Note: Descriptions are shown in the official language in which they were submitted.
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CA 03069544 2020-01-09
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COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF
ANDROGEN RECEPTOR
CROSS-REFERENCE TO RELATED APPLICATIONS
1001] The present disclosure is an International Patent Application
claiming priority to
U.S. Patent Application Serial No. 15/663,273, which is a Continuation-In-Part
of U.S.
Nonprovisional Application Serial No. 15/002,303, filed 20 January 2016, which
claims the
benefit of, and priority to, U.S. Provisional Patent Application Serial No.
62/105,210, filed 20
January 2015 and entitled: Compounds and Methods for the Targeted Degradation
of the
Androgen Receptor, all of which are incorporated herein by reference in their
entireties.
BACKGROUND
10021 1. Field of the Discovery. The present description relates to
bifunctional
compounds, which are useful for the modifying the ubiquitination and
subsequent degradation of
target polypeptides and proteins, in particular, androgen receptor. In certain
aspects, the
compounds comprise a Von Hippel-Lindau (VHL) binding moiety, which binds to
the VHL E3
ubiquitin ligase, a target protein binding moiety, which binds to the target
protein (e.g., androgen
receptor), and optionally a linker moiety which links the VHL binding moiety
and target protein
binding moiety.These compounds work in such way that the target
protein/polypeptide is placed
in proximity to the ubiquitin ligase to effect degradation (and inhibition) of
that protein (e.g.,
androgen receptor).
1003] 2. Background Information. Androgen Receptor (AR) belongs to a
nuclear
hormone receptor family that is activated by androgens, such as testosterone
and
dihydrotestosterone (Phctrmacol. Rev. 2006, 58(4), 782-97; Dim. Horm. 1999,
55:309-52.). In
the absence of androgens, AR is bound by Heat Shock Protein 90 (Hsp90) in the
cytosol. When
an androgen binds AR, its conformation changes to release AR from Hsp90 and to
expose the
Nuclear Localization Signal (NLS). The latter enables AR to translocate into
the nucleus where
AR acts as a transcription factor to promote gene expression responsible for
male sexual
characteristics (Endoc.r. Rev. 1987, 8(1):1-28; Mo/. Endocrinol. 2002, 16(10),
2181-7). AR
deficiency leads to Androgen Insensitivity Syndrome, formerly termed
testicular feminization.
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10041 While AR is responsible for development of male sexual
characteristics, it is also
a well-documented oncogene in certain forms cancers including prostate cancers
(Enclocr. Rev.
2004, 25(2), 276-308). A commonly measured target gene of AR activity is the
secreted Prostate
Specific Antigen (PSA) protein. The current treatment regimen for prostate
cancer involves
inhibiting the androgen-AR axis by two methods. The first approach relies on
reduction of
androgens, while the second strategy aims to inhibit AR function (Nat. Rev.
Drug Discovery,
2013, 12,823-824). Despite the development of effective targeted therapies,
most patients
develop resistance and the disease progresses. An alternative approach for the
treatment of
prostate cancer involves eliminating the AR protein. Because AR is a critical
driver of
tumorigenesis in many forms of prostate cancers, its elimination should lead
to therapeutically
benefical response.
[005] There exists an ongoing need in the art for effective treatments
for diseases and
conditions that are related to aberrant AR regulation or activity, such as,
for example, cancer,
prostate cancer, and Kennedy's Disease.
SUMMARY
1006] The present disclosure describes compounds, including compositions
comprising
the same, which function to recruit endogenous proteins to an E3 ubiquitin
ligase, e.g., Von
Hippel-Lindau (VHL) E3 ubiquitin ligase, for ubiquitination and subsequent
degradation, and
methods of using the same. In particular, the present disclosure provides
bifunctional or
proteolysis targeting chimeric (PROTAC) compounds, which find utility as
modulators of
targeted ubiquitination and degradation of androgen receptor (AR). In
addition, the description
provides methods of using an effective amount of the compounds as described
herein for the
treatment or amelioration of a disease condition including cancer, e.g.,
prostate cancer, and
Kennedy's Disease.
[007] Thus, in one aspect, the disclosure provides compounds which function
to recruit
endogenous proteins, e.g., AR proteins, to E3 Ubiquitin Ligase for
ubiquintination and
degradation. In certain embodiments, the compounds have the following general
structure:
[008] ABM ¨ L-ULM
[009] wherein ABM is an AR binding moiety, ULM is an E3 ligase binding
moiety,
e.g., a VHL E3 ligase binding moiety (VLM), and L is a bond or a linker moiety
which links the
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ABM and ULM. As such, in certain embodiments, the description provides
compounds having
the following general structure:
[010] ABM ¨ L-VLM (II),
[011] wherein ABM is an AR binding moiety, VLM is a VHL E3 ligase binding
moiety
and L is a bond or a linker moiety which links the ABM and VLM. In certain
embodiments, the
VLM comprises a hydroxyl prolyl moiety.
[012] In certain embodiments, the ULM is a moiety specific for an E3
ubiquitin ligase
such as, e.g., cereblon, mouse double minute 2 homolog (Mdm2), or inhibitor of
apoptosis (IAP),
wherein the ULM moiety is coupled to an ABM as described herein.
[013] It will be understood that the general structures are exemplary and
the respective
moieties can be arranged spatially in any desired order or configuration,
e.g., ULM-L-ABM, and
VLM-L-ABM respectively.
[014] In another aspect, the description provides AR binding moieties
(ABM). In an
additional embodiment, the description provides compounds having the following
general
structure: ABM-L, wherein ABM is an AR binding moiety as described herein, and
L is a
chemical linker moiety, or optionally a bond. In certain embodiments, the ABM
and/or L are
coupled to a ULM as described herein.
[015] In any of the aspects or embodiments described herein, the ABM is
selected from
following structures:
y2 R1 Q
(R)o-6
R2
Y3 N)./.\jNr
yl CO --
0 y4
ABM-a ABM-b
yl _3 ,R3
T
,
N I
õ
Rb
Y2 I -
ABM-c , and Arif.A4
3
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wherein WI is aryl or heteroaryl, independently substituted by 1 or more halo,
hydroxyl,
nitro, CN, CaCH, CF3, C1_6 alkyl (linear, branched, optionally substituted by
1 or more halo,
C1-6 alkoxyl), C1-6 alkoxyl (linear, branched, optionally substituted by 1 or
more halo), C2_6
alkenyl, C2-6 alkynyl;
I, Y2 are each independently NR', 0, S;
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRY1RY2, C=0, C=S, SO, SO2;
Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms,
optionally
substituted with 0-6 RQ, each RQ is independently H, OH, C1_6 alkyl (linear,
branched,
optionally substituted by 1 or more halo, C1.6 alkoxyl), or 2 R groups taken
together with
the atom they are attached to, form a 3-8 membered ring system containing 0-2
heteroatoms);
RI, R2, le, Rb, RY1, RY2 are each independently H, OH, CI.6 alkyl (linear,
branched,
optionally substituted by 1 or more halo, Ci_6 alkoxyl), or RI, R2 together
with the atom they
are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms;
W2 is a bond, C1.6 alkyl, alicyclic (e.g., C1-6 alicyclic), heterocyclic,
aryl, heteroaryl,
bicyclic, biaryl, biheteroaryl, biheterocyclic, each optionally substituted by
1, 2 or 3 Rw2; and
each Rw2 is independently H, halo, C1.45 alkyl (optionally substituted by 1 or
more F),
0C1_3alky1 (optionally substituted by 1 or more F), OH, NH2, NRYIRY2, CN.
10161 In any of the aspects or embodiments described herein, the ABM can
comprise or
consist of a structure as set forth herein, in particular in any of the ABMs
as provided in
Examples 1-870.
[017] In certain embodiments, the ULM (derivatized or configured to be
linked or
coupled to an ABM via a linker (as indicated by the dashed line)) has the
structure,
H
N I
s sst R .
,.***"%tk,( = =
,,,,
0 ss"
W4 '0
swr"
s
(Rt6) R ,
4
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wherein, W3 is optionally substituted aryl, optionally substituted heteroaryl,
or
R0
each R9 and R10 is independently hydrogen, optionally substituted alkyl,
optionally
substituted cycloalkyl, optionally substituted hydroxyallcyl, optionally
substituted heteroaryl,
or haloalkyl; or R9, R10, and the carbon atom to which they are attached form
an optionally
substituted cycloalkyl;
RI I is optionally substituted heterocyclic, optionally substituted alkoxy,
optionally
0
k-11 i¨N ¨IR
IS.
substituted heteroaryl, optionally substituted aryl, or
0
LNJ= )
1,3 i3
RI, is H or optionally substituted alkyl;
RI3 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl,
optionally
substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl,
optionally
substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or
optionally
substituted aralkyl;
R14a, R14b, is each independently H, haloallcyl, or optionally substituted
alkyl;
W5 is a phenyl or a 5-10 membered heteroaryl,
R15 is H, halogen, CN, OH, NO2, N R142R14b, OR14a, CONRI4aR14b, NR14aCOR14b,
SO2NRI4aR141), NR14a SO2R14b, optionally substituted alkyl, optionally
substituted haloallcyl,
optionally substituted haloalkoxy, optionally substituted aryl, optionally
substituted heteroaryl,
R=o.
/
= Ny;::::::\
14
.õ
optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or
¨
wherein R17 is H, halo, optionally substituted C3_6cycloa1kyl, optionally
substituted C1_6alkyl,
optionally substituted C1_6alkenyl, or C1_6haloalkyl; Xa is S or 0;
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each R16 is independently halo, optionally substituted alkyl, optionally
substituted
haloalkyl, hydroxy, or optionally substituted haloalkoxy;
o is 0, 1, 2, 3, or 4;
each R18 is independently halo, optionally substituted alkoxy, cyano,
optionally
substituted alkyl, haloalkyl, haloalkoxy or a linker; and
p is 0, 1, 2, 3, or 4.
[018] In another embodiments, the ULM has the structure
HO
H
N ,,,roorci 4a 1
1.
N 36..64414
k9
b
.) 1
R
R I
A15
wherein:
R9 is H;
Rio is isopropyl, tert-butyl, sec-butyl, eyclopentyl, or cyclohexyl;
Ri2
R11 is R13
R12 is H;
R13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl,
optionally
substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl,
optionally
substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or
optionally
substituted arylalkyl;
Rga is H, haloalkyl, methyl, ethyl, isopropyl, cyclopropyl, or C1-C6 alkyl
(linear, branched,
optionally substituted), each optionally substituted with 1 or more halo,
hydroxyl, nitro,
CN, C1-C6 alkyl (linear, branched, optionally substituted), or Ci-Co alkoxyl
(linear,
branched, optionally substituted); and
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R17
Xa /14
R15 is
wherein R17 is H, halo, optionally substituted C3.6cycloalkyl, optionally
substituted Ci_6alkyl, optionally substituted Ci_6alkenyl, and Ci_6haloalkyl;
and Xa is S or
0.
[019] In certain embodiments, an androgen receptor binding moiety has a
structure of
(10sR.6
sKO
( )
ABM-e
wherein:
WI is aryl or heteroaryl, independently substituted by 1 or more halo, CF3,
hydroxyl, nitro,
CN, CECH, C1_6 alkyl (linear, branched, optionally substituted by 1 or more
halo, C1_6
alkoxyl), C.6 alkoxyl (linear, branched, optionally substituted by 1 or more
halo). C2.6
alkenyl, C2-6 alkynyl;
1(1, y2 are each independently Nei, 0, s;
Y3, y4, y5 are each independently a bond, 0, NRY2, CRYIRY2, C=0, C=S, SO, SO2;
Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms,
optionally substituted
with 0-6 RQ, each R is independently H, OH, C1.6 alkyl (linear, branched,
optionally
substituted by 1 or more halo. C1_6 alkoxyl), or 2 RQ groups taken together
with the atom
they are attached to, form a 3-8 membered ring system containing 0-2
heteroatoms);
RY1, RY2 are each independently H, OH, C1_6 alkyl (linear, branched,
optionally substituted
by 1 or more halo, C1_6 alkoxyl);
w2 is a bond, C1_6 alkyl, alicyclic, heterocyclic, aryl, heteroaryl, bicyclic,
biaryl,
biheteroaryl,or biheterocyclic, each optionally substituted by 1, 2 or 3 Rw2;
and
each Rw2is independently H, halo, C1_6 alkyl (optionally substituted by 1 or
more F), 0C1.
3alkyl (optionally substituted by 1 or more F), OH, Nfli, NRY1RY2, CN.
[020] In certain additional embodiments, the compounds comprise a plurality
of E3
ligase binding moieties and/or a plurality of ABMs.
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1021] In certain embodiments, the linker group (L) comprises a chemical
structural unit
represented by the formula:
-Ay-
wherein
q is an integer greater than 1; and
A is independently selected from the group consisting of a bond, CRultu, 0, S,
SO,
SO2, NR, SO2NRI-3, SONRI-3, CONRI-3, NRI-3CONRI-4, NRI-3S02NR", CO, CRLI=CRI-
2,
CEC, SiRLiRU, p(0)K -L1,
P(0)ORLI, NRI3C(=NCN)NR", NRuC(=NCN),
NR1-3C(=CNO2)NR", C3-iicycloa1kyl optionally substituted with 0-6 Ru and/or Ru
groups,
C34 iheteocyclyl optionally substituted with 0-6 Ru and/or R1-2 groups, aryl
optionally
substituted with 0-6 Ru and/or RU groups, heteroaryl optionally substituted
with 0-6 Ru
and/or RU groups;
wherein Ru, RU, RL3, Rt.4 and -- xL.5
are each, independently, selected from the group
consisting of H, halo, Ci_8alkyl, 0C1_8alkyl, SCi_8alkyl, NHCi_salkyl,
N(Ci_8alky1)2, C3-
lieycloalkyl, aryl, heteroaryl, C3-I1heterocyc1y1, OCI_Bcycloalkyl,
SCI4cycloalkyl, NHC1-
8eycloalkyl, N(Ci_8cycloalky1)2, N(C1.8cycloalkyl)(C1.8a1ky1), OH, NH2, SH,
SO2C1.8alkyl,
P(0)(0C1_8allcyl)(Ci_salkyl), P(0)(0C1_8alky1)2, CC-Cl_8alkyl, CCH,
CH=CH(CI_Balkyl),
C(Ci_8allcyl)=CH(Ci_8allcyl), C(Ci_salky1)=C(Ci_salky1)2, Si(OH)3,
Si(C1.8alky1)3, Si(OH)(Ci.
salky1)2, COCi_salkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5,
502NHC1_8alkyl,
SO2N(C14a1ky1)2, SONHC1_8alkyl. SON(Ci_8allcy1)2. CONHC1.8alkyl.
CON(Ci_8a1ky1)2.=
N(Ci_8alkyl)CONH(Ci_8alkyl), N(Ci_8alkyl)CON(Ci_8alky1)2, NHCONH(Ci_8alkyl),
NHCON(C1.salky1)2, NHCONH2, N(C1.8alkyl)S02NH(Ci_8allcyl), N(Ci_salkyl)
502N(C1-
8alky1)2, NH SO2NH(Ci_salkyl), NH SO2N(Ci_8alky1)2, and NH SO2NH2; and
wherein when q is greater than 1, Ru or Ru each, independently, can be linked
to
another A group to form cycloalkyl and/or heterocyclyl moeity that can be
further substituted
with 0-4 RL5 groups.
1022) In certain embodiments, the description provides a bifunctional
compound having
a structure selected from the group consisting of Examples 1-870, a salt, a
polymotph, and a
prodrug thereof.
[023] In another aspect, the description provides compositions
comprising compounds
as described herein, and a pharmaceutically acceptable carrier. In certain
embodiments, the
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compositions are therapeutic or pharmaceutical compositions comprising an
effective amount of
a compound as described herein and a pharmaceutally acceptable carrier. In
certain
embodiments, the therapeutic or pharmaceutical compositions comprise an
additional
biologically active agent, e.g., an agent effective for the treatment of
cancer.
1024] In any of the aspects or embodiments described herein, the
therapeutic
compositions comprising compounds described herein can be in any suitable
dosage form, e.g.,
solid, or liquid, and configured to be delivered by any suitable route, e.g.,
oral, parenteral,
intravenous, intraperitoneal, subcutaneous, intramuscular, etc., and in any
desired unit dosage
form. For example, in certain embodimetns, the therapeutic composition as
described herein is
configured to be administered or consumed by a subject one or more times over
a descired time
period, e.g., day, week, month, etc.
[025] In another aspect, the disclosure provides methods of modulating
protein
ubiquitination and degradation in a subject, e.g., a cell, a tissue, mammal,
or human patient, the
method comprising administering an effective amount of a compound as described
herein or a
composition comprising an effective amount of the same to a subject, wherein
the compound or
composition comprising the same is effective in modulating protein
ubquitination and degration
of the protiein in the subject. In certain embodiments, the protein is
androgen receptor (AR).
[026] In another aspect, the disclosure provides methods of modulating AR
protein
ubiquitination and degradation in a subject, e.g., a cell, a tissue, mammal,
or human patient, the
method comprising administering an effective amount of a compound as described
herein or a
composition comprising an effective amount of the same to a subject, wherein
the compound or
composition comprising the same is effective in modulating AR protein
ubquitination and
degration of the protiein in the subject.
[027] In another aspect, the disclosure provides methods of treating or
ameliorating a
symptom of a disease related to AR activity in a subject, e.g., a cell, a
tissue, mammal, or human
patient, the method comprising administering an effective amount of a compound
as described
herein or a composition comprising an effective amount of the same to a
subject in need thereof,
wherein the compound or composition comprising the same is effective in
treating or
ameliorating a symptom of a disease related to AR activity in the subject. In
certain
embodiments, the disease to be treated is cancer, e.g., prostate cancer, or
Kennedy's Disease. In
a preferred embodiment, the subject is a human.
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1028] In another aspect, the disclosure provides methods for identifying
the effects of
the degradation of proteins of interest in a biological system using compounds
according to the
present invention.
[029] In another aspect, the description provides kits comprising
compounds or
compositions as described herein. The kit may be promoted, distributed, or
sold as a unit for
performing the methods of the present invention. In addition, the kits of the
present invention
may preferably contain instructions which describe a suitable use. Such kits
can be conveniently
used, e.g., in clinical settings, to treat patients exhibiting symptoms of,
e.g., cancer or Kennedy's
Disease.
1030] Where applicable or not specifically disclaimed, any one of the
embodiments
described herein are contemplated to be able to combine with any other one or
more
embodiments, even though the embodiments are described under different aspects
of the
invention. As such, the preceding general areas of utility are given by way of
example only and
are not intended to be limiting on the scope of the present disclosure and
appended claims.
Additional objects and advantages associated with the compositions, methods,
and processes of
the present invention will be appreciated by one of ordinary skill in the art
in light of the instant
claims, description, and examples. For example, the various aspects and
embodiments of the
invention may be utilized in numerous combinations, all of which are expressly
contemplated by
the present description. These additional advantages objects and embodiments
are expressly
included within the scope of the present invention. The publications and other
materials used
herein to illuminate the background of the invention, and in particular cases,
to provide
additional details respecting the practice, are incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[031] The accompanying drawings, which are incorporated into and form a
part of the
specification, illustrate several embodiments of the present invention and,
together with the
description, serve to explain the principles of the invention. The drawings
are only for the
purpose of illustrating an embodiment of the invention and are not to be
construed as limiting the
invention. Further objects, features and advantages of the invention will
become apparent from
the following detailed description taken in conjunction with the accompanying
figures showing
illustrative embodiments of the invention, in which:
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1032] Figure 1A and Figure 1B. Illustration of general principle for
PROTAC
function. Figure 1A: Exemplary PROTACs comprise an androgen receptor targeting
moiety
(ABM; darkly shaded rectangle), a Von Hippel-Lindau (VHL) E3 ubiquitin ligase
binding
moiety (VLM; lightly shaded triangle), and a linker moiety (L; black line)
coupling or tethering
the ABM to the VLM (as described herein, L can be absent or a bond or a
chemical linker
moiety). Figure 1B Illustrates the functional use of the PROTACs as described
herein. Briefly,
the VLM recognizes and binds to Von Hippel-Lindau (VHL) E3 ubiquitin ligase,
and the ABM
binds and recruits androgen receptor and brings it into close proximity to the
Von Hippel-Lindau
(VHL) E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed
with an E2 ubiquitin-
conjugating protein, and either alone or via the E2 protein catalyzes
attachment of ubiquitin
(dark circles) to a lysine on the target protein via an isopeptide bond. The
poly-ubiquitinated
protein (far right) is then targeted for degration by the proteosomal
machinery of the cell.
1033] Figure 2. Apoptosis in VCaP cells. VCaP cells were cultured in
Charcoal
Stripped Serum containing media supplemented with 0.1 nM R1881 for 48 hrs. The
degree of
apoptosis was ascertained with CaspaseGlo assay (Promega). These results
demonstrated that
PROTACs are much more potent in inducing apoptosis than an AR antagonist
enzalutamide.
Further, the degree of AR degradation correlates with their ability to induce
apoptosis in VCaP
cells.
1034] Figure 3. Anti-proliferation in LNCaP F876L. Anti-proliferation in
LNCaP
F876L cells observed with treatment with Example 1 as compared to
enzalutamide. LNCaP cells
transduced with AR F876L construct were cultured in Charcoal Stripped Serum
containing
media.
1035] Figure 4. PSA suppression in LNCaP F876L. LNCaP cells transduced
with AR
F876L construct were cultured in Charcoal Stripped Serum containing media
supplemented with
0.1 nM R1881 for 7 days. The results demonstrated that AR PROTAC is able to
suppress the
transcriptional activity of AR in F876L containing cells.
10361 Figure 5. Prostate involution in C57B6 mouse model. 12-week old
male
C57B1J6 mice were treated with AR PROTAC Example 163 and its inactive epimer
analog
Compound A which is unable to bind to VHL E3 ligase. Enzalutamide (PO, QD, 30
mpk),
Example 163 (IP, QD, 1 and 3 mpk) and Compound A (IP, QD, 1 and 3 mpk) were
administered
for 10 days, upon which the prostates were isolated and weighed. These results
demonstrated that
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the ability of PROTAC Example 163 to degrade AR leads to significant prostate
involution in
mice at very low doses.
[037] Figure 6. Tumor growth inhibition in VCaP xenograft model. VCaP cells
were implanted into CB17 scid mice subcutaneously. Once the tumors were
palpable, the mice
were castrated, leading to temporary tumor stasis. Upon regrowth of tumors,
the mice were
dosed with enzalutamide (PO. QD, 30 mpk) or AR PROTAC Example 163 (lP, QD, at
30, 10
and 3 inpk) as indicated. Tumor growth inhibition was observed in all
treatment arms.
[038] Figure 7A and Figure 7B. AR degradation of PROTAC is E3 ligase
dependent. Figure 7A: AR PROTAC Example 1 was added to LNCaP cells at
indicated
concentrations for 24 hours in the presence or absence of 10 uM VHL E3 ligase
ligand
compound B. Figure 7B: LNCaP cells were treated with AR PROTAC Example 1 and
its
inactive epimer analog compound C which is unable to bind to VHL E3 ligase."
DETAILED DESCRIPTION
1039] The following is a detailed description provided to aid those
skilled in the art in
practicing the present invention. Those of ordinary skill in the art may make
modifications and
variations in the embodiments described herein without departing from the
spirit or scope of the
present disclosure. All publications, patent applications, patents, figures
and other references
mentioned herein are expressly incorporated by reference in their entirety.
10401 The present description relates to the surprising and unexpected
discovery that an
E3 ubiquitin ligase protein can ubiquitinate a target protein, in particular
androgen receptor, once
the E3 ubiquitin ligase protein and the target protein are brought into
proximity by a chimeric
construct (e.g., PROTAC) as described herein, in which a moiety that binds the
E3 ubiquitin
ligase protein is coupled, e.g., covalently, to a moiety that bind the
androgen receptortarget
protein. Accordingly, the present description provides compounds, compositions
comprising the
same, and associated methods of use for ubiquitination and degradation of a
chosen target
protein, e.g.. androgen receptor (See Figure lA and Figure 1B).
[041] The present description is related in certain aspects to U.S.
Patent Publication
2014/0356322A1, which is incorporated herein by reference in its entirety for
all purposes.
1042] Unless otherwise defined, all technical and scientific terms used
herein have the
same meaning as commonly understood by one of ordinary skill in the art to
which this invention
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belongs. The terminology used in the description is for describing particular
embodiments only
and is not intended to be limiting of the invention.
[043] Where a range of values is provided, it is understood that each
intervening value,
to the tenth of the unit of the lower limit unless the context clearly
dictates otherwise (such as in
the case of a group containing a number of carbon atoms in which case each
carbon atom
number falling within the range is provided), between the upper and lower
limit of that range and
any other stated or intervening value in that stated range is encompassed
within the invention.
The upper and lower limits of these smaller ranges may independently be
included in the smaller
ranges is also encompassed within the invention, subject to any specifically
excluded limit in the
stated range. Where the stated range includes one or both of the limits,
ranges excluding either
both of those included limits are also included in the invention.
[044] The following terms are used to describe the present invention. In
instances where
a term is not specifically defined herein, that term is given an art-
recognized meaning by those of
ordinary skill applying that term in context to its use in describing the
present invention.
[045] The articles "a" and "an" as used herein and in the appended claims
are used
herein to refer to one or to more than one (i.e., to at least one) of the
grammatical object of the
article unless the context clearly indicates otherwise. By way of example, "an
element" means
one element or more than one element.
1046] The phrase "and/or," as used herein in the specification and in
the claims, should
be understood to mean "either or both" of the elements so conjoined, i.e..
elements that are
conjunctively present in some cases and disjunctively present in other cases.
Multiple elements
listed with "and/or" should be construed in the same fashion, i.e., "one or
more" of the elements
so conjoined. Other elements may optionally be present other than the elements
specifically
identified by the "and/or" clause, whether related or unrelated to those
elements specifically
identified. Thus, as a non-limiting example, a reference to "A and/or B", when
used in
conjunction with open-ended language such as "comprising" can refer, in one
embodiment, to A
only (optionally including elements other than B); in another embodiment, to B
only (optionally
including elements other than A); in yet another embodiment, to both A and B
(optionally
including other elements); etc.
[047] As used herein in the specification and in the claims, "or" should
be understood to
have the same meaning as "and/or" as defined above. For example, when
separating items in a
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list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but
also including more than one, of a number or list of elements, and,
optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only one of or
"exactly one of," or,
when used in the claims, "consisting of," will refer to the inclusion of
exactly one element of a
number or list of elements. In general, the term "or" as used herein shall
only be interpreted as
indicating exclusive alternatives (i.e., "one or the other but not both") when
preceded by terms of
exclusivity, such as "either," "one of," "only one of," or "exactly one of."
1048] The term "about" and the like, as used herein, in association with
numeric values
or ranges, reflects the fact that there is a certain level of variation that
is recognized and tolerated
in the art due to practical and/or theoretical limitations. For example, minor
variation is tolerated
due to inherent variances in the manner in which certain devices operate
and/or measurements
are taken. In accordance with the above, the phrase "about" is normally used
to encompass
values within the standard deviation or standard error.
1049] In the claims, as well as in the specification above, all
transitional phrases such as
"comprising," "including," "carrying," "having," "containing," "involving,"
"holding,"
"composed of," and the like are to be understood to be open-ended, i.e., to
mean including but
not limited to. Only the transitional phrases "consisting of and "consisting
essentially of shall be
closed or semi-closed transitional phrases, respectively, as set forth in the
United States Patent
Office Manual of Patent Examining Procedures, Section 2111.03.
[050] As used herein in the specification and in the claims, the phrase
"at least one," in
reference to a list of one or more elements, should be understood to mean at
least one element
selected from anyone or more of the elements in the list of elements, but not
necessarily
including at least one of each and every element specifically listed within
the list of elements and
not excluding any combinations of elements in the list of elements. This
definition also allows
that elements may optionally be present other than the elements specifically
identified within the
list of elements to which the phrase "at least one" refers, whether related or
unrelated to those
elements specifically identified. Thus, as a nonlimiting example, "at least
one of A and B" (or,
equivalently, "at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in
one embodiment, to at least one, optionally including more than one, A, with
no B present (and
optionally including elements other than B); in another embodiment, to at
least one, optionally
including more than one, B, with no A present (and optionally including
elements other than A);
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in yet another embodiment, to at least one, optionally including more than
one, A, and at least
one, optionally including more than one. B (and optionally including other
elements); etc.
[051] It should also be understood that, in certain methods described
herein that include
more than one step or act, the order of the steps or acts of the method is not
necessarily limited to
the order in which the steps or acts of the method are recited unless the
context indicates
otherwise.
[052] The terms "co-administration" and "co-administering" or "combination
therapy"
can refer to both concurrent administration (administration of two or more
therapeutic agents at
the same time) and time varied administration (administration of one or more
therapeutic agents
at a time different from that of the administration of an additional
therapeutic agent or agents), as
long as the therapeutic agents are present in the patient to some extent,
preferably at effective
amounts, at the same time. In certain preferred aspects, one or more of the
present compounds
described herein, are coadministered in combination with at least one
additional bioactive agent,
especially including an anticancer agent. In particularly preferred aspects,
the co-administration
of compounds results in synergistic activity and/or therapy, including
anticancer activity.
[053] The term "effective" can mean, but is in no way limited to, that
amount/dose of
the active pharmaceutical ingredient, which, when used in the context of its
intended use,
effectuates or is sufficient to prevent, inhibit the occurrence, ameliorate,
delay or treat (alleviate
a symptom to some extent, preferably all) the symptoms of a condition,
disorder or disease state
in a subject in need of such treatment or receiving such treatment. The term
effective subsumes
all other effective amount or effective concentration terms, e.g., "effective
amount/dose,"
"pharmaceutically effective amount/dose" or "therapeutically effective
amount/dose," which are
otherwise described or used in the present application.
[054] The effective amount depends on the type and severity of disease, the
composition used, the route of administration, the type of mammal being
treated, the physical
characteristics of the specific mammal under consideration, concurrent
medication, and other
factors which those skilled in the medical arts will recognize. The exact
amount can be
ascertainable by one skilled in the art using known techniques (see, e.g.,
Lieberman,
Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and
Technology of
Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and
Remington: The
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Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed.,
Lippincott, Williams &
Wilkins).
[055] The term "pharmacological composition," "therapeutic composition,"
"therapeutic formulation" or "pharmaceutically acceptable formulation" can
mean, but is in no
way limited to, a composition or formulation that allows for the effective
distribution of an agent
provided by the invention, which is in a form suitable for administration to
the physical location
most suitable for their desired activity, e.g., systemic administration.
1056] The term "pharmaceutically acceptable" or "pharmacologically
acceptable" can
mean, but is in no way limited to, entities and compositions that do not
produce an adverse,
allergic or other untoward reaction when administered to an animal, or a
human, as appropriate.
[057] The term "pharmaceutically acceptable carrier" or
"pharmacologically acceptable
carrier" can mean, but is in no way limited to, any and all solvents,
dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption delaying agents,
and the like,
compatible with pharmaceutical administration. Suitable carriers are described
in the most recent
edition of Remington's Pharmaceutical Sciences, a standard reference text in
the field, which is
incorporated herein by reference. Preferred examples of such carriers or
diluents include, but are
not limited to, water, saline, finger's solutions, dextrose solution, and 5%
human serum albumin.
Liposomes and non-aqueous vehicles such as fixed oils may also be used. The
use of such media
and agents for pharmaceutically active substances is well known in the art.
Except insofar as any
conventional media or agent is incompatible with the active compound, use
thereof in the
compositions is contemplated. Supplementary active compounds can also be
incorporated into
the compositions.
1058] The term "systemic administration" refers to a route of
administration that is, e.g.,
enteral or parenteral, and results in the systemic distribution of an agent
leading to systemic
absorption or accumulation of drugs in the blood stream followed by
distribution throughout the
entire body. Suitable forms, in part, depend upon the use or the route of
entry, for example oral,
transdermal, or by injection. Such forms should not prevent the composition or
formulation from
reaching a target cell (i.e., a cell to which the negatively charged polymer
is desired to be
delivered to). For example, pharmacological compositions injected into the
blood stream should
be soluble. Other factors are known in the art, and include considerations
such as toxicity and
forms which prevent the composition or formulation from exerting its effect.
Administration
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routes which lead to systemic absorption include, without limitations:
intravenous, subcutaneous,
intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. The rate
of entry of a drug
into the circulation has been shown to be a function of molecular weight or
size. The use of a
liposome or other drug carrier comprising the compounds of the instant
invention can potentially
localize the drug, for example, in certain tissue types, such as the tissues
of the reticular
endothelial system (RES). A liposome formulation which can facilitate the
association of drug
with the surface of cells, such as, lymphocytes and inacrophages is also
useful.
1059] The term "local administration" refers to a route of
administration in which the
agent is delivered to a site that is apposite or proximal, e.g., within about
10 cm, to the site of the
lesion or disease.
[060] The term "compound", as used herein, unless otherwise indicated,
refers to any
specific chemical compound disclosed herein and includes tautomers,
regioisomers, geometric
isomers, and where applicable, stereoisomers, including optical isomers
(enffiniomers) and other
steroisomers (diastereoiners) thereof, as well as pharmaceutically acceptable
salts and derivatives
(including prodrug forms) thereof where applicable, in context. Within its use
in context, the
term compound generally refers to a single compound, but also may include
other compounds
such as stereoisomers, regioisomers and/or optical isomers (including racemic
mixtures) as well
as specific enantiomers or enantiomerically enriched mixtures of disclosed
compounds. The term
also refers, in context to prodrug forms of compounds which have been modified
to facilitate the
administration and delivery of compounds to a site of activity. It is noted
that in describing the
present compounds, numerous substituents and variables associated with same,
among others,
are described.
[061] It is understood by those of ordinary skill that molecules which are
described
herein are stable compounds as generally described hereunder. When the bond
is
shown, both a double bond and single bond are represented within the context
of the compound
shown.
[062] As used herein, "derivatives" can mean compositions formed from the
native
compounds either directly, by modification, or by partial substitution. As
used herein, "analogs"
can mean compositions that have a structure similar to, but not identical to,
the native compound.
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1063] The term "Ubiquitin Ligase" refers to a family of proteins that
facilitate the
transfer of ubiquitin to a specific substrate protein, targeting the substrate
protein for
degradation. By way of example, Von Hippel-Lindau E3 Ubiquitin Ligase or VCB
E3 Ubiquitin
Ligase is protein that alone or in combination with an E2 ubiquitin-
conjugating enzyme causes
the attachment of ubiquitin to a lysine on a target protein, and subsequently
targets the specific
protein substrates for degradation by the proteasome. Thus, E3 ubiquitin
ligase alone or in
complex with an E2 ubiquitin conjugating enzyme is responsible for the
transfer of ubiquitin to
targeted proteins. In general, the ubiquitin ligase is involved in
polyubiquitination such that a
second ubiquitin is attached to the first; a third is attached to the second,
and so forth.
Polyubiquitination marks proteins for degradation by the proteasome. However,
there are some
ubiquitination events that are limited to mono-ubiquitination, in which only a
single ubiquitin is
added by the ubiquitin ligase to a substrate molecule. Mono-ubiquitinated
proteins are not
targeted to the proteasome for degradation, but may instead be altered in
their cellular location or
function, for example, via binding other proteins that have domains capable of
binding ubiquitin.
Further complicating matters, different lysines on ubiquitin can be targeted
by an E3 to make
chains. The most common lysine is Lys48 on the ubiquitin chain. This is the
lysine used to make
polyubiquitin, which is recognized by the proteasome.
[064] The term "subject" is used throughout the specification to describe a
cell, tissue,
or animal, preferably a mammal, e.g., a human or a domesticated animal, to
whom treatment,
including prophylactic treatment, with the compositions according to the
present invention is
provided. For treatment of those infections, conditions or disease states
which are specific for a
specific animal such as a human patient, the term patient refers to that
specific animal, including
a domesticated animal such as a dog or cat or a farm animal such as a horse,
cow, sheep, etc. In
general, in the present invention, the term patient refers to a human patient
unless otherwise
stated or implied from the context of the use of the term.
[065] Compounds
[066] In one aspect, the present invention provides compounds useful for
regulating
protein activity. The composition comprises a ubiquitin pathway protein
binding moiety
(preferably for an E3 ubiquitin ligase, alone or in complex with an E2
ubiquitin conjugating
enzyme which is responsible for the transfer of ubiquitin to targeted
proteins) according to a
defined chemical structure and a protein targeting moiety which are linked or
coupled together,
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preferably through a linker, wherein the ubiquitin pathway protein binding
moiety recognizes an
ubiquitin pathway protein and the targeting moiety recognizes a target protein
(e.g., androgen
receptor). Such compounds may be referred to herein as PROTAC compounds or
PROTACs.
[067] In one aspect, the description provides AR binding moieties (ABM). In
certain
embodiments, the compounds having the following general structure: ABM-L,
wherein ABM is
an AR binding moiety as described herein, and L is a chemical linker moiety,
e.g., a linker as
described herein, or optionally a bond. In certain embodiments, the ABM and/or
L are coupled
to a ULM as described herein below.
[068] In another aspect, the disclosure provides compounds which function
to recruit
androgen receptor (AR) proteins to E3 LTbiquitin Ligase for ubiquintination
and degradation. In
certain embodiments, the compounds have the following general structure:
[069] ABM ¨L¨ULM (I),
1070]
wherein ULM is an E3 ligase binding moiety, ABM is an AR binding moiety,
which binds to an AR protein and L is a bond or a chemical linker moiety which
links the ABM
and ULM.
[071] In certain embodiments, the ULM is a moiety specific for an E3
ubiquitin ligase
such as, e.g., Von Hippel-Lindau E3 ubiquitin ligase (VHL), cereblon, mouse
double minute 2
homolog (Mdm2), or inhibitor of apoptosis (IAP), wherein the ULM moiety is
coupled to an
ABM as described herein.
[072] Without being bound by any particular theory, it is hypothesized that
due at least
in part to the proximity of AR and the E3 ubiquitin ligase, the AR is
ubiquitinated by the
ubiquitin ligase and degraded. In certain embodiments, the ABM is chemically
linked or
coupled directly to the ULM: group. In certain additional embodiments, the ABM
is chemically
linked or coupled to the ULM via a chemical linker moiety. In additional
embodiments, the
description provides compounds having the following general structure:
[073] ABM ¨L¨VLM (11),
[074] wherein ABM is an AR binding moiety and VLM is a Von Hippel-Lindau E3
Ubiquitin Ligase (VHL) binding moiety,and L is a bond or a chemical linker
moiety which links
the ABM and VLM. The ULM or VLM group and ABM group may be covalently linked
to the
linker group through any covalent bond which is appropriate and stable to the
chemistry of the
linker.
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1075] In certain embodiments, the ULM or VLM comprises a hydroxyproly1
moiety.
The hydroxyl prolyl moiety has been shown to be importantn for binding and
recruiting of the
VHL protein.
[076] It will be understood that the general structures are exemplary
and the respective
moieties can be arranged in any desired order or configuration, e.g., ULM-L-AB
M, and VLM-L-
ABM respectively. In certain additional embodiments, the compounds comprise a
plurality of
E3 ligase binding moieties and/or a plurality of ABMs.
1077] In certain embodiments, ABM alone, without forming ABM-L-ULM,
provides
desired properties in regulating protein activity.
1078] In any of the aspects or embodiments of compounds described
herein, unless
indicated otherwise, the compounds are intended to encompass pharmaceutically
acceptable
salts, enantiomers, stereoisomers, solvates or polymorphs thereof.
[079] Exemplary ULMs
[080] In certain embodiments of the compounds as described herein, the ULM:
comprises a chemical structure selected from the group ULM-a:
x20W xi
ULM-a
wherein:
a dashed line indicates the attachment of at least one ABM, another ULM or VLM
(i.e.,
ULM' or VLM'), or a chemical linker moiety coupling at least one ABM, a ULM'
or
VLM' to the other end of the linker;
X1, X2 are each independently a bond, 0, NRY3, CRY3RY4, C=0, C=S, SO, SO2;
RY3, RY4 are each independently H, linear or branched C1_6 alkyl, optionally
substituted by 1
or more halo, optionally substituted C1_6 alkoxyl (e.g., optionally
substituted with 0-3 RP
groups);
RP is 0, 1, 2, or 3, groups, each independently selected from H, halo, -OH,
C1.3 alkyl, C=0;
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W3 is an optionally substituted -T-N(R1aRi)), -T-Aryl, an optionally
substituted -T-
Heteroaryl, an optionally substituted -T-Heterocycle, an optionally
substituted -NR1-T-
Aryl, an optionally substituted -NR'-T-Heteroaryl or an optionally substituted
-NR1-T-
Heterocycle, where T is covalently bonded to Xi'
each Ri , Ria , Rib is independently H, a Ci-C6 alkyl group (linear, branched,
optionally
substituted by 1 or more halo, -OH), RY3C=0, RY3C=S, RY3S0, RY3S02,
N(RY3RY4)C=0,
N(Ry3Ry4)c=s, N(Ry3RY4)"..,
N(RY3RY4)S02;
W4 is an optionally substituted -NR1-T-Aryl, an optionally substituted -NR1-T-
Heteroaryl
group or an optionally substituted -NR1-T-Heterocycle, wherein -NR' is
covalently
bonded to X2; R1 is H or CH3, preferably H; and
T is an optionally substituted -(CH2)0- group, wherein each one of the
methylene groups may
be optionally substituted with one or two substituents, preferably selected
from halogen, a
Ci-Co alkyl group (linear, branched, optionally substituted by 1 or more
halogen, -OH) or
the sidechain of an amino acid as otherwise described herein, preferably
methyl, which
may be optionally substituted; and n is 0 to 6, often 0, 1, 2, or 3,
preferably 0.
[081] Alternatively, T may also be a -(CH20).- group, a -(OCH2).- group,
a -
(CH2CH20).- group, a -(OCH2CH2).- group, each of which groups is optionally
substituted; and
10821 Alternatively. T is an optionally substituted -(CH2).- group,
wherein each one of
the methylene groups may be optionally substituted with one or two
substituents, preferably
selected from halogen, an amino acid sidechain as otherwise described herein
or a C1-C6 alkyl
group (linear, branched, optionally substituted by 1 or more halo, -OH),
preferably one or two
methyl groups, which may be optionally substituted; and n is 0 to 6. often 0,
1, 2 or 3, preferably
0 or I.
[083] Alternatively, T may also be a -(CH20).- group, a -(OCH2).- group, a -
(CH2CH20).- group, a -(OCH2CH2).- group, all of which groups are optionally
substituted.
[084] In any of the embodiments described herein, W3 and/or W4 can be
attached to a
linker moiety as described herein.
1085] In certain embodiments, aryl groups for W3 include optionally
substituted phenyl
or naphthyl groups, preferably phenyl groups, wherein the phenyl or naphthyl
group is optionally
substituted with a linker group to which is attached a ABM group (including a
ULM' group)
and/or a halogen (preferably F or Cl), an amine, monoalkyl- or dialkyl amine
(preferably,
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dimethylamine), an amido group (preferably a ¨(CH2).-NRIC(0)R2 group wherein
m, R1 and R2
are the same as for RI), a halogen (often F or Cl), OH, CH3, CF3, OMe, OCF3,
NO2, CN or a
S(0)2Rs group (Rs is a a Ci-Co alkyl group, an optionally substituted aryl,
heteroaryl or
heterocycle group or a -(CH1).NRIR2 group), each of which may be substituted
in ortho-, meta-
and/or para- positions of the phenyl ring, preferably para-), or an Aryl
(preferably phenyl),
heteroaryl or heterocycle. Preferably said substituent phenyl group is an
optionally substituted
phenyl group (i.e., the substituent phenyl group itself is preferably
substituted with at least one of
F, Cl, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN or a linker group to which
is attached a
ABM group (including a ULM' group), wherein the substitution occurs in ortho-,
meta- and/or
para- positions of the phenyl ring, preferably para-), a naphthyl group, which
may be optionally
substituted including as described above, an optionally substituted heteroaryl
(preferably an
optionally substituted isoxazole including a methylsubstituted isoxazole, an
optionally
substituted oxazole including a methylsubstituted oxazole, an optionally
substituted thiazole
including a methyl substituted thiazole, an optionally substituted pyrrole
including a
methylsubstituted pyrrole, an optionally substituted imidazole including a
methylimidazole, a
benzylimidazole or methoxybenzylimidazole, an oximidazole or
methyloximidazole, an
optionally substituted diazole group, including a methyldiazole group, an
optionally substituted
triazole group, including a methylsubstituted triazole group, a pyridine
group, including a halo-
(preferably, F) or methylsubstitutedpyridine group or an oxapyridine group
(wherein the pyridine
group is linked to the phenyl group by an oxygen) or an optionally substituted
heterocycle
(tetrahydrofuran, tetrahydrothiophene, pyffolidine, piperidine, morpholine,
piperazine,
tetxahydroquinoline, oxane or thiane. Each of the aryl, heteroaryl or
heterocyclic groups may be
optionally substituted with a linker group to which is attached a ABM group
(including a ULM'
group).
[086] In certain embodiments, heteroaryl groups for W3 include an
optionally
substituted quinoline (which may be attached to the pharinacophore or
substituted on any carbon
atom within the quinoline ring), an optionally substituted indole (including
dihydroindole), an
optionally substituted indolizine, an optionally substituted azaindolizine (2,
3 or 4-azaindolizine)
an optionally substituted benzimidazole, benzodiazole, benzoxofuran, an
optionally substituted
imidazole, an optionally substituted isoxazole, an optionally substituted
oxazole (preferably
methyl substituted), an optionally substituted diazole, an optionally
substituted triazole, a
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tetrazole, an optionally substituted benzofuran, an optionally substituted
thiophene, an optionally
substituted thiazole (preferably methyl and/or thiol substituted), an
optionally substituted
isothiazole, an optionally substituted triazole (preferably a 1,2,3-triazole
substituted with a
methyl group, a triisopropylsilyl group, an optionally substituted -(CH2).-0-
Ci-C6 alkyl group or
an optionally substituted -(CH2)m-C(0)-0-C1-C6 alkyl group), an optionally
substituted pyridine
(2-, 3, or 4-pyridine) or a group according to the chemical structure:
________________________ RHET 0 _________________ RFIET
RURE
RURE
s
RHET ____________________
Ni-
RHEr
=P.I;N
N-µ1
RHE or j
wherein:
Sc is CHRss, NRuRE, or 0;
RHET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6
alkyl (preferably
substituted with one or two hydroxyl groups or up to three halo groups (e.g.
CF3),
optionally substituted 0(C1-C6 alkyl) (preferably substituted with one or two
hydroxyl
groups or up to three halo groups) or an optionally substituted acetylenic
group ¨CEC-R2
wherein Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
Rss is H, CN, NO2, halo (preferably F or Cl), optionally substituted Ci-C6
alkyl (preferably
substituted with one or two hydroxyl groups or up to three halo groups),
optionally
substituted 0-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl
groups or up
to three halo groups) or an optionally substituted -C(0)(C1-C6 alkyl)
(preferably
substituted with one or two hydroxyl groups or up to three halo groups);
RURE =s
1 H a CI-C6 alkyl (preferably H or Ci-C3 alkyl) or a ¨C(0)(CI-C6 alkyl), each
of
which groups is optionally substituted with one or two hydroxyl groups or up
to three
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halogen, preferably fluorine groups, or an optionally substituted heterocycle,
for example
piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,
piperidine,
piperazine, each of which is optionally substituted; and
Yc is N or C-R, wherein RYc is H, OH, CN, NO2, halo (preferably CI or F),
optionally
substituted C1-Co alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups (e.g. CF3), optionally substituted 0(C1-C6 alkyl)
(preferably substituted
with one or two hydroxyl groups or up to three halo groups) or an optionally
substituted
acetylenic group -CC-Ra wherein Ra is H or a C1-C6 alkyl group (preferably C1-
C3
alkyl). Each of said heteroaryl groups may be optionally substituted with a
linker group
to which is attached a ABM group (including a ULM' group).
[087] In additional embodiments, heterocycle groups for W3 include
tetrahythoquinoline, piperidine, piperazine, pyrrollidine, morpholine,
tetrahydrofuran,
tetrahydrothiophene, oxane and thiane, each of which groups may be optionally
substituted or a
group according to the chemical structure:
RpRol RpRoi
,RPRO2 zRPRO2
RPRO
RHET rr-
0 0
RpRo 0
RpRo
N¨(CH2),
or N¨(CH2),
0 group,
wherein:
RPR is H, optionally substituted C1-Co alkyl or an optionally substituted
aryl (phenyl or
napthyl), heteroaryl or heterocyclic group selected from the group consisting
of oxazole,
isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole,
pyrollidine,
furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene,
pyridine,
piperidine, piperazine, morpholine, quinoline, (each preferably substituted
with a Ci-C3
alkyl group, preferably methyl or a halo group, preferably F or Cl).
benzofuran, indole,
indolizine, azaindolizine;
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RpRoi and RPR 2 are each independently H. an optionally subsituted Ci-C3 alkyl
group or
together form a keto group, and
each n is 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), wherein each of said
Heteocycle groups may
be optionally substituted with a linker group to which is attached a ABM group
(including a ULM' group) or a pharmaceutically acceptable salt, stereoisomer,
solvate or
polymorph thereof.
[088] In certain embodiments, W3 substituents for use in the present
invention also
include specifically (and without limitation to the specific compound
disclosed) the W3
substituents which are found in the identified compounds disclosed herein
(which includes the
specific compounds which are disclosed in the present specification, and the
figures which are
attached hereto). Each of these W3 substituents may be used in conjunction
with any number of
W4 substituents, which are also disclosed herein.
1089] In certain embodiments, Aryl groups for W4 include optionally
substituted phenyl
or naphthyl groups, preferably phenyl groups, wherein the phenyl group is
optionally substituted
with a linker group to which is attached an ABM group (including a ULM'
group), a halogen
(preferably F or Cl), an amine, monoalkyl- or dialkyl amine (preferably,
dimethylamine), F, Cl,
OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (each
of which
may be substituted in ortho-, meta- and/or para- positions of the phenyl ring,
preferably para-),
an optionally substituted phenyl group (the phenyl group itself is preferably
substituted with a
linker group attached to a ABM group, including a ULM' group), and/or at least
one of F, Cl,
OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (in ortho-, meta- and/or para-
positions
of the phenyl ring, preferably para-), a naphthyl group, which may be
optionally substituted, an
optionally substituted heteroaryl, preferably an optionally substituted
isoxazole including a
methylsubstituted isoxazole, an optionally substituted oxazole including a
methylsubstituted
oxazole, an optionally substituted thiazole including a methyl substituted
thiazole, an optionally
substituted isothiazole including a methyl substituted isothiazole, an
optionally substituted
pyrrole including a methylsubstituted pyrrole, an optionally substituted
imidazole including a
methylimidazole, an optionally substituted benzimidazole or
methoxybenzylimidazole, an
optionally substituted oximidazole or methyloximidazole, an optionally
substituted diazole
group, including a methyldiazole group, an optionally substituted triazole
group, including a
methylsubstituted triazole group, an optionally substituted pyridine group,
including a halo-
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(preferably, F) or methylsubstitutedpyridine group or an oxapyridine group
(wherein the pyridine
group is linked to the phenyl group by an oxygen), an optionally substituted
furan, an optionally
substituted benzofuran, an optionally substituted dihydrobenzofuran, an
optionally substituted
indole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), an optionally
substituted quinoline,
an optionally substituted group according to the chemical structure:
1 __________________________________________________________ RHET
__________________ R HET '2( 0
N
RURE
RURE
0
/I
Ri IET _______
N
R HET I I or
RETõ
RPRo\ RPRO2
RpRo
/
7¨(cH2)n
0
wherein:
Sc is CHRss, NRIJRE, or 0;
RHET is H, CN, NO2, halo (preferably Cl or F), optionally substituted Ci-C6
alkyl (preferably
substituted with one or two hydroxyl groups or up to three halo groups (e.g.
CF3),
optionally substituted 0(C1-C6 alkyl) (preferably substituted with one or two
hydroxyl
groups or up to three halo groups) or an optionally substituted acetylenic
group
wherein Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
Rss is H, CN, NO2, halo (preferably F or CI), optionally substituted C1-C6
alkyl (preferably
substituted with one or two hydroxyl groups or up to three halo groups),
optionally
substituted 0-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl
groups or up
to three halo groups) or an optionally substituted -C(0)(Ci-C6 alkyl)
(preferably
substituted with one or two hydroxyl groups or up to three halo groups);
RIME is
H a C1-C6 alkyl (preferably H or Ci-C3 alkyl) or a ¨C(0)(C1-C6 alkyl) each of
which
groups is optionally substituted with one or two hydroxyl groups or up to
three halogen,
preferably fluorine groups, or an optionally substituted phenyl group, an
optionally
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substituted heteroaryl, or an optionally substituted heterocycle, preferably
for example
piperidine, morpholine, pyrrolidine, tetrahydrofuran);
RpRo is ¨,
optionally substituted C1-C6 alkyl or an optionally substituted aryl (phenyl
or
napthyl), heteroaryl or heterocyclic group selected from the group consisting
of oxazole,
isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole,
pyrollidine,
furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene,
pyridine,
piperidine, piperazine, inorpholine, quinoline, (each preferably substituted
with a Ci-C3
alkyl group, preferably methyl or a halo group, preferably F or Cl),
benzofuran, indole,
indolizine, azaindolizine;
RpRoi and RPR 2 are each independently H, an optionally subsituted CI-C3 alkyl
group or
together form a keto group; and
each n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), or an
optionally substituted
heterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine,
piperazine or
inorpholine (each of which groups when substituted, are preferably substituted
with a
methyl or halo (F, Br, Cl), each of which groups may be optionally substituted
with a
linker group to which is attached a ABM group (including a ULM' group).
RPRO\I RPRO2
R PRO
7¨(cH2)n
1090] In certain preferred aspects, 0 is a
RpRo
0
:=22aqN¨(CH2),
or RpRo
N - (C H2)
[091] 0 or group,
1092] wherein RPR and n are the same as above.
1093] In certain embodiments, heteroaryl groups for W4 include an
optionally
substituted quinoline (which may be attached to the pharmacophore or
substituted on any carbon
atom within the quinoline ring), an optionally substituted indole, an
optionally substituted
indolizine, an optionally substituted azaindolizine, an optionally substituted
benzofuran,
including an optionally substituted benzofuran, an optionally substituted
isoxazole, an optionally
substituted thiazole, an optionally substituted isothiazole, an optionally
substituted thiophene, an
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optionally substituted pyridine (2-, 3, or 4-pyridine), an optionally
substituted imidazole, an
optionally substituted pyrrole, an optionally substituted diazole, an
optionally substituted
triazole, a tetrazole, an optionally substituted oximidazole, or a group
according to the chemical
structure:
S"
______________________________________________________________ R HET
____________________ RI-ET 0
,
RURE RURE
RI-IET ____________________________________________ 5
RHET ____________________________________________ N
N
0 0
N(;t1i.
RHET or RHET__2_
LNJ
yC
wherein:
Sc is CHRss, NRuRE, or 0;
RHET is H, CN, NO2, halo (preferably CI or F), optionally substituted Ci-C6
alkyl (preferably
substituted with one or two hydroxyl groups or up to three halo groups (e.g.
CF3),
optionally substituted 0(C1-C6 alkyl) (preferably substituted with one or two
hydroxyl
groups or up to three halo groups) or an optionally substituted acetylenic
group ¨CC-Ra
wherein Ra is H or a Ci-C6 alkyl group (preferably Ci-C3 alkyl);
Rss is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6
alkyl (preferably
substituted with one or two hydroxyl groups or up to three halo groups),
optionally
substituted 0-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl
groups or up
to three halo groups) or an optionally substituted -C(0)(C1-C6 alkyl)
(preferably
substituted with one or two hydroxyl groups or up to three halo groups);
RuRE is H, a C1-C6 alkyl (preferably H or C1-C3 alkyl) or a ¨C(0)(C1-C6
alkyl), each of
which groups is optionally substituted with one or two hydroxyl groups or up
to three
halogen, preferably fluorine groups, or an optionally substituted heterocycle,
for example
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piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,
piperidine,
piperazine, each of which is optionally substituted, and
Yc is N or C-R', wherein RYc is H, OH, CN, NO2, halo (preferably Cl or F),
optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups (e.g. CF3), optionally substituted O(Ci-Co alkyl)
(preferably substituted
with one or two hydroxyl groups or up to three halo groups) or an optionally
substituted
acetylenic group ¨CC-Ra wherein Ra is H or a Ci-C6 alkyl group (preferably Ci-
C3
alkyl), each of which groups may be optionally substituted with a linker group
to which is
attached a ABM group (including a ULM' group).
10941 4 In certain embodiments,
heterocycle groups for W include tetrahydrofuran,
tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrollidine,
morpholine, oxane or
thiane, each of which groups may be optionally substituted, or a group
according to the chemical
structure:
õ....k RHET __
RPRO2 RPRO RPRR 1 \,R PRO
/
iN¨(CH2)n ,
0 Or 0
RPRO
0
N--(CH2)1. RPRO
or
\* N¨(CH2)1
preferably, a 0 or group,
wherein:
RpRo is 11 ¨,
optionally substituted Ci-C6 alkyl or an optionally substituted aryl,
heteroaryl or
heterocyclic group;
RpRoi and RPR 2 are each independently H, an optionally subsituted C1-C3 alkyl
group or
together form a keto group and
each n is independently 0. 1, 2, 3, 4. 5, or 6 (often 0 or 1), each of which
groups may be
optionally substituted with a linker group to which is attached a ABM group
(including a
ULM' group) In additional embodiments, W4 substituents for use in the present
invention
also include specifically (and without limitation to the specific compound
disclosed) the
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substituents which are found in the identified compounds disclosed herein
(which
includes the specific compounds which are disclosed in the present
specification, and the
figures which are attached hereto).Each of these W4 substituents may be used
in
conjunction with any number of W3 substituents which are also disclosed
herein.
1095] In certain additional embodiments, ULM-a, is optionally
substituted by 1-3 RP
groups in the pyrrolidine moiety. Each RP is independently H, halo, -OH,
Ci_3alkyl.
[096] 3 4
In any of the embodiments described herein, the W , W can independently be
covalently coupled to a linker which is attached one or more ABM groups.
[097] In certain embodiments, ULM is a group (derivatized or configured to
be linked
or coupled to an ABM via a linker (as indicated by the dashed line) according
to the chemical
structure:
HO,
HR-14a
' 'Rub
0
41,
(R16)0 R15
=
[098] wherein, W3 is optionally substituted aryl, optionally substituted
heteroaryl, or
R9
R11 ;
1099] each R9 and R10 is independently hydrogen, optionally substituted
alkyl,
optionally substituted cycloalkyl, optionally substituted hydroxyalkyl,
optionally substituted
heteroaryl, or haloalkyl; or R9. Rio, and the carbon atom to which they are
attached form an
optionally substituted cycloalkyl;
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[0100] R11 is optionally substituted heterocyclic, optionally substituted
alkoxy, optionally
0
c R12
18 p
substituted heteroaryl, optionally substituted aryl, µRi.3
or
0
1¨N I
(R18)P
=
[0101] R12 is H or optionally substituted alkyl;
[0102] R13 is H, optionally substituted alkyl, optionally substituted
alkylcarbonyl,
optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted
aralkylcarbonyl,
optionally substituted arylcarbonyl, optionally substituted (heterocycl
yl)carbonyl, or optionally
substituted aralkyl;
[0103] R14a, R14b, is each independently 1-1, haloalkyl, or optionally
substituted alkyl;
[0104] W5 is a phenyl or a 5-10 membered heteroaryl,
[0105] R15 is H, halogen, CN, OH, NO2, NRI4aRiab, ORi4a. CONR14õRi4b,
NRI4aCORi4b,
SO2NRi4aRi4b, NIZI4aSO2Ri4b, optionally substituted alkyl, optionally
substituted haloalkyl,
optionally substituted haloalkoxy; optionally substituted aryl; optionally
substituted heteroaryl;
optionally substituted cycloalkyl; optionally substituted cycloheteroalkyl;
[0106] each R16 is independently halo, optionally substituted alkyl,
haloalkyl, hydroxy,
optionally substituted alkoxy, or haloalkoxy;
[0107] o is 0, 1, 2, 3, or 4;
[0108] each R18 is independently halo, optionally substituted alkoxy,
cyano, optionally
substituted alkyl, haloalkyl, haloalkoxy or a linker; and
[0109] p is 0, 1, 2, 3, or 4.
R17
[0110] In certain embodiments, R15 is .
wherein R17 is H, halo, optionally
substituted C1.6cycloalkyl, optionally substituted Ci_6alkyl, optionally
substituted Ci_6alkenyl,
and C1_6haloalkyl; and
[0111] Xa is S or O.
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[0112] In certain embodiments. Ri7 is selected from the group methyl,
ethyl, isopropyl,
and cyclopropyl.
[0113] In certain additional embodiments, Ri5 is selected from the group
consisting of:
F a Br /
Sisy
N N 14 1---11 s`r--N-- 1 ______________________ h 1 ir 3
S: . s.,õ . sj; = s . s =
, ,
F3C
N 1¨el 1¨ell 1¨elNI __________________________________________
1 __ ill 1 __ al 1-4-i
S---- = S ; S ; N-11
NN H = /- = N.." ell H ;
O'N =
,
i_eN 1 _____ es-N
N
NJ Ni 1 __________ kli 1_0 1
CNN i_e:INJ
/ - / = 0 ;and
,
1-----bN
[01.14] In certain embodiments, RI I is selected from the group consisting
of:
0 0 F 0 0
F Br
1¨N 1111
; .
0
0 0 0
CN s 1¨N
----1µ1 1¨N ¨N
F . ; Br; Br;
0 0
0 0 CN
1¨N 1¨N
1¨N 1¨N
F ; CN =
, CN =
, =
,
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0
0
OMe N
¨N I
OMe
= CI ;
0
9A
CI 9
OMe ; ; and
[0115] In certain embodiments, the ULM (derivatized or configured to be
linked or
coupled to an ABM via a linker (as indicated by the dashed line)) has the
structure:
HO,
R14a
0 IAR9
0
R,,)^
R1 I
Ri5
101161 wherein
[0117] R9 is H;
[0118] R10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or
cyclohexyl;
R12
101191 Rii is R13
[0120] R12 is H;
[0121] R13 is H, optionally substituted alkyl, optionally substituted
alkylcarbonyl,
optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted
aralkylcarbonyl,
optionally substituted arylcarbonyl, optionally substituted
(heterocyclyl)carbonyl, or optionally
substituted aralkyl;
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[01221 R14a is H. haloalkyl, methyl, ethyl, isopropyl, cyclopropyl, or C1-
C6 alkyl (linear,
branched, optionally substituted), each optionally substituted with 1 or more
halo, hydroxyl,
nitro, CN, C1-C6 alkyl (linear, branched, optionally substituted), or C1-
C6alkoxyl (linear,
branched, optionally substituted);and
RI,
.,,
[0123] R15 is )1.'"4/ wherein R17 is H, halo, optionally substituted
C3-6cyc1oa1ky1,
optionally substituted C1-6alkyl, optionally substituted C1-6alkenyl, or C1-
6ha1oa1ky1; and Xa is
S or O.
[0.1241 In certain embodiments, the ULM or VIA is selected from the group
consisting
of:
N N
HO I) HQ / ) HQ . CI
S S
(1'.1),rNH .....)õ,.....(</sN'arNH ....._NH
V---NH 0 V---NH 0
N
* CN
N / 0
)
HQ HO / ) HO
-:
: 1 * S gik
_..,..40N1-i (1.-3)::NH
0
0 V---NH 0
N N N
HQ
._......__.4.t\<-=NH ......2\t/...-NH ....i4(1-31,NH
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HO HO \N
0
µ--NH µ--NH
gH
OH
o
0
H n HN
0 00 10 OH
NC
µN
µ,
;and N
attached to the linker moiety at the position indicated.
10125] In certain embodiments the ULM is selected from the group
consisting of:
(2S,4R)-14(S)-2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-
yl)benzyppyrrolidine-2-carbox amide; (25 ,4R)-1-((S )-2-amino-3,3-
dimethylbutanoy1)-4-
hydroxy-N-(4-(thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-
amino-3,3-
dimethylbutanoy1)-4-hydroxy-N-((S)-1.-(4-(4-methylthiazol-5-
yl)phenypethyl)pyrrolidine-2-
carboxamide; (2S,4R)-14(S)-2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-
(oxazol-5-
yl)benzyl)pyrrolidine-2-carboxamide hydrochloride; (2S,4R)-14(S)-2-amino-3,3-
dimethylbutanoy1)-4-hydroxy-N-(4-(4-methyloxazol-5-yObenzyl)pyffolidine-2-
carboxamide;
(2S,4R)-14(S)-2-amino-3,3-dimethylbutanoy1)-N-(4-chlorobenzy1)-4-
hydroxypyrrolidine-2-
carboxamide hydrochloride; (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoy1)-N-(4-
cyanobenzy1)-
4-hydroxypyrrolidine-2-carboxamide hydrochloride; (2S,4R)-14(S)-2-amino-3-
methylbutanoy1)-
4-hydroxy-N-(4-(4-inethylthiazol-5-yl)benzyppyrrolidine-2-carboxamide
hydrochloride;
(2S,4R)-14(S)-2-amino-3-methylbutanoy1)-4-hydroxy-N-(4-(thiazol-5-
yObenzyl)pyrrolidine-2-
carboxamide hydrochloride; (2S,4R)-1.4(S)-2-amino-3-methylbutanoy1)-4-hydroxy-
N-(4-(4-
methyloxazol-5-yObenzyl)pyffolidine-2-carboxamide hydrochloride; (2S,4R)-14(S)-
2-amino-
3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(1-methyl-1H-pyrazol-5-
yObenzyl)pyrrolidine-2-
carboxamide hydrochloride; (2S,4R)-4-tert-butoxy-N-(2-hydroxy-4-(4-
methylthiazol-5-
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yObenzyl)-1-((5)-3-methyl-2-(1-oxoisoindolin-2-y1)butanoyl)pyrrolidine-2-
carboxamide;
(25,4R)-4-tert-butoxy-14(S)-2-(6-fluoro-1-oxoisoindolin-2-y1)-3-
methylbutanoy1)-N-(2-
hydroxy-4-(4-methylthiazol-5-yl)benzyppyrrolidine-2-carboxamide; (25,4R)-4-
tert-butoxy-1-
((5)-2-(7-cyano-1-oxoisoindolin-2-y1)-3-methylbutanoy1)-N-(2-hydroxy-4-(4-
methylthiazol-5-
yObenzyppyrrolidine-2-carboxamide; and (25,4R)-1-((5)-2-Amino-3,3-
dimethylbutanoy1)-4-
hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-y1)phenyl)ethyl)pyrrolidine-2-
carboxamide
hydrochloride.
[0126] Exemplary Linkers
10127] In certain embodiments, the compounds as described herein include
one or more
ABM chemically linked or coupled to one or more ULMs or VLMs via a chemical
linker (L). In
certain embodiments, the linker group L is a group comprises one or more
covalently connected
structural units of A (e.g. -A1. .Aq ), wherein A1 is coupled to an ABM
moiety, and q is an
integer greater than or equal to 0. In certain embodiments, q is an integer
greater than or equal to
I.
[0128] In certain embodiments, e. g., wherein q is greater than 2. Aq is
a group which is
connected to a ULM or VLM moiety, and A1 and Aq are connected via structural
units of A
(number of such structural units of A: q-2).
101291 In certain embodiments, e. g., wherein q is 2, Aq is a group which
is connected to
Aland to a ULM or VLM moiety.
[0130] In certain embodiments, e. g., wherein q is 1, the structure of
the linker group L is
¨A1¨, and A1 is a group which is connected to a ULM or VLM moiety and an ABM
moiety.
10131] In additional embodiments, q is an integer from 1 to 100, 1 to 90,
1 to 80, 1 to 70,
1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.
[0132] In certain embodiments, Ai to Aq are, each independently, a bond,
CRLIRu, 0, S.
SO, SO2, NR13, SO2NRI2, SONRI-3, CONRu, NRL3CONR", NW-3502NR". CO, CRLI=CR12,
CC, SiRLIRL2, P(0)R'1, P(0)01211, NR13C(=NCN)NRIA, NRI-3C(=NCN),
NRL3C(=CNO2)NRIA, icycloalkyl optionally substituted with 0-6 Ru and/or Ru
groups , C3.
liheteocycly1 optionally substituted with 0-6 Ru and/or Ru groups, aryl
optionally substituted
with 0-6 RLI and/or Ru groups, heteroaryl optionally substituted with 0-6 RLI
and/or Ru groups,
wherein Ru or RL,, each independently, can be linked to other A groups to form
cycloalkyl
and/or heterocyclyl moeity which can be further substituted with 0-4 RL5
groups;
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10133]
wherein R1-1, R12, le3,12" and lei are, each independently, H, halo,
Ci_8alkyl,
OCi_sallcyl, SCi_salkyl, NHC1.8alkyl, N(C1_8alky1)2, C3-1 icycloalkyl. aryl,
heteroaryl, C3-
llheterocyclyl, 0C1_8cycloalkyl, SCi_8cycloalkyl, NHC1_8cycloalkyl,
N(Ci_scycloalky1)2, WI-
scycloalkyl)(C1,8aay1), OH, NH2, SH, SO2C1.8a1kyl,
P(0)(0C1.8a1kyl)(C1_salkyl), P(0)(0C1-
8alky1)2, CC-Ci_8alkyl, CCH, CH=CH(Ci_salkyl), C(Ci_8alky1)=CH(Ci_8alkyl),
C(Ci_
8alky1)=C(Ci_8alkyl)2, Si(OH)3, Si(C1.8alky1)3, Si(OH)(C1.8alky1)2,
COCi_salkyl, CO2H, halogen,
CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1.8alky1, SO2N(C1.8alky1)2,
SONHCi_salkyl, SON(C1-
salky1)2, CONHC1_8a.lkyl, CON(Ci_sallcy1)2, N(Ci_galkyl)CONH(Ci_galkyl),
N(Ci_salkyl)CON(Ci-
salkyl)2, NHCONH(Ci-galkyl), NHCON(Ci-ga1ky1)2, NHCONH2,
N(C1_8alkyl)S02NH(C1_8alky1),
N(C1_8allcyl) SO2N(Ci_8alky1)2, NH SO2NH(C1_8alkyl), NH SO2N(Ci_8alky1)2, NH
SO2NH2.=
[0134] In
certain embodiments, the linker (L) is selected from the group consisting of:
\ \
`17.,WOCYY 41.,<-00'--).(
0 ; 0 ;
OH
\ t.
\L. 0
11- ,,,======,....,...0 =,,,,,....--,,o..----
,,...õ... 0 J-1...,,,ro. .
0 = \
0 r 0
\ c....--..õ,.. 0 0,.",..../.õ 0 ,....õ,-
4.,,,,rs ,N...õ,====õ,..õõ 0 ..,,.,....-;-..,0 õ,=-=...,....,..0
..,.....õ.......... .., 0
-2,1..--"" ".=,...- ===-..../',....,'-cy'Nr;\
,
..,..õ,========õ,,,.../...,.....,,¨..õ....õ 0 0 ,,)1..,". .
0 = 41-
µ11/.. .,.i.
0 0
-.....-'kcsis
cs's =
-tti. ===,...........--" -N.,. 0
..õ......:.........õ.............õ.....õ
\ 0
..'"==
())'L is) EN 0., = 0 . -t.tc-
--..,--0-"-=,....,-
Ts' =
0 0 0
H i 1
11( N .õ...õ......^...õ,.,---...,, 0 ..,..,...1-......
ii = 'Ilr N ..,..,..--,,00
/ = ''11- N .,...,,,-...,-.^...õ,
0 ... iõ..L.........,
=
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0 0
11 ,., õ......^..õ..,..0 o
. ,
N...,.,-^.õ,,O,s.õ,====,..02.L.,," "1/4. 8 . N.....--....Ø....---,0---
....A.,
,.,9
\ / = o = o -
0 0 o
.i.,,....--wo----,,--ky . .1/4,..,---,..õ---...---vit-õ,, . -1/4t.,=-=^==,---
"==¨=,(1-,)1".=._fs
e- =
r , ,
0 0 ,111..,
.....,_.,-0 s,, . ,--
..,00re .r, O;
= 0
c'
0
r--N '-`-' ')Lie
N N)
fr.' '
4.11,,,,,,0
.
; 0
, =
,
0
x
(---N,--,-0-,A, 00,1 -
0
)
\..N,..)
;
N
I 0 N .,' 1 '''' I
..,-
ahl
0 0
%Pi
;
--- jar
o
911' 0------- '----ki . N ilk 0
Pli O'''' J1Y V illi 0
N 0 SI
I / N J)
0 As.OL' r 0
0
* ..,.- I 0 i? . ti
NO/ N
;
0
-,'
40, /
0
;
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0
0
\--K.,-
U N)/¨> ____________________________________________ CIA
\ ,,.. - 0 =
; 7
r.---,--Th 0
N , ,,, N.11.,s4 "pq.." .. \--:---N
N ./.N1 0
vvyv
; 1
0
õ,..3.N N..1)
N 0
= = 0 ; ,
0
'*(NI''-''C)'=-Als4 0 0
,k..N1,)
It: NZN j\-
; -
,
HO
Nil q
0
A-
0.....Ø....NT---\N_J---ct .i...N/ __ \N j¨O
1-N N
\,/
;
/------N
0
1--N N¨CN¨ -i-
) N N-4
\/ : and \------/ .
101351 In additional embodiments, the linker (L) comprises a structure
selected from, but
not limited to the structure shown below, wherein a dashed line indicates the
attachment point to
the ABM or til.,M moieties:
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(yLl ),_,
4110 u L Oa 0
wherein:
W' and Wu are each independently a 4-8 membered ring with 0-4 heteroatoms,
optionally
substituted with R. each RQ is independently a H, halo, OH, CN, CF3, NH2,
carboxyl,
Ci-Co alkyl (linear, branched, optionally substituted), C1-C6 alkoxy (linear,
branched,
optionally substituted), or 2 R groups taken together with the atom they are
attached to,
form a 4-8 membered ring system containing 0-4 heteroatoms;
Yu is each independently a bond, C1-C6 alkyl (linear, branched, optionally
substituted) and
optionally one or more C atoms are replaced with 0; or CI-Co alkoxy (linear,
branched,
optionally substituted); and
n is 0-10.
10136] In additional embodiments, the linker (L) comprises a structure
selected from, but
not limited to the structure shown below, wherein a dashed line indicates the
attachment point to
the ABM or ULM moieties:
(RQ)0-6
(yLl
)0-2 0
II,
wherein:
Wu and Wu are each independently aryl, heteroaryl, cyclic, heterocyclic, C1_6
alkyl (linear,
branched, optionally substituted), Ci-Co alkoxy (linear, branched, optionally
substituted),
bicyclic, biaryl, biheteroaryl,or biheterocyclic, each optionally substituted
with RQ, each
RQ is independently a H, halo, OH, CN, CF3, NH2, carboxyl, hydroxyl, nitro, C
CH,
C2-6 alkenyl, C1-6 alkynyl, C1-Co alkyl (linear, branched, optionally
substituted), C1-C6
alkoxy (linear, branched, optionally substituted), 0C1_3alkyl (optionally
substituted by 1
or more F), OH, NH2, NRYIRY2, CN, or 2 RQ groups taken together with the atom
they
are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
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Yu is each independently a bond, Nei, 0, S. NRY2, CRY1RY2, C=0, C=S, SO, SO2,
C1-C6
alkyl (linear, branched, optionally substituted) and optionally one or more C
atoms are
replaced with 0; C1-C6 alkoxy (linear, branched, optionally substituted);
QL is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms,
biheterocyclic, or
bicyclic, optionally bridged, optionally substituted with 0-6 RQ, each RQ is
independently
H, C1_6 alkyl (linear, branched, optionally substituted by 1 or more halo,
C1_6 alkoxyl), or
2 RQ groups taken together with the atom they are attached to, form a 3-8
membered ring
system containing 0-2 heteroatoms);
RY2 are each independently H, OH, Ci.6 alkyl (linear, branched, optionally
substituted
by 1 or more halo, C1_6 alkoxyl), or RI, R2 together with the atom they are
attached to,
form a 3-8 membered ring system containing 0-2 heteroatoms; and
n is 0-10.
10137] In additional embodiments, the linker group is optionally
substituted
(poly)ethyleneglycol having between 1 and about 100 ethylene glycol units,
between about 1 and
about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units,
between about 1
and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units and
1 and 6 ethylene
glycol units, between 2 and 4 ethylene glycol units,or optionally substituted
alkyl groups
interdispersed with optionally substituted, 0, N, S, P or Si atoms. In certain
embodiments, the
linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or
heterocycle group. In certain
embodiments, the linker may be asymmetric or symmetrical.
[0138] In certain aspects the description provides a PROTAC compound in
which the
linker is cleavable in vivo into a functional E3 ligase binding moiety, and
target protein binding
moiety. In this regard, and without being bound by any particular theory, it
is hypothesized that
such a configuration can potentiate the beneficial effects of the degradation
activity of the intact
PROTAC molecule. Thus, in certain embodiments, the linker is configured or
"tuned" to have
the desired kinetics of cleavage into functional component molecules or active
metabolites. In
certain embodiments, the enzyme responsible for cleavage of the linker is a
liver enzyme, such
as, e.g., oxidases, peroxidase, reductases, transferases, dehydrogenases,
peroxidases. In certain
embodiments, the enzyme is at least one of cytochrome P450 oxidase, e.g.,
CYP3A4, Flavin-
containing monooxygenase, alcohol dehydrogenase, aldehyde dehydrogenase,
monoamine
oxidase, peroxidase, glutathione S-transferase, cytochrome P450 reductase,
sulfotransferase,
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methyltransferase, N-acetyltransferase, glucuronosyltransferase,
transpeptidase, or combination
thereof.
[0139] Exemplary Androaen Bindina Moieties (ABMs)
101401 In another aspect, the description provides AR binding moieties
(ABM), which in
certain aspects and embodiments are coupled to a linker and/or a ULM as
described herein.
[0141] In any of the compounds described herein, the ABM comprises a
chemical moiety
that binds to the androgen receptor (AR). Various androgen receptor binding
compounds have
been described in literature, including various androgen derivatives such as
testosterone,
dihydrotestosterone, and metribolone (also known as methyltrienolone or
R1881), and non-
steroidal compounds such as bicalutamide, enzalutamide. Those of ordinary
skill in the art would
appreciate that these androgen receptor binding compounds could be potentially
used as an ABM
moiety in a PROTAC compound. Such literature includes, but not limited to, G.
F. Allan et. al,
Nuclear Receptor Signaling, 2003, 1, e009; R. H. Bradbury et. al, Bioorganic &
Medicinal
Chemistry Letters, 2011 5442-5445; C. Guo et. al, Bioorganic & Medicinal
Chemistry Letters,
2012 2572-2578; P. K. Poutiainen et. al, J. Med Chem. 2012, 55, 6316 ¨ 6327 A.
Pepe et. al, J.
Med. Chem. 2013, 56, 8280 ¨ 8297; M. E. Jung eta!, J. Med. Chem. 2010, 53,
2779-2796,
which are incorporated by reference herein.
[0142] In certain embodiments, the ABM comprises a structure selected
from, but not
limited to the structures shown below, wherein a dashed line indicates the
attachment point of
linker moiety:
y2 R1
R2
yk-
ABM-a
(R0)o-6
y5 0 Y3 GO I.
ABM-b
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yl 3R' 0
0 N
Rh
y2
ABM-c ;and
(0)04
W2 I
Y.,õf4s`N
\,2,--V? )6,6
( )
ASM-k1
wherein:
W' is aryl or heteroatyl, independently substituted by 1 or more halo,
hydroxyl, nitro, CF3,
CN, CCH, C 1_6 alkyl (linear, branched, optionally substituted by 1 or more
halo, C1-6
alkoxyl), C1.6 alkoxyl (linear, branched, optionally substituted by 1 or more
halo), C2.6
alkenyl, C2..6 alkynyl;
Y1, y2 are each independently NR'. 0, S;
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRYIRY2, C=0, C=S, SO, SO2;
Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms,
optionally substituted
with 0-6 RQ, each RQ is independently H, OH, C1_6 alkyl (linear, branched,
optionally
substituted by 1 or more halo, C1_6 alkoxyl), or 2 RQ groups taken together
with the atom
they are attached to, form a 3-8 membered ring system containing 0-2
heteroatoms);
R', R2, le, Rb, RY', RY2 are each independently H, OH, C 1_6 alkyl (linear,
branched,
optionally substituted by 1 or more halo, C1.6 alkoxyl), or R', R2 together
with the atom
they are attached to, form a 3-8 membered ring system containing 0-2
heteroatoms;
W2 is a bond, C1.6 alkyl, alicyclic, heterocyclic, aryl, heteroaryl, bicyclic,
biaryl, biheteroaryl,
or biheterocyclic, each optionally substituted by 1, 2 or 3 Rw2; and
each Rw2 is independently H, halo, OH, NH2, C1.6 alkyl (optionally substituted
by 1 or more
F), OC1.3alkyl Optionally substituted by 1 or more F), NRY'RY2, or CN.
[0143] In certain embodiments described herein, the ABM comprises a
structure shown
below, wherein a dashed line indicates the point of attachment to a linker
moiety:
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to-s
Y3 (Y3)0.5
ABM-dt
wherein:
W1 is aryl or heteroaryl, each optionally substituted by 1 or more halo,
hydroxyl, nitro, CN,
CF3, C1_6 alkyl (linear, branched, optionally substituted by 1 or more halo,
C1_6 alkoxyl),
or C1_6 alkoxyl (linear, branched, optionally substituted by 1 or more halo);
each Y3 is independently a bond, 0, NRY2, CRY1RY2, or C=0;
each RQ is independently H, OH, C1_6 alkyl (linear, branched, optionally
substituted by 1 or
more halo, C1_6 alkoxyl), or 2 RQ groups taken together with the atom they are
attached
to, form a 3-8 membered ring system containing 0-2 heteroatoms);
RY1. RY2 are each independently H, OH, or C1_6 alkyl (linear, branched,
optionally substituted
by 1 or more halo, Ci_6 alkoxyl);
W2 is a bond, C1_6 alkyl, aryl, heteroaryl, alicyclic, heterocyclic, bicyclic,
biaryl, biheteroaryl,
biheterocyclic, each optionally substituted by 1, 2 or 3 Rw2; and
each Rw2 is independently H, OH, NH2, CRY'RY2, halo, C1_6 alkyl (optionally
substituted by 1
or more F), 0C1_3a1ky1 (optionally substituted by 1 or more F).
[0144] 2 =
In any of the embodiments described herein, the W covalently coupled to one
or more ULM or VLM groups, or a linker to which is attached one or more ULM or
VLM
groups as described herein.
(R23)o-3
(R23)0-4
R22 R 22
[0145] In certain embodiments, W1 is or ¨N
wherein each R,), is independently halo, optionally substituted alkyl,
haloalkyl, cyano, or nitro;
and
each R23 is independently H, halo, optionally substituted alkyl, haloalkyl,
cyano, or nitro.
[0146] In certain additional embodiments, W1 is selected from the group
consisting of:
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CF3 CF3 F CI
1 lik CN 1 it NO2 ii CN 1 * CN 1 * CN
,
CI
CI CF3
OMe F CI .
CN ...___C---....
1 . t . \ / CN F¨CS---CN
N N
and CN CN F
[0147] In certain embodiments. ABM is selected from the group consisting
of:
0 0
Nrz * NH-- N.1---:::-p..NH--
F F )1.-NN.ss
S
F F F F
1 1
NC NI 1 / 0\1._ / /
NC 41 Nn
. eN .,, 02N 41 Nrs tr-
F3C S ,
I 40
ft
F30 t 40 ,z. 0), F30
0-%.= F Cr" =
1 1 1 i
NC Ni
%._ /
IT NC * NTT
S lb \ F e
s
0\ io õt, ci r 401
0- = 0-- = - .
, ,
0, NC Ni , F ____9 0_ ,
N \
NC = Ni ---1¨ NC4, ---r-
11 1 )7....N --N
C s 410
Me0 r 40
'21t. F3
csA F3C g to
0- = F Cr\- =
, ; ,
0
)1--- NC NC 0 N)L-14
NC * Nur- 11 N 2,1
)r.,Eki
ci Me0 r 1110
\
'44
F3C g , ip
0-- 0--.
N cy'" . F : F =
,
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ry.
NC 441 N),...-N NC ill Ni---V
N
F3C g F3C S . 0 =,_
0"--.1- = ---It. =
= =
01µ i 0
NC 411 N :
NC A N ri '
I F30 )7,
s
F30 0
0
(
NC ----p-Ni ---1-- NC II N N
F3c S
F3C S
F N
0-)1/4 = =-=,/ .
to 01...\::: 0 0::_c"
,-- NH
NH
CI 0 1110
NA N
CI
H = N
--i .
so ......\:::
NH
0 ,:-
--
NH CI 0
...,.
N -/-
CI 0 IS
NA
H ; H =
,
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idth
11110
NV- NH
CF3 0 EIN
NA
OA ; H =
,
to 0::\: = 0 0
NH
.,= N'- N''.
INV CI 0 . CF3 0 0
CI 0 *
OA = tes = / =
0
F eN F F 14= 4 N H----=
S F eN
S
F F
F
N--
µ
H : 0-/µ =
0
N----13..._Nik4--
eN 011NFI
>ss 00' ',NH
>,
S
F F
a * Ci *
\
0.' = NC = NC =
. ,
01,-...INH 08.-.....8NH 00-===-eNH
\ ,
fe- =14: \fs#
CI it CI * CI *
NC = NC ; NC ;
00-6===INH Os.= NH 01- .iiNH
04-
CI * CI * CI *
NC =, NC ; NC ;
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0¨.¨NH
\irss \cs,
CI ilk, ci * c c,
NC ; NC ; NC, = 011:1.... NH. :
CI
*-....4111
061,..= N.....N.2%
r*,,,,,/-='-'
NC NC NI;
H
NH
0:110...*--..mi NH 1
'''''''-'==`N µY
)./õ.=,.."\.õf,%¨' 0:111,... 1.-.11.-NY
CI 0 CI 0
NC. ; NC =
,
7õ Nõ.......õ0.,...../
.. H.
0:111.... NH
Om NH 1
r*NN./7
C:I 0
a =
;and NC .
[0148] In certain embodiments, the ABM comprises the structure:
(Fek.,4
7."-.'s \
( wi )
ABM.,
,
wherein:
WI is aryl or heteroaryl, independently substituted by 1 or more halo,
hydroxyl, nitro, CF3,
CN, C.---ECH, C1_6 alkyl (linear, branched, optionally substituted by 1 or
more halo, C1.6
alkoxyl), C1_6 alkoxyl (linear, branched, optionally substituted by 1 or more
halo), C2_6
alkenyl, C2-6 alkynyl;
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRYIRY2, C=0, C=S, SO, SO2;
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Q is a 4 membered alicyclic ring with 0-2 heteroatoms, optionally substituted
with 0-6 0,
each 0 is independently H, C1.6 alkyl (linear, branched, optionally
substituted by 1 or
more halo, C1_6 alkoxyl), or 2 RQ groups taken together with the atom they are
attached
to, form a 3-8 membered ring system containing 0-2 heteroatoms);
RY2 are each independently H, OH, C1_6 alkyl (linear, branched, optionally
substituted
by 1 or more halo, C1_6 alkoxyl);
VV2 is a bond, C1.6 alkyl, alicyclic (e.g., C1.6 alicyclic), heterocyclic,
aryl, heteroaryl, bicyclic,
biheterocyclic, biaryl, or biheteroaryl each optionally substituted by 1, 2 or
3 Rw2; and
each Rw2 is independently H, halo, C1_6 alkyl (optionally substituted by 1 or
more F), OCI.
3alkyl (optionally substituted by 1 or more F), OH, NH2, Nei RY2, CN.
[0149] In an additional aspect, the description provides an androgen
receptor
bindingcompound comprising a structure of:
(R%4
j- NA.-{ w" )
e"\ ..................................... '
V4 .......
,===¨ssvN-1. = ,
ASM-0
wherein:
WI is aryl or heteroaryl, independently substituted by 1 or more halo,
hydroxyl, nitro, CN,
CF3, CaCH, C1-6 alkyl (linear, branched, optionally substituted by 1 or more
halo, C1_6
alkoxyl), C1-6 alkoxyl (linear, branched, optionally substituted by 1 or more
halo), C2_6
alkenyl, C2_6 alkynyl;
YI, Y2 are each independently NR', 0, S;
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRY'RY2, C=0, C=S, SO, SO2;
Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms,
optionally substituted
with 0-6 0, each 0 is independently H, OH, C1_6 alkyl (linear, branched,
optionally
substituted by 1 or more halo, C1.6 alkoxyl), or 2 0 groups taken together
with the atom
they are attached to, form a 3-8 membered ring system containing 0-2
heteroatoms);
RY2 are each independently H, OH, C1_6 alkyl (linear, branched, optionally
substituted
by 1 or more halo, C1_6 alkoxyl);
VV2 is a bond, C1.6 alkyl, alicyclic, heterocyclic, aryl, heteroaryl,
bicyclic, biheterocyclic,
biaryl, biheteroaryl, each optionally substituted by 1, 2 or 3 Rw2; and
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each Rw2is independently H, halo, Ci_6 alkyl (optionally substituted by 1 or
more F), CI_
3alkyl (optionally substituted by 1 or more F), OH. NH2, NRY1RY2, CN.
[0150] In certain embodimetns, the androgen receptor binding compound of ABM-e
is selected
from the group consisting of:
trans-2-Chloro-4-13-amino-2,2,4,4-tetramethylcyclobutoxylbenzonitrile;
cis-2-Chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile;
trans 6-Amino-N-(3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]pyridazine-3-
carboxamide;
trans tert-Butyl N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]carbamate;
trans 4-Amino-N43-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]benzamide;
trans 5-Amino-N43-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]pyrazine-2-
carboxamide;
trans 2-Amino-N43-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyllpyrimidine-5-
carboxamide;
4-Methoxy-N-R1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyllbenzamide;
trans 1-(2-Hydroxyethyl)-N4343-chloro-4-cyanophenoxy)-2,2,4,4-
tdramethylcyclobutyl]-
1H-pyrazole-4-carboxamide;
trans 6-Amino-N-(3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]pyridine-3-
carboxamide;
trans 4-[(5-Hydroxypentyl)amino]-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]benzamide;
trans tert-Butyl 24(5-[(4-([3-(3-chloro-4-cyanophenoxy)-2,2.4,4-
tetramethylcyclobutyl]carbamoyl}phenypaminopentyl)oxy)acetate;
trans-2-Chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile;
tert-butyl trans-(3-(3-chloro-4-cyanophenoxy)-2,2-
dimethylcyclobutyl)carbamate; and
tert-butyl cis-(3-(3-chloro-4-cyanophenoxy)-2,2-dimethylcyclobutyl)carbamate.
[0151] The term "hydrocarbyl" shall mean a compound which contains carbon
and
hydrogen and which may be fully saturated, partially unsaturated or aromatic
and includes aryl
groups, alkyl groups, alkenyl groups and alkynyl groups.
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10152] The term "alkyl" shall mean within its context a linear, branch-
chained or cyclic
fully saturated hydrocarbon radical or alkyl group, preferably a Ci-Cio, more
preferably a Ci-Co,
alternatively a C1-C3 alkyl group, which may be optionally substituted.
Examples of alkyl
groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-
nonyl, n-decyl,
isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl,
cyclopentyl, cyclopen-
tylethyl, cyclohexylethyl and cyclohexyl, among others. In certain preferred
embodiments,
compounds according to the present invention which may be used to covalently
bind to
dehalogenase enzymes. These compounds generally contain a side chain (often
linked through a
polyethylene glycol group) which terminates in an alkyl group which has a
halogen substituent
(often chlorine or bromine) on its distil end which results in covalent
binding of the compound
containing such a moiety to the protein.
[0153] The term "Alkenyl" refers to linear, branch-chained or cyclic C2-
C10 (preferably
C2-C6) hydrocarbon radicals containing at least one C=C bond.
10154] The term "Alkynyl" refers to linear, branch-chained or cyclic C2-
C10 (preferably
C2-C6) hydrocarbon radicals containing at least one CC bond.
[0155] The term "alkylene" when used, refers to a ¨(CH2)5- group (n is an
integer
generally from 0-6), which may be optionally substituted. When substituted,
the alkylene group
preferably is substituted on one or more of the methylene groups with a Ci-C6
alkyl group
(including a cyclopropyl group or a t-butyl group), more preferably a methyl
group, but may also
be substituted with one or more halo groups, preferably from 1 to 3 halo
groups or one or two
hydroxyl groups, 0-(Ci-C6 alkyl) groups or amino acid sidechains as otherwise
disclosed herein.
In certain embodiments, an alkylene group may be substituted with a urethane
or alkoxy group
(or other group) which is further substituted with a polyethylene glycol chain
(of from 1 to 10,
preferably 1 to 6, often 1 to 4 ethylene glycol units) to which is substituted
(preferably, but not
exclusively on the distal end of the polyethylene glycol chain) an alkyl chain
substituted with a
single halogen group, preferably a chlorine group. In still other embodiments,
the alkylene
(often, a methylene) group, may be substituted with an amino acid sidechain
group such as a
sidechain group of a natural or unnatural amino acid, for example, alanine, P-
alanine, arginine,
asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,
glycine, phenylalanine,
histidine, isoleucine, lysine, leucine, inethionine, proline, serine,
threonine, valine, tryptophan or
tyrosine.
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10156] The
term "unsubstituted" shall mean substituted only with hydrogen atoms. A
range of carbon atoms which includes Co means that carbon is absent and is
replaced with H.
Thus, a range of carbon atoms which is Co-C6 includes carbons atoms of 1, 2,
3,4, 5 and 6 and
for Co, H stands in place of carbon. The term "substituted" or "optionally
substituted" shall
mean independently (i.e., where more than substituent occurs, each substituent
is independent of
another substituent) one or more substituents (independently up to five
substitutents, preferably
up to three substituents, often 1 or 2 substituents on a moiety in a compound
according to the
present invention and may include substituents which themselves may be further
substituted) at a
carbon (or nitrogen) position anywhere on a molecule within context, and
includes as
substituents hydroxyl, thiol, carboxyl, cyano (C1µ1), nitro (NO2), halogen
(preferably, 1, 2 or 3
halogens, especially on an alkyl, especially a methyl group such as a
trifluoromethyl), an alkyl
group (preferably, C1-C1o, more preferably, C1-C6), aryl (especially phenyl
and substituted
phenyl for example benzyl or benzoyl), alkoxy group (preferably, C1-C6 alkyl
or aryl, including
phenyl and substituted phenyl), thioether (Ci-C6 alkyl or aryl), acyl
(preferably, Ci-C6 acyl),
ester or thioester (preferably, C1-C6 alkyl or aryl) including alkylenc ester
(such that attachment
is on the alkylene group, rather than at the ester function which is
preferably substituted with a
CI-C6 alkyl or aryl group), preferably, C1-C6 alkyl or aryl, halogen
(preferably, F or Cl), amine
(including a five- or six-membered cyclic alkylene amine, further including a
Ci-C6 alkyl amine
or a C1-C6 dialkyl amine which alkyl groups may be substituted with one or two
hydroxyl
groups) or an optionally substituted ¨N(C0-C6 alkyl)C(0)(0-Ci-Co alkyl) group
(which may be
optionally substituted with a polyethylene glycol chain to which is further
bound an alkyl group
containing a single halogen, preferably chlorine substituent), hydrazine,
amido, which is
preferably substituted with one or two Ci-C6 alkyl groups (including a
carboxamide which is
optionally substituted with one or two C1-Co alkyl groups), allmol
(preferably, Ci-C6 alkyl or
aryl), or alkanoic acid (preferably, Ci-C6 alkyl or aryl). Substituents
according to the present
invention may include, for example ¨SiR1R2R3 groups wherein each of R1 and R2
is as otherwise
described herein and R3 is H or a C1-C6 alkyl group, preferably RI, R2, R3 in
this context is a C1-
C3 alkyl group (including an isopropyl or t-butyl group). Each of the above-
described groups
may be linked directly to the substituted moiety or alternatively, the
substituent may be linked to
the substituted moiety (preferably in the case of an aryl or heteraryl moiety)
through an
optionally substituted ¨(CH2).- or alternatively an optionally substituted -
(00-10.-, -
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(OCH2CH2).- or ¨(CH2CH20).- group, which may be substituted with any one or
more of the
above-described substituents. Alkylene groups ¨(CH2).- or ¨(CH2)5- groups or
other chains
such as ethylene glycol chains, as identified above, may be substituted
anywhere on the chain.
Preferred substitutents on alkylene groups include halogen or C1-C6
(preferably C1-C3) alkyl
groups, which may be optionally substituted with one or two hydroxyl groups,
one or two ether
groups (0-C1-C6 groups), up to three halo groups (preferably F), or a
sideshain of an amino acid
as otherwise described herein and optionally substituted amide (preferably
carboxamide
substituted as described above) or urethane groups (often with one or two Co-
C6 alkyl
substitutents, which group(s) may be further substituted). In certain
embodiments, the alkylene
group (often a single methylene group) is substituted with one or two
optionally substituted CI-
C6 alkyl groups, preferably C1-C4 alkyl group, most often methyl or 0-methyl
groups or a
sidechain of an amino acid as otherwise described herein. In the present
invention, a moiety in a
molecule may be optionally substituted with up to five substituents,
preferably up to three
substituents. Most often, in the present invention moieties which are
substituted are substituted
with one or two substituents.
[0157] The term "substituted" (each substituent being independent of any
other
substituent) shall also mean within its context of use C i-C6 alkyl, C1-C6
alkoxy, halogen, amido,
carboxamido, sulfone, including sulfonamide, keto, carboxy. Ci-C6ester
(oxyester or
carbonylester), C1-C6keto, urethane -0-C(0)-NRIR2 or ¨N(R1)-C(0)-0-R1, nitro,
cyano and
amine (especially including a C1-C6 alkylene-NRI R2, a mono- or di- C1-C6
alkyl substituted
amines which may be optionally substituted with one or two hydroxyl groups).
Each of these
groups contain unless otherwise indicated, within context, between 1 and 6
carbon atoms. In
certain embodiments, preferred substituents will include for example, ¨NH-, -
NHC(0)-, -0-, =0,
-(CH,)õ,- (here, m and n are in context, 1, 2, 3,4. 5 or 6), -S-, -S(0)-, SO2-
or ¨NH-C(0)-NH-, -
(CH2).0H, -(CH2).SH, -(CH2).000H, C1-C6 alkyl, -(CH2).0-(C1-C6 alkyl), -
(CH2).C(0)-(C1-C6
alkyl), -(CH2).0C(0)-(C1-C6 alkyl), -(CH2).C(0)0-(C1-C6 -(CF12.)11NFIC(0)-
R1, -
(CH2)0C(0)-NRIR2, -(OCH2)50H, -(CH,O)õCOOH, CI-C6 alkyl, -(0CH2),0-(CI-C6
alkyl), -
(CH2O)11C(0)-(C1-C6 alkyl), -(OCH2)5NHC(0)-R1, -(CH20).C(0)-NRIR2, -S(0)2-R5, -
S(0)-Rs
(Rs is CI-C6 alkyl or a ¨(CH2).-NR1R2 group), NO2, CN or halogen (F, Cl, Br,
I, preferably F or
Cl), depending on the context of the use of the substituent. R1 and R2 are
each, within context, H
or a C1-C6 alkyl group (which may be optionally substituted with one or two
hydroxyl groups or
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up to three halogen groups, preferably fluorine). The term "substituted" shall
also mean, within
the chemical context of the compound defined and substituent used, an
optionally substituted
aryl or heteroaryl group or an optionally substituted heterocyclic group as
otherwise described
herein. Alkylene groups may also be substituted as otherwise disclosed herein,
preferably with
optionally substituted C1-C6 alkyl groups (methyl, ethyl or hydroxymethyl or
hydroxyethyl is
preferred, thus providing a chiral center), a sidechain of an amino acid group
as otherwise
described herein, an amido group as described hereinabove, or a urethane group
O-C(0)-NR1122
group wherein R1 and R2 are as otherwise described herein, although numerous
other groups may
also be used as substituents. Various optionally substituted moieties may be
substituted with 3 or
more substituents, preferably no more than 3 substituents and preferably with
1 or 2 substituents.
It is noted that in instances where, in a compound at a particular position of
the molecule
substitution is required (principally, because of valency), but no
substitution is indicated, then
that substituent is construed or understood to be H, unless the context of the
substitution suggests
otherwise.
[0158] The
term "aryl" or "aromatic", in context, refers to a substituted (as otherwise
described herein) or unsubstituted monovalent aromatic radical having a single
ring (e.g.,
benzene, phenyl, benzyl) or condensed rings (e.g., naphthyl, anthracenyl,
phenanthrenyl, etc.)
and can be bound to the compound according to the present invention at any
available stable
position on the ring(s) or as otherwise indicated in the chemical structure
presented. Other
examples of aryl groups, in context, may include heterocyclic aromatic ring
systems "heteroaryl"
groups having one or more nitrogen, oxygen, or sulfur atoms in the ring
(moncyclic) such as
imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine,
pyrazine, triazole,
oxazole or fused ring systems such as indole, quinoline, indolizine,
azaindolizine, benzofurazan,
etc., among others, which may be optionally substituted as described above.
Among the
heteroaryl groups which may be mentioned include nitrogen-containing
heteroaryl groups such
as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole,
imidazole, triazole,
triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine,
indazole, quinoline,
dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline,
tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline,
quinazoline,
cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine,
acridine,
phenanthridine, carbazole, carbazoline, perimidine, phenanthroline, phenacene,
oxadiazole,
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benzimidazole, pyrrolopyridine, pyffolopyrimidine and pyridopyrimidine; sulfur-
containing
aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing
aromatic
heterocycles such as furan, pyran, cyclopentapyran, benzofuran and
isobenzofuran; and aromatic
heterocycles comprising 2 or more hetero atoms selected from among nitrogen,
sulfur and
oxygen, such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole,
benzothiadiazole,
phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,
imidazothiazole, thienofuran,
furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienoppimidine and
oxazole, among
others, all of which may be optionally substituted.
101591 The term "substituted aryl" refers to an aromatic carbocyclic
group comprised of
at least one aromatic ring or of multiple condensed rings at least one of
which being aromatic,
wherein the ring(s) are substituted with one or more substituents. For
example, an aryl group can
comprise a substituent(s) selected from: -(CH2)OH, -(0-12)11-0-(Ci-C6)alkYl, -
(CH2)0-0-(CH2)-
(C1-C6)alkyl, -(CH2)5-C(0)(C0-C6) alkyl, -(CH2)5-C(0)0(Co-C6)alkyl, -(CH2),-
0C(0)(Co-
C6)alkyl, amine, mono- or di-(Ci-C6 alkyl) amine wherein the alkyl group on
the amine is
optionally substituted with 1 or 2 hydroxyl groups or up to three halo
(preferably F, Cl) groups,
OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (each
of which
may be substituted in ortho-, meta- and/or para- positions of the phenyl ring,
preferably para-),
an optionally substituted phenyl group (the phenyl group itself is preferably
substituted with a
linker group attached to a ABM group, including a ULM group), and/or at least
one of F, Cl,
OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (in ortho-, meta- and/or para-
positions
of the phenyl ring, preferably para-), a naphthyl group, which may be
optionally substituted, an
optionally substituted heteroaryl, preferably an optionally substituted
isoxazole including a
methylsubstituted isoxazole, an optionally substituted oxazole including a
methylsubstituted
oxazole, an optionally substituted thiazole including a methyl substituted
thiazole, an optionally
substituted isothiazole including a methyl substituted isothiazole, an
optionally substituted
pyrrole including a methylsubstituted pyrrole, an optionally substituted
imidazole including a
methylimidazole, an optionally substituted benzimidazole or
methoxybenzylimidazole, an
optionally substituted oximidazole or methyloximidazole, an optionally
substituted diazole
group, including a methyldiazole group, an optionally substituted triazole
group, including a
methylsubstituted triazole group, an optionally substituted pyridine group,
including a halo-
(preferably, F) or methylsubstitutedpyridine group or an oxapyridine group
(where the pyridine
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group is linked to the phenyl group by an oxygen), an optionally substituted
furan, an optionally
substituted benzofuran, an optionally substituted dihydrobenzofuran, an
optionally substituted
indole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), an optionally
substituted quinoline,
and combinations thereof.
10160] "Carboxyl" denotes the group -C(0)0R, wherein R is hydrogen,
alkyl, substituted
alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl , whereas
these generic
substituents have meanings which are identical with definitions of the
corresponding groups
defined herein.
101611 The term "heteroaryl"or "hetaryl" can mean but is in no way
limited to an
optionally substituted quinoline (which may be attached to the pharmacophore
or substituted on
any carbon atom within the quinoline ring), an optionally substituted indole
(including
dihydroindole), an optionally substituted indolizine, an optionally
substituted azaindolizine (2, 3
or 4-azaindolizine) an optionally substituted benzimidazole, benzodiazole,
benzoxofuran, an
optionally substituted imidazole, an optionally substituted isoxazole, an
optionally substituted
oxazole (preferably methyl substituted), an optionally substituted diazole, an
optionally
substituted triazole, a tetrazole, an optionally substituted benzofuran, an
optionally substituted
thiophene, an optionally substituted thiazole (preferably methyl and/or thiol
substituted), an
optionally substituted isothiazole, an optionally substituted triazole
(preferably a 1,2,3-triazole
substituted with a methyl group, a triisopropylsilyl group, an optionally
substituted -(CF12)1-O-
C1-C6 alkyl group or an optionally substituted -(C1-11).-C(0)-0-CI-C6 alkyl
group), an optionally
substituted pyridine (2-, 3, or 4-pyridine) or a group according to the
chemical structure:
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Sc
r HET
_____________________ HET
R R
N
N ¨
"RURE
RURE
0
Re IET I >
RI
.-T _______________________________________
iL
N N -
0 0
N . N
RI 1E1 . or R HET
Yc
wherein:
Sc is CHRss, NRuRE, or 0;
RHET is
H CN, NO2, halo (preferably Cl or F), optionally substituted Ci-C6 alkyl
(preferably
substituted with one or two hydroxyl groups or up to three halo groups (e.g.
CF3),
optionally substituted 0(C1-C6 alkyl) (preferably substituted with one or two
hydroxyl
groups or up to three halo groups) or an optionally substituted acetylenic
group ¨CEC-Ra
wherein Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
Rss is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6
alkyl (preferably
substituted with one or two hydroxyl groups or up to three halo groups),
optionally
substituted 0-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl
groups or up
to three halo groups) or an optionally substituted -C(0)(C1-C6 alkyl)
(preferably
substituted with one or two hydroxyl groups or up to three halo groups);
RI-41E is H, a Ci-Co alkyl (preferably H or C1-C3 alkyl) or a ¨C(0)(CI-C6
alkyl), each of
which groups is optionally substituted with one or two hydroxyl groups or up
to three
halogen, preferably fluorine groups, or an optionally substituted heterocycle,
for example
piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,
piperidine,
piperazine, each of which is optionally substituted, and
Yc is N or C-R, wherein lec is H, OH, CN, NO2, halo (preferably Cl or F),
optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups (e.g. CF3), optionally substituted 0(C1-C6 alkyl)
(preferably substituted
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with one or two hydroxyl groups or up to three halo groups) or an optionally
substituted
acetylenic group ¨CEC-Ra wherein Ra is H or a Ci-C6 alkyl group (preferably Ci-
C3
alkyl).
101621 The terms "arylkyl" and "heteroarylalkyl" refer to groups that
comprise both aryl
or, respectively, heteroaryl as well as alkyl and/or heteroalkyl and/or
carbocyclic and/or
heterocycloallcyl ring systems according to the above definitions.
[0163] The terin "arylalkyl" as used herein refers to an aryl group as
defined above
appended to an alkyl group defined above. The arylalkyl group is attached to
the parent moiety
through an alkyl group wherein the alkyl group is one to six carbon atoms. The
aryl group in the
arylalkyl group may be substituted as defined above.
[0164] The term "heterocycle" refers to a cyclic group which contains at
least one
heteroatom, i.e., 0, N or S, and may be aromatic (heteroaryl) or non-aromatic.
Thus, the
heteroaryl moieties are subsumed under the definition of heterocycle,
depending on the context
of its use. Exemplary heterocyclics include: azetidinyl, benziinidazolyl, 1,4-
benzodioxanyl, 1,3-
benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl,
dihydropyranyl,
dihydrofuranyl, dioxa.nyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-
dioxane, 1,4-dioxane,
fury!, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl,
indolyi,
isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,
morpholinyl,
naphthpidinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine,
piperazinyl, N-
methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl,
pyrazolinyl, pyridyl,
pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl,
tetrahydrofura.nyl, tetrahydropyranyl,
tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene,
oxane, oxetanyl,
oxathiolanyl, thiane among others.
[0165] Heterocyclic groups can be optionally substituted with a member
selected from
the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloallcyl,
cycloallcenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,
substituted amino,
aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto,
thioketo,
carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy,
substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy,
heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, ¨50-alkyl, ¨SO-substituted alkyl, ¨SOaryl,
¨SO-
heteroaryl, ¨502-alkyl, ¨502-substituted alkyl, ¨502-aryl, oxo (=)), and -502-
heteroaryl.
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Such heterocyclic groups can have a single ring or multiple condensed rings.
Examples of
nitrogen heterocycles and heteroaryls include, but are not limited to,
pyrrole, imidazole,
pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,
indole, indazole,
purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,
quinoxaline,
quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine,
acridine, phenanthroline,
isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine,
imidazoline,
piperidine, piperazine, indoline, moipholino, piperidinyl, tetrahydrofuranyl,
and the like as well
as N-alkoxy-nitrogen containing heterocycles. The term "heterocyclic" also
includes bicyclic
groups in which any of the heterocyclic rings is fused to a benzene ring or a
cyclohexane ring or
another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,
tetrahydroquinolyl, and the
like).
[0166] The term "cycloalkyl" can mean but is in no way limited to
univalent groups
derived from monocyclic or polycyclic alkyl groups or cycloalkanes, as defnied
herein, e.g.,
saturated monocyclic hydrocarbon groups having from three to twenty carbon
atoms in the ring,
including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and
the like. The term "substituted cycloalkyl" can mean but is in no way limited
to a monocyclic or
polycyclic alkyl group and being substituted by one or more substituents, for
example, amino,
halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro,
mercapto or sulfo,
whereas these generic substituent groups have meanings which are identical
with definitions of
the corresponding groups as defined in this legend.
[0167] "lieterocycloalkyl" refers to a monocyclic or polycyclic alkyl
group in which at
least one ring carbon atom of its cyclic structure being replaced with a
heteroatom selected from
the group consisting of N, 0, S or P. "Substituted heterocycloalkyl" refers to
a monocyclic or
polycyclic alkyl group in which at least one ring carbon atom of its cyclic
structure being
replaced with a heteroatom selected from the group consisting of N, 0, S or P
and the group is
containing one or more substituents selected from the group consisting of
halogen, alkyl,
substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo,
whereas these
generic substituent group have meanings which are identical with definitions
of the
corresponding groups as defined in this legend.
[0168] Exemplary AR-PROTAC Compounds
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[0169] As described above, in certain aspects, the description provides
bifuctional
PROTAC compounds comprising at least one ABM group, a linker, and at least one
ULM (or
VLM) group as described herein.
101701 In certain embodiments, the compound is selected from the group
consisting of
compounds 1-864 (as described in Tables 2-30), and salts and polymorphs
thereof.
[0171] In certain embodiments, the compound is selected from the group
consisting of:
F F 0
F aiL\ ,--'--
N----- IN NN At.
H I
S
0 d.p..011
/FS 0
N , 110, NH
0
NO * N"--K,
)/...... ah, F
µ
F3 S I = - -\.. \ _...\
0
F F 0 i
2
N:----- N ,b_.
N- -, H I Nr-\
S 0 s o?
q
''N`NA\--- NH
H =-,
OH =
;
0 0
Nc_r_yr.?-1<
k-N N NO2N * r is
F3 s ik s
F3C 0-\.....\.....\
0
b
)
;
o) Nrx\ 0
N'S
NH
NH
4 NOt.../N.,1
N
H
H \--J
'OH ; -OH ;
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(C Or "..r..-- .0H
HN Ny
H 1\1::. N
0 (50 NH
c) 0
0' NH
I
-,-,-'3\---
1
S="-""..-t,..
a ll
.c.-:
*
N1.- N , /
,
6N . F
0H
FiN' N
c,,CY'N'''-'-0'--Y
a 0 --i \,) 0 NH
0' NH
argil ) fj
1 0
S= gip r
s ..-.,..õ.õ
0 1 0 4. I
N
cli\l'i I/
I ' Ni---' = N
\f-Ns
0-.-N,S
."--N
0 \
( \
---0/"---CN
C: µ CN .
C y niDH
1 ri, 0 IN
6 0
(Si 0 NH
P s .k.,01
9¨F
s
S
?-11
=-"7--N
u .
)-..
4 -CF3 \(CF3
CN
; CN
;
61
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0H
, pH
/0-0`Thi" HN N
, I
\o") 0 NH , r-
0 '--)
0' 'NH
--,)
--,'''''---, i
1 HO?/r
...:Ci.)-j
1 er,,,--
0 a µ 1
ci N
õAõ
, ,,
NI )-11 N
1-N
/=Nis
),----s
0 t
F '=
--e-CF3 \-----,CY
F
CN =
µ;µ
; N ;
Y____ õOH
H...... HN---K Z
. tl./....."µ,N1 rjAOH v-N
HN' -
rjr-
t Oil) Cli
-- tl
0
i
c.)
N?: =!.,.
F N r,/-Fk
9
N\\
F., b n
F N-1
01 4 *
f--.1
\--))
0-10
S V 0,1 pH 0
....,. 4
..." Tr 0 0' trsirrsil
H HN OH
0 0 NH " -I
N". F 004
F F
,NH
N = .
) ,
62
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a,
....0-,õ. = -1
pH0
1.,
I '1
F H ,/
0
0 NH \ / (-0
. 02N CF i
.
--3/c71Lsrs s.. 1 ;
0
0,
--:".-cCN r IP , '....7H
. Tr .
9
O/ /-----,
e:---k.--N,N--(/ v
if ) ii .,..,,,,/---6--"\-0
NC--y--i-
F3C Ci 54.
17, N,n,N eik
) NC --- g 14F "-N-0
Co F3c
1k
Cro i
\0
HN.../
Ne7,s c-.0
HNI /
O'rr:Kf A
0-=K 1-
-NH
0H .
F 0 1
,....1
\ 1--
0
N) o,
o----- _._..:¨ DH ) V
H'N' /-- ' 0,,---,, If -
õOH
-N ) HN--- \
(
SO2 ,tr-N
0
NH 0
H
S i'nr-I ,S
--(1-.)--j
N-A N
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F _ 0
F-j\--L. pr,
NN(
..
-,,--
---il
S '''' .-\---\-s0 NC--2.17r
-14N 0 0.
F3C S
F -
0
Cc
H. N''''''
N.----
.,
-N - T./
S O
-NH
; .
9
0.0µ......
0
NC;3944''irN
* NyN 411 NC---F3p-NrN,c1.11..
'1
I \ F--- S ir \---\--\0
F
F F
/
N'-' \--
HN>-' )
N 0 T_-1
" \
'OH : %C 41 E)7.01-1 = ji_i v1-
1 =
0µµ i
NC-c)---c-
F3C S N. fl-N-"Ni ,Ikl
0-Th NC---4,
M. F3 --\
N. `----N
---0 \ ---0
1µ1,
0 0
Cr0 Cr.
HN ., H gi.õ.r..1
N4-Ns
- 0--r-c)-Ks
- ,
\ /
)-4
)N
-NH ==,
OH . N4..'S
, / \
C),.,...0
;
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0 1
:.----1---.
F-\\,õ
---02''' I 41
,
NC NN"
, 11 1 '1,0 =--,\_
r
Cr0
c0
t
N Htµ...../, HN,,......(
S NS
0 ¨
fi 0
0 µ,.....".,
OH
-NH
; NH =
,
0 ,
0
F3CY= eN411
S NZZ-D¨N)Lis-
'),--N
S * F
0---µ S *
\_.s.
`..,_
0
..(:)
c0 )=0
...,\
N ' s HN\ z
N."0 HN/
Nest
¨ Hrsk /
0--,\
... I<Di ' 'OH .
NH 'OH
=
9 9
Q 1
N- -1--._ -c),
0
õ...._, ).._0...N)14.....
01 s
õ0...0
\
--\--\-0
"Z.0
0
-1-_-,-/
Or=t\ NS
¨ 0 \
l
Ilp 0 N-- 4,
NH ''OH = NH `OH .
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0
......._\ t.õ_. j
N= NI' 1-
,
CI S . 0 '1
--t---
0.--A.
',._ tr-,,._N...,.,N=
'0 N -- A- 0
(10 Clf
Clb
cro C,0
1-iN Firsu
N u 1%0
'''''-j".,....-NH . 4\--141 ="' 'OH
'
0 ,
N \)"...4._
-,--- ---N k
.'' ,
¨
\-o CI 1 ,,-:,,),,
0 .,_
; 0-\
F
- \--0
<0
0
NV" \ tr0
(
)"---..3 HN
N'N it=0
HN ,
s -----' \
\ ( 0µ.
-Nt\--1'.
0H . NH
-'0H ;
9...L 1
0.c5)
_24,1 T---
Ma-.
S II
F
\---s0 ----\ \ -0
CO 0
e
(,.
N
:. HN 1.1%, N S HNT
,),---\ 0-,:h _ (..)
( ¨ =.{>¨/
c.,
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Q , o .
, >\-------- r-
1\1"--=-=:-----/c
---1 i T---1 NFis.---\/_,, j
_
T 0---, 0-Th
F F x
\-?0
e
0 0
{ /
N=:\0 ,,,0 'co
HN 1--z---1 Hisi
c? 0 0,-,C?\/
H '--- ''µOH ; 'OH =
N,'EE:"---jc)
-*---N j'`..-.- 0 ,
II- )r-I'L-------,
1 0---,, F.,, s ., 11
F\--- i 'F ''-e*----",
-, F, 1 0---\
\ -(0 F
-\-c0
CO
HN Y
(0
-'0
Hrs4>=0
\--- 0/
\µ,...!,_ f \ I ,
-N)---i.,
H 'OH = OH ;
0
__________________________________ \\ )1.---f-I
_ NE::
-0
F s''
1: . 0--
'
F F \.____ -\\-(0
\
-0
/
(b
0
/
)-''(.
V's
-N \---+,
-NH "OH'-- H 'OHS
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- ? 1 NE--.-:-..--- %___=N
--7
CI
N---------- ' "),..N.,a0
......0
/0
\\O
N 3,,
HN1-0/ N
- Oz.- X
'OH = --41 ...40H ;
, ----s, -------------------------------- \ ---
1
NC' r'',-- s
NI- F S \F
F36 F F
0 0
CF.-..0
HA,1_7( Ns HN ,
--'-4
0 1 ' ' /)_\ 0--z(o<>7(/"--- = 0,j-1
.
OH NH 'OH =
;
0
NC -0 1-
..... * /
N---
F3C =,-.!':1. ',,_
8 Q 9
NC -.1/.......)... A i
\ / -_ N- 1----
0 F3C
o
\..... o
C.\\,...
N- ?
H
\--\ 54,
0 NH r -
0
l 010õ,c,...?' = qDH
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F ---- N
S
),......_ N i
F30 S * \
0
0
\...._
0 0
0 pH
---\ Nr-,.-
H ri
. A
0 NH 0
J NH
....''''''..--.."
I , S r-
N-\
N
S....,- .=,,:," /i---- ---
µ _il
N---\\
; N----{\
;
0 0
*""N r----- VV.._
CI N
S' '-'="-----)s S )-------
,..\.... /
0 ,
'.\\...... \\\._
o P , /
o, u
01-I
0 NH OX
J NH
ey.,,,:
, ,,
N-''
1 7
0
N/V..... 0
fl I
N. 111
N").L.1------
S )-.---= F 1/---N1
C\Y-4 F F S Cz
F 0
/ 0
F \\....\\.....
C\,.....
s;\\
0 . / 1.--`)
N ,N 0 0
,-,.
01.-- NH ,...,
1.1[-1
frk'Nr- I
-,-..--
% ii U
N¨ = N ¨ =
9 9
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1 N--0--- .)---
F3CT,;,..õ,
I S >/---NH
0 \ \ NC-
0
0 1
..,
1"..
0 ''0
4.0 L-...,0
I 1
Fit/ HNI,.õ4,
, ¨ r I'
/ 0/1 A
1\ OH //----
N ,. OH
11-i ' . / *
NH .
;
F3C.x,s___¨__N N
* \
F3C .--,.-,jõ-N-1 /- \ _
NC' ---- S ----,
I .,.- S Ni --Nii
'NI
L.
o 9
L-TO
1 i
HN 1 41,,.....1\
"¨INI i
(:).\ N---\
...-' NH . -..-_,Lõ-h=IFI .
F
F---4--F 0 F
1 ,
N= __ -6¨Nlf ---r NI= -- t:\)---N?:1;
gi II :I ,...õ,,,,,r. ..,..,....,
I
'L. ,=-=
\-0 \--0
C. '')
C5\r-0
r)J.,
0"---(N,
N a _. ,,,,
/
....
-NH ' '0H N.f..:=µ---{.....___NH
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0
õOH
N---N2. H
0
0 0 NH
0
NH
4
N..{-1 .....N
--
0
F F S-...N 0 F __ F
F F =
pH
HN.-Ny
0 0 NH ,OH
j1õ,õ :
N Hy
H
0
i \ 0 NH
14111
WAN *
=N S
S-.
/N
"fs-i Aqs1 * N
0 F F 0 F F
F - F =
; ,
F
F F 0
Nz.: * NX.1,-=
--N/
S
0 pH
ci X.Ny 0
0 k---,
0 NH 07
\O
S 0 --= (sr0
WAN *
=N s_sN
NS
HN...i
0 F F .
F ; NH "'OH -
,
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F
F--(-F
0 F
---N,
e n
_
q___. _
0......\\
N'-;\s
/---- EN /
-- 0--;27( N/ \,......,
- 0----\
\ / O\U\I ,1
DH
I * 0).......0,
--N/4--- \---1.A = -NH 'OH
;
F
r.---,Z
N,7----=-- _.:i
S 1 ,=-' -,, F\ )\---r(
NCI i---N\fr.,j,,,,
1 1 '
F 7 ==-=0_, F3C
,2.1..
,
\.
-7
0 0
"==== 0
H NI 4 \/
_2õ.....i.7 (
14'S
Ni.........õ: ..c. \\k. _"-'S of::: N
-
H %i
\ --\,,N1H NH e ."01-i =
;
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Clt
(?µ ,
)--- F3C N
5'1 )n,
\ /
F3C 1 =
F
0.-.
*. \
0 L-0
H i
6 oõ,
0
N:,:::-\s
2:47-:- (:),-.\;7\/ , oi7H-I (
i
i---'N?-7----'=.
/OH = ''OH ;
0 N.,
==,
NO- itNN
sir------ i f. F
/
--o \
t, y,0 /
-1" o \----/ N
4j.4.., ........--)......4
.._1
r \ I S
y=ot..)
=F'S
4 1 7,
N'
=
N ---
'..."--,r.',=-1 S
FN N -õ0--- Oõ...
- \,----
0 / \
() E ' I µ
0
6
0
N
Ui--
'S
t1 \ h NH
-i NH
0=-
0
--==c):...,7 0, 7,...,-,
F-------------- r
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t O.
HN
"Or ,
0
0 Thl, --\
N
WA,S y
0
/ pH L-0 Fer
\it\
F-- "1
f fo
/2/ 1
0
\.--S CY- '1--- \
0 N,7,HL'
F-IN-4
0
CI it r
,r\S 0Z r--
. ..õ
;
1 1
.N.
NH
0...v.(
0 N .
Cit,<::\tv
ttlaC ________________________________________ ON
(. . NC c:133: talk 'PR
0
ItC CH:sy -'== .4 \-1
,
p H
N.,,,71 L'=,,,-/\1"--"")''''N i
irTi H i
0 0
Oy'L,õ...p* ¨ HN
1\1,,,,,,,,r,,,,i 0 H
N. H
1
CI 0µ
/ S
4.µ 1
N :
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CI
NH OH
n
0
HN
jcICZ
sy
N
H
0 0
p
O
r
-
N 0 0 H HN
CI IF
µN
OH
z
0 0 NH
p// CI
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OH
NZN
CI
S
; and
H0,1
OH
0
HN
#NH
0 0 0S.
CI
10172] In another embodiment, the present invention provides a library of
compounds.
The library comprises more than one compound wherein each compound has a
formula of ABM-
L-ULM, wherein ULM is a ubiquitin pathway protein binding moiety (preferably,
an E3
ubiquitin ligase moiety as otherwise disclosed herein), e.g., a VLM, and ABM
is an AR protein
binding moiety, wherein ABM is coupled (preferably, through a linker moiety)
to ULM, and
wherein the ubiquitin pathway protein binding moiety recognizes an ubiquitin
pathway protein,
in particular, an E3 ubiquitin ligase.
[0173] The present description includes, where applicable, the
compositions comprising
the pharmaceutically acceptable salts, in particular, acid or base addition
salts of compounds of
the present invention.
10174] The term "pharmaceutically acceptable salt" is used throughout the
specification
to describe, where applicable, a salt form of one or more of the compounds
described herein
which are presented to increase the solubility of the compound in the gastic
juices of the patient's
gastrointestinal tract in order to promote dissolution and the bioavailability
of the compounds.
Pharmaceutically acceptable salts include those derived from pharmaceutically
acceptable
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inorganic or organic bases and acids, where applicable. Suitable salts include
those derived from
alkali metals such as potassium and sodium, alkaline earth metals such as
calcium, magnesium
and ammonium salts, among numerous other acids and bases well known in the
pharmaceutical
art. Sodium and potassium salts are particularly preferred as neutralization
salts of the
phosphates according to the present invention.
[0175] The acids which are used to prepare the pharmaceutically
acceptable acid addition
salts of the aforementioned base compounds useful in this invention are those
which form non-
toxic acid addition salts, i.e., salts containing pharmacologically acceptable
anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,
phosphate, acid phosphate,
acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate,
maleate, fumarate, gluconate,
saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-
toluenesulfonate
and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3 naphthoate)]salts, among
numerous others.
10176] Pharmaceutically acceptable base addition salts may also be used
to produce
pharmaceutically acceptable salt forms of the compounds or derivatives
according to the present
invention. The chemical bases that may be used as reagents to prepare
pharmaceutically
acceptable base salts of the present compounds that are acidic in nature are
those that form non-
toxic base salts with such compounds. Such non-toxic base salts include, but
are not limited to
those derived from such pharmacologically acceptable cations such as alkali
metal cations (eg.,
potassium and sodium) and alkaline earth metal cations (eg, calcium, zinc and
magnesium),
ammonium or water-soluble amine addition salts such as N-methylglucamine-
(meglumine), and
the lower alkanolammonium and other base salts of pharmaceutically acceptable
organic amines,
among others.
[0177] Compositions
[0178] In another aspect, the description provides compositions
comprising compounds
as described herein, including salts thereof, and a pharmaceutically
acceptable carrier. In certain
embodiments, the compositions are therapeutic or pharmaceutical compositions
comprising an
effective amount of a compound as described herein and a pharmaceutally
acceptable carrier.
[0179] The amount of compound in a pharmaceutical composition of the
instant
invention that may be combined with the carrier materials to produce a single
dosage form will
vary depending upon the host and disease treated, the particular mode of
administration.
Generally, an amount between 0.1 mg/kg and 1000 mg/kg body weight/day of
active ingredients
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is administered dependent upon potency of the agent. Toxicity and therapeutic
efficacy of such
compounds can be determined by standard pharmaceutical procedures in cell
cultures or
experimental animals, e.g., for determining the LD50 (the dose lethal to 50%
of the population)
and the ED50 (the dose therapeutically effective in 50% of the population).
The dose ratio
between toxic and therapeutic effects is the therapeutic index and it can be
expressed as the ratio
LD50/ED50. Compounds that exhibit large therapeutic indices are preferred.
While compounds
that exhibit toxic side effects may be used, care should be taken to design a
delivery system that
targets such compounds to the site of affected tissue in order to minimize
potential damage to
uninfected cells and, thereby, reduce side effects. The data obtained from the
cell culture assays
and animal studies can be used in formulating a range of dosage for use in
humans. The dosage
of such compounds lies preferably within a range of circulating concentrations
that include the
ED50 with little or no toxicity. The dosage may vary within this range
depending upon the
dosage form employed and the route of administration utilized. For any
compound used in the
method of the invention, the therapeutically effective dose can be estimated
initially from cell
culture assays. A dose may be formulated in animal models to achieve a
circulating plasma
concentration range that includes the IC50 (i.e., the concentration of the
test compound which
achieves a half-maximal inhibition of symptoms) as determined in cell culture.
Such information
can be used to more accurately determine useful doses in humans. Levels in
plasma may be
measured, for example, by high performance liquid chromatography.
[0180] The compositions of the present invention may be formulated in a
conventional
manner using one or more pharmaceutically acceptable carriers and may also be
administered in
controlled-release formulations. Pharmaceutically acceptable carriers that may
be used in these
pharmaceutical compositions include, but are not limited to, ion exchangers,
alumina, aluminum
stearate, lecithin, serum proteins, such as human serum albumin, buffer
substances such as
phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride
mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as prolamine
sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,
colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol,
sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-
polyoxypropylene-block
polymers, polyethylene glycol and wool fat.
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[0181] The active compound is included in the pharmaceutically acceptable
carrier or
diluent in an amount sufficient to deliver to a patient a therapeutically
effective amount for the
desired indication, without causing serious toxic effects in the patient
treated. A preferred dose of
the active compound for all of the herein-mentioned conditions is in the range
from about 10
ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to
about 25 ing per
kilogram body weight of the recipient/patient per day. A typical topical
dosage will range from
0.01-5% wt/wt in a suitable carrier.
10182] The compound is conveniently administered in any suitable unit
dosage form,
including but not limited to one containing less than lmg, 1 mg to 3000 mg,
preferably 5 to 500
mg of active ingredient per unit dosage form. An oral dosage of about 25-250
mg is often
convenient.
[0183] The active ingredient is preferably administered to achieve peak
plasma
concentrations of the active compound of about 0.00001-30 mM, preferably about
0.1-30 M.
This may be achieved, for example, by the intravenous injection of a solution
or formulation of
the active ingredient, optionally in saline, or an aqueous medium or
administered as a bolus of
the active ingredient. Oral administration is also appropriate to generate
effective plasma
concentrations of active agent.
101841 The concentration of active compound in the drug composition will
depend on
absorption, distribution, inactivation, and excretion rates of the drug as
well as other factors
known to those of skill in the art. It is to be noted that dosage values will
also vary with the
severity of the condition to be alleviated. It is to be further understood
that for any particular
subject, specific dosage regimens should be adjusted over time according to
the individual need
and the professional judgment of the person administering or supervising the
administration of
the compositions, and that the concentration ranges set forth herein are
exemplary only and are
not intended to limit the scope or practice of the claimed composition. The
active ingredient may
be administered at once, or may be divided into a number of smaller doses to
be administered at
varying intervals of time.
[0185] If administered intravenously, preferred carriers are
physiological saline or
phosphate buffered saline (PBS).
[0186] In one embodiment, the active compounds are prepared with carriers
that will
protect the compound against rapid elimination from the body, such as a
controlled release
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formulation, including implants and microencapsulated delivery systems.
Biodegradable,
biocompatible polymers can be used, such as ethylene vinyl acetate,
polyanhydrides,
polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for
preparation of such
formulations will be apparent to those skilled in the art.
10187] Liposoinal suspensions may also be pharmaceutically acceptable
carriers. These
may be prepared according to methods known to those skilled in the art, for
example, as
described in U.S. Pat. No. 4,522,811 (which is incorporated herein by
reference in its entirety).
For example, liposome formulations may be prepared by dissolving appropriate
lipid(s) (such as
stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl
phosphatidyl
choline, and cholesterol) in an inorganic solvent that is then evaporated,
leaving behind a thin
film of dried lipid on the surface of the container. An aqueous solution of
the active compound
are then introduced into the container. The container is then swirled by hand
to free lipid material
from the sides of the container and to disperse lipid aggregates, thereby
forming the liposomal
suspension.
[0188] Modes of Adminstration
[0189] In any of the aspects or embodiments described herein, the
therapeutic
compositions comprising compounds described herein can be in any suitable
dosage form
configured to be delivered by any suitable route. For example, the compounds
can be
administered by any appropriate route, for example, orally, parenterally,
intravenously,
intradermally, subcutaneously, or topically, including transdermally, in
liquid, cream, gel, or
solid form, rectally, nasally, buccally, vaginally or via an implanted
reservoir or by aerosol form.
10190] The term "parenteral" as used herein includes subcutaneous,
intravenous,
intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal,
intrahepatic, intralesional
and intracranial injection or infusion techniques. Preferably, the
compositions are administered
orally, intraperitoneally or intravenously.
[0191] The compounds as described herein may be administered in single or
divided
doses by the oral, parenteral or topical routes. Administration of the active
compound may range
from continuous (intravenous drip) to several oral administrations per day
(for example, Q.I.D.)
and may include oral, topical, parenteral, intramuscular, intravenous, sub-
cutaneous, transdermal
(which may include a penetration enhancement agent), buccal, sublingual and
suppository
administration, among other routes of administration. Enteric coated oral
tablets may also be
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used to enhance bioavailability of the compounds from an oral route of
administration. The most
effective dosage form will depend upon the pharmacolcinetics of the particular
agent chosen as
well as the severity of disease in the patient.
101921 Administration of compounds as sprays, mists, or aerosols for
intra-nasal, intra-
tracheal or pulmonary administration may also be used. Compounds as described
herein may be
administered in immediate release, intermediate release or sustained or
controlled release forms.
Sustained or controlled release forms are preferably administered orally, but
also in suppository
and transdermal or other topical forms. Intramuscular injections in liposomal
form may also be
used to control or sustain the release of compound at an injection site.
10193] Sterile injectable forms of the compositions as described herein
may be aqueous
or oleaginous suspension. These suspensions may be formulated according to
techniques known
in the art using suitable dispersing or wetting agents and suspending agents.
The sterile injectable
preparation may also be a sterile injectable solution or suspension in a non-
toxic parenterally-
acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
Among the
acceptable vehicles and solvents that may be employed are water, Ringer's
solution and isotonic
sodium chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent
or suspending medium. For this purpose, any bland fixed oil may be employed
including
synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its
glyceride derivatives are
useful in the preparation of injectables, as are natural pharmaceutically-
acceptable oils, such as
olive oil or castor oil, especially in their polyoxyethylated versions. These
oil solutions or
suspensions may also contain a long-chain alcohol diluent or dispersant, such
as Ph. Hely or
similar alcohol.
101941 The pharmaceutical compositions as described herein may be orally
administered
in any orally acceptable dosage form including, but not limited to, capsules,
tablets, aqueous
suspensions or solutions. In the case of tablets for oral use, carriers which
are commonly used
include lactose and corn starch. Lubricating agents, such as magnesium
stearate, are also
typically added. For oral administration in a capsule form, useful diluents
include lactose and
dried corn starch. When aqueous suspensions are required for oral use, the
active ingredient is
combined with emulsifying and suspending agents. If desired, certain
sweetening, flavoring or
coloring agents may also be added. Oral compositions will generally include an
inert diluent or
an edible carrier. They may be enclosed in gelatin capsules or compressed into
tablets. For the
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purpose of oral therapeutic administration, the active compound or its prodrug
derivative can be
incorporated with excipients and used in the form of tablets, troches, or
capsules.
Pharmaceutically compatible binding agents, and/or adjuvant materials are
included as part of
the composition.
10195] The tablets, pills, capsules, troches and the like can contain any
of the following
ingredients, or compounds of a similar nature: a binder such as
microcrystalline cellulose, gum
tragacanth or gelatin; an excipient such as starch or lactose, a dispersing
agent such as alginic
acid, Primogel, or corn starch; a lubricant such as magnesium stearate or
Sterotes; a glidant such
as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin;
or a flavoring agent
such as peppermint, methyl salicylate, or orange flavoring. When the dosage
unit form is a
capsule, it can contain, in addition to material of the above type, a liquid
carrier such as a fatty
oil. In addition, dosage unit forms can contain various other materials which
modify the physical
form of the dosage unit, for example, coatings of sugar, shellac, or enteric
agents.
10196] The active compound or pharmaceutically acceptable salt thereof
can be
administered as a component of an elixir, suspension, syrup, wafer, chewing
gum or the like. A
syrup may contain, in addition to the active compounds, sucrose as a
sweetening agent and
certain preservatives, dyes and colorings and flavors.
101971 Alternatively, the pharmaceutical compositions as described herein
may be
administered in the form of suppositories for rectal administration. These can
be prepared by
mixing the agent with a suitable non-irritating excipient, which is solid at
room temperature but
liquid at rectal temperature and therefore will melt in the rectum to release
the drug. Such
materials include cocoa butter, beeswax and polyethylene glycols.
10198] The pharmaceutical compositions of this invention may also be
administered
topically. Suitable topical formulations are readily prepared for each of
these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal
suppository
formulation (see above) or in a suitable enema formulation. Topically-
acceptable transdermal
patches may also be used. For topical applications, the pharmaceutical
compositions may be
formulated in a suitable ointment containing the active component suspended or
dissolved in one
or more carriers. Carriers for topical administration of the compounds of this
invention include,
but are not limited to, mineral oil, liquid petrolatum, white petrolatum,
propylene glycol,
polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. In
certain preferred
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aspects of the invention, the compounds may be coated onto a stent which is to
be surgically
implanted into a patient in order to inhibit or reduce the likelihood of
occlusion occurring in the
stent in the patient.
101991 Alternatively, the pharmaceutical compositions can be formulated
in a suitable
lotion or cream containing the active components suspended or dissolved in one
or more
pharmaceutically acceptable carriers. Suitable carriers include, but are not
limited to, mineral oil,
sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-
octyldodecanol,
benzyl alcohol and water.
102001 For ophthalmic use, the pharmaceutical compositions may be
formulated as
micronized suspensions in isotonic, pH adjusted sterile saline, or,
preferably, as solutions in
isotonic, pH adjusted sterile saline, either with our without a preservative
such as
benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutical compositions
may be formulated in an ointment such as petrolatum.
102011 The pharmaceutical compositions of this invention may also be
administered by
nasal aerosol or inhalation. Such compositions are prepared according to
techniques well-known
in the art of pharmaceutical formulation and may be prepared as solutions in
saline, employing
benzyl alcohol or other suitable preservatives, absorption promoters to
enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[0202] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical
application can include the following components: a sterile diluent such as
water for injection,
saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol
or other synthetic
solvents; antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as
ascorbic acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid;
buffers such as acetates, citrates or phosphates and agents for the adjustment
of tonicity such as
sodium chloride or dextrose. The parental preparation can be enclosed in
ampoules, disposable
syringes or multiple dose vials made of glass or plastic.
102031 It should also be understood that a specific dosage and treatment
regimen for any
particular patient will depend upon a variety of factors, including the
activity of the specific
compound employed, the age, body weight, general health, sex, diet, time of
administration, rate
of excretion, drug combination, and the judgment of the treating physician and
the severity of the
particular disease or condition being treated.
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[0204] A patient or subject in need of therapy using compounds as
described herein can
be treated by administering to the patient (subject) an effective amount of
the compound
including pharmaceutically acceptable salts, solvates or polymorphs, thereof
optionally in a
pharmaceutically acceptable carrier or diluent, either alone, or in
combination with other known
agents.
[0205] Co-administration
[0206] Disease states of conditions which may be treated using compounds
or
compositions according to the present description include, but not limited to,
for example, cancer
(e.g., prostate cancer), and Kennedy's disease. In certain embodiments, the
therapeutic or
pharmaceutical compositions comprise an effective amount of an additional
biologically or
bioactive active agent, e.g., an agent effective for the treatment of cancer,
that is co-administered.
[0207] The term "coadministration" or "combination therapy" shall mean
that at least
two compounds or compositions are administered to the patient at the same
time, such that
effective amounts or concentrations of each of the two or more compounds may
be found in the
patient at a given point in time. Although compounds according to the present
invention may be
co-administered to a patient at the same time, the term embraces both
administration of two or
more agents at the same time or at different times, provided that effective
concentrations of all
coadministered compounds or compositions are found in the subject at a given
time. In certain
preferred aspects of the present invention, one or more of the present
compounds described
above, are coadministered in combination with at least one additional
bioactive agent, especially
including an anticancer agent. In particularly preferred aspects of the
invention, the co-
administration of compounds results in synergistic therapeutic, including
anticancer therapy.
[0208] In another aspect, the description provides a composition
comprising an effective
amount of two or more of the PROTAC compounds as described herein, and a
pharmaceutically
acceptable carrier. In certain embodiments, the composition further comprises
an effective or
synergistic amount of another bioactive agent that is not a PROTAC compound.
[0209] Pharmaceutical compositions comprising combinations of an
effective amount of
at least one bifunctional compound according to the present invention, and one
or more of the
compounds otherwise described herein, all in effective amounts, in combination
with a
pharmaceutically effective amount of a carrier, additive or excipient,
represents a further aspect
of the present invention.
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[0210] The term "bioactive agent" is used to describe an agent, other
than the PROTAC
compounds described herein, which is used in combination with the present
compounds as an
agent with biological activity to assist in effecting an intended therapy,
inhibition and/or
prevention/prophylaxis for which the present compounds are used. Preferred
bioactive agents
for use herein include those agents which have pharmacological activity
similar to that for which
the present compounds are used or administered and include for example, anti-
cancer agents.
[0211] The term "additional anti-cancer agent" is used to describe an
anti-cancer agent,
which may be combined with PROTAC compounds according to the present
description to treat
cancer. These agents include, for example, everolimus, trabectedin, abraxane.
TLK 286, AV-
299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-
142886),
AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-
0457,
MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, an androgen receptor
inhibitor, a
VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1
modulator, a Bc1-2
inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk
inhibitor, an EGFR TK
inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase
inhibitors, an AKT
inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal
adhesion kinase inhibitor,
a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed,
erlotinib, dasatanib,
nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed,
azd2171,
batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan,
tesmilifene,
oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110,
BIO 140,
CC 8490, cilengitide, gimatecan, 1L13-PE38QQR, INO 1(X)1, IPdRi KRX-0402,
lucanthone,
LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr
311, romidepsin,
ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine,
doxorubicin,
liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-
304709,
seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N4442-(2-amino-
4,7-
dihydro-4-oxo-1 H - pyrrolo[2,3- d]pyrimidin-5-yDethyl]benzoy1]-, disodium
salt, heptahydrate,
camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate,
anastrazole, exemestane,
letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,
bevacizumab, IMC-
1C11, CHIR-258); 3[5-(methylsulfonylpiperadinemethyl)- indolylj-quinolone,
vatalanib, AG-
013736, AVE-0005, the acetate salt of [D- Ser(Bu t ) 6 ,Azgly 10] (pyro-Glu-
His-Trp-Ser-Tyr-
D-Ser(Bu t )-Leu-Arg-Pro- Azgly-NH 2 acetate [C541841\11804 -(C2H402)x wherein
x = 1 to 2.4],
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goserelin acetate, leuprolide acetate, triptorelin pamoate,
medroxyprogesterone acetate,
hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide,
flutamide,
nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib,
lapatanib, canertinib,
ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-
214662,
tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic
acid,
trichostatin A, FK-228, SU11248, sorafenib, KRN951 , aminoglutethimide,
arnsacrine,
anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine,
adriamycin, bleomycin,
buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin,
cladribine, clodronate,
cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin,
diethylstilbestrol, epirubicin,
fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec,
gemcitabine, hydroxyurea,
idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine,
mechlorethamine, melphalan,
6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone,
nilutamide,
octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,
procarbazine, raltitrexed,
iituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine,
thiotepa, tretinoin,
vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard,
estramustine, altretamine,
floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine,
deoxycoformycin,
calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan,
razoxin, marimastat,
COL-3, neovastat, BMS-275291 , squalamine, endostatin, SU5416, SU6668,
EMD121974,
interleukin-12, IM862, angiostatin, vitaxin, clroloxifene, idoxyfene,
spironolactone, finasteride,
cimitidine, trastuzumab, denileukin diftitox,gefitinib, bortezimib,
paclitaxel, cremophor-free
paclitaxel, docetaxel, epithilone B, BMS- 247550, BMS-310705, droloxifene, 4-
hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene,
lasofoxifene,
idoxifene, TSE-424, HMR- 3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745,
PD
184352, rapamycin, 40-0-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573,
RAD001,
ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin,
ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte
colony-
stimulating factor, zolendronate, prednisone, cetuximab, granulocyte
macrophage colony-
stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-
2a, pegylated interferon
alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide,
gemtuzumab,
hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic
acid, ketoconazole,
interleukin-2, megestrol, immune globulin, nitrogen mustard,
methylprednisolone, ibritgumomab
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tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab,
arsenic
trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal
daunorubicin, Edwina-
asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor
antagonist, palonosetron,
aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam,
alprazolam, haloperidol,
droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine,
granisetron,
ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin
alfa, darbepoetin alfa
and mixtures thereof.
[0212] Methods of Treatment
[0213] In another aspect, the disclosure provides methods of modulating
protein
ubiquitination and degradation in a subject, e.g., a cell, a tissue, mammal,
or human patient, the
method comprising administering an effective amount of a PROTAC compound as
described
herein or a composition comprising an effective amount of the same to a
subject, wherein the
compound or composition comprising the same is effective in modulating protein
ubquitination
and degration of the protein in the subject. In certain embodiments, the
protein is androgen
receptor (AR).
[0214] In certain embodiments, the description provides a method for
regulating protein
activity of the androgen receptor in a patient in need comprising
administering to said patient an
amount of a compound as described herein to a patient.
[0215] In still additional embodiments, the description provides a method
of treating a
disease state or condition in a patient wherein dysregulated protein activity
is responsible for said
disease state or condition, said method comprising administering to said
patient an effective
amount of a compound as described herein to said patient in order to regulate
said protein
activity in said patient. In certain embodiments, the protein is AR.
[0216] The terms "treat", "treating", and "treatment", etc., as used
herein, refer to any
action providing a benefit to a patient for which the present compounds may be
administered,
including the treatment of any disease state or condition which is modulated
through the protein
to which the present compounds bind. Disease states or conditions, including
cancer, which may
be treated using compounds according to the present invention are set forth
hereinabove.
[0217] In another aspect, the disclosure provides methods of modulating
AR protein
ubiquitination and degradation in a subject, e.g., a cell, a tissue, mammal,
or human patient, the
method comprising administering an effective amount of a compound as described
herein or a
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composition comprising an effective amount of the same to a subject, wherein
the compound or
composition comprising the same is effective in modulating AR protein
ubquitination and
degration of the protein in the subject.
102181 In another aspect, the disclosure provides methods of treating or
ameliorating a
symptom of a disease related to AR activity in a subject, e.g., a cell, a
tissue, mammal, or human
patient, the method comprising administering an effective amount of a compound
as described
herein or a composition comprising an effective amount of the same to a
subject in need thereof,
wherein the compound or composition comprising the same is effective in
treating or
ameliorating a symptom of a disease related to AR activity in the subject.
10219] In certain embodiments, the disease or disorder is asthma,
multiple sclerosis,
cancer, prostate cancer, Kenney's disease, ciliopathies, cleft palate,
diabetes, heart disease,
hypertension, inflammatory bowel disease, mental retardation, mood disorder,
obesity, refractive
error, infertility, Angelman syndrome, Canavan disease, Coeliac disease,
Charcot¨Marie¨Tooth
disease, Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis,
Haemophilia,
Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney
disease, (PKD1)
or 4 (PKD2) Prader¨Willi syndrome, Sickle-cell disease, Tay¨Sachs disease,
Turner syndrome.
The method according to claim 48 wherein said cancer is squamous-cell
carcinoma, basal cell
carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell
carcinomas, cancer of the
bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung,
neck, ovary, pancreas,
prostate, and stomach; leukemias; benign and malignant lymphomas, particularly
Burkitt's
lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;
myeloproliferative
diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's
sarcoma,
liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma,
gliomas,
astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,
ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,
meningiomas,
meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast
cancer, prostate
cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer,
testicular cancer, thyroid
cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer,
liver cancer, colon
cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor or
temtocarcinomas. In
certain embodiments, the disease to be treated is cancer, e.g., prostate
cancer, or Kennedy's
Disease. In a preferred embodiment, the subject is a human.
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[0220] In another aspect, the disclosure provides methods of treating or
ameliorating a
symptom of a disease related to AR activity in a subject, e.g., a cell, a
tissue, mammal, or human
patient, the method comprising administering an effective amount of a compound
as described
herein or a composition comprising an effective amount of the same and an
effective or
synergistic amount of another bioactive agent to a subject in need thereof,
wherein the
composition comprising the same is effective in treating or ameliorating a
symptom of a disease
related to AR activity in the subject. In certain embodiments, the disease to
be treated is cancer,
e.g., prostate cancer, or Kennedy's Disease. In a preferred embodiment, the
subject is a human.
In certain additional embodiments, the additional bioactive agent is an anti-
cancer agent.
[0221] In alternative aspects, the present invention relates to a method
for treating a
disease state by degrading a protein or polypeptide through which a disease
state or condition is
modulated comprising administering to said patient or subject an effective
amount of at least one
compound as described hereinabove, optionally in combination with an
additional bioactive
agent. The method according to the present invention may be used to treat a
large number of
disease states or conditions including cancer, by virtue of the administration
of effective amounts
of at least one compound described herein.
[0222] In another aspect, the disclosure provides methods for identifying
the effects of
the degradation of proteins of interest in a biological system using compounds
according to the
present invention.
[0223] Kits
[0224] In another aspect, the description provides kits comprising
compounds or
compositions as described herein. The kit may be promoted, distributed, or
sold as a unit for
performing the methods of the present invention. In addition, the kits of the
present invention
may preferably contain instructions which describe a suitable use. Such kits
can be conveniently
used, e.g., in clinical settings, to treat patients exhibiting symptoms of,
e.g., cancer or Kennedy's
Disease.
[0225] EXAMPLES
[0226] General Chemistry ¨ Analysis and Synthesis
[0227] Unless otherwise noted, all materials/reagents were obtained from
commercial
suppliers and used without further purification. Reactions were monitored by
LC-MS and/or thin
layer chromatography (TLC) on silica gel 60 F254 (0.2mm) pre-coated aluminum
foil or glass-
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backed and visualized using UV light. Flash chromatography (alternatively
called "ISCO
chromatography") was performed using an ISCO CombiFiash RF 75 PSI or
equivalent with
RediSep normal-phase silica gel cartridges. Preparative TLC was performed on
Whatman LK6F
Silica Gel 60A size 20x20 cm plates with a thickness of 1000 pm or equivalent.
[0228] 1HNMR (300 or 400 MHz) and I3CNMR (100.6 MHz) spectra were
recorded on
Bruker spectrometers at room temperature with TMS or the residual solvent peak
as the internal
standard. The line positions or multiples are given in (5) and the coupling
constants (J) are given
as absolute values in Hertz (Hz). The multiplicities in ifINMR spectra are
abbreviated as
follows: s (singlet), d (doublet), t (triplet), q (quartet), in (multiplet),
br or broad (broadened).
[0229] Preparative HPLC purifications were performed on a Waters UV-
Directed
Purification System equipped with 2545 Binary Gradient Module, 2767 Sample
Manager and
2489 UV/Visible Detector, controlled by :MassLynx V4.1 software. All
purification work was
completed using the following columns: Atlantis Prep T3 OBD Column, SunFire
Prep C18 OBD
Column and XBridge Prep Phenyl OBD Column. The mobile phases were water (with
0.1%TFA
or 0.01% NH4HCO3) and acetonitrile; all reagents used were of HPLC grade. The
flow rate was
30m1imin. After the columns, a 1:1000 LC packings flow splitter allowed
transfer of a small
portion of the eluent into the UV detector. The electrospray source was set at
3.0 kV capillary
voltage, 30 V conevoltage, 110 C source temperature, 350 C desolvation
temperature, 600L/h
desolvation gas flow, and 60L/h cone gas flow. For the analyzer, the
multiplier was set at 550
for preparative tune method.
[0230] Analytical LC-MS data was collected on a Shimadzu LCMS-2020 with a
mobile
phase of 0.05% TFA in Acetonitrile (A) and 0.05% TFA in HPLC grade water (B);
0.1% FA in
Acetonitrile (A) and 0.1% FA in HPLC grade water (B); Acetonitrile (A) and 5
mM ammonium
bicarbonate in HPLC grade water (B).
[0231] Shimadzu LCMS-2020 equipped with LC-20AD or 30AD pumps, SPD-M20A
PDA and Alltech 3300 ELSD. The system uses the following conditions for 2.0
min, 2.6 min, 3
mm, 3.6 mm, 5 min or 5.6 min run time.
[0232] 2.0 minute run: Kinetex XB-C 18 100A column, 2.6 pm, 3.0x 50 mm.
The flow
rate is 1.5 mUmin, the run time is 2.0 min, and the gradient profiles are 0.01
min 10% A, 1.10
min 100% A, 1.60 min 100% A, 1.70 min 10% A, 2.00 min 10% A.
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[0233] 2.6 minute run: Shim-pack VP-ODS column, 2.2 pm, 3.0x 50 mm. The
flow rate
is 1.5 mL/min, the run time is 2.6 min, and the gradient profiles are 0.01 min
5% A, 1.20 inin
100% A, 2.20 mm 100% A, 2.30 min 5% A, 2.60 min 5% A.
[0234] 3.0 minute run: ACE UltraCore Super C18 column, 2.5 pm, 3.0x 50
mm. The
flow rate is 1.5 mL/min, the run time is 3.0 min, and the gradient profiles
are 0.01 min 10% A,
2.00 min 95% A, 2.60 min 95% A, 2.70 min 10% A, 3.00 mm 10% A.
[0235] 3.6 minute run: Shim-pack VP-ODS column, 2.2 pm, 3.0x 50 mm. The
flow rate
is 1.5 mL/min, the run time is 3.6 min, and the gradient profiles are 0.01 min
5% A, 2.20 min
100% A, 3.20 min 100% A, 3.30 mm 5% A, 3.60 mm 5% A.
[0236] 5.0 minute run: ACE UltraCore Super C18 column, 2.5 pm, 3.0x 50
mm. The
flow rate is 1.5 mL/min, the run time is 5.0 min, and the gradient profiles
are 0.01 min 10% A,
4.00 mm 60% A, 4.70 min 60% A, 4.80 mm 10% A, 5.00 min 10% A.
[0237] 5.6 minute run: Shim-pack VP-ODS column, 2.2 pm, 3.0x 50 mm. The
flow rate
is 1.5 mL/min, the run time is 5.6 mm, and the gradient profiles are 0.01 min
5% A, 3.00 min
50% A, 5.00 mm 50% A, 5.20 min 5% A. 5.60 min 5% A
[0238] Alternatively, analytical LC-MS data was collected on Agilent
infinity 1260 LC,
Agilent 6230 TOF mass spectrometer. The analysis is conducted on a Poroshell
120 EC C18
column (50mm x 3.0mm internal diameter 2.7 m packing diameter) at 45 C.
[0239] The solvents employed are:
[0240] A = 0.1% v/v solution of formic acid in water.
[0241] B = 0.1% v/v solution of formic acid in acetonitrile.
[0242] The gradient employed are as follows:
[0243] Table 1. Exemplary Column Gradients.
Time Flow Rate
%A %H
(minutes) (mL/min)
0 1 95 5
0.5 1 95
3.0 1 1 99
4.0 1 1 99
4.1 1 95 5
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4.5 1 95 5
[0244]
[0245] The UV detection is an averaged signal from wavelength of 210nm to
350nm and
mass spectra are recorded on a mass spectrometer using positive mode
electrospray ionization.
[0246] Unless otherwise noted, all compounds were prepared with LC-MS
purity >95%.
[0247] Chemical Synthesis
[0248] A PROTAC of ABM-L-ULM, or their pharmaceutically acceptable salts,
polymorphic forms, prodrugs, solvate forms and isotope containing derivatives
thereof, may be
prepared by the general approaches described below (scheme 3-4), together with
synthetic
methods known in the art of organic chemistry, or modifications and
derivatizations that are
familiar to those of ordinary skill in the art.
[0249] Scheme 3:
RG2
411111 RG3
ULM HRG4 ________________________________________________
tatermediate L
ABM ¨RG' ........ 40. ABM <7>RG3 ------------- 4- ABM ___ L ULM
Stage I Stage 2
Scheme 3
[0250] Scheme 4:
RG2
MP RG3
RG2 ABM ___ I-RG1
intermedtate L
ULM ¨RG4 -- ----------- C- ULM FE-1117 ULM
Stage 1 Stage 2
Scheme 4
10251] More specifically, The compounds of the Formula I. or their
pharmaceutically
acceptable salts, may be prepared by the general approaches described below
(scheme 5-6),
together with synthetic methods known in the art of organic chemistry, or
modifications and
derivatizations that are familiar to those of ordinary skill in the art.
[0252] Scheme 5:
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RG2
y2 R'
Y2 RI ).....A.,R2
W2
0 )r-N co ..
Yql ----
!Wei-mediate I.
Stage 1 . CO N' ril
V'
RG1
Intermediate A
P
eR)....
RG4
CP) ,N X>,.....\2
X1
LI.N.4) N' , ,2 RI R2 RP
Intermediate V 1.--r 413=-= 2
.. CO 171:-.)- __ 0 xi,N X0
Stage 2 gl
Formula I
Scheme 5
[0253] Scheme 6:
RG2
Ro
cri., ,
RG4 4.1-,
...
0 Intermediate L It..D 0
X1
QV Stage 1 .. .- X'
(7,0)
intermediate V
R r.p2
RG1 &P
Intermediate A
.......................... ''' '?4-- 0 41111.0 0 ,N X2
Stage 2 X' CI
Formula I
Scheme 6
[0254] In schemes 3-6, L, ABM, ULM groups, WI, W2, vv3, ve, xl, )(2, yl,
y2, RI, R2,
and RP are as define above. RG1, RG2, RG3 and RG4 are moieties with suitable
reacting groups
that would be necessary to enable the synthetic chemistry to connect
intermediate A,
intermediate L and intermediate V together into PROTAC compounds of Formula I
via covalent
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bond formation chemistries. These chemistries, depends on specific reacting
groups, include but
not limited to, amide formation, ester formation, carbamate formation, urea
formation, ether
formation, amine formation and various C-C, C=C bond formation. The stage 1
and stage 2
transformations in scheme 5 and scheme 6 may involve 1 or multiple synthetic
steps. These are
routine methods known in the art such as those methods disclosed in standard
reference books
such as the Compendium qf Organic Synthetic Methods, Vol. 1-VI (Wiley-
lnterscience); or the
Comprehensive Organic Transformations, by R.C. Larock (Wiley-lnterscience).
Unless
otherwise indicated, the substituents in the schemes are defined as above.
Isolation and
purification of the products is accomplished by standard procedures, which are
known to a
chemist of ordinary skill.
[0255]
In certain examples, for the chemistry described in schemes 3-6. RG is a
moiety
with a suitable nucleophile such as -OH and RG2 is a moiety with a suitable
leaving group such
as halogen, -OMs, or ¨0Ts. In a typical procedure, a RG1 containing
intermediate is reacted with
a RG2 containing intermediate in a suitable solvent. Suitable solvents
include, but are not limited
to, water, ethers such as THF, glyme, and the like; chlorinated solvents such
as DCM, 1,2-
dichloroethane (DCE) or CHCI3 and the like, toluene, benzene and the like,
DMF, DMSO,
MeCN. If desired, mixtures of these solvents are used. A base may be added to
the reaction to
facilitate the reaction. Suitable bases include, but are not limited to,
Cs2CO3, K2CO3, and the
like. The above process may be carried out at temperatures between about -78
C and about
150 C. Preferably, the reaction is carried out between about 20 C and about
120 C.
[0256] In another example, chemistry described in in schemes 3-6, RG3 is
a moiety
contains a ¨COOH group and RG4 is a moiety contains a suitable amine group. In
a typical
procedure, a RG3 containing intermediate is reacted with a RG4 containing
intermediate in a
suitable solvent in the presence of a suitable amide coupling reagent.
Suitable solvents include,
but are not limited to, water, ethers such as THF, glyme, and the like;
chlorinated solvents such
as DCM, 1,2-dichloroethane (DCE) or CHC13 and the like, toluene, benzene and
the like, DMF,
DMSO, MeCN. If desired, mixtures of these solvents are used. In this case, the
preferred
solvents are DMF or DCM. A suitable amide coupling reagent include, but are
not limited to,
DCC, EDC, HATU, HBTU, PyBOP and the like. A base is often added to the
reaction. Suitable
bases include, but are not limited to, TEA, DIPEA, and the like. The above
process may be
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carried out at temperatures between about -78 C and about 150 C. Preferably,
the reaction is
carried out between about 0 C and about 100 C.
[0257] Although not explicitly shown in schemes 3-6, a chemist of
ordinary skill would
realize that during any of the synthetic sequences it may be necessary and/or
desirable to protect
sensitive or reactive groups on any of the molecules concerned. This can be
achieved by means
of conventional protecting groups, such as those described in T.W. Greene,
Protective Groups in
Organic Chemistry, John Wiley & Sons (1981); T.W. Greene and P.G.M. Wuts,
Protective
Groups in Organic Chemistry, John Wiley & Sons (1991), and T.W. Greene and
P.G.M. Wuts,
Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are
hereby
incorporated by reference in their entireties.
[0258] When a general or exemplary synthetic procedure is referred to,
one skilled in the
art can readily determine the appropriate reagents, if not indicated,
extrapolating from the
general or exemplary procedures. Some of the general procedures are given as
examples for
preparing specific compounds. One skilled in the art can readily adapt such
procedures to the
synthesis of other compounds. Representation of an unsubstituted position in
structures shown or
referred to in the general procedures is for convenience and does not preclude
substitution as
described elsewhere herein. For specific groups that can be present, either as
R groups in the
general procedures or as optional substituents not shown, refer to the
descriptions in the
remainder of this document, including the claims, summary and detailed
description.
[0259] The process to produce compounds of the present invention is
preferably carried
out at about atmospheric pressure although higher or lower pressures can be
used if desired.
Substantially equimolar amounts of reactants are preferably used although
higher or lower
amounts can also be used.
[0260] The compounds of Formulae II-IV (below), or their pharmaceutically
acceptable
salts, may be prepared by the methods similar to chemistry illustrated above
for synthesis of
compounds of Formula I (scheme 3-6), together with synthetic methods known in
the art of
organic chemistry, or modifications and derivatizations that are familiar to
those of ordinary skill
in the art:
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r").....RP
YLR1 Xl-N R 0
0 NI 74 R.: N
R H sm. x,.NR-fe
____________________________ CP Rd
Formula III
Formula II ; and
Rb 0
g ,x2
0 R. ri 4M 'AO
Rd
Formula IV
[0261] For compounds of Formulae II-IV, L, ABM, ULM groups, WI, W2, W3,
W4,
X2, 111, Y.2, RI, R2, RP, Ra, Rb, 12 and Rd are as define above.
[0262] In certain embodiments, ABM compounds are active without forming
bifunctional compounds of formular II-TV.
[0263] Synthesis of ABM Moieties
[0264] ABM-1: 2-chloro-4-(3-(4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
thioxoimidazolidin-1-yl)benzonitrile
\N
CI 1-est
CI NH 2 crACI NCS ON _b....Nr..1¨
N C . NC ytt
NC SteP I NC Step 2
11"-IP OH
A
Cl
Step 3r NC =µ,14
g p
OH
[0265] ABM-1
[0266] Step 1: Synthesis of 2-chloro-4-isothiocyanatobenzonitrile (B).
[0267] To a stirred solution of 4-amino-2-chlorobenzonitrile (A, 1 g,
6.55 mmol) in
dichloromethane (9 mL) was added sodium bicarbonate (2.21 g, 26.31 mmol) and
water (9 mL).
The resulting mixture was cooled to 0 C, to which thiophosgene (817 mg, 7.11
mmol) was
added in drop wise in 30 min at 0 C. The resulting mixture was then warmed up
to room
temperature and stirred at room temperature for 1 hour. The reaction mixture
was diluted with
dichloromethane (200 mL), washed with brine (50 mL x 2), dried over anhydrous
sodium sulfate
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and then concentrated under reduced pressure to give a crude residue. The
residue was purified
by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:
v = 1: 30)) to give
desired product (yield: 71%) 1HNMR (400 MHz, CDC13): 8 7.69 (d, J= 8.0 Hz,
1H), 7.38 (s,
1H), 7.28 (m, 1H);
10268] Step 2: Synthesis of 2-chloro-443-(4-hydroxypheny1)-5-imino-4, 4-
dimethy1-2-
sulfanylideneimidazolidin-l-yl]benzonitrile (D).
[0269] To a stirred solution of 2-chloro-4-isothiocyanatobenzonitrile (B,
399 mg, 2.05
mmol) in toluene (5 mL) was added 2-[(4-hydroxyphenyDamino[-2-
methylpropanenitrile (C,
300 mg, 1.70 mmol) and 4-dimethylaminopyridine (312 mg, 2.55 mmol). The
resulting solution
was then heated in an oil bath to 100 C and stirred at the same temperature
for 16h. LC-MS
indicated formation of the desired product. The reaction mixture was
concentrated under vacuum
to give a crude reside which was purified by flash silica gel chromatography
(eluent: ethyl
acetate/petroleum ether (v: v =1:1)) to give desired product (yield: 48%) as a
brown solid. LC-
MS (ES): nt/z 370.95 [M H+], tR =0.74 min (2.0 minute run);
[0270] Step 3: Synthesis of 2-chloro-4-[3-(4-hydroxypheny1)-4,4-dimethyl-
5-oxo- 2-
sulfanylideneimidazolidin-1-yl[benzonitrile (ABM-1).
[0271] To a stirred solution of 2-chloro-443-(4-hydroxypheny1)-5-imino-4,
4-dimethy1-
2-sulfanylideneimidazolidin-1-Abenzonitrile (D, 300 mg, 0.81 minol) in
methanol (6 mL) was
added aqueous hydrogen chloride (2N, 3.0 mL). The resulting solution was then
heated in an oil
bath to 100 C and stirred at the same temperature for 2h. The reaction
mixture was diluted with
water (30 mL), extracted with ethyl acetate (60 mL x 3), washed with water (50
mL), dried over
anhydrous sodium sulfate and concentrated under vacuum to give titled product
(yield: 93%) as a
yellow solid, which was used for the next step without any further
purifications. LC-MS (ES+):
m/z 372.00 [MHI, tR =0.97 min (2.0 minute run).
10272] Unless otherwise noted, the following intermediates and their
analogs (for
examples, but not limited to, analogs with substitutions such as halogens)
were synthesized
according to similar procedures described above for the synthesis of ABM-1, by
utilizing
corresponding starting materials and reagents.
10273] ABM-2: 2-fluoro-4-(3-(4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
thioxoimidazolidin-1-yl)benzonitrile:
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czµ
NC N N
I SO
OH
ABM-2
[0274] ABM-3: 4-(3-(4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
thioxoimidazolidin-1-
y1)-2-(trifluoromethyObenzonitrile:
F3c %
411 Nr1
NC
)N
Sr 1.1
OH
ABM-3
14)275] ABM-4: 5-(3-(4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
thioxoimidazolidin-l-
y1)-3-(trifluoromethyl)picolinonitrile:
%
N¨
S
-OH
ABM-4
[0276] ABM-5: 4-(3-(4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
thioxoimidazolidin-l-
y1)-2-methoxybenzonitrile:
c),\
Me0
NC 4fit N N
r
s
ABM-5
10277] ABM-6: 4-(3-(4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
thioxoimidazolidin-1-
y1)-2-methylbenzonitrile:
cz\
NC it N N
)r-
s
- -OH
ABM-6
[0278] ABM-7: 3-chloro-5-(3-(4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
thioxoimidazolidin-l-yl)picolinonitrile:
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o\\
ci
_b¨Nr1
NC N
N
41" OH
ABM-7
[0279] ABM-8: 441-(4-hydroxypheny1)-4-axo-2-th ioxo-8-oxa- I 3-
diazaspira[4.5]decan-3-y1)-2-(trifluoromethyl)benzonitrile:
F3C
NC r N 41,kb
S
OH
ABM-8
[0280] ABM-9: 4-(1-(4-hydroxypheny1)-8-methyl-4-oxo-2-thioxo-1,3,8-
triazaspiro[4.5]decan-3-y1)-2-(trifluoromethyl)benzonitrile:
O\\ r'N\/
F3C
NC NIT/
s
OH
ABM-9
[0281] ABM-10: 4-(5-(4-hydroxypheny1)-8-oxe-6-thioxo-5,7-
diazaspiro[3.4]octan-7-
y1)-2-(trifluoromethyl)benzonitrile
F3c
NC = I\11 r\,4
s
ABM-10
[0282] ABM-11: 5-(5-(4-hydroxyphenyI)-8-oxo-6-th ioxo-5,7-diazaspi
ro[3.4locta n-7-
y1)-3-(trifluoromethyl)picolinonitrile:
F3c
NC
N¨
SOH
ABM-11
10283] ABM-12: 4-(4-(3-(4-cyano-3-(trifluoromethyl)pheny1)-5,5-dimethyl-4-
oxo-2-
thioxoimidazolidin-1-yl)phenyl)butanaic acid:
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F F Ot_ y
N= Ni
ABM-12 OH
10284] ABM-13: 2-chloro-4-(3-(4'-hydroxybipheny1-4-y1)-4,4-dimethy1-5-oxo-
2-
thioxoimidazolidin-1-yl)benzonitrile:
NC N N
SL
ABM-13
OH
[0285] ABM-14: 4-(3-(4'-hydroxybipheny1-4-y1)-4,4-dimethy1-5-oxo-2-
thioxoimidazolidin-1-y1)-2-(trifluoromethyl)benzonitrile:
F3c
NC N N
)Sr 1.1 rah
ABM-14
LWP OH
=
[0286] ABM-15: 5-(3-(4'-hydroxybipheny1-4-y1)-4,4-dimethyl-5-oxo-2-
thioxoimidazolidin-l-y1)-3-(trifluoromethyl)picolinonitrile:
\
F3c R
\ 7-1
NC N'
\,-N
g
ABM-15
OH
10287] ABM-16: 4-(3-(3-fluoro-4-hydroxypheny1)-4,4-dimethy1-5-oxo-2-
thioxoimidazolidin-1-y1)-2-(trifluoromethyDbenzonitrile:
o,\
F3c
7-1¨
NC N N F
OH
ABM-16
102881 ABM-17: 1-(4-hydroxypheny1)-5,5-dimethy1-3-(4-nitro-3-
(trifluoromethyl)pheny1)-2-thioxoimidazolidin-4-one:
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F3c 0µ\
ON =NN
OH
ABM-17
10289] ABM-18: 4-(3-(3,5-dill noro-4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
thioxoimidazolidin-1-y1)-2-(trifluorolt lethyl)benzoni trite:
\\
F3c 0
N7-1¨
NC N
t
OH
ABM-18
[0290] ABM-19: 4-(3-(4-hydroxypheny1)-4,4-dimethy1-2,5-dioxohnidazolidin.
l-371 )-2-
(trifluoromethyl)benzonitrile:
\µ
F3c ci
NC NN 40
OH
ABM-19
[0291] ABM-20: 4-(3-(6-hydroxypyridin-3-y1)-4,4-dimethy1-5-oxo-2-
thioxoimidazolidin-1-y1)-2-(trifluoromethyl)benzonitrile:
F3C ox\
NC-\/
g
N OH
ABM-20
10292] ABM-21: 2-chloro-4-(3-(3-fluoro-4-hydroxypheny1)-4,4-dimethy1-5-oxo-
2-
thioxoimidazolidin-1-Abenzonitrile:
cl,\
CI
7-1
NC NiN OF
OH
ABM-21
102931 ABM-22: 4-(3-(3-fluoro-4-hydroxypheny1)-4,4-d imethy 1-5-oxo-2-
thioxo tl azolidin-1-y1)-2-methoxybenzonitrile:
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Met) 0\\,_
Nct)¨N/
=IT-N ash, F
'11P OH
ABM-22
10294] ABM-23: 5-(3-(3-fluoro-4-hydroxypheny0-4,4-dimethy1-5-oxo-2-
thioxoimidazolidin-l-y1)-3-(trifluorovziethyl)picolinonitrile:
F3C
N¨ N
OH
ABM-23
[0295] ABM-24: 5-(3-(2-fluoro-4'-hydroxybipheny1-4-y1)-4,4-dimethyl-5-oxo-
2-
thioxoimidazolidin-l-y1)-3-(trifluoromethyDpicolinonitrile:
0
F,c
N¨ N
ABM-24
OH
[0296] ABM-25: 4-(4,4-dimethy1-5-oxo-344-(piperidin-4-yl)pheny1)-2-
thioxoimidazolidin-l-y1)-2-(trifluoromethyDbenzonitrile:
(:),µ
F.,3C
NC "1rN
ABM-25 NH
[0297] ABM-26: trans-2-Chloro-443-amino-2,2,4,4-
tetramethylcydobutoxylbenzonitrile.
0.. NH2
ci 44Ik
r4
[0298] ABM-27: cis-2-Chloro-4-13-amino-2,2,4,4-
tetramethylcyclobutoxylbenzonitrile
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0 NH2
+
cl II
N
[0299] ABM-28: trans 6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]pyridazine-3-carboxamide
vss, ..\#'42:isitssiotz
0, ==,*# \ 1
..,...c A.
/1
d'
[0300] ABM-29: trans tert-Butyl N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]carbamate.
oa-
0...NH
//
N
10301] ABM-30: trans 4-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]benzamide
J
,.. y..-.., 0
r4
0-A1
[0302] Step 1: Synthesis of tert-butyl (4-((trans-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)carbamoyl)phenyl)carbamate.
[0303] A suspension of 4-((tert-butoxycarbonyl)amino)benzoic acid (1.50
g, 6.34 mmol)
in methylene dichloride (40 mL) was charged with.NN-diisopropylethylamine
(3.30 mL, 19.0
mmol), followed by 4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-
chlorobenzonitrile
hydrochloride (2.0 g, 6.34 mmol). The mixture was stirred for several minutes
and then charged
with HATU (2.41 g, 6.34 mmol). The reaction mixture was allowed to stir at
room temperature
for 2 hours. The mixture was diluted with methylene dichloride (40 mL), washed
with aqueous
IN HCl (2 x), saturated aqueous sodium bicarbonate (2 x), brine, and dried
over anhydrous
Na2SO4. The crude product was used in next step;
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10304] Step 2: Synthesis of trans 4-Amino-N-[3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobutyl]benzamide.
10305] 4M HC1 in Dioxane (1.38 mL, 40.0 mmol) was added to a pre-mixed
solution of
tert-butyl (4-((trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl)carbamoyl)phenyl)carbamate (2.00 g, 4.01 mmol) in Me0H
(2 mL) and
left to stir at room temperature for 1 hour till completion. The reaction
mixture was concentrated
in vacuo to a solid, which was dissolved with 5% Me0H in DCM. The organic
layer was washed
with sodium bicarbonate (2 x), filtered through a Biotage Universal Phase
Separator and then
concentrated in vacuo to a solid. The crude product was recrystallized from
Et0H/Heptanes to
afford the desired product as a white solid, 1.2 g, 75% yield. 114 NMR (400
MHz,
METHANOL-d4) 8 7.72 (d, i . 8.80 Hz, 1H), 7.61 (d, J = 8.61 Hz, 2H), 7.13 (d,
J = 2.35 Hz,
1H), 6.98 (dd, J = 2.45, 8.71 Hz, 1H), 6.69 (d, J = 8.61 Hz, 2H), 4.28 (s,
1H), 4.12 (s, 1H), 1.27
(s, 6H), 1.22 (s, 6H). LC-MS (ES+): m/z 398.16/400.15 [MHI.
[0306] Unless otherwise noted, the following intermediates and their
analogs (for
examples, but not limited to, analogs with substitutions such as halogens)
were synthesized
according to similar procedures described above for the synthesis of ABM-30,
by utilizing
corresponding starting materials and reagents.
10307] ABM-31: trans 5-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]pyrazine-2-carboxamide
<\.....
,
k i
d ,4
[0308] ABM-32: trans 2-Amino-N-I3-(3-chloro-4-cputophenoxy)-2,2,4,4-
tetramethylcyclobutyl]pyrimidine-5-carboxamid
,....: z..,,,
e '
[0309] ABM-33: 4-Methoxy-N-R1r,30-343-chlora-4-cyanophenoxy)-2,2,4,4-
tetrarnethylcydobutyllbenzamide
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/-*"`¨\õ,,=51
=''''=
103101 ABM-34: trans 1 -(2-Hydroxyethyl)-N-[3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyc1obutyll-IH-pyrazole-4-earboxamide
o¶ =0'
A
[0311] ABM-35: trans 6-Amino-N-I3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcydobutyllpyridine-3-carboxamide.
4>===I'M
< ====,'
sssse
10312] ABM-36: trans 4-[(5-Hydroxypentyl)amino]-N13-(3-chloro-4-
cyanophenoxy)-2,2,4,4-tetramethylcydobutyllbenzamide
10313] ABM-37: trans tert-Butyl 24(5-[(4-([3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobutyl]carbamoyl)phenyl)aminopentylioxy)acetate
0
=
[0314] ABM-38: tert-butyl trans-(3-(3-chloro-4-cyanophenoxy)-2,2-
dimethylcyclobutyl)carbamatel and ABM-39: tert-butyl cis-(3-(3-chloro-4-
cyanophenoxy)-
2,2-dimethylcyclobutyl)carbamate.
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40
tBuOK, THE 40 8 ottNH2OH.HCI
A B TEA,MeCN OBn Na0Ac,Et0I-1
r.t.,1.5 hours
BecHNtt
M-A Alloy H2N
Boc20,THE,1 hBocHNtt
Pd/C, H2
Na0H,60 C 95% OH
OBn
2 hours OBn OBn
CI ipOt.. NHBoc 0,.= = ,N1F-1Boc
NC
-=-= CI CI
NaH,DMF,
0 C NC NC
ABM-38 ABM-39
[0315] Step 1: Synthesis of ((vinyloxy)methyl)benzene (B).
[0316] To a stirred solution of potassium tert-butanolate (A) (23 g, 205
mmol) in
tetrahydrofuran (120 ml) was added ((2-bromoethoxy)methyl)benzene (30 g, 140
mmol) in
tetrahydrofuran (70 ml) at 0 C. The resulting mixture was allowed to warm to
room temperature
and stirred for 3 hours. TLC showed the reaction was complete. The mixture was
partitioned
between anhydrous dichloromethane (300 ml) and water (100 m1). The organic
layer was
collected, washed with brine (100 ml), dried over anhydrous sodium sulfate,
and concentrated
under reduced pressure to afford crude ((vinyloxy)methyl)benzene (14.8 g,
yield 80%) as
colorless oil. 1H NMR (400 Hz, CDC13): 5 4.09 (dd,J= 2.0, 6.8 Hz, 1H), 4.29-
4.33 (in, 1H),
4.77 (s, 2H), 6.54-6.60 (m, 1H), 7.28-7.39 (m, 5H). Chemical Formula: C9H100;
Molecular
Weight: 134.18.
10317] Step 2: Synthesis of 3-(benzyloxy)-2,2-dimethylcyclobutanone (C).
[0318] To a stirred solution of benzyl vinyl ether (2 g, 15.2 mmol) and
triethylamine (1.3
ml, 9.2 mmol) in anhydrous acetonitrile (6 ml) was added slowly a solution of
isobutyryl
chloride (0.8 ml, 7.6 mmol) in dry acetonitrile (3 ml) at reflux. The
resulting mixture was
refluxed for 0.5 hour. TLC showed the reaction was complete. The reaction
mixture was allowed
to cool to room temperature and partitioned between ethyl acetate (30 ml) and
water (20 ml). The
organic layer was collected, and the aqueous layer was extracted with ethyl
acetate (20 ml x 2).
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The combined organic layers were washed with brine (20 ml), dried over
anhydrous sodium
sulfate, and concentrated under reduced pressure to afford a crude residue
which was purified by
silica gel flash chromatography (eluted with 5-10% ethyl acetate in hexane) to
afford 3-
(benzyloxy)-2,2-dimethylcyclobutanone (1.5 g, yield 50%) as colorless oil. 1H
NMR (400 Hz,
CDC13): 8 1.19 (s, 3H), 1.26 (s, 3H), 3.08-3.24 (m, 2H), 3.96-3.99 (m, 1H),
4.55 (s, 2H), 7.29-
7.39 (m, 5H). Chemical Formula: CI3H1602; Molecular Weight: 204.26.
[0319] Step 3: Synthesis of 3-(benzyloxy)-2,2-dimethylcyclobutanone oxime
(D)
10320] To a solution of hydroxylamine hydrochloride (3.0g, 44.1 mmol) in
ethanol (100
ml) was added 3-(benzyloxy)-2,2-dimethylcyclobutanone (7.5 g, 36.7 mmol) and
sodium acetate
trihythate (6.5 g, 47.7 mmol). The resulting mixture was stirred at room
temperature for 2 hours.
TLC showed the reaction was complete. The volatiles were evaporated under
reduced pressure.
The residue was taken up in ethyl acetate (80 ml) and water (50 ml). The
organic layer was
collected, and the aqueous layer was extracted with ethyl acetate (50 ml x 2).
The combined
organic layers were washed with brine (50 ml), dried over anhydrous sodium
sulfate, and
concentrated under reduced pressure to give crude 3-(benzyloxy)-2,2-
dimethylcyclobutanone
oxime (8.3 g, crude) as colorless oil which was used in next step without
further purification.
LC_MS: (ES): m/z 220.2 [M+H]. tR = 2.550 min.
103211 Step 4: Synthesis of 3-(benzyloxy)-2,2-dimethylcyclobutanamine (E)
[0322] To a solution of 3-(benzyloxy)-2,2-dimethylcyclobutanone oxime
(8.3 g, crude) in
tetrahydrofuran (75 ml) was added Ni/A1 alloy (13.3 g, 155 mmol) under
nitrogen atmosphere.
The suspension was stirred at 60 C for 30 minutes. To the resulting mixture
was added aqueous
sodium hydroxide solution (6.9 g in 75 ml water, 172 mmol) dropwise to keep
the mixture
refluxing. After addition, the mixture was refluxed for another 2 hours. TLC
showed the reaction
was complete. The solid was removed through filtration and the filter cake was
washed with
tetrahydrofuran (10 ml x 2). The organic layer was separated, and the aqueous
layer was
extracted with ethyl acetate (75 m1). The combined organic layers were washed
with brine (50
ml) and dried over sodium sulfate and concentrated to give 3-(benzyloxy)-2,2-
dimethylcyclobutanamine (6.3 g, crude) as colorless oil. The crude product was
used in next step
without further purification. IHNMR shows it was a mixture of trans/cis
isomers (ratio: cis:
trans: 1:1). LC_MS: (ES): m/z 206.3 [M+11]+. tR = 1.675 min. I HNMR (400MHz,
CDC13):
Trans isomer: 8 1.01 (s, 3H), 1.11 (s, 3H), 2.22-2.28 (m, 1H), 2.44-2.53 (m,
1H), 3.11-3.14 (m,
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1H), 3.73-3.75 (m, 1H), 4.39-4.74 (m, 2H), 7.25-7.36 (m, 5H). Cis isomer: 8
1.02 (s, 31-1), 1.11
(s, 3H), 1.57-1.62 (m, 1H), 1.80-1.86 (m, 11-1), 2.58-2.65 (in, 1H), 3.41-3.45
(m, 1H), 4.39-4.74
(m, 2H), 7.25-7.36 (m, 5H). Chemical Formula: C13H0N0; Molecular Weight:
205.30.
[0323] Step 5: Synthesis of tert-butyl (3-(benzyloxy)-2,2-
dimethylcyclobutyl)carbamate
(F).
103241 To a stirred solution of 3-(benzyloxy)-2,2-dimethylcyclobutanamine
(6.3 g,
crude) in tetrahydrofuran (70 ml) was added di-tert-butyl dicarbonate (7 nil,
30.7 mmol) slowly
at room temperature. The reaction mixture was stirred at room temperature for
1 hour. TLC
showed the reaction was complete. The volatiles were removed under reduced
pressure to give a
crude residue which was purified by silica gel flash chromatography (eluted
with 5-10% ethyl
acetate in hexane) to afford tert-butyl (3-(benzyloxy)-2,2-
dimethylcyclobutyl)carbamate (6.0 g,
yield 53% over 3 steps) as colorless oil. LC_MS: (ES): nilz 306.2 [M+H]. tR =
3.167 min.
[0325] Step 6: Synthesis of tert-butyl (3-hydroxy-2,2-
dimethylcyclobutyl)carbamate
(G).
103261 A mixture of tert-butyl (3-(benzyloxy)-2,2-
dimethylcyclobutyl)carbamate (6.3 g,
20.6 mmol) and palladium on carbon (10%, 700 mg) in methanol (110 ml) was
stirred at room
temperature overnight under hydrogen atmosphere (hydrogen balloon). TLC showed
the reaction
was complete. Palladium on carbon was removed through filtration and the
filter cake was
washed with methanol (25 ml x 2). The combined filtrates were concentrated
under reduced
pressure to afford tert-butyl (3-hydroxy-2,2-dimethylcyclobutyl)carbamate (4.5
g, yield 95%) as
white solid.1HNMR shows it was a mixture of trans/cis isomers (ratio: - 1:1).
IHNMR
(400MHz, CD3OD): Trans isomer: 60.95 (s, 3H), 1.08 (s, 3H), 1.45 (s, 9H), 2.07-
2.19 (m, 1H),
2.43-2.50 (in, 1H), 3.61-3.65 (m, 1H), 3.82-3.85 (m, 1H). Cis isomer: 60.91
(s, 3H), 1.13 (s,
3H), 1.45 (s, 9H), 1.72-1.79 (m, 1H), 2.43-2.50 (m, 1H), 3.35-3.38 (m, 1H),
3.69-3.73 (m, 1H).
Chemical Formula: C11H21NO3; Molecular Weight: 215.29.
[0327] Step 7: Synthesis of tert-butyl trans-(3-(3-chloro-4-cyanophenoxy)-
2,2-
dimethylcyclobutyl)carbamate (ABM-38) and tert-butyl cis-(3-(3-chloro-4-
cyanophenoxy)-2,2-
dimethylcyclobutyl)carbamate (ABM-39).
103281 To a stirred solution of tert-butyl (3-hydroxy-2,2-
dimethylcyclobutyl)carbamate
(280 mg, 1.29 mmol) in N,N-dimethylformamide (6 ml) was added sodium hydride
(60% in
mineral oil, 103 mg, 2.58 mmol) at 0 C. The mixture was stirred at 0 C for 0.5
hour, followed by
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addition of 2-Chloro-4-fluorobenzonitrile (200 mg, 1.29 mmol); the resulting
mixture was stirred
at 0 C for 1 hour. TLC showed the reaction was complete. The reaction mixture
was quenched
with water (3 nil) at 0 C and extracted with ethyl acetate (5 ml x 3). The
combined organic
layers were washed with brine (15 ml), dried over anhydrous sodium sulfate,
and concentrated
under reduced pressure to afford a crude residue which was purified by silica
gel flash column
chromatography (eluted with 20% tert-Butyl methyl ether in hexane) to afford
ABM-38 (110
mg, yield 26%) as white solid and ABM-39 (120 ing, yield 26%) as white solid.
ABM-38:
LC_MS: (ES): m/z 351.2 [M+H]. tR = 3.222 min. 1HNMR (400MHz, CDC13): 8 1.15
(s, 3H),
1.18 (s, 3H), 1.45 (s, 9H), 2.17-2.24 (m, 1H), 2.39-2.46 (m, 1H), 3.96-4.07
(m, 1H), 4.29-4.32
(m, 1H), 4.59-4.67 (m, 1H), 6.75 (dd, J. 2.4, 8.8 Hz, 1H), 6.89 (d, J= 2.0 Hz,
1H), 7.54 (d, .1=
8.8 Hz, 1H). Chemical Formula: C18H23C1N203; Molecular Weight: 350.84. ABM-39:
LC_MS:
(ES+): m/z 351.2 [M+H]. tR = 3.173 min. 1HNMR (400MHz, CDC13): 8 1.03 (s, 3H),
1.32 (s,
3H), 1.45 (s, 9H), 1.80-1.87 (m, 1H), 2.79-2.86 (m, 1H), 3.64-3.72 (m, 1H),
4.16-4.20 (m, 1H),
4.57-4.59 (m, 1H), 6.77 (dd, J= 2.0, 8.8 Hz, 1H), 6.89 (d, J= 2.4 Hz, 11-1),
7.54 (dõ/. 8.4 Hz,
1H). Chemical Formula: CI8H23C1N203; Molecular Weight: 350.84.
[0329] The experimental procedure used to make ABM-30, may be used to
synthesize
the free amine, which is used for further coupling.
10330] Synthesis of ULM Moieties
[0331] ULM-1: (2S,4R)-14(S)-2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-
(4-
methylthiazol-5-yObenzyl)pyrrolidine-2-carboxamide
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NC-0¨Br F
' NC Li N
A1
Pc1(0Ac)2, KOAc 10, 114 "2" .4*
Sj
Step 2
Step 1
HQ,
S
N
I HO,
60c 0 N =
HCI 10 s
HATU, DIEA OMF r rH H
Step 4
J HCI o K
Step 3
*.k),
HQ, HO,r1 H S
O
NHBoc.H
HO ..,krIrIS
HATU" UFA ,..)S.,,La
Step 5 Step 6 0
Boe'NH HCI NH2 ULM-1
[0332] Step 1: Synthesis of 4-(4-methy1-1,3-thiazol-5-yObenzonitrile (G)
[0333] To a stirred solution of 4-bromobenzonitrile (E, 20 g, 109.88
mmol) in DMA (250
mL) under a nitrogen atmosphere was added 4-methyl-1,3-thiazole (F, 21.88 g,
220.67 mmol),
palladium (II) acetate (743 mg, 3.31 mmol) and potassium acetate (21.66 g,
220.71 mmol) at
room temperature. The resulting solution was heated to 150 C and stirred at
this temperature for
hours, LC-MS indicated formation of the desired product. The reaction was
cooled to room
temperature, diluted with 1 L of water and extracted with ethyl acetate (300
mL x 3). The
organic layers were combined, washed with saturated aqueous solution of sodium
chloride (200
mL), dried over anhydrous sodium sulfate and then concentrated under reduced
pressure to give
a crude residue, which was purified by flash silica gel chromatography
(eluent: ethyl
acetate/petroleum ether, v: v = 1:5) to give the G (yield: 91%) as a white
solid.
[0334] Step 2: Synthesis of [4-(4-methyl-1,3-thiazol-5-
yi)phenyl]methanamine (H)
103351 To a stirred solution of 4-(4-methyl-1,3-thiazol-5-yObenzonitrile
(G, 35.0 g, 174.8
mmol) in tetrahydrofuran (1000 mL) was added LiA1H4 (20.0 g, 526.3 mmol) in
portions at 0 C
in 10 mm under a nitrogen atmosphere. The resulting solution was then stirred
at 60 C for 3h.
LC-MS indicated formation of the desired product. The reaction was then cooled
to 0 C,
quenched by the addition water (20 mL, added slowly), aq. solution of
Na0H(15%, 20 mL) and
water (60 mL). The resulting mixture was then extracted with ethyl acetate
(300 mL x 2). The
organic layers were combined, washed with saturated aqueous solution of sodium
chloride (100
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mL), dried over anhydrous sodium sulfate and then concentrated under reduced
pressure to give
a crude residue, which was purified by flash silica gel chromatography
(eluent:
dichloromethane/methanol (v:v = 10:1)) to give H (yield: 56%) as a yellow oil.
[0336] Step 3: Synthesis of tert-butyl (2S,4R)-4-hydroxy-2-(1[4-(4-methy1-
1,3-thiazol-
5-yl)phenyl]methylIcarbamoyl)pyrrolidine-1-carboxylate (J)
[0337] To a stirred solution of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-
hydroxypyrrolidine-
2-carboxylic acid (I, 2.7 g, 11.7 inmol) in N,N-dimethylformamide (20 mL) was
added DIEA
(2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and [4-(4-methy1-1,3-thiazol-5-
yl)phenylimethanamine (H, 2.0 g, 9.79 minol) at room temperature. The
resulting mixture was
stirred at room temperature overnight, LC-MS indicated formation of the
desired product. The
reaction mixture was diluted with water (20 mL) and extracted with ethyl
acetate (50 mL x 3).
The organic layers were combined, washed with saturated aqueous solution of
sodium chloride
(50 mL), dried over anhydrous sodium sulfate and then concentrated under
reduced pressure to
give a crude residue, which was purified by flash silica gel chromatography
(eluent:
dichloromethane/methanol (v:v = 20:1)) to give J (yield: 56%) as a yellow
solid.
103381 Step 4: Synthesis of (25,4R)-4-hydroxy-N-1[4-(4-methy1-1,3-thiazol-
5-
yl)phenyl]methyl )pyrrolidine-2-carboxamide hydrochloride (K)
[0339] To a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(1[4-(4-
methyl-1,3-
thiazol-5-yl)phenylimethyl)carbamoyppyrrolidine-1-carboxylate (J, 45 g, 107.78
mmol), was
added a solution of hydrogen chloride in dioxane (4N, 300 mL) . The resulting
solution was
stirred at 20 C for 2 hours. The solids were collected by filtration to give
K (yield: 98%) as a
yellow solid, which was used for the next step without any further
purification.
[0340] Step 5: Synthesis of tert-butyl N-[(2S)-1-[(25,4R)-4-hydroxy-2-
(1[4-(4-methy1-
1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-y1]-3,3-dimethyl-1-
oxobutan-2-
yl]carbamate (M)
[0341] To a stirred solution of (2S)-2-{ Rtert-butoxy)carbonyflamino) -
3,3-
dimethylbutanoic acid (L, 15.7 g, 68.0 inmol) in N,N-dimethylformamide (500
mL) was added
DIEA (29.2 g, 225.9 mmol), HATU (25.9 g, 68.1 mmol) and (25,4R)-4-hydroxy-N-
{[4-(4-
methy1-1,3-thiazol-5-yl)phenyl]methyl) pyrrolidine-2-carboxamide hydrochloride
(K, 20.0 g,
56.5 mmol) at room temperature. The resulting solution was stirred at room
temperature for 16
hours, LC-MS indicated formation of the desired product. The reaction mixture
was diluted by
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water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic
layers were
combined, washed with saturated aqueous solution of sodium chloride (50 mL x
2), dried over
anhydrous sodium sulfate and then concentrated under reduced pressure to give
a crude residue,
which was purified by flash silica gel chromatography (eluent: ethyl
acetate/petroleum ether (v:v
= 2:1)) to give M (yield: 51%) as a yellow solid.
[0342] Step 6: Synthesis of (25,4R)-1-[(25)-2-amino-3,3-dimethylbutanoy1]-
4-hydroxy-
N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyflmethyl)pyrrolidine-2-carboxamide
hydrochloride
(ULM-1)
[0343] To a stirred solution of tert-butyl N-R2S)-1-[(25,4R)-4-hydroxy-2-
(1[4-(4-
methy1-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-y1J-3,3-dimethy1-
1-oxobutan-2-
ylicarbamate (M, 12 g, 22.61 mmol) in dioxane (20 mL) was added a solution of
hydrogen
chloride in dioxane (4N, 80 mL) at room temperature. The resulting solution
was stirred at room
temperature for 2 h, LC-MS indicated formation of the desired product.
Precipitated solids
were collected by filtration to give ULM-1 (yield: 48%) as a yellow solid.
1HNMR (400 MHz,
CD30D): 9.84-9.82 (s, 1H), 7.58-7.54 (m, 4H), 4.71-4.41 (m, 4H), 4.13-4.08
(in, 1H), 3.86-
3.71 (in, 2H), 3.36 (s, 1H), 2.60-2.58 (s, 3H), 2.35-2.07 (in, 2H), 1.19-
1.12(m, 9H). LC-MS
(ES+): m/z 431.11 [MH1, 1R = 0.73 min (2.0 minute run).
103441 ULM-2: (2S,4R)-14(S)-2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-
(thiazol-5-y1)benzyl)pyrrolidine-2-carboxamide:
HQ
s,
)(r10,41sN
0
HCI NH2 ULNI-2
10345] ULM-2 was synthesized according to similar procedure described
above for the
synthesis of ULM-1, utilizing 4-bromobenzonitrile and 1,3-thiazole as starting
materials. LC-MS
(ES+): nvz 417.10 [MH1, tR = 0.51 min (2.0 minute run).
[0346] ULM-3: (2S,4R)-14(S)-2-amino-3,3-dimethylbu Ea noy1)-4-hydroxy-N-
((S)-1-
(4-(4-methylthiazol-5-yl)phenypethyppyrrolidine-2-carboxamide:
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H2N 010 (Boc)20 BocHN BocHN
" F
Br Pc1(0Ac)2, KOAc
s-N
Stop =I Step 2
s
_____________________ HCI
Step 3 , N _____________
[0347] Ha 1`11-42 ULM-3
10348] Step 1: Synthesis of tert-butyl N-[(1S)-1-(4-
bromophenypethyl]carbamate (0)
[0349] To a stirred mixture of (1S)-1-(4-bromophenypethan-1-amine (N,
10.0 g. 49.98
mmol) in dichloromethane (100 mL) was added Et3N (10.0 g, 99.01 mmol) and
(Boc)20 (13.0g.
59.63 mmol). The resulting mixture was stirred at room temperature for 2
hours. The bulk of
solvent was then removed under reduced pressure to give a crude residue, which
was purified by
flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v: v =
1:10) to give 0
(yield: 99%) as a white solid.
[0350] Step 2: Synthesis of tert-butyl N-[(1S)-1-[4-(4-methy1-1,3-thiazol-
5-
yl)phenyl Jethyl]carbamate (P)
10351] To a stirred solution of tert-butyl N-[(1S)-1-(4-
bromophenypethyl]carbamate (0,
15.0 g, 49.97 mmol) in DMA (100 mL), under an atmosphere of nitrogen, was
added 4-methyl-
1,3-thiazole (9.9 g, 99.84 mmol), potassium acetate (9.8 g, 99.86 mmol) and
Pd(OAc), (112.5
mg. 0.50 mmol) at room temperature. The resulting mixture was then stirred at
120 C for 2
hours. The reaction mixture was then cooled to room temperature, diluted by
water (120mL), and
extracted with ethyl acetate (200 mL x 3). The organic layers were combined,
dried over
anhydrous sodium sulfate and then concentrated under reduced pressure to give
a crude residue,
which was purified by flash silica gel chromatography (eluent: ethyl
acetate/petroleum ether, v: v
= 1:5) to give P (yield: 47%) as a white solid. LC-MS (ES): nvi 319.13 [Miff],
tR = 0.97 min
(2.0 minute run).
103521 Step 3. Synthesis of (1S)-1-[4-(4-methy1-1,3-thiazol-5-
yl)phenyflethan-l-amine
hydrochloride (Q)
[0353] To a stirred solution of tert-butyl N-[(1S)-1-[4-(4-methy1-1,3-
thiazol-5-
yl)phenyl]ethyl]carbamate (P, 7.5 g, 23.55 mmol) in methanol (20 mL) was
bubbled in hydrogen
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chloride (gas) at room temperature for 2 hours. Then the resulting mixture was
concentrated
under vacuum to give Q (yield: 86%) as a white solid, which was used in the
next step without
any further purifications.
103541 Intermediate Q was converted tolULM-3 in a similar manner as
described for the
conversion of H to ULM-1. NMR (300MHz, DMS0): 8 8.99 (s, 1 H), 8.57-8.55 (d,
J= 7.8
Hz, 1 H), 8.01 (br. s, 3 H), 7.46-7.43 (d, J= 8.4 Hz, 2 H), 7.39-7.37 (d, J=
8.4 Hz, 2 H), 4.98-
4.90 (m, 1 H), 4.57-4.51 (m, 1 H), 4.34 (br. s, 1 H), 3.94-3.92 (in, 1 H),
3.69-3.66 (in, 1 H), 3.53-
3.49 (m, 1 H), 2.52 (s, 3 H), 2.10-2.07 (m, 1 H), 1.83-1.81 (m, 1 H), 1.40-
1.30 (m, 3 H), 1.03 (s,
9 H). LC-MS (ES): nez 445.05 [MH1,1R = 0.53 inin (2.0 minute run).
103551 ULM-4: (2S,4R)-14(S)-2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-
(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride:
'N+ 0
ON \_.g= ON 8 Raney-Ni
Ste p 1 Step 2
0-
9H
N 2
H2N)c
HCI 0
0 NH
µo I
ULM-4
[0356] Step 1: 1. Synthesis of 4-(1,3-oxazol-5-yl)benzonitrile (S)
[0357] To a stirred solution of 4-formylbenzonitrile (R, 1.0 g, 7.63
mmol) in methanol
(40 mL) was added [[(4-
methylbenzene)sulfonyl]methyllimethyliumylidyne)azanuide (1.6 g,
8.40 mmol) and potassium carbonate (1.4 g, 9.91 mmol), the resulting mixture
was stirred at
room temperature for 1.5 hours. The bulk of solvent was then removed under
reduced pressure.
The residue was diluted with saturated aqueous sodium bicarbonate (20 mL) and
was extracted
with dichloromethane (30 mL x 3). The organic layers were combined, washed
with brine (30
mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give
a crude
product, which was purified by re-crystallization using dichloromethane and
hexane to give S
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(1.0 g) as a white solid. NMR (400 MHz, DMSO) 5 8.56 (s, 1H), 7.97-7.83 (m,
5H); LC-MS
(ES+): nyi 170.95 [MM. tR = 0.79 min (2.0 minute run).
[0358] Step 2. Synthesis of [4-(1,3-oxazol-5-yl)phenyl]methanamine (T)
[0359] To a stirred solution of 4-(1,3-oxazol-5-yObenzonitrile (S, 900.0
mg, 5.29 mmol)
in methanol (15 mL) was added Raney-Ni (900 mg) and aq. ammonium hydroxide
(3.0 mL).
Hydrogen gas was then introduced into the reaction mixture via a balloon. The
resulting mixture
was stirred at room temperature for 16 hours. The solids were then removed by
filtration and the
solution was concentrated under vacuum to give T (yield: 81%) as brown oil,
which was used in
the next step without any further purifications. LC-MS (ES+): m/z 175.90 [MHI,
1R = 0.26 inin
(2.0 minute run).
[0360] Intermediate T was converted to ULM-4 in a similar manner as
described for the
conversion of H to ULM-1. LC-MS (ES+): m/z 400.96 [MF11, tR = 0.66 min (2.0
minute run).
[0361] ULM-5: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-
(4-
methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide:
'N+ 0
1CN ?¨& CN
Raney-Ni
0¨
pH
NH2
N __________________________________________________ H C I 0 NH 0
V 0
µN I
ULM-5
[0362] [4-(4-methy1-1,3-oxazol-5-yOphenyl]methanamine (V) was synthesized
according
to similar procedure described above for the synthesis of [4-(1,3-oxazol-5-
yl)phenyl]methanamine (T).
[0363] Intermediate V was converted to ULM-5 in a similar manner as
described for the
conversion of H to ULM-1. LC-MS (ES+): m/z 415.10 I MH1, tR = 1.17 min (2.6
minute run).
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103641 ULM-6: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoy1)-N-(4-
chlorobenzyl)-4-
hydroxypyrrolidine-2-carboxamide hydrochloride:
CI
HO,.
410
HCI NH2 ULM-6
[0365] ULM-6 was synthesized according to similar procedure described
above for the
synthesis of ULM-1. utilizing 4-chlorobenzonitrile as the starting material.
103661 ULM-7: (2S,4R)-14(S)-2-amino-3,3-dimethylbutanoy1)-N-(4-
cyanobenzy1)-4-
hydroxypyrrolidine-2-carboxamide hydrochloride:
Hq CN
INCI).µ11/H
0
HCI NH2 ULM-7
[0367] ULM-7 was synthesized according to similar procedure described
above for the
synthesis of ULM-1, utilizing 4-cyanobenzonitrile as the starting material.
10368] ULM-8: (2S,4R)-14(S)-2-amino-3-methylbutanoy1)-4-hydroxy-N-(4-(4-
methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride:
)
HS
HCI ti L
NI-12 ULM-8
103691 ULM-8 was synthesized according to similar procedure described
above for the
synthesis of ULM-1, utilizing (S)-2-(tert-butoxycarbonylamino)-3-
methylbutanoic acid and 4-
methyl-1 ,3-thiazole (F) as starting materials.
[0370] ULM-9: (2S,4R)-14(S)-2-amino-3-methylbutanoy1)-4-hydroxy-N-(4-
(thiazol-
5-yObenzyl)pyrrolidine-2-carboxamide hydrochloride:
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)
HQ
HCI NH2 ULM-9
[0371] ULM-9 was synthesized according to similar procedure described
above for the
synthesis of ULM-1, utilizing (S)-2-(tert-butoxycarbonylamino)-3-
methylbutanoic acid and 13-
thiazole as starting materials.
103721 ULM-10: (2S,4R)-14(S)-2-amino-3-methylbutanoyl)-4-hydroxy-N-(4-(4-
methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride:
)
HQ,
iLi
,LrtigH
0
HCI NH2 ULM-10
10373] ULM-10 was synthesized according to similar procedure described
above for the
synthesis of ULM-5, utilizing (S)-2-(tert-butoxycarbonylamino)-3-
methylbutanoic acid as
starting material.
[0374] ULM-11: (2S,4R)-14(S)-2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-
(1-
methyl-1H-pyrazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride:
)(rtaisH
0
HC1 NH2 ULM-11
103751 ULM-11 was synthesized according to similar procedure described
above for the
synthesis of ULM-1, utilizing 1-methylpyrazole as the starting material.
[0376] ULM-12: (2S,4R)-4-tert-butoxy-N-(2-hydroxy-4-(4-methylthiazol-5-
yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-y1)butanoyl)pyrrolidine-2-
carboxamide:
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N
HO a Br
_______________________________ HO 0, s LAH HO s
NC BC Pd(OAc) NC , KOAc Step 2 H2N
Step 1 BH Bi
o
=(---)yiNi
= (-,?...õ01-i
OH
Fmoc Frnoci pipericline
HATU DIEA, DIV1F BJ Step 4
Step 3
S N
)1¨ 0
0,
H
CN)YI4
Nt0H
H 0 OF I 0 0 OH
HATU DIEA, DMF 0 40
Step 5
S
S N
BK ULM-12
[0377] Step 1: Synthesis of 2-hydroxy-4-(4-methy1-1,3-thiazol-5-
yObenzonitrile (BH)
[0378] To a stirred solution of 4-bromo-2-hydroxybenzonitrile (BG, 28 g,
141.40 mmol)
in DMA (300 mL) was added 4-methyl-1,3-thiazole (28.1 g, 283.40 mmol),
potassium acetate
(28 g, 285.31 mmol) and palladium (I1) acetate (940 mg, 4.19 mol) at room
temperature under an
atmosphere of nitrogen. The resulting mixture was then heated to 150 C and
stirred at this
temperature for 2.5 h, LC-MS indicated formation of the desired product. The
reaction was then
cooled to room temperature, diluted by water (1000 mL) and then extracted with
ethyl acetate
(500 mL x 3). The organic layers were combined, dried over anhydrous sodium
sulfate and
concentrated under reduced pressure to give a crude residue, which was
purified by a flash silica
gel chromatography (eluent: ethyl acetate/petroleum ether (v : v = 1: 1) to
give BH (yield: 78%)
as a yellow solid. LC-MS (ES): viz 216.95 [MH-1, tR = 1.25 min (2.6 minute
run).
[0379] Step 1: 2-(aminomethyl)-5-(4-methyl-1,3-thiazol-5-yl)phenol (RI)
[0380] To a stirred solution of 2-hydroxy-4-(4-methyl-1,3-thiazol-5-
yObenzonitrile (BH,
15.6 g, 72.14 mmol) in tetrahydrofuran (400 mL) under an atmosphere of
nitrogen was added
LiA1H4 (11 g, 289.86 mmol) in several portions at 10 C. The resulting mixture
was then heated
to reflux for 3 h, LC-MS indicated formation of the desired product. The
reaction was then
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cooled to 0 C, quenched by the water (10 mL, added slowly and drop wise), 15%
NaOH (aq.)
(30 mL) and water (10 mL). The solids precipitated were removed by filtration,
the solution
phase was concentrated under reduced pressure followed by high vacuum pump to
give BI
(yield: 65%). LC-MS (ES): mrz 220.85 (MH+), tR = 1.02 inin (2.6 minute run).
[0381] Step 3. Synthesis of 9H-fluoren-9-ylmethyl (2S,4R)-4-(tert-butoxy)-
2-({ [2-
ydroxy-4-(4-methy1-1,3 -thi azol-5-yl)phen yflmethyl) carbamoyl)pyrrolidine-l-
carboxylate (11J)
103821 To a stirred solution of (2S,4R)-4-(tert-butoxy)-1-1(9H-fluoren-9-
ylmethoxy)carbonyl]pyrrolidine-2-carboxylic acid (BI, 18.6 g) in N,N-
dimethylformamide (250
mL) was added DIEA (7.9 g, 61.24 mmol), HATU (17.3 g, 45.53 mmol) and 2-
(aminomethyl)-5-
(4-methy1-1,3-thiazol-5-ypphenol (20 g, 90.79 mmol) at room temperature. The
resulting
mixture was stirred overnight at room temperature, and LC-MS indicated
formation of the
desired product. The reaction mixture was diluted by water (200 mL) and then
extracted with
ethyl acetate (300 mL x 3). The organic layers were combined, dried over
anhydrous sodium
sulfate and concentrated under reduced pressure to give a crude residue, which
was purified by
flash silica gel chromatography (eluent: dichloromethane/methanol (v: v =
25:1)) to give BJ
(yield: 31%) as a yellow oil. LC-MS (ES): m,'z 611.20 (MH+), tR = 1.12 min
(2.0 minute run).
[0383] Step 4: Synthesis of (2S,4R)-4-(tert-butoxy)-N-1(2-hydroxy-4-(4-
methy1-1,3-
thiazol-5-yl)phenyflmethyl}pyrrolidine-2-carboxamide (BK)
[0384] To a stirred solution of 9H-fluoren-9-ylmethyl (2S,4R)-4-(tert-
butoxy)-2-({ (2-
hydroxy-4-(4-methy1-1,3-thiazol-5-yl)phenyflmethylicarbamoyl)pyrrolidine-1-
carboxylate (BJ,
17.2 g, 28.12 mmol) in dichloromethane (270 mL) was added piperidine (30 mL,
280.00 mmol)
at room temperature. The resulting solution was stirred at room temperature
for 3 h, and LC-
MS indicated formation of the desired product. The reaction mixture was
concentrated under
vacuum to give a crude residue, which was then diluted by dichloromethane (300
mL), washed
with water (300 mL x 2), dried over anhydrous sodium sulfate and concentrated
under reduced
pressure to give a crude residue, which was purified by flash silica gel
chromatography (eluent:
dichloromethane/methanol (v: v = 20:1)) to give BK (yield: 71%) as a yellow
oil. LC-MS (ES):
m/z 389.95 [MH+J, iR = 0.88 min (2.0 minute run).
[0385] Step 5: Synthesis of (25,4R)-4-(tert-butoxy)-N- (12-hydroxy-4-(4-
methy1-1,3-
thiazol -5-yl)phen y1J methyl }-14(25)-3-methy1-2-(1-oxo-2,3-dihydro-1H-
isoindo1-2-
yl)butanoyflpyrrolidine-2-carboxamide ULM-12)
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10386] To a stirred solution of (2S)-3-methy1-2-(1-oxo-2,3-dihydro-1H-
isoindol-2-
y1)butanoic acid (3.6 g, 15.43 mmol) in N,N-dimethylformamide (50 mL) was
added DIEA (2.7
g, 20.93 mmol), HATU (5.89 g, 15.49 mmol) and (2S,4R)-4-(tert-butoxy)-N-{ [2-
hydroxy-4-(4-
methy1-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (BK, 4.0 g,
10.27 mmol) at
room temperature. The resulting solution was stirred overnight at room
temperature, and LC-
MS indicated formation of the desired product. The reaction was diluted by the
water (100 mL)
and extracted with dichloromethane (100 mL x 3). The organic layers were
combined, dried over
anhydrous sodium sulfate and concentrated under reduced pressure to give a
crude residue,
which was purified by a flash silica gel chromatography (eluent: ethyl
acetate/petroleum ether
(v:v = 2:1)) to give ULM-12 (yield: 43%) as a yellow solid. NMR (400 MHz,
CD30D) ö 8.88
(s, 1 H), 7.83-7.81 (d, J. 7.6 Hz, 1 H). 7.66-7.63 (m, 2 H). 7.61-7.59 (m, 1
H), 7.36-7.34 (d, J.
8.0 Hz, 1 H), 6.94-6.87 (d, J= 6.4 Hz, 1 H), 4.88 (s, 1 H), 4.56-4.39 (m, 6
H), 3.88-3.81 (m, 2
H), 2.51 (s, 3 H), 2.47-2.45 (m, 1 H), 2.15-2.13 (m, 2H), 1.16-1.14 (d, J =
6.4 Hz, 3 H) 1.02 (s.
9 H), 0.89-0.86 (d, J. 6.4 Hz, 3 H); LC-MS (ES+): m/z 605.40 [MH+], tR = 1.91
min (3.6
minute run).
103871 Unless otherwise noted, the following intermediates and their
analogs (for
examples, but not limited to, analogs with substitutions such as halogens)
were synthesized
according to similar procedures described above for the synthesis of ULM-12,
by utilizing
corresponding starting materials and reagents.
103881 ULM-13: (2S,4R)-4-tert-butoxy-14(S)-2-(6-fluoro-1-oxoisoindolin-2-
y1)-3-
methyl butanoy1)-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyppyrrolidine-2-
carboxamide:
Y-
0 N
= NJ
F ULM-13
10389] ULM-14: (2S,4R)-4-tert-butoxy-14(S)-2-(7-cyano-l-oxoisoindolin-2-
y1)-3-
methylbutanoy1)-N-(2-hydroxy-4-(4-methylthiazol-5-yObenzyl)pyrrolidine-2-
carboxamide:
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Y--
0,
N
OH
0- N
NC
ULM-14 .
103901 ULM 15: (2S,4R)-14(S)-2-Amino-3,3-di ITIethyibutanoy1)-4-hydroxy-N-
OR)-
2-hydroxy-114-(4-methylthiazol-5-y1)phenyOethyl)pyrrolidine-2-carboxamide
hydrochloride.
0
0 0 0 .
...\,õ
P = Hg
ores H2N, -..1. N --µ
r,--- , er HCOONa ..., Imidazole, DMAP, l BH3
. THF.
Rr \ t
85%Et0H, reflux * TBSCI. DCM, ft, 142 * Ti(0114)4, THF,
Br Br reflux
(A) 8r
OP (C)
ID)
0
p-:-)--
1 HCI, CH30H 0)µ...0)4. r"\_
S-J HIV = H CIS H2N
')11
H 1 ____________ ' H .................. .- HCl/claoxene.
2. B oc20, TEA. DCM KOAc. Pd(OAC)2, N2. * 41
111 Br OTBS B 4 OH DMF.100 C Et:O. 1S
t \ 1
N
(E) (P) N
(G) (H)
9"
BocHN It
frs:
0HO
Boc1;;Isqft CIH H21,--11
0 ACCl/CH3011 0HN
HN
HATU, TEA, DCM
# OH = OH
S
\
ZN µ \ fs:
(I) ULM-16
[0391] Step 1: Synthesis of 1-(4-Bromopheny1)-2-hydroxyethanone (B).
[0392] To a suspension of 2-bromo-1-(4-bromophenyl)ethanone (A) (60.0 g,
0.217
mmol) in Et0H (85%, 600 mL) was added NaOCHO (44.37 g, 0.652 mol) at room
temperature.
The mixture was heated to 110 C until all solid was dissolved and stirred for
another 3 hours.
Then it was reduced to one-third of its volume in vacuo. The residue was
poured into ice water
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(200 mL). After stirring for 30 minutes, the resulting off-white precipitate
was filtered, washed
with cold water (100 mL), and dried to afford the desired product (B) (39.0 g,
84%) as a white
solid. IFINMR (400 MHz, CDC13): 5 7.79 (d, J. 8.8 Hz, 2H), 7.66 (d, J. 8.8 Hz,
2H), 4.85(s,
2H), 3.43(t, J. 4.4 Hz, 1H).
[0393] Step 2: Synthesis of 1-(4-Bromopheny1)-2-(tert-
butyldimethylsilyloxy)ethanone
(C).
[0394] To a solution of (B) (39.0 g, 0.181 mol) and imidazole (37.0 g,
0.544 mol) in
DCM (500 mL) was added TBSC1 ( 32.75 g, 0.218 mmol) at 0 C. The reaction
mixture was
warmed to room temperature and stirred for another 3 hours. After it was
quenched with H20
(200 mL), the organic phase was washed with brine (100 mL x 3), dried over
Na2S204 and
concentrated under vacuum to afford the desired product (C) (55.0 g, crude,
92%) as a white
solid. IFINMR (400 MHz, CDC13): 5 7.70 (d, J. 8.4 Hz, 2H), 7.49 (d, J. 8.8 Hz,
2H), 4.73 (s,
2H), 1.46 (d, J= 6.4 Hz, 1H), 0.81 (s, 9H), 0.00 (s, 6H).
[0395] Step 3: Synthesis of (S,Z)-N-(1-(4-Bromopheny1)-2-(tert-
butyldimethylsilyloxy)ethylidene)-2-methylprome-2-sulfinamide (D).
[0396] To a solution of (C) (55.0 g, 0.167 mmol) and (S)-2-methylpropane-
2-sulfinamide
(30.36 g, 0.25 mmol) in THF (600 mL) was added Ti(OiPr)4 (142.4 g, 0.501 mol)
at 25 C. The
mixture was heated to 80 C overnight. After it was cooled to 0 C, the
reaction was quenched by
addition of H20 (100 mL). The mixture was filtered through Celite, and the
solid was washed
with Et0Ac (1000 mL). The combined organic layers were washed with brine (200
mL x 3), and
concentrated under vacuum. The residue was purified by silica gel column
chromatography with
Et0Ac/PE (1/100-10) to afford the desired product (D) (20.0 g, 41%) as a brown
syrup.
NMR (400 M Hz, CDC13): 5 7.66 ( br, 2H), 7.47 (d, J. 8.4 Hz, 2H), 4.92-4.96 (
m, 1H), 3.63-
3.69 (m, 1H), 1.24 (s, 9H), 0.76 (s, 9H), 0.03 (d, J. 5.2 Hz, 6H.
[0397] Step 4: Synthesis of (S)-N-OR)-1-(4-Bromopheny1)-2-(tert-
butyldimethylsilyloxy)ethyl)-2-methylpropane-2-sulfinamide. (E).
[0398] To a suspension of (D) (18.0 g, 41.61 mmol ) in THF (100 mL) was
added
BH3/1'HF(104 mL, 1.0 M, 104 mmol) at -78 C. The resulting solution was stirred
-78 C for 4
hours. It was quenched by addition of acetone at -78 C (20 mL), and H20 (20
mL) subsequently.
The organic phase was washed with brine, dried over Na2SO4, and concentrated
under vacuum.
The residue was purified by silica gel column chromatography with PE/EA (10-5
/1) to afford
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the desired product (E) (15.0 g, 83% ) as a light brown solid. Ili NMR (400
MHz, CDC13): 5
7.52 (d, J= 8.4Hz, 2H), 7.431 (d, J= 8.4 Hz, 2H), 4.44-4.48(m. 1H), 4.16(m,
1H). 3.83-3.90
(m, 2H), 2.11 (t, J. 2.4 Hz, 1H), 1.27 (s, 9H), 0.90 (s, 9H), 0.01 (d, J= 5.2
Hz, 6H).
[0399] Step 5: Synthesis of (R)-Tert-butyl 1-(4-bromopheny1)-2-
hydroxyethylcarbamate
(F).
[0400] A solution of (E) (10.0 g, 23.0 mmol) in HC1(g)/CH3OH (50 mL) was
stirred at
room temperature for 3 hours. The solvent was removed under vacuum to afford
the desired
product of (R)-2-amino-2-(4-bromophenypethanol hydrochloride (6.0 g, crude).
To a solution of
(R)-2-amino-2-(4-bromophenyl)ethanol hydrochloride in CH3OH (50 mL) were added
TEA
(11.6 g, 116 mmol) and Boc20 (7.5 g, 45.0 mmol) subsequently at 0 C. The
resulting solution
was stirred for 3 hours. The solvent was removed under vacuum. The residue was
taken up with
Et0Ac (200 mL), and the mixture was washed with brine (100 mL x 2), dried over
Na2SO4, and
concentrated under vacuum. The residue was purified by silica gel column
chromatography
(ethyl acetate/petroleum ether = 1/4-1) to afford the desired product (F) (6.0
g, 82% yield) as a
colorless oil. Ili NMR (400 MHz, DMSO-d6): 6 7.50 (d, J= 8.4 Hz. 2H), 7.25 (d,
J. 8.4 Hz,
2H), 4.81 (s, 1H), 4.48-4.50 (m, 1H), 3.47-.349 (m, 2H), 1.40 (s, 9H).
[0401] Step 6: Synthesis of (R)-Tert-butyl 2-hydroxy-1-(4-(4-
methylthiazol-5-
yl)phenypethylearbamate (G).
[0402] To a solution of (F) (6.0 g, 18.97mmo1) in DMA (50 mL) were added
4-
methylthiazole (3.79 g, 38.2 mmol). KOAc (3.72 g, 38.5 mmol) and Pd(OAc)2(426
mg, 1.90
mmol) subsequently. The solution was stirred at 130 C for 5 h under N2
atmosphere. After
cooling to room temperature, the mixture was filtered through Celite, and the
solid was washed
with Et0Ac (200 mL). The resulting solution was washed with brine (100 mL x
3). The organic
phase was dried over anhydrous sodium sulfate, filtered and concentrated under
vacuum. The
residue was purified by silica gel column chromatography (ethyl
acetate/petroleum ether =
1/4-1) to afford (G) (2.0 g, 32% yield) as a light brown solid.
[0403] Step 7: Synthesis of (R)-2-Amino-2-(4-(4-methylthiazol-5-
yl)phenyl)ethanol
hydrochloride (H).
[0404] To a solution of (G) (2.0 g, 5.98 mmol) in DCM (20 mL) was added
HCl (g) 4M
dioxene (10 mL) at 25 C. The resulting solution was stirred at room
temperature for 2 hours. The
solvent was removed under vacuum to afford the desired product (H) (1.1 g,
68%) as a light
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yellow solid. 1HNMR (400 MHz, CD30D): 8 9.20 (s, 1H), 7.58-7.63 (m, 4H), 4.42-
4.45 (m,
1H), 3.93-3.97 (m, 1H), 3.82-3.87 (m, 1H), 2.53 (s 3H).
[0405] Step 8: Synthesis of tert-butyl (S)-1-((2S,4R)-2-(((R)-2-Hydroxy-1-
(4-(4-
methylthiazol-5-y1) phenypethyl)carbamoy1)-4-hydroxypyrrolidin-1-y1)-3,3-
dimethyl-1-
oxobutan-2-ylcarbamate (1).
[0406] To a solution of (H) (1.1 g, 4.06 mmol), (2S,4R)-14(S)-2-(tert-
butoxycarbony1)-
3,3-dimethylbutanoy1)-4-hydroxypyrrolidine-2-carboxylic acid (2.10 g, 6.09
mmol) and DIEA
(1.60 g, 13.0 mmol) in DCM (20 mL) was added HATU (2.30 g, 6.08 mmol) at 25 C.
The
reaction mixture was stirred at 25 C for 2 hours. Then it was quenched by
addition of H20 (20
mL). The mixture was washed with brine, dried over Na2SO4, and concentrated
under vacuum.
The residue was purified by column chromatography with DCM/CH3OH (30-20:1) as
eluent to
afford (I) (1.7 g, 75%) as a light yellow solid. 11-1 NMR (400 MHz, CDC13): 8
8.68 (s, 1H), 7.28-
7.42 (m, 5H), 5.14-5.30 (m, 2H), 4.65 (t, J= 8.4 Hz, 1H), 4.52 (s, 1H), 4.21
(d, J= 9.2 Hz, 1H),
4.10-4.13 (m, 1H), 3.94 (m, 1H), 3.84 (m, 1H), 3.68-3.75 (m, 1H), 2.96 (s,
1H), 2.53 (s, 3H),
2.35 (m, 1H), 2.16-2.19 (m, 1H), 1.42 (s, 9H), 1.26 (s, 9H).
104071 Step 9: Synthesis of (2S,4R)-14(S)-2-Amino-3,3-dimethylbutanoy1)-4-
hydroxy-
N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide
hydrochloride (ULM-15).
[0408] To a solution of (I) (1.7 g, 3.03 mmol) in CH3OH (20 mL) was added
AcC1/CH3OH (v:v=1:10, 10 mL, AcC1 was added dropwise to the methanol solution
at 0 C and
the solution was stirred for 1 hour). The resulting solution was stirred at 25
C for 1 hour. Then
the solvent was removed under vacuum to afford the desired product (ULM-15)
(1.5 g, 94%) as
a yellow solid. 1H NM R (400 MHz, CD30D): 8 9.77 (s, 1H), 7.52-7.56 (m, 41-1),
5.02 (t, J= 6.0
Hz, 1H), 4.73 (t, J= 8.0 Hz, 1H), 4.49 (s, 1H), 4.06 (s, 1H), 3.82 (d, J= 4.8
Hz, 3H), 3.65-3.69
(m, 1H), 2.58 (s, 3H), 2.28-2.34 (m, 1H), 1.94-2.01 (m, 1H), 1.14 (s, 9H).
Chemical Formula:
C23H32N404S / C23H32N404S HCl; Molecular Weight: 460.59 / 497.05.
[0409] Synthesis of Linker Chemistry, L
10410] L-1: 2-(3-(5-(tosyloxy)pentyloxy)propoxy)acetic acid
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15.-=-="Br 9-80N
Step Step 2
X
8
Step 3 8
P&G Ei2 TsC.:, TEA. DMA!.
SW! a AA 0 Step 5
,
0 8
[0411] AB Step6 L-1
[0412] Step 1: Synthesis of ({ [5-(prop-2-en-l-
yloxy)pentylJoxy}methyl)benzene
[0413] To a stirred solution of 5-(benzyloxy)pentan-1 -ol (W, 4.0 g,
20.59 mmol) in N,N-
dimethylformamide (50 mL) was added sodium hydride (1.24 g, 51.67 mmol) in
portions at 0 C
under an atmosphere of nitrogen. The resulting mixture was then stirred at
room temperature for
1 hour. To this mixture was added 3-bromoprop-1-ene (3.71 g, 30.67 mmol), the
reaction
mixture was stirred overnight at 60 C in an oil bath. LC-MS indicated
formation of the desired
product. The reaction mixture was cooled to 0 C and then quenched by water
(100 mL), the
resulting mixture was extracted with ethyl acetate (200 mL x 2). The organic
layers were
combined, washed with saturated aqueous solution of sodium chloride (60 mL),
dried over
anhydrous sodium sulfate and then concentrated under reduced pressure to give
a crude residue.
The residue was purified by a flash silica gel chromatography (eluent: ethyl
acetate/petroleum
ether (v:v = 1:40)) to give 4.57 g of X. 1H NMR (300MHz, CDC13): 5 7.36(s, 4
H), 7.32 (m, 1
H), 5.98 (m, 1 H), 5.33 (m, 1H), 5.21 (in, 1H), 4.53 (s, 2H), 3.99 (m, 2H),
3.53 (m, 4H), 1.72 (m,
4H), 1.52 (m, 2H). LC-MS (ES): nilz 235.00 [MHI, tR = 1.18 min (2.0 minute
run).
[0414] Step 2: Synthesis of 3-1[5-(benzyloxy)pentyl]oxy}propan-1-ol (Y)
[0415] To a 250-mL round-bottom flask with 9-BBN (0.5 M in THF, 77 mL)
was added
a solution of (1[5-(prop-2-en-1-yloxy)pentyl]oxy methyDbenzene (X, 3.0 g,
12.80 mmol) in
anhydrous tetrahydrofuran (20 mL) with stirring at 0 C under an atmosphere of
nitrogen. The
resulting solution was stirred overnight at room temperature. LC-MS indicated
formation of the
desired product. Methanol (15 mL, with 30% sodium hydroxide and 30% H202) was
added to
the reaction and the resulting mixture was stirred at room temperature for 2
hours. This mixture
was then extracted with ethyl acetate (20 mL x 3). The organic layers were
combined, washed
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with saturated aqueous solution of sodium chloride (100 mL), dried over
anhydrous sodium
sulfate and then concentrated under reduced pressure to give a crude residue.
The residue was
purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum
ether (v: v = 1:1))
to provide 1.96 g of Y as light yellow oil. 11-1 NMR (300MHz, CDC13): 57.34
(m, 5H), 4.49 (s,
2H), 3.75 (m, 21-1), 3.59 (in, 2H), 3.49 (m, 4H), 2.65 (bs, 1 H), 1.84 (m,
2H), 1.68 (m, 4H), 1.50
(m, 2H). LC-MS (ES): m/z 253.17 1MH1, tR = 1.44 min (2.6 minute run).
[0416] Step 3: Synthesis of tert-butyl 2-(3-115-
(benzyloxy)pentyfloxy)propoxy)acetate
[0417] To a stirred solution of 3-115-(benzyloxy)pentyfloxy}propan-1-ol
(Y, 3.7 g, 14.66
mmol) in dichloromethane (30 mL) was added a solution of NaOH in water (37%,
30 mL)
followed by tert-butyl 2-bromoacetate (11.39 g, 58.39 mmol) and TBAC1 (4.17
g). The resulting
mixture was stirred at room temperature overnight. LC-MS indicated formation
of the desired
product. The reaction mixture was then extracted with ethyl acetate (50 mL x
3). The organic
layers were combined, washed with saturated aqueous solution of sodium
chloride (60 mL),
dried over anhydrous sodium sulfate and then concentrated under reduced
pressure to give a
crude residue. The residue was purified by a flash silica gel chromatography
(eluent: ethyl
acetate/petroleum ether (v:v = 1:2) to give 3.2g of Z as a yellow oil. Ili NMR
(400MHz, CDC13):
57.34(s, 4 H), 7.29 (m, 1 H), 4.50 (s, 4H), 4.3 (m, 2H), 3.51 (m, 4H), 3.42
(m, 2H), 1.98 (m, 2H),
1.67 (m, 4H), 1.48 (s, 9H), 1.46 (m, 2H). LC-MS (ES): m/z 367.25 1MH1, tR =
1.28 min (2.0
minute run).
[0418] Step 4: Synthesis of tert-butyl 2-13-1(5-
hydroxypentyl)oxyjpropoxy]acetate (AA)
[0419] To a stirred solution of tert-butyl 243-115-
(benzyloxy)pentyfloxy)propoxy)acetate (Z, 3.2 g, 8.73 mmol) in methanol (30
mL) was added
AcOH (1.5 mL), palladium on carbon (1.5 g) under an atmosphere of nitrogen.
Hydrogen was
then introduced to the reaction mixture via a hydrogen balloon, and the
reaction was stirred at
room temperature for 3h. The solid material was removed by filtration, the
solution was
concentrated under vacuum to provide 2.3 g of AA as light yellow oil, which
was used for the
next step without any further purifications. LC-MS (ES+): m/z 277.10 1MH1, tR
= 0.86 min (2.0
minute run).
[0420] Step 5: Synthesis of tert-butyl 2-13-(f 54(4-
methylbenzenesulfonypox ylpentyl ioxy)propoxyJacetate (AB)
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[0421] To a stirred solution of tert-butyl 243-[(5-
hydroxypentypoxy]propoxy]acetate (AA, 2.3
g, 8.32 mmol) in dichloroinethane (30 mL) was added 4-methylbenzene-1-sulfonyl
chloride
(3.17 g, 16.63 mmol), triethylamine (2.52 g, 24.90 mmol) and 4-
dimethylaminopyridine (203
mg, 1.66 mmol) at room temperature. The resulting mixture was stirred
overnight at room
temperature. The resulting mixture was concentrated under reduced pressure to
give a crude
residue, which was purified by a flash silica gel chromatography (eluent:
ethyl acetate/petroleum
ether (v:v = 1:2) to give 2.6 g of AB as a yellow oil. IFINMR (300MHz, CDC13):
8 7.77 (d, .1=
8.1 Hz, 2 H), 7.36 (d, J= 8.1 Hz, 2 H), 4.51 (s, 2H), 4.31 (m, 2H), 4.13 (m,
2H), 3.52 (m, 4H),
2.05 (s, 3H), 1.97 (m, 2H), 1.69 (m, 4H), 1.48 (s, 9H), 1.46 (m, 2H). LC-MS
(ES+): ink 431.20
[MH1, tR = 1.21 min (2.0 minute run).
[0422] Step 1: Synthesis of 243-({5-[(4-methylbenzenesulfonyl)oxy]pentyl I
oxy)propoxy]acetic
acid (L-1)
[0423] To a stirred solution of tert-butyl 243-((5-[(4-
methylbenzenesulfonypoxy]pentyl}oxy)propoxy]acetate (AB, 1.3 g, 3.02 mmol) in
dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at room
temperature. The
resulting solution was stirred at room temperature for 3 hours. The reaction
mixture was then
concentrated under vacuum to give 1.5 g (crude) of L-1, which was used for
next step without
any further purification. LC-MS (ES+): nz/z 375.34 EM H+], tR = 1.39 min (2.6
minute run).
[0424] The following Linkers (L) were prepared in a similar manner as for the
preparation of L-
1.
10425] L-2: 2-(3-(3,3-dimethy1-5-(tosyloxy)pentyloxy)propoxy)acetic acid
OH
L-2 0
10426] L-3: 2-(3(3-hydroxy-5-(tosyloxy)pentyloxy)propoxylacetic acid
OH
TsOOO
L-3 0
[0427] L-4: 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetic acid
0 NaOH
IsO _____________________________________ -
Et01-1/M20, rt, 2 h
AC L-4
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[0428] To a stirred solution of ethyl 2-[2-(2-12-[(4-
methylbenzenesulfonypoxy]ethoxylethoxy)ethoxy]acetate (AC, 2 g, 5.12 mmol,
1.00 equiv) in
methanol (20 mL) was added a solution of NaOH (500 mg, 12.50 mmol) in water (4
mL), and
the resulting mixture was stirred at room temperature for 2 hours. Aqueous
hydrogen chloride (1
M) was then added to the reaction mixture to adjust pH to -5. Solids
precipitated were collected
by filtration to give L-4 (yield: 98%). Mass (ES+): mh, 363, [MH+].
[0429] The following Linkers (L) were prepared in a similar manner as for the
preparation of L-
4.
[0430] L-5: 2-(24(2R,3R)-3-(2-(tosyloxy)ethoxy)butan-2-yloxy)ethoxy)acetic
acid
TsOOOOOH
L-5
[0431] L-6: 2-(24(28,38)-3-(24tosyloxy)ethoxy)butan-2-yloxy)ethoxy)acetic acid
0
L-6
[0432] L-7: 2-(4-(4-(tosyloxy)butoxy)butoxy)acetic acid
TsCi
___________________________________ Ts0"-'-`-' 03-1 ____________
AD Step 1 AE Step 2
NaOH/H20Ts()
AF 0 Step 3 L-7
[0433] Step 1: Synthesis of 4-14-[(4-methylbenzenesulfonyl)oxy]butoxy}butari-1-
ol (AE)
[0434] To a stirred solution of 4-(4-hydroxybutoxy)butan-1-ol (AD, 2 g, 12.33
mmol) in
dichloroinethane (20 mL) was added Ag2O (4.25 g, 18.49 mmol), KI (409 mg, 2.46
mmol) and
TsC1 (2.345 g, 12.30 mmol). The resulting mixture was stirred at room
temperature for 12 hours.
The inorganic salt formed was removed by filtration and the organic solution
was concentrated
under reduced pressure to give a crude residue. The residue was purified by
flash silica gel
chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:1)) to give AE
(yield: 28%) as a
colorless oil.
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[0435] Step 2: Synthesis of ethyl 2-(4-(4-[(4-
methylbenzenesulfonypoxy]butoxy}butoxy)acetate
(AF)
[0436] To a stirred solution of 4-(4-[(4-
methylbenzenesulfonyl)oxy]butoxy}butan-1-01 (AE. 1.1
g, 3.48 mmol) in dichloromethane (10 mL) was slowly added BF3.Et20 (49.4 mg,
0.35 mmol)
followed by ethyl 2-diazoacetate (794 mg, 6.96 mmol) at 0 C. The resulting
mixture was stirred
overnight at room temperature. The reaction was then quenched by water (2.0
mL). The resulting
mixture was extracted with dichloromethane (50mL x 3), the organic layers were
combined,
dried over anhydrous sodium sulfate and then concentrated under reduced
pressure to give a
crude residue. The residue was purified by flash silica gel chromatography
(eluent: ethyl
acetate/petroleum ether (v: v = 1:4) to give AF (yield: 93 as light yellow
oil. Mass (ES): nvz
403.10 [MH+].
[0437] Step 3: Synthesis of 2-(4-(4-[(4-
methylbenzenesulfonyl)oxy]butoxy}butoxy)acetic acid
(L-7)
[0438] To a stirred solution of ethyl 2-(4-(4-[(4-
methylbenzenesulfonyl)oxy]butoxy}butoxy)acetate (AF. 1.3 g, 3.23 mmol) in
methanol (25mL)
was added a solution of NaOH (388 mg, 9.70 mmol) in water (6 mL) at room
temperature. The
resulting solution was stirred at room temperature for 4 hours. The bulk of
organic solvent was
removed under reduced pressure, to the resulting mixture was added aqueous
hydrogen chloride
(1.0 M) to adjust the pH = -5. The solution was then extracted with ethyl
acetate (250 mL x 3),
the organic layers were combined and dried over anhydrous sodium sulfate,
concentrated under
reduced pressure to give 1-7 (yield: 93%) as light yellow oil. Mass (ES): nez
375.05 [MH+].
[0439] L-8: tert-butyl 2-(3-(4-(tosyloxy)butoxy)propoxy)acetate
o
Br"yoHO OHt-
=C(D)
0
__________________________ 1:3n0A)
Step 2
AG Step 1 AH AI
H2, Pd/C 0\ TsCI 0 \
Step 3 Step 4
AJ L-13
104401 Step 1. Synthesis of 344-(benzyloxy)butoxy]propan-1-ol (AH)
[0441] To a stirred solution of propane-1, 3-diol (1.52 g, 19.98 mmol) in N, N-
dimethylformamide (20 mL) was added sodium hydride (840 mg, 35.00 mmol) at
room
temperature, the resulting mixture was stirred at room temperature for 30min.
Then to the
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mixture was added 4-(benzyloxy) butyl 4-methylbenzene-1-sulfonate (AG, 6.68 g,
19.97 mmol)
and the reaction was stirred overnight at 50 C. TLC indicated formation of
the desired product,
at this time the reaction was allowed to cool down to room temperature. Water
(10 mL) was
added slowly to quench the reaction; the resulting mixture was then extracted
with ethyl acetate
(80 mL x 2). The organic layers were combined, washed with saturated aqueous
solution of
sodium chloride (20 mL), dried over anhydrous sodium sulfate and then
concentrated under
reduced pressure to give a crude residue, which was purified by flash silica
gel chromatography
(eluent: ethyl acetate/petroleum ether (v:v = 1:2)) to give AH (yield: 67%) as
a light yellow oil.
1HNMR (300 MHz, CDC13) 8 7.38-7.29 (m, 5H), 4.52 (m, 2H), 3.80 (m, 2H), 3.61
(m, 2H),
3.49-3.46 (m, 4H), 2.04 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H); Mass (ES): m/z
239.05 [MH+].
[0442] Step 2. Synthesis of tert-butyl 2-[3[4-
(benzyloxy)butoxy]propoxy]acetate (AI).
10443] To a stirred solution of 344-(benzyloxy)butoxy]propan-1-ol (AR, 2.38 g,
9.99 mmol) in
dichloromethane (15 mL) was added tert-butyl 2-bromoacetate (7.76 g, 39.78
mmol), TBAC
(2.78 g, 10.00 mmol) followed by aqueous sodium hydroxide (37 %, 15 mL). The
resulting
mixture was stirred overnight at room temperature. The reaction mixture was
then extracted with
dichloromethane (100 mL x 3), the organic layers were combined, washed with
saturated aqueous
solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate and
then concentrated
under reduced pressure to give a crude residue. The residue was purified by
flash silica gel
chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1: 5)) to give AI
(yield 57%) as a
yellow oil. Mass (ES): m/z 353.10 [MH+].
[0444] Step 3. Synthesis of tert-butyl 243-(4-hydroxybutoxy)propoxy]acetate
(AJ)
[0445] To a stirred mixture of tert-butyl 243-[4-
(benzyloxy)butoxy]propoxy]acetate (AI, 1 g,
2.84 mmol), palladium on carbon (10%, 2(X) mg) in methanol (20 mL) was added
acetic acid
(0.05 mL) under a nitrogen atmosphere. Hydrogen was then introduced to the
reaction mixture via
a balloon, the reaction was then stirred overnight at room temperature. The
insoluble solids were
removed by filtration and the solution phase was concentrated under reduced
pressure to give the
desired product (yield: 94%) as a yellow oil. Mass (ES+): m/Z 263.05 [MF1+]
[0446] Step 4. Synthesis of tert-butyl 2-(3-{44(4-
methylbenzenesulfonypoxylbutoxy}propoxy)acetate (L-8)
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[0447] To a stirred solution of tert-butyl 2-[3-(4-
hydroxybutoxy)propoxy]acetate (AJ, 700 mg,
2.67 mmol) in dichloromethane (10 mL) was added 4-methylbenzene-1-sulfonyl
chloride (558.4
mg, 2.93 mmol), TEA (539.5 mg, 5.33 mmol) and 4-dimethylaminopyridine (32.6
mg, 0.27
mmol). The resulting mixture was stirred overnight at room temperature. The
bulk of solvent was
removed under reduced pressure to give a crude residue, which was purified by
flash silica gel
chromatography (eluent: ethyl acetate/petroleum ether (v:v= 1: 2)) to give
titled product (yield:
52%) as a yellow oil. Ill NMR (3(X) MHz, CDC13) 87.79 (dõ/ = 8.4 Hz, 2H), 7.35
(d, J = 8.0 Hz,
2H), 4.05 (m, 2H), 3.95 (s, 2H), 3.59 (m, 2H), 3.48 (m, 2H), 3.38 (m, 2H),
2.46 (s, 3H), 1.82 (m,
2H), 1.70 (m, 2H), 1.57 (m, 2H), 1.50 (s, 9H); Mass (ES): nyi 417.05 [MH+].
[0448]
[0449] L-9: tert-butyl 2-(4-(3-(tosyloxy)propoxy)butoxy)acetate
HOOH
Bn(Y'"OTs ,BflOOOH 0-
AK AL
H2, P&G
___________________________________________ H
AM 0 AN 0
TsCi
L-9 0 I
[0450] L-9 was prepared in a similar manner as that used to prepare L-8,
except that AK was
used in place of AG. Mass (ES): miz 439.15 [MNal.
[0451] L-10: tert-butyl 2-(6-(tosyloxy)hexa-2,4-diynyloxy)acetate
HO /OH ______________ .HO 0¨/
Step 1 _____________________________________________ /
AO AP
0
TsCI, KOH Tso 0
Step 2 \ _____ = =
L-10
[0452] Step!: Synthesis of tert-butyl 2-[(6-hydroxyhexa-2,4-diyn-1-
yDoxy]acetate (AP)
[0453] To a stirred solution of hexa-2, 4-diyne-1, 6-diol (AO, 100 mg, 0.91
mmol) in N, N-
dimethylformamide (5 mL) was added sodium hydride (32 mg, 1.33 mmol) at 0 C.
The resulting
mixture was then warmed up to room temperature and stirred at room temperature
for 30 min.
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The reaction mixture was cooled to 0 C followed by addition of tert-butyl 2-
bromoacetate (176
mg, 0.90 mmol), and the resulting mixture was stirred at 0 C for 2h. LC-MS
indicated formation
of the desired product. The reaction was then quenched by water (10 mL, added
slowly) at 0 C,
and was extracted with ethyl acetate (20 x 2 mL). The organic layers were
combined, dried over
anhydrous sodium sulfate and then concentrated under reduced pressure to give
a crude residue,
which was purified by flash silica gel chromatography (eluent: ethyl
acetate/petroleum ether (v:v
= 1:2)) to give AP (yield: 49%) as a yellow oil.
[0454] Step 2. Synthesis of tert-butyl 2-(16-[(4-
methylbenzenesulfonyl)oxy]hexa-2,4-diyn-1-
yl I oxy)acetate (L-10)
[0455] To a stirred solution of tert-butyl 2-[(6-hydroxyhexa-2, 4-diyn-1-y1)
oxy] acetate (AP, 50
mg, 0.22 mmol) in ether (2 mL) was added 4-toluenesulfonyl chloride (51 mg,
0.27 mmol) at 0
C, followed by potassium hydroxide (125 mg, 2.23 mmol) in several batches at 0
C. The
resulting mixture was stirred at 0 C for 4 hours. LC-MS indicated formation
of the desired
product. Water (10 mL) was added to the reaction, and the resulting mixture
was extracted with
ethyl acetate (20 mL x 2). The organic layers were combined, dried over
anhydrous sodium
sulfate and then concentrated under reduced pressure to give a crude residue,
which was purified
by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v
= 1:2)) to give L-
(yield: 71%) as a yellow oil. NMR (300 MHz, CDC13): 5 7.83 (d, J= 6.0 Hz,
2H), 7.39 (d,
J= 6.0 Hz, 2H), 4.79 (s, 2H), 4.37 (s, 2H), 4.05 (s, 2H), 2.48 (s, 3H), 1.51
(s, 9H); LC-MS (ES):
iniz 401.05 [MNal, tR = 1.71 min (2.6 minute run).
10456] The following Linkers (L) were prepared in a similar manner as for the
preparation of L-
10.
[0457] L-11: tert-butyl 3-(6-(tosyloxy)hexa-2,4-diynyloxy)propanoate
0-
Ts0
L-11
10458] L-12: tert-butyl 4-(6-(tosyloxy)hexa-2,4-diynyloxy)butanoate
Ts
= ____________________________________ / 0
L-12
[0459] L-13: ethyl 2-(2-(2-aminoethoxy)ethoxy)acetate hydrochloride
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0
(B c)20
_________________________________ BocHN"--as-"-"OH ________
Step 1
AQ AR Step 2
0 StepHC1(g) HCI 0 0
___________________________________________ H2N"
3-
AS 0 L-13
[0460] Step 1: Synthesis of tert-butyl N42-(2-hydroxyethoxy)ethylicarbamate
(AR)
10461] To a stirred solution of 2-(2-aminoethoxy)ethan-1-ol (AQ, 5.25 g, 49.94
mmol) in
tetrahydrofuran (100 mL) was added aqueous solution of sodium bicarbonate (20%
(w/w), 40
ml) and (Boc)20 (11.4 g, 52.23 mmol, added in several batches) at 0 C. The
resulting mixture
was then warmed up slowly to room temperature and stirred at room temperature
for 5h. The
bulk of organic solvent was removed under reduced pressure and the resulting
residue was
diluted with water (300 mL), extracted with of ethyl acetate (100 mL x 3). The
organic layers
were combined, washed with saturated aqueous solution of sodium chloride (20
mL x 2), dried
over anhydrous sodium sulfate and then concentrated under reduced pressure to
give AR (yield:
98%) as colorless oil.
[0462] Step 2: Synthesis of ethyl 242-(2-{[(tert-
butoxy)carbonyl]amino}ethoxy)ethoxy]acetate
(AS)
[0463] To a stirred solution of tert-butyl N42-(2-
hydroxyethoxy)ethyl]carbamate (AR, 4.0 g,
19.49 mmol) in dichloromethane (30 mL) was added 1-diazo-3-methoxypropan-2-one
(3.34 g,
29.27 mmol) and BF3-Et20 (0.2 mL) at room temperature. The resulting solution
was stirred at
room temperature for 2 hours. Water (20 mL) was added to the reaction mixture,
organic layer
was separated and washed with brine (20 mL), dried over anhydrous sodium
sulfate and
concentrated under reduced pressure to give a crude residue. The residue was
purified by flash
silica gel chromatography (eluent: ethyl acetate/petroleum ether (v: v = 1:2))
to give AS (yield:
18%) as yellow solid. 1H NM R (400MHz, CDC13): 5 4.25-4.22 (qõ/. 7.2 Hz, 2 H),
4.14 (s, 2
H), 3.74 (b, 2 H), 3.72 (b, 1 H), 3.67-3.32 (m, 4 H), 1.414 (s, 9 H), 1.31 (t,
./. 7.2 Hz, 3 H).
[0464] Step 3: Synthesis of ethyl 242-(2-aminoethoxy)ethoxy]acetate
hydrochloride (L-13)
[0465] To a stirred solution of ethyl 242421 [(tert-
butoxy)carbonyl]amino}ethoxy)ethoxy]acetate (AS, 500 mg, 1.72 mmol) in 1,4-
dioxane (10 mL)
was introduced hydrogen chloride (gas) via bubbling at room temperature for
2h. The solvent
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was then removed under vacuum to give L-13 (yield: 99%). LC-MS (ES): tn/z
192.00 [MH+],
= 0.41 min (2.0 minute run).
[0466] L-14: ethyl 2-(5-aminopentyloxy)acetate
Boc20 B BF3Et20
ocOH
H2NWOH
Step 1 Step 2
AT H AU
TFA
Boc.N
Step 3
H AV 0 L-14 0
[0467] Step 1: Synthesis of tert-butyl 5-hydroxypentylcarbamate (AU)
[0468] To a stirred solution of 5-aminopentan-l-ol (AT, 3.1 g, 30.05 mmol) in
dichloromethane
(30 mL) was added di-tert-butyl dicarbonate (6.56 g, 30.06 mmol) at 0 C. The
resulting mixture
was then stirred at room temperature for 4h. The solvent was removed under
reduced pressure to
give a crude residue which was purified by flash silica gel chromatography
(eluent: ethyl
acetate/petroleum ether (v:v= 1: 2)) to give AU (yield: 98%) as a colorless
oil. LC-MS (ES):
//viz 204.00 [MF11, tR =1.29 min (2.6 minute run).
[0469] Step 2: Synthesis of ethyl 2-[(5-{[(tert-
butoxy)carbonyl]amino)pentyl)oxy]acetate (AV)
[0470] To a stirred solution of tert-butyl N-(5-hydroxypentyl)carbamate (AU,
1.5 g, 7.38 mmol)
in dichloromethane (10 mL) was added BF3Et20 (0.1 mL) at 0 C. To this mixture
was then
added a solution of ethyl 2-diazoacetate (850 mg, 7.45 mmol) in
dichloromethane (2 mL) at
0 C. The resulting mixture was allowed to warm up to room temperature and
stirred at room
temperature for 2 hours. Saturated aqueous sodium bicarbonate (30 mL) was
added to the
reaction, the resulting mixture was extracted with ethyl acetate (150 mL x 3).
The organic layers
were combined, dried over anhydrous sodium sulfate and then concentrated under
reduced
pressure to give a crude residue, which was purified by flash silica gel
chromatography (eluent:
ethyl acetate/petroleum ether (v:v= 1: 7)) to give AV (yield: 15%) as a
colorless oil. LC-MS
(ES): nez 290.05 [MH1, =1.55 min (2.6 minute run).
[0471] Step 3: Synthesis of ethyl 2-(5-aminopentyloxy)acetate (L-14)
[0472] To a stirred solution of ethyl ethyl 2-[(5-{[(tert-
butoxy)carbonyl]aminolpentyl)oxy]acetate (AV, 400 mg, 1.38 mmol) in
dichloromethane (5
mL) was added trifluoroacetic acid (5 mL) at room temperature. The resulting
solution was
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stirred at room temperature for 2 hours. The reaction mixture was then
concentrated under
vacuum to give L-14 (yield: 84%) as a yellow oil. LC-MS (ES): miz 190.00
[Mir]. 1R =1.01
min (2.6 minute run).
[0473] L-15: methyl 2-(2-(2-(methylamino)ethoxy)ethoxy)acetate
41 CHO
HCHO
AW Stepl AX Step2
Step3
I AY IAZ 8
Pd/C, H2
Step 4 L45
[0474] Step 1: Synthesis of 2-[2-(benzylamino)ethoxy]ethan-1-ol (AX)
10475] To a stirred solution of 2-(2-aminoethoxy)ethan-1-ol (AW, 5.0 g) and
benzaldehyde (5.0
g) in THF (50 mL) was added sodium triacetoxyborohydride (15.8 g, 74.5 mmol)
at 0 C. The
resulting solution was then stirred at room temperature for 4 hours. Water (50
mL) was added to
the reaction and the resulting mixture was extracted with ethyl acetate (50 mL
x 2). The organic
layers were combined, dried over anhydrous sodium sulfate and then
concentrated under reduced
pressure to give a crude residue, which was purified by flash silica gel
chromatography (eluent:
dichloromethaneimethanol (v:v = 3:1) to give AX (yield: 85%) as a white solid.
LC-MS (ES):
m/z 195.95[MH1, 1R = 0.22 min (2.0 minute run).
[0476] Step 2: Synthesis of 2-12-[benzyl(methyl)amino]ethoxy }ethan-l-ol (AY)
[0477] To a stirred solution of of 2-12-(benzylamino)ethoxy]ethan-1-01 (AX,
10.0 g) in methanol
(200 mL) was added formaldehyde (38% in water) (4.9 mL) and
triacetoxyborohydride (17.0 g)
at room temperature. The resulting solution was stirred at room temperature
for 2 hours.
Saturated aq. sodium bicarbonate (100 mL) was added to the reaction, and bulk
of organic
solvent was then removed under reduced pressure. The resulting mixture was
extracted with
ethyl acetate (200 mL x 3). The organic layers were combined, dried over
anhydrous sodium
sulfate and then concentrated under reduced pressure followed by high vacuum
pump to give AY
(yield: 33%) as a yellow oil. LC-MS (ES): m,'z 210.00 [MH+], tR = 0.43 min
(2.0 minute run).
[0478] Step 3: Synthesis of methyl 2-(2-12-
[benzyl(methyl)amino]ethoxy}ethoxy)acetate (AZ)
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[0479] To a stirred solution of 2-12-[benzyl(methyDamino]ethoxy}ethan-1-ol
(AY, 2 g) in
dichloromethane (20 mL) was added a solution of sodium hydroxide (37%) in
water (20 mL)
followed by tert-butyl 2-bromoacetate (7.76 g) and TBAC (2.78 g) at room
temperature. The
resulting mixture was stirred at room temperature for 15 hours. The aqueous
layer was separated,
and to which aq. hydrogen chloride (4N) was added to adjust the pH to -3
before it was
concentrated under reduced pressure to give a crude residue. Methanol (20 mL)
was then added to
this residue and insoluble salts were filtered out. The solution was
concentrated under vacuum to
give 2-(2[2-(benzyl(methypaminoJethoxyJethoxy)acetic acid (yield: 78%) as a
yellow oil. To a
stirred solution of 2-(2-12-[benzyl(methyDamino]ethoxylethoxy)acetic acid (2
g, 7.48 mmol, 1.00
equiv) prepare above in methanol (50 mL) was slowly added sulfuric acid (2 mL)
at room
temperature. The resulting solution was stirred at 70 C in an oil bath for
3h. The bulk of solvent
was removed under reduced pressure to give a residue, which was diluted with
H20 (30 mL).
Sodium carbonate was then added to the mixture to adjust the pH to -8. The
mixture was then
extracted with ethyl acetate (50 mL x 2), the organic layers were combined,
dried over anhydrous
sodium sulfate and then concentrated under reduced pressure followed by high
vacuum pump to
give AZ (yield: 29%) as a yellow oil. LC-MS (ES): ritiz 281.95 [MH+], tR =
0.30 min (2.0 minute
run).
[0480] Step 4: Synthesis of methyl 2-{2-[2-(methylamino)ethoxy]ethoxy}acetate
(L-15)
[0481] To a stirred mixture of methyl 2-(2-{2-
[benzyl(methyDamino]ethoxy}ethoxy)acetate
(AZ, 600 mg, 2.13 mmol) and palladium on carbon (300 mg) in methanol (30 mL)
under a
nitrogen atmosphere was charged with hydrogen gas via a balloon. The resulting
mixture was
stirred at room temperature for 15 hours. The solid material was removed by
filtration and the
solution was concentrated under vacuum to give L-15 (400 mg) as yellow oil,
which was used for
next step without any further purifications. LC-MS (ES+): //viz 191.95 [MH+],
tR = 0.31 min (2.0
minute run).
[0482] L-16: ethyl 2(5-(methylamino)pentyloxy)acetate
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CH31, NaH Bops
N 0
BA 0 Step 1
BB 0
TFA
_
Step 2 H 0
L-16
[0483] Step 1: Synthesis of ethyl 2-[(5-{[(tert-
butoxy)carbony1](methyDamino}pentypoxy]acetate (BB)
[0484] To a stirred solution of ethyl 2-[(5-{Rtert-
butoxy)carbonyliamino}pentypoxy]acetate
(BA, 1.1 g, 3.8 mmol) in N,N-dimethylformamide (10 mL) was added CH3I (0.71
mL, 11.4
mmol) at 0 C, followed by sodium hydride (304 mg, 7.60 mmol, 60% in mineral
oil) in several
portions at 0 C. The resulting mixture was stirred at room temperature for 16
hours. Water (1.0
mL) was added and the resulting mixture was extracted with ethyl acetate (50
mL x 2). The
organic layers were combined, washed with saturated aqueous solution of sodium
chloride (100
mL), dried over anhydrous sodium sulfate and then concentrated under reduced
pressure to give a
crude residue which was purified by a flash silica gel chromatography (eluent:
ethyl
acetate/petroleum ether (v: v = 1: 10)) to give BB (yield: 21%) as a yellow
oil. LC-MS (ES): m/z
326.20 [MNal, tR = 1.55 min (2.6 minute run).
[0485] Step 2: Synthesis of ethyl 2-{[5-(methylamino)pentyl]oxy)acetate (L-16)
[0486] To a stirred solution of ethyl 24(51 [(tert-
butoxy)carbonyl](methyDamino)pentypoxy]acetate (BB, 240 mg, 0.79 mmol) in
dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL). The resulting
solution was
stirred at room temperature for 16 hours. The solvents were removed under
recued pressure
followed by high vacuum pump to give L-16 (yield: 99%) as a yellow oil. LC-MS
(ES): mh
204.20 [MH+], tR = 0.56 inin (2.0 minute run).
[0487] L-17: 2-(3-(2-(tosyloxy)ethoxy)propoxy)acetic acid
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0 0
Step 1
BC BD
0 _
Pd/C, 1-1?, TsCI
_______________________ HO - 0 ________________
Step 2 BE Step 3
0 TFA 0
OH
Step 4
BF L-17
[0488] Step 1: Synthesis of tert-butyl 2-{3-[2-
(benzyloxy)ethoxy]propoxy)acetate (BD)
[0489] To a stirred solution of 3424benzy10xy)ethoxy]propan-1-ol (BC, 1.8 g,
8.56 mmol) and
tert-butyl 2-bromoacetate (6.6 g, 33.84 mmol, 4.00 equiv) in dichloromethane
(40 mL) was added
TBAC (2.4 g) and aq. Solution of sodium hydroxide (37%, 40 mL). The resulting
mixture was
stirred at room temperature overnight. LC-MS indicated formation of the
desired product. The
reaction mixture was then extracted with ethyl acetate (150 x 3 mL), the
organic layers combined,
dried over anhydrous sodium sulfate and concentrated under reduced pressure to
give a crude
residue, which was purified by a flash silica gel chromatography (eluent:
ethyl acetate/petroleum
ether (v : v = 1: 2) to give BD (yield: 90%) as a colorless oil. Ili NMR (300
MHz, CDC13): 8
7.35-7.27 (m, 5H), 4.57 (s, 2H), 3.94 (s, 2H), 3.63-3.57 (in, 8H), 1.96-1.87
(m, 2H), 1.47 (s, 9H);
LC-MS (ES): mrz 347.10 [MNal, 1R = 1.72 min (2.6 minute run).
10490] Step 2: Synthesis of tert-butyl 243-(2-hydroxyethoxy)propoxylacetate
(BE)
[0491] To a stirred mixture of tert-butyl 2-{3-[2-
(benzyloxy)ethoxy]propoxy}acetate (BD, 2.5 g,
7.71 mmol) and palladium on carbon (2.0 g) in methanol (20 mL) under a
nitrogen atmosphere
was introduced hydrogen gas via a balloon. The resulting mixture was stirred
overnight at room
temperature under hydrogen gas atmosphere. LC-MS indicated completion of the
reaction. The
solids were removed by filtration, the solution was concentrated under vacuum
to give BE (yield:
99%) as a colorless oil. LC-MS (ES): m/z 257.10 [MNa], tR = 1.21 min (2.6
minute run).
[0492] Step 3: Synthesis of tert-butyl 2431 2-[(4-
methylbenzenesulfonyfloxy]ethoxy}propoxy)acetate (BF)
[0493] To a stirred solution of tert-butyl 243-(2-
hydroxyethoxy)propoxy]acetate (BE, 1.8 g,
7.68 mmol) in dichloromethane (50 mL) was added 4-toluenesulfonyl chloride
(2.2 g, 11.54
mmol), triethylamine (2.33 g, 23.03 mmol) and 4-dimethylaminopyridine (95 mg,
0.78 mmol).
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The resulting mixture was stirred overnight at room temperature. LC-MS
indicated formation of
the desired product. The reaction mixture was concentrated under reduced
pressure to give a
crude residue, which was purified by a flash silica gel chromatography
(eluent: ethyl
acetate/petroleum ether (v: v = 1: 2) to give BF (yield: 80%) as a yellow
oi1.1H NMR (400 MHz,
CDC13): 5 7.80 (dõ/= 8.0 Hz, 2H), 7.34 (d, J= 8.4 Hz, 2H), 4.15 (t, J= 3.6 Hz,
2H), 3.93 (s, 2H),
3.61 (t, J= 3.6 Hz, 2H), 3.55-3.49 (m, 4H), 2.45 (s, 3H), 1.85-1.78 (m, 2H),
1.48 (s, 9H); LC-MS
(ES+): mtz 411.00 [MNal, tR = 1.12 min (2.0 minute run).
[0494] Step 4: Synthesis of 2-(3-{2-[(4-
methylbenzenesulfonyl)oxy]ethoxy}propoxy)acetic acid
(L-17)
[0495] To a stirred solution of tert-butyl 2-(3-{ 2-[(4-
methylbenzenesulfonyl)oxy]ethoxy}propoxy)acetate (BF, 400 mg, 1.03 mmol) in
dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room
temperature. The resulting
solution was stirred at room temperature for 1 hour. LC-MS indicated
completion of the reaction.
The reaction mixture was concentrated under reduced pressure to give L-17 (350
mg) as a yellow
oil, which was used for next step without further purifications. LC-MS (ES+):
ntiz 332.90 [MF11,
= 0.81 min (2.0 minute run).
[0496] Unless otherwise noted, the following intermediates and their analogs
(for examples, but
not limited to, analogs with substitutions such as halogens) were synthesized
according to similar
procedures described above for the synthesis of L-17, by utilizing
corresponding starting
materials and reagents.
[0497] L-18: 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate
[0498] L-19: ethyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate
=
[0499] L-20: ethyl 3-(2-(2-(tosyloxy)ethoxy)ethoxy)propanoate
002Et
[0500] L-21: ethyl 5-(tosyloxy)pentanoate
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Ts0
[0501] 14-22: ethyl 3-(2-(tosyloxy)ethoxy)propanoate
C 02Et
[0502] L-23: ethyl 2-(5-(tosyloxy)pentyloxy)acetate
[0503] L-24: ethyl 3-(5-(tosyloxy)pentyloxy)propanoate
C 2Et
[0504] L-25: 5-hydroxypentyl 4-methylbenzenesulfonate
[0505] L-26: ethyl 2-(5-(tosyloxy)pentyloxy)acetate
TsOO..,CO2 Et
[0506] L-27: ethyl 2-(3-(tosyloxy)propoxy)acetate
TsOOCO2Et
[0507] L-28: ethyl 2-(2-(tosyloxy)ethok3 )acetate
Ts0,
0-00 2E t
[0508] L-29: ethyl 2-(4-(2-(tosyloxy)ethoxy)butoxy)acetate
Ts(Y-".--C)CY'-'t 02 Et
L-29
[0509] L-30: 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate
TsOQOOH
[0510] L-31: 2-((2R,3R)-3-(2-hydroxyethoxy)butan-2-yloxy)ethyl 4-
methylbenzenesulfonate
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TsOOO¨ OH
[0511] L-32: 2-(2-piperazin-1-yl)-ethoxy-acetic acid
0
N )LOH
HN.,)
[0512] L-33: methyl 6-(4-(2-(2-(tert-butoxy)-2-oxoethoxy)ethyl)piperazin-1-
yl)nicotinate
Boc
known compound
jcyk
F 0
N) N
Alrij N ,or(:rN.'"/) TFA
0
DIPEA.NMP
0 80 C K2CO3, DM F
0 L-33
[0513] Step 1: Synthesis of tert-butyl 4-(5-(methoxycarbonyl)pyridin-2-
yDpiperazine-1-
carboxylate:
r.N.Boc
Nõ.I
[0514] A mixture of methyl 6-fluoronicotinate (2.0 g, 13.2 mmol), tert-butyl
piperazine-l-
carboxylate (2.4 g, 13.2 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.3 g,
26.4 mmol) in
anhydrous 1-methylpyrrolidin-2-one (10 ml) was stirred at 90 C for 12 hours.
TLC showed the
reaction was complete. The cooled reaction mixture was partitioned between
water (10 ml) and
ethyl acetate (50 ml). The organic layer was collected, washed with brine (50
ml x 2), dried over
anhydrous sodium sulfate, and concentrated under reduced pressure to give a
crude residue which
was purified by column (eluted with 20% ethyl acetate in hexane) to afford
tert-butyl 445-
(methoxycarbonyppyridin-2-yDpiperazine-1-carboxylate (4.0 g, yield 95%) as
yellow solid.
1HNMR (400 MHz. CDC13): 1.48 (s, 9H), 3.53-3.56 (m, 4H). 3.67-3.69 (m, 4H),
3.87 (s, 3H),
6.58 (d, J= 8.8 Hz, 2H), 8.02-8.05 (m, 1H), 8.79-8.80 (m, 1H). Chemical
Formula: C16H23N304,
Molecular Weight: 321.37.
[0515] Step 2: Synthesis of methyl 6-(piperazin-1-yl)nicotinate
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N
0
()
[0516] A mixture of tert-butyl 4-(5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-
carboxylate
(4.0 g, 12.4 mol) and 2,2,2-trifluoroacetic acid (10 ml) in dichloromethane
(10 ml) was stirred at
room temperature for 2 hours. TLC showed the reaction was complete. The
volatiles were
evaporated under reduced pressure. The residue was taken up with
dichloromethane (50 ml) and
washed with aqueous sodium bicarbonate solution (iN, 15 in!), dried over
sodium sulfate to give
methyl 6-(piperazin-1-yl)nicotinate (3.8 g, crude) as yellow oil which was
used in next step
without further purification. 1HNMR (400 MHz, DMSO-d): 8 3.13-3.16 (m. 4H),
3.80 (s. 3H),
3.82-3.85 (m, 4H), 6.96 (d, J= 9.2 Hz, 1H), 8.00-8.03 (m, 1H), 8.67-8.68 (m,
1H). Chemical
Formula: C11 H15N302, Molecular Weight: 221.26.
[0517] Step 3: Synthesis of methyl 6-(4-(2-(2-(tert-butoxy)-2-
oxoethoxy)ethyppiperazin-1-
yl)nicotinate.
Jo/I<
A mixture of methyl 6-(piperazin-l-yl)nicotinate (500 mg, 2.3 mmol), tert-
butyl 2-(2-
(tosyloxy)ethoxy)acetate (745 mg, 2.3 mmol) and potassium carbonate (1.2 g,
9.0 mmol) in
anhydrous N,N-dimethylformamide (10 nil) was stirred at 40 C for 12 hours. TLC
showed the
reaction was complete. The cooled reaction mixture was partitioned between
water (20 ml) and
ethyl acetate (20 ml). The organic layer was collected, washed with brine (100
ml x 2). dried over
anhydrous sodium sulfate, and concentrated under reduced pressure to give a
crude residue which
was purified by silica gel flash chromatography (eluted with 20% ethyl acetate
in hexane) to
afford methyl 6-(4-(2-(2-(tert-butoxy)-2-oxoethoxy)ethyDpiperazin-1-
yDnicotinate (L-33) (400
mg, yield 46%) as yellow solid.
[0518] Synthesis of Examples
[0519] Example 1: (2S,4R)-1-0S)-242-(345-(4-(344-cyano-3-
(trifluoromethyl)phenyl)-5,5-
dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)phenoxy)pentyloxy)propoxy)acetamido)-
3,3-
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dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazoll-5-Abenzyppyrrolidine-2-
carboxamide:
F
F --IF 01 1, ---
Step 1 ,
ABM-3 FF. F 0,--1¨
K2CO3
S
OH AB owo---,....----.0----e-x--
F F 0
Step 2
2N HO
Swc,.............Ø..-10H
BH
0 i
Step 3 F ---, ¨ \\¨N N
Amide coupling )1- 'T. H
ULM-1
S ,
1
.=-.
Op.,OH
0
Example 1 irS
NH
=
[0520] Step 1: Synthesis of tert-butyl2-(3-( (5-(4-13-(4-cyano-3-
(trifluoromethyl)pheny1)-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-y1
)phenoxy)pentylioxy)propoxy)acetate (BG)
[0521] To a stirred solution of tert-butyl 243-[(5-([(4-
methylbenzene)sulfonyl]oxy]pentyl)oxy)propoxy)acetate (AB, 150 mg, 0.35 mmol)
in
acetonitrile (10 mL) was added 443-(4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
sulfanylideneimidazolidin-l-y1]-2-(trifluoromethyDbenzonitrile (ABM-3, 141 mg,
0.35 mmol)
and potassium carbonate (144 mg, 1.04 mmol). The resulting mixture was stirred
overnight at
80 C in an oil bath. LC-MS indicated formation of the desired product. The
reaction mixture was
then extracted with ethyl acetate (20 mL x 2). The organic layers were
combined, washed with
saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous
sodium sulfate and
then concentrated under reduced pressure to give a crude residue, which was
purified by flash
silica gel chromatography (eluent: ethyl acetate/petroleum ether, v: v = 1:1)
to give 0.22 g of BG
as a yellow oil. 1H NMR (400 MHz, CDC13): 8 7.96 (s, 2H), 7.86 (d, J. 8.6 Hz,
1H), 7.19 (d, J.
8.8 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 4.50(s, 2H), 4.30 (t, J= 6.4 Hz, 2H),
4.02 (t, J= 6.4 Hz,
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2H), 3.53 (m, 2H), 3.44 (m, 2H), 1.96-1.80 (m, 4H), 1.69-1.53 (m, 2H), 1.49
(s, 6H), 1.48 (s,
9H), 1.44-1.22 (m, 2H); Mass (ES): m/z 686.35 [MNal.
[0522] Step 2: Synthesis of 2-(34(5-(4-(344-cyano-3-(trifluoromethypphenyl:1-
5,5-dimethy1-4-
oxo-2-sulfanylideneimidazolidin-1-yl]phenoxy)pentyl]oxy]propoxy)acetic acid
(BR)
[0523] To a stirred solution of tert-butyl 2-(3-([5-(4-13-[4-cyano-3-
(trifluoromethyl)phenyl]-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
yl)phenoxy)pentyl]oxy)propoxy)acetate (BG, 220
mg, 0.33 mmol) in dioxane (4.0 mL) was added hydrogen chloride (2N in water,
1.0 mL). The
resulting mixture was stirred at 80 C for 2h. LC-MS indicated formation of
the desired product.
The resulting mixture was concentrated under reduced pressure to provide 200
mg of BR as light
yellow oil. Mass (ES): miz 608.25 I MH+].
[0524] Step 3: Synthesis of Example 1:
[0525] To a stirred solution of 2-(3-R5-(443-[4-cyano-3-
(trifluoromethyl)pheny1]-5,5-dimethyl-
4-oxo-2-sulfanylideneimidazolidin-1-yl]phenoxy)pentyl]oxy]propoxy)acetic acid
(BH, 160 mg,
0.26 mmol) in N,N-dimethylformamide (5 mL) was added (2S,4R)-14(2S)-2-amino-
3,3-
dimethylbutanoy1]-4-hydroxy-N-(14-(4-methy1-1,3-thiazol-5-
yl)phenylimethyl)pyrrolidine-2-
carboxamide hydrochloride (ULM-1, 182 mg, 0.39 mmol), DIPEA (151 mg, 1.17
mmol), EDCI
(101 mg, 0.53 mmol) and HOBt (70 mg, 0.52 mmol). The resulting mixture was
stirred at room
temperature for 5 h and LC-MS indicated formation of the desired product.
Water (20 mL) was
added to the reaction, the resulting mixture was extracted with ethyl acetate
(20 mL x 2). The
organic layers were combined, washed with saturated aqueous solution of sodium
chloride (20
mL), dried over anhydrous sodium sulfate and then concentrated under reduced
pressure to give a
crude residue. The residue was purified by Prep-HPLC to give 60 mg of Example
1 as a white
solid. NMR (400 MHz, CD30D): 5 8.88 (s, 1H), 8.16 (d, J. 8.0 Hz, 2H), 8.00
(s, 1H), 7.49-
7.42 (m, 4H), 7.28 (d, J = 8.8 Hz, 2H), 7.06 (m, 2H), 4.87 (s, 1H), 4.59 (m,
3H), 4.37 (m, 1H),
4.05 (m, 4H), 3.88 (m, 2H), 3.65 (in, 2H), 3.58 (m, 2H), 3.50 (m, 2H), 2.48
(s, 3H), 2.25 (m, 1H),
2.10 (m, 1H), 1.90 (m, 2H), 1.80 (m, 2H), 1.66 (m, 2H), 1.56 (s, 8H), 1.04 (s,
9H); LC-MS (ES):
m,'z 1020.20 [ MH1, tR = 2.28 min (3.6 minute run).
[0526] Example 2: (2S,4R)-14(S)-2-(2-(3-(5-(4-(3-(6-cyano-5-
(trifluoromethyl)pyridin-3-y1)-
5,5-dimethy1-4-oxo-2-thioxoimidazolidin-l-
y1)phenoxy)pentyloxy)propoxy)acetamido)-3,3-
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dinietbylbutanoy1)-4-hydroxy-N-(1-(4-methylthiazol-5-y1)benzyl)pyrradine-2-
carboxamide:
Step 1
0
AB L-1 0
N=
sOH
Step 2 ABM-4
ULM-1
rS 0p Step 3
N NH
BI
/ N N
N:::
N-
0
Op-OH
Example 2 rs 0
N 11# NH
=
10527] Step 1: Synthesis of 2-[3-({5-[(4-
methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetic
acid (L-1)
[0528] To a stirred solution of tert-butyl 2-(34(5-[(4-
methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetate (AB, 1.3 g, 3.02 mmol) in
dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at room
temperature. The
resulting solution was stirred at room temperature for 3 hours. The reaction
mixture was then
concentrated under vacuum to give 1.5 g (crude) of L-1, which was used for
next step without any
further purification. LC-MS (ES): ny'z 375.34 [MITI, tR = 1.39 mm (2.6 minute
run).
[0529] Step 2: Synthesis of (2S,4R)-1-1(2S)-3,3-dimethy1-2-{243-((5-[(4-
methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetamido}butanoy1]-4-hydroxy-N-(
methy1-1,3-thiazol-5-yOphenylimethyl )pyrrolidine-2-carbox amide (B1)
[0530] To a stirred solution 243-({5-[(4-
methylbenzenesulfonypoxy]pentyl}oxy)propoxy]acetic acid (L-1, 1.5 g, 4.01
inmol) in N,N-
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dimethylfonnamide (20 mL) was added HATU (1.36 g, 3.58 mmol), DIEA (0.7 mL)
and (2S,4R)-
1-[(2S)-2-amino-3,3-dimethylbutanoy1]-4-hydroxy-N-([4-(4-methy1-1,3-thiazol-5-
yl)phenyl]methyl}pyffolidine-2-carboxamide (ULM-1, 1.3 g, 3.02 mmol) at room
temperature.
The resulting mixture was stirred for 2h at room temperature. It was then
diluted with water (100
mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were
combined, washed
with saturated aqueous solution of sodium chloride (60 mL), dried over
anhydrous sodium sulfate
and then concentrated under reduced pressure to give a crude residue, which
was purified by flash
silica gel chromatography (eluent: dichloromethane/methanol (v: v = 10:1)) to
give 0.5 g of BI.
LC-MS (ES+): ntiz 787.34 [MH1, 1R= 1.87 min (3.0 minute run).
[0531] Step 3: Synthesis of (2SAR)-1-[(2S)-2-[2-(3-([5-(4-(346-cyano-5-
(trifluoromethyl)pyridin-3-y1}-5,5-dimethy1-4-oxo-2-sulfanylideneimidazolidin-
1-
y1}phenoxy)pentyl]oxy}propoxy)acetamido]-3,3-dimethylbutanoy1]-4-hydroxy-N-{
[4-(4-methyl-
1.3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (Example 2)
[0532] To a stirred solution of 5-[3-(4-hydroxypheny1)-4,4-dimethyl-5-oxo-2-
sulfanylideneimidazolidin-l-y1]-3-(trifluoromethyppyridine-2-carbonitrile (ABM-
4, 52 mg, 0.13
mmol), (2S,4R)-1-[(2S)-3,3-dimethy1-2-{ 243-0 5 -[(4-
methylbenzenesulfonypoxy]pentyl}oxy)propoxy]acetamido}butanoy1]-4-hydroxy-N-{
[4-(4-
methy1-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (BI, 100 mg,
0.13 mmol) in
N,N-dimethylformamide (10 mL) was added potassium carbonate (34 mg, 0.25 mmol)
under an
atmosphere of nitrogen. The resulting solution was stirred for 2 h at 80 C.
The resulting mixture
was concentrated under vacuum to give a crude residue, which was purified by
Prep-HPLC to
give 38.1 mg of Example 2 as a white solid. ill NMR (300 MHz. CD30D): 8 9.12
(s. 1H),
8.83(s, 1H), 8.63 (s, 1H), 7.44-7.39 (m, 4H), 7.00 (d, J= 9.0 Hz, 2H), 7.20
(d, J= 9.0 Hz, 2H),
4.80-4.26 (m, 5H), 4.06-3.65 (m, 6H). 3.62-3.35 (m. 6H). 2.43 (s. 3H) , 2.21-
2.01 (m. 2H), 1.85-
1.65 (m, 4H), 1.60-1.42 (m, 10H), 1.00 (s, 9H): LC-MS (ES+): nvz 1021.12 [MH1,
tR= 2.36 min
(3.6 minute run).
[0533] Unless otherwise noted, the following examples were synthesized
according to analogous
procedures described above for synthesis of examples 1 and 2, utilizing
corresponding reagents,
intermediates, and starting materials.
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[0534] When referring to the specific exemplary compounds presented herein,
the specification
uses the terms "example #." For example, compound 1 (Table 2) is also referred
to as Example 1.
105351 Table 2. Exemplary Compounds.
Ex
Structure Compound name and Analytical data
(2S,4R)-14(S)-2-(2-(3-(5-(4-(3-(4-cyano-3-(trifluoromethyl)pheny1)-5,5-
dimethyl-4-oxo-2-
thioxoimidazolidin- 1 -yl)phenoxy)pentyloxy)propoxy)acetamido)-3.3-
dimethylbutanoy1)-4-
F ,5L4_ hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-
carboxamide
r'0.0
1
re. 0 111 NMR (400 MHz, CDC13): 5 7.96 (s, 211), 7.86
(d, J = 8.6 Hz, 1/I), 7.19 (d, J = 8.8 Hz,
rifLO--7?" 2H), 7.02 (d, J = 8.6 Hz, 2H), 4.50 (s, 2H), 4.30
(t, J = 6.4 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H),
3.53 (m, 2H), 3.44 (in, 2H), 1.96-1.80 (in, 411), 1.69-1.53 (rn, 211), 1.49
(s, 611), 1.48 (s,
9H), 1.44-1.22 (m, 2H); Mass (FS+): m/z 686.35 [MNa+]
(2S,4R)-14(S)-2-(2-(3-(5-(4-(3-(6-cyano-5-(tifluoromethyl)pyridin-3-y1)-5,5-
dimethyl-4-
oxo-2-thioxoimidazolidin-l-yl)phenoxy)pentyloxy)propoxy)acetarnido)-3,3-
dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-
carboxamide
N )Nap
_
2
19`.6M11 1/1 NMR (300 MHz, CD30D): 5 9.12 (s, 1I1), 8.83(s,
1I1), 8.63 (s, 1I1), 7.44-7.39 (m,
411), 7.00 (d, J = 9.0 Hz, 214), 7.20 (d. J = 9.0 Hz, 2H), 4.80-4.26 (m, 514).
4.06-3.65 (rn,
611), 3.62-3.35 (m, 614), 2.43 (s, 311) ,2.21-2.01 (m, 214), L85-1.65 (in,
414), L60-1.42 (iii,
1011), 1.00 (s, 914): LC-MS (FS+): intz 1021.12 [MH+], tR = 2.36 min (3.6
minute run).
NC =
Prepared from ABM-16, L-1, and ULM-1
Nnl,
F3 r F
(2 S,4R)-1-[(2S)-212-(34 [5441 344-cyano-3-(trilluoromethyl)phenyl]
= oxo-2-sulfanylideneimidazolidin-1 -y1) -241 uomphenoxppentyl]oxy
Jpropoxy)acetamidoi -
3 3,3-dimethylbutanoy1]-4-hydroxy-N-(14-(4-methy1-
1,3-thiazol-5-
yl)plienyl]methyl}pyrrolidine-2-carboxamide
NMR (300 MHz, CD:10D) : 5 8.84 (s, 1H), 8.13-8.09 (m, 2H), 8.01-7.93 (m, 1H),
7.51-
7.31 (m, 414), 7.21-7.01 (m, 3H), 4.70-4.41 (in, 4H), 4.35-4.22(m, 114), 4.15-
4.03 (m, 2H).
0 3.95-3.90 (m, 2 II), 3.90-333 (m, 211), 3.61-3.56
(m, 2 II), 336-331 (m, 2 II), 3.50-342
NH
1m, 2 H), 2.45 (s, 3H), 2.21-2.10 (m, 1 H), 2.10-2.12 (m, 1H), 1.92-1.70 (m,
4H), 1.63-1.50
44110 CL1, (ifk, 3 H), 3.50-1.45(m, 711), 1.04 (s, 914); LC-
MS (ES*): m,'z 1038.31 [MW], IR = 2.35 min
)1'0,
(..) ^ .6 minute run)
H OH
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Structure Compound name and Analytical data
#
o
NC¨[)¨N(
-,-= )r-N Prepared from ABM-3. L-1, and LIM-3
F3C .
1) (25,4R )-1-[(2S)-212-(3- ( [5444 3-(4-cyano-3-
(trifluoromerbyl )pheny1)-5,5-dimerbyl-4-
oxo-2-sulfanylideneimidazolidin-l-yl)phenoxy)pentyl]oxy } propoxy)acetamido] -
3,3-
4
dimethylbuianoy11-4-hydroxy-N-[(1S)-1-14-(4-methy1-1,3-thiazol-5-
0 yl)phenynethylipyrrolidine-2-carboxamide
III NMR (300 MHz, CD30D):88.88 (s, 1H), 8.58 (d, J = 7.5 Hz, 111), 8.16 (m,
211), 8.00
N1"-% 0-=--- (m, 1H), 7.53 (d,./ = 9.3 Hz, 1H), 7.42 (m,
4H), 7.26 (m, 2H), 7.05(m, 2H), 5.01 (m, 1H),
4.72 (d, J = 9.3 Hz, 1H), 4.58 (m, 1H), 4.44 (s, 1H), 4.04 (m, 4H), 3.83-3.49
(rn, 8H), 2.48
/ \ cs V (s, 311), 2.20 (m, 11-1), 1.83 (m, 511), 1.50 (m,
1311), 1.03 (s, 911); LC-MS (ES'): nez 518.20
H . [M+.2] /2, IR = 3.67 min, (5.6 minute run)
bH
0
)"--(,1. Prepared from ABM-17, L-1, and ULM-1
02N
/ \ N N
s 4 ( 25,4R)-1-[(25 )-2 4243- { [5-14- ( 5,5-dimerby1-
314-nitro-3-(trifluoromethyl)phenyl] -4-ox o-
F3C
--\---\._\ 2-sulfanylideneimidazolidin-1-yl}phenoxy)pentylloxy
}propoxy)acetamido]-3,3-
0 dimethylbutanoy1]-4-hydroxy-N-(14-(4-methy1-1,3-
thiazol-5-y1)phenyllmethyl }pyrrolidiue-
2-carboxamide
0
N--1.1 11-1 NMR (300 MHz, CD30D) : 68.82 (s, 111), 8.15-
8.13 (in, 2H), 8.01-7.93 (m, 1H),
..,_s CD)
7.51-7.31 (m, 411), 7.22-7.22 (m, 211), 7.22-7.05 (m, 211), 4.71 (s, 111),
4.60-4.35 (m, 3
NH
4 0 0y5r.r H), 4.32-4.24 (m, 1H). 4.120-3.95 (in. 4H), 3.93-
3.75 (m, 2H), 3.62- 3.52 (m, 2 H), 3.51-
3.41 (m, 2 H), 3.40-3.35 (in, 21-1), 2.45 (s, 3H), 2.24-2.10 (in, 11-1), 2.09-
2.01 (m, 1H),
14)LCI15
H 1.90-1.72 (m, 4H), 1.65-1.52 (m, 3 H), 1.51-
1.34(m, 7H), 1.00 (s, 9H); IC-MS (ES'):
t:.
OH
nez 1040.32 (MH+]. IR = 2.52 min (3.6 minute run)
HN N PH Prepared from ABM-6, L-1, and ULM-1
(5,0"-"b")c 0
4 ;11 NH
µ (2S,4R)-1-[(2S)-2-(2-(3-[(5- (4 -13-(4-cyano-3-
methylpheny1)-5,5-dimethy1-4-oxo-2 -
sulfanylidenei midazolidin-1-yl]phenoxy } pentyl)oxy]propoxylacetamido)-3,3-
s
dimethylbutanoy1]-4-hydmxy-N-([4-(4-methy1-1,3-thiazol-5-yl)phenyl]methyl }
pyrrolidine-
6
0 N I 2-carboxamid
1H NMR (400 MHz, CD30D):88.88 (s, 111), 7.83 (d, J = 8.0 Hz, 111), 7.53 (rn,
611),7.28 (d,
J = 9.2 Hz, 211), 7.06 (d, J = 8.8 Hz, 211), 4.71 (s, 1I-1), 4.59 (m, 31-1),
4.39 (d, J = 15.61-h,
0 N 111), 4.05 (m, 411), 3.88 (m, 211), 3.68 (in.
411). 3.52 (m. 211). 2.61 (s, 311), 2.50 (s, 3H),
?) 2.25 (m, 111), 2.10 (m, 111), 1.93 (in, 411), 1.68 (m,
1011), 1.06 (s, 911); LC-MS (ES*): miz
CN 483.95 [M+2] /2, IR =2.28 min (3.60 minute run).
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Structure Compound name and Analytical data
#
PH Prepared from ABM-2, 1A, and ULM-1
,....,1pN..N
y0-------0
? 0 o 0 NH (25,4R)-11( 25)-24 2-( 31(5- j 443-(4-cyano-3-
fluoropheny1)-5,5 -di methy1-4-oxo-2-
se su. Ifanyl.i deneimidazolidi n -1-y1 Iphenoxy I
pentyl )oxy] propcx y } acetamido)-3,3-
dtmethylbutanoy1]-4-hydroxy-N-( [4-(4-methy1-1,3-thiazol-5-yl)phenyl] methyl I
pyrrolidine-
7 0 1
N¨ 2-carboxamide
4ItIH NMR (300 MHz, CD30D): 68.87 (s, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.63 (d,
J = 8.1 Hz,
s. .N 111), 7.54-7.41 (m, 51-1), 7.26 (d, J= 8.7, 2H), 7.03 (d. J = 9.0
Hz, 2H). 4.70 (s, 1H), 4.61-
S
0 N 4.4.51 (m, 311), 4.37-4.32 (m, 111), 4.04-3.98
(m, 411), 3.98-3.81 (m, 211), 3.67-3.63 (m,
11
---"---r!.. 2H), 3.57 (t,J= 6.6 HZ, 211), 3.57 (t,.! = 6.6Hz, 1H),
2.48 (s, 3H), 2.23-2.09(m, 2H), 1.92-
F''
1.79 (m, 4H), 1.67-1.53 (in, 1011), 1.03 (s, 9H); LC-MS (ES*): m,'z 970.55 [M1-
11, tR = 1.55
CN
min (3.6 minute run)
OH
Prepared from ABM-1, L-1, and ULM-1
? 0 0 25,4R)-1-[(25)-2-(2-( 3-[(5-(4434 3-cb loro-4-cyanopheny1)-
5,5-dimethyl-4-oxo-2-
0 NH
s. ,, 1 sttlfanylideneimidamlidin-l-yl]phenoxy j pentyl
)oxy]propoxy I acetamido)-3,3-
dunethylbu tanoyll -4-hydroxy -N- ( [4-(4-metity1-1,3-thiazol-5-
yl)phenyl]methyl I pyrrolidine-
8
9 3
N-- -.\ 2-carboxamide
c\--- IH NMR (400 MHz, CD30D):69.00 (s, 1H), 7.98 (d, J
= 8.4 HZ, 1H), 7.87 (s, 1H),7.66 (d.J
N.4.-Ns = 10.4114111), 7.50 (m. 4H). 7.29 (d, J = 8.8 Hz, 2H),
7.06 (d..1 = 8.8 Hz. 2H). 4.71 (s.
(11), 4.62 (m, 311), 4.39 (d, J = 15.6 Ilz, 1/1), 4.05 (m, 41-1), 3.89 (m,
2H), 3.68 (m, 4I1),
0
(.10 CN 3.52 (m, 2H), 2.50 (s, 3H), 2.25 (m, 1H), 2.10 (m, 111),
1.93(m, 4H), 1.68 (m, 2H), 1.59(m,
`-''
811), 1.05 (s, 911); LC-MS (ES*): miz 986.25 [M1-11 , tR =3.44 min. (5.00
minute run)
..2.4,1 .01 Prepared from ABM-5, L-1, and ULM-1
rr(Ø--...õ...,-.0,-.41. N 0
0 NH
(25,4R)-14(25)-2-(2-{ 3-1.(5-{443-(4-cyano-3-methoxypheny1)-5,5-dimethyl-4-oxo-
2-
0 sulfanylideneimidazolidin-l-yl]phenoxy Jpentyl
)ox A propoxy I acetamido)-3.3-
$ d imethylbutanoyll-4-hydroxy-N-( [4-(4-metliy1-1,3-thiazol-5-
yl)phenyl]inethyl I pyrrolidine-
9 0 µ i
N 2-carboxamide
\-6
-1,1 II-1 NMR (400 MHz, CD30D) 68.88 (s, 1H), 7.77 (d,
J = 8.0 Hz, 111), 7.49-7.42 (m, 411),
0 NX--,S 7.37 (d, .1= 1.6 Hz, 1H). 7.18-7.16 (m. 3H), 7.06-
7.04 (m, 2H), 4.71 (s, 1H). 4.62-4.54 (m.
3/1), 4.39 (d, J = 15.6 Hz, 1H), 4.05-4.00 (m, 71-1), 3.91-3.80 (m, 2/1), 3.72-
3.49 (m, 6I1),
-..0 .-:.-._ 2.50 (s, 3H), 2.27-2.07 (m, 211), 1.93-1.81 (m,
4H), J.66-1.56(m, 10H), 1.06 (s, 9H); LC-
MS (ES): miz 982.55 [MHI, IR =2.67 min (5.0 minute run)
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Structure Compound name and Analytical data
#
H ,OH Prepared from ABM-16, L-1, and ULM-3
O---N---' -'NirN-- N . (2S,4R)-1-[(2S)-/-1.2-(3-( [5444 314-cyano-3-
(trifluoromethyl)phenyl] -5,5 -dimettly1-4 -
1 0 d
s o
r......Niry\H oxo-2-sulfanylideneimidazolidin-1 -y1) -2-
fluorophenoxy)pentyli oxy )propoxy)acetamidoj-
3,3-dimethylbutanoy1)-4-hydroxy-N1( 1 S)-1 -(444-methyl-I ,3-thiazol-5-
* F N-- yl)phenyl]ethyllpyrrolidine-2-carboxamide
11-1 NMR (300 MHz, DMSO) 8 8.98 (s, 1H), 8.44-8.40 (m, 2H), 8.27 (s, 1H), 8.08
(d, J =
S
0 N 8.4 Hz, 111), 7.45-7.28 (m, 711), 7.17 (d, J = 8.7
I1z, 1I-1), 5.12 (d, J = 3.3 Hz, III), 4.92-
4.88(m, 1H), 452-4.45 (m, 2H), 4.28 (s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.92
(s, 2H), 3.58-
* CFa
3.38 (in, 811), 2.45 (s, 3H), 2.08-2.02 (in, 1H), 1.83-1.74 (in, 5H), 1.61-
1.46 (m, 11H), 1.38
CN
N .4
HN (d, J= 6.9 Hz, 2H), 0.93 (s, 9H); LC-MS (ES`): miz 1052.40 [MIT], tR =
1.79 mm
::m
n
; 0
... Prepared from ABM-18, L-1, and ULM-3
0'''''01
1 1 s 4k
µ i
N 0 NH (2S,4R)-1-[(2S)-242-(31 [5441 3-14-cyano-3-(trifluoromedly 1
1phenyl] -5,5 -d imethy1-4-
oxo-2-sul fanylideneimidazolidin-l-yl ) -2,6-
difluorophenoxy)pentyl]oxy Ipropoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-
N-
F
* F [I IS)-114-(4-methy1-1,3-th iazol-5 -
yl)phenyl]ethyl)pyrrol i dine-2-carboxamide
III NMR (400 MHz, DMSO) 8 8.98 (s, 11-1), 8.45-8.39 (m, 211), 8.26 (s, 11-1),
8.07 (d, J=
" N).s
8.4 Hz, 1H), 7.44-7.28 (m, 7H), 5.12 (d, J = 3.6 Hz, 1H), 4.92-4.88 (m, 1H),
4.55 (cl, J = 9.6
0 N
Hz, 1H),4.44 (t, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.20 (t, J = 6.8 Hz, 2H), 3.91
(s, 2H), 3.57-
3.37 (m, 811), 2.45 (s, 311), 2.08-2.02 (m, 111), 1.80-1.71 (m, 51-1), 1.61-
1.46 (m, 1011), 1.38
N (d,J = 6.8 Hz, 3H), 0.93 (s, 9H): Mass (ES): Irv:
1070.50 [MH1
PH Prepared from ABM-3, L-2, and ULM-1
=
(2S,4R)-1-[(2S)-212-(3-1[5-(4-( 344-cyano-3-(trilluorotiledlyl)phenyl]-5,5-
dimethyl-4-
0
0 NH oxo-2-sulfanylideneimidaztalidin-1-yl)phenoxy)-3,3-
s * dimethylpentyl]oxy}propoxy)acetamido]-3,3-dimethylbutanoy1]-4-hydmxy-
N-( [444-
12 µ 1
0 N me thy1-1,3-thiazol-5-yl)phenyl] methyllpyrrolid
ine-2-carbox.lunide
ifl NMR (400 MHz, CD30D): 8 8.88 (s. 111). 8.15 (m, 211), 8.01 (m, 1H), 7.49
(m, 411),
NI-Nxµs
7.30 (d, J = 9.2 Hz, 2H), 7.06 (d, J =8.8 Hz, 2H), 4.71 (s, 1H),4.61 (m, 3H),
4.39 (n, 111),
ON
4.13 (m, 2H), 3.98 (m, 2H), 3.88 (n, 111), 3.$4(m, 1H), 3.66 (m, 211), 359 (m,
4H), 2.49
4 F3 (s, 3H). 2.28 (m. 1H), 2.14 (m, 11-1), 1.91 (m,
2H), 1.81 (m. 21-1), 1.64 (m, 21-1). 1.56 (s, 61-1).
CN 1.05 (m, 1511); LC-MS (ES*): nez 1048.55 [MI11, IR
= 1.86 min (3.0 minute run).
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Structure Compound name and Analytical data
#
pH
Ht4.1
0'-'-'0/ Prepared from ABM-3. L-3, and 1LM-1
0
0 H0.5 NH(2S,4R)-1-1(2S)-2-12-(3-1[5-(4-(3-[4-cyano-3-
(trifluoromethyl)phenyl]-5,5-dimethyl--1-
S . oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)-3-
µ i
N hydroxypentyl]oxy Jpropoxy)acetamido]-3.3-
dimethylbutanoy1]-4-hydroxy-N-{ [4-4-
13 \.¨
methyl-1,3-thiazol-5-yl)phenyllmethyllpyrrolidine-2-carboxamide
' Nx.rs IH NMR (300 MHz, CD30D): 6 8.86(s, 1H), 8.16-8.13
(d, J = 7.8 Hz, 2H), 8.00-7.96 (dõ/
0 N = 9.9 Hz, III), 7.78-7.40 (m, 4/1), 7.29-7.26 (d,
J = 9.9 Hz, 211), 7.07-7.04 (d, J= 8.7 Hz,
di F F
2H) , 4.70-4.33 (m, 5H), 4.19-4.13 (m, 2H). 4.04-3.81 (m, 5H). 3.65-3.56 (in.
6H), 2.47 (s,
F 311), 2.23-1.70 (m, 8H), 1.54 (s, 611), 1.02 (d, J
= 6.0 Hz, 911). LC-MS (ES*): miz
\\
N 1036.35 [M111, tR = 1.51 min (3.0 minute run).
H Prepared from ABM-3, L-1, and 1.7LM-6
H
(2S,4R)-N-[(4-chlorophenyI)nethy1]-1-[(2S)-2-12-(3-{ [5-(4-(344-cyano-3-
1 4
H N
(tritluoromethyl)phenyl.1-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
y1)phenoxy)pentylioxy }pmpoxy)acetamido)-3,3-dimethylbutanoy1]-4-
hydroxypyrrolidine-
2-carboxamide
NMR (400 MHz, CD30D) 6 8.13-8.17 (m, 2H), 7.99 (d, J = 7.8 Hz, 1/1), 7.32-7.36
(m,
211), 7.25-7.31 (in, 411), 7.05 (d, J = 9.0 Hz, 211), 4.51-4.57 (m, 211), 4.47
(d, J = 16.0 Hz,
S ,; 211), 4.27 (d,./ = 14.9 Hz, 211), 4.04 (t, J = 6.5
Hz, 1H), 3.99 (d, J = 3.5 HZ, 2H), 3.64-3.68
T.....(.
N. (m, 211), 3.56-3.61 (m, 211), 3.50 (t, J = 6.3 Hz.
2H), 2.17-2.24 (in. 1H), 2.07 (dd, J = 3.9,
13.3 Hz, 1/1), 1.89-1.92 (m, 211), 1.81-1.86 (m, 111), 1.64-1.70 (m, III),
1.57-1.61 (m, III),
N4
1.30 (br. s., 611), 0.99-1.07 (m, 911), 0.91 (t../ = 6.8 Hz, 4H). IC-MS (ES
twr. *): 957.35 ):::
[MW]
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Structure Compound name and Analytical data
#
HN---U)
Prepared from ABM-3, L-1. and ULM-7
= i
(2S,4R)-1-[(2S)-2-12-(3-{ (5-(4-(344-cyano-3-(trifluoromethyl)phenylj-5,5-
dimethyl-4-
=
oxo-2-sulfanylideneim idazolidin-l-yl }phenoxy)pentylloxy ) propoxy)acetamidol
-3,3-
d imethylbutanoyll-N-R4-cyanophenyl)methyl]-4-hydroxypyrrolidine-2-carboxamide
= '11 NMR (400 MHz, CD30D) 68.11-8.17 (m, 211), 7.98 (d,J= 8.6 Hz, 114 7.64
(d, J = 8.6
Hz, 2H), 7.53 (d,J = 8.2 Hz, 2H), 7.26 (d, J= 9.0 Hz, 2H), 7.03 (d, J = 9.0
Hz, 211), 4.68 (s,
,
1/1), 4.58 (d, J= 16.0 Hz, 211), 4.54 (d, J= 9.4 Hz, 1.11), 4.48 (br. s.,
111), 4.03 (t, J= 6.3
S I. liNt . Hz, 2H), 3.97 (d, J = 2.7 Hz, 1H). 3.84-3.88 (in,
1H), 3.78 (dd, J = 3.5, 11.0 Hz. 1H),3.61-
3.66 (in, 211), 3.55-3.60 (in, 2H), 3.49 (t, J = 6.3 Hz, 2H), 1.88-1.92 (in,
111), 1.80-1.85 (in,
2H), 1.63-1.68 (m, 2H), 1.55-1.59 (m, 2H), 1.25-1.33 (m, 6H), 1.00 (br. s.,
9H), 0.89 (t, f=
NIP-F 6.8 Hz, 4H). LC-MS (ES): /n/z 949.38 [Mel
F F
Prepared from ABM-3, L-4, and ULM-1
c (2S,4R)-1-1(2S)-2-12-(2-12-12-(4-(3-[4-cyano-3-
(trifluoromethyl)pheny1]-5,5-dimethy1-4-
s Ol% oxo-2-sullanylidenennidazolidin-1-y1}p1
reiroxy)ethoxy]ethoxy}ethoxy)acetainido]-3,3-
_ )... ;9H dimerbylbutanoyI]-4-hydroxy-N-([4-(4-methy1-1,3-
thiazol-5-
16 7.0eAl \
-.. 1 O 11 N ylwhenyl]methyl)pyrrolidine-2-carboxamide
H
N=' õie 114 NMR (400 MHz, CD30D) 68.89 (s, 1 H), 8.18-
8.15 (d, J - 8.4 Hz, 2 H), 8.01-7.99
r 6
IS (rn, 1 H), 7.49-7.42 (m, 411), 7.31-7.28 (d, J
=10.0 Hz, 211), 7.10-7.07 (in, 211), 4.72(s,
I 1 H), 4.61-4.52(m, 3 H), 4.38-4.34(m, 1 H), 4.19-
4.17(m, 2H), 4.10-4.051m, 211), 3.91-
3.80 (m, 411). 3.77-3.72 (m. 8 H), 2.49 (s, 311). 2.24-2.05 (m. 2 H), 1.54 (s,
611). 1.06 (s,
911); LC-MS (ES): nez 1008.50 [Nm], IR = 1.49 min (3.0 minute run).
Prepared from ABM-19. L-4, and ULM-1
F
* F p (2S,4R)-1-1(2S)-2-12-(2-12-12-14-(3-14-cyano-3-
(trifluoromethyl)phenyll-5,5-dimethyl-
F ...N.--'t
o
4 o
L.\ 2,4-dioxorillidazolidin-1-
yl}pbenoxy)ethoxy]etboxy iethoxy)acetamido]-3,3-
dirnethylbutanoy1J-4-hydroxy-N-{ (4-(4-methy1-1,3-thiawl-5-
07
yl)phenyilmetbyl}pyrrolidine-2-carboxamide
17
' NMR (400 MHz, CD30D) 6 8.84 - 8.89 On, 1
H),8.67 (t, J = 5.67 Hz, 1 H), 8.25 (s, 1
0> II
H), 8.08 - 8.15 (rn, 2 H), 7.67 (d, J= 9.00 Hz, 1 H), 7.43 (q, J= 8.22 Hz, 4
H), 7.30 (d, J=
0 1.44 (8.2d2 Hz, 2 H), 7.00 - 7.08 (m, 2 H), 4.701d, J
= 9.78 Hz., 1 H), 4.45 - 4.61 (m, 3 H), 4.35
d , J = 15.85, 4.89 Hz, 1 H), 4.12 - 4.17 (m. 2 H), 4.04 (d. J= 3.91 Hz, 2 H),
3.77 - 3.90
(m, 411), 3.67 - 3.75 (m, 811). 2.47 (d, J = 0.78 Hz, 311), 2.22 (dd, J =
12.91, 8.61 Hz, 1
04-
NH H), 2.03 - 2.12 (m, 1 H), 1.46 - 1.55 1m, 611).
0.98- 1.10 (n. 9 H); Mass (ES'): nez
r It
N = , 992.38 [MH1
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Structure Compound name and Analytical data
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Prepared from ABM-16, L-4, and ULM-1
pH (2S,4R)-1-[(2S)-242-(2-1212-(4-(344-cyano-3-OrilluoromethyOphenyl]-5,5-
dimethyl-4-
0..".,..c.õ....-Ø...-..õ..o.
(r-ty oxo-2-sulfanylideneimidazolidin-1-y1) -2-
...aim F
RP 0
0 NH fluorophenoxy)ethoxylethoxy}ethoxy)acetamido1-3,3-dimethylbutanoy1]-4-
hydroxy-N-
1 8
:-.- 1 ( [4-(4-methyl-1,3-thiazol-5-
yl)phenyl]methyl}pyrrolidine-2-earboxamide
N
"=====
t N 6 µ I 1H NMR (400 MHz, CD30D): 8 8.89 (s, IH), 8.18-
8.16 (d,./ = 7.2Hz, 2H), 8.01-7.99 (d, J
N
-CF3
= 8.4 Hz, 1H), 7.49-744 (in, 411), 7.28-7.21 (in, 2H), 7.16-7.14 (in, 1H),
4.71 (s, 1H),
CN
4.61-4.53 (m, 3I1), 4.35-4.31(m, 1/I), 4.28-4.26 (m, 2/1), 4.10-4.06 (m, 2I1),
3.94-3.81
(in, 3H), 3.81-3.80 (m, 1H), 3.80-3.75 (in, 8H), 2.49 (s, 3H), 2.26-2.24 (in,
1H), 2.11-
2.09 (m, 1H), 1.57 (s, 6H), 1.03 (s, 9H); LC-MS (ES): nilz 1026.34 [MI-11, /R
=2.73 min
(5.6 minute run).
Prepared from ABM-17, L-4, and ULM-1
. .,.0
1 11..z)). (2S,4R)-14(2S)-212-(2-1212 -(4- (5,5-dimethy1-344-ni tro-3-
(trifluoromethyl)phenyl] -4-
't.
oxo-2-sullanylideneimidazolidin-1 -y1) phenoxy)ethoxy]ethoxy } ethoxy)ace
tamido] -3,3-
dimethy lbutanoyl ) -4-hydrox y-N- ( [4-(4-methy1-1,3-thiazol-5-
1 9 4 (0
yl)phenyl]methyl)pyrrolidine-2-carboxamide
o7N F3 (r0
(400MHz, CD30D): 8 8.89 (s, 1H), 8.19-8.16 (m, 2H), 8.05-8.02 (m, 111). 7.49-
7.42 (m,
tiN 41.......
411), 7.31-7.29 (d, J = 8.8Hz, 211), 7.09-7.07 (d, J= 8.8Hz, 211), 4.71(s,
111), 4.61-4.52 (in,
N1 3H), 4.38-4.34 (m, 1/1), 4.23-4.17 (m, 211),
4.06-4.01 (m, 211), 3.91-3.80 (m, 411), 3.78-
...../i .. ..., uy,1õ../1 "OH
3.68 (m .8H), 2.49 (s, 311). 2.27-2.22 (m, 1H), 2.13-2.07 (m, 1H), 1.56 (s,
6H), 1.06 (s.
i ,..... NH
911); LC-MS (ES*): iniz 1028.50 [MH*], IR = 2.62 min (5.0 minute run).
Prepared from ABM-3, L-4, and ULM-3
(2S,4R)-1-[(2S)-212-(2-{212-(4-{344-cyano-3-(trifluoromethyl)phenyl]-5,5-
dirnethyl-4-
NC (f3 õ.(7.- N ,S --10_0.... \....0
oxo-2-sulfanylideneimidazol idin-1 -y1 }phenoxy>ethoxy]ethoxy )
ethoxyjacetamido]-3,3-
F3C -
dimethylbutanoy1]-4-hydroxy-N-R1S)-144-(4-methyl-1,3-tbiazol-5-
0)
SO yl)phenyllethyl]pyrrolidine-2-earboxamide
Cr0 III NMR (300MHz, CD30D): 8 8.90 (s, 111), 8.16-
8.13 (d, J = 8.1 Hz, 211), 8.00-7.97 (d, J
= 8.1 Hz, 1H), 7.45-7.35 (m. 4H), 7.30-7.27 (d, J = 9.0 Hz, 211), 7.11-7.08
(d. J = 9.0 Hz.
HAIN..."
leS 211), 5.03-5.00(m, 111), 4.69 (s, 111), 4.60-
4.57(m, Ili), 4.54-4.43 (in, 111), 4.23-4.22 (m,
)=--c o N-. / \
2H), 4.12-4.10 (m, 211), 3.99-3.88 (m, 3H), 3.83-3.71 (m, 9H), 2.54(s, 3H),
2.24-2.04(m,
, I
=vii 1H), 2.00-1.94 (m, 1H), 1.57 (s, 9H), 1.03 (s, 9H). LC-MS (ES*): nez
1022.56 [MW],
q
-NH
=2.07 mm (3.6 minute run).
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Structure Compound name and Analytical data
#
O Prepared from ABM-4. L-4, and ULM-1
----
Nit,1-..(2).... 0...\\...0 (2S,4R)-1-[(2S)-2-[2-(2- ( 21244- [ 346-cyano-54
trill uommethyl )pyridin-3-y1)-5,5-
NCI)-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
FT
yl}phenoxpethoxylethoxy ) ethoxy)aeetamido] -3,3-di metbylbutanoyl] -4-hydroxy-
N-( [4-
21
(4-methyl-1,3-thiazol-5-y1)phenyl]methyl)pynnlidine-2-carboxamide
(0
Cr IHNMR (300 MHz. CD30D): ö 9.12 (s. 1H), 8.83(s,
1H), 8.63 (5, 1H), 7.70-7.50 (in, 1
H), 7.47-7.30 (m, 4 H), 7.22 (d, J =9 Hz, 211), 7.02 (d, J = 9 Hz, 211), 4.80-
4.26 (m, 5H),
t