the HCVR amino acid sequences listed in Table B, or a substantially
similar sequence
thereof having at least 90%, at least 95%, at least 98% or at least 99%
sequence identity thereto.
[00218] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising an LCVR comprising an amino acid sequence
selected from
any of the LCVR amino acid sequences listed in Table B, or a substantially
similar sequence
thereof having at least 90%, at least 95%, at least 98% or at least 99%
sequence identity thereto.
[00219] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising an HCVR and an LCVR amino acid sequence
pair
(HCVR/LCVR) comprising any of the HCVR amino acid sequences listed in Table B
paired with
any of the LCVR amino acid sequences listed in Table B. According to certain
embodiments, this
disclosure provides antibodies, or antigen-binding fragments thereof,
comprising an HCVR/LCVR
161
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
amino acid sequence pair contained within any of the exemplary anti-MSR1
antibodies listed in
Table B. In certain embodiments, the HCVR/LCVR amino acid sequence pair is
selected from the
group consisting of: 2/10, 23/42, 50/58; 90/98, and 282/290; as described in
International
Publication No. WO 2019/217597 Al, the contents of which are incorporated
herein by reference
in its entirety.
[00220] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising a heavy chain CDR1 (HCDR1 ) comprising an
amino acid
sequence selected from any of the HCDR1 amino acid sequences listed in Table B
or a
substantially similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least
99% sequence identity.
[00221] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising a heavy chain CDR2 (HCDR2) comprising an
amino acid
sequence selected from any of the HCDR2 amino acid sequences listed in Table B
or a
substantially similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least
99% sequence identity.
[00222] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising a heavy chain CDR3 (HCDR3) comprising an
amino acid
sequence selected from any of the HCDR3 amino acid sequences listed in Table B
or a
substantially similar sequence thereof having at least 90%, at least 95%, at
least 98% or at least
99% sequence identity.
[00223] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising a light chain CDR1 (LCDR1 ) comprising an
amino acid
sequence selected from any of the LCDR1 amino acid sequences listed in Table B
or a substantially
similar sequence thereof having at least 90%, at least 95%, at least 98% or at
least 99% sequence
identity.
[00224] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising a light chain CDR2 (LCDR2) comprising an
amino acid
sequence selected from any of the LCDR2 amino acid sequences listed in Table B
or a substantially
similar sequence thereof having at least 90%, at least 95%, at least 98% or at
least 99% sequence
identity.
162
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00225] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising a light chain CDR3 (LCDR3) comprising an
amino acid
sequence selected from any of the LCDR3 amino acid sequences listed in Table B
or a substantially
similar sequence thereof having at least 90%, at least 95%, at least 98% or at
least 99% sequence
identity.
[00226] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising an HCDR3 and an LCDR3 amino acid sequence
pair
(HCDR3/LCDR3) comprising any of the HCDR3 amino acid sequences listed in Table
B paired
with any of the LCDR3 amino acid sequences listed in Table B. According to
certain embodiments,
this disclosure provides antibodies, or antigen-binding fragments thereof,
comprising an
HCDR3/LCDR3 amino acid sequence pair contained within any of the exemplary
anti-MSR1
antibodies listed in Table B. In certain embodiments, the HCDR3/LCDR3 amino
acid sequence
pair is selected from the group consisting of: 8,16, 40/48, 56/64; 96/104, and
288/296; as described
in International Publication No. WO 2019/217591 Al, the contents of which are
incorporated
herein by reference in its entirety.
[00227] This disclosure also provides antibodies or antigen-binding fragments
thereof that
specifically bind MSR1, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-
LCDR1-
LCDR2-LCDR3) contained within any of the exemplary anti-MSR1 antibodies listed
in Table B.
In certain embodiments, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid
sequence set is selected from the group consisting of: 4-6-8- I 2-14-16; 36-38-
40-44-4648; 52-54-
56-60-62-64; 92-94-96-100-102-104, and 284-286-288-292-294-296; as described
in International
Publication No. WO 2019/217591 Al, the contents of which are incorporated
herein by reference
in its entirety.
[00228] In a related embodiment, this disclosure provides antibodies, or
antigen-binding
fragments thereof that specifically bind MSR1, comprising a set of six CDRs
(i.e., HCDR1-
HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within an HCVR/LCVR amino acid
sequence pair as defined by any of the exemplary anti-MSR1 antibodies listed
in Table B. For
example, this disclosure includes antibodies or antigen-binding fragments
thereof that specifically
bind MSR1, comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid
sequence set contained within an HCVR/LCVR amino acid sequence pair selected
from the group
163
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
consisting of: 2110, 23/42, 50/58, 90/98, and 282/290; as described in
International Publication
No. WO 2019/217591 Al, the contents of which are incorporated herein by
reference in its
entirety. Methods and techniques for identifying CDRs within HCVR and LCVR
amino acid
sequences are well known in the art and can be used to identify CDRs within
the specified HCVR
and/or LCVR amino acid sequences disclosed herein. Exemplary conventions that
can be used to
identify the boundaries of CDRs include, e.g., the Kabat definition, the
Chothia definition, and the
AbM definition. In general terms, the Kabat definition is based on sequence
variability, the Chothia
definition is based on the location of the structural loop regions, and the
AbM definition is a
compromise between the Kabat and Chothia approaches. See, e.g., Kabat,
"Sequences of Proteins
of Immunological Interest," National Institutes of Health, Bethesda, Md.
(1991); Al-Lazikani et
al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad.
Sci. USA 86:9268-9272
(1989). Public databases are also available for identifying CDR sequences
within an antibody.
Table B. Sequences of Exemplary anti-MSR1 Antibodies
SEQ Molecule / Region Sequence
ID Antibody
NO:
18 H1H21234N HCVR caggtgcagc tgcaggagtc gggcccagga
ctggtgaagc cttcggagac cctgtccctc
acctgcactg tcactggtgg ctccatcagt
aggaactact ggagttggat ccggcagccc
ccagggaagg gactggaatg gattggatat
atctattaca gtgggagtat cgactacaat
ccctccctca agagtcgagt caccatatca
gtagacacgt ccaagaacca gttctccctg
aagctgagtt ctatgaccgc tgcggacacg
gccgtatact actgtgcgag agatcggtgg
aactggaaat acggtatgga cgtctggggc
caagggacca cggtcatcgt ctcgtca
19 H1H21234N HCVR Gin Val Gin Leu Gin Glu Ser Gly Pro Gly
Leu Val Lys Pro Ser Glu Thr Leu Ser Leu
Thr Cys Thr Val Thr Gly Gly Ser Ile Ser
Arg Asn Tyr Trp Ser Trp Ile Arg Gin Pro
Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr
Ile Tyr Tyr Ser Gly Ser Ile Asp Tyr Asn
Pro Ser Leu Lys Ser Arg Val Thr Ile Ser
Val Asp Thr Ser Lys Asn Gin Phe Ser Leu
Lys Leu Ser Ser Net Thr Ala Ala Asp Thr
Ala Val Tyr Tyr Cys Ala Arg Asp Arg Trp
164
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
SEQ Molecule / Region Sequence
ID Antibody
NO:
Asn Trp Lys Tyr Gly Net Asp Val Trp Gly
Gin Gly Thr Thr Val Ile Val Ser Ser
20 H1H21234N HCDR1 ggtggctcca tcagtaggaa ctac
21 H1H21234N HCDR1 Gly Gly Ser Ile Ser Arg Asn Tyr
22 H1H21234N HCDR2 atctattaca gtgggagtat c
23 H1H21234N HCDR2 Ile Tyr Tyr Ser Gly Ser Ile
24 H1H21234N HCDR3 gcgagagatc ggtggaactg gaaatacggt
atggacgtc
25 H1H21234N HCDR3 Ala Arg Asp Arg Trp Asn Trp Lys Tyr Gly
Net Asp Val
26 H1H21234N LCVR gaaattgtgt tgacgcagtc tccaggcacc
ctgtctttgt ctccagggga aagagccacc
ctctcctgca gggccagtca gactgttaga
aacaactact tagcctggta ccaccagaaa
cctggccagg ctcccaggct cctcatctat
ggtgcatcca gcagggccac
tggcatccca gacaggttca gtggcagtgg
gtctgggaca gacttcactc tcaccatcag
cagactggag cctgaagatt ttacagtgta
ttactgtcac cagtatggta actcaccttg
gacgttcggc caagggacca aaatggaaat
caaacga
27 H1H21234N LCVR Glu Ile Val Leu Thr Gin Ser Pro Gly Thr
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gin Thr Val Arg
Asn Asn Tyr Leu Ala Trp Tyr His Gin Lys
Pro Gly Gin Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
Pro Glu Asp Phe Thr Val Tyr Tyr Cys His
Gin Tyr Gly Asn Ser Pro Trp Thr Phe Gly
Gin Gly Thr Lys Net Glu Ile Lys Arg
28 H1H21234N LCDR1 cagactgtta gaaacaacta c
29 H1H21234N LCDR1 Gin Thr Val Arg Asn Asn Tyr
30 H1H21234N LCDR2 ggtgcatcc
165
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
SEQ Molecule / Region Sequence
ID Antibody
NO:
31 H1H21234N LCDR2 Gly Ala Ser
32 H1H21234N LCDR3 caccagtatg gtaactcacc ttggacg
33 H1H21234N LCDR3 His Gln Tyr Gly Asn Ser Pro Trp Thr
[00229] The binding agent linkers can be bonded to the binding agent, e.g.,
antibody or antigen-
binding molecule, through an attachment at a particular amino acid within the
antibody or antigen-
binding molecule. Exemplary amino acid attachments that can be used in the
context of this
embodiment of the disclosure include, e.g., lysine (see, e.g., US 5,208,020;
US 2010/0129314;
Hollander et al., Bioconjugate Chem., 2008, 19:358-361; WO 2005/089808; US
5,714,586; US
2013/0101546; and US 2012/0585592), cysteine (see, e.g., US 2007/0258987; WO
2013/055993;
WO 2013/055990; WO 2013/053873; WO 2013/053872; WO 2011/130598; US
2013/0101546;
and US 7,750,116), selenocysteine (see, e.g., WO 2008/122039; and Hofer et
al., Proc. Natl. Acad.
Sci., USA, 2008, 105:12451-12456), formyl glycine (see, e.g., Carrico et al.,
Nat. Chem. Biol.,
2007, 3:321-322; Agarwal et al., Proc. Natl. Acad. Sci., USA, 2013, /10:46-51,
and Rabuka et al.,
Nat. Protocols, 2012, 10:1052-1067), non-natural amino acids (see, e.g., WO
2013/068874, and
WO 2012/166559), and acidic amino acids (see, e.g., WO 2012/05982). Linkers
can also be
conjugated to an antigen-binding protein via attachment to carbohydrates (see,
e.g., US
2008/0305497, WO 2014/065661, and Ryan et al., Food & Agriculture Immunol.,
2001, /3:127-
130).
[00230] In some examples, the binding agent is an antibody or antigen binding
molecule, and
the antibody is bonded to the linker through a lysine residue. In some
embodiments, the antibody
or antigen binding molecule is bonded to the linker through a cysteine
residue.
[00231] Linkers can also be conjugated to one or more glutamine residues via
transglutaminase-
based chemo-enzymatic conjugation (see, e.g., Dennler et al., Bioconjugate
Chem. 2014, 25, 569-
578). For example, in the presence of transglutaminase, one or more glutamine
residues of an
antibody can be coupled to a primary amine compound. Primary amine compounds
include, e.g.,
payloads or linker-payloads, which directly provide antibody drug conjugates
via
166
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
transglutaminase-mediated coupling. Primary amine compounds also include
linkers and spacers
that are functionalized with reactive groups that can be subsequently reacted
with further
compounds towards the synthesis of antibody drug conjugates. Antibodies
comprising glutamine
residues can be isolated from natural sources or engineered to comprise one or
more glutamine
residues. Techniques for engineering glutamine residues into an antibody
polypeptide chain
(glutaminyl-modified antibodies or antigen binding molecules) are within the
skill of the
practitioners in the art. In certain embodiments, the antibody is
aglycosylated.
[00232] In certain embodiments, the antibody or a glutaminyl-modified antibody
or antigen
binding molecule comprises at least one glutamine residue in at least one
polypeptide chain
sequence. In certain embodiments, the antibody or a glutaminyl-modified
antibody or antigen
binding molecule comprises two heavy chain polypeptides, each with one Gln295
or Q295 residue.
In further embodiments, the antibody or a glutaminyl-modified antibody or
antigen binding
molecule comprises one or more glutamine residues at a site other than a heavy
chain 295. Included
herein are antibodies of this section bearing N297Q mutation(s) described
herein.
Primary Amine Compounds
[00233] In certain embodiments, primary amine compounds useful for the
transglutaminase
mediated coupling of an antibody (or antigen binding compound) comprising a
glutamine can be
any primary amine compound deemed useful by the practitioner of ordinary
skill. Generally, the
primary amine compound has the formula H2N-R, where R can be any group
compatible with the
antibody and reaction conditions. In certain embodiments, R is alkyl,
substituted alkyl, heteroalkyl,
or substituted heteroalkyl.
[00234] In some embodiments, the primary amine compound comprises a reactive
group or
protected reactive group. Useful reactive groups include azides, alkynes,
cycloalkynes, thiols,
alcohols, ketones, aldehydes, carboxylic acids, esters, amides, hydrazides,
anilines, and amines. In
certain embodiments, the reactive group is selected from the group consisting
of azide, alkyne,
sulfhydryl, cycloalkyne, aldehyde, and carboxyl.
[00235] In certain embodiments, the primary amine compound is according to the
formula H2N-
LL-X, where LL is a divalent spacer and X is a reactive group or protected
reactive group. In
particular embodiments, LL is a divalent polyethylene glycol (PEG) group. In
certain
167
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
embodiments, X is selected from the group consisting of ¨SH, ¨N3, alkyne,
aldehyde, and
tetrazole. In particular embodiments, X is ¨N3.
[00236] In certain embodiments, the primary amine compound is according to one
of the
following formulae:
H2N-(CH2)n-X;
H2N-(CH2CH20)11-(CH2)p-X;
H2N-(CH2)n-N(H)C(0)-(CH2)m-X;
H2N-(CH2CH20)n-N(H)C(0)-(CH2CH20)m-(CH2)p-X;
H2N-(CH2)n-C(0)N(H)-(CH2)m-X;
H2N-(CH2CH20)n-C(0)N(H)-(CH2CH20)m-(CH2)p-X;
H2N-(CH2)n-N(H)C(0)-(CH2CH20)m-(CH2)p-X;
H2N-(CH2CH20)n-N(H)C(0)-(CH2)m-X;
H2N-(CH2)n-C(0)N(H)-(CH2CH20)m-(CH2)p-X; and
H2N-(CH2CH20)n-C(0)N(H)-(CH2)m-X;
where n is an integer selected from 1 to 12;
m is an integer selected from 0 to 12;
p is an integer selected from 0 to 2;
and X is selected from the group consisting of ¨SH, ¨N3, ¨CCH, ¨C(0)H,
tetrazole, and any of
0
hr ,,,yN 11 Ift 0-
'W PPh2
0
kA N=)
> 1-0 11 \NI = Ni)
--S N-N
[00237] In the above, any of the alkyl or alkylene (i.e., ¨CH2¨) groups can
optionally be
substituted, for example with C1-8 alkyl, methylformyl, or ¨S03H. In certain
embodiments, the
alkyl groups are unsubstituted.
[00238] In certain embodiments, the primary amine compound is selected from
the group
consisting of:
168
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
0
N3 (
)LNH 0H20H20)120H3
0 .
OyOti
0(CH2CH20)12CH3
H2N NH
0 N)S-S H2N
0 N
Q-Q
H2N
0
H2N
0
H2N
0
NI)=SH
H2N
0
H2N
H2N 00'0 N3
0
H2N N3
and
0
H2N N N3
[00239] In particular embodiments, the primary amine compound is
H2N N3
[00240] Exemplary conditions for the above reactions are provided in the
Examples below.
169
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Linkers
[00241] In certain embodiments, the linker L portion of the conjugates
described herein is a
moiety, for instance a divalent moiety, that covalently links a binding agent
to a payload compound
described herein. In other instances, the linker L is a trivalent or
multivalent moiety that covalently
links a binding agent to a payload compound described herein. Suitable linkers
may be found, for
example, in Antibody-Drug Conjugates and Immunotoxins; Phillips, G. L., Ed.;
Springer Verlag:
New York, 2013; Antibody-Drug Conjugates; Ducry, L., Ed.; Humana Press, 2013;
Antibody-
Drug Conjugates; Wang, J., Shen, W.-C., and Zaro, J. L., Eds.; Springer
International Publishing,
2015, the contents of each incorporated herein in their entirety by reference.
In certain
embodiments, the linker L portion of the linker-payloads described herein is a
moiety covalently
linked to a payload compound described herein, capable of divalently and
covalently linking a
binding agent to a payload compound described herein. In other instances, the
linker L portion of
the linker-payloads described herein is a moiety covalently linked to a
payload compound
described herein, capable of covalently linking, as a trivalent or multivalent
moiety, a binding
agent to a payload compound described herein. Payload compounds include
compounds of
Formulae I, Ib, Ibb, and Ibbb above, and their residues following bonding or
incorporation with
linker L are linker-payload compounds. The linker-payloads can be further
bonded to binding
agents such as antibodies or antigen binding fragments thereof to form
antibody-drug conjugates.
Those of skill in the art will recognize that certain functional groups of
payload moieties are
convenient for linking to linkers and/or binding agents. For example, in
certain embodiments, the
linker is absent and payloads are directly bonded to binding agents. In
certain embodiments,
prodrugs or payloads include hydroxyl, amine, or thiol functionality capable
of bonding with
peptide residues within binding agents.
[00242] In certain embodiments, the linkers are stable in physiological
conditions. In certain
embodiments, the linkers are cleavable, for instance, able to release at least
the payload portion in
the presence of an enzyme or at a particular pH range or value. In some
embodiments, a linker
comprises an enzyme-cleavable moiety. Illustrative enzyme-cleavable moieties
include, but are
not limited to, peptide bonds, ester linkages, hydrazones, and disulfide
linkages. In some
embodiments, the linker comprises a cathepsin-cleavable linker. In some
embodiments, the linker
comprises a moiety that is stable at certain pHs and cleavable to release the
payload portion at
170
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
other pHs. For instance, in certain embodiments, the linker is stable at
physiological pH and
capable of releasing the payload portion at a local pH in the vicinity of a
target.
[00243] In some embodiments, the linker comprises a non-cleavable moiety. In
some
embodiments, the non-cleavable linker is derived from maleimide. In some
embodiments, the non-
cleavable linkers are derived from an ester. In some embodiments, the non-
cleavable linker is
derived from an N-hydroxysuccinimide ester. In some embodiments, the non-
cleavable linker is
0
0
Payload
derived from 0 or
a residue thereof In some embodiments, the non-
0
A cif 0
Payload
cleavable linker-payload residue is 0
, or a regioisomer thereof
0 0
1-131-Payload
0
In some embodiments, the non-cleavable linker is derived from 0
Or
a residue thereof. In some embodiments, the non-cleavable linker-payload
residue is
0
A
Payload
0 ,
or a regioisomer thereof In one embodiment, the linker is maleimide
cyclohexane carboxylate or 4-(N-maleimidomethyl)cyclohexanecarboxylic acid
(MCC), where
the payload can be added to either end of the MCC linker. In another
embodiment, the linker is
0 0
0
0 ,
where the payload can be added to either
end of this linker. In certain embodiments, the linker is a self-stabilizing
maleimide. In one
0
--irsj¨payload
exemplary embodiment, the self-stabilizing maleimide linker is NH2
, where the
bond from the amide nitrogen to the payload can be a direct bond to the
payload; or the bond from
the amide nitrogen to the payload, as shown, contemplates the remainder of the
linker. In another
171
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
A
oNA/V
0
¨payload
exemplary embodiment, the self-stabilizing linker manifests as NH2
, where the
bond from the amide nitrogen to the payload can be a direct bond to the
payload; or the bond from
the amide nitrogen to the payload, as shown, contemplates the remainder of the
linker. Without
being bound by any particular theory, the self-stabilizing linker includes
moieties that stabilize the
bond from the self-stabilizing linker to a binding agent. For example, in some
embodiments, when
the bond from a binding agent to a self-stabilizing linker is a carbon-sulfur
bond (e.g., following a
Michael addition of a binding agent cysteine to the self-stabilizing maleimide
linker), the self-
stabilizing linker mitigates retro-Michael additions. More specifically, in
the self-stabilizing
maleimide (or succinimide) linkers shown, the aminomethyl functionality
facilitates rapid
A
%NW
H
H N
N¨payload
hydrolysis of the succinimide Michael addition product to provide NH2
where the bond from the amide nitrogen to the payload can be a direct bond to
the payload; or the
bond from the amide nitrogen to the payload, as shown, contemplates the
remainder of the linker;
thus, decreasing susceptibility to retro-Michael additions. Moieties other
than aminomethyl within
self-stabilizing maleimide linkers that stablilize conjugates will be
appreciated by those of skill in
the art. In the structures,
indicates a bond to a binding agent. In the structures, in some
examples,
indicates a click chemistry residue which results from the reaction of, for
example,
a binding agent having an azide or alkyne functionality and a linker-payload
having a
complementary alkyne or azide functionality. In the structures, in other
examples, indicates a
divalent sulfide which results from the reaction of, for example, one or more
binding agent
cysteines with one or more linkers or linker-payloads having maleimide
functionality via Michael
addition reactions. In the structures, in other examples,
indicates an amide bond which results
172
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
from the reaction of, for example, one or more binding agent lysines with one
or more linkers or
linker-payloads having activated or unactivated carboxyl functionality, as
would be appreciated
by a person of skill in the art. In one embodiment, -1A- indicates an amide
bond which results from
the reaction of, for example, one or more binding agent lysines with one or
more linkers or linker-
payloads having activated carboxyl functionality, as would be appreciated by a
person of skill in
the art.
[00244] In some embodiments, suitable linkers include, but are not limited to,
those that are
chemically bonded to two cysteine residues of a single binding agent, e.g.,
antibody. Such linkers
can serve to mimic the antibody's disulfide bonds that are disrupted as a
result of the conjugation
process.
[00245] In some embodiments, the linker comprises one or more amino acids.
Suitable amino
acids include natural, non-natural, standard, non-standard, proteinogenic, non-
proteinogenic, and
L- or D- a-amino acids. In some embodiments, the linker comprises alanine,
valine, glycine,
leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine,
threonine, cysteine,
tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine,
arginine, histidine, or
citrulline, a derivative thereof, or any combination thereof (e.g.,
dipeptides, tripeptides,
oligopeptides, polypeptides, and the like). In certain embodiments, one or
more side chains of the
amino acids are linked to a side chain group, described below. In some
embodiments, the linker is
a peptide comprising or consisting of the amino acids valine and citrulline
(e.g., divalent -Val-
Cit- or divalent -VCit-). In some embodiments, the linker is a peptide
comprising or consisting
of the amino acids alanine and alanine, or divalent -AA-. In some embodiments,
the linker is a
peptide comprising or consisting of the amino acids glutamic acid and alanine,
or -EA-. In some
embodiments, the linker is a peptide comprising or consisting of the amino
acids glutamic acid
and glycine, or -EG-. In some embodiments, the linker is a peptide comprising
or consisting of
the amino acids glycine and glycine, or -GG-. In some embodiments, the linker
is a peptide
comprising or consisting of the amino acids glutamine, valine, and citrulline,
or -Q-V-Cit- or
-QVCit-. In some embodiments, the linker is a peptide comprising or consisting
of the amino
acids glutamic acid, valine, and citrulline, or -E-V-Cit- or -EVCit-. In some
embodiments, the
linker is a peptide comprising or consisting of the amino acids -GGGGS-. In
some embodiments,
the linker is a peptide comprising or consisting of the amino acids
173
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
-GGGGG-. In some embodiments, the linker is a peptide comprising or consisting
of the amino
acids -GGGGK-. In some embodiments, the linker is a peptide comprising or
consisting of the
amino acids -GFGG-. In some embodiments, the linker is a peptide comprising or
consisting of
the amino acids lysine, valine, and citrulline, or -KVCit-. In some
embodiments, the linker is a
peptide comprising or consisting of the amino acids -KVA-. In some
embodiments, the linker is
a peptide comprising or consisting of the amino acids -VA-. In any of the
embodiments in this
paragraph, and throughout this disclosure, the standard three-letter or one-
letter amino acid
designations are used, as would be appreciated by a person of skill in the
art. Exemplary single-
letter amino acid designations include, G for glycine, K for lysine, S for
serine, V for valine, A for
alanine, and F for phenylalanine.
[00246] In some embodiments, the linker comprises a self-immolative group. The
self-immolative group can be any such group known to those of skill. In
particular embodiments,
the self-immolative group is p-aminobenzyl (PAB), or a derivative thereof.
Useful derivatives
include p-aminobenzyloxycarbonyl (PABC). Those of skill will recognize that a
self-immolative
group is capable of carrying out a chemical reaction which releases the
remaining atoms of a linker
from a payload.
[00247] In some embodiments, the linker is:
A P
-I-SP1-(AA)SP2-1-
wherein:
SP' is a spacer;
SP2 is a spacer;
-r- is one or more bonds to the binding agent;
-1- is one or more bonds to the payload;
each AA is an amino acid residue; and
n is an integer from 0 to 10.
[00248] The SP' spacer is a moiety that connects the (AA)11 moiety or residue
to the binding
agent (BA) or to a reactive group residue which is bonded to BA. Suitable SP'
spacers include,
but are not limited to, those comprising alkylene or polyether, or both. The
ends of the spacers,
174
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
for example, the portion of the spacer bonded to the BA or an AA, can be
moieties derived from
reactive moieties that are used for purposes of coupling the antibody or an AA
to the spacer during
chemical synthesis of the conjugate. In certain embodiments, n is 1, 2, 3, or
4. In particular
embodiments, n is 2. In particular embodiments, n is 3. In particular
embodiments, n is 4. In certain
embodiments, when n is zero, then (AA)11 is a bond.
[00249] In some embodiments, the SP' spacer comprises an alkylene. In some
embodiments,
the SP' spacer comprises a C5-7 alkylene. In some embodiments, the SP' spacer
comprises a
polyether. In some embodiments, the SP' spacer comprises a polymer of ethylene
oxide such as
polyethylene glycol.
[00250] In some embodiments, the SP' spacer is:
0 0
A H A
+RG1-N-(CH2)b-q- 1-RG'-N-(CH2)2-(OCH2CH2)1-4-
, Or
wherein:
RG' is a reactive group residue following reaction of a reactive group RG with
a
binding agent;
-it is a bond to the binding agent;
-1- is a bond to (AA)11 wherein n is an integer from 0 to 10; and
b is an integer from 2 to 8.
[00251] The reactive group RG can be any reactive group known to those of
skill in the art to
be capable of forming one or more bonds to the binding agent. The reactive
group RG is a moiety
comprising a portion in its structure that is capable of reacting with the
binding agent (e.g., reacting
with an antibody at its cysteine or lysine residues, or at an azide moiety,
for example, a PEG-N3
functionalized antibody at one or more glutamine residues) to form a compound
of Formula III.
Following conjugation to the binding agent, the reactive group becomes the
reactive group residue
(RG'). Illustrative reactive groups include, but are not limited to, those
that comprise haloacetyl,
isothiocyanate, succinimide, N-hydroxysuccinimide, or maleimide portions that
are capable of
reacting with the binding agent.
175
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00252] In certain embodiments, reactive groups include, but are not limited
to, alkynes. In
certain embodiments, the alkynes are alkynes capable of undergoing 1,3-
cycloaddition reactions
with azides in the absence of copper catalysts, such as strained alkynes.
Strained alkynes are
suitable for strain-promoted alkyne-azide cycloadditions (SPAAC), and include
cycloalkynes, for
example, cyclooctynes and benzannulated alkynes. Suitable alkynes include, but
are not limited
_
¨
N
H
to, dibenzoazacyclooctyne or 0
(DIBAC); dibenzocyclooctyne or
_
_
_
0 N
(DIB0); biarylazacyclooctynone or 0 ,..-\''''
(BARAC);
0
1_110 2F F F difluorinated cyclooctyne or 1 \--0
, Or , Or
(DIF0); substituted, for example, fluorinated alkynes, aza-cycloalkynes,
bicycle[6.1.0]nonyne or
0-1
II
(BCN); and derivatives thereof
Particularly useful alkynes include
=0
= I 1 "jc..-----13µ
=
0
=
an 1 Of
d .
[00253] In certain embodiments, the binding agent is bonded directly to RG'.
In certain
embodiments, the binding agent is bonded to RG' via a spacer, for instance
SP4, located between
-/A- and RG'. In particular embodiments, the binding agent is bonded
indirectly to RG' via SP4,
for example, a PEG spacer. As discussed in detail below, in certain
embodiments, the binding
agent is prepared by functionalizing with one or more azido groups. Each azido
group is capable
176
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
of reacting with RG to form RG'. In particular embodiments, the binding agent
is derivatized with
¨PEG-N3 linked to a glutamine residue. Exemplary ¨N3 derivatized binding
agents, methods for
their preparation, and methods for their use in reacting with RG are provided
herein. In certain
embodiments, RG is an alkyne suitable for participation in 1,3-cycloadditions,
and RG' is a
regioisomeric 1,2,3-triazoly1 moiety formed from the reaction of RG with an
azido-functionalized
binding agent. By way of further example, in certain embodiments, RG' is
linked to the binding
(0
0 A )
0 N 0H
-rNH N-N
NfL
R'
agent as shown in R Or , or a mixture of each regioisomer.
Each R
and R' is as described or exemplified herein.
[00254] The SP2 spacer, when present, is a moiety that connects the (AA)11
moiety to the
payload. Suitable spacers include, but are not limited to, those described
above as Slil spacers.
Further suitable SP2 spacers include, but are not limited to, those comprising
alkylene or polyether,
or both. The ends of the SP2 spacers, for example, the portion of the spacer
directly bonded to the
payload or an AA, can be moieties derived from reactive moieties that are used
for purposes of
coupling the payload or AA to the SP2 spacer during the chemical synthesis of
the conjugate. In
some examples, the ends of the SP2 spacers, for example, the portion of the
SP2 spacer directly
bonded to the payload or an AA, can be residues of reactive moieties that are
used for purposes of
coupling the payload or an AA to the spacer during the chemical synthesis of
the conjugate.
[00255] In some embodiments, the SP2 spacer, when present, is selected from
the group
consisting of ¨NH-(p-C6H4)-CH2¨, ¨NH-(p-C6H4)-CH20C(0)¨, an amino acid, a
dipeptide, a
P
1-NH od
tripeptide, an oligopeptide, ¨0¨, ¨N(H)--,
HO pH
HO pH o pH P
H2N 0 HOI,.
P 1-01*0 HOI.. 0 H01.= 0
P HO P
I- 0 Ft1-1 1-0
, HO
177
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
risni
N ....V:r, joi.....
1-0 0 0
P 1-4
0 I¨NH HNH
P 'cll.. P rIP
I_N/-\N_IP 1-04-0-I P N
H-1 NH2 NH ,s,,,NH
g \__/ ' H6
and any
, , N
combinations thereof In certain embodiments, each -F is a bond to the payload,
and each -1- is
a bond to (AA)n .
[00256] In the above formulae, each (AA)11 is an amino acid or, optionally, a
00H 0
HO,, A0
0 css'
HOIO
OH
H N 0
?
N H
p-aminobenzyloxycarbonyl residue (PABC), V ,
Or
OH
0
HO,,
0 csJ
.9-1=1.
HO _ 0
OH
HN 0
?
NH
V .
If PABC is present, in certain embodiments, then only one
PABC is present. In certain embodiments, the PABC residue, if present, is
bonded to a terminal
0 csss
OH
H N 0
?
NH
AA in the (AA)11 group, proximal to the payload. If V Or
178
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
OH 0 OH
0 0
HOILO HO - 0
OH OH HN 0 HN 0
? ?
NH NH
V is present, then only V Or
OH
0
HO,,,A
0 0).,ssc
H0491..*0
1:5H
HN 0
?
NH
V is present.
In certain embodiments, the
00H OH
0 0
0 0),sss 0 0).1
(5H OH HN 0 HN 0
? ?
NH NH
V Or V residue, if
present, is
bonded to the payload via the benzyloxycarbonyl moiety, and no AA is present.
Suitable amino
acids for each AA include natural, non-natural, standard, non-standard,
proteinogenic, non-
proteinogenic, and L- or D- a-amino acids. In some embodiments, the AA
comprises alanine,
valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline,
serine, threonine,
cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid,
lysine, arginine, histidine,
or citrulline, a derivative thereof, or any combinations thereof (e.g.,
dipeptides, tripeptides, and
oligopeptides, and the like). In certain embodiments, one or more side chains
of the amino acids
is linked to a side chain group, described below. In some embodiments, n is
two. In some
embodiments, the (AA)11 is valine-citrulline. In some embodiments, (AA)11 is
citrulline-valine. In
some embodiments, (AA)11 is valine-alanine. In some embodiments, (AA)11 is
alanine-valine. In
some embodiments, (AA)11 is valine-glycine. In some embodiments, (AA)11 is
glycine-valine. In
179
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
some embodiments, n is three. In some embodiments, the (AA)11 is valine-
citrulline-PABC. In
some embodiments, (AA)11 is citrulline-valine-PABC. In some embodiments,
(AA)11 is glutamate-
valine-citrulline. In some embodiments, (AA)11 is glutamine-valine-citrulline.
In some
embodiments, (AA)11 is lysine-valine-alanine. In some embodiments, (AA), is
lysine-valine-
citrulline. In some embodiments, n is four. In some embodiments, (AA)11 is
glutamate-valine-
citrulline-PABC. In some embodiments, (AA)11 is glutamine-valine-citrulline-
PABC. Those of
skill will recognize PABC as a residue ofp-aminobenzyloxycarbonyl with the
following structure:
N
yµ
0
=
The PABC residue has been shown to facilitate cleavage of certain linkers in
vitro and in vivo.
Those of skill will recognize PAB as a divalent residue of p-aminobenzyl or
¨NH-(p-C6H4)-CH2¨.
[00257] In some embodiments, the linker is:
0
A
)/f
LO:$
0 0
1-1111 ,LAA
R9
H2
Or
180
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
N )C/I II 0
re 1
)%1
-...1,õ. 1
A (:)1
0.,..,... 0
0
HN )Lii 11 -Ltk)µ
12 9
IH2 .
,
A,,,,,
\
N
H I
0 0 0
1 I )
0 0 0
H
H
0 R9
Or
,N
N ' 1 0
'N
A'111- H I
0 0 0
1 I )
0 0 0
H
N)cr YLA;\
H
0 R9 ;or
181
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
A.,,,,,v
\
N
N, 1 0
IV N).LN
0 H OI x0)H00
0 0 0 0
H
NJL
H
0 R9
N Or
N
'' 1 0
'INJ
, J NLN
0 0 OHO 0
0 0 0 0
H
N-1 , A
H
0 R9
wherein:
each -r- is a bond to the binding agent;
each 1- is a bond to the payload;
each R9 is -CH3 or -(CH2)3N(H)C(0)NH2; and
0
¨NH 1K
= 0¨
,
each A is ¨0¨, ¨N(H)--, , Or
Dlb
p o 'µDl-i¨a" 1
0-4K¨N
¨NH = N sR3
1
R4 ZZ
, where ZZ is hydrogen, alkylene, heteroalkylene, or a side
chain for an amino acid as discussed elsewhere herein. As discussed above, the
bond to the binding
agent can be direct, or via a spacer. In certain embodiments, the bond to the
binding agent is via a
PEG spacer to a glutamine residue of the binding agent.
182
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00258] In some embodiments, the linker is:
Wriljc -A
0 0
HN,Aii 1;1 j-LAA,
R9
NH2
0
A/ N
\
0 0
fN.:==N 0 0 0 H 0
)(1=1 YLA21/4.
0 R9 =
Or
0
A 0 N
0 0 HO 0
rij-(1Y I
N z=N 0 0 0
H
.)(1=1-1N
0 R9 wherein:
each r is a bond to the binding agent;
each is a bond to the payload;
each R9 is ¨CH3 or ¨(CH2)3N(H)C(0)NH2; and
183
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
0-1K
¨NH =
each A is ¨0¨, ¨N(H)--, Or
o1b
Rla
p o
H 0-
N
¨N
R4 ZZ
, where ZZ is hydrogen, alkylene, heteroalkylene, or a side
chain for an amino acid as discussed elsewhere herein. As discussed above, the
bond to the binding
agent can be direct, or via a spacer. In certain embodiments, the bond to the
binding agent is via a
PEG spacer to a glutamine residue of the binding agent.
[00259] In any of the above embodiments, the (AA)11 group can be modified with
one or more
enhancement groups. Advantageously, the enhancement group can be linked to the
side chain of
any amino acid in (AA)n. Useful amino acids for linking enhancement groups
include lysine,
asparagine, aspartate, glutamine, glutamate, and citrulline. The link to the
enhancement group can
be a direct bond to the amino acid side chain, or the link can be indirect via
a spacer and/or reactive
group. Useful spacers and reactive groups include any described above. The
enhancement group
can be any group deemed useful by those of skill in the art. For example, the
enhancement group
can be any group that imparts a beneficial effect to the compound, prodrug,
payload, linker-
payload, or antibody conjugate including, but not limited to, biological,
biochemical, synthetic,
solubilizing, imaging, detecting, and reactivity effects, and the like. In
certain embodiments, the
enhancement group is a hydrophilic group. In certain embodiments, the
enhancement group is a
cyclodextrin. In certain embodiments, the enhancement group is an alkyl,
heteroalkyl, alkylenyl,
heteroalkylenyl sulfonic acid, heteroalkylenyl taurine, heteroalkylenyl
phosphoric acid or
phosphate, heteroalkylenyl amine (e.g., quaternary amine), or heteroalkylenyl
sugar. In certain
embodiments, sugars include, without limitation, monosaccharides,
disaccharides, and
polysaccharides. Exemplary monosaccharides include glucose, ribose,
deoxyribose, xylose,
arabinose, mannose, galactose, fructose. and the like. In certain embodiments,
sugars include sugar
acids such as glucuronic acid, further including conjugated forms such as
glucuronides (i.e., via
glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose,
lactulose, trehalose,
and the like. Exemplary polysaccharides include amylose, amylopectin,
glycogen, inulin,
cellulose, and the like. The cyclodextrin can be any cyclodextrin known to
those of skill. In certain
184
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
embodiments, the cyclodextrin is alpha cyclodextrin, beta cyclodextrin, or
gamma cyclodextrin,
or mixtures thereof In certain embodiments, the cyclodextrin is alpha
cyclodextrin. In certain
embodiments, the cyclodextrin is beta cyclodextrin. In certain embodiments,
the cyclodextrin is
gamma cyclodextrin. In certain embodiments, the enhancement group is capable
of improving
solublity of the remainder of the conjugate. In certain embodiments, the
alkyl, heteroalkyl,
alkylenyl, or heteroalkylenyl sulfonic acid is substituted or non-substituted.
In certain
embodiments, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic
acid is -(CH2)1-5S03H,
-(CH2)n-NH-(CH2)1-5S03H, -
(CH2)n-C(0)NH-(CH2)1-5S03H,
-(CH2CH20)m-C(0)NH-(CH2)1-5S03H, -
(CH2)11-M(CH2)1_5C(0)NH(CH2)1_5S03H)2,
-(CH2)11-C(0)1\1((CH2)1_5C(0)NH(CH2)1_5S03I-112, Or
-(CH2CH20)m-C(0)N((CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5,
and m is 1,
2, 3, 4, or 5. In one embodiment, the alkyl or alkylenyl sulfonic acid is -
(CH2)1_5S03H. In another
embodiment, the heteroalkyl or heteroalkylenyl sulfonic acid is -(CH2)11-NH-
(CH2)1_5S03H,
wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl,
alkylenyl, or
heteroalkylenyl sulfonic acid is -(CH2)11-C(0)NH-(CH2)1_5S03H, wherein n is 1,
2, 3, 4, or 5. In
another embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl
sulfonic acid is
-(CH2CH20)m-C(0)NH-(CH2)1_5S03H, wherein m is 1, 2, 3, 4, or 5. In another
embodiment, the
alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl
sulfonic acid is
-(CH2)11-N((CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5. In
another embodiment,
the alkyl, heteroalkyl, alkylenyl, or
heteroalkylenyl sulfonic acid is
-(CH2)11-C(0)N((CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5. In
another
embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic
acid is
-(CH2CH20)m-C(0)N((CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein m is 1, 2, 3, 4, or 5.
In some
embodiments, the linker is:
A
SP3
wherein:
Sr- is a spacer;
SP2 is a spacer;
185
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
SP3 is a spacer, linked to one AA of (AA)n;
-it is one or more bonds to the binding agent;
sP
1- is one or more bonds to the payload;
+ is one or more bonds to the enhancement group EG;
each AA is an amino acid; and
n is an integer from 1 to 10.
As discussed above, the bond to the binding agent can be direct, or via a
spacer. In certain
embodiments, the bond to the binding agent is via a PEG spacer to a glutamine
residue of the
binding agent.
[00260] The SP' spacer group is as described above. The SP2 spacer group is as
described
above. Each (AA)11 group is as described above.
[00261] The SP3 spacer is a moiety that connects the (AA)11 moiety to the
enhancement group
(EG). Suitable SP3 spacers include, but are not limited to, those comprising
alkylene or polyether,
or both. The ends of the SP3 spacers, i.e., the portion of the SP3 spacer
directly bonded to the
enhancement group or an AA, can be moieties derived from reactive moieties
that are used for
purposes of coupling the enhancement group or an AA to the SP3 spacer during
the chemical
synthesis of the conjugate. In some examples, the ends of the SP3 spacers,
i.e., the portion of the
spacer directly bonded to the enhancement group or an AA, can be residues of
reactive moieties
that are used for purposes of coupling the enhancement group or an AA to the
spacer during the
chemical synthesis of the conjugate. In certain embodiments, SP3 is a spacer,
linked to one and
only one AA of (AA)n. In certain embodiments, the SP3 spacer is linked to the
side chain of a
lysine residue of (AA)n.
[00262] In some embodiments, the SP3 spacer is:
0 0
-1-RG'¨N¨(CH2)aki- -1-RG1¨N¨(CH2)2¨(OCH2CH2)a¨LLI-
, Or
wherein:
186
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
RG' is a reactive group residue following reaction of a reactive group RG with
an
enhancement agent EG;
5E
1¨ is a bond to the enhancement agent;
is a bond to (AA)n;
a is an integer from 2 to 8; and
n is an integer from 1 to 4.
[00263] The reactive group RG can be any reactive group known to those of
skill in the art to be
capable of forming one or more bonds to the enhancement agent. The reactive
group RG is a
moiety comprising a portion in its structure that is capable of reacting with
the enhancement group
to form a compound of Formulae II or III. Following conjugation to the
enhancement group, the
reactive group becomes the reactive group residue (RG'). The reactive group RG
can be any
reactive group described above. Illustrative reactive groups include, but are
not limited to, those
that comprise haloacetyl, isothiocyanate, succinimide, N-hydroxysuccinimide,
or maleimide
portions that are capable of reacting with the binding agent.
[00264] In certain embodiments, reactive groups include, but are not limited
to, alkynes. In certain
embodiments, the alkynes are alkynes capable of undergoing 1,3-cycloaddition
reactions with
azides in the absence of copper catalysts such as strained alkynes. Strained
alkynes are suitable for
strain-promoted alkyne-azide cycloadditions (SPAAC), cycloalkynes, e.g.,
cyclooctynes, ane
benzannulated alkynes. Suitable alkynes include, but are not limited to,
dibenzoazacyclooctyne
0
Or 0 (DIBAC), dibenzocyclooctyne or
(DIBO),
0
biarylazacyclooctynone or
(BARAC), difluorinated cyclooctyne or
187
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
¨ F 0
viccg-F ¨ F ¨ F
F
0 , Or , or
(DIFO), substituted, e.g.,
0-1
fluorinated alkynes, aza-cycloalkynes, bicycle[6.1.0]nonyne or
(BCN), and
= 0
Lo
= I
=
derivatives thereof Particularly useful alkynes include ¨ ,
and
[00265] In some embodiments, the linker is:
A
RG'-PEG-(AA),SP2+
1133
wherein:
RG' is a reactive group residue following reaction of a reactive group RG with
a
binding agent;
PEG is ¨NH¨PEG4¨C(0)¨;
SP2 is a spacer;
SP' is a spacer, linked to one AA residue of (AA)n;
- is one or more bonds to the binding agent;
5P
1- is one or more bonds to the payload;
- is one or more bonds to the enhancement group EG;
each AA is an amino acid residue; and
188
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
n is an integer from 1 to 10.
As discussed above, the bond to the binding agent can be direct, or via a
spacer. In certain
embodiments, the bond to the binding agent is via a PEG spacer to a glutamine
residue of the
binding agent.
[00266] In certain embodiments, the linker is:
0
Ai:
)11:1 0
Isi 1 0
i4
0--zo
0
0 0
HN)-L kij-L A
r_ i , A
R9
I-1Neo
L0j;_R
,
or a pharmaceutically acceptable salt, solvate, or stereoisomeric form
thereof, or a regioisomer
thereof, or a mixture of regioisomers thereof, wherein:
_
each r- is a bond to the binding agent;
each -I- is a bond to the payload;
sE
each 1- is a bond to the enhancement agent;
each R9 is -CH3 or -(CH2)3N(H)C(0)NH2; and
189
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
¨NEI =
each A is ¨0¨, ¨N(H)--, Or
co lb
R1 a FN
b0 0
H 0-4 ¨N
KN_\,R3
¨N
Ra ZZ
, where ZZ is hydrogen, alkylene, heteroalkylene, or a side
chain for an amino acid as discussed elsewhere herein. In certain embodiments,
1,3-cycloaddition
or SPAAC regioisomers, or mixture of regioisomers, are derived from PEG-N3
derivitized
antibodies treated with suitable alkynes. For example, in one embodiment, the
linker is:
0
re I
A
C)
0 0
H ii;LA A
N . A
R9
E
or a pharmaceutically
acceptable salt, solvate, or stereoisomeric form thereof, or a regioisomer
thereof, or a mixture of
regioisomers thereof By way of further example, in one embodiment, the linker
is:
190
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
A j4,ri 41. 0
N
0
LOP
0 0
Hr!i ,A 11 ,LA),õ.
o R9
H N
LO _________________________________________________
E N ,N
Nõ
or a pharmaceutically
acceptable salt, solvate, or stereoisomeric form thereof, or a regioisomer
thereof, or a mixture of
regioisomers thereof By way of further example, the linker is:
A
)c/114
i4(\
I071
0 0
Hgl.õ}L
AA.
R9
LONOR
141'
Or a
pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or
a regioisomer thereof,
or a mixture of regioisomers thereof By way of further example, in one
embodiment, the linker
191
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
= 0
)1(1;10
re 0
A'14' LO:$
0 0
MLA ))-L A
N . A
R9
LOc_R
141'
is: E Or a
pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or
a regioisomer thereof,
or a mixture of regioisomers thereof. As discussed above, the bond to the
binding agent can be
direct, or via a spacer. In certain embodiments, the bond to the binding agent
is via a PEG spacer
to a glutamine residue of the binding agent. In certain embodiments, the
enhancement agent is a
hydrophilic group. In certain embodiments, the enhancement agent is
cyclodextrin. In certain
embodiments, the enhancement group is an alkyl, heteroalkyl, alkylenyl,
heteroalkylenyl sulfonic
acid, heteroalkylenyl taurine, heteroalkylenyl phosphoric acid or phosphate,
heteroalkylenyl amine
(e.g., quaternary amine), or heteroalkylenyl sugar. In certain embodiments,
sugars include, without
limitation, monosaccharides, disaccharides, and polysaccharides. Exemplary
monosaccharides
include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose,
fructose. and the like.
In certain embodiments, sugars include sugar acids such as glucuronic acid,
further including
conjugated forms such as glucuronides (i.e., via glucuronidation). Exemplary
disaccharides
include maltose, sucrose, lactose, lactulose, trehalose, and the like.
Exemplary polysaccharides
include amylose, amylopectin, glycogen, inulin, cellulose, and the like. The
cyclodextrin can be
any cyclodextrin known to those of skill. In certain embodiments, the
cyclodextrin is alpha
cyclodextrin, beta cyclodextrin, or gamma cyclodextrin, or mixtures thereof In
certain
embodiments, the cyclodextrin is alpha cyclodextrin. In certain embodiments,
the cyclodextrin is
beta cyclodextrin. In certain embodiments, the cyclodextrin is gamma
cyclodextrin. In certain
192
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
embodiments, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic
acid is
-(CH2)1_5S03H, -(CH2)11-NH-(CH2)1_5S03H, -
(CH2)11-C(0)NH-(CH2)1-5 S 03H,
-(CH2CH2 0)m-C( 0)NH- (CH2)1-5 S 03H, -
(CH2)n-M(CH2)1_5C(0)NH(CH2)1_5S03H)2,
-(CH2)11-C(0)1\1((CH2)1_5C(0)NH(CH2)1_5S03I-112, Or
-(CH2CH20)m-C(0)1\4(CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or
5, and m is 1,
2, 3, 4, or 5. In one embodiment, the alkyl or alkylenyl sulfonic acid is -
(CH2)1_5S03H. In another
embodiment, the heteroalkyl or heteroalkylenyl sulfonic
acid is
-(CH2),-NH-(CH2)1_5S03H, wherein n is 1, 2, 3, 4, or 5. In another embodiment,
the alkyl,
heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2),-C(0)1\11-1-
(CH2)1_5S03H,
wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl,
alkylenyl, or
heteroalkylenyl sulfonic acid is -(CH2CH20)m-C(0)NH-(CH2)1_5S03H, wherein m is
1, 2, 3, 4,
or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or
heteroalkylenyl sulfonic acid is
-(CH2)11-1\4(CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5. In
another embodiment,
the alkyl, heteroalkyl, alkylenyl, or
heteroalkylenyl sulfonic acid is
-(CH2)11-C(0)1\4(CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5.
In another
embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic
acid is
-(CH2CH20)m-C(0)1\4(CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein m is 1, 2, 3, 4, or
5.
[00267] In some embodiments, the linker is:
193
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
A,,,,\.,,,,
N
o 11 ,0
N _______
0 0
0--2,
0
0 0
H N .....).L /4 AA
R9
HN 0
Q.
0
E
or a pharmaceutically acceptable salt, solvate, or stereoisomeric form
thereof, or a regioisomer
thereof, or mixture of regioisomers thereof, wherein:
_
each r- is a bond to the binding agent;
s E
each 1- is a bond to the enhancement agent;
each -I- is a bond to the payload;
each R9 is -CH3 or -(CH2)3N(H)C(0)NH2; and
0
H = 0-1(
¨N ,
each A is ¨0¨, ¨N(H)--, , Or
Rla R1b
p
¨N o
H = 0¨l<N\¨Ns izz3
I
R4 ZZ
, where ZZ is hydrogen, alkylene, heteroalkylene, or a side
chain for an amino acid as discussed elsewhere herein. As discussed above, the
bond to the binding
agent can be direct, or via a spacer. In certain embodiments, the bond to the
binding agent is via a
194
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
PEG spacer to a glutamine residue of the binding agent. In certain
embodiments, the enhancement
agent is a hydrophilic group. In certain embodiments, the enhancement agent is
cyclodextrin. In
certain embodiments, the enhancement group is an alkyl, heteroalkyl,
alkylenyl, heteroalkylenyl
sulfonic acid, heteroalkylenyl taurine, heteroalkylenyl phosphoric acid or
phosphate,
heteroalkylenyl amine (e.g., quaternary amine), or heteroalkylenyl sugar. In
certain embodiments,
sugars include, without limitation, monosaccharides, disaccharides, and
polysaccharides.
Exemplary monosaccharides include glucose, ribose, deoxyribose, xylose,
arabinose, mannose,
galactose, fructose. and the like. In certain embodiments, sugars include
sugar acids such as
glucuronic acid, further including conjugated forms such as glucuronides
(i.e., via
glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose,
lactulose, trehalose,
and the like. Exemplary polysaccharides include amylose, amylopectin,
glycogen, inulin,
cellulose, and the like. The cyclodextrin can be any cyclodextrin known to
those of skill. In certain
embodiments, the cyclodextrin is alpha cyclodextrin, beta cyclodextrin, or
gamma cyclodextrin,
or mixtures thereof In certain embodiments, the cyclodextrin is alpha
cyclodextrin. In certain
embodiments, the cyclodextrin is beta cyclodextrin. In certain embodiments,
the cyclodextrin is
gamma cyclodextrin. In certain embodiments, the alkyl, heteroalkyl, alkylenyl,
or heteroalkylenyl
sulfonic acid is
-(CH2)1_5S03H, -(CH2)11-NH-(CH2)1_5S03H, -
(CH2)11-C(0)NH-(CH2)1-5 S 03H,
-(CH2CH2 0)m-C( 0)NH- (CH2)1-5 S 03H, -
(CH2)11-M(CH2)1_5C(0)NH(CH2)1_5S03H)2,
-(CH2)11-C(0)1\1((CH2)1_5C(0)1\TH(CH2)1_5S03H)2, Or
-(CH2CH20)m-C(0)N((CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5,
and m is 1,
2, 3, 4, or 5. In one embodiment, the alkyl or alkylenyl sulfonic acid is -
(CH2)1_5S03H. In another
embodiment, the heteroalkyl Or heteroalkylenyl sulfonic
acid is
-(CH2)11-NH-(CH2)1_5S03H, wherein n is 1, 2, 3, 4, or 5. In another
embodiment, the alkyl,
heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2)n-C(0)NH-
(CH2)1_5S03H,
wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl,
alkylenyl, or
heteroalkylenyl sulfonic acid is -(CH2CH20)m-C(0)NH-(CH2)1_5S03H, wherein m is
1, 2, 3, 4,
or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or
heteroalkylenyl sulfonic acid is
-(CH2)11-N((CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5. In
another embodiment,
the alkyl, heteroalkyl, alkylenyl, or
heteroalkylenyl .. sulfonic .. acid .. is
-(CH2)11-C(0)N((CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5. In
another
195
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic
acid is
¨(CH2CH20)m¨C(0)Nt(CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein m is 1, 2, 3, 4, or 5.
[00268] In some embodiments, the linker is:
196
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
Ai:)1N____=)õ,11....,....õ,---..,0,---.2
Isc 1
N
I0:1
0
H N )-L kUL A
N , A
R9
H
HO N
cie) NCC1---
OH 10. ,
HO?H Ikr
0
oH
Hoz_ HO
O43OH
0
H
,
197
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
r0-
0, N H (:)
/ LO H jOci 11 ok -'-
Ti ,.,.,_
N Or N
N '
1 H = 9
A AN N 0 0 R
N=N
r
0,NH
o Nõ N
__/- N'
r-NH
HO3S-j CO
j--NH
HO3S
,
f0...,.--..,0
0
H
H
HN 0 0 H
0 R9
\
0N SO3H
N0 H
A
N=N ,
,,,)o
N Nci,, N
-eµ111-
L _
0 L H 0 R9
0
H \
HN 0 HNIroQ
/Th
N
0 NI . ,N----7- 0--\
'
o)
N0
H /2 \
N
A ,N X
HO3S
N=N ,
198
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
or a pharmaceutically acceptable salt, solvate, or stereoisomeric form
thereof, or a regioisomer
thereof, or mixture of regioisomers thereof, wherein:
each -r- is a bond to the binding agent;
each -1- is a bond to the payload;
R9 is -CH3 or -(CH2)3N(H)C(0)NH2; and
_la Rib
0 1
0 11 0-4\-N
-N
H = 0-/K -NH N R3
.1=Ijj I
ZZ
A is -0-, -N(H)--, , Or R4
, where ZZ is hydrogen, alkylene, heteroalkylene, or a side chain for an amino
acid as discussed
elsewhere herein. As discussed above, the bond to the binding agent can be
direct, or via a spacer.
In certain embodiments, the bond to the binding agent is via a PEG spacer to a
glutamine residue
of the binding agent.
[00269] In some embodiments, the linker is:
199
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
A,,co
N 14
Nõ j0j¨A1/
N
le ;:$
0
0 0
litHi 14j-L A
_ A
Ii9
HO HNe0
cl(C)OH L Q
HO 0 N N'N,,
HO -r
0
OH
Ho 1.0 3
H0/1
Otill OH
0
H
200
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
A
/
NI, N
' CI r0-
NH C)
_____________________ 0 LO
H j V
Or N
N fik)11-
0
r
0 NH
c--)e
o
N Nõ N
r- NH
-1 CO
HO3S
r NH
HO3S---j
, ,
(0,......,..--,0
A
H
I
H
NN
N - iok
N / HN yO H
0 Ii9
0
ON /S03H
H ,
r0- (0 H 0
L
a A
A H
0 0 I:Z
O
i
,N
N 0
111 y N ' HN ).reci)
0 0 N
N . ,N----/.. 0 ----\
'
0)
7-----/
HO3S
,
201
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
or a pharmaceutically acceptable salt, solvate, or stereoisomeric form
thereof, or a regioisomer
thereof, or mixture of regioisomers thereof, wherein:
_
each r- is a bond to the binding agent;
each -1- is a bond to the payload;
R9 is -CH3 or -(CH2)3N(H)C(0)NH2; and
R1
¨N lb
04 VNR .. 1
0
H =_H .
N N4 R3
I .1=Prj ZZ
A is -0-, -N(H)--, , Or R4
, where ZZ is hydrogen, alkylene, heteroalkylene, or a side chain for an amino
acid as discussed
elsewhere herein. As discussed above, the bond to the binding agent can be
direct, or via a spacer.
In certain embodiments, the bond to the binding agent is via a PEG spacer to a
glutamine residue
of the binding agent.
[00270] In some embodiments, the linker is:
0
A.,<
N N )./111 0
N
OTh
0
E x14,LD Hla 1-4 AA
R9
0
1..?HN 0
N.G.
Io\Ae\A/
or a pharmaceutically acceptable salt, solvate, or stereoisomeric form
thereof, or a regioisomer
thereof, or mixture of regioisomers thereof, wherein:
_
each IA- is a bond to the binding agent;
202
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
each is a bond to the payload;
sE
each 1- is a bond to the enhancement group;
each R9 is -CH3 or -(CH2)3N(H)C(0)NH2; and
0
H = 0-1K
¨N
each A is -0-, -N(H)--, Or
la Rib
O¨'
0
H = 0¨l<Ns3
¨N N¨< izz
R4 ZZ
, where ZZ is hydrogen, alkylene, heteroalkylene, or a side
chain for an amino acid as discussed elsewhere herein. As discussed above, the
bond to the binding
agent can be direct, or via a spacer. In certain embodiments, the bond to the
binding agent is via a
PEG spacer to a glutamine residue of the binding agent. In certain
embodiments, the enhancement
agent is a hydrophilic group. In certain embodiments, the enhancement agent is
cyclodextrin. In
certain embodiments, the enhancement group is an alkyl, heteroalkyl,
alkylenyl, heteroalkylenyl
sulfonic acid, heteroalkylenyl taurine, heteroalkylenyl phosphoric acid or
phosphate,
heteroalkylenyl amine (e.g., quaternary amine), or heteroalkylenyl sugar. In
certain embodiments,
sugars include, without limitation, monosaccharides, disaccharides, and
polysaccharides.
Exemplary monosaccharides include glucose, ribose, deoxyribose, xylose,
arabinose, mannose,
galactose, fructose. and the like. In certain embodiments, sugars include
sugar acids such as
glucuronic acid, further including conjugated forms such as glucuronides
(i.e., via
glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose,
lactulose, trehalose,
and the like. Exemplary polysaccharides include amylose, amylopectin,
glycogen, inulin,
cellulose, and the like. The cyclodextrin can be any cyclodextrin known to
those of skill. In certain
embodiments, the cyclodextrin is alpha cyclodextrin, beta cyclodextrin, or
gamma cyclodextrin,
or mixtures thereof In certain embodiments, the cyclodextrin is alpha
cyclodextrin. In certain
embodiments, the cyclodextrin is beta cyclodextrin. In certain embodiments,
the cyclodextrin is
gamma cyclodextrin. In certain embodiments, the alkyl, heteroalkyl, alkylenyl,
or heteroalkylenyl
sulfonic acid is -(CH2)1_5S03H, -(CH2)11-NH-(CH2)1_5S03H, -(CH2)11-C(0)NI-1-
(CH2)1_5S03H,
-(CH2CH20)m-C(0)NI-1-(CH2)1_5S03H, -
(CH2)n-N((CH2)1_5C(0)NH(CH2)1_5S03H)2,
203
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
-(CH2)11-C(0)N((CH2)1_5C(0)NH(CH2)1_5S03H)2, Or
-(CH2CH20)m-C(0)1\4(CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or
5, and m is 1,
2, 3, 4, or 5. In one embodiment, the alkyl or alkylenyl sulfonic acid is -
(CH2)1_5S03H. In another
embodiment, the heteroalkyl or heteroalkylenyl
sulfonic acid is
-(CH2)11-NH-(CH2)1_5S03H, wherein n is 1, 2, 3, 4, or 5. In another
embodiment, the alkyl,
heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2)11-C(0)NH-
(CH2)1_5S03H,
wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl,
alkylenyl, or
heteroalkylenyl sulfonic acid is -(CH2CH20)m-C(0)NH-(CH2)1_5S03H, wherein m is
1, 2, 3, 4,
or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or
heteroalkylenyl sulfonic acid is
-(CH2)11-Nt(CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5. In
another embodiment,
the alkyl, heteroalkyl, alkylenyl, or
heteroalkylenyl sulfonic acid is
-(CH2)11-C(0)1\4(CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5.
In another
embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic
acid is
-(CH2CH20)m-C(0)1\4(CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein m is 1, 2, 3, 4, or
5.
[00271] In some embodiments, the linker is:
Aç
0
0 0
E N N A
R9
0
HN HN 0
or a pharmaceutically acceptable salt, solvate, or stereoisomeric form
thereof, or a regioisomer
thereof, or mixture of regioisomers thereof, wherein:
204
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
each IA- ¨ is a bond to the binding agent;
each - is a bond to the payload;
each R9 is ¨CH3 or ¨(CH2)3N(H)C(0)NH2; and
0
0-1(
11
each A is ¨0¨, ¨N(H)--, Or
la Rib
p
H O- -N
-N N
R4 ZZ
, where ZZ is hydrogen, alkylene, heteroalkylene, or a side
chain for an amino acid as discussed elsewhere herein. As discussed above, the
bond to the binding
agent can be direct, or via a spacer. In certain embodiments, the bond to the
binding agent is via a
PEG spacer to a glutamine residue of the binding agent. In certain
embodiments, the enhancement
agent is a hydrophilic group. In certain embodiments, the enhancement agent is
cyclodextrin. In
certain embodiments, the enhancement group is an alkyl, heteroalkyl,
alkylenyl, heteroalkylenyl
sulfonic acid, heteroalkylenyl taurine, heteroalkylenyl phosphoric acid or
phosphate,
heteroalkylenyl amine (e.g., quaternary amine), or heteroalkylenyl sugar. In
certain embodiments,
sugars include, without limitation, monosaccharides, disaccharides, and
polysaccharides.
Exemplary monosaccharides include glucose, ribose, deoxyribose, xylose,
arabinose, mannose,
galactose, fructose. and the like. In certain embodiments, sugars include
sugar acids such as
glucuronic acid, further including conjugated forms such as glucuronides
(i.e., via
glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose,
lactulose, trehalose,
and the like. Exemplary polysaccharides include amylose, amylopectin,
glycogen, inulin,
cellulose, and the like. The cyclodextrin can be any cyclodextrin known to
those of skill. In certain
embodiments, the cyclodextrin is alpha cyclodextrin, beta cyclodextrin, or
gamma cyclodextrin,
or mixtures thereof In certain embodiments, the cyclodextrin is alpha
cyclodextrin. In certain
embodiments, the cyclodextrin is beta cyclodextrin. In certain embodiments,
the cyclodextrin is
gamma cyclodextrin. In certain embodiments, the alkyl, heteroalkyl, alkylenyl,
or heteroalkylenyl
sulfonic acid is ¨(CH2)1_5S03H, ¨(CH2)11¨NH-(CH2)1_5S03H, ¨(CH2)11¨C(0)NI-1-
(CH2)1_5S03H,
¨(CH2CH20)m¨C(0)NI-1-(CH2)1_5S03H,
¨(CH2)n¨N((CH2)1_5C(0)NH(CH2)1_5S03H)2,
¨(CH2)11¨C(0)N((CH2)1_5C(0)NH(CH2)1_5S03H)2, Or
205
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
-(CH2CH20)m-C(0)1\4(CH2)1_5C(0)1\11-1(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4,
or 5, and m is 1,
2, 3, 4, or 5. In one embodiment, the alkyl or alkylenyl sulfonic acid is -
(CH2)1_5S03H. In another
embodiment, the heteroalkyl or heteroalkylenyl sulfonic
acid is
-(CH2)11-NH-(CH2)1_5S03H, wherein n is 1, 2, 3, 4, or 5. In another
embodiment, the alkyl,
heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid is -(CH2)11-C(0)NH-
(CH2)1_5S03H,
wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkyl, heteroalkyl,
alkylenyl, or
heteroalkylenyl sulfonic acid is -(CH2CH20)m-C(0)NH-(CH2)1_5S03H, wherein m is
1, 2, 3, 4,
or 5. In another embodiment, the alkyl, heteroalkyl, alkylenyl, or
heteroalkylenyl sulfonic acid is
-(CH2)11-N((CH2)1_5C(0)NH(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or 5. In
another embodiment,
the alkyl, heteroalkyl, alkylenyl, or
heteroalkylenyl sulfonic acid is
-(CH2)11-C(0)1\4(CH2)1_5C(0)1\11-1(CH2)1_5S03H)2, wherein n is 1, 2, 3, 4, or
5. In another
embodiment, the alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic
acid is
-(CH2CH20)m-C(0)1\4(CH2)1_5C(0)1\11-1(CH2)1_5S03H)2, wherein m is 1, 2, 3, 4,
or 5.
[00272] In some embodiments, the linker is:
206
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
A,õ\.,
11 0
N N)(
Ns, 1 C)
N
H043
C)
-N 0
HO 0
OH Ho 0 111:0 FULNA
11,AA A
-r N /
R-9
00EO
oH
E.: 1) iiiro
Hoz1 El 0
HO 1
0 1 OH OC)0C)
0
H
ro-
ONH C)
,,,
N 0.r N
N '1'
0 H 0 R9A s&N X
i=J'N
r
0,r0 ONH
)--\NI-- N- HN 0
r¨NH ? ()
HO3S¨/ CO
0c)
r NH
HO3S--/
, ,
207
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
ro-
H(.1L .rH sil?
N _ A
L 0 H z 0
0 IR'
0
HN 0
HN ? HNIrec)
0 0 0 0 Cof NkN,N 0---\
N0 )
1_...õ((i 0.õ ,
A N X
HO3S
or a pharmaceutically acceptable salt, solvate, or stereoisomeric form
thereof, or a regioisomer
thereof, or mixture of regioisomers thereof, wherein:
each -r- is a bond to the binding agent;
each 1- is a bond to the payload;
R9 is -CH3 or -(CH2)3N(H)C(0)NH2; and
la Rlb
R
¨
040 C1/4- _______________________________________________________________ 1
0 N
NH .
H .
"4
-N
N4 R3
I 77
A is -0-, -N(H)--, , Or R4
, where ZZ is hydrogen, alkylene, heteroalkylene, or a side chain for an amino
acid as discussed
elsewhere herein. As discussed above, the bond to the binding agent can be
direct, or via a spacer.
In certain embodiments, the bond to the binding agent is via a PEG spacer to a
glutamine residue
of the binding agent.
[00273] In some embodiments, the linker is:
208
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
A\,,.
N'Nj0j¨A1/11
N ___________________________________ C)
Lep) HO
Ho 0 Ccii(0
0
OH
o
0 0
1.,.._/J '4 ,..0 H1)-L
N
o
oH
HO
.. i.,,:) 3 Liir0
ii0/1_
OkS1=40/4) OH
0
H
,
,N
,-__0,, ro-
N / Oy NH 0
A 0 L 0
H jt H
0 r N
N N
- e
0 H 0 Ii9
0 c
0 r
0,r 0,NH i
N , N
0
----\ j--- sN '
HN
N
r-NH ()
HO3S-j CO 0o)
j-- NH
HO3S
,
209
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
A
-N
ro
N ONH (0
1
L
0
0
0
H?(
N
=O
r
NH HHN
r0
0 0 0 0
0of
so3H
or a pharmaceutically acceptable salt, solvate, or stereoisomeric form
thereof, or a regioisomer
thereof, or mixture of regioisomers thereof, wherein:
each is a bond to the binding agent;
each 1- is a bond to the payload;
R9 is -CH3 or -(CH2)3N(H)C(0)NH2; and
la Rib
040 0\x_R-1
0
41 = 0-1K
.rx-rj
¨N
4
N¨< R33
1 77
¨
A is -0-, -N(H)--, , Or R ,
where
ZZ is hydrogen, alkylene, heteroalkylene, or a side chain for an amino acid as
discussed elsewhere
herein. As discussed above, the bond to the binding agent can be direct, or
via a spacer. In certain
embodiments, the bond to the binding agent is via a PEG spacer to a glutamine
residue of the
binding agent.
Linker-Payloads
210
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00274] In certain embodiments, linker-payloads include any specific compound,
prodrug, or
payload embraced by any one or more of Formulae I, Ia, Iaa, Iaaa, Ib, Ibb, and
Ibbb above, bonded
to a linker, wherein the linker(s) described herein include a moiety that is
reactive with an antibody
or antigen binding fragment thereof described herein. In particular
embodiments, the linker is
bonded to a primary or secondary nitrogen in any one or more of Formulae I,
Ia, Iaa, Iaaa, Ib, Ibb,
Ibbb, or IV. In one embodiment of Formula II, when D* is a residue of a
biologically active
compound comprising hydroxyl, amino, or thiol, then the biologically active
compound or residue
thereof is an anti-inflammatory biologically active compound or residue
thereof In another
embodiment of Formula II, the anti-inflammatory biologically active compound
is a steroid or a
residue thereof In another embodiment of Formula II, the anti-inflammatory
biologically active
compound is an LXR agonist or a residue thereof. In one embodiment, the linker-
payload has a
structure of Formula IIa:
1 0 Rla Rib
L'.-NY(110¨D*
R2 R3
- - n
(lla)
or a pharmaceutically acceptable salt thereof, wherein L is a linker
comprising a moiety reactive
with an antibody or an antigen binding fragment thereof; RI-a and Rib are,
independently,
hydrogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or
alkylene, wherein when
RI-a is alkylene, the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
R2 is hydrogen or an amino acid side chain; R3 is hydrogen, alkyl, or
alkylene, wherein when R3
is alkylene, the alkylene is further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is acyl, or a residue of a biologically active compound comprising
hydroxyl; and n is zero, one,
two, three, four, five, or six. In another embodiment, the linker-payload has
a structure of Formula
IIaa:
1 0 Ria Rib
LN)(11¨D*
R2 R3 Rs
- - n
(IIaa)
211
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
or a pharmaceutically acceptable salt thereof, wherein L is a linker
comprising a moiety reactive
with an antibody or an antigen binding fragment thereof; R" and Rib are,
independently,
hydrogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
alkylene, or heteroalkylene,
wherein when Ria is alkylene or heteroalkylene, the alkylene or
hetereoalkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or
an amino acid side chain, wherein when R2 is alkylene or heteroalkylene, the
alkylene or
heteroalkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; R3 is
hydrogen, alkyl, alkylene, or heteroalkylene, wherein when R3 is alkylene or
heteroalkylene, the
alkylene or heteroalkylene is further bonded to Ria or R2 to form the 4-, 5-,
or 6-membered
heterocyclyl; R6 is hydrogen or alkyl; D* is acyl, or a residue of a
biologically active compound
comprising hydroxyl, amino, or thiol; and n is zero, one, two, three, four, or
five. In another
embodiment, the linker payload has a structure of Formula IIaaa:
1 0 Rla Rib
L'' N
R2 R3
- -n
(IIaaa)
or a pharmaceutically acceptable salt thereof, wherein L is a linker
comprising a moiety reactive
with an antibody or an antigen binding fragment thereof; R" and Rib are,
independently,
hydrogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
alkylene, or heteroalkylene,
wherein when R" is alkylene or heteroalkylene, the alkylene or hetereoalkylene
is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or
an amino acid side chain, wherein when R2 is alkylene or heteroalkylene, the
alkylene or
heteroalkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; R3 is
hydrogen, alkyl, alkylene, or heteroalkylene, wherein when R3 is alkylene or
heteroalkylene, the
alkylene or heteroalkylene is further bonded to Ria or R2 to form the 4-, 5-,
or 6-membered
heterocyclyl; D* is acyl, or a residue of a biologically active compound
comprising hydroxyl,
amino, or thiol; and n is zero, one, two, three, four, or five. In another
embodiment, the linker-
payload has a structure of Formula IIb:
212
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
0 Ria Rib
L
Nj-
,
R2 R3
- -n
(llb)
or a pharmaceutically acceptable salt thereof, wherein L is a linker
comprising a moiety reactive
with an antibody or an antigen binding fragment thereof; R" and Rib are,
independently,
hydrogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or
alkylene, wherein when
R" is alkylene, the alkylene is further bonded to R3 to form a 4-, 5-, or 6-
membered heterocyclyl;
R2 is hydrogen or an amino acid side chain; R3 is hydrogen, alkyl, or
alkylene, wherein when R3
is alkylene, the alkylene is further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
D* is acyl, or a residue of a biologically active compound comprising
hydroxyl; and n is zero, one,
two, three, four, five, or six. In another embodiment, the linker-payload has
a structure of Formula
IIbb:
H
0 Ria Rib
Nj=L )(
L N N¨D*
,
R2 R3 Rs
- -n
(IIbb)
or a pharmaceutically acceptable salt thereof, wherein L is a linker
comprising a moiety reactive
with an antibody or an antigen binding fragment thereof; R" and Rib are,
independently,
hydrogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
alkylene, or heteroalkylene,
wherein when R" is alkylene or heteroalkylene, the alkylene or hetereoalkylene
is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or
an amino acid side chain, wherein when R2 is alkylene or heteroalkylene, the
alkylene or
heteroalkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; R3 is
hydrogen, alkyl, alkylene, or heteroalkylene, wherein when R3 is alkylene or
heteroalkylene, the
alkylene or heteroalkylene is further bonded to Rla or R2 to form the 4-, 5-,
or 6-membered
heterocyclyl; R6 is hydrogen or alkyl; D* is acyl, or a residue of a
biologically active compound
comprising hydroxyl, amino, or thiol; and n is zero, one, two, three, four, or
five. In another
embodiment, the linker-payload has a structure of Formula IIbbb:
213
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0 Ria Rib
H
L N S¨D*
,
R2 R3
- -n
(IIbbb)
or a pharmaceutically acceptable salt thereof, wherein L is a linker
comprising a moiety reactive
with an antibody or an antigen binding fragment thereof; RI-a and Rib are,
independently,
hydrogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
alkylene, or heteroalkylene,
wherein when Rla is alkylene or heteroalkylene, the alkylene or
hetereoalkylene is further bonded
to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene,
heteroalkylene, or
an amino acid side chain, wherein when R2 is alkylene or heteroalkylene, the
alkylene or
heteroalkylene is further bonded to R3 to form a 4-, 5-, or 6-membered
heterocyclyl; R3 is
hydrogen, alkyl, alkylene, or heteroalkylene, wherein when R3 is alkylene or
heteroalkylene, the
alkylene or heteroalkylene is further bonded to Rla or R2 to form the 4-, 5-,
or 6-membered
heterocyclyl; D* is acyl, or a residue of a biologically active compound
comprising hydroxyl,
amino, or thiol; and n is zero, one, two, three, four, or five. In any of the
foregoing Ha, IIaa, IIaaa,
H
N
V 1.1
IIb, IIbb, and IIbbb embodiments, the linker further comprises 0 . In
one
embodiment, the linker-payload has a structure of Formula IV:
0 ¨Cla .-+113
A )
SP1¨(AA)p¨SP2 N O¨D*
R2 R3
- -n
IV
or a pharmaceutically acceptable salt thereof, wherein Rla, Rib, R2, R3, I,
¨*,
and n are as described
in any of the embodiments disclosed herein, and wherein SP1 and SP2, when
present, are spacer
groups wherein SP1 further comprises a moiety reactive with an antibody or an
antigen binding
fragment thereof; each AA is an amino acid; and p is an integer from 1 to 10.
In one embodiment,
the linker-payload has a structure of Formula IVa:
214
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
SP1¨(AA)p¨N
O.-1a Rib
0 R2 R3
- n or a pharmaceutically acceptable
salt
thereof, wherein Ria, Rib, R2, R3, ty ¨*,
and n are as described in any of the embodiments disclosed
herein, and wherein SP1, when present, is a spacer group wherein SP1 further
comprises a moiety
reactive with an antibody or an antigen binding fragment thereof; each AA is
an amino acid; and
p is an integer from 1 to 10. In certain embodiments of Formula IV or Formula
IVa, Rla and Rib
are hydrogen; R2 is hydrogen or methyl; R3 is hydrogen; and n is two. In
another embodiment of
Formula IV or Formula IVa, D* is hydrogen. In another embodiment of Formula IV
or Formula
IVa, D* is a residue of a biologically active compound comprising hydroxyl. In
another
embodiment of Formula IV or Formula IVa, the linker payload is selected from
the group
consisting of
\-o
.'" 0 0 H I. 0AH-Y N
N6, N 0 0
HO
0
NH
Cd.'NH2
0
0 0
0 0
H N OH
N 0 =
H II
0 0
NH
Cd'NH2
; and
215
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
AO m,AN-0
0 ,H
N 0 0
F:
0 0
HO
0
NH
(:).*.NH2
; or a pharmaceutically acceptable salt thereof. In certain embodiments within
this paragraph, all
diastereomers are contemplated. For example, in one embodiment, the
stereochemistry at the acetal
is undefined or racemic. By way of further example, in one embodiment, the
stereochemistry at
the acetal is (R)-. By way of further example, in one embodiment, the
stereochemistry at the acetal
is (S)-. By way of further example, in one embodiment, the stereochemistry at
the acetal is (R)- in
excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)- in excess of (R)-. In any of the embodiments in this paragraph, p is 1,
2, 3, 4, 5, 6, 7, 8, 9, or
10. In any of the embodiments in this paragraph, n is 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, or
15.
[00275] In certain embodiments of Formula IV or Formula IVa, 12" and Rib are
hydrogen; R2
is hydrogen, methyl, or ¨CH2Ph; R3 is hydrogen or alkyl; and n is one. In
another embodiment of
Formula IV or Formula IVa, D* is hydrogen. In another embodiment of Formula IV
or Formula
IVa, D* is a residue of a biologically active compound comprising hydroxyl. In
another
embodiment of Formula IV or Formula IVa, the linker-payload is
selected from the group consisting of
0.y. NH2
;NH
H H
0 0 0
N)r N [qir N
õ 0
0 0 000 jL,Isi
fl N 0
OH
0
=
216
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H H 0
U0 . OH
0
I 0
1 I 0
0 H 0 0 0)1-iir NH
0 H H 0 H
...1
NI NH2
H
,
F
H H 0
., -.
-..
...-^.........--1.- F
0 OH
I 0
o 0-NH
I 1 0 0
H 0 0 0-it-r,"
N ,y---,,,A.N...-..õØ,.......--.,0...".........Ø.õ----Ø.----,,.....-
k.N."..y...N,,, N
H HI H
0L. 0
0
N A N H2
I-I
,
H
.,.H
0
---- \ .¨
0 0 0
H 0 0 N H lir NO
0
OH
NI.r,...,..k..N..--.......õ.Ø..,.......--,,0..---,õ...õØ....õ,..----Ø..--
....}.. N , .....-11..
0
H H 0 H
0
..1 0
NA N H2
H
;
H
0
1 0
I 1 0 0 0 N lir
H 0 0 H ...... 0 OH
NIr..........1.,N..--........,.Ø..,....."..Ø--,,......O...,..,--",.Ø.--
\_,...K.N N,õõ...-11...N 0
H H , H
0
''' 0
L.
N A N H2
H
,
217
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0 --o
H
0 dish,
0
H
111/
ii o 0 H 0 0 0N
H N 0
-.....--
0 CH
N.,r.,........k, N ...--..õØ.......õ..^...0,--..õ.Ø......õ.--..,0...--
...,õ)..,N isi ,, ....--11. N 0
H H H HO
Al
0 0
IIIP'
..'Isl AN H2
H 0
,
E
H H 0
0 . =
-F
--'-N----0
õ.õ.0 OH
I 0
0..,_,NH
0 '---
.11.
0 H jOcril .:1L 101 0 11
N N,
= H H
0 0 .....; 0
..**µ::=: 0
......,,,
HO 0 ''N AN H2
H
=
,
H
....õ,-
NH'r() kLA Nrilj MIN 0
- N HO's'
0H H
0 0 t
=====NNN
el µ110
HOF' .
0.
______________________________________________________________ H H u
0 0
0, 14 o o Ilj rkl, 0 Inil OH
_____ cy.-^,..ir ......õ..".Ø."..._, ...........-
.ب.,.... ....,........i i N ,. N
0 0 r 0 0
HO---..0 NAN H2
=
,
H
H H
0 0
0
0
OH
0 0 =
,
218
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
H H
\ (0 z
O 0 0
0 OJLN Thr IA ,A 11 kl ,o _
H 0
0
OH
O 0
,
H
H H
\ <0 z
O 0 0
to
H 0
N 11 i N 11 o
OH
O - 0
,
H
H H
\ (0 z
0 0
0 OjNjIrlyLNILO _ 0
H
0
OH
O 0
;
H
0 H H
4110 0
--- 0-114)LNThill o \ <
N IT o
o _
H
OH 0
O 0 0 =
,
H
H H
0 0 0 0
H 0
-,....--
Nri;LANI"NThrN 0
0 _
H
OH
0 0 0
0 .
,
H
H H
OH \ <0 ziTh
O 0 0
03L H
H
H N 11 Nf o
OH
O 0 0
;
219
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
NH2
) H
zH H
\ <0
0 0 0 0
H 0
irk- 0J-Nrkl,)-LNikl,ANIN 0
glir 0 0 0 0 A
OH
;
H
z1-1 H
¨\ <0
0 0 0
H 0
0 0j.LNoo()(y.).L11rN 0 :-.
H
0
OH
0
,
H
H H
\ <0
0 0 0
N).ii-N-1 00c)0 N :
H
0
0 0 I I OH
;
H
)-I \ <0
HO 0 0
H
O
HO,, Ao A N ,.r N 0 0
0
H OH
ioe\)== 0
OH
HN 0
?
0 e..r NH
0 =
,
220
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
F
:-.
H H 0
0 -F
OH
0 0 H H 9 al o H 0
N
N .111...'
4=r H H H
\ H 0 ..,
0
N.NH2
H
,
H T
H H :
_ \ <0
O 0
0
0 OThrilJLNII 0
OH
O 0 =
H T
7:
O 0
0 o,)-NJIr .....õo
kINirkl -- o 0
OH
O 0
H T
H H .-
\ <0 ..
O 0 0
0
0 0..----yllj..cyllji,..N.m.ill,,,,0 0
OH
O 0 0 =
,
II 0
N..r...,..),NH
0
H
rõ.0
..-J
0 0 0 0 0
l'...1
0 Y , 0 )1.
o NThiL()AN
L, ..--
0 0 NH-..oNH2
,
221
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
OH
0
H 131' 0 0 O-01
0 s= ¨
11.1 0
0 0 = 0
; and
H H 0
o = ,
=
OH
0 0
0 H oyH 0 cAN....".y0
o
0 0 0
HO 0 HN
H2N
; or a pharmaceutically acceptable salt thereof In certain embodiments within
this paragraph, all
diastereomers are contemplated. For example, in one embodiment, the
stereochemistry at the acetal
is undefined or racemic. By way of further example, in one embodiment, the
stereochemistry at
the acetal is (R)-. By way of further example, in one embodiment, the
stereochemistry at the acetal
is (S)-. By way of further example, in one embodiment, the stereochemistry at
the acetal is (R)- in
excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)- in excess of (R)-.
[00276] In certain embodiments of Formula IV or Formula IVa, Ria and Rib are
hydrogen; R2
is hydrogen; R3 is alkyl; and n is one. In another embodiment of Formula IV or
Formula IVa, D*
is hydrogen. In another embodiment of Formula IV or Formula IVa, D* is a
residue of a
biologically active compound comprising hydroxyl. In another embodiment of
Formula IV or
Formula IVa, the linker-payload has a structure
222
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0 := H
O 0
0
II 0 0
0 101 CAN
..õ.0
OH
0
H 8
0
0
N N H2
; or a pharmaceutically acceptable salt thereof In certain embodiments within
this paragraph, all
diastereomers are contemplated. For example, in one embodiment, the
stereochemistry at the acetal
is undefined or racemic. By way of further example, in one embodiment, the
stereochemistry at
the acetal is (R)-. By way of further example, in one embodiment, the
stereochemistry at the acetal
is (S)-. By way of further example, in one embodiment, the stereochemistry at
the acetal is (R)- in
excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)- in excess of (R)-.
[00277] In certain embodiments of Formula IV or Formula IVa, RI-a is alkyl or
arylalkyl; Rib is
hydrogen; R2 is hydrogen; R3 is hydrogen; and n is one. In another embodiment
of Formula IV or
Formula IVa, D* is hydrogen. In another embodiment of Formula IV or Formula
IVa, D* is a
residue of a biologically active compound comprising hydroxyl. In another
embodiment of
Formula IV or Formula IVa, the linker-payload is selected from the group
consisting of
0 := H
O 0
0
II 0 0
o =o rE,ii NH 0
0 OH
0
H 8
0
0
N NH2
; and
0 := H
O 0
0
II 0 0 H 0 0 H
N 0 0
OH
0 H 8 H
101
N NH2
; or a pharmaceutically acceptable salt thereof In certain embodiments within
this paragraph, all
diastereomers are contemplated. For example, in one embodiment, the
stereochemistry at the
223
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
hemiaminal ether (or hemiaminal, or N-acyl-N,0-acetal, wherein each name for
this functional
group is used interchangeably throughout this disclosure) is undefined or
racemic. By way of
further example, in one embodiment, the stereochemistry at the hemiaminal
ether is (R)-. By way
of further example, in one embodiment, the stereochemistry at the hemiaminal
ether is (S)-. By
way of further example, in one embodiment, the stereochemistry at the
hemiaminal ether is (R)- in
excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the
hemiaminal ether is (S)- in excess of (R)-. For example, in one embodiment,
the stereochemistry
at the acetal is undefined or racemic. By way of further example, in one
embodiment, the
stereochemistry at the acetal is (R)-. By way of further example, in one
embodiment, the
stereochemistry at the acetal is (S)-. By way of further example, in one
embodiment, the
stereochemistry at the acetal is (R)- in excess of (S)-. By way of further
example, in one
embodiment, the stereochemistry at the acetal is (S)- in excess of (R)-.
[00278] In certain embodiments of Formula IV or Formula IVa, R" is alkylene,
where the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
Rib is hydrogen; R2
is hydrogen; R3 is alkylene further bonded to Rla to form the 4-, 5-, or 6-
membered heterocyclyl;
and n is one. In another embodiment of Formula IV or Formula IVa, D* is
hydrogen. In another
embodiment of Formula IV or Formula IVa, D* is a residue of a biologically
active compound
comprising hydroxyl. In another embodiment of Formula IV or Formula IVa, the
linker-payload
is selected from the group consisting of
H
4
N NH2 8
0 0 H
H
, N 0
H
0 0 0 140
11 0
0 z
H
OH 0
; and
224
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
)N H2
0 0 8
H
0
H NI 0
0
0 0 011 411 0
0 HO Fl
0
; or a pharmaceutically acceptable salt thereof In another embodiment of
Formula IV or Formula
IVa, the linker-payload has a structure
H
0 0 o
0
0
0 0
HO
0
or a pharmaceutically acceptable salt thereof In certain embodiments within
this paragraph, all
diastereomers are contemplated. For example, in one embodiment, the
stereochemistry at the
hemiaminal ether (or hemiaminal, or N-acyl-N,0-acetal, wherein each name for
this functional
group is used interchangeably throughout this disclosure) is undefined or
racemic. By way of
further example, in one embodiment, the stereochemistry at the hemiaminal
ether is (R)-. By way
of further example, in one embodiment, the stereochemistry at the hemiaminal
ether is (S)-. By
way of further example, in one embodiment, the stereochemistry at the
hemiaminal ether is (R)- in
excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the
hemiaminal ether is (S)- in excess of (R)-. For example, in one embodiment,
the stereochemistry
at the acetal is undefined or racemic. By way of further example, in one
embodiment, the
stereochemistry at the acetal is (R)-. By way of further example, in one
embodiment, the
stereochemistry at the acetal is (S)-. By way of further example, in one
embodiment, the
stereochemistry at the acetal is (R)- in excess of (S)-. By way of further
example, in one
embodiment, the stereochemistry at the acetal is (S)- in excess of (R)-.
[00279] In certain embodiments of Formula W or Formula IVa, Rla and Rib are
hydrogen; R2
is hydrogen; R3 is hydrogen; and n is one. In another embodiment of Formula W
or Formula IVa,
D* is hydrogen. In another embodiment of Formula IV or Formula IVa, D* is a
residue of a
biologically active compound comprising hydroxyl. In another embodiment of
Formula IV or
Formula IVa, the linker-payload has the following structure
225
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
H H
\ <0
0 0
H - 0
0 I:1
H 0 H
0 0 or
a pharmaceutically
acceptable salt thereof. In certain embodiments within this paragraph, all
diastereomers are
contemplated.
[00280] In certain embodiments of Formula IV or Formula IVa, Ria and Rib are
hydrogen; R2
is hydrogen or ¨CH2Ph; R3 is hydrogen; and n is four. In another embodiment of
Formula IV or
Formula IVa, D* is hydrogen. In another embodiment of Formula IV or Formula
IVa, D* is a
residue of a biologically active compound comprising hydroxyl. In another
embodiment of
Formula IV or Formula IVa, the linker-payload is selected from the group
consisting of
NIH=LN .Ø0....--..õ,0,.,,,..---..0,----..,),..N kL)L N 14 JL .---
,, 0 . =sH H
H H N o
o o o 0
HO
0
=
,
0
0 0 0
N 1.r)-L 11,A
, H
N Thr N N 0 , H
0 0 0 0 ,oF
H 0 r
0; and
R:IToN )-( i=I j=L NH j ICI 0j.( N .,, H N 0 0
0 H
.."' OH
z r
IW
; or a pharmaceutically acceptable salt thereof In certain embodiments within
this paragraph, all
diastereomers are contemplated. For example, in one embodiment, the
stereochemistry at the acetal
226
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
is undefined or racemic. By way of further example, in one embodiment, the
stereochemistry at
the acetal is (R)-. By way of further example, in one embodiment, the
stereochemistry at the acetal
is (S)-. By way of further example, in one embodiment, the stereochemistry at
the acetal is (R)- in
excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)- in excess of (R)-.
[00281] In certain embodiments, of Formula IV or Formula IVa, 12" and Rib are
hydrogen; R2
is hydrogen or ¨CH2OH; R3 is hydrogen; and n is six. In another embodiment of
Formula IV or
Formula IVa, D* is hydrogen. In another embodiment of Formula IV or Formula
IVa, D* is a
residue of a biologically active compound comprising hydroxyl. In another
embodiment of
Formula IV or Formula IVa, the linker-payload has the following structure
OH
H
N1r-)-LNrNj-
H H N Thr N 0
.0 F
0 0 0 0 0
:=
HO F
0
or a pharmaceutically acceptable salt thereof In certain embodiments within
this paragraph, all
diastereomers are contemplated.
[00282] In certain embodiments of Formula IV or Formula IVa, 12" and Rib are
hydrogen; R2
is alkylene, wherein the alkylene is further bonded to R3 to form a 6-membered
heterocyclyl; R3
is alkylene, wherein the alkylene is further bonded to R2 to form the 6-
membered heterocyclyl;
and n is one. In another embodiment of Formula IV or Formula IVa, D* is
hydrogen. In another
embodiment of Formula IV or Formula IVa, D* is a residue of a biologically
active compound
comprising hydroxyl. In another embodiment of Formula IV or Formula IVa, the
linker-payload
has the following structure
227
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0 :H
0 0 0
0 0 H 0 0)L N
OH
N 0
0 0
0
A
N NH2
; or a pharmaceutically acceptable salt thereof.
[00283] In certain embodiments, other linker-payloads are contemplated. In
certain
embodiments of Formula IIb, Rla and Rib are hydrogen; R3 is hydrogen; and n is
zero. In another
embodiment of Formula IIb, D* is hydrogen. In another embodiment of Formula
IIb, D* is a
residue of a biologically active compound comprising hydroxyl. In certain
embodiments of
Formula IV or Formula IVa, Rla and Rib are hydrogen; R2 is hydrogen; R3 is
alkyl; R4 is alkyl;
and n is one. In another embodiment of Formula IV or Formula IVa, D* is
hydrogen. In another
embodiment of Formula IV or Formula IVa, D* is a residue of a biologically
active compound
comprising hydroxyl. Exemplary linker-payloads contemplated include, without
limitation,
H H 0
0
OH
0 0
0)'N-Y-
IL [1
0 0 0
H 0 0 H N
H 2N
H H 0
0 -
=
OH
0 0
0 0 H 0 ,3A
H u
o
N 4=1;.;' N N
0 0 0
H 0 0 H N
H 2N
228
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H2N y0
F
NH
4
H
H %
0 :
----\____-(
0
0 ,4 0
o 4 0 14 ,o 0 OH
Nlir k-r a
- N -1(
0
0
,
H2N yO
H
NH H -
0
0 . . 9 4N
id 0 o OH
H H /
0,--,r
.,,, ----,,,()
o il
gr 0 N , /4 8 ,-;,.., o
\ H
F
z
H H 0
0" ,
OH
0 0
H
0 0 (:))-11.rN 0
-,../
H
0
Fi
1-121)crN'N
0
HN
H2N 0
, ,
F
z
H H 0
0 .
:
0 F
OH
0 0
H
0 0 0AENirN 0
=,...--
0
H
H2N,,,AN N',.AN 0
(S)
H H
/ 0
HO 0 HN
H2N 0
,
229
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
z
H H(0
0
OH
0 0
0 0 0 AThr No
H2N,,,,A)crNõ,)-LN 0
(R) "
0
HN HO 0
H2N 0
priHO O-
__________ -
0 N=NHO N
OH
0 0 110 0 N'Th:' 0 OH
HO HO
OH 0 0
0 OH0H0 OH
07NH2
HO
, and
O
0 NH
0
of
H 0
0
0 I
OH
0 0 10N N 0
======.--- 0
NI A 1 0
['ir
0
N AN H2
=
Conjugates/Antibody-Drug Conjugates (ADCs)
[00284] Provided herein are antibodies, or an antigen binding fragment
thereof, wherein said
antibody is conjugated to one or more compounds of Formula I, Ia, Iaa, Iaaa,
Ib, Ibb, Ibbb, II, IIa,
230
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Iaa, Iaaa, IIb, IIbb, IIbbb, and/or IV as described herein. In one embodiment
of Formula III, D* is
a residue of an anti-inflammatory biologically active compound comprising
hydroxyl, amino, or
thiol. In another embodiment of Formula III, the anti-inflammatory
biologically active compound
is a steroid or a residue thereof In another embodiment of Formula III, the
anti-inflammatory
biologically active compound is an LXR agonist or a residue thereof
[00285] Provided herein are conjugates of Formula Ma:
Ria Rib
NO¨D*
R2 R3
- n
¨k
(Ma)
wherein L is a linker; BA is a binding agent; RI-a and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or alkylene, wherein
when Rla is alkylene, the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
R2 is hydrogen or
an amino acid side chain; R3 is hydrogen, alkyl, or alkylene, wherein when R3
is alkylene, the
alkylene is further bonded to RI-a to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue
of a biologically active compound comprising hydroxyl; n is zero, one, two,
three, four, five, or
six; and k is an integer from one to thirty. In another embodiment, provided
is a conjugate of
Formula IIIaa:
Ria Rib
N
N N¨E)*
R2 R3 R6
-n
¨k
(IIIaa)
wherein L is a linker; BA is a binding agent; Rla and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein when RI-a
is alkylene or heteroalkylene, the alkylene or heteroalkylene is further
bonded to R3 to form a 4-,
5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene, heteroalkylene, or
an amino acid side
chain, wherein when R2 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is further
231
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is hydrogen,
alkyl, alkylene, or
heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is
further bonded to R" or R2 to form the 4-, 5-, or 6-membered heterocyclyl; R6
is hydrogen or
alkyl; D* is a residue of a biologically active compound comprising hydroxyl,
amino, or thiol; n
is zero, one, two, three, four, or five; and k is an integer from one to
thirty. In another embodiment,
provided is a conjugate of Formula IIIaaa:
Rla Rib
BA-1:"-N
R2 R3
-n
¨k
(IIIaaa)
wherein L is a linker; BA is a binding agent; RI-a and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein when RI-a
is alkylene or heteroalkylene, the alkylene or heteroalkylene is further
bonded to R3 to form a 4-,
5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene, heteroalkylene, or
an amino acid side
chain, wherein when R2 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is hydrogen,
alkyl, alkylene, or
heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is
further bonded to RI-a or R2 to form the 4-, 5-, or 6-membered heterocyclyl;
D* is a residue of a
biologically active compound comprising hydroxyl, amino, or thiol; n is zero,
one, two, three, four,
or five; and k is an integer from one to thirty. Also provided herein are
conjugates of Formula Illb:
0 Ria Rib
ENI1J'L
0¨D*
R2 R3
-n
¨k
(Tub)
wherein L is a linker; BA is a binding agent; Rla and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or alkylene, wherein
when Rla is alkylene, the
alkylene is further bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl;
R2 is hydrogen or
232
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
an amino acid side chain; R3 is hydrogen, alkyl, or alkylene, wherein when R3
is alkylene, the
alkylene is further bonded to 1216 to form the 4-, 5-, or 6-membered
heterocyclyl; D* is a residue
of a biologically active compound comprising hydroxyl; n is zero, one, two,
three, four, five, or
six; and k is an integer from one to thirty. In another embodiment, provided
is a conjugate of
Formula IIIbb:
0 Ria Rib
'-ENIIL
BA¨L
R2 R3 R6
-n
¨k
(IIIbb)
wherein L is a linker; BA is a binding agent; RI-a and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein when 12"
is alkylene or heteroalkylene, the alkylene or heteroalkylene is further
bonded to R3 to form a 4-,
5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene, heteroalkylene, or
an amino acid side
chain, wherein when R2 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is hydrogen,
alkyl, alkylene, or
heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is
further bonded to R" or R2 to form the 4-, 5-, or 6-membered heterocyclyl; R6
is hydrogen or
alkyl; D* is a residue of a biologically active compound comprising hydroxyl,
amino, or thiol; n
is zero, one, two, three, four, or five; and k is an integer from one to
thirty. In another embodiment,
provided is a conjugate of Formula IIIbbb:
0 Ria Rib
EN1
R2 R3
-n
¨k
(IIIbbb)
wherein L is a linker; BA is a binding agent; Rla and Rib are, independently,
hydrogen, alkyl,
alkoxy, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkylene, or
heteroalkylene, wherein when 12"
is alkylene or heteroalkylene, the alkylene or heteroalkylene is further
bonded to R3 to form a 4-,
233
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
5-, or 6-membered heterocyclyl; R2 is hydrogen, alkylene, heteroalkylene, or
an amino acid side
chain, wherein when R2 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is further
bonded to R3 to form a 4-, 5-, or 6-membered heterocyclyl; R3 is hydrogen,
alkyl, alkylene, or
heteroalkylene, wherein when R3 is alkylene or heteroalkylene, the alkylene or
heteroalkylene is
further bonded to R" or R2 to form the 4-, 5-, or 6-membered heterocyclyl; D*
is a residue of a
biologically active compound comprising hydroxyl, amino, or thiol; n is zero,
one, two, three, four,
or five; and k is an integer from one to thirty. Also provided herein are
conjugates of Formula V:
0 Rin Rib
BA¨
R2 R3
-n
-k
(V)
wherein BA, R", Rib, R2, R3, D*,
n and k are as described in any of the embodiments disclosed
herein, and wherein SP1 and SP2, when present, are spacer groups wherein SP1
further comprises
a moiety reactive with an antibody or an antigen binding fragment thereof;
each AA is an amino
acid; and p is an integer from 1 to 10. In certain embodiments of Formula V,
the binding agent is
an antibody modified with a primary amine compound according to the Formula
H2N-LL-X,
wherein LL is a divalent linker selected from the group consisting of
a divalent polyethylene glycol (PEG) group;
-(CH2CH20)n-(CH2)p-;
-(CH2)n-N(H)C(0)-(CH2)m-;
-(CH2CH20)n-N(H)C(0)-(CH2CH20)m-(CH2)p-;
-(CH2)n-C(0)N(H)-(CH2)m-;
-(CH2CH20)n-C(0)N(H)-(CH2CH20)m-(CH2)p-;
-(CH2)n-N(H)C(0)-(CH2CH20)m-(CH2)p-;
-(CH2CH20)n-N(H)C(0)-(CH2)m-;
-(CH2)n-C(0)N(H)-(CH2CH20)m-(CH2)p-; and
-(CH2CH20)n-C(0)N(H)-(CH2)m-,
wherein
234
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
n is an integer selected from 1 to 12;
m is an integer selected from 0 to 12;
p is an integer selected from 0 to 2; and
hr
X is selected from the group consisting of ¨SH, ¨N3, ¨CCH, ¨C(0)H, tetrazole,
'1/41- ,
1¨NH 1¨NH
. 0
H
,
, 'N N
, 0
N, N ..___ > N N
\N=/PPh2
S , and
1=1¨/ . In another embodiment of
,
Formula V, the binding agent is an antibody modified with a primary amine
having the following
structure H2N
()()C)N3 . In another embodiment of Formula V, the
compound is selected from the group consisting of
o.y HH2
o¨\
H j
0/
o
BA __ N N 0
H
f.1)-r N H 0 NH
H
õ,,õ,...a...^..õ0,---Ø..",õ0 N, N N dik, ti H
0
N. \ 0 0 H 1 H I
0 SP 0 N ,,,,..
.,=--, -F
N N 0
0
H OH
0H 0
¨k
=
,
Oy NH2
NH
0
H H
N.IHT, N õ,,,,,,,,cr.,0,-^,0....^,,O..,õThr N=11,,,,. N
0
N 0
;L
N \ 0 0 " 00 11 11 .14 N 0 F
BA __ ViTh c? 0 H 0 OH
0
1 )
0
¨ k
,
235
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
_
-
s H H= 0
. .
OH
0 (3
r 0
BA __ N/ (
it 0 NH
,N 1.-
N, i 0 0 N 0 0 0 ril
N
H H H
0 0 0
NA NH2
H
_ -k
,
_
_
H H 0
IN....1) '
(0 cr
0 H
1
0 NH
0
)-
110 0 irl
H
BAN--) 11,1
Nk.N..."...,,,O,..^..0,.."...õ.õ.Ø..õ,..--Ø..--..õ....A.N
H H H
0 > 0 0
0
0\
N A NH2
H
_ -k
,
_
_
(0.....1
0)
H
BA __ N-...,)
0 0
H
N
N 0
N , / OH 0 0
NI
H 0 OA le.y
'
N 0
0...,N..."...õ0,,,o..."0.õ..."...Ø..- ,11-2Nir N ,õ N
H H H
0 0
0
NANH2
H
_ -k
,
H
0 ti
,N
N 0
H 0 0 0
BA __ N-- IN N .1.r.õ..)-1,.. N ,..--
,,,,...0,..-.Ø..--,O,..^.Ø.."*N N N 0
H H
0 ) 0 0 H
0
0\
N ..-1-1, N H2
Oj H
- k
,
236
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
_ _
o(o.....1
) o)
0 ---- 0
0 H
BA ¨NH -..) c")
0
H
N
N 0
N I 0 0 0 0 cti ....õ...
isl H 0
0
H H H
0 0 C HO
0
,.. A
N NH2
I-1 0
_
¨k
,
_ _
0 --- 0
0 H
0
H
,'N
N 0
BA
N I 0 0
H 0 0 0'1'11 -....õ..,
-- N 1 ;
H H H HO
0\
0 ) 0 0 0
N A NH2
01 H 0
¨k
,
501
0
H
BA __ N 0 0
N / 0 0 X[r, H 0 0 0"-j1A ri
µ1, 0 N 0
0
H H 0 H
HO
0
NH
C:i''' NH2
¨k
,
0 0
,N 0 ' ,H
H N: / 0 0 0 0
H
BA __ N iN N-0õ--.,cy.--0,,e-J-LN N N 0
0
H H 0 ) 0 0 H
HO
0\
NH 0
0¨/
0...' NH2
¨k
,
237
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
o
H
0 0
1-1
0
BA ____ /F,I1J ? 0 0¨ \ ---( ,
0
N /
il 0 0
N..r....N.,--,,,,.Ø...,_,-...Ø...,õ õ..0,,,,-....0 N,,, N
H 0 N,) 1!1
0
0= OH
H H H
0 0
NH
0.''' NH2
¨ k
,
H
N
0
0 0---
0
H N' I 0 0 iir H 0 0 if
BA ___ N¨ 71 N
11.,.N.,,,,,...0õ-^.Ø..,0"..õ}..N N N ONNO 0 OH
0 =
H H H
0 ) 0 0
0\
NH
0-7
0.''' NH2
¨ k
,
) )
H
0 0
0 1-1
H 0
BA __ N-..,./ \
0 0
N H
N I
N 0 0
H N 0
0 = 01Esl.n-r OH
N,, N 0
H H H
0 0
0
N 'It' NH2
H
¨ k
,
H
0
0 0 0
N H
N 0
H N" / 0 0
H 0 0 0/E,I.n-i OH
BA __ N /N N10.,^.Ø..,---.õ I-L,N N 0
H H H
0 ) 0 0
0
0\
,11...
N NH2
0-7 H
¨ k
,
238
62
,
m ¨
H r 0
'HN, N
I I
0 0
0 ,.., 0 1
0
HO 0
H
N
H "Nji-e-',..,o(111
0.--,.NN0 H
0 0 1 I I
0 N'
14'
H
g
M ¨
H
II
0
H 0 N
H 0 H
N
0 H
,
H
HO 0 0N N0 0 0 0 o I Isi
0 0 I I I
0 111'
N __ V9
..-
(0
H
c. H
L-0)
c
)1 ¨
H 0
0
'HN, N
I I
0 0
0 H H 0 H 0 0
HO 0
N N N 0,,...0,-,........0,0õ..,,,,,, ill
iiõ N
, 11 N V9
0 NN,0 H
H II
N'
0 0 0
>---_.¨
,
14 0
H
c
)1 ¨
H
'HN,N
I I
0 o u 0
H 0 H 0
N N N 0,---0õ,-..õ0,...,,,_,õ,
/1:11,,...õ11õN
H i N,'
HO 0 0 NJ-isio 0 o o 0 N
N
H
0 0 0
(----N _________________________________________________________________ V9
>--- \ -- H ..- 0
(0
H
(0 H
\ "0)
86LZIO/OZOZSII/I3c1
Iti9tI/OZOZ OM
LO-LO-TZOZ 866SZTE0 VD
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
_ _
O-
())
..,..õ..NH N H2
0
00 0
H
H
Plx.X., 4N II
BA __ N-7
Ist, H
0 0 100 0.....õ1,1
.1s1\ 0
Ad
0
HO a
0
_ ¨k
,
_
¨
H
N NH2
, 40
0
H
0
N
N'' = \
'N 0 0
11 0
0
BA __ N ¨NI (.1 0
HO a
0
0,) 0
C0--)
_ ¨ k
,
_ _
H
NN
H2
t)
II NINi 0 H
0
0 ) 0 1..c.k.
0 4H
.. ji,,...,..m.r,H N
H) \ H N 0
BA __ N N N N.,õõ....0,-..,..Øõ.."...0,..."..õ,0,....,, N
H 0
0
11 -:
sN 0 HO H
0
_ ¨ k
,
_
H
N NH2
OH _
4 0
0 H H Cl 0 pH
N
)1....,...õThr kil...,..õ..,-,.Ø."..,....-0-...,"-e '''.-.. ,==== ,..===-Thr
N 4' N N 0
N N H 0 0 0 -,,, 0 .
.,õ.. ..= . .L 0
11 0
HON'
.14 0
BA __ ilTh IN)
0
CO-)
_ ¨k
,
240
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
_
_
F
H H 0
(0,1
) ) L)...,.) =
-..
F
0 0 r,0 0 OH
0
0
H (...)
BA __ N...j 0,,,NH
*".=-
N
N, i 0 0 H 0 0 0.--ity-.
NN . N,. N
H H H
0 0
0
NAN H2
H
- k
_
,
_ _
F
H H 0
U =
--F
0 0 OH
r 0
0 0-NH
N
,
H N, i 0 0 0 10 (Air
BA __ N-) IN N..r.J.I,N..^...õØ.õ..^..Ø...-
,õØ..õõ.õ.,.Ø......,..õ.1.,N NI,N
H H I H
0 ) 0 0
0
0\
NritµNH2
0-7 H
_ -k
,
F
H H 0
j...._)
H-/
0 -F
C\ 0 0 0
0 11 o
o)-Hi-i "
o 0 OH
0 H HNN Nõ N
BA __ N 1,1
H H
0
N Ox 0
HO 0 NANH2
H
- k
2
241
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
F
H H 0 0
I . .
0 F
ICIC) OH
11
0 14'r " 0 0
N
H
'N
--.- 0
BA ____ [Jr) ci HO 0 N NH2
H
0, 0
(.0)
- k
,
0)
(õ,0-.,1
)
(.3
BA __ N--,./
H )
,N so \-0
N, / 0 0 0
,11
, H N 0
0 0 0 0
:
HO F'
0
- - k
,
- _
N,,N I 4111 0
H 0 0 0
BA ____ N- ;N Ny.,-....,.AN...".O.---,0...---,.Ø.----Ø..-
.."..1.{11...,õ..A.N 11,AN^0 0 ,H
, H
H H II .,,F
0 ) 0 0 0 0
0\ :
HO r
0-7 0
- k
,
242
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
I )
L., 0 0
BA ___________ IN1) ?
,N 410
N
µµ /
N 0
*
0 FNiiriU 0 --0
0 N I;U(
0
's H
0
:
HO Fs
0
_______________________________________________________________________ k
,
N 41
H Isl, /
0
*
BA __ N¨ 0
0 ' ji
N ,¨,
c\ 0 0 11 .' H
0¨/ s=
HO r
0
¨ ¨k
,
243
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
I )
, 0 0
BA ___________ NJ 1)/
,N
N
N /
N)i_......i.i( ir.--OH
NW
0 H riAN J
N 0
0
0 Nri;Uk
0
' H
0
,
HO Fµ
0
_________________________________________________________________________ k
,
_ _
,N
H N' /
0 OH
0\ NN
BA ______ N¨ IN
0 ) 0
NrN---ILN o 0 0 - H
0
0¨/
HO F.
0
¨ ¨k
,
0
0 0
BA __ rVIJ ? : \-0 J.Dt 11 0
,N
N I 0 N 10 H
X,rr
H H 0 0 H
HO F'
0
07NH2
- k
,
244
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
NINT-0
N ol) li 0t, c)
H rsl. I 0 H 0 N'or N
BA __ N¨ IN N,O--..Ø..--0,....0,-.jN,, I N
0 I
H H 0 H F'
0 ) 0
_5 HO
0
0 0 N H2
¨ k
,
o
)31
0 H
0\ 0 H
N 0 4,1-1 H
H j,...
....11,ir,..õ...õ..---,0.,,.."..,0,..--..,,,,.Ø,,.......m.r.N..õ..--..,...0
BA __ N-7 N N
Nis, \ 0 0 0
1-1:
N HO 0
¨ ¨k
,
0 N
0 .z.H H
H H
N,K,..........N........õ...--...0,-....,....,Ø..,........^-,0,--
...,,,.0õ...õ..Thi.,.N ,.o
N
N" \ 0 0
1-1
srl HO
BA __ riTh (õ) 0
0,) 0
Co)
_ ¨k
,
245
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
I )
u 0 0
BA __ N ?
,N
N
H
0 ti H
Ny.N.,.. jk
H 0
0 NN
\,-0 .
0 0 Fi o
OH
_ - k ;
H
--\__<0
:-.
0
H N ' /
BA __ N- N
Ny.N.A 0 NTh 0
r il 00
_
0
0 H
0\ OH
0 -/
- - k ;
246
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0 0 0
H 0 's
H 0\ = Is j)1; L)H;L)
0 Alm H
BA _________ N¨ N ' NIN''' Ho'lis H
N'õ \ 0 0 0
N *
Oil 111111.
HO F' .
0
¨ ¨k
,
_
O 0 0 0
H 0 "S
N
====..,,--
N).11;1jLN-illjNIN 0 ,,
' ri HO' 40611
N',' \ 0 0 0
N *
Op
HO 1
BA _________ N'N, (,i
H /
0 0 0
Co)
_
¨ k
,
050c)
H ,,\ ?
BA __ N,,- ......
,N
N I 0
H I
0 (0
o)
0 H J-I
( 0
0 ----\_.-(
HI
I 0 0
0) 0 0 0 cy.l..N i.r N 0 0
H ii
N,, 2-c H 0 OH
,l'i . 1,1
0 0
LN)'LNH2
H
_________________________________________________________________________ k
,
247
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
N
H N,, i 0
BA __ N¨ N1r-.).(re=
H I
0 0 0
0\
Of
0¨/
rj 0 H ztl
0
r0 -----\---(
I 0
0) 0 N
)*L
0 0 0-1--Nr ........0
0 OH ikilõ A
N ' N H
0
H H
0 -.õ....
0
====. ...*
N NH2
H
_________________________________________________________________________ k
,
5OTh )
0
BA __ INI,) (/)
,N
N / 0
isl NIr..).(isi
H I
0 (0
0)
r.) H
0
,
(...0 ¨ \--<
0 0
H -Thr
0
H H
0 ,....,
0
N NH2
H
_________________________________________________________________________ k
248
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
N
,
H N I 0
BA __ N¨ ;N
H I
0 0 0
0\
01
0-7
0 H ,H
(0 ----\-
0
0 0
0) 0 0
-,...- 0
H 0 N HN ----i- OH
1...._.A i-).rN, A
N ' N 0
H H
0 -...,..
0
=-. A
N NH2
H
_______________________________________________________________________ k
,
BA ___ NH
\---\
0
rj
c0o Icl-0.r111
C¨N ---
N 0
?
( 0
0
Ox
H
\ <
0 0
0
0
ri OAN-ricl i jXii,,, jt 01 0
H OH
0
0 N 0 0
)-
HO 0 '11 NH2
_______________________________________________________________________ k
,
249
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
I )
0 0
H 1
BA¨N
? ofil
o Lo
N
N-
?
0
of H
? 0 0
0
0
0 0 0 OANThill0 0
OH
" 0
o o 0
HO 0 NANH2
k
,
_
TO
BA __ NH ----) H
H H
0 \ __ (0
0 0
CO (:::ef kLAN ,f11,0 0
0
0 0 OH
N
¨ ¨ k ;
foO) H
H H
H 0 0 0 0
BA __ N N..) J
0
r orkl.AN(1100 0
OH
N
µ1 /
N
¨ ¨ k ;
250
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
H
_______________________________________________ 0 H
N, \
rtN5,,) <0 , 0
KIJ. riL0 A 0
,0 0 N N 0
OH
0 0
BA __ NH
j0
_
- k ;
H
FI, H
N---c
NI ) \ <0
', \
0
NI_ 0 J.L Klj( , ,I4,o Fi
0
OH
BA-Nr.''')
o N IT
0
H 0T0.)
0
- - k.
_
BA __ N11---)1_\
2
CO
H
p 0 [71 H
N,
\ __ <
9
N i N 0
OH
0 - 0
_________________________________________________________________ k.
251
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
H
N-c) \ <0 H H
:-.
N 0 0 0
I 0
BA-N7'')
H 0 z 0 OH
1 )
0
- k.
BA __ NH r,
CO
H
p _________________________________________ 0 H H
, 0N,
\ <
Nt5N 0 j 1 m ,r11,0 o
o
N g i N 0
OH
- k.
H
H H
i.r`r(7
N , 0 0 \ <0
0 ,
ril 0 j.
OH
BA __ N''')
H 0 ' 0
010)
0
- k.
252
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
BA __ NH
Zo
\ 0 H H H
0 0
0
(--0oCirilNrkLAIlriL 0 H-
OH
c¨NTA u 0 0 0
N
_ ¨k.
'0\ H
H H
_________________________________________________ <0
H 0 0 0 0 0
BA __ N,) ri _ 0
Qro14')N111')Nill' o I:I
OH
N
N
_
¨k.
H
N
Hz H
\ <0
0\ /It 0 0 0
H
H N 11,.AN,y
BA¨N--/ N - 1 INo OH
_
0 0
N 4.
0
¨ ¨k
,
253
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
\ 0 H, H
<
. 0 0 0 0
0
N Ni)-(11j-NKLA H
i N H N 0
...... 0 A
OH
NI' \ 0 0 - 0
N
1.
BA __ NTh .
H
(:) 0
C --)
0
- -k
,
BA __ Nr1--\
0--\
)
CO
H
H H
O \ o
___Ncicjc,N,k, 0 jLo 41-11;1)(kiii)L
o
'ii o 0
H 0
N H li Ni ' 0
OH
0 0 0
- -k
,
_
BA __ N(:))
H H
-
$0
,N, ) OH 0 0 H
N 0 -
NN 0jy)L ,Y1,)N./ -' 0 OH
--- 0
N N o o
o
-k
,
254
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
BA __ Nr1---\0___)
CO NH2
H
0 ) H H
,
H \ <C)0 . 0
0,AN I;LA ,,k1,A ,N 0 A
N ii N fl 0
OH
0 0 0
_ -k
,
)
NH2 H
ztl H
N2) \ <0
N 0 0 0
H Ojc 11 j-L H 0
BA __ N7'')
OH
H 0 0 0 0
_ 1o)
-k
,
255
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
sc-
0
sZ) ZN
BA __ N¨J i <7
H Nrsj
,Z)
ONH
H
0
of
?
I
0 __________ H
\ _____________________________ <0 H H
_
0 0 0
H
m.rNO
OH 0
0
__________________________________________________ k.
BA __ N()0
H
?
,N. 0
N ' N
(-:50
ONH
H
0
of
?
0 __________ H
I \ <0 H H
z
0 0 0
ANrH
NO
OH
0
____________________________________________ k.
256
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
)
0 0
)-r0
BA¨N N
H ___ )
N'õ \ HN
N
0)
?
(0
o)
? H
Hz H
\ <0
0
0 0
H 0
N j=
li T-10
0 H-
OH
0
____________________________________________________ k.
0
)0
N N
N',' \ HN
N
BA _____ isli M 0)
(:) 0
?
r0
CO")
0)
? H
\ <0 H H
0
0
H jLN 0
i 1 0 H--
OH
0
___________________________________________________ k.
257
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
HO \ <0
0 0
Ao
OAN(NO 0
0
OH
0
BA __ NELJO--) OH
HN 0
c
or
NH
NN 0
\ <0
HOr 0 0
HO,,, Ao
N 0
0
OH
0
OH
HN 0
0,NH
BA __ N
NIõ---A
0 N
H OV
0)
k.
258
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
_
0
(:-MO H
ri--OH
)
0
HO
BA __ N NN F
0
11 H 0
H
(0
0
0) 0 H H 0
)'L N, 0
[1--r µ, N
H
0 0
NANH2
H
_______________________________________________________________________ k
,
0
H
H
(0
110H
NN F
0)
BA ¨1 11 H 0
(0 (:)
0 0) 0
'F
H 9 110 )EiNThrN0 o
N, 2L 0 0 OH
H H
0 0
LNANH2
H
k
,
¨ _
r
BA¨N--\H 0---
0 H H H f
(-0 \ <
0 0
0 11 0
===,..õ--
0 0
OH
ci C---2 C11 Nll
sie
- -k.
259
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
r 0
H s:) 0) -----\_<0 H H H ,,,F
BA-NN....) _..... ...] w 0
_N:16 NThrkl 0
N 0 0
_ 0 OH
N
- k.
BA-NFITho___\
2
CO
H ,F
/0 H H .-
V... N,
0
0 (11 )11 o
Cif ')LN 'LN ,o
0
OH
0 0
k.
H T
\_<0 H H .-
IVI,N\ 0 0 0
OAN)r klNir La
o o
BA __ N7''') 1 OH
H 0 0 0 0
1)
0
- k ;
r--
BA-NH\0 ----) H T
\ <0o H H .-
_
Co
0 0
0
/ c1ØThrl4J1,..r-,TIAJI,,N.--",i1L0 0 0
0 0 OH
N
- -k
,
260
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
x0 H F
H H
\ <0
H 0 0 0 0 0
BA __ N ?
orkljc 14 ,)LN kJ 0
....õ 0 0
OH
O
N , N
... 0 0
N___O
_ ¨ k ;
0
5,oc)
H (,)
BA-N-.)
,N
N, /
N 0
Nõtr,ANH
0 ?
0,1
)
rj 0 0 0 0ANThrlAri
01
cril'''N
o o
0
NH
..
0 NH2
_______________________________________________________________________ k
,
,N
H N 0
0
BA-N- ;N N.1(NH
0 ) 0 ?
f)
0,1
0-7 ...J
ri 0 ? 0
o NThr N
H 0 0 H
01 Lcr õ. N
0
NH
0..NH2
_______________________________________________________________________ k
,
261
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
- _
c)
N
BA __ N¨/ N
Nõ
0
11 0
0 io
_ -k
; and
¨ _
0 H OH
=,,,,
N,
NJL
Hf a N 0
BA __ N H
H 0 /10
0 0
1o)
¨ ¨k
wherein k is 1, 2, 3, or 4. In certain embodiments within this paragraph, all
diastereomers are
contemplated. For example, in one embodiment, the stereochemistry at the
hemiaminal ether (or
hemiaminal, or N-acyl-N,0-acetal, wherein each name for this functional group
is used
interchangeably throughout this disclosure) is undefined or racemic. By way of
further example,
in one embodiment, the stereochemistry at the hemiaminal ether is (R)-. By way
of further
example, in one embodiment, the stereochemistry at the hemiaminal ether is (S)-
. By way of further
example, in one embodiment, the stereochemistry at the hemiaminal ether is (R)-
in excess of
(S)-. By way of further example, in one embodiment, the stereochemistry at the
hemiaminal ether
is (S)- in excess of (R)-. For example, in one embodiment, the stereochemistry
at the acetal is
undefined or racemic. By way of further example, in one embodiment, the
stereochemistry at the
acetal is (R)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)-. By way of further example, in one embodiment, the stereochemistry at the
acetal is (R)- in
excess of (S)-. By way of further example, in one embodiment, the
stereochemistry at the acetal is
(S)- in excess of (R)- . In any of the embodiments in this paragraph, p is 1,
2, 3, 4, 5, 6, 7, 8, 9, or
10.
262
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00286] In certain embodiments, Formulae III, Ma, IIIaa, IIIaaa, 11th,
IIIbb, IIIbbb, and/or V is
an antibody-drug conjugate including an antibody, or an antigen binding
fragment thereof, where
said antibody or antigen binding fragment thereof is conjugated to a compound
of Formula I, Ia,
Iaa, Iaaa, Ib, Ibb, Ibbb, II, Ha, IIaa, IIaaa, IIb, IIbb, and/or IIbbb. In
another embodiment of
Formulae III, Ma, IIIaa, IIIaaa, Tub, IIIbb, IIIbbb, and/or V, the antibody-
drug conjugate is
selected from the group consisting of
0
N 0
µazz.
OH 0 H
0 =
0 =
0 0
N 0 0 0 H
N
H 0
0
0 0
N 0 OH
HN (s) 0
= \ <0 H H
0
N (s) N0 0
0 sCo
0
0 =
0 0
H 0 H
N 0 0 H
H 0 =
263
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
0 0
)LN 0 OH
H 0
0
O 0
N = 0
c&N7( OH
H 0
0
O 0
0 0
OH
H 0
0
O 0
t SS 0
Ths/7( OH
H 0
H
H
0
0--0
0
HN 0
OH 0
264
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
O
NO 0 WO
HN
H01-1
o ;
0 =µ"
0 0
0
0 OH
H 0
H H 0
0
ThNI-rN(3 OH
0
1 0
0
=
0 0
14,0 0 OH
OH
0 ErN 0
sso
0
0
265
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
O 0
0 OH
N
H 0 =
0
\
O 0
0 OH
N
H 0 =
0
H 0 0 0
_KO 0 OH
NI'
0 = 0` :FI
O 0
0 OH
H 0
0
\
0 0
M 0
0 OH
and
¨\\_<
0 0
0 H õ
N N 0 OH
N yf
H 0 . In certain
embodiments within this
paragraph, all diastereomers are contemplated. For example, in one embodiment,
the
stereochemistry at the hemiaminal ether (or hemiaminal, or N-acyl-N,0-acetal,
wherein each name
266
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
for this functional group is used interchangeably throughout this disclosure)
is undefined or
racemic. By way of further example, in one embodiment, the stereochemistry at
the hemiaminal
ether is (R)-. By way of further example, in one embodiment, the
stereochemistry at the
hemiaminal ether is (S)-. By way of further example, in one embodiment, the
stereochemistry at
the hemiaminal ether is (R)- in excess of (S)-. By way of further example, in
one embodiment, the
stereochemistry at the hemiaminal ether is (S)- in excess of (R)-. For
example, in one embodiment,
the stereochemistry at the acetal is undefined or racemic. By way of further
example, in one
embodiment, the stereochemistry at the acetal is (R)-. By way of further
example, in one
embodiment, the stereochemistry at the acetal is (S)-. By way of further
example, in one
embodiment, the stereochemistry at the acetal is (R)- in excess of (S)-. By
way of further example,
in one embodiment, the stereochemistry at the acetal is (S)- in excess of
(R)-.
[00287] In one embodiment of Formula III, Ma, IIIaa, IIIaaa, Mb, Bibb, or
IIIbbb, BA is an
antibody or antigen-binding fragment thereof In another embodiment of Formula
III, Ma, IIIaa,
IIIaaa, Mb, Bibb, or IIIbbb, BA is a transglutaminase-modified antibody or
antigen-binding
fragment thereof comprising at least one glutamine residue used for
conjugation. In another
embodiment of Formula III, Ma, IIIaa, IIIaaa, Mb, Bibb, or IIIbbb, BA is a
transglutaminase-
modified antibody or antigen-binding fragment thereof comprising at least two
glutamine residues
used for conjugation. In another embodiment of Formula III, Ma, IIIaa, IIIaaa,
Mb, IIIbb, or
IIIbbb, BA is a transglutaminase-modified antibody or antigen-binding fragment
thereof
comprising at least four glutamine residues used for conjugation. In another
embodiment of
Formula III, Ma, IIIaa, IIIaaa, Mb, Bibb, or IIIbbb, BA is a transglutaminase-
modified antibody
or antigen-binding fragment thereof wherein conjugation is at two Q295
residues; and k is 2. In
another embodiment of Formula III, Ma, IIIaa, IIIaaa, Mb, IIIbb, or IIIbbb, BA
is a
transglutaminase-modified antibody or antigen-binding fragment thereof wherein
conjugation is
at two Q295 residues and two N297Q residues; and k is 4.
[00288] In certain embodiments, other antibody-drug conjugates are
contemplated. Exemplary
antibody-drug conjugates contemplated include, without limitation,
267
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
F
HH 0
BA
\ 0
-F
N 0
N,..0 OH
No / 0 0 H 0 N 1111- O'll'N-----ri-
0
N 1 0
H H H
0 0 0
N *--1( N H2
H
_ ¨z
and
_ _
F
HH 0
-___, 0 = ,F
0 N
)'(N Thr N ,,,..0 0 OH
N ,, / 0 0 H 0 N 0 ill 0
1 0
H H H
0 0 0
NANH2
H
_ ¨z
or a mixture thereof;
_ _
H2NyO
f
NH H
FI
0
N=N
?
----\__.-
BA,Ni Z =o o
I 4.,N
0 OH
1 0 of110
0 -z_
and
_ _
BA
H2N y0
F
rNH
N-N -----\_- .
NI 0 0 0
Z
0 ICIJL /c 11 4
0 OH
0 11
0
0 -z
_
or a mixture thereof;
268
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
_
¨
H2N yO
f 1.1
NH H
0 =
N=N -----\--(
BA 0 0 0
0 N'YI .
NI.r).L 0
:
8 z...., 0 0.õM-,r0
11 0 OH
N' r4
0 0
_ ¨z
BA
H2N yO
H
NH H
,H
0
IT 0
Z 0
0 lc j 41c1
n \ Id 0
0..i.= = -,-, 0 OH
0 il
'4 o,-
00
_ ¨z
BAN
,N
N If 0
NN...},NH
0
0
f
0 0 0 0 0
r) 0 N j A
0 N-Y
0 OAN
O 1.1
I ?Lr õ. N
0 0 ..NH
0NH2
_________________________________________________________________________ z
N
N., If 0
'N N,r.,..),NH
B/ 0
H
0
ox 0 0 0 0
rj 0 p A 0 ),L
0 ,Thill--0-AN
H H
h
0 ..NH
0...-NH2
_________________________________________________________________________ k
269
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
BA 0
\N
HN
0NH 1_1 0 0 0 0
.õH
_
OH
0 - 0
- z
and
0
N Njr
HN
BA/ 0NH 1.4 0 0
oj.LN 0 0
.õ N OH
" H ..'"
0 0
- z
; or a mixture thereof. In any of the embodiments in this paragraph, z or k is
1, 2, 3, or 4.
Methods of Preparing Compounds, Prodrugs, or Payloads, and Linker-Payloads
[00289] The compounds provided herein can be prepared, isolated, or obtained
by any method
apparent to those of skill in the art. Exemplary methods of preparation are
described in detail in
the Examples below. In certain embodiments, compounds provided herein can
generally be
prepared according to Schemes A-H, J, and K. In the following Exemplary
Preparation Schemes,
Rla, Rib, R2, R3, R4, I, -"*,
and n are are described in the context of Formulae described herein.
Scheme A. Exemplary Preparation Scheme
peptide
[0]
CORIa Rlb R4 ()RI\ ,R 1 b 0 HO¨D* o R1 b
homologation R4 0 R2 R3
Fmoc,N,TAN.yH HN
,cNO¨D*
R2 R3 0 R2 R3 R2 R3
" 1 1b 1\
R2 R OR R
[00290] In Scheme A, amino acids were oxidatively decarboxylated, and then
substituted with
payloads (HO _____________________________________________________________
D*). Payload derivatives where then subjected to further peptide
homologations.
Scheme B. Exemplary Preparation Scheme
270
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
R2
FmocNiN7 [01 FmocN N coupling
_________________________________ "- ( 6)--O¨D*
R4 0 HO 0 R4 0 OH
HN:t
R4 R2
[00291] In Scheme B, amino acid derivatives were subjected to oxidative
decarboxylation,
followed by coupling with payloads (HO D*).
Scheme C. Exemplary Preparation Scheme
-1,4 o Rivib
0 0 NO2 H ..,N
?-----N 0¨D*
R2 R3
0 0 OA - n
101 fo 0 klõ.AN
H
0
NH
0.-NH2
0 R2 R3
- n
H
0 NH
0.---NH2
[00292] In Scheme C, linker-payloads were assembled using p-nitrophenyl
carbonates.
271
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Scheme D. Exemplary Preparation Scheme
0
-...-- o I. OH Boom õ--11,
OH 0 0
kl I
0 0
1 i o N 0 : 040 OH
____________________________________________________________________________
,.
H2N1I 4. N H2N,A c)..LN 0 0 0
NH then deprotection eCa NANH2
1
0 NH2
0 0 0 OH
0 . H 0
_._
00 NH
i
0 NH2
- R4 0 Wax/Rib
0 0 NO2
Fl---"rj))L.----N 0-D*
R2 R3
- - n
_______________________________________________________________________________
...
0
......
0 0 NANH2
1
_
Q R2 R3
i hydrolysis
0 0 ,rFi 0A 0 0)-----.N)--N
N....r,A 4 H)N,...,c,o...,......ryN,rLN
Nõ'N R4 0 R a R a
H µ = H H - - n
0
0
N NH2
H
0 R2 R3
1
c0¨D*
Nõ R4 0 R a R b
0
).L
HO 0
H
[00293] Scheme D also shows an alternative linker-payload synthesis. Dipeptide
derivatives
were homologated under peptide coupling conditions, followed by deprotection.
Tripeptide
coupling with N-hydroxysuccinimide esters provided the benzyl alcohol shown.
The benzyl
alcohol was converted to ap-nitrophenyl carbonate which was treated with a
payload that provided
the penultimate linker-payload. Final hydrolysis provided the linker-payload
shown.
272
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Scheme E. Exemplary Preparation Scheme
-o
0 0
N-Jr11¨(--0---0-N'-e
R4 0 R2 0 R2 0 0 0 _
OH _____________________________________ O
HNyyr14,)-LT _ n 0- Fr
Ny-).L,N,I,.N yLykly(c)OH
..
R2 R4 0 R2
0 0 R2 R4 0 R2
-n
_
o 11 R2 o R2 R3
-.- Njj 1ofo1ofoVI4j ,_ii ,y,_..
T Y n Y
0 R2 R4 0 R2 R4 0 Ria Rib
[00294] Scheme E shows yet another linker-payload synthesis. Tripeptide
derivatives were
coupled with N-hydroxysuccinimide esters and provided carboxylic acids like
the one shown. The
carboxylic acids were activated and coupled with payloads.
Scheme F. Exemplary Preparation Scheme
- R4 o Ria\ Rib
H---"IYL---NO-D* _ -
R2 R3 R2 H 0 R2 0 R2 R4 0 Ri
a Rib
R2 0 R2 0 R2 It - - n 1,1,11 NyNclyyyNi
ylle,irlyley0H ________________________ ..- H
Fmocyy then deprotection 1
R4 0 R2 H II
0 R2 0 R2 R3
II o
Nyoil 0 R2 0 R2 0 R2 R4 0 R1 a Rib
0 H
H
0 R4 0 R2 0 R2 0 R2 R3
- n
[00295] Other linker-payloads were synthesized according to Scheme F.
Protected
pentapeptides were coupled to payloads under peptide coupling conditions, and
then deprotected.
Subsequent peptide couplings with carboxylic acids provided the linker-payload
shown.
Scheme G. Exemplary Preparation Scheme
- R4 o RiavRib
i
H----11-1--11-1;,---o-o* _ _
N.._
o o 3 o R2 R3
- R2 - R
n
0 _n 0 0 4 n R4 0 Ra Rb
- n
273
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
[00296] Yet other linker-payloads were synthesized according to Scheme G.
Payloads were
coupled to N-hydroxysuccinimide esters.
Scheme H. Exemplary Preparation Scheme
0
FmocHN
OH
0 R2 R3
coupling
i!Ri4 (it R1a\ /Rib then deprotection 0 -D*
_______________________________ H2rs,r114'N R4 OR a Rib 0 0
-n
R2 R3 0
-n
NH
0 R2 R3
N O¨D*
0
F,2N R4 0
R'a Rib
FN1 -n
0
0 HO 0 HN
0 0
H Ft" N 'r0"--PLOH R,N+0J)L0 H2NO
4 4 0
0
Rm= 0
Q11
Rm =
6
o R2 Fie
¨D*
o
H
R4 0 Ria Rib
- n
H 11
0 0 0
HOO HN
H2N
[00297] In Scheme H, the synthesis of multiple linker-payloads is shown.
Payloads were
coupled to protected p-nitrophenyl carbonates, followed by deprotection.
Peptide homologation
provided linker-payload intermediates terminating with (R)- or (S)- amino
acids. These terminal
amino acids were coupled to N-hydroxysuccinimide esters, derived from
corresponding carboxylic
acids, to provide the linker-payloads shown.
274
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Scheme J. Exemplary Preparation Scheme
transglutaminase Linker payload
________________________________________________________ - Q2ga 295 <2>
9q: NH-PEG3-N3
.5Mft, H2N-PEG3-N3 297 gt.
WM 0
4
,NN
NH-PEG3¨ N NH2
NH
0
0
0 0
R4 0 WaRib x/
OJLN
0 R2 R3
- - n
[00298] Scheme J shows general conjugation of linker-payloads to antibodies or
antigen
binding fragments thereof Antibodies or antigen binding fragments thereof are
modified via a
transglutaminase to incorporate a terminal azide useful for participation in
click chemistry with an
alkyne. Accordingly, suitbale linker-payloads are conjugated to the antibodies
or antigen binding
fragments thereof
[00299] The conjugates described herein can be synthesized by coupling the
linker-payloads
described herein with a binding agent, for example, an antibody under standard
conjugation
conditions (see, e.g., Doronina et al. Nature Biotechnology 2003, 21, 778,
which is incorporated
herein by reference in its entirety). When the binding agent is an antibody,
the antibody may be
coupled to a linker-payload via one or more cysteine or lysine residues of the
antibody. Linker-
payloads can be coupled to cysteine residues, for example, by subjecting the
antibody to a reducing
agent, for example, dithiotheritol, to cleave the disulfide bonds of the
antibody, purifying the
reduced antibody, for example, by gel filtration, and subsequently treating
the antibody with a
linker-payload containing a suitable reactive moiety, for example, a maleimido
group. Suitable
solvents include, but are not limited to water, DMA, DMF, and DMSO. Linker-
payloads
containing a reactive group, for example, an activated ester or acid halide
group, can be coupled
to lysine residues of the antibody. Suitable solvents include, but are not
limited to water, DMA,
DMF, and DMSO. Conjugates can be purified using known protein techniques,
including, for
example, size exclusion chromatography, dialysis, and
ultrafiltration/diafiltration.
275
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00300] Binding agents, for example antibodies, can also be conjugated via
click chemistry
reactions. In some embodiments of said click chemistry reactions, the linker-
payload includes a
reactive group, for example an alkyne, that is capable of undergoing a
regioisomeric
1,3-cycloaddition reaction with an azide. Such suitable reactive groups are
described above. The
antibody includes one or more azide groups. Such antibodies include antibodies
functionalized
with, for example, azido-polyethylene glycol groups. In certain embodiments,
such functionalized
antibody is derived by treating an antibody having at least one glutamine
residue, for example,
heavy chain Gln295, with a primary amine compound in the presence of the
enzyme
transglutaminase. In certain embodiments, such functionalized antibody is
derived by treating an
antibody having at least one glutamine residue, for example, heavy chain
Gln297, with a primary
amine compound in the presence of the enzyme transglutaminase. Such antibodies
include
Asn297Gln (N297Q) mutants. In certain embodiments, such functionalized
antibody is derived by
treating an antibody having at least two glutamine residues, for example,
heavy chain Gln295 and
heavy chain Gln297, with a primary amine compound in the presence of the
enzyme
transglutaminase. Such antibodies include Asn297Gln (N297Q) mutants. In
certain embodiments,
the antibody has two heavy chains as described in this paragraph for a total
of two or a total of four
glutamine residues.
[00301] In certain embodiments, the antibody comprises two glutamine residues,
one in each
heavy chain. In particular embodiments, the antibody comprises a Q295 residue
in each heavy
chain. In further embodiments, the antibody comprises one, two, three, four,
five, six, seven, eight,
or more glutamine residues. These glutamine residues can be in heavy chains,
light chains, or in
both heavy chains and light chains. These glutamine residues can be
wild-type residues, or engineered residues. The antibodies can be prepared
according to standard
techniques.
[00302] Those of skill will recognize that antibodies are often glycosylated
at residue N297,
near residue Q295 in a heavy chain sequence. Glycosylation at residue N297 can
interfere with a
transglutaminase at residue Q295 (Dennler et al., supra). Accordingly, in
advantageous
embodiments, the antibody is not glycosylated. In certain embodiments, the
antibody is
deglycoslated or aglycosylated. In particular embodiments, an antibody heavy
chain has an N297
mutation. Alternatively stated, the antibody is mutated to no longer have an
asparagine residue at
position 297. In particular embodiments, an antibody heavy chain has an N297Q
mutation. Such
276
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
an antibody can be prepared by site-directed mutagenesis to remove or disable
a glycosylation
sequence or by site-directed mutagenesis to insert a glutamine residue at a
site apart from any
interfering glycosylation site or any other interfering structure. Such an
antibody also can be
isolated from natural or artificial sources.
[00303] The antibody without interfering glycosylation is then reacted or
treated with a primary
amine compound. In certain embodiments, an aglycosylated antibody is reacted
or treated with a
primary amine compound to produce a glutaminyl-modified antibody. In certain
embodiments, a
deglycosylated antibody is reacted or treated with a primary amine compound to
produce a
glutaminyl-modified antibody.
[00304] The primary amine can be any primary amine that is capable of forming
a covalent
bond with a glutamine residue in the presence of a transglutaminase. Useful
primary amines are
described herein. The transglutaminase can be any transglutaminase deemed
suitable by those of
skill in the art. In certain embodiments, the transglutaminase is an enzyme
that catalyzes the
formation of an isopeptide bond between a free amine group on the primary
amine compound and
the acyl group on the side chain of a glutamine residue. Transglutaminase is
also known as protein-
glutamine-y-glutamyltransferase. In particular embodiments, the
transglutaminase is classified as
EC 2.3.2.13. The transglutaminase can be from any source deemed suitable. In
certain
embodiments, the transglutaminase is microbial. Useful transglutaminases have
been isolated from
Streptomyces mobaraense, Streptomyces cinnamoneum, Streptomyces griseo-
carneum,
Streptomyces lavendulae, and Bacillus subtilis. Non-microbial
transglutaminases, including
mammalian transglutaminases, can also be used. In certain embodiments, the
transglutaminase can
be produced by any technique or obtained from any source deemed suitable by
the practitioner of
skill. In particular embodiments, the transglutaminase is obtained from a
commercial source.
[00305] In particular embodiments, the primary amine compound comprises a
reactive group
capable of further reaction after transglutamination. In these embodiments,
the glutaminyl-
modified antibody can be reacted or treated with a reactive payload compound
or a reactive linker-
payload compound to form an antibody-payload conjugate. In certain
embodiments, the primary
amine compound comprises an azide.
[00306] In certain embodiments, the glutaminyl-modified antibody is reacted or
treated with a
reactive linker-payload to form an antibody-payload conjugate. The reaction
can proceed under
277
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
conditions deemed suitable by those of skill in the art. In certain
embodiments, the glutaminyl-
modified antibody is contacted with the reactive linker-payload compound under
conditions
suitable for forming a bond between the glutaminyl-modified antibody and the
linker-payload
compound. Suitable reaction conditions are well known to those in the art.
Exemplary reactions
are provided in the Examples below. Accordingly, provided herein is a method
of preparing an
antibody-drug conjugate comprising contacting a binding agent, as described
herein, with a linker-
payload, also as described herein.
Pharmaceutical Compositions and Methods of Treatment
[00307] Provided herein are methods of treating and preventing diseases,
conditions, or
disorders comprising administering a therapeutically or prophylactically
effective amount or one
or more of the compounds disclosed herein, for example, one or more of the
compounds of a
formula provided herein. Diseases, disorders, and/or conditions include, but
are not limited to,
those associated with the antigens listed herein.
[00308] The compounds described herein can be administered alone or together
with one or
more additional therapeutic agents. The one or more additional therapeutic
agents can be
administered just prior to, concurrent with, or shortly after the
administration of the compounds
described herein. The present disclosure also includes pharmaceutical
compositions comprising
any of the compounds described herein in combination with one or more
additional therapeutic
agents, and methods of treatment comprising administering such combinations to
subjects in need
thereof
[00309] Suitable additional therapeutic agents include, but are not limited
to: a second
glucocorticoid, steroid, LXR modulator, an inflammatory therapeutic agent, an
autoimmune
therapeutic agent, a hormone, a biologic, or a monoclonal antibody. Suitable
therapeutic agents
also include, but are not limited to any pharmaceutically acceptable salts,
acids, or derivatives of
a compound set forth herein. The compounds described herein can also be
administered and/or co-
formulated in combination with antivirals, antibiotics, analgesics,
corticosteroids, steroids,
oxygen, antioxidants, COX inhibitors, cardioprotectants, metal chelators, IFN-
gamma, and/or
NSAIDs.
278
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00310] In some embodiments of the methods described herein, multiple doses of
a compound
described herein (or a pharmaceutical composition comprising a combination of
a compound
described herein and any of the additional therapeutic agents mentioned
herein) may be
administered to a subject over a defined time course. The methods according to
this embodiment
of the disclosure comprise sequentially administering to a subject multiple
doses of a compound
described herein. As used herein, "sequentially administering" means that each
dose of the
compound is administered to the subject at a different point in time, e.g., on
different days
separated by a predetermined interval (e.g., hours, days, weeks, or months).
The present disclosure
includes methods which comprise sequentially administering to the patient a
single initial dose of
a compound described herein, followed by one or more secondary doses of the
compound, and
optionally followed by one or more tertiary doses of the compound.
[00311] The terms "initial dose," "secondary doses," and "tertiary doses,"
refer to the temporal
sequence of administration of the compounds described herein. Thus, the
"initial dose" is the dose
which is administered at the beginning of the treatment regimen (also referred
to as the "baseline
dose"); the "secondary doses" are the doses which are administered after the
initial dose; and the
"tertiary doses" are the doses which are administered after the secondary
doses. The initial,
secondary, and tertiary doses can all include the same amount the compound
described herein, but
generally can differ from one another in terms of frequency of administration.
In certain
embodiments, the amount of the compound included in the initial, secondary
and/or tertiary doses
varies from one another (e.g., adjusted up or down as appropriate) during the
course of treatment.
In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are
administered at the beginning
of the treatment regimen as "loading doses" followed by subsequent doses that
are administered
on a less frequent basis (e.g., "maintenance doses").
[00312] In certain exemplary embodiments of the present disclosure, each
secondary and/or
tertiary dose is administered 1 to 26 (e.g., 1, P/2, 2, 2%2, 3, 3'/2, 4, 41/2,
5, 51/2, 6, 61/2, 7, 71/2, 8, 81/2,
9, 91/2, 10, 101/2, 11, 1P/2, 12, 121/2, 13, 131/2, 14, 141/2, 15, 151/2, 16,
161/2, 17, 171/2, 18, 181/2, 19,
191/2, 20, 201/2, 21, 211/2, 22, 221/2, 23, 231/2, 24, 241/2, 25, 251/2, 26,
261/2, or more) weeks after the
immediately preceding dose. The phrase "the immediately preceding dose," as
used herein, means,
in a sequence of multiple administrations, the dose the compound which is
administered to a patient
prior to the administration of the very next dose in the sequence with no
intervening doses.
279
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00313] The methods according to this embodiment of the disclosure may
comprise
administering to a patient any number of secondary and/or tertiary doses of
the compound. For
example, in certain embodiments, only a single secondary dose is administered
to the patient. In
other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary
doses are administered
to the patient. Likewise, in certain embodiments, only a single tertiary dose
is administered to the
patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or
more) tertiary doses are
administered to the patient. The administration regimen may be carried out
indefinitely over the
lifetime of a particular subject, or until such treatment is no longer
therapeutically needed or
advantageous.
[00314] In embodiments involving multiple secondary doses, each secondary dose
may be
administered at the same frequency as the other secondary doses. For example,
each secondary
dose may be administered to the patient 1 to 2 weeks or 1 to 2 months after
the immediately
preceding dose. Similarly, in embodiments involving multiple tertiary doses,
each tertiary dose
may be administered at the same frequency as the other tertiary doses. For
example, each tertiary
dose may be administered to the patient 2 to 12 weeks after the immediately
preceding dose. In
certain embodiments of the disclosure, the frequency at which the secondary
and/or tertiary doses
are administered to a patient can vary over the course of the treatment
regimen. The frequency of
administration may also be adjusted during the course of treatment by a
physician depending on
the needs of the individual patient following clinical examination.
[00315] The present disclosure includes administration regimens in which 2 to
6 loading doses
are administered to a patient at a first frequency (e.g., once a week, once
every two weeks, once
every three weeks, once a month, once every two months, etc.), followed by
administration of two
or more maintenance doses to the patient on a less frequent basis. For
example, according to this
embodiment of the disclosure, if the loading doses are administered at a
frequency of once a month,
then the maintenance doses may be administered to the patient once every six
weeks, once every
two months, once every three months, etc.
[00316] The present disclosure includes pharmaceutical compositions of the
compounds and/or
conjugates described herein, e.g., the compounds Formulae I, Ia, Iaa, Iaaa,
lb, Ibb, Ibbb, II, Ha,
IIaa, IIaaa, Ilb, Ilbb, Ilbbb, III, Ma, IIIaa, IIIaaa, Mb, IIIbb, IIIbbb, IV,
and/or V, e.g.,
compositions comprising a compound described herein, a salt, stereoisomer,
regioisomer,
280
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
polymorph thereof, and a pharmaceutically acceptable carrier, diluent, and/or
excipient. Examples
of suitable carriers, diluents and excipients include, but are not limited to,
buffers for maintenance
of proper composition pH (e.g., citrate buffers, succinate buffers, acetate
buffers, phosphate
buffers, lactate buffers, oxalate buffers, and the like), carrier proteins
(e.g., human serum albumin),
saline, polyols (e.g., trehalose, sucrose, xylitol, sorbitol, and the like),
surfactants (e.g., polysorbate
20, polysorbate 80, polyoxolate, and the like), antimicrobials, and
antioxidants. In one
embodiment, provided is a pharmaceutical composition including the compounds
of any of
Formulae I, Ia, Iaa, Iaaa, lb, Ibb, Ibbb, II, Ha, IIaa, IIaaa, Hb, IIbb,
Ilbbb, III, Ma, IIIaa, IIIaaa,
Illb, IIIbb, IIIbbb, IV, and/or V, and a pharmaceutically acceptable
excipient, carrier, or diluent.
[00317] In some examples, set forth herein is a method of treating a disease,
disorder or
condition including administering to a patient having said disorder a
therapeutically effective
amount of a compound set forth herein, or a pharmaceutical composition thereof
[00318] In some examples, set forth herein is a method of treating a disease,
disorder or
condition including administering to a patient having said disorder a
therapeutically effective
amount of a compound of Formulae I, Ia, Iaa, Iaaa, lb, Ibb, Ibbb, II, Ha,
IIaa, IIaaa, Hb, IIbb, Ilbbb,
III, Ma, IIIaa, IIIaaa, Mb, IIIbb, IIIbbb, IV, and/or V, or a pharmaceutical
composition thereof
[00319] In some examples, set forth herein are methods of treating a disease,
disorder, or
condition associated with the glucocorticoid receptor comprising administering
a compound of
Formulae I, Ia, Iaa, Iaaa, lb, Ibb, Ibbb, II, Ha, IIaa, IIaaa, Hb, IIbb,
Ilbbb, III, Ma, IIIaa, IIIaaa,
Illb, IIIbb, IIIbbb, IV, and/or V, to a patient having said disease, disorder,
or condition, and
combinations thereof
[00320] The present disclosure includes methods of preventing certain
disorders or conditions
comprising administering a therapeutically effective amount of one or more of
the compounds
disclosed herein (i.e., prophylactic uses). Examples include, but are not
limited to preventing
cytokine release syndrome for CD3 bispecifics, and adoptive cellular therapies
such as CAR T
cells, systemic IL-2 administration, graft-versus-host disease, and post-
operative nausea and
vomiting. Examples also include, but are not limited to, therapeutic
antibodies such as
alemtuzumab, muromonab, rituximab, tosituzumab, and agonistic antiboides where
immune
stimulation might be part of the intended mechanism of action..
281
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00321] In some embodiments, the disease, disorder, or condition is an
allergic state, including,
but not limited to, asthma, atopic dermatitis, contact dermatitis, drug
hypersensitivity reactions,
anaphylactic rhinitis, perennial or seasonal allergic rhinitis, and serum
sickness; dermatologic
diseases and conditions including, but not limited to, skin itching,
seborrheic dermatitis,
neurodermatitis, bullous dermatitis herpetiformis, exfoliative erythroderma,
mycosis fungoides,
pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome);
endocrine disorders
including, but not limited to, primary or secondary adrenocortical
insufficiency, congenital adrenal
hyperplasia, hypercalcemia associated with cancer, and nonsuppurative
thyroiditis;
gastrointestinal diseases; hematologic disorders including, but not limited
to, acquired
(autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia
(Diamond-Blackfan
anemia), idiopathic thrombocytopenic purpura in adults, pure red cell aplasia,
and secondary
thrombocytopenia; trichinosis; tuberculous meningitis with subarachnoid block
or impending
block; neoplastic diseases including, but not limited to, leukemias and
lymphomas; nervous system
disorders including, but not limited to, acute exacerbations of multiple
sclerosis, cerebral edema
associated with primary or metastatic brain tumor, craniotomy, or head injury;
ophthalmic diseases
including, but not limited to, sympathetic ophthalmia, temporal arteritis,
uveitis, and ocular
inflammatory conditions unresponsive to topical corticosteroids; renal
diseases including, but not
limited to, for inducing a diuresis or remission of proteinuria in idiopathic
nephrotic syndrome or
that due to lupus erythematosus; respiratory diseases including, but not
limited to, berylliosis,
fulminating or disseminated pulmonary tuberculosis when used concurrently with
appropriate
antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic
sarcoidosis; and
Rheumatic disorders including, but not limited to, use as adjunctive therapy
for short-term
administration (to tide the patient over an acute episode or exacerbation) in
acute gouty arthritis,
acute rheumatic carditis, ankylosing spondylitis, psoriaticarthritis,
rheumatoid arthritis, including
juvenile rheumatoid arthritis, and for use in dermatomyositis, polymyositis,
and systemic lupus
erythematosus.
[00322] In some examples, set forth herein is a method for treating a disease,
disorder, or
condition selected from an autoimmune disease, an allergy, arthritis, asthma,
a breathing disorder,
a blood disorder, a cancer, a collagen disease, a connective tissue disorder,
a dermatological
disease, an eye disease, an endocrine problem, an immunological disease, an
inflammatory disease,
an intestinal disorder, a gastrointestinal disease, a neurological disorder,
an organ transplant
282
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
condition, a rheumatoid disorder, a skin disorder, a swelling condition, a
wound healing condition,
and combinations thereof, comprising administering a steroid payload or
conjugate thereof
described herein.
[00323] In some examples, the autoimmune disorder is selected from multiple
sclerosis,
autoimmune hepatitis, shingles, systemic lupus erythematosus (i.e., lupus),
myasthenia gravis,
Duchenne muscular dystrophy, and sarcoidosis. In some examples, the breathing
disorder is
selected from asthma, chronic respiratory disease, chronic obstructive
pulmonary disease,
bronchial inflammation, and acute bronchitis. In some examples, the cancer is
selected from
leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, chronic
lymphoblastic
leukemia, Hodgkin's lymphoma, Non-Hodgkin's lymphoma (NHL), and multiple
myeloma. In
some examples, the collagen disease is systemic lupus erythematosus. In some
examples, the eye
disease is keratitis. In some examples, the endocrine problem is selected from
Addison's Disease,
adrenal insufficiency, adrenal cortical dysfunction, adrenocortical, and
congenital adrenal
hyperplasia. In some examples, the inflammatory disease is selected from
inflammation after
cataract surgery, joint inflammation, immune inflammation, tendon
inflammation, bursitis,
epicondylitis, Crohn's disease, inflammatory bowels disease, lipid pneumonitis
thyroiditis,
urticaria (hives), pericarditis, nephrotic syndrome, and uveitis. In some
examples, the intestinal
disorder is selected from ulcerative colitis, Crohn's disease, and
inflammatory bowel disease. In
some examples, the rheumatoid disorder is selected from rheumatoid arthritis,
polymyalgia
rheumatic, psoriatic arthritis, ankylosing spondylitis, and systemic lupus
erythematosus. In some
examples, the skin disorder is selected from psoriasis, eczema, and poison
ivy. In some examples,
the neurological disorder is chronic inflammatory demyelinating
polyradiculoneuropathy.
[00324] In some embodiments, the compounds described herein are administered
to a patient to
treat an acute inflammatory event including, but not limited to, shock, brain
edema, and graft-vs-
host disease. In some embodiments, the compounds described herein are
administered to treat
lympholytic effects including, but not limited to, those associated with
hematological
malignancies, for example, leukemias, lymphomas, and myelomas.
[00325] In some examples, set forth herein is a method for reducing
inflammation in a subject
in need thereof, comprising administering to a subject in need thereof a
therapeutically effective
amount of a steroid or conjugate thereof described herein. In some examples,
set forth herein is a
283
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
method for modulating the immune system in a subject in need thereof,
comprising administering
to a subject in need thereof a therapeutically effective amount of a steroid
or conjugate thereof
described herein. In some examples, set forth herein is a method for
modulating cortisol levels in
a subject in need thereof, comprising administering to a subject in need
thereof a therapeutically
effective amount of a steroid or conjugate thereof described herein. In some
examples, set forth
herein is a method of reducing lymphocyte migration in a subject in need
thereof, comprising
administering to a subject in need thereof a therapeutically effective amount
of a steroid or
conjugate thereof described herein. In some examples, set forth herein is a
method of treating
hypercalcemia due to cancer, Meniere's disease, a migraine headache, a cluster
headache, a severe
aphthous ulcer, laryngitis, severe tuberculosis, a Herxheimer reaction to
syphilis, a decompensated
heart failure, allergic rhinitis or nasal polyps, comprising administering to
a subject in need thereof
a steroid payload or conjugate thereof described herein. In some examples, the
compounds
disclosed herein can be used for treating inflammatory bowel disease, Crohn's
disease, or
ulcerative colitis. In some examples, the disease, disorder, or condition is a
chronic inflammatory
condition including, but not limited to, asthma, skin infections, and ocular
infections. In some
examples, compounds described herein are used for immunosuppression in
patients undergoing
organ transplantation.
[00326] In some embodiments, the steroid payloads and conjugates thereof
described herein are
administered to a patient to treat a nervous disorder associated with GR
signalling including, but
not limited to, psychiatric disorders such as schizophrenia, drug addiction,
post-traumatic stress
disorder (PTSD), and mood disorders, substance abuse, stress, and anxiety. In
some embodiments,
the steroid payloads and conjugates thereof described herein are administered
to a patient to treat
a visual system disorder including, but not limited to, ocular inflammation
(e.g., conjunctivitis,
keratitis, uveitis), macular edema, and macular degeneration. In some
embodiments, the steroid
payloads and conjugates thereof described herein are administered to a patient
to treat a
cardiovascular disorder. In some embodiments, the steroid payloads and
conjugates thereof
described herein are administered to a patient to treat a glucose and/or liver
metabolism disorder.
In some embodiments, the steroid payloads and conjugates thereof described
herein are
administered to a patient to treat a musculoskeletal system disorder. In some
embodiments, the
steroid payloads and conjugates thereof described herein are administered to a
patient to treat a
cutaneous inflammatory condition, such as eczema and psoriasis.
284
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00327] The protein conjugates described herein provide a means for targeted
delivery of its
steroid payload to particular cells or organ systems, thereby reducing or
preventing side effects
that result from administration of the free unconjugated steroid payload.
Examples of such
potential side effects to be reduced or prevented include those listed in the
approved drug label for
Decadront (dexamethasome), which is incorporated herein by reference in its
entirety. In some
embodiments, the side effect to be reduced or prevented is selected from
elevation of blood
pressure; sodium retention; water/fluid retention (edema, angioedema,
pulmonary edema);
increased excretion of potassium; reversible hypothalamic-pituitary adrenal
(HPA) axis
suppression; potential corticosteroid insufficiency after withdrawal of
treatment; susceptibility to
infecctions; exacerbation of systemic fungal infections; worsening of severity
of chickenpox in
pediatric and adult patients; worsening of severity of measles in pediatric
and adult patients;
posterior subcapsular cataracts; glaucoma with possible damage to the optic
nerves; enhancement
of the establishment of secondary ocular infections due to bacteria, fungi, or
viruses; increase in
new episodes of optic neuritis; Kaposi's sarcoma; drug-induced secondary
adrenocortical
insufficiency; increased risk of a perforation when active or latent peptic
ulcers, diverticulitis, fresh
intestinal anastomoses, and nonspecific ulcerative colitis, are present;
peritoneal irritation
following gastrointestinal perforation; decreased bone formation; increased
bone resorption;
inhibition of osteoblast function; inhibition of bone growth in pediatric
patients; development of
osteoporosis at any age; acute myopathy (possibly involving ocular and
respiratory muscles, and
potentially resulting in quadriparesis); elevation of creatinine kinase;
psychic derangements,
ranging from euphoria, insomnia, mood swings, personality changes, and severe
depression, to
frank psychotic manifestations; aggravation of existing emotional instability
or psychotic
tendencies; elevated intraocular pressure; bradycardia; cardiac arrest;
cardiac arrhythmias; cardiac
enlargement; circulatory collapse; congestive heart failure; fat embolism;
hypertension;
hypertrophic cardiomyopathy in premature infants; myocardial rupture following
recent
myocardial infarction; syncope; tachycardia; thromboembolism;
thrombophlebitis; vasculitis;
acne; allergic dermatitis; dry scaly skin; ecchymoses and petechiae; erythema;
impaired wound
healing; increased sweating; rash; striae; suppression of reactions to skin
tests; thin fragile skin;
thinning scalp hair; urticarial; decreased carbohydrate and glucose tolerance;
development of
cushingoid state; hyperglycemia; glycosuria; hirsutism; hypertrichosis;
increased requirements for
insulin or oral hypoglycemic agents in diabetes (insulin resistance);
manifestations of latent
285
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
diabetes mellitus; menstrual irregularities; secondary adrenocortical and
pituitary
unresponsiveness (particularly in times of stress; as in trauma; surgery; or
illness); suppression of
growth in pediatric patients; congestive heart failure in susceptible
patients; fluid retention;
hypokalemic alkalosis; potassium loss; sodium retention; abdominal distention;
elevation in serum
liver enzyme levels (usually reversible upon discontinuation); hepatomegaly;
increased appetite;
nausea; pancreatitis; peptic ulcer with possible perforation and hemorrhage;
perforation of the
small and large intestine (particularly in patients with inflammatory bowel
disease); ulcerative
esophagitis; negative nitrogen balance due to protein catabolism; aseptic
necrosis of femoral and
humeral heads; loss of muscle mass; muscle weakness; osteoporosis; pathologic
fracture of long
bones; steroid myopathy; tendon rupture; vertebral compression fractures;
convulsions;
depression; emotional instability; euphoria; headache; increased intracranial
pressure with
papilledema (pseudotumor cerebri) usually following discontinuation of
treatment; insomnia;
mood swings; neuritis; neuropathy; paresthesia; personality changes; psychic
disorders; vertigo;
exophthalmos; glaucoma; increased intraocular pressure; posterior subcapsular
cataracts;
abnormal fat deposits; decreased resistance to infection; hiccups; increased
or decreased motility
and number of spermatozoa; malaise; moon face; and weight gain; and and those
side effects
associated with drug-drug interactions. In some embodiments, the side effect
to be reduced or
prevented are those associated with drug-drug interactions. In some
embodiments, the side effect
to be reduced or prevented is associated with drug-drug interactions from the
use of a corticosteroid
with aminoglutethimide including diminishment of adrenal suppression by
corticosteroids;
amphotericin B injection and potassium-depleting agents, including development
of hypokalemia,
cardiac enlargement, and congestive heart failure; antibiotics including a
significant decrease in
corticosteroid clearance; anticholinesterases including producing severe
weakness in patients with
myasthenia gravis; oral anticoagulants including inhibition of response to
warfarin; antidiabetics
including increased blood glucose concentrations; antitubercular drugs
including decreased serum
concentrations of isoniazid; cholestyramine including increased clearance of
corticosteroids;
cyclosporine including increased activity of both cyclosporine and
corticosteroids, and incidence
of convulsions; dexamethasone suppression test (DST) interference including
false-negative
results in patients being treated with indomethacin; digitalis glycosides
including increased risk of
arrhythmias due to hypokalemia; ephedrine including enhancement of the
metabolic clearance of
corticosteroids, resulting in decreased blood levels and lessened physiologic
activity; estrogens,
286
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
including oral contraceptives, including decreased hepatic metabolism of
certain corticosteroids
and associated increase in their effect; hepatic enzyme inducers, inhibitors
and substrates (drugs
which induce cytochrome P450 3A4 (CYP 3A4) enzyme activity e.g., barbiturates,
phenytoin,
carbamazepine, rifampin), including enhancing of metabolism of
corticosteroids; drugs which
inhibit CYP 3A4 (e.g., ketoconazole, macrolide antibiotics such as
erythromycin), including the
potential for increased plasma concentrations of corticosteroids; drugs that
are metabolized by
CYP 3A4 (e.g., indinayir, erythromycin), including increase in their
clearance, resulting in
decreased plasma concentration; ketoconazole including decreased metabolism of
certain
corticosteroids by up to 60%, leading to increased risk of corticosteroid side
effects, and inhibition
of adrenal corticosteroid synthesis potentially causing adrenal insufficiency
during corticosteroid
withdrawal; nonsteroidal anti-inflammatory agents (NSAIDS), including
increased risk of
gastrointestinal side effects and increased clearance of salicylates;
phenytoin, including increases
or decreases in phenytoin level, altered seizure control; skin tests,
including suppression of
reactions to skin tests; thalidomide including toxic epidermal necrolysis; and
vaccines including a
diminished response to toxoids and live or inactivated vaccines due to
inhibition of antibody
response or potentiation of the replication of some organisms contained in
live attenuated
vaccines). Thus, provided herein are methods for treating a disease, disorder,
or condition
associated with the glucocorticoid receptor comprising administering a
conjugate of Formulae I,
Ia, Iaa, Iaaa, Ib, Ibb, Ibbb, II, IIa, IIaa, IIaaa, TTb, Ilbb, IIbbb, III, Ma,
IIIaa, IIIaaa, Mb, IIIbb,
IIIbbb, IV, and/or V, to a patient haying said disease, disorder, or
condition, wherein the side
effects associated with administration of the free steroid payload of said
conjugate is reduced.
Furthermore, provided herein are methods of delivering a compound of Formulae
I, Ia, Iaa, Iaaa,
lb, Ibb, Ibbb, II, IIa, IIaa, IIaaa, TTb, Ilbb, IIbbb, III, Ma, IIIaa, IIIaaa,
Mb, IIIbb, IIIbbb, IV, and/or
V, to a cell comprising contacting said cell with a protein conjugate the
compound of Formulae I,
Ia, Iaa, Iaaa, Ib, Ibb, Ibbb, II, IIa, IIaa, IIaaa, TTb, Ilbb, IIbbb, III, Ma,
IIIaa, IIIaaa, Mb, IIIbb,
IIIbbb, IV, and/or V, wherein the protein conjugate comprises an antibody or
antigen binding
fragment thereof that binds a surface antigen of said cell.
[00328] In some examples, set forth herein is a method of treating a disease,
disorder or
condition selected from the group consisting of an immunological disease,
autoimmune disease,
inflammation, asthma, or an inflammatory bowel disorder, Crohn's disease,
ulcerative colitis.
287
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00329] In some examples, set forth herein is a method of treating a disease,
disorder or
condition by targeting an antigen, e.g., cell-surface expressing antigen, to
which steroid delivery
can achieve a therapeutic benefit comprising administering the conjugates
described herein. In
some embodiments, the antigen is AXL, BAFFR, BCMA, BCR-list components, BDCA2,
BDCA4, BTLA, BTNL2, BTNL3, BTNL8, BTNL9, C10orf54, CCR1, CCR3, CCR4, CCR5,
CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD168, CD177, CD19, CD20,
CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD274, CD276, CD28, CD30,
CD300A,
CD33, CD37, CD38, CD4, CD40, CD44, CD45, CD47, CD46, CD48, CD5, CD52, CD55,
CD56,
CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.2,
CD96,
CLEC12A, CLEC12B, CLEC7A, CLEC9A, CR1, CR3, CRTAM, CSF1R, CTLA4, CXCR1/2,
CXCR4, CXCR5, DDR1, DDR2, DEC-205, DLL4, DR6, FAP, FCamR, FCMR, FcR's, Fire,
GITR, HHLA2, HLA class II, HVEM, ICOSLG, IFNLR1, ILlOR1, IL1OR2, IL12R,
IL13RA1,
IL13RA2, IL15R, IL17RA, IL17RB, IL17RC, IL17RE, IL20R1, IL20R2, IL21R, IL22R1,
IL22RA, IL23R, IL27R, IL29R, IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R,
IL7R, IL9R,
Integrins, LAG3, LIFR, MAG/Siglec-4, MMR, MSR1, NCR3LG1, NKG2D, NKp30, NKp46,
PDCD1, PROKR1, PVR, PVRIG, PVRL2, PVRL3, RELT, SIGIRR, Siglec-1, Siglec-10,
Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, SIRPA, SLAMF7, TACT, TCR-
list
components/assoc, PTCRA, TCRb, CD3z, CD3, TEK, TGFBR1, TGFBR2, TGFBR3, TIGIT,
TLR2, TLR4, TROY, TSLPR, TYRO, VLDLR, VSIG4, or VTCN1. In some embodiments,
the
antigen is IL2R-y.
[00330] In some examples, set forth herein is a method for treating a disease,
disorder, or
condition selected from an immunological disease, an autoimmune disease, an
inflammatory
disease, a dermatological disease, or a gastrointestinal disease.
[00331] In some examples, the disease is Crohn's disease, ulcerative
colitis, Cushing's
syndrome, adrenal insufficiency, or congenital adrenal hyperplasia.
[00332] In some examples, the disease is inflammation, asthma, or an
inflammatory bowel
disorder.
[00333] In some examples, the disease is an autoimmune diseases selected from
multiple
sclerosis, rheumatoid arthritis, inflammatory bowel disease, ulcerative
colitis, psoriasis, or eczema
288
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00334] In some examples, set forth herein is a method for reducing or
ameliorating the side
effects of chemotherapy, wherein the method includes administering to a
patient having said
disorder a therapeutically effective amount of a compound or a composition
described herein.
[00335] In some examples, set forth herein is a method for reducing or
ameliorating the side
effects of immunosuppressive therapy, wherein the method includes
administering to a patient
having said disorder a therapeutically effective amount of a compound or a
composition described
herein.
[00336] In some examples, set forth herein is a method for treating cancer,
wherein the method
includes administering to a patient having said disorder a therapeutically
effective amount of a
compound or a composition described herein. In some examples, the cancer is
selected from acute
lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's lymphoma,
Non¨Hodgkin's
lymphoma (NHL), or multiple myeloma, as well as others.
[00337] In some examples, set forth herein are methods for treating or
preventing any disease,
disorder, or condition responsive to modulation of LXR signalling. In some
examples, the disease
or disorder is associated with LXR function, LXR polymorphisms, LXR agonist
activity, or LXR
antagonist activity. In some examples, set forth herein is a method of
treating or preventing a
disease, disorder, or condition selected from the group consisting of a
proliferative disorder, a
neurodegenerative disorder, an immunological disorder, an autoimmune disease,
an inflammatory
disorder, a dermatological disease, a metabolic disease, cardiovascular
disease, and a
gastrointestinal disease.
[00338] The proliferative disorder can be any proliferative disorder known to
those of skill. In
certain embodiments, proliferative disorders include, without limitation,
oncology disorders,
where the oncology disorder can be any cancer disorder known to those of
skill. In certain
embodiments, provided herein are methods of treating or preventing a melanoma.
In certain
embodiments, provided herein are methods of treating or preventing metastatic
melanoma. In
certain embodiments, provided herein are methods of treating or preventing
lung cancer. In certain
embodiments, provided herein are methods of treating or preventing EGFR-
tyrosine kinase
inhibitor resistant lung cancer. In certain embodiments, provided herein are
methods of treating or
preventing oral cancer. In certain embodiments, provided herein are methods of
treating or
preventing oral squamous cell carcinoma. In certain embodiments, provided
herein are methods of
289
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
treating or preventing prostate cancer. In certain embodiments, provided
herein are methods of
treating or preventing Hodgkin's lymphoma. In certain embodiments, provided
herein are methods
of treating or preventing breast cancer.
[00339] The neurodegenerative disorder can be any neurodegenerative disorder
known to those
of skill. In certain embodiments, provided herein are methods of treating or
preventing
Alzheimer's disease. In certain embodiments, provided herein are methods of
treating or
preventing Parkinson's disease. In certain embodiments, provided herein are
methods of treating
or preventing Huntington's disease. In certain embodiments, provided herein
are methods of
treating or preventing amyotrophic lateral sclerosis. In certain embodiments,
provided herein are
methods of treating or preventing myelin gene expression. In certain
embodiments, provided
herein are methods of treating or preventing myelination and remyelination
conditions, diseases,
or disorders.
[00340] The immunological disorder can be any immunological disorder known to
those of
skill. In certain embodiments, provided herein are methods of treating or
preventing imflammatory
bowel disease. In certain embodiments, provided herein are methods of treating
or preventing
ulcerative colitis. In certain embodiments, provided herein are methods of
treating or preventing
Crohn's disease.
[00341] The inflammatory disorder can be any inflammatory disorder known to
those of skill.
In certain embodiments, provided herein are methods of treating or preventing
arthritis. In certain
embodiments, provided herein are methods of treating or preventing rheumatoid
arthritis.
[00342] The metabolic disease can be any metabolic disease known to those of
skill. In certain
embodiments, the metabolic disease is dyslipidemia. Dyslipidemia can be any
dyslipidemia known
to those of skill. In certain embodiments, dyslipidemia is selected from the
group consisting of
hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,
hyperlipoproteinemia, HDL
deficiency, ApoA-I deficiency, and cardiovascular disease such as coronary
artery disease
(including, for example, treatment and prevention of angina, myocardial
infarction, and sudden
cardiac death); atherosclerosis (including, for example, treatment and
prevention of
atherosclerosis); and restenosis (including, for example, preventing or
treating atherosclerotic
plaques which develop as a consequence of medical procedures such as balloon
angioplasty). In
certain embodiments, provided herein are methods of treating or preventing
diabetes.
290
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00343] The cardiovascular disease can be any cardiovascular disease known to
those of skill.
In certain embodiments, provided herein are methods of treating or preventing
atherosclerosis. In
certain embodiments, provided herein are methods of treating or preventing
atherosclerosis
derived from abnormal macrophage processing. In certain embodiments, provided
herein are
methods of treating or preventing atherosclerosis derived from the formation
of oxidized low-
density lipoproteins (oxLDLs), where marcrophages fail to process oxLDLs. In
certain
embodiments, provided herein are methods of treating or preventing ischemic
heart disease. In
certain embodiments, provided herein are methods of treating or preventing
stroke. In certain
embodiments, provided herein are methods of treating or preventing
hypertensive heart disease. In
certain embodiments, provided herein are methods of treating or preventing
aortic aneurysm. In
certain embodiments, provided herein are methods of treating or preventing
endocarditis. In certain
embodiments, provided herein are methods of treating or preventing peripheral
artery disease. In
certain embodiments, provided herein are methods of treating or preventing
combinations of any
of the diseases provided in this paragraph.
[00344] In some examples, set forth herein is a method for modulating the
function of a nuclear
receptor. By way of non-limiting example, the function may be selected from
expression/secretion
of inflammatory mediators (e.g. cytokines, chemokines), cholesterol
regulation, cholesterol intake,
cholesterol efflux, cholesterol oxidation, migration, chemotaxis, apoptosis
and necrosis, an
inflammatory activity, lipid regulation, apoptosis, migration, chemotaxis,
gene transcription, and
protein expression.
EXAMPLES
[00345] Provided herein are novel steroid and LXR modulator compounds,
prodrugs, or
payloads, protein conjugates thereof, and methods for treating diseases,
disorders, and conditions
including administering the steroid and LXR modulator compounds, prodrugs, or
payloads and
conjugates.
Table 1. List of Hydroxyl-Glucocorticoid Receptor Agonists
Drug/Payload
Drug#/Payload Structure cLogP
Name
HO
Dexamethasone 1.68
0 HO
OH
291
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
Drug/Payload
Drug#/Payload Structure cLogP
Name
H
II Budesonide ----\_4
2.73
o o
HO n
,F
H
,Il -
6,11-2F-
III ---N____<c) . 2.44
Budesonide o 0
HO n
'-' OH
0 0 0
H
IV LXR Agonist HO,AN = OH 6.53
H
Table 2a. List of N-C-O-Steroid Prodrugs
D*-
Cpd No. n R2 R3 I21 Structure
OH
H 0
I
PI 1 H H H
(Dex) H2NJ30
H OH OH
II o o
P11-1 1 H H H
(Bud) H
OH
H2N- 11
0
H
II
PII-2 1 Me H H o o
(Bud) H ,
H2N 1.-- N ''' OH
0
H
¨\_<0V N H
II
PII-3 1 Bn H H H 0
(Bud) ( 0
n2N s) N ,0 0 A
OH
0
II o o
PII-4 2 H H H 0 H
(Bud) o o on
H2N,..-k.NN
H 0
H
II
PII-5 2 Me H H 0 H 0 0
(Bud) N,0 0
H2N-.1.--f OH
H 0
H
0 :11
II
PII-6 1 H H Et o o
(Bud) H
N v 0
H2N-Ir
0
292
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
D*-
Cpd No. n R2 R3 122 Structure
OH
H
H
II o
PII-7 1 H H Bn H
N 0 0 OH
(Bud)
H2N7-'f
op
H
PII-8 1 H Me H o o
(Bud) ,N,,, 0
H2N' OH
0
II 0 .11 H
PII-9 1 H ,,,,, r\ro
(Bud)
H2N 2
_O 1-1
OH 0
võ0 H
II 0¨o
PII-10 1 H
(Bud) N
0 0
H2N-'
HO H
0
,F
0 ='" ,I-1 .
----V-K .
PIII-1 1 H H H III o o
H ,-,
õ,..,_õN,-' 0 OH
H2N ¨It;
,F
.
----\-- '
PIII-4 2 H H H III o o
0 H
H2N )LN.,---1, N ---/ 0 OH
H o
H
O 1-1
P11-l1 1 Me Me H 0 0
(Bud)
)
H2N---,(1L--C) OH
0
H
O ,FI
õõ----,,.
II
PII-12 1 H 0 0
(Bud)
Nvo 0 OH
N2N
0
H
O tl
PII-13 1 H
. 0 0
- - (Bud) H2N
0 N 0¨v OH
I
293
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
D*-
Cpd No. n R2 R3 R1 Structure
OH
f
-\_-(
PIII-5 1 Me H H III 0 0
H ,
H2N).õ1.(N,,,,' 0 OH
0
0 0 0
H ssH H
Ply 1 H H H IV H2N-M---N--- --.)L-N
H " H
0
Table 2b. Properties of N-C-O-Steroid Prodrugs
HPLC
Cpd No. n R2 R3 R1 D*-0H cLogP MF MW Purity
Rt (min)
(%)
PI 1 H H H I (Dex) 0.53 C25H35FN206
478.6 99 5.42 (A)
II
P11-1 1 H H H 1.58 C28H4oN207 516.6 96
7.55(B)
(Bud)
II
PII-2 1 Me H H 2.15 C29H42N207 530.7 96 7.40
(B)
(Bud)
II
PII-3 1 Bn H H 3.81 C35H46N207 606.8 99 8.39
(B)
(Bud)
II
PII-4 2 H H H 0.48 C3oH43N308 573.7 98 6.90
(B)
(Bud)
II
P11-5 2 Me H H 1.62 C32H47N308 601.7 >99 7.25
(B)
(Bud)
II
PII-6 1 H H Et 2.45 C3oH44N207 544.7 95 7.96,
8.15 (B)
(Bud)
II
PII-7 1 H H Bn 3.59 C35H46N207 606.7 99 8.49,
8.66 (B)
(Bud)
II
PII-8 1 H Me H 1.81 C29H42N207 530.7 >99 7.42
(B)
(Bud)
II
P11-9 1 H 2.20 C311-144N207 556.7 >99
7.87 (B)
(Bud)
II
P11-10 1 H 41T.. 2.65 C32H46N207 570.7
(Bud)
PIII-1 1 H H H III 1.29 C28H38F2N207 552.6
99 6.97 (B)
PIII-4 2 H H H III 0.18 C3oH41F2N308 609.7
99 6.95 (B)
II
PII-11 1 Me Me H 2.38 C30H44N207 544.7
>99 7.62 (B)
(Bud)
......--........
II
P11-12 1 H 2.43 C311-144N207 556.7 >99
8.05, 8.12 (B)
(Bud)
PII-13 1 H 7 ii
2.65 C32H46N207 570.7 99 9.93 (B)
(Bud)
PIII-5 1 Me H H III 1.86
C29H4oF2N207 566.6
Ply 1 H H H IV 5.25 C39H52N406 672.9 99
7.83 (B)
294
Table 3a. List of Linker-N-C-O-Steroid Prodrugs
0
Cpd# P Name
Structures r..)
o
o.,,NH, l'.)
0
NH
I..,
.6,
DIBAC-suc-PEG4- o
0
H
Li-PI PI
t! H Url
o
vcPAB-PI PrIH-rill
'-'-'0'''"za..""e'"*.CL'eeTh-r H N,:lj'N4NI
1 4111,11
H .6,
0 O,,-) 0
0 gir 0T.
I..,
y
N 0 F
0
H 0 OH OH
0 =
H
9 ro 0
DIBAC-suc-PEG4-
Li-PH-1 P11-1 1
vcPAB-PII-1 NI.H-Lo,..--....,o,,)-L,NrIst, N
8
H
0 H 0 H
0
N'll'NH2
H
P
0 H
,H 0
La
--- \--<
=' I-
IV
0 I H 0
0 Ul
ts.) DIBAC-suc-PEG4- / o H o 40) 0-
'LLN-""-Tor"----- 0 OH Low
0
a'
un L 1-PII-2 PII-2 Ny...-,LLjrrrN
vcPAB-PII-2 H
N)0
0 H 0 H
IV
1-`
I
N1NH2
0
H
...3
i
0
...3
---00
H
0
0
H
DIBAC-PEG4-vcPAB-
N 0
Li-PII-3 PII-3
N
F-NHCH2-Bud N
H H
H HO
0 0
0
A
N NH2
.0
H
0 n
0
0 .f....0 ,,
(1)'m
t..)
DIBAC-suc-PEG4- I o o
rs'int, 0 N 0
t..)
Li-PII-4 PII-4 õco,-..Ø.-,,o,-,0.....,}L.
=
vcPAB-PII-4 o H H- -01
HO
I..,
`...1
0
07NH2 oo
H
"
0
0
DIBAC suc PEG4 0
ii o o ii
c) 0 o N 0 N 0 om
n.)
L 1-PII-5 PII-5 )1e..,....0,,,.Ø..,õ}L. N N N
=
vcPAB PII-5 o H H 0 H
k...)
=
I..,
NH
CA
IDNH2
Url
.6,
0 H H I..L
0, J.LO ria,,,,I.,orNN co 0 OH
--- \ -<
0
DIBAC suc PEG4 II 0 0 y N
L 1-PII-6 PII-6 Ir"----- N"----c)------o- ---- ---^o^---
--J'I' Nrisi 7)N *
vcPAB PII-6 H
0 H 0 H
0
A
N NH2
H
0 H H
¨ \ --K
0
0 N 0
DIBAC suc PEG4 li o o y N IL N
0 n OH
0 N Tr -
L 1-PII-7 PII-7 ye'-AN^A^o'-' --0- Nrr`l :)N
P
vcPAB PII-7 H
110 0
o H 0 H
0
la
A
N)
N) N NH2
H Ul
to
IV
0 j
0 0 0
IV
DIBAC suc PEG4 H 0 0 IL )r-
¨N 0 0 OH
I-k
1
L 1-PII-8 PII-8 Nir.--õ,)-L,N.--õ.....oõ,o,õoõ......õ11
::' N 0 N--
0 H 0
0
-.1
vcPAB PII-8 H
1
0 0 H 0
H 0
..]
N 1L'NH2
H
H
N freNH2
0
0
H 4H
DIBAC suc PEG4
,C,?-( H
L 1-PII-9 PII-9NXLL N
0 0 11 El
vcPAB PII-9 o 0 H 0 0
N,A.
0 0
0
HO H
0
H
'A .0
NNH2 .r..
n
H
ei
DIBAC suc PEG4 o i H 0 4H
H N 0
a
0 ,H H
L 1-PII-1 0 PII-10
CP
vcPAB PII-1 0 ri-rF N 0
0 H 0 0
lie N,,,0,,,L 0 t=.)
0
=
=
0
a
w
-...,
,,,,
F
0
E. JO, 0
DIBAC-suc-PEG4-
Li-Pill-1 PIII-1
ts.)
vcPAB-PIII-1 0----...Ø---Ø---
,ANc11,. N
H
0 H 0 H
I..,
0
=P
0
NANH2
Url
H
=P
F
1-,
,õ FIFI
0
DIBAC-suc-PEG4-
0 OH
L2-PIII-1 PIII-1
G1u-vcPAB-PIII-1
Fri vi
'w
0 0 0
-L 0
HO 0
NANH2
H
0 P DIBAC-suc-PEG4-
N,I(,)t.N,,ONõ.,,0,",....-- --.../''cj'.'ThTN 0 0 0 11,AN^c) -
L3-PIII-1 PIII-1
GGF-PIII-1 o 'I 0 0
o 2
N)
HO HO F' Ul
to
0
00
'NI
IV
0
"
I-' Ny)L0 Nii,A0 N il j N0
DIBAC-suc-GGF-PIII-
0
-3
L4-PIII-1 PIII-1 o " o o o
,
0 1
,J
HO Fr
0
OH
o
DIBAC-suc-SGGG- N N,crljNThr11,)-Himr101c0
''',J1
L5-PIII-1 PIII-1
PIII-1 o 0
HO Fr
0
IV
0
0
,-i
DIBAC-suc-PEG4- N
1 o o irrH
ci)
Li-PIII-4 PIII-4 tiy¨,),N,,,o,,,..0,,o,-Ø-,j1,N N,
vcPAB-PIII-4 o H H 0 H
HO F' N0
0
NH
0
-a-,
I..,
CI.NFI2
l'.)
---1
0
oe
CD ro H
H
0
H H N,
0 ' H C
L6-PII-9 PII-9
9
DIBAC-suc-PEG4-PII- o
o
o
o A w
o
HO
0 I..,
4=,
H
CA
0 ki H
Uvi
I..,
L7-PII-1 P11-1 DIBAC-suc-PII-1 0
H 0 0
N
NN '-'-' 0 glEi
H 8
0
kLA I;L)- H
ji
DIBAC-GGFG- 0 o - ,i 0
L4-PI PI
Vj
HO F.
NHCH2-Dex
o
P
H
Lo
r
N)
__ JO. Lrr,I,,,,, 0 0 ul
,0
N
N,TH,L,0 ,,,,o,....,õtr,,).., JN il N 0 0 N N 0
,o
00
DIBAC-PEG4-vcPAB- II 0
0
OH
pe
Li-Ph-l1 PII-11
" o N,
0
A-NMeCH2-Bud H
N,
0 H H
r 0 ,
0
A
..J
1
o
N NH
..]
H
H
0 -H
-- \
0
0 0
DIBAC-PEG4-vcPAB-
1 1 o o 1.4
o ill o'll'N N,0 0
OH
L 1-PII-12 PII-12 amino-piperidinone- N.11...
''Cls..-..')N isi'' N 4111111" H 0
CH2-Bud 0 H H 0
H
0
N )1'N H2
.0 H
n
H
ei
-- \ <0 H H
0
0 CP
14,0
0 N
0
COT-PEG4-EvcPAB- 9 o
la 0 r4 'r o
OH
N
L8-PII-1 P11-1 ki 0 kiL lq,
o
G-NHCH2-Bud
N 11111j"
cz
w
--.1
,4z
Ho o
N-jj-N H2 oe
H
kri H
L9-PII-1 P11-1 COT-GG-NHCH2-Bud
0 o
ki ki o o
OH 0 0
N
0
0 0
N
0
H I-,
01
COT-GGG-NHCH2- o
N 00 u,
L10-PII-1 P11-1
Bud --
0,0ji(y4,AN - 0
OH
O 0
H
L1 1-PII-2 PII-2 o
<0 H
COT-AAA-NHCH2- o
Bud ¨ oj0
0 N N- 0HH
O z 0
H
COT-AdAA-NHCH2- 0
P
L12-PII-2 PII-2 0
Bud 0,-
oi'LNWNJ11,0 0 2
OH
r,
0 0
w
.,
2
COT-GGGG-NHCH2- n
L13-PII-1 P11-1 O
Bud 14 o 14 o 14 0 o
;1
0 H
--\--:-_-,''-' .C. 0"-Th-or ------N-M-or ----2'N-Thoi-
OH
DIBAC-GGFG- o o
L14-PII-1 PII-1 N II CL) mill 0
.Thi,,c,
NHCH2-Bud N 'zN O HH
0 - 0
0
H
COT-SGGGG-NHCH2- r, OH 0 ti 0
L15-PII-1 P11-1
0 IV
Bud OH
n
,-i
o o o
cp
NH2
w
H
0
COT-KGGGG-
o
0 0 0
L16-PII-1 PII-1
14 14 H 0
NHCH2-Bud ¨ o ,o 0 H
0
N
0 '"-'11 ">-"Nr 'N OH
-1
o o 0
oe
H H H
COT-PEG4-G-NHCH2-
0
L17-PII-1 P11-1 o 0 0
o
Bud 0,o,5),N.---,...õ0.----0------- ------
0-N-I ¨ al t..)
o
t..)
o
H
11
4=,
Uvi
DIBAC-PEG4-G- o H 0
etidine-Bud
0
0
4=,
I..,
L6-PII-13 PII-13
0 H
Az N
Li '0''-C)'"'OAIN')NLI'-'() OH
0
H
HO 0 0
H 0
COT-EDA-
HO:AD O/[si OHrrsi'-() 0
L18-PII-1 P11-1 (GLC)PAB-G-NHCH2- HO : 0
OH
Bud HN 0
0, ?
P
L.
0,Thc,r,,NH
r
Iv
ul
u,
F
u,
W
oo
0
0
H H
0 "
0
Iv,
1
0
-F 0
..J
BCN-PEG4-vcPAB-G- 0 0 H 0
I& Oisil-rN 0
0
-JL19-PIII-1 PIII-1
H
NHCH2-III .0-,
,LL,_,,,,,..õoõ,-...0,o.,,,cy..-õ,11..N tq N Mr o
Air = 0 Eri
H H
111, H 0
0
N NH2
H
H 11 H -''F
L9-PIII-1 PIII-1 COT-GG-NHCH2-III o
Oon-:1 N Tr 0 OH
.0
0 n
,-i
COT-AdAA-NHCH2- o I
(4
L12-PIII-5 PIII-5
o
III
t.)
0---- ))0r1111¨ 0 .
,z.
-
" H H
=''F N
---1
0
COT-GGGG-NHCH2-
o oe
L13-PIII-1 PIII-1 o
III 0 1.4 :1) 14 o kJ 0
¨ N"--'"Nr -----'N'r ' OH
0 0 0
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
o
zI
z=
o)
o
0
IZ ZI
"
z.
to
z ZI
z.
0=U¨/ 0
xi 0)
x_t0
z=
tO
0
iz
0
iz
z.
0 0
cOD
c.)
(.7
1-1
ifr= ifr=
ifr=
4
301
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
Table 3b. Properties of Linker-N-C-0-Glueocorticoids
HPLC
Cpd# P Name cLogP MF MW Purity Rt
( % )
(min)1
Li-PI PI DIBAC-suc-PEG4-vcPAB-PI 2.60
C741496FN9018 1418.6 97 7.71
Li-PH-1 P11-1 DIBAC-suc-PEG4-vcPAB-PII-1 3.65
C77H1o1N9019 1456.7 96 8.07
Li-PII-2 PII-2 DIBAC-suc-PEG4-vcPAB-PII-2 4.22
C78H1o3N9019 1470.7 95 8.27
L1-PII-3 PII-3 DIBAC-suc-PEG4-vcPAB-PII-3 5.87
C84H1o7N9019 1546.8 96 8.70
L1-PII-4 PII-4 DIBAC-suc-PEG4-vcPAB-PII-4 2.54
C79H1o4N1002o 1513.8 98 7.94
L1-PII-5 PII-5 DIBAC-suc-PEG4-vcPAB-PII-5 3.68
C81H1o8N1002o 1541.8 >99 8.15
8.61,
L1-PII-6 PII-6 DIBAC-suc-PEG4-vcPAB-PII-6 4.51
C79H1o5N9019 1484.8 >99
8.71
8.89,
L1-PII-7 PII-7 DIBAC-suc-PEG4-vcPAB-PII-7 5.65
C84H1o7N9019 1546.8 97
8.96
L1-PII-8 PII-8 DIBAC-suc-PEG4-vcPAB-PII-8 3.87
C78H1o3N9019 1470.7 >99 8.41
L1-PII-9 PII-9 DIBAC-suc-PEG4-vcPAB-PII-9 4.26
C8oH1o5N9019 1496.8 >99 8.78
Li-PII-1 0 P11-10 DIBAC-suc-PEG4-vcPAB-PII-10
4.71 C81H1o7N9019 1510.8
Li-Pill-1 PIII-1 DIBAC-suc-PEG4-vcPAB-PIII-1 3.35
C77H99F2N9019 1492.7 >99 7.99
DIBAC-suc-PEG4-Glu-vcPAB-
L2-PIII-1 PIII-1 1.98 C82H1o6F2N10022 1621.8 97 7.23
PIII-1
L3-PIII-1 PIII-1 DIBAC-suc-PEG4-GGF-PIII-1 1.96 C711-
187F2N7017 1348.5 97 8.57
L4-PIII-1 PIII-1 DIBAC-suc-GGF-PIII-1 3.01
C6oH66F2N6012 1101.2 96 9.08
L5-PIII-1 PIII-1 DIBAC-suc-SGGG-PIII-1 -1.90 C581468F2N8015 1155.2 >99
7.78
Li-PIII-4 PI11-4 DIBAC-suc-PEG4-vcPAB-PIII-4 2.25
C79H1o2F2N1002o 1549.7 98 7.94
L6-PII-9 PII-9 DIBAC-suc-PEG4-PII-9 3.96 C611478N4014 1091.3
99 9.04
9.30,
L7-PII-1 P11-1 DIBAC-suc-PII-1 4.40 C47H53N309 804.0 98
9.49
L4-PI PI DIBAC-GGFG-NHCH2-Dex 2.26 C57H63FN6011 1027.2 >99
8.24
DIBAC-PEG4-vcPAB-A-
Ll-PH-1 1 PII-1 1 4.44 C79H1o5N9019 1484.8
98 8.23
NMeCH2-Bud
DIBAC-PEG4-vcPAB-amino-
Ll-PII-1 2 P11-12 . õ 4.49 C8oH1o5N9019 1496.8
.. 8.57
piperidinone-CH2-Bud
COT-PEG4-EvcPAB-G-NHCH2-
L8-PII-1 P11-1 2.02 C73H1o7N9022 1462.7 99 6.73
Bud
L9-PII-1 P11-1 COT-GG-NHCH2-Bud 2.55 C4oH55N3O10 737.9 99 8.45
L10-PH-1 P11-1 COT-GGG-NHCH2-Bud 1.45 C42H58N4011 794.9 >99 7.96
8.36,
L 1 1 -PII-2 PII-2 COT-AAA-NHCH2-Bud 3.15
C45H641\14011 837.0 >99
8.40
8.21,
L 12-PII-2 PII-2 COT-AdAA-NHCH2-Bud 3.15
C45H641\14011 837.0 >99
8.24
L13-PII-1 P11-1 COT-GGGG-NHCH2-Bud 0.34 C441461N5012 852.0 99 7.86
L14-PII-1 P11-1 DIBAC-GGFG-NHCH2-Bud 3.31 C6oH68N6012 1065.2
>99 8.97
L 15-PII-1 P11-1 COT-SGGGG-NHCH2-Bud -1.24
C47H66N6014 939.1 98 7.56
L16-PII-1 P11-1 COT-KGGGG-NHCH2-Bud -0.53 C5oH73N7013 980.2 99 6.57
L17-PII-1 P11-1 COT-PEG4-G-NHCH2-Bud 2.60 C49H73N3014 928.1 >99 8.73
L6-PII-1 3 P11-13 DIBAC-PEG4-G- Azetidine-Bud
3.88 C6oH761\14014 1077.3 >99 10.01
COT-EDA-(GLC)PAB-G-
L18-PII-1 P11-1 1.53 C55H741\14018 1079.2
8.39
NHCH2-Bud
BCN-PEG4-vcPAB-G-NHCH2-
L19-PIII-1 P111-1 3.23 C69H98F2N8019 1381.6 >99 8.04
III
L9-PIII-1 PIII-1 COT-GG-NHCH2-III 2.26 C4oH53F2N3O10 773.9 >99
9.52
302
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
L12-PIII-5 PIII-5 COT-AdAA-NHCH2-III 2.86 C45H62F2N4011 873.0 97 8.31
L13-PIII-1 PIII-1 COT-GGGG-NHCH2-III 0.05 C44H59F2N5012 888.0 >99
7.90
DIBAC-PEG4-vcPAB-G-NHCH2-
Li-PIV PIV 4.33 C7IF197N9015 1316.6 97
8.38
IV
L14-PIV PIV DIBAC-GGFG-NHCH2-IV 7.10 C71H8oN8011 1221.4 >99
8.88
1. All the linker-payloads were tested in HPLC using method B; for the
compounds containing two chiral
centers, two representative peaks were observed by LCMS.
Table 3c. Cleavage of Linker-N-C-O-Glucocorticoids
Quenched
HPLC Rt
Solubility
linker- Azides Linker-payloads m/z
(min)
(mg/mL)
payloads
taurine-PEG4- DIBAC-suc-PEG4-vcPAB- 1.74 (B) 712.8 [(M-
Q1L1-PI >1
azide PI [LCMS] Bud)/2+H]
DIBAC-suc-PEG4-vcPAB-
Q2L1-PII-1 CD-N3 6.76 (B) 819.0 (M/3+H) >1
P11-1
taurine-PEG4- DIBAC-suc-PEG4-vcPAB-
623.8 (M/3+H),
Q1L1-PII-2 6.83 (B) 720.0 [(M- >1
azide PII-2
Bud)/2+H]
taurine-PEG4- DIBAC-suc-PEG4-vcPAB- 757.8 [(M-
7.21 (B) >1
Q1L1-PII-3
azide PII-3 Bud)/2+H]
taurine-PEG4- DIBAC-suc-PEG4-vcPAB- 741.5 [(M-
6.65 (B) >1
Q1L1-PII-4
azide PII-4 Bud)/2+H]
taurine-PEG4- DIBAC-suc-PEG4-vcPAB- 755.5 [(M-
6.82 (B) >1
Q1L1-PII-5
azide PII-5 Bud)/2+H]
taurine-PEG4- DIBAC-suc-PEG4-vcPAB- 6.99, 7.05 726.7 [(M-
Q1L1-PII-6 . >1
azide PII-6 (B) Bud)/2+H]
taurine-PEG4- DIBAC-suc-PEG4-vcPAB- 8.21, 8.27 648.0 (M/3+H),
Q1L1-PII-7 . 758.0 [(M- >1
azide PII-7 (B)
Bud)/2+H]
taurine-PEG4- DIBAC-suc-PEG4-vcPAB-
935.0 (M/2+H),
Q1L1-PII-8 6.92 (B) 720.0 [(M- >1
azide PII-8
Bud)/2+H]
taurine-PEG4- DIBAC-suc-PEG4-vcPAB- 732.8 [(M-
7.03 (B) >1
Q1L1-PII-9
azide PII-9 Bud)/2+H]
taurine-PEG4- DIBAC-suc-PEG4-vcPAB- 741.4 [(M-
6.68 (B) >1
Q1L1-PIII-4
azide PI11-4 Bud)/2+H]
DIBAC-suc-PEG4-GGF- 940.5 [(M-
Q2L3-PIII-1 CD-N3 6.88 (B) >1
PIII-1 Bud)/2+H]
taurine-PEG4-
Q1L5-PIII-1 DIBAC-suc-SGGG-PIII-1 6.24 (B) 1087.3 (M-Bud) >1
azide
Q2L6-PII-9 CD-N3 DIBAC-suc-PEG4-PII-9 6.94 (B) 1067.6
(M/2+Na), >1
Q2L7-PII-1 CD-N3 DIBAC-suc-PII-1 6.74 (B) 901.7 (M/2+H)
>1
303
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Table 3d. Structures of Quenched Linker-N-C-O-Glucocorticoids
QLP# Structures
H
ay NH2
O [-Ny ?- ?- r NH
Q1L1- HO s7 0 0,7 0,7
O Nil I Nyjcf lof 1 f ri2q *11
PI 'I o o o
11
o 0 rFi 8 la H
8 H 0 OH
HHO
0
H
0 H
Pi
0 XriFN1 (1110 O.; 0
i' ---IN'''''
HO NOrNI f 1 f 1 ill 0 irl
N
0 0 0 0
________________ eiE-iVi
Q2L1- N )1' NH2
H H
P11-1
OH
HO OH 0
OH
HO OH
0
' (:-
HO 0- H 0
OH
0 H H
0
0
Q1L1- o
H N 0 H 0rl 0 0
0
O NI0 'O
- OH
PII-2
N 0
)NI f I f 1 ??C0r i I* Fi 'If-
0
N
HO cs,I . .----, . -- 'N 0 0 0 0
N)-) C)) C)) A
N NH2
H H
H H
N NH2
Y 0 H H H
0 0õ7 Oõ,) ,N 0 0 0
Q1L1- 0
N N yjNf lof Iof iyi.DL i,i 0
o
PII-3 o, H 0,,,,,N N
8 H
O 0
,HH
Q1L1- o H 0 XH la 0 N'i Co
P
P
II-4 N-11-.--Thc;eNI f I f I .11'N 0N
[1 qur
0 0 0 HO ,!:1, yt, jr.'1,r i0 hl
NH 0 0
11 HO
ONH2
H
0 OC)L
rli
Q1L1- 0 H
PII-5 Pi N-k-Thol-NI ,facLI, ,I I. H0 N 1
.1112-P
N' \
HO S 0 0 OTh 'N 0 0 0
NH
li)c)0,)'0,)
t
ONH2
0 H H
--- \¨<
0 H 0 0
Q1L1- o o Li .. 0 1,1 011,NNo 0 OH
PII-6 0 N N
^ I.
Iof Iof 10J H 0 H 0
HO ,SDIN¶..' ]r0,1:N
N NH2
H H
304
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
0 H ,F1
0
H 0
Q1L1- 0 [41 0 0 IL cir41 01 vi'l,r
),... N 0 ,
- OH
PII-7 0 14 \ PriHc 1 f I f 1 HN 0 " N
IS
HO*) 0 0"Th 0-Th % 0 0 0 0
N)-) 0,) 0, )-
N NH2
H H
0 H il
,?1,
Q1L1- _ Y H, " a
0 N--orN¨. OH
PII-8 9
N N) I f I f 1 fil%iN''
0 0
HO 61N MC-Thai¨U.1
N NH2
H H
H H
NNH2
HO+, 0 0õ) 0,) ,N 0 0 0 8
Q1L1- O Nii I N_ iji Nf --t,of --t,of iivy, 0 N411 C H
.-H H
PII-9 lcr¨H 0 H 0 0
0
8 Liif
OH 0
o
o H 0 0
' 0
HO N NJ.rNI f01 f01 NiThill,)N
N' \ H 0
HH
= OF: 3" HO F
F.
'
Q2L3- 0 0
PIII-1 HO H OH 0
OH
HO OH
HO 01101-1 7-4
0 7 0
OH
H
n r-N ,,,- c,-
Hak 0 0õ,,J OH
,N
Q1L5- O N. 1 0 0 N . u N r J 14 j
ll
PIII-1
0 0
HO F'
0
0 0 .,,
'm
Q1L1- 0
H
flO.t:IrHOO ON-"Tor NO
ri.INI x01 j,0,1, N 0 Nõ, ri
N o
PIII-4 9
H011 0 O'M 0-1 =NN_2 0
0 0 0 HO
Vi) 0,) 0,) NH 0
ONH2
OH
HO\ 0 c7,110F.0 L.:,
ii ¨ s ,.
OH HO OH
0 0
Q2L6- HO
OH 0
PII-9 e
OH Oho C,),121 c(-7H C) H
0 0 0
N I
HO µi N y)%if 10f 10f IVI,/
H 0 0
0 0 Fi
OH 0
305
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
HO 0 ¨\L710
-)H HOTh
0
HO OH
OH
0
Q2L7- 0
0
HO 0,
P11-1
oH HH
OH0 OH.__721 01zpi,,N
0 , 0 0
HO N ri,m(;,,N,.õ0 c)li
Abbreviations
ADC Antibody-drug conjugate
Aglycosylated antibody Antibody that does not have any glycan
aq. Aqueous
Boc N-tert-butoxycarbonyl
Thermo Scientific Prod# 28372, containing 100 mM sodium
BupH phosphate and 150
mM sodium chloride, potassium free, pH was
adjusted from 7.2 to 7.6-7.8 MQ, unless otherwise noted.
COT Cyclooctynol
CD cyclodextrin
Da Dalton
DAR Drug to antibody ratio
DCM Dichloromethane
DIBAC Dibenz[b,f]azocine, 11,12-didehydro-5,6-dihydro-
DIBAC-Suc Dibenz[b,f]azocine-5(6H)-butanoic acid, 11,12-
didehydro
DIBACT 3H-Benzo[c]-1,2,3-
triazolo[4,5-e][1]benzazocine, 8,9-dihydro-
DIPEA Diisopropylethylamine
DMF N,N-dimethylformamide
DMSO Dimethylsulfoxide
EC Enzyme commission
ELSD Evaporating light scattering detector
Equiv. Equivalent
ESI Electrospray ionization
Gram
HATU 2-(7-Aza-1H-benzotriazole-1-y1)-1,1,3,3-
tetramethyluronium
hexafluorophosphate
HC Heavy chain of immunoglobulin
HEK Human embryonic kidney (cells)
HPLC High performance liquid chromatography
h, hr, or hrs Hours
306
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
LC Light chain of
immunoglobulin
LCh Liquid chromatography
MALDI Matrix-assisted laser desorption/ionization
mg milligrams
min minutes
mL milliliters
mmh myc-myc-hexahistidine tag
n L microliters
mM millimolar
11M micromolar
MS Mass spectrometry
MSD Mass-selective detector
MW Molecular weight
NHS N-hydroxy succinimide
nM nanomolar
NMR Nuclear magnetic resonance
PAB Para-
aminobenzyloxy(carbonyl)
PBS 10 mM
sodium phosphate buffer and 150 mM sodium chloride
PBSg 10 mM phosphate, 150 mM sodium chloride, 5% glycerol
PEG Polyethyleneglycol
PPm Parts per million
(chemical shift)
PPTS pyridinium p-
toluenesulfonate
RP Reversed phase
RT or rt Room temperature
Sat. Saturated
SDS-PAGE Sodium dodecylsulfate polyacrylamide gel electrophoresis
SEC Size exclusion
chromatography
Suc Succinic acid
TCEP Tris(2-carboxyethyl)phosphine hydrochloride
TEA Triethylamine
TFA Trifluoroacetic acid
TG Transglutaminase
THF Tetrahydrofuran
TOF Time-of-flight
UPLC Ultra Performance Liquid Chromatography
UV Ultraviolet
VC Valine-citrulline
307
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Synthesis of Drug/Payload D*-0H
[00346] Dexamethasone I and Budesonide II are commercially available steroidal
drugs (D
OH). 6,11-2F-budesonide III is reported in WO 2018/213077 Al. LXR Agonist IV
was
synthesized from LXR Agonist 7 (LXR Agonist 7 is reported in WO 2018/213077 Al
and WO
2018/213082 Al), as shown below.
[00347] (1S,4aS,1 OaR)-N-[(1S,4aS,1 OaR)-6-(2-Hydroxyacetamido)-1,4a-dimethyl-
1,2,3,4,4a,9,1 0,1 0a-oetahydrophenanthrene-1 -earbony1]-6-hydroxy-1,4a-
dimethyl-
1,2,3,4,4a,9,1 0,1 0a-oetahydrophenanthrene-1 -earboxamide (IV)
o o o 0
HOjoH HOAN
H2N OH _________________________________________ OH
H H
HATU, DIPEA
rt, 2 h
7 IV
[00348] To a solution of 7 (10 mg, 19 !Arno', see WO 2018213082 Al) in DMF (2
mL) were
added HATU (14 mg, 38 !Arno') and DIPEA (9.8 mg, 76 !Arno') at RT. The mixture
was stirred at
RT for 15 minutes before the addition of Glycolic acid (1.7 mg, 23 jAmol). The
reaction mixture
was stirred at RT for 2 hours, which was monitored by LCMS. The resulting
mixture was directly
purified by prep-HPLC to give compound IV (5.7 mg, 51% yield) as a white
solid. ESI m/z: 587
(M + 1)+. NMR
(400 MHz, DMS0d6) 6 9.46 (s, 1H), 9.00 (s, 1H), 8.11 (s, 1H), 7.59 (d, J= 1.8
Hz, 1H), 7.49 (dd, J= 8.3, 1.8 Hz, 1H), 6.96 (d, J= 8.3 Hz, 1H), 6.82 (d, J=
8.3 Hz, 1H), 6.63 (d,
J= 2.3 Hz, 1H), 6.50 (dd, J= 8.3, 2.3 Hz, 1H), 5.64 (t, J= 5.9 Hz, 1H), 3.94
(d, J= 5.9 Hz, 2H),
2.93-2.66 (m, 4H), 2.37-2.06 (m, 6H), 2.03-1.75 (m, 4H), 1.68-1.50 (m, 4H),
1.28 (s, 3H), 1.27 (s,
3H), 1.36-1.20 (m, 2H), 1.20-1.08 (m, 2H), 1.00 (s, 3H), 0.99 (s, 3H) ppm.
[00349] Most payloads were synthesized according to FIG. 1, except payloads
PII-9 FIG. 2 and
FIG. 2A; and PII-10 FIG. 2. Intermediates 5a and 6a, were synthesized as
described in WO
2015/155998 Al.
FIG. 1 Starting Dipeptides 3a-h
3a: Fmoc-Gly-Gly-OH, CAS: 35665-38-4
3b: Fmoc-Ala-Gly-OH, CAS: 116747-54-7
3c: Fmoc-Phe-Gly-OIL CAS: 169624-67-3
3d: Fmoc-Gly-Abu-OH, CAS: 2171191-91-4
308
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
3e: Fmoc-Gly-Phe-OH, CAS: 117370-45-3
3f: Fmoc-Gly-Sar-OH, CAS: 1499188-24-7
3g and 3j: Fmoc-Gly-Pro-OH, CAS: 212651-48-4
3g1: Fmoc-Ala-Sar-OH, CAS: 2171221-36-4
3h1: Fmoc-(R,S)-3 -amino -1-carboxymethyl-valerolactame, CAS: 209163-25-7
3i: Fmoc-Gly-2-azetidinecarboxylic acid, 2171729-15-8
[00350] 1424 R9H-Fluoren-9-ylmethoxy)carbonyl] amino} acetyppip eridine-2-
carboxylic
acid (3h, Fmoc-Gly-Pip-OH)
)(DH
NHFmoc
0
To a mixture of Pipecolinic acid (0.59 g, 4.6 mmol) and Fmoc-Gly-OSu (1.80 g,
4.6 mmol) in
DMF (10 mL) was added DIPEA (1.8 g, 14 mmol), and the mixture was stirred at
RT for 2 hours,
which was monitored by LCMS. The resulting mixture was directly purified by
prep-HPLC to give
compound 3h (1.0 g, 53% yield) as a white solid. ESI m/z: 409 (M + 1)+. NMR
(400 MHz,
DMS0d6) 6 7.89 (d, J = 7.6 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H), 7.42 (t, J = 7.2
Hz, 2H), 7.35-7.29
(m, 3H), 4.32-4.21 (m, 4H), 4.03-3.95 (m, 1H), 3.67-3.61 (m, 1H), 2.78-2.73
(m, 2H), 2.23-2.14
(m, 1H), 1.61-1.59 (m, 2H), 1.50-1.25 (m, 4H) ppm.
Synthesis of Intermediates 4
General Procedure A For Intermediates 4
[00351] To a mixture of peptide 3 (1.0 equiv.) in THF (30 mL per gram of 3)
and toluene (10
mL per gram of 3) were added pyridine (1.2 equiv.) and lead tetraacetate (1.2
equiv.). The resulting
mixture was stirred for 5 hours at 80 C, and monitored by LCMS. After cooling
to RT, the mixture
was filtered through Celite, and the filtrate was concentrated in vacuo or
directly diluted with
ethyl acetate. The organic solution was washed with water and brine, dried
over anhydrous sodium
sulfate, and concentrated in vacuo. The residue was purified by silica gel
column chromatography
(0-10% ethyl acetate in petroleum ether) to give compound 4 (67-67% yield) as
a white solid.
309
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
General Procedure B For Intermediates 4
[00352] To a mixture of peptide 3 (1.0 equiv.) in dry DMF (2 mL per gram of 3)
was added
lead tetraacetate (1.2 equiv.). The resulting mixture was stirred at RT for 5-
30 minutes, and
monitored by LCMS. The resulting mixture was filtered through Celite, and the
filtrate was diluted
with ethyl acetate, washed with water and brine, dried over anhydrous sodium
sulfate, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (0-10%
ethyl acetate in petroleum ether) to give compound 4 (48-78% yield) as a white
solid.
Table 3e. Results of Intermediates 4 With Different IV Substituents
H 0 R1 H 0 R1 0 õ
N 0 R1
j=LisirOH pbp FmoeN
Ac)4, DMF 3.. P1
FmoJLIN10) + Fmoe J.LN1 OH
e H H H
0 0 C to rt.
3 4 4'
Content in LCMS (`)/0)
Separated Reaction
Entry IV Starting Side- Desired
yield (`)/0) time (h)
material 3 product 4' product 4
1 70 10 20
1 H 40
30 20 50
1 90 10 Trace
2 Me 0
5 0 >95 Trace
1 10 40 50
3 Et Crude*
5 0 85 Trace
1 80 0 20
4 Bn 48
5 10 10 80
5 Ph 0 1 0 75 0
* The acetate was easily hydrolyzed during the purification.
Table 4. Summary of the Synthesis of Intermediates 4
o R1 , 0 R1 0 R1 0
H Pb(0A44,
ONJ=Ln, H DMF or THF/toluene F=11 j=L Nj-L
- ii ____________ .. Fmoe - N1 OH + Fmoe . N.1 0
R-2 R3 0 0 C to rt. I2 R3 IEZ2 R3
3a-j 4A-J 4a-j
Contents of reaction mixture in LCMS (/0)
Entry R2 R3 R1
Separated Reaction yield CVO time (h) Starting
material 3 Alcohol 4A-J
Acetate 4a-j
1 70 10 20
a/A H H H 5 30 20 50
67 5 0 20 70
b/B Me H H 78 1 0 0 74
310
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
c/C Bn H H 30 0.5 0 0 80
1 10 40 50
d/D H H Et Crudel
0 85 Trace
1 80 0 20
e/E H H Bn 48
5 10 10 80
f/F H Me H 19 (crude)1 1 0 20
70
g/G Me Me H 53 3 0 0 66
h/H H 15 2 5 25 47
i/I H 4.4. 54 1 0 0 69
j/J H µ4, 532 4 0 74 0
1. The acetate was easily hydrolyzed, and was contaminated with alcohol.
2. The yield of alcohol 4J.
[00353] (2-(((9H-Fluoren-9-yl)methoxy)carbonylamino)acetamido)methyl acetate
(4a)
(CAS: 1599440-06-8)
H
N ..
FmocHN 0y
O 0
Following General Procedure A for intermediate 4, or the synthesis reported in
Tetrahedron 74
(2018) 1951-1956, compound 4a (3.0 g, 67% yield) was obtained as a white
solid. ESI m/z: 391
(M + 23)+.
[00354] R2S)-2-11(9H-Fluoren-9-ylmethoxy)carbonyl]aminolpropanamido]methyl
acetate (4b)
H
FmocHN(s))
O 0
Following General Procedure B for intermediate 4, compound 4b (30 mg, 78%
yield) was obtained
as a white solid. ESI m/z: 405 (M + 23)+.
[00355] R2S)-2-11(9H-Fluoren-9-ylmethoxy)carbonyl]aminol-3-
phenylpropanamido]methyl acetate (4c)
0
H
FmocHN NO(
O 0
311
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Following General Procedure B for intermediate 4, compound 4c (0.31 g, 30%
yield) was obtained
as a white solid. ESI m/z: 481 (M + 23)11. 1H NMR (400 MHz, DMS0d6) 6 9.14 (t,
J = 6.8 Hz, 1H),
7.88 (d, J = 7.6 Hz, 2H), 7.73-7.70 (m, 1H), 7.64 (t, J = 8.8 Hz, 2H), 7.43-
7.39 (m, 2H), 7.34-7.24
(m, 6H), 7.22-7.17 (m, 1H), 5.12 (dd, J= 7.2, 2.8 Hz, 2H), 4.31-4.26 (m, 1H),
4.19-4.11 (m, 3H),
3.01-2.94 (m, 1H), 2.84-2.78 (m, 1H), 2.00 (s, 3H) ppm.
[00356] 1-(2-11(9H-Fluoren-9-ylmethoxy)carbonyl]aminolacetamido)propyl acetate
(4d)
FmocHN
0 X ?
N 0
Following General Procedure B for intermediate 4, crude compound 4d (0.35 g)
was obtained, and
was used in the next step without purification. ESI m/z: 419 (M + 23)11.
[00357] 1-(2-11(9H-Fluoren-9-ylmethoxy)carbonyl] amino} acetamido)-2-
phenylethyl
acetate (4e)
el
o
FmocHN
N 7
Following General Procedure B for intermediate 4, compound 4e (0.30 g, 48%
yield) was obtained
as a white solid. ESI m/z: 481 (M + 23)11.
[00358] (2-11(9H-Fluoren-9-ylmethoxy)carbonyl]aminol-N-methy1acetamido)methy1
acetate (40
o o
FmocHN j=LN (3).=
I
Following General Procedure B for intermediate 4, crude compound 4f (0.40 g,
19% yield) was
obtained as a white solid, which was contaminated with the hydrolysis product
alcohol after
purification. The mixture was used in the next step without further
purification. ESI m/z: 405 (M
+23)t
312
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00359] R2S)-2-11(9H-Fluoren-9-ylmethoxy)carbonyl] amino} -N-
methylpropanamido]methyl acetate (4g)
o o
FmocHN
_ N 0
1
Following the General Procedure B for intermediate 4, crude compound 4g (0.44
g, 53% yield)
was obtained as a white solid after purification by prep-HPLC. ESI m/z: 419 (M
+ 23)11.
[00360] (3-11(9H-Fluoren-9-ylmethoxy)carbonyl] amino1-2-oxopiperidin-1-
yOmethyl
acetate (4h)
o 0
FmoeN,AN0
\)
Following the General Procedure B for intermediate 4, crude compound 4h (0.10
g, 15% yield)
was obtained as a white solid. ESI m/z: 431 (M + 23)11.
[00361] 1-(2-11(9H-Fluoren-9-ylmethoxy)carbonyl] amino} acetypazetidin-2-y1
acetate (4i)
o
H
FmoeNN_rOr
Following the General Procedure B for intermediate 4, crude compound 4i (0.18
g, 47% yield)
was obtained as a white solid. ESI m/z: 395 (M + 1)11.
[00362] 9H-Fluoren-9-ylmethyl N- [2-(2-hydroxypyrrolidin-1 -y1)-2-oxoethyl]
carbamate
(4J)
FmocHNNR
0 OH
Following the general procedure B for intermediate 4, crude compound 4J (50
mg, 53% yield) was
obtained as a white solid. No acetate intermediate was obtained. ESI m/z: 389
(M + 23)11.1H NMR
(400 MHz, DMS0d6) 6 7.90 (d, J = 7.4 Hz, 2H), 7.73 (d, J = 7.5 Hz, 2H), 7.47-
7.37 (m, 3H), 7.33
(t, J= 7.3 Hz, 2H), 5.86 (br s, 1H), 5.48 (d, J = 4.0 Hz, 0.25H), 5.39 (d, J =
4.0 Hz, 0.75H), 4.33-
313
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
4.18 (m, 3H), 3.96 (d, J= 6.0 Hz, 1.5H), 3.75 (d, J= 6.0 Hz, 0.5H), 3.59-3.33
(m, 1H), 3.22-3.11
(m, 1H), 2.00-1.59 (m, 4H) ppm.
Synthesis of Intermediate 5a and Payloads PI, P11-1, PII-2, PII-3, PII-6, PII-
7, PII-8, P11-i1,
PII-12, PII-13, and PIII-1 (FIG. 1)
o R1 0 0 R1 0 R1
,EN1j=L )= Frnoc 11 0 HO¨D* FrnocHN 11 O¨D H 2N
. 11 O¨D*
. *
R2 R3 Procedure B: PPTS, DCM, 5000 R2 R3 Piperidine
i2 R3
Procedure C: tBuOK, THE or DMF
4a-f Fmoc-P
0 F21 0 0 F 0 0
rnocHN JL. õy
0Bn
11 0
Frnoc'OBn
R2 R3 Procedure C: PPTS, DCM, 50 C i2 R3 0 Piperidine
R2 R3 0
4a Fmoc-5a 5a
General Procedure A For Payloads
[00363] A mixture of compound 4 (1 equiv.), corresponding alcohol (HOD* or
benzyl
glycolate) (1 equiv.) and PPTS (0.1 equiv.) in DCM (40 mL per gram of alcohol)
was added into
a 10 mL-sealed tube. The mixture was sealed and stirred at 50 C overnight,
and monitored by
LCMS. The resulting mixture was concentrated in vacuo and the residue was
directly purified by
prep-HPLC to give Fmoc-P or intermediate 5a. Fmoc-P was dissolved in DMF (40
mM). To the
solution was added piperidine (4 equiv.), and the mixture was stirred at RT
for an hour until Fmoc
was totally removed, as monitored by LCMS. The reaction mixture was directly
purified by prep-
HPLC to give payload P (4.1-28% yield) as a white solid.
General Procedure B For Payloads
[00364] To a solution of compound 4 (1.0 equiv.) and corresponding alcohol
(HOD*) (1.0
equiv.) in THF (0.25 M) was added potassium tert-butoxide (2.0 equiv.) at 0
'C. The mixture was
stirred at RT for 3 hours until the concentration of Fmoc-P remained static,
as monitored by LCMS
(neither compound 4 nor alcohol was completely consumed). The reaction mixture
was diluted
with ethyl acetate and carefully quenched with water at 0 C. The aq. layer
was extracted with
ethyl acetate and chloroform. The organic layers were combined, dried over
anhydrous sodium
sulfate, and concentrated in vacuo. The residue was purified by silica gel
column chromatography
(25-70% ethyl acetate in petroleum ether) to give Fmoc-P (containing payload
P), which was
dissolved in DMF (40 mM). To the solution was added piperidine (4 equiv.), and
the mixture was
314
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
stirred at RT for 2 hours until Fmoc was totally removed, as monitored by
LCMS. The reaction
mixture was directly purified by prep-HPLC to give payload P (6.7-28% yield)
as a white solid.
Table 5. Conditions For Generic Synthesis of Payloads
0 n1 0 0 ni
- ENI j-L HO-D* FmocHNJ-L
N, O-D*
IZ2 R3 Method A: PPTS, DCM, 50 C Ii2 R3
or Method B: t-BuOK, THF or DMF
4a-f Fmoc-P
Entry Product Fmoc-P R2 R3 R1 Cpd 4 HOD* Method Content in LCMS (%)
1 Fmoc-PI H H H 4a I (Dex) A 27
A 40
2 Fmoc-PII-1 H H H 4a II (Bud)
B 23
A No reaction
3 Fmoc-PII-2 Me H H 4b II (Bud)
B 11
4 Fmoc-PII-3 Bn H H 4c II (Bud) B 42
Fmoc-PII-6 H H Et 4d (crude) II (Bud) A 25
A No reaction
6 Fmoc-PII-7 H H Bn 4e II (Bud)
B 30
7 Fmoc-PII-8 H Me H 4f II (Bud) A 15
A 42
8 Fmoc-PIII-1 H H H 4a III
B 21
[00365] 2-Amino-N-(12-1(1R,2S,10S,11S,13R,14R,15S,17S)-1-fluoro-14,17-
dihydroxy-
2,13,15-trimethy1-5-oxotetracyclo[8.7Ø02,7.011,151heptadeca-3,6-dien-14-y1]-
2-
oxoethoxylmethyl)acetamide, TFA salt (PI)
H H 0
0
H2NJL .-----. --F
N 0 -
H a OH
Following General Procedure A for payloads, starting from compound 4a and
dexamethasone,
payload PI (0.26 g, 18% yield) as a white solid was obtained (TFA salt). ESI
m/z: 501 (M + 23)+.
41 NMR (400 MHz, DMS0d6) 6 9.14 (t, J= 6.5 Hz, 1H), 8.02 (s, 3H), 7.30 (d, J=
10.2 Hz, 1H),
6.23 (dd, J = 10.2, 2.0 Hz, 1H), 6.02 (s, 1H), 5.29 (d, J = 2.0 Hz, 1H), 5.00
(s, 1H), 4.68-4.52 (m,
3H), 4.17 (d, J= 18.4 Hz, 1H), 4.17-4.11 (m, 1H), 3.60 (s, 2H), 2.99-2.83 (m,
1H), 2.70-2.56 (m,
315
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
1H), 2.44-2.27 (m, 2H), 2.17-2.03 (m, 2H), 1.83-1.71 (m, 1H), 1.62 (q, J= 11.1
Hz, 1H), 1.49 (s,
3H), 1.47-1.29 (m, 2H), 1.15-0.99 (m, 1H), 0.87 (s, 3H), 0.79 (d, J= 7.2 Hz,
3H) ppm.
[00366] 2-Amino-N-(12-1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-
16-
oxo-6-propy1-5,7-dioxapentacyclo[10.8Ø02,9.04,8.013,18]icosa-14,17-dien-8-
y1]-2-
oxoethoxylmethyl)acetamide (P11-1)
o
H 0
H2NINI 0 OH
0
Following General Procedure B for payloads, starting from compound 4a and
budesonide, payload
P11-1 (50 mg, 28% yield) as a white solid was obtained. ESI m/z: 517 (M +
1)11. 1H NMR (400
MHz, CDC13) 6 8.08- 8.04 (m, 1H), 7.30 (d, J= 10.4 Hz, 1H), 6.25 (d, J= 10.4
Hz, 1H), 6.02 (s,
1H), 5.20-5.18 (m, 1H), 4.95-4.60 (m, 3H), 4.60-4.25 (m, 3H), 3.42 (s, 2H),
3.25 (br s, 2H), 2.57-
2.54 (m, 1H), 2.35- 2.32 (m, 1H), 2.22-2.00 (m, 2H), 2.00-1.50 (m, 7H), 1.46
(s, 3H), 1.46-1.25
(m, 2H), 1.15- 1.00 (m, 2H), 1.00- 0.80 (m, 6H) ppm.
[00367] (2S)-2-Amino-N-(12-1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-
dimethy1-
16-oxo-6-propy1-5,7-dioxapentacyclo 110.8Ø02,9.04,8.0"M icosa-14,17-dien-8-
y1]-2-
oxoethoxyl methyl)propanamide TFA salt (PII-2)
\
H 0
N, ,0
H2Ni - 0 OH
0
Following General Procedure B for payloads, starting from compound 4b and
budesonide, payload
P11-2 (6.0 mg, 6.7% yield) as a white solid was obtained (TFA salt). ESI m/z:
531 (M + 1)11. 1H
NMR (400 MHz, DMS0d6) (59.12-8.92 (m, 1H), 7.33 (d, J= 10.1 Hz, 1H), 6.59 (br
s, 2H), 6.17
(dd, J= 10.1 and 1.6 Hz, 1H)), 5.92 (s, 1H), 5.17 (t, J= 4.7 Hz, 0.3H), 5.03
(d, J= 7.2 Hz, 0.3H),
4.78 (d, J= 3.2 Hz, 1H), 4.72 (d, J= 4.2 Hz, 0.7H), 4.70-4.54 (m, 3H), 4.49
(d,J= 18.6 Hz, 0.7H),
4.30 (s, 1H), 4.23 (d, J= 18.8 Hz, 0.7H), 4.17 (d, J= 18.5 Hz, 0.3H), 3.68-
3.57 (m, 1H), 3.01-3.00
(m, 1H), 2.36-2.25 (m 1H), 2.15-1.92 (m, 2H), 1.83-1.68 (m, 2H), 1.68-1.41 (m,
6H), 1.38 (s, 3H),
316
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
1.37-1.30 (m, 1H), 1.27 (d, J= 7.0 Hz, 3H), 1.15-0.91 (m, 2H), 0.86 (t, J =
7.4 Hz, 3H), 0.81 (s,
3H) ppm.
[00368] (2S)-2-Amino-N-(12-1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-
dimethy1-
16-oxo-6-propy1-5,7-dioxapentacyclo [10.8Ø02,9.04,8.0"M icosa-14,17-dien-8-
y1]-2-
oxoethoxyl methyl)-3-phenylpropanamide TFAsalt (PII-3)
40
0
H 0
õ
H2N N 0¨ 0 OH
0
Following General Procedure B for payloads, starting from compound 4c and
budesonide, payload
PII-3 (84 mg, 21% yield) as a white solid was obtained (TFA salt). ESI m/z:
607 (M + 1)+. 41
NMR (400 MHz, DMS0d6) 6 8.73 (t, J= 6.2 Hz, 1H), 7.40-7.13 (m, 6H), 6.17 (d, J
= 10.1 Hz,
1H), 5.92 (s, 1H), 5.17 (t, J= 4.7 Hz, 0.4H), 5.03 (d, J= 7.1 Hz, 0.4H),
4.77(s, 1H), 4.73 (d, J =
4.1 Hz, 0.6H), 4.68-4.53 (m, 2.8H), 4.49 (d, J= 2.4 Hz, 0.4H), 4.44 (s, 0.4H),
4.31 (br s, 1H), 4.18
(d, J= 8.4 Hz, 0.6H), 4.13 (d, J= 8.1 Hz, 0.4H), 3.52-3.36 (m, 1H), 3.02-2.85
(m, 1H), 2.70-2.55
(m, 1H), 2.36-2.22 (m, 1H), 2.16-1.92 (m, 3H), 1.88-1.64 (m, 4H), 1.63-1.48
(m, 4H), 1.48-1.40
(m, 1H), 1.381 (s, 1.8H), 1.376 (s, 1.2H), 1.36-1.23 (m, 2H), 1.18-0.91 (m,
2H), 0.90-0.75 (m, 6H)
ppm.
[00369] 2-Amino-N-{ [(12-1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-
dimethyl-16-
oxo-6-propy1-5,7-dioxapentacyclo 110.8Ø02,9.04,8.013,1 icosa-14,17-dien-8-
y1]-2-
oxoethoxyl methypcarbamoyl] methyl} acetamide (PII-4)
\
0
H2Nj=L ,INI 0
N Tor ¨ 0 OH 0
To a solution of compound P11-1 (52 mg, 0.10 mmol) in DMF (2.0 mL) were added
DIPEA (40
mg, 0.31 mmol), Fmoc-Glycine (30 mg, 0.10 mmol) and HATU (50 mg, 0.13 mmol),
respectively,
at RT. The reaction mixture was stirred at RT for 2 hours, and monitored by
LCMS. To the solution
was then added piperidine (43 mg, 0.50 mmol), and the mixture was stirred at
RT for an hour until
Fmoc was removed, which was monitored by LCMS. The mixture was directly
purified by
317
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
reversed phase flash chromatography (0-100% acetonitrile in aq. ammonium
bicarbonate (0.08%)
to give compound PII-4 (50 mg, 91% yield) as a white solid. ESI m/z: 574 (M +
1)11. 1H NMR
(500 MHz, DMS0d6) 6 8.71 (t, J= 6.7 Hz, 0.5H), 8.70 (t, J= 6.7 Hz, 0.5H), 8.20
(br s, 1H), 7.314
(d, J = 10 Hz, 0.5H), 7.307 (d, J = 10 Hz, 0.5H), 6.17 (dd, J = 10 and 3.2 Hz,
0.5H), 6.16 (dd, J=
and 1.7 Hz, 0.5H), 5.92 (s, 1H), 5.17 (t, J= 4.8 Hz, 0.5H), 5.03 (d, J = 7.3
Hz, 0.5H), 4.81 (s,
1H), 4.72 (d, J= 4.4 Hz, 0.5H), 4.62-4.56 (m, 2.5H), 4.51 (d, J= 18.9 Hz,
0.5H), 4.47 (d, J= 18.6
Hz, 0.5H), 4.30 (s, 1H), 4.20 (d, J= 18.9 Hz, 0.5H), 4.16 (d, J= 18.6 Hz,
0.5H), 3.74 (s, 2H), 3.15
(s, 2H), 2.58-2.52 (m, 1H), 2.32-2.25 (m, 1H), 2.11-1.95 (m, 2.5H), 1.77-1.70
(m, 2.5H), 1.60-
1.39 (m, 5H), 1.383 (s, 0.5H), 1.377 (s, 0.5H), 1.36-1.23 (m, 4H), 1.11-0.92
(m, 2H), 0.87-0.80
(m, 7H) ppm.
[00370] (2S)-2-1(2S)-2-Aminopropanamido]-N-(12-1(1S,2S,4R,8S,9S,11S,12S,13R)-
11-
hydroxy-9,13-dimethyl-16-oxo-6-propy1-5,7-dioxapentacyclo
110.8Ø02,9.04,8.013,1 icosa-
14,17-dien-8-y1]-2-oxoethoxylmethyl)propanamide, TFA salt (PII-5)
H2Nj ,0
. N v OH 0
H 0
Following a similar procedure used for payload PII-5 (10 mg, 44% yield, TFA
salt) was
obtained from PII-2 and Fmoc-Alanine. ESI m/z: 602.2 (M + 1)11.1H NMR (400
MHz, DMS0d6)
6 8.85 (t, J = 6.2 Hz, 0.6H), 8.84 (t, J = 5.8 Hz, 0.4H), 8.46 (s, 1H), 7.321
(d, J = 10.1 Hz, 0.6H),
7.320 (br s, 3H), 7.313 (d, J= 10.1 Hz, 0.4H), 6.170 (dd, J= 10.1 and 1.6 Hz,
0.6H), 6.166 (dd, J
= 10.1 and 1.6 Hz, 0.4H), 5.92 (s, 1H), 5.17 (t, J= 4.8 Hz, 0.4H), 5.03 (d, J
= 7.2 Hz, 0.4H), 4.764
(s, 0.4H), 4.756 (s, 0.6H), 4.73-4.62 (m, 1.6H), 4.60 (t, J= 4.4 Hz, 0.6H),
4.57-4.41 (m, 2H), 4.29
(br s, 2H), 4.20 (d, J = 18.9 Hz, 0.6H), 4.15 (d, J = 18.5 Hz, 0.4H), 3.77-
3.67 (m, 1H), 3.08-2.94
(m, 2H), 2.35-2.22 (m, 1H), 2.14-1.91 (m, 2H), 1.83-1.47 (m, 7H), 1.382 (s,
1.8H), 1.377 (s, 1.2H),
1.46-1.31 (m, 1H), 1.31-1.22 (m, 6H), 1.15-0.90 (m, 2H), 0.90-0.76 (m, 6H)
ppm.
[00371] 2-Amino-N-(1-12-1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-
16-
oxo-6-propy1-5,7-dioxapentacyclo 110.8Ø02,9.04,8.013,1 icosa-14,17-dien-8-
y1]-2-
oxoethoxylpropypacetamide (PII-6)
318
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
H 0
H2N ThN 0 0
r 0
OH
0
Following General Procedure A for payloads, starting from compound 4d and
budesonide, payload
PII-6 (40 mg, 4.1% yield) as a white solid was obtained. ESI: 567.2 (M +
23)11. 1H NMR (400
MHz, DMS0d6) 6 8.20-8.10 (m, 1H), 7.34-7.29 (m, 1H), 6.16 (dd, J= 10 and
1.6Hz, 1H), 5.92 (s,
1H), 5.15 (t, J= 4.8 Hz, 0.4H), 5.10-4.95 (m, 1.8H), 4.83-4.40 (m, 2.8H), 4.29
(br s, 1H), 4.28-
4.05 (m, 1H), 3.13 (d, J= 7.9 Hz, 2H), 2.60-2.50 (m, 1H), 2.36-2.22 (m, 1H),
2.14-1.87 (m, 3H),
1.81-1.62 (m, 4H), 1.62-1.44 (m, 5H), 1.38 (s, 3H), 1.38-1.18 (m, 3H), 1.13-
0.90 (m, 2H), 0.90-
0.70 (m, 9H) ppm.
[00372] 2-Amino-N-(1-12-1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-
16-
oxo-6-propy1-5,7-dioxapentacyclo110.8Ø02,9.04,8.013,18]icosa-14,17-dien-8-
y1]-2-oxoethoxy1-
2-phenylethypacetamide (PII-7)
H
H
H2N Thr N 0 0
0
OH
0 0
Following General Procedure B for payloads, starting from compound 4e and
budesonide, payload
PII-7 (80 mg, 29% yield) as a white solid was obtained. ESI m/z: 629 (M +
23)11. 1H NMR (400
MHz, DMS0d6) 6 8.45-8.26 (m, 1H), 7.35-7.23 (m, 5H), 7.22-7.16 (m, 1H), 6.16
(dd, J= 10.2, 1.9
Hz, 1H), 5.91 (s, 1H), 5.37-5.23 (m, 1H), 5.17-5.12 (m, 0.5H), 5.08 (s, 0.5H),
5.02 (d, J= 7.6 Hz,
0.5H), 4.78 (dd, J = 9.6, 3.6 Hz, 0.5H), 4.74-4.68 (m, 0.5H), 4.60-4.46 (m,
1.5H), 4.31-4.11 (m,
2H), 3.13-3.01 (m, 3H), 2.93-2.84 (m, 1H), 2.33-2.23 (m, 1H), 2.12-1.92 (m,
2H), 1.79-1.39 (m,
7H), 1.38 (s, 1.5H), 1.37 (s, 1.5H), 1.35-1.22 (m, 2H), 1.14-0.89 (m, 3H),
0.88-0.75 (m, 6H) ppm.
[00373] 2-Amino-N-(12-1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-
16-
oxo-6-propy1-5,7-dioxapentacyclo[10.8Ø02,9.04,8.013,18]icosa-14,17-dien-8-
y1]-2-
oxoethoxylmethyl)-N-methylacetamide (PII-8)
319
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H
\ <0 ski
I 0
0
H2N'-I N 0
OH
Following General Procedure A for payloads, starting from compound 4f and
budesonide, payload
PII-8 (64 mg, 12% yield) as a white solid was obtained. ESI m/z: 531 (M + 1)+.
1H NMR (500
MHz, DMS0d6) 6 7.35-7.23 (m, 1H), 6.20-6.13 (d, J= 10 Hz, 1H), 5.92 (s, 1H),
5.20-4.44 (m,
6H), 4.33-4.08 (m, 2H), 3.441 (s, 0.5H), 3.436 (s, 0.5H), 3.37 (s, 1H), 2.91
(s, 1.5H), 2.895 (s,
0.75H), 2.891 (s, 0.75H), 2.57-2.52 (m, 1H), 2.33-2.24 (m, 1H), 2.13-1.65 (m,
6H), 1.61-1.46 (m,
4H), 1.45-1.41 (m, 1H), 1.383 (s, 1.5H), 1.377 (s, 1.5H), 1.35-1.21 (m, 2H),
1.14-0.91 (m, 2H),
0.89-0.78 (m, 6H) ppm.
Variable-temperature NMR (T = 60 C) indicated the presence of rotamers.
[00374] (2S)-2-Amino-N-(12-1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-
dimethy1-
16-oxo-6-propy1-5,7-dioxapentacyclo [10.8Ø02,9.04,8.0"M icosa-14,17-dien-8-
y1]-2-
oxoethoxyl methyl)-N-methylpropanamide (P11-11)
\
I
H2N N
0
Following the General Procedure A for payloads, starting from compound 4g and
budesonide,
payload PII-11 (0.13 g, 23% yield) as a white solid was obtained. ESI m/z: 545
(M + 1)+. 1H NMR
(500 MHz, DMS0d6) 6 7.31 (d, J = 10,4 Hz, 1H), 6.20-6.13 (m, 1H), 5.92 (s,
1H), 5.20-5.13 (m,
0.5H), 5.08-5.01 (m, 0.5H), 4.92-4.39 (m, 5H), 4.34-4.07 (m, 2H), 3.88-3.80
(m, 0.5H), 3.76-3.69
(m, 0.5H), 3.02 (s, 1.5H), 2.88 (s, 1.5H), 2.57-2.51 (m, 1H), 2.33-2.25 (m,
1H), 2.12-1.93 (m, 2H),
1.83-1.67 (m, 4H), 1.63-1.23 (m, 10H), 1.12-1.06 (m, 3H), 1.02-0.90 (m, 2H),
0.89-0.78 (m, 6H)
ppm.
[00375] 3-Amino-1-(12-1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-
16-oxo-
6-propy1-5,7-dioxapentacyclo [10.8Ø02,9.04,8.013,1 icosa-14,17-dien-8-y1]-2-
oxoethoxyl methyl)piperidin-2-one (PII-12)
320
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
\ <0 H
0
0
0
H2N 0 0HH
0
Following the General Procedure A for payloads, starting from compound 4h and
budesonide,
payload PII-12 (19 mg, 15% yield) as a white solid was obtained. ESI m/z: 557
(M + 1)11. NMR
(400 MHz, DMS0d6) 6 7.33-7.30 (m, 1H), 6.17 (d, J= 10 Hz, 1H), 5.92 (s, 1H),
5.20-4.97 (m,
2H), 4.92-4.48 (m, 5H), 4.32-4.12 (m, 2H), 3.27-3.17 (m, 2H), 2.33-2.24 (m,
1H), 2.12-1.92 (m,
6H), 1.82-1.69 (m, 4H), 1.61-1.24 (m, 12H), 0.99-0.92 (m, 1H), 0.87-0.81 (m,
6H) ppm.
[00376] (1S,2S,4R,8S,9S,11S,12S,13R)-8-(2-111-(2-Aminoacetyppyrrolidin-2-
yl]oxylacety1)-11-hydroxy-9,13-dimethyl-6-propyl-5,7-
dioxapentacyclo [10.8Ø02,9.04,8.0"M icosa-14,17-dien-16-one (PII-9) (FIG.
2A)
H
H
0
0 z:
OH 0
H2N¨'
To a solution of compound 4J (0.40 g, 1.1 mmol) in DCM (15 mL) was added
chlorotrimethylsilane (TMSC1) (0.35 g, 3.3 mmol). The mixture was stirred at
RT for 3 hours,
which was monitored by LCMS. The volatiles were removed and the residue was
redissolved in
DCM (6 mL). To the solution were added budesonide (0.94 g, 2.2 mmol) and DIPEA
(0.28 g, 2.2
mmol). The mixture was stirred at RT for an hour, which was monitored by LCMS.
The resulting
mixture was concentrated in vacuo and the residue was purified by reversed
phase chromatography
(0-100% acetonitrile in aq. ammonium bicarbonate (0.05%)) to give Fmoc-P-GCII-
9 (ESI m/z:
801 (M + 23)11), which was dissolved into DMF (3 mL). To the solution was
added piperidine (0.12
g, 1.4 mmol) and the mixture was stirred at RT for an hour until Fmoc was
totally removed
according to LCMS. The reaction solution was directly purified by prep-HPLC to
give payload
PII-9 (0.10 g, 17% yield) as a white solid. ESI m/z: 579 (M + 23)11.1H NMR
(400 MHz, DMS0d6)
(57.34-7.29 (m, 1H), 6.16 (dd, J = 10.4 and 1.6 Hz, 1H), 5.92 (s, 1H), 5.52-
4.99 (m, 2.3H), 4.81-
4.47 (m, 3H), 4.35-4.15 (m, 1.7H), 3.47-3.36 (m, 2H), 3.27-3.21 (m, 2H), 2.30-
2.28 (m, 1H), 2.09-
321
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
1.88 (m, 4.7H), 1.84-1.66 (m, 5.7H), 1.61-1.42 (m, 4.6H), 1.38 (s, 3H), 1.38-
1.25 (m, 3H), 1.00-
0.91 (m, 2H), 0.88-0.77 (m, 6H) ppm.
[00377] (1S,2S,4R,8S,9S,11S,12S,13R)-8-(2-{ [1-(2-Aminoacetypazetidin-2-
yfloxylacety1)-
11-hydroxy-9,13-dimethy1-6-propyl-5,7-dioxapentacyclo [10.8Ø02,9.04,8.0"M
icosa-14,17-
dien-16-one (PII-13)
H
0 11
----\_-- =
0
H2N4 0 0
ILy OH
Following the General Procedure A for payloads, starting from compound 4i and
budesonide,
payload PII-13 (30 mg, 7% yield) as a white solid was obtained. ESI m/z: 543
(M + 1)11. 1H NMR
(400 MHz, DMS0d6) 6 8.35 (br s, 1H), 8.05 (br s, 1H), 7.40-7.35 (m, 1H), 6.20-
6.15 (m,1H), 5.95
(s, 1H), 5.20-5.15 (m, 0.55H), 5.05-5.00 (m, 0.55H), 4.80-4.60 (m, 3H), 4.40-
4.20 (m, 2.45H),
3.80-3.20 (m, 6.45H), 3.20 (s, 2H), 2.25-2.20 (m, 1H), 2.05-1.95 (m, 2H), 1.80-
1.30 (m, 13H),
1.20-1.00 (m, 2H), 0.90-0.85 (m, 6H) ppm.
[00378] (2S)-2-Amino-N-(12-1(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-
hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-dioxapentacyclo
110.8Ø02,9.04,8.013,1 icosa-
14,17-dien-8-34]-2-oxoethoxyl methyppropanamide (PIII-5)
,F
H2N1H 0
Nõ0
r - 0 OH
0
Following the general procedure A for payloads, starting from compound 4b and
drug III, payload
PIII-5 (90 mg, 61% yield) as a white solid was obtained. ESI m/z: 567 (M +
1)11.
[00379] 2-Amino-N-(12-1(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-
hydroxy-
9,13-dimethy1-16-oxo-6-propy1-5,7-dioxapentacyclo 110.8Ø02,9.04,8.013,1
icosa-14,17-dien-8-
34]-2-oxoethoxylmethy1)acetamide (P111-1)
322
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
\ <0
0
H2N
0 OH
Following General Procedure A for payloads, starting from compound 4a and
drug/payload III,
payload PIII-1 (0.26 g, 23% yield) as a white solid was obtained. ESI m/z: 553
(M + 1)+. 1H NMR
(400 MHz, DMS0d6) 6 8.75 (t, J = 5.9 Hz, 1H), 7.27 (d, J = 10.2 Hz, 1H), 6.30
(dd, J = 10.2, 1.7
Hz, 1H), 6.11 (s, 1H), 5.73-5.49 (m, 2H), 5.19 (t, J= 4.9 Hz, 0.25H), 5.08 (d,
J= 7.1 Hz, 0.25H),
4.75 (s, 0.75H), 4.69-4.63 (m, 3.75H), 4.26 (d, J= 18.9 Hz, 1H), 4.23-4.13 (m,
1H), 3.17 (s, 2H),
3.00 (br s, 2H), 2.69-2.54 (m, 1H), 2.30-2.18 (m, 1H), 2.08-1.92 (m, 2H), 1.83-
1.21 (m, 8H), 1.48
(s, 3H), 0.86 (t, J= 7.4 Hz, 3H), 0.81 (s, 3H) ppm.
[00380] 2-Amino-N-{ [(12-1(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-dinuoro-11-
hydroxy-
9,13-dimethy1-16-oxo-6-propy1-5,7-dioxapentacyclo 110.8Ø02,9.04,8.013,1
icosa-14,17-dien-8-
y1]-2-oxoethoxylmethyl)carbamoyl] methyl} acetamide (PIII-4)
,F
H H
0
H !NI 0
2 m OH
To a solution of compound PIII-1 (55 mg, 0.10 mmol) in DMF (2.0 mL) were added
DIPEA (40
mg, 0.31 mmol), Fmoc-Glycine (30 mg, 0.10 mmol) and HATU (50 mg, 0.13 mmol),
respectively,
at RT. The reaction mixture was stirred at RT for 2 hours, and monitored by
LCMS. To the solution
was then added piperidine (43 mg, 0.50 mmol), and the mixture was stirred at
RT for an hour until
Fmoc was removed, which was monitored by LCMS. The mixture was directly
purified by
reversed phase flash chromatography (0-100% acetonitrile in aq. ammonium
bicarbonate (0.08%))
to give compound PIII-4 (50 mg, 82% yield) as a white solid. ESI m/z: 610 (M +
0+. 1H NMR
(400 MHz, DMS0d6) 6 8.71 (t, J = 6.8 Hz, 1H), 8.21 (br s, 1H), 7.27 (d, J =
10.2 Hz, 1H), 6.30
(dd, J= 10.2, 1.9 Hz, 1H), 6.11 (s, 1H), 5.72-5.54 (m, 2H), 4.78-4.74 (m, 1H),
4.64 (t, J= 4.1 Hz,
1H), 4.61 (d, J= 6.8 Hz, 2H), 4.49 (d, J= 18.9 Hz, 1H), 4.23 (d, J= 18.9 Hz,
1H), 4.21-4.16 (m,
1H), 3.74 (s, 2H), 3.16 (s, 2H), 2.71-2.56 (m, 1H), 2.30-2.20 (m, 1H), 2.04-
1.96 (m, 2H), 1.70 (d,
J= 13.7 Hz, 1H), 1.61-1.52 (m, 4H), 1.49 (s, 3H), 1.44-1.27 (m, 4H), 0.86 (t,
J= 7.4 Hz, 3H), 0.81
(s, 3H) ppm.
323
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
[00381] (1S,4aS,1 OaR)-N-[(1S,4aS,1 OaR)-6-{2- [(2-amino acetamido)methoxy]
acetamidol -
1,4 a-dimethy1-1,2,3,4,4a,9,1 0,1 Oa-octahydrophenanthrene-1 -carbonyl] -6-
hydroxy-1,4a-
dimethy1-1,2,3,4,4a,9,1 0,1 Oa-octahydrophenanthrene-1 -carboxamide (PIV)
0 0 0
.õH H
kl,o,AN
H2Nr '",, IITOH
H
0
To a solution of LXR Agonist 7 (63 mg, 0.12 mmol, see WO 2018/213082 Al) in
DMF (5 mL)
were added HATU (79 mg, 0.21 mmol) and DIPEA (54 mg, 0.44 mmol) at RT, and the
mixture
was stirred at RT for 15 minutes before the addition of intermediate 6a (42
mg, 0.11 mmol). The
reaction mixture was stirred at RT 4 hours, which was monitored by LCMS. To
the mixture was
added piperidine (0.2 mL), and the reaction mixture was stirred at RT for an
hour until Fmoc was
totally removed, which was monitored by LCMS. The mixture was directly
purified by prep-HPLC
to give payload PIV (34 mg, 47% yield) as a white solid. ESI m/z: 673 (M +
1)11. 1H NMR (400
MHz, DMS0d6) (59.54 (s, 1H), 8.99 (s, 1H), 8.85 (br s, 1H), 8.11 (s, 1H), 7.59
(d, J= 1.5 Hz, 1H),
7.45 (dd, J= 8.4, 1.5 Hz, 1H), 6.97 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 8.4 Hz,
1H), 6.63 (d, J= 2.2
Hz, 1H), 6.50 (dd, J= 8.4, 2.2 Hz, 1H), 4.66 (d, J= 1.6 Hz, 2H), 4.00 (s, 2H),
3.14 (s, 2H), 2.94-
2.64 (m, 4H), 2.35-2.32 (m, 1H), 2.32-2.22 (m, 2H), 2.22-2.09 (m, 4H), 1.95-
1.78 (m, 4H), 1.68-
1.52 (m, 4H), 1.36-1.28 (m, 2H), 1.28 (s, 3H), 1.27 (s, 3H), 1.20-1.09 (m,
2H), 1.01 (s, 3H), 0.99
(s, 3H) ppm.
Synthesis of Payloads PII-9 and PII-10 FIG. 2
[00382] Payloads PII-9 and PII-10 were synthesized according to FIG. 2 and the
following
procedures.
[00383] 9H-Fluoren-9-ylmethyl N- [2-(2-hydroxypyrrolidin-1 -y1)-2-oxoethyl]
carbamate
(4G)
FmocHNrc
0 OH
324
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Following General Procedure B for intermediate 4, crude compound 4G (50 mg,
53% yield) was
obtained as a white solid. No acetate intermediate was obtained. ESI m/z: 389
(M + 23)+. 41 NMR
(400 MHz, DMS0d6) 6 7.90 (d, J= 7.4 Hz, 2H), 7.73 (d, J= 7.5 Hz, 2H), 7.47-
7.37 (m, 3H), 7.33
(t, J= 7.3 Hz, 2H), 5.86 (br s, 1H), 5.48 (d, J = 4.0 Hz, 0.25H), 5.39 (d, J =
4.0 Hz, 0.75H), 4.33-
4.18 (m, 3H), 3.96 (d, J= 6.0 Hz, 1.5H), 3.75 (d, J= 6.0 Hz, 0.5H), 3.59-3.33
(m, 1H), 3.22-3.11
(m, 1H), 2.00-1.59 (m, 4H) ppm.
[00384] 9H-Fluoren-9-ylmethyl N-I2-(2-hydroxypiperidin-1-y1)-2-
oxoethyl]carbamate
(411)
FmocHNNI'r
0 OH
Following General Procedure B for intermediate 4, compound 411 (40 mg, 31%
yield) was
obtained after prep-HPLC as a white solid. No acetate intermediate was
obtained. ESI m/z: 403
(M + 23)+.
[00385] (1S,2S,4R,8S,9S,11S,12S,13R)-8-(2-1[1-(2-Aminoacetyppyrrolidin-2-
yl]oxylacety1)-11-hydroxy-9,13-dimethy1-6-propy1-5,7-
dioxapentacyclo [10.8Ø02,9.04,8.0"M icosa-14,17-dien-16-one (PII-9)
n--O
¨i .'-
0 H
OH 0
H2N
To a solution of compound 4G (0.40 g, 1.1 mmol) in DCM (15 mL) was added
chlorotrimethylsilane (TMS-C1) (0.35 g, 3.3 mmol). The mixture was stirred at
RT for 3 hours
until the alcohol was consumed, as monitored by LCMS. The volatiles were
removed and the
residue was dissolved again in DCM (6 mL). To the solution were added
budesonide (0.94 g, 2.2
mmol) and DIPEA (0.28 g, 2.2 mmol). The mixture was stirred at RT for an hour,
and monitored
by LCMS. The resulting mixture was concentrated in vacuo and the residue was
purified by
reversed phase chromatography (0-100% acetonitrile in aq. ammonium bicarbonate
(0.05%)) to
give Fmoc-P-GCII-9 (ESI m/z: 801 (M + 23)+), which was dissolved in DMF (3
mL). To the
325
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
solution was added piperidine (0.12 g, 1.4 mmol) and the mixture was stirred
at RT for an hour
until Fmoc was totally removed according to LCMS. The reaction solution was
directly purified
by prep-HPLC to give payload PII-9 (0.10 g, 17% yield) as a white solid. ESI
m/z: 579 (M + 23)+.
41 NMR (400 MHz, DMS0d6) 6 7.34-7.29 (m, 1H), 6.16 (dd, J= 10.4 and 1.6 Hz,
1H), 5.92 (s,
1H), 5.52-4.99 (m, 2.3H), 4.81-4.47 (m, 3H), 4.35-4.15 (m, 1.7H), 3.47-3.36
(m, 2H), 3.27-3.21
(m, 2H), 2.30-2.28 (m, 1H), 2.09-1.88 (m, 4.7H), 1.84-1.66 (m, 5.7H), 1.61-
1.42 (m, 4.6H), 1.38
(s, 3H), 1.38-1.25 (m, 3H), 1.00-0.91 (m, 2H), 0.88-0.77 (m, 6H) ppm.
[00386] (1S,2S,4R,8S,9S,11S,12S,13R)-8-(2-1[1-(2-Aminoacetyppiperidin-2-
yl]oxylacety1)-11-hydroxy-9,13-dimethyl-6-propy1-5,7-
dioxapentacyclo [10.8Ø02,9.04,8.0"M icosa-14,17-dien-16-one (PII-10)
0-0 0 ,z-E1 H
N
0 0
H2N¨/
HO H
0
Following a similar procedure used for PII-9, payload PII-10 (0.10 g, 20%
yield) was obtained as
a white solid. ESI m/z: 593 (M + 23)+.
[00387] Benzyl 2-1[1-(2-11(9H-fluoren-9-ylmethoxy)earbonyl] amino}
acetyppyrrolidin-2-
yl] oxyl acetate (5b)
p
FmocHN/¨ C/¨\
0 ¨0Bn
0
To a solution of compound 4J (0.30 g, 0.82 mmol) in DCM (25 mL) was added
chlorotrimethylsilane (TMSC1) (0.27 g, 2.5 mmol). The reaction mixture was
stirred at room
temperature for 3 hours, which was monitored by LCMS. The resulting mixture
was concentrated
in vacuo and the residue was diluted with DCM (25 mL). To the solution were
added benzyl
glycolate (0.27 g, 1.6 mmol) and DIPEA (0.21 g, 1.6 mmol), and the reaction
mixture was stirred
at room temperature for an hour, which was monitored by LCMS. The resulting
mixture was
concentrated in vacuo and the residue was purified by reversed phase flash
chromatography (0-
326
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
100% acetonitrile in aq. ammonium bicarbonate (0.05%)) to give compound 5b
(0.11 g, 25% yield,
purity >99%; and 50 mg at purity 75%) as a white solid. ESI m/z: 537.3 (M +
Na)11. 1H NMR (400
MHz, DMS0d6) 6 7.91-7.89 (m, 2H), 7.74-7.69 (m, 2H), 7.63-7.48 (m, 1H), 7.42-
7.25 (m, 9H),
5.51-5.09 (m, 2H), 4.35-4.21 (m, 5H), 4.00-3.77 (m, 2H), 3.52-3.38 (m, 2H),
3.30-3.18 (m, 1H),
2.19-1.64 (m, 4H) ppm.
[00388] 2-1[1-(2-11(9H-Fluoren-9-ylmethoxy)carbonyl]aminolacetyppyrrolidin-2-
yl]oxylacetic acid (6b)
p
FmocHNIP--- O-
0 >/-0H
0
To a solution of compound 5b (89 mg, 0.17 mmol) in methanol (3 mL) and THF (7
mL) was added
wet palladium on carbon (10% Pd, 20 mg) under nitrogen. The mixture was
degassed, purged with
hydrogen, and stirred under a hydrogen balloon at room temperature for 2
hours, which was
monitored by LCMS. The reaction mixture was filtered through Celite and the
filtrate was
concentrated in vacuo. The residue was purified by reversed phase flash
chromatography (0-100%
acetonitrile in aq. ammonium bicarbonate (0.05%)) to give compound 6b (36 mg,
49% yield) as a
white solid. ESI m/z: 447.1 (M + Na)11.
Synthesis of Linker-Payloads
Synthesis of Linker-Payloads Ll-P-#
[00389] Linker-payloads Li-PI, Li-PH-1, Li-PII-2, Li-PII-3, Li-PII-4, Li-PII-
5, Li-Ph!-
6, Li-PII-7, Li-PII-8, Li-PII-11, Li-PII-12, Li-PII-9, Li-Pill-1, L19-PIII-1,
and Li-PIII-4,
were synthesized according to FIG. 3 and the following procedures; linker-
payloads L8-PII-1 and
L2-PIII-1 were synthesized according to FIG. 4 and the following procedures.
The intermediate
L-3b was synthesized according to WO 2018/089373. The linkers ycPAB (CAS:
1497404-26-8),
L-la (CAS: 1427004-19-0), and L-lb (CAS: 2101206-50-0) L-lc (CAS: 1702356-19-
1) were
commercially available.
327
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Synthesis of Intermediate L-3a (FIG. 3)
[00390] N-R1S)-1-11(1S)-4-(Carbamoylamino)-1-114-
(hydroxymethypphenyl] carbamoyll butyl] carbamoy11-2-methylpropyl] -1-12-
(cyclooct-2-yn-
1-yloxy)acetamido] -3 ,6,9,12-tetraoxapentadecan-15-amide (L-2a)
H 0 OH
1110
0
To a solution of compound L-la (0.17 g, 0.33 mmol) in DMF (10 mL) were added
DIPEA (0.13
g, 1.0 mmol) and vcPAB (0.13 g, 0.34 mmol) successively, and the reaction
mixture was stirred
at room temperature for an hour, which was monitored by LCMS. The resulting
mixture was
directly purified by reversed phase flash chromatography (0-80% acetonitrile
in water) to give
compound L-2a (0.18 g, 70% yield) as colorless oil. ESI m/z: 791.3 (M + H)11.
1H NMR (400 MHz,
DMS0d6) 6 9.91 (s, 1H), 8.11 (d, J= 8.4 Hz, 1H), 7.89 (d, J= 8.8 Hz, 1H), 7.61
(t, J = 5.6 Hz,
1H), 7.55 (d, J= 8.4 Hz, 2H), 7.23 (d, J= 8.4 Hz, 2H), 5.98 (t, J= 5.6 Hz,
1H), 5.42 (s, 2H), 5.10
(br s, 1H), ), 4.43 (s, 2H), 4.39-4.37 (m, 1H), 4.30-4.21 (m, 2H), 3.87 (d, J=
14.8 Hz, 1H), 3.75(d,
J= 14.8 Hz, 1H), 3.62-3.58 (m, 2H), 3.50-3.46 (m, 12H), 3.43 (t, J= 6.0 Hz,
2H), 3.27-3.22 (m,
2H), 3.06-2.92 (m, 2H), 2.41-2.32 (m, 2H), 2.26-2.05 (m, 3H), 1.99-1.66 (m,
6H), 1.62-1.55 (m,
3H), 1.44-1.35 (m, 3H), 0.89 (d, J= 6.8 Hz, 3H), 0.83 (d, J= 6.8 Hz, 3H) ppm.
[00391] 14-1(2S)-5-(Carbamoylamino)-2-1(2S)-2-11-12-(cyclooct-2-yn-1-
yloxy)acetamido]-
3,6,9,12-tetraoxapentadecan-15-amido1-3-methylbutanamido] pentanamido phenyl}
methyl
4-nitrophenyl carbonate (L-3a)
Am NO2
j j, 0ON
N 0)0
CD H
0
NINH2
A suspension of compound L-2a (80 mg, 0.10 mmol), DMAP (12 mg, 0.10 mmol), and
DIPEA
(26 mg, 0.20 mmol) in dry DMF (5 mL) was stirred at room temperature for 10
minutes before the
addition of bis(4-nitrophenyl) carbonate (61 mg, 0.20 mmol). The reaction
mixture was stirred at
room temperature for 2 hours, which was monitored by LCMS. The resulting
mixture was directly
328
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
purified by reversed phase flash chromatography (0-80% acetonitrile in water)
to give compound
L-3a (53 mg, 55% yield) as a white solid. ESI m/z: 956.3 (M + H)+.
General Procedure For vcPAB Linker-Payloads Li-PI, Li-PH-1, Li-PII-2, Li-PII-
3, Li-
P11-4, Li-PII-5, Li-PII-6, Li-PII-7, Li-PII-8, Ll-PH-11, Li-PII-12, Li-PII-9,
Li-Pill-1,
L19-PIII-1, and Li-PIII-4 (FIG. 3)
[00392] To a solution of payload (1.0 equiv.) in DMF (5-10 mM) were added
compound L-
3a,b (1.0 equiv.), HOBt (0-0.05 equiv.) and DIPEA (2.0 equiv.), and the
mixture was stirred at RT
overnight, which was monitored by LCMS. The resulting mixture was directly
purified by prep-
HPLC to give vcPAB linker-payloads Li-PI, Li-PH-1, Li-PII-2, Li-PII-3, Li-PII-
4, Ll-PII-
5, Li-PII-6, Li-PII-7, Li-PII-8, Ll-PH-11, Li-PII-12, Li-PII-9, Li-Pill-1, L19-
PIII-1, and
Li-PIII-4 (11-68% yield; see Table 3) as white solids.
[00393] 14 -[(2S)-2-1(2S)-241 -(4-12-Azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4 -oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3 -
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyllmethyl N-
11(12-
[(1R,2S,10S,11S,13R,14R,15S,17S)-1-fluoro-14,17-dihydroxy-2,13,15-trimethy1-5-
oxotetracyclo [8.7Ø02,7.011,15]heptadeca-3,6-dien-14 -y1]-2-
oxoethoxyl methypcarbamoyl] methyl} carbamate (L1 -PI)
o
N
\ \ FIN1
o)
?
r0
0) ? CirIHN'
>,0
HH
_ 0
0 0 OH OH
Following the general procedure for vc PAB linker-payloads, starting from
Payload PI and
compound L-3b, linker-payload Li-PI (8.2 mg, 17% yield) was obtained as a
white solid. ESI
m/z: 710 (M/2 + 1)+. 1H NMR (400 MHz, DMS0d6) 6 10.01 (s, 1H), 8.72 (t, J =
6.7 Hz, 1H), 8.14
329
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
(d, J = 7.1 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 5.6 Hz, 1H), 7.68
(d, J= 8.0 Hz, 1H),
7.65-7.54 (m, 3H), 7.54-7.42 (m, 4H), 7.42-7.21 (m, 6H), 6.22 (d, J= 10.0 Hz,
1H), 6.05-5.96 (m,
2H), 5.43 (s, 2H), 5.26 (s, 1H), 5.06-4.90 (m, 4H), 4.63-4.48 (m, 3H), 4.44-
4.31 (m, 1H), 4.27-
4.08 (m, 3H), 3.66-3.54 (m, 4H), 3.52-3.35 (m, 12H), 3.33-3.24 (m, 2H), 3.14-
2.84 (m, 4H), 2.70-
2.53 (m, 2H), 2.48-1.88 (m, 10H), 1.82-1.53 (m, 4H), 1.48 (s, 3H), 1.47-1.27
(m, 4H), 1.23 (s,
2H), 1.10-1.00 (m, 1H), 0.87 (s, 3H), 0.86 (d, J= 6.5 Hz, 3H), 0.82 (d, J= 6.7
Hz, 3H), 0.78 (d, J
= 7.2 Hz, 3H) ppm.
[00394] 14-1(2S)-2-1(2S)-241-(4-12-Azatricyclo[10.4Ø04,91hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyllmethyl N-
{[(12-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,11icosa-14,17-dien-8-y1]-2-
oxoethoxylmethypearbamoyl]methylIcarbamate (Ll-PII-1)
Ny=
0 0NH
0)
H H
.== 0
r0 I 10
9 OH
Ojt N Ersii
0}cNorNO .. 0
0
1µ1 NH2
Following the general procedure for vcPAB linker-payloads, starting from
Payload P11-1 and
compound L-3b, linker-payload Li-PH-1 (5.0 mg, 11% yield) was obtained as a
white solid. ESI
m/z: 729 (M/2 + 1H
NMR (400 MHz, DMS0d6) 6 10.00 (s, 1H), 8.70-8.60 (m, 1H), 8.20-8.10
(m, 1H), 7.90-7.50 (m, 5H), 7.50-7.20 (m, 10H), 6.15-6.10 (m, 1H), 6.05-6.00
(m, 1H), 5.95 (s,
1H), 5.50 (s, 2H), 5.05-5.00 (m, 3H), 4.80-4.30 (m, 8H), 3.60-3.55 (m, 4H),
3.50-3.45 (m, 14H),
330
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
3.40-3.30 (m, 4H), 3.10-2.80 (m, 4H), 2.60-2.55 (m, 1H), 2.40-2.20 (m, 5H),
2.00-1.90 (m, 4H),
1.80-1.60 (m, 4H), 1.60-1.50 (m, 5H), 1.40-1.30 (m, 8H), 1.00-0.80 (m, 14H)
ppm.
[00395] 14-1(2S)-2-1(2S)-241-(4-{2-Azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y1I-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido] phenyl} methyl N-
R{R{2-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
dioxapentacyclo [10.8Ø02,9.04,8.013,18] icosa-14,17-dien-8-y1]-2-
oxoethoxyl methypcarbamoyl] methyl} carbamoypmethyl] carbamate (L1 -PII-2)
II 0
NI.r.ANH
0
0)
(0 -\_400 .z=H
0
0 0
H 9 i&
0 OH
0
I
N NH2
Following the general procedure for vcPAB linker-payloads, starting from
Payload PII-2 and
compound L-3b, linker-payload Li-PII-2 (1.0 mg, 18% yield) was obtained as a
white solid. ESI
m/z: 1041 (M - Bud), 736 (M/2 + 1)+, 521 [(M - Bud)/2]+. NMR (400 MHz, DMS0d6)
6 9.95
(s, 1H), 8.60-8.55 (m, 1H), 8.00 (d, J= 10.0 Hz, 1H), 7.75-7.70 (d, J= 6.4 Hz,
1H), 7.65-7.20 (m,
15H), 6.05-6.00 (m, 1H), 5.90-5.85 (m, 1H), 5.80 (s, 1H), 5.30 (s, 2H), 5.10-
4.60 (m, 4H), 4.55-
4.10 (m, 11H), 3.90-3.85 (m, 2H), 3.50-3.45 (m, 4H), 3.40-3.30 (m, 14H), 3.20-
3.15 (m, 2H), 3.00-
2.80 (m, 3H), 2.50-2.45 (m, 2H), 2.30-2.10 (m, 3H), 2.00-1.80 (m, 4H), 1.75-
1.50 (m, 4H), 1.45-
1.25 (m, 5H), 1.20-1.05 (m, 6H), 1.05-1.00 (m, 3H), 0.85-0.75 (m, 12H) ppm.
[00396] 14-1(2S)-2-1(2S)-241-(4-{2-Azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
331
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
methylbutanamido]-5-(earbamoylamino)pentanamido]phenyllmethyl N-
{[(1-{2-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,11icosa-14,17-dien-8-y1]-2-
oxoethoxylpropypearbamoyl]methyllearbamate (Li -P11-3)
0
NI
0
HN
o
(0
0)
NyNH2
0 0
0
YULIV.-rENI 0 H
0 ,F1
H 0 W OyN No H
0 a 0
HOH
0
Following the general procedure for vcPAB linker-payloads, starting from
Payload PII-3 and
compound L-3b, linker-payload Li-PII-3 (0.10 g, 47% yield) was obtained as a
white solid. ESI
m/z: 774 (M/2 + 1)+, 1116.5 (M ¨ Bud), 558.9 [(M-Bud)/2]+. NMR
(400 MHz, DMS0d6) 6
9.96 (s, 1H), 8.93-8.91 (m, 1H), 8.11 (d, J= 7.2 Hz, 1H), 7.87 (d, J= 8.4 Hz,
1H), 7.75 (t, J= 4.8
Hz, 1H), 7.69-7.45 (m, 9H), 7.39-7.26 (m, 9H), 7.24-7.16 (m, 3H), 6.16 (d, J=
10.0Hz, 1H), 5.97-
5.92 (m, 2H), 5.41 (s, 2H), 5.17-5.01 (m, 2H), 4.91-4.82 (m, 2H), 4.73-4.54
(m, 5H), 4.49-4.13
(m, 6H), 3.62-3.57 (m, 3H), 3.47-3.45 (m, 13H), 3.11-2.92 (m, 5H), 2.78-2.72
(m, 1H), 2.40-2.20
(m, 4H), 2.07-1.94 (m, 3H), 1.80-1.67 (m, 4H), 1.60-1.51 (m, 4H), 1.43-1.24
(m, 9H), 0.99-0.82
(m, 15H) ppm.
[00397] {4-1(2S)-2-1(2S)-241-(4-{2-Azatricyclo[10.4Ø04,91hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(earbamoylamino)pentanamido]phenyllmethyl N-
R{R{2-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
332
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
dioxapentacyclo[10.8Ø02,9.04,8.013,1licosa-14,17-dien-8-y1]-2-
oxoethoxyl methypcarbamoyl] methyl} carbamoypmethyl] carbamate (L1-PII-4)
0
N1(ANH
0 H
(0
0)
01 11 ')C.L 0 sH
H
00..) õIN NThor N 0
0
H H
0 HO
0
ON H2
Following the general procedure for vcPAB linker-payloads, starting from
Payload PII-4 and
compound L-3b, linker-payload Li-PII-4 (45 mg, 68% yield) was obtained as a
white solid. ESI
m/z: 757.5 (M/2 + 1)11. 1fINMR (400 MHz, DMS0d6) (59.99 (s, 1H), 8.69-8.65 (m,
1H), 8.23-8.20
(m, 1H), 8.13 (d, J= 7.0 Hz, 1H), 7.87 (d, J= 8.5 Hz, 1H), 7.76 (t, J = 6.0
Hz, 1H), 7.68-7.67 (m,
1H), 7.62-7.58 (m, 3H), 7.51-7.42 (m, 4H), 7.39-7.28 (m, 6H), 6.17-6.15 (m,
1H), 5.97 (t, J= 6.0
Hz, 1H), 5.91 (s, 1H), 5.41 (s, 2H), 5.16 (t, J= 5.5 Hz, 0.5H), 5.04-5.01 (m,
1.5H), 4.96 (s, 2H),
4.73-4.71 (m, 1.5H), 4.61-4.58 (m, 2.5H), 4.49 (t, J= 19.0 Hz, 1H), 4.40-4.35
(m, 1H), 4.30-4.28
(m, 1H), 4.24-4.14 (m, 2H), 3.72 (d, J= 5.5 Hz, 2H), 3.67 (d, J = 6.0 Hz, 2H),
3.62-3.56 (m, 3H),
3.47-3.45 (m, 10H), 3.44-3.43 (m, 2H), 3.31-3.28 (m, 3H), 3.10-3.05 (m, 2H),
3.04-3.00 (m, 1H),
2.97-2.90 (m, 1H), 2.60-2.54 (m, 1H), 2.47-2.44 (m, 1H), 2.39-2.34 (m, 1H),
2.30-2.20 (m, 2H),
2.08-1.94 (m, 4H), 1.78-1.66 (m, 4H), 1.59-1.49 (m, 5H), 1.45-1.39 (m, 2H),
1.37 (d, J = 3.0 Hz,
3H), 1.35-1.30 (m, 2H), 1.28-1.21 (m, 2H), 0.99-0.91 (m, 1H), 0.86-0.80 (m,
12H) ppm.
[00398] 14-1(2S)-2-1(2S)-241-(4-12-Azatricyclo[10.4Ø04,91hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyllmethyl N-
R{R{2-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,11icosa-14,17-dien-8-y1]-2-
oxoethoxyl methypcarbamoyl] methyl} carbamoypmethyl] carbamate (Li -PII-5)
333
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
00 NH
0 NH
0)
H H
01 -0 0
N N o OH
0 =
0
OIHNH2
Following the general procedure for vcPAB linker-payloads, starting from
Payload PII-5 and
compound L-3b, linker-payload Li-PII-5 (4 mg, 25% yield) was obtained as a
white solid. ESI
m/z: 771.5 (M/2 + 1)11, 556.3 [(M ¨ Bud)]. 1H NMR (400 MHz, DMS0d6) 6 9.99 (s,
1H), 8.79-
8.63 (m, 1H), 8.13 (d, J = 7.4 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.88 (d, J=
8.6 Hz, 1H), 7.77 (t,
J = 5.6 Hz, 1H), 7.71-7.54 (m, 4H), 7.54-7.42 (m, 3H), 7.42-7.21 (m, 7H), 6.16
(d, J = 10.1 Hz,
1H), 5.99 (t, J= 5.5 Hz, 1H), 5.92 (s, 1H), 5.42 (s, 2H), 5.24-4.87 (m, 4H),
4.80-4.00 (m, 11H),
3.66-3.54 (m, 3H), 3.53-3.41 (m, 12H), 3.32-3.27 (m, 2H), 3.13-2.87 (m, 4H),
2.68-2.45 (m, 2H),
2.42-2.17 (m, 4H), 2.08 (s, 1H), 2.05-1.90 (m, 4H), 1.83-1.64 (m, 4H), 1.64-
1.39 (m, 7H), 1.377
(s, 1.8H), 1.371 (s, 1.2H), 1.36-1.26 (m, 2H), 1.23 (d, J= 7.0 Hz, 3H), 1.19
(d, J = 7.0 Hz, 3H),
1.12-0.89 (m, 2H), 1.12-0.91 (m, 12H) ppm.
[00399] 14-1(2S)-2-1(2S)-241-(4-12-Azatricyclo[10.4Ø04,91hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyllmethyl N-
{[(1-12-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,11icosa-14,17-dien-8-y1]-2-
oxoethoxylpropyl)carbamoyl]methylIcarbamate (Li -P11-6)
334
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Ny=
0 0=,NH
0)
H 0
(0 0 IL,Zo
0 OH
NI(N6C 11 9
rµl)LNH2
Following the general procedure for vcPAB linker-payloads, starting from
Payload PII-6 and
compound L-3b, linker-payload Li-PII-6 (20 mg, 50% yield) was obtained as a
white solid. ESI
m/z: 1055 (M - Bud), 528 [(M - Bud)/2], 1H NMR (500 MHz, DMS0d6) 6 9.98 (s,
1H), 8.31-
8.19 (m, 1H), 8.11 (d, J= 7.4 Hz, 1H), 7.86 (d, J= 8.6 Hz, 1H), 7.75 (t, J=
5.6 Hz, 1H), 7.68 (d,
J= 7.2 Hz, 1H), 7.63-7.55 (m, 3H), 7.52-7.43 (m, 3H), 7.43-7.32 (m, 3H), 7.32-
7.21 (m, 4H), 6.15
(d, J= 10.0 Hz, 1H), 5.97 (t, J= 5.6 Hz, 1H), 5.91 (s, 1H), 5.40 (s, 2H), 5.20-
4.88 (m, 5H), 4.75-
4.08 (m, 7H), 3.70-3.53 (m, 5H), 3.51-3.40 (m, 12H), 3.30-3.27 (m, 2H), 3.13-
2.89 (m, 4H), 2.65-
2.53 (m, 1H), 2.47-2.43 (m, 1H), 2.41-2.18 (m, 4H), 2.04-1.97 (m, 4H), 1.80-
1.64 (m, 5H), 1.63-
1.47 (m, 6H), 1.47-1.21 (m, 8H), 1.11-0.90 (m, 2H), 0.89-0.76 (m, 15H) ppm.
[00400] 14-1(2S)-2-1(2S)-241-(4-{2-Azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y1I-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido] phenyl} methyl N-
{[(1-12-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
dioxapentacyclo [10.8Ø02,9.04,8.0"M icosa-14,17-dien-8-y1]-2-oxoethoxy1-2-
phenylethypcarbamoyl] methyl} carbamate (L1 -PII-7)
335
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
(Th
o 0NH
H
(0
0)
1-1
r.0 0
) -,....õ..--
out Isii . ): t 401 0 Frnc N 0
0 OH
11 '' N 1101
1
N NH2
H
Following the general procedure for vcPAB linker-payloads, starting from
Payload PII-7 and
compound L-3b, linker-payload Li-PII-7 (25 mg, 33% yield) was obtained as a
white solid. ESI
m/z: 1116.5 (M ¨ Bud). 1H NMR (500 MHz, DMS0d6) 6 9.98 (s, 1H), 8.46 (d, J =
9.7 Hz, 1H),
8.12 (d, J = 8.3 Hz, 1H), 7.87 (d, J= 8.9 Hz, 1H), 7.75 (t, J= 5.6 Hz, 1H),
7.68 (d, J = 7.8 Hz,
1H), 7.64-7.55 (m, 3H), 7.53-7.42 (m, 3H), 7.41-7.31 (m, 3H), 7.31-7.14 (m,
9H), 6.14 (d, J = 9.6
Hz, 1H), 5.97 (br s, 1H), 5.91 (s, 1H), 5.41 (s, 2H), 5.31-5.21 (m, 1H), 5.18-
5.11 (m, 0.5H), 5.05-
5.00 (m, 1.5H), 4.99-4.89 (m, 2H), 4.76-4.63 (m, 1H), 4.59-4.47 (m, 2H), 4.38
(m, 1H), 4.31-4.13
(m, 3H), 3.67-3.54 (m, 3H), 3.51-3.40 (m, 12H), 3.33-3.25 (m, 2H), 3.13-2.83
(m, 6H), 2.65-2.54
(m, 1H), 2.41-2.18 (m, 5H), 2.10-1.91 (m, 4H), 1.80-1.64 (m, 4H), 1.63-1.20
(m, 15H), 1.11-0.89
(m, 2H), 0.88-0.76 (m, 12H) ppm.
[00401] 14-1(2S)-2-1(2S)-241-(4-12-Azatricyclo[10.4Ø04,91hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyllmethyl N-
{[(12-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,11icosa-14,17-dien-8-y1]-2-
oxoethoxylmethyl)(methypearbamoyl]methylIcarbamate (Li -P11-8)
336
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Nly.)(NH
0
(0
0)
H õ
01 IL 0 0
igior OH
H õ H
0
NANH2
Following the general procedure for vcPAB linker-payloads, starting from
Payload PII-8 and
compound L-3b, linker-payload L1-PII-8 (60 mg, 44% yield) was obtained as a
white solid. ESI
m/z: 736 (M/2 + 1)11. 1fINMR (500 MHz, DMS0d6) 6 10.00 (s, 1H), 8.14 (d, J=
7.5 Hz, 1H), 7.89
(d, J = 8.5 Hz, 1H), 7.76 (d, J = 5.9 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.64-
7.54 (m, 3H), 7.52-
7.42 (m, 3H), 7.40-7.18 (m, 5H), 6.19-6.12 (m, 1H), 6.00 (t, J= 5.1 Hz, 1H),
5.92 (s, 1H), 5.41 (s,
2H), 5.20-5.13 (m, 0.5H), 5.08-4.99 (m, 1.5H), 4.96 (s, 2H), 4.85-4.08 (m,
10H), 4.02-3.95 (m,
1H), 3.92-3.85 (m, 1H), 3.64-3.54 (m, 3H), 3.51-3.40 (m, 12H), 3.33-3.27 (m,
2H), 2.91-2.86 (m,
5H), 2.90 (s, 2H), 2.65-2.53 (m, 1H), 2.47-2.42 (m, 1H), 2.41-2.32 (m, 1H),
2.32-2.19 (m, 2H),
2.13-1.91 (m, 4H), 1.81-1.65 (m, 5H), 1.63-1.47 (m, 5H), 1.46-1.40 (m, 2H),
1.38 (s, 3H), 1.36-
1.21 (m, 4H), 1.15-0.90 (m, 2H), 0.89-0.77 (m, 12H) ppm.
[00402] 14-1(2S)-2-1(2S)-241-(4-{2-Azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyll methyl N-R1S)-1-[(12-
1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,18]icosa-14,17-dien-8-y1]-2-
oxoethoxylmethyl)(methyl)carbamoyl] ethyl] carbamate (L1-PH-11)
337
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
(0
0)
0
0
0 OH
" 0
0
N NH2
Following the general procedure for vcPAB-linker-payloads, starting from
Payload PII-11 and
compound L-3b, linker-payload Li-PH-11 (50 mg, 61% yield) was obtained as a
white solid. ESI
m/z: 743 (M/2 + 1)+. 1H NMR (400 MHz, DMS0d6) 6 9.98 (s, 1H), 8.12 (d, J = 7.6
Hz, 1H), 7.87
(d, J = 8.4 Hz, 1H), 7.76 (t, J = 5.6 Hz, 1H), 7.80-7.74 (m, 1H), 7.71-7.66
(m, 1H), 7.64-7.54 (m,
3H), 7.53-7.43 (m, 3H), 7.40-7.24 (m, 6H), 6.15 (d, J= 13.2 Hz, 1H), 5.97 (t,
J= 5.6 Hz, 1H),5.92
(s, 1H), 5.41 (s, 2H), 5.20-4.83 (m, 5H), 4.78-4.68 (m, 2H), 4.67-4.50 (m,
2H), 4.49-4.34 (m, 2H),
4.33-4.12 (m, 3H), 3.67-3.55 (m, 3H), 3.52-3.41 (m, 12H), 3.31-3.27 (m, 2H),
3.12-2.84 (m, 7H),
2.62-2.53 (m, 2H), 2.47-2.43 (m, 1H), 2.41-2.34 (m, 1H), 2.33-2.19 (m, 2H),
2.11-1.91 (m, 4H),
1.82-1.67 (m, 4H), 1.63-1.49 (m, 4H), 1.47-1.40 (m, 2H), 1.39-1.35 (m, 3H),
1.25-1.15 (m, 4H),
1.01-0.89 (m, 2H), 0.89-0.79 (m, 12H) ppm.
[00403] 14-1(2S)-2-1(2S)-241-(4-{2-Azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y1I-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido] phenyl} methyl N-I1-(12-
1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethyl-16-oxo-6-propy1-5,7-
dioxapentacyclo [10.8Ø02,9.04,8.0"M icosa-14,17-dien-8-y1]-2-oxoethoxyl
methyl)-2-
oxopiperidin-3-yl] carbamate (Li-PII-12)
338
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
In
1%11,H=LNH
0
(0
0)
=
0YLNcNO 0 0H 0
1.14. N
0
; 1 H
0
NINH2
Following the general procedure for vcPAB-linker-payloads, starting from
Payload PII-12 and
compound L-3b, linker-payload L1-PII-12 (5.0 mg, 19% yield) was obtained as a
white solid. ESI
m/z: 749 (M/2 + 1)+. 1H NMR (400 MHz, DMS0d6) 6 9.99 (s, 1H), 8.11 (d, J = 7.0
Hz, 1H), 7.87
(d, J = 8.5 Hz, 1H), 7.79-7.74 (m, 1H), 7.69-7.67 (m, 1H), 7.63-7.58 (m, 3H),
7.51-7.25 (m, 9H),
6.17-6.14 (m, 1H), 6.00-5.97 (m, 1H), 5.92 (s, 1H), 5.41 (s, 2H), 5.33-5.15
(m, 1H), 5.04-5.01 (m,
1H), 4.95-4.47 (m, 7H), 4.40-4.18 (m, 4H), 4.00-3.93 (m, 1H), 3.62-3.56 (m,
3H), 3.47-3.42 (m,
11H), 3.32-3.26 (m, 5H), 3.12-2.93 (m, 4H), 2.62-2.55 (m, 1H), 2.50-2.20 (m,
4H), 2.02-1.68 (m,
13H), 1.60-1.28 (m, 14H), 0.99-0.90 (m, 2H), 0.86-0.81 (m, 12H) ppm.
[00404] 14-1(2S)-2-1(2S)-241-(4-12-Azatricyclo[10.4Ø04,91hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyllmethyl N-
I2-(2-12-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,11icosa-14,17-dien-8-y1]-2-
oxoethoxylpyrrolidin-1-y1)-2-
oxoethyl]carbamate (L1-PII-9)
339
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
\ 0
0)
lqyNH2
0
6
H H ' N
0 0 0
o
OH 0
Following the general procedure for vcPAB linker-payloads, starting from
Payload PII-9 and
compound L-3b, linker-payload L1-PII-9 (42 mg, 44% yield) was obtained as a
white solid. ESI
m/z: 1066 (M - Bud), 534 [(M-Bud)/2]+. NMR
(500 MHz, DMS0d6) 10.04 (s, 1H), 8.20 (d,
J = 7.8 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 5.7 Hz, 1H), 7.68 (d,
J = 7.5 Hz, 1H), 7.64-
7.56 (m, 3H), 7.53-7.43 (m, 3H), 7.40-7.23 (m, 7H), 6.18-6.16 (m, 1H), 6.03-
6.02 (m, 1H), 5.92
(s, 1H), 5.42 (s, 2H), 5.32 (s, 1H), 5.04-4.94 (m, 4H), 4.74-4.50 (m, 4H),
4.38-4.37 (m, 1H), 4.29-
4.21 (m, 3H), 3.79-3.78 (m, 1H), 3.62-3.55 (m, 3H), 3.47-3.45 (m, 12H), 3.31-
3.19 (m, 2H), 3.10-
2.93 (m, 4H), 2.64-2.54 (m, 1H), 2.48-2.45 (m, 1H), 2.40-2.20 (m, 2H), 2.11-
1.88 (m, 7H), 1.85-
1.64 (m, 7H), 1.60-1.40 (m, 8H), 1.38 (s, 3H), 1.36-1.19 (m, 4H), 1.00-0.91
(m, 2H), 0.89-0.75
(m, 12H) ppm.
[00405] 14-1(2S)-2-1(2S)-241-(4-12-Azatricyclo[10.4Ø04,91hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyllmethyl N-
I2-(2-12-
[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethy1-16-oxo-6-propy1-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,11icosa-14,17-dien-8-y1]-2-
oxoethoxylpiperidin-l-y1)-2-
oxoethyl]carbamate (Li-PH-10)
340
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
0
H
0 0
0 ,HH
N
H N 0
0 H 0 y NL 0
0
0 HO H
0
Following the general procedure for vcPAB linker-payloads, starting from
Payload PII-10 and
compound L-3b, linker-payload Li-PH-10 (50 mg, 50% yield) was obtained as a
white solid. ESI
m/z: 1080 (M - Bud), 541 [(M-Bud)/2]t
[00406] 14-1(2S)-2-1(2S)-241-(4-12-Azatricyclo[10.4Ø04,91hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyflmethyl N-{[(12-
[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-9,13-dimethy1-16-
oxo-6-
propy1-5,7-dioxapentacyclo[10.8Ø02,9.04,8.013,18]icosa-14,17-dien-8-34]-2-
oxoethoxylmethyflcarbamoyflmethylicarbamate (Li -P111-b)
II
0
NH
0
(0
0)
H 0
(0
0
0
)L) FrscrENIõ,rii N
0 [gi o 0 OH
0
0
N NH2
Following the general procedure for vcPAB linker-payloads, starting from
Payload P11I-1 and
compound L-3b, linker-payload Lb-PIII-1 (23 mg, 58% yield) was obtained as a
white solid. ESI
m/z: 747 (M/2 + 1)11. 1f1NMR (400 MHz, DMS0d6) 6 10.08 (s, 1H), 8.83-8.71 (m,
1H), 8.15 (d, J
341
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
= 6.6 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.78 (t, J = 5.4 Hz, 1H), 7.68 (d, J=
7.7 Hz, 1H), 7.65-
7.55 (m, 3H), 7.52-7.44 (m, 4H), 7.41-7.22 (m, 6H), 6.29 (d, J= 10.2 Hz, 1H),
6.11 (s, 1H), 5.99
(t, J= 5.0 Hz, 1H), 5.73-5.36 (m, 4H), 5.22-4.93 (m, 3H), 4.78-4.45 (m, 4H),
4.42-4.33 (m, 1H),
4.28-4.14 (m, 3H), 3.67-3.54 (m, 5H), 3.52-3.41 (m, 12H), 3.29 (t, J= 5.9 Hz,
2H), 3.18-2.89 (m,
4H), 2.72-2.42 (m, 3H), 2.42-2.18 (m, 4H), 2.10-1.89 (m, 4H), 1.82-1.65 (m,
3H), 1.63-1.51 (m,
4H), 1.48 (s, 3H), 1.47-1.19 (m, 6H), 0.90-0.75 (m, 12H) ppm.
[00407] 14-1(2S)-2-1(2S)-2-Amino-3-methylbutanamido]-5-
(carbamoylamino)pentanamido]phenyll methyl N-{[(12-
1(1S,2S,4R,8S,9S,11S,12R,13S,19S)-
12,19-difluoro-11-hydroxy-9,13-dimethyl-16-oxo-6-propy1-5,7-
dioxapentacyclo [10.8Ø02,9.04,8.013,"flcosa-14,17-dien-8-34]-2-
oxoethoxyl methypearbarnoyfl methyl} carbamate
0
0 j)L H 0
H2NrN OH
0
),IHNH2
To a solution of Fmoc-vcPAB-PNP (L-4) (60 mg, 78 nmol) in DMF (2 mL) were
added payload
PIII-1 (44 mg, 80 nmol) and DIPEA (31 mg, 0.24 mmol), and the mixture was
stirred at room
temperature for 2 hours, which was monitored by LCMS. To the resulting mixture
was added
piperidine (34 mg, 0.40 mmol), and the mixture was stirred at room temperature
for an hour until
Fmoc was totally removed, which was monitored by LCMS. The reaction mixture
was directly
purified by reversed phase flash chromatography (0-100% acetonitrile in aq.
ammonium
bicarbonate (0.05%)) to give compound L-5 (45 mg, 60% yield) as a yellow
solid. ESI m/z: 958
(M + 1)+.
[00408] (1R,8S,9R)-Bicyclo16.1.01non-4-yn-9-ylmethyl N-(14-11(1S)-1-11(1S)-
4-
(carbarnoylarnino)-1-1(4-11({1({2-1(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-
difluoro-11-
hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo
110.8Ø02,9.04,8.013,1 icosa-
14,17-dien-8-y11-2-
342
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
oxoethoxyl methyl)carbamoyl] methyl} carb amoyDoxy] methyllphenyflcarbamoyl]
butyl] carb
amoy11-2-methylpropyl]carbamoy11-3,6,9,12-tetraoxatetradecan-1-yflcarbamate
(L19-PIII-
1)
='H 0
0) z
H 0
r0
0 EU
_ NIO 0 OH
00 o
, õ r
y.L,,,, 0 0
0 ,
NNH2
To a solution of compound L-5 (30 mg, 31 umol) in DMF (2 mL) were added
compound L-lc (34
mg, 63 umol) and DIPEA (12 mg, 93 umol), and the reaction mixture was stirred
at room
temperature for 2 hours, which was monitored by LCMS. The resulting mixture
was directly
purified by reversed phase flash chromatography (0-100% acetonitrile in aq.
ammonium
bicarbonate (0.05%)) to give linker-payload L19-PIII-1 (8.0 mg, 14% yield) as
a white solid. ESI
m/z: 691 (M/2 + 1)11. 1H NMR (400 MHz, DMS0d6) 10.00 (s, 1H), 8.75 (t, J= 6.8
Hz, 1H), 8.14
(d, J= 7.6 Hz, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.47 (t,
J= 6.0 Hz, 1H),
7.31-7.25 (m, 3H), 7.12-7.09 (m, 1H), 6.29 (dd, J= 10.4 and 1.6 Hz, 1H), 6.11
(s, 1H), 5.99-5.97
(m, 1H), 5.72-5.56 (m, 1H), 5.48-5.46 (m, 1H), 5.42 (s, 2H), 4.96 (s, 2H),
4.76-4.75 (m, 1H), 4.67-
4.49 (m, 4H), 4.41-4.36 (m, 1H), 4.27-4.19 (m, 3H), 4.04-4.02 (m, 2H), 3.67-
3.56 (m, 4H), 3.50-
3.45 (m, 12H), 3.41-3.38 (m, 2H), 3.14-3.09 (m, 2H), 3.05-2.92 (m, 2H), 2.43-
2.33 (m, 1H), 2.27-
2.13 (m, 7H), 2.07-1.94 (m, 3H), 1.72-1.69 (m, 2H), 1.59-1.22 (m, 17H), 0.87-
0.82 (m, 15H) ppm.
[00409] 14-1(2S)-2-1(2S)-241-(4-12-Azatricyclo[10.4Ø04,91hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenylimethyl N-
R{R{2-
[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-9,13-dimethy1-16-
oxo-6-
propy1-5,7-dioxapentacyclo[10.8Ø02,9.04,8.013,licosa-14,17-dien-8-34]-2-
oxoethoxyl methyl)carbamoyl] methyl} carb amoypmethyl] carbamate (Li -PIII-4)
343
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
N
0
(0
0)
\-0
) 1 11 1:? =õ,
0 =,HH
0 HThor =.`fC
'n 0
HO
0
011N H2
Following the general procedure for vcPAB linker-payloads, starting from
Payload PIII-4 and
compound L-3b, linker-payload L1-PIII-4 (30 mg, 43% yield) was obtained as a
white solid. ESI
m/z: 775 (M/2 + 1)+.1fINMR (400 MHz, DMS0d6) 10.00 (s, 1H), 8.71-8.64 (m, 1H),
8.26-8.20
(m, 1H), 8.13 (d, J= 7.0 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.79-7.73 (m, 1H),
7.68 (d, J= 7.5 Hz,
1H), 7.64-7.57 (m, 3H), 7.53-7.43 (m, 4H), 7.39-7.33 (m, 2H), 7.32-7.25 (m,
4H), 6.29 (d, J = 8.5
Hz, 1H), 6.11 (s, 1H), 6.01-5.95 (m, 1H), 5.72-5.66 (m, 0.5H), 5.60-5.53 (m,
0.5H), 5.48 (s, 1H),
5.42 (s, 2H), 5.03 (d, J = 14.1 Hz, 1H), 4.96 (s, 2H), 4.75 (s, 1H), 4.67-4.57
(m, 3H), 4.50 (d, J=
18.7 Hz, 1H), 4.41-4.34 (m, 1H), 4.28-4.17 (m, 3H), 3.72 (d, J= 5.3 Hz, 2H),
3.67 (d, J= 5.8 Hz,
2H), 3.64-3.56 (m, 3H), 3.52-3.41 (m, 13H), 3.31-3.28 (m, 2H), 3.12-2.93 (m,
4H), 2.63-2.57 (m,
1H), 2.41-2.36 (m, 1H), 2.28-2.20 (m, 2H), 2.06-1.93 (m, 4H), 1.80-1.65 (m,
3H), 1.62-1.51 (m,
4H), 1.48 (s, 3H), 1.47-1.20 (m, 7H), 0.95-0.75 (m, 12H) ppm.
[00410] 14-
1(2S)-2-1(2S)-241-(4-{2-Azatricyclo [1 0.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,1 5-
hexaen-1 0-yn-2-y11-4-oxobutanamido)-3,6,9,1 2-tetraoxapentadecan-1 5-amido]-3-
methylbutanamido]-5-(carbamoylamino)pentanamido]phenyll methyl N-
({R{[(4bS,8S,8aR)-
8-{[(1S,4aS,1 OaR)-6-hydroxy-1,4a-dimethy1-1 0a-
octahydrophenanthrene-1-
carbonyl] carbamoy11-4b,8-dimethy1-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-
yl]carbamoyllmethoxy)methyl] carbamoyllmethypearbamate (Ll-PIV)
344
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
11
NLNH
0 H
Of0
Of 0 Oj 0 0
,,H H
N
0 00
H H
0
071NH2
Following the general procedure for vcPAB-linker-payloads, starting from
Payload PIV and
compound L-3b, linker-payload Li-PIV (20 mg, 53% yield) was obtained as a
white solid. ESI
m/z: 807 (M/2 + 1)+. 1H NMR (400 MHz, DMS0d6) 10.00 (s, 1H), 9.53 (s, 1H),
8.99 (s, 1H),
8.92-8.83 (m, 1H), 8.19-8.07 (m, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.77 (t, J=
5.6 Hz, 1H), 7.68 (d, J
= 6.0 Hz, 1H), 7.64-7.56 (m, 4H), 7.53-7.25 (m, 9H), 6.96 (d, J= 8.5 Hz, 1H),
6.81 (d, J= 8.3 Hz,
1H), 6.63 (s, 1H), 6.50 (d, J= 7.9 Hz, 1H), 6.02-5.94 (m, 1H), 5.42 (s, 2H),
5.02 (d, J = 14 Hz,
1H), 4.95 (s, 2H), 4.65 (d, J= 6.5 Hz, 2H), 4.43-4.32 (m, 1H), 4.26-4.19 (m,
1H), 4.00 (s, 2H),
3.70-3.54 (m, 5H), 3.50-3.41 (m, 12H), 3.31-3.26 (m, 1H), 3.13-2.54 (m, 8H),
2.41-2.08 (m, 11H),
2.06-1.52 (m, 14H), 1.47-1.08 (m, 12H), 1.00 (s, 3H), 0.98 (s, 3H), 0.86 (d,
J= 6.8 Hz, 3H), 0.82
(d, J = 6.8 Hz, 3H) ppm.
Synthesis of Linker-Payload L2-PIII-1
[00411] Linker-payload L8-PII-1 and L2-PIII-1 were synthesized according to
FIG. 4 and the
following procedures.
[00412] Methyl (4S)-4-amino-4-11(1S)-1-11(1S)-4-(earbamoylamino)-1-
114-
(hydroxymethyl)phenyl] earbamoyll butyl] earbamoy11-2-
methylpropyl]earbamoyllbutanoate (L-7)
H2N c1;14. 5i OH
0
0 0 `NANH2
345
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
To a solution of compound L-6 (26 mg, 0.10 mmol) in DMF (1 mL) were added HATU
(38 mg,
0.10 mmol) and DIPEA (26 mg, 0.20 mmol). The reaction mixture was stirred at
RT for 10 min
before the addition of vel'AB (38 mg, 0.10 mmol). The mixture was stirred at
RT for 16 hours,
and monitored by LCMS. The resulting mixture was subjected to prep-HPLC to
give impure Boc-
L-7 (ESI m/z: 623 (M + 1)+), which was dissolved in DCM (3 mL). To the
solution was added
TFA (0.3 mL), and the reaction mixture was stirred at RT for 4 hours until Boc
was totally removed
according to LCMS. The mixture was concentrated in vacuo and the residue was
dissolved in
methanol (2 mL). After stirring at RT overnight, the mixture was concentrated
in vacuo. The
residue was purified by prep-HPLC to give compound L-7 (23 mg, 43% yield) as
colorless oil.
ESI m/z: 523 (M+ 0+.
[00413] Methyl (4S)-4-11(1S)-1-11(1S)-4-(carbamoylamino)-1-114-
(hydroxymethypphenyl] carbamoyllbutyl] carbamoy11-2-methylpropyl] carbamoy11-4-
{1-12-
(cyclooct-2-yn-1-yloxy)acetamido]-3,6,9,12-tetraoxapentadecan-15-
amidolbutanoate (L-8a)
,0,0,0,0,rajiXajtm 40 OH
0, 11
o o
o o pANH2
To a solution of compound L-7 (0.10 g, 0.19 mmol) in DMF (5 mL) were added
compound L-la
(0.10 mg, 0.19 mmol) and DIPEA (49 mg, 0.38 mmol), and the reaction mixture
was stirred at
room temperature for 4 hours, which was monitored by LCMS. The resulting
mixture was directly
purified by prep-HPLC to give compound L-8a (0.11 g, 63% yield) as a white
solid. ESI m/z: 934
(M + 0+.
[00414] Methyl (4S)-4-11(1S)-1-11(1S)-4-(carbamoylamino)-1-[(4-11({1({2-
1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-
dioxapentacyclo [10.8Ø02,9.04,8.0"M icosa-14,17-dien-8-y1]-2-
oxo ethoxyl methypcarbamoyl] methyl} carbamoyDoxy] methyllphenyl)carbamoyl]
butyl] carb
amoy11-2-methylpropyl] carbamoy11-4-{1-12-(cyclooct-2-yn-1-yloxy)acetamido]-
3,6,9,12-
tetraoxapentadecan-15-amidolbutanoate (L-10a)
346
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
oH
Eaorl4o
(0
0 0
0
I4,0
ro y 0 riThr OH
0
- NThr N
0 0 0
0 0 NANH2
To a solution of compound L-8a (0.10 g, 0.11 mmol) in DMF (3 mL) were added 4-
nitrophenyl
chloroformate (24 mg, 0.12 mmol) and DIPEA (70 mg, 54 mmol). The reaction
mixture was stirred
at room temperature for 4 hours, which was monitored by LCMS. The solution
containing
compound L-9a was used for the next step directly. ESI m/z: 550.5 (M/2 + 1)+.
To this solution
(0.50 mL) were added P11-1 (9.5 mg, 18 ilmol) and DIPEA (4.7 mg, 36 ilmol).
The reaction
mixture was stirred at room temperature for 4 hours, which was monitored by
LCMS. The mixture
was purified by prep-HPLC to give compound L-10a (14 mg, 76% yield) as a white
solid. ESI
m/z: 1499 (M + 23)+.
[00415] (4S)-4-11(1S)-1-11(1S)-4-(Carbarnoylarnino)-1-[(4-{R{R{2-
1(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.u"13,181icosa-14,17-dien-8-y1]-2-
oxoethoxyl methyl) carbamoyl] methyl} carb amoyDoxy] methyllphenyl)carbamoyl]
butyl] carb
amoy11-2-methylpropyl]carbamoy11-4-1142-(cyclooct-2-yn-l-yloxy)acetamido]-
3,6,9,12-
tetraoxapentadecan-15-amidolbutanoic acid (L8-PII-1)
o
) H ;11
0 =
0 0 0
_ A 140 0
OH
N N
0 0
HO 0 NANI-12
347
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
To a solution of compound L-10a (30 mg, 20 ilmol) in dioxane (0.6 mL) and
water (0.2 mL) was
added lithium hydroxide (3.0 mg, 0.12 mmol), and the reaction mixture was
stirred at room
temperature for 18 hours, which was monitored by LCMS. The residue was
purified by prep-HPLC
to give L8-PII-1 (24 mg, 75% yield) as a white solid. ESI m/z: 1463 (M + 1)11.
1H NMR (400
MHz, DMS0d6) 6 10.03 (s, 1H), 8.74 (d, J= 4.8 Hz, 1H), 8.22 (s, 1H), 8.09 (d,
J = 8.0 Hz, 1H),
7.75 (d, J= 8.5 Hz, 1H), 7.59 (d, J= 8.3 Hz, 3H), 7.46 (t, J= 6.1 Hz, 1H),
7.30 (dd, J= 11.4, 6.0
Hz, 3H), 6.16 (d, J= 10.1 Hz, 1H), 5.92 (s, 1H), 5.46-5.31 (m, 2H), 5.17-4.96
(m, 3H), 4.71-4.58
(m, 4H), 4.53-4.44 (m, 1H), 4.40-4.25 (m, 4H), 4.20 (m, 2H), 3.87 (d, J= 14.8
Hz, 1H), 3.75 (d, J
= 14.7 Hz, 1H), 3.64-3.56 (m, 4H), 3.42 (t, J= 6.0 Hz, 3H), 3.25 (m, 3H), 3.14-
2.84 (m, 3H), 2.44-
1.80 (m, 18H), 1.80-1.67 (m, 6H), 1.63-1.40 (m, 10H), 1.40-1.32 (m, 6H), 1.28-
1.22 (m, 6H), 0.96
(m, 2H), 0.90-0.75 (m, 14H) ppm.
[00416] Methyl (4S)-441-(4-12-azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-4-{
[(1S)-1-
{ R1S)-4-(carbamoylamino)-1-{ [4-(hydroxymethyl)phenyl] carbamoyll butyl]
carbamoy11-2-
methylpropyl]carbamoyllbutanoate (L-8b)
KII-o -" OH
--11-----T..õ----Ø----,.,,Ø.õ,--,00..,..,,,...k_ 140 JN 0
0 0 NH
I
0 NH2
Following a similar procedure as L-8a, except substituting L-lb for L-la,
compound L-8b (70
mg, 47% yield) was obtained as a white solid. ESI m/z: 529 (M/2 + 1)11.
[00417] Methyl (4S)-441-(4-12-azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-4-
{[(1S)-1-
{[(1S)-4-(carbamoylamino)-1-[(4-{R{R{2-1(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-
difluoro-
11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,18]icosa-
14,17-dien-8-y1]-2-
oxoethoxyl methyl)carbamoyl] methyl} carbamoyDoxy] methyl} phenyl)carbamoyl]
butyl] carb
amoy11-2-methylpropyl]carbamoyllbutanoate (L-10b)
348
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
\ 0 Lo
0
of H 0
0
O 14 0 OH
oA k."1r;
c"?ci[siõ.11
0 0
0 0 N NH2
To a solution of compound L-8b (7.0 mg, 6.6 [tmol) in DMF (0.5 mL) were added
4-nitrophenyl
chloroformate (1.3 mg, 6.7 mop and DIPEA (1.7 mg, 13 mop. The reaction
mixture was stirred
at RT for 4 hours, which was monitored by LCMS. The solution containing
compound L-9b was
used in the next step without purification. ESI m/z: 612 (M/2 + 1)+. To this
solution (2.4 [tmol
(calc.)) were added PIII-1 (1.4 mg, 2.4 mol) and DIPEA (0.6 mg, 4.8 [tmol).
The reaction mixture
was stirred at RT for 4 hours, which was monitored by LCMS. The mixture was
purified by prep-
HPLC to give compound L-10b (3 mg, 76% yield) as a white solid. ESI m/z: 819
(M/2 + 1)+.
[00418] (4S)-441-(4-12-Azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-hexaen-10-
yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-amido]-4-11(1S)-1-
11(1S)-4-
(carbamoylamino)-1-[(4-{R{R{2-1(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-
11-
hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-
dioxapentacyclo[10.8Ø02,9.04,8.013,181icosa-
14,17-dien-8-y1]-2-
oxoethoxyl methyl)carbarnoyl] methyl} carbarnoyDoxy] methyllphenyl)carbamoyl]
butyl] carb
amoy11-2-methylpropyflcarbamoy1ibutanoic acid (L2-PIII-1)
0
\\ 0
0
of H H 0
.."
O KJ,0 OH
0 0 0 NThor cki,)0is.,?cr[sii4.vi =
O 0 0
HO 0 N HH2
349
CA 03125998 2021-07-07
WO 2020/146541
PCT/US2020/012798
To a solution of compound L-10b (9 mg, 5.5 ilmol) in dioxane (0.6 mL) and
water (0.2 mL) was
added lithium hydroxide (0.42 mg, 16.7 ilmol). The reaction mixture was
stirred at RT for 4 hours,
and monitored by LCMS. The volatiles were removed in vacuo and the residue was
purified by
prep-HPLC to give linker-payload L2-PIII-1 (3 mg, 32% yield) as a white solid.
ESI m/z: 812
(M/2 + 1)11. 1f1NMR (400 MHz, DMS0d6) 10.20 (s, 1H), 8.70-8.60 (m, 1H), 8.55-
8.50 (m, 1H),
8.20-8.10 (m, 1H), 7.90-7.20 (m, 13H), 6.15-6.10 (m, 1H), 6.05 (s, 1H), 5.80-
5.50 (m, 4H), 5.10-
4.95 (m, 3H), 4.80 (s, 1H), 4.75-4.50 (m, 4H), 4.40-4.10 (m, 5H), 3.60-3.55
(m, 26H), 3.50-3.25
(m, 6H), 3.10-2.80 (m, 4H), 2.60-2.50 (m, 3H), 2.40-2.20 (m, 5H), 2.05-1.95
(m, 3H), 1.90-1.20
(m, 15H), 0.90-0.80 (m, 8H) ppm.
Synthesis of Linker-Payloads L4-PI, L9-PII-1, L10-PH-1, LH-PH-2, L12-PII-2,
L13-PII-1,
L14-PII-1, L3-PIII-1, L9-PIII-1, L12-PIII-5, L13-PIII-1, L4-PIII-1, and L14-
PIV
[00419] Linker-payloads L4-PI, L9-PII-1, L10-PII-1, LH-PH-2, L12-PII-2, L13-
PII-1, L14-
PII-1, L3-PIII-1, L9-PIII-1, L12-PIII-5, L13-PIII-1, L4-PIII-1, and L14-
PIVwere synthesized
according to FIG. 5 and the following procedures.
Synthesis of Intermediates L-12a-g
[00420] (2S)-
2-1242-(4-{2-Azatricyclo [10.4Ø04,9] hexadeca-1(12),4(9),5,7,13,15-hexaen-
10-yn-2-y11-4-oxobutanamido)acetamido]acetamido1-3-phenylpropanoic acid (L-
12a)
kLA OH
NrAnr
N
To a solution of compound L-le (0.28 g, 0.69 mmol) and peptide L-11a (Gly-Gly-
Phe-OH, 0.19
g, 0.69 mmol) in DMF (10 mL) was added DIPEA (0.37 mL, 2.1 mmol), and the
reaction mixture
was stirred at room temperature for an hour, which was monitored by LCMS. The
resulting mixture
was directly purified by reversed phase flash chromatography (0-100%
acetonitrile in aq.
ammonium bicarbonate (10 mM)) to give compound L-12a (0.31 g, 78% yield) as a
white solid.
ESI m/z: 567.0 (M + H)11.
[00421] 2-1242-(Cyclooct-2-yn-l-yloxy)acetamido]acetamidolacetic acid (L-12b)
350
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
H 0
N OH
Following a similar procedure as L-12a, except substituting Gly-Gly-OH (L-11b)
for Gly-Gly-
Phe-OH and substituting L-ld for L-le, intermediate L-12b (36 mg, 60% yield)
was obtained as
a white solid. ESI m/z: 297.2 (M + 1)+.
[00422] (2S)-2-1(2S)-242-(Cyclooct-2-yn-1-
yloxy)acetamido]propanamido]propanoic
acid (L-12c)
JLeyo ,11,A
N OH
= 0 =
Following a similar procedure as L-12a, except substituting Ala-Ala-OH (L-11c)
for Gly-Gly-
Phe-OH and substituting L-ld for L-le, intermediate L-12c (35 mg, 91% yield)
was obtained as
a white solid. ESI m/z: 325.3 (M + 1)+.
[00423] (2R)-2-1(2S)-242-(Cyclooct-2-yn-1-
yloxy)acetamido]propanamido]propanoic
acid (L-12d)
o
JL N)YYLOH
= 0
Following a similar procedure as L-12a, except substituting Ala-(D)-Ala-OH (L-
11d) for Gly-
Gly-Phe-OH and substituting L-1 d for L-1 e, intermediate L-12 d (38 mg, 64%
yield) was obtained
as a white solid. ESI m/z: 325.2 (M + 1)+.
[00424] 2-(2-1242-(Cyclooct-2-yn-1-yloxy)acetamido] acetamidolacetamido)acetic
acid
(L-12e)
H
H 0 H 0
351
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
To a suspension of peptide L-11e (Gly-Gly-Gly-OH, 0.34 g, 1.8 mmol) in DMF (13
mL) were
added a solution of L-ld (0.50 g, 1.8 mmol) in THF (6 mL) and DIPEA (0.69 g,
5.4 mmol), and
the turbid mixture was stirred at room temperature for 20 hours. The mixture
was filtered, the clear
filtrate solution was concentrated in vacuo, and the residue was purified by
reversed phase flash
chromatography (0-20% acetonitrile in water) to give compound L-12e (0.13 g,
21% yield) as a
white solid. ESI m/z: 354.2 (M + H)11. 1H NMR (400 MHz, DMS0d6) 6 12.6 (s,
1H), 8.20 (t, J=
5.6 Hz, 1H), 8.15 (t, J= 6.0 Hz, 1H), 7.82 (t, J= 5.6 Hz, 1H), 4.35-4.31 (m,
1H), 3.94 (d, J= 14.8
Hz, 1H), 3.83-3.73 (m, 7H), 2.29-2.06 (m, 3H), 1.99-1.93 (m, 1H), 1.91-1.71
(m, 3H), 1.63-1.56
(m, 2H), 1.46-1.37 (m, 1H) ppm.
[00425] (2S)-2-(2-1241-(4-{2-Azatricyclo [10.4Ø04,9] hexadeca-
1(12),4(9),5,7,13,15-
hexaen-10-yn-2-y11-4-oxobutanamido)-3,6,9,12-tetraoxapentadecan-15-
amido]acetamidolacetamido)-3-phenylpropanoic acid (L-120
,kL)(
OH
0 0 0 -
=
Following the similar procedure as L-12a, except substituting compound L-lb
for L-le,
intermediate L-12f (15 mg, 51% yield) was obtained as a white solid. ESI m/z:
408.2 (M/2 + 1)11.
[00426] 2-[2-(Cyclooct-2-yn-1-yloxy)acetamido]acetic acid (L-12g)
oojil .ccOH
Following a similar procedure as L-12a, except substituting glycine for Gly-
Gly-Phe-OH and
substituting L-ld for L-le, intermediate L-12g (0.10 g, 61% yield) was
obtained as colorless oil.
ESI m/z: 240.2 (M + 1)11.
[00427] (2S)-242-(Cyclooct-2-yn-1-yloxy)acetamido]-3-hydroxypropanoic acid (L-
12h)
OH
0
0
352
CA 03125998 2021-07-07
WO 2020/146541 PCT/US2020/012798
Following a similar procedure as L-12a, except substituting serine for Gly-Gly-
Phe-OH and
substituting L-ld for L-le, intermediate L-12h (90 mg, 93% yield) was obtained
as yellow oil.
ESI m/z: 270.3 (M + 1)+.
[00428] (2S)-242-(Cyclooct-2-yn-1-yloxy)acetamido]-6-11(9H-fluoren-9-
ylmethoxy)carbonyllaminolhexanoic acid (L-12i)
)HFmoc
0
Ca0j.LNOH
0
Following a similar procedure as L-12a, except substituting H-Lys(Fmoc)-OH for
Gly-Gly-Phe-
OH and substituting L-ld for L-le, intermediate L-12i (30 mg, 78% yield) was
obtained as a white
solid. ESI m/z: 533.1 (M + 1)+.
General Procedure for Peptide Linker-Payloads (FIG. 5)
[00429] To a mixture of intermediate L-12 (1.0 equiv.) in DMF or DCM (25 mM)
were added
HATU, EDCI, or HOSu (1.5 equiv.) and DIPEA (3.0 equiv.), and the reaction
mixture was stirred
for 2 h at room temperature before the addition of the corresponding payload
(1.0 equiv.), HOBt,
and DIPEA in DMF. The reaction mixture was stirred at RT for 2-20 hours, and
was monitored by
LCMS. The reaction mixture was directly purified by prep-HPLC to give peptide
linker-payload
(22-56% yield) as a white solid.
[00430] 4-{2-Azatricyclo [10.4Ø04,9] hexadeca-1(12),4(9),5,7,13,15-hexaen-
10-yn-2-yll-N-
{ [({ [(1S)-1-({ [(12-1(1R,2S,10S,11S,13R,14R,15S,17S)-1-fluoro-14,17-
dihydroxy-2,13,15-
trimethyl-5-oxotetracyclo 18.7Ø02,7.011,1 heptadeca-3,6-dien-14-yl] -2-
oxo ethoxyl methyl) carbamoyl] methyl} carb amoy1)-2-
phenylethyl] carbamoyll methyl) carbamoyl] methyl} -4-oxobutanamide (L4-PI)
o
NrFNI
0 0
HO r
0
353
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
CONTENANT LES PAGES 1 A 353
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
THIS IS VOLUME 1 OF 2
CONTAINING PAGES 1 TO 353
NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:
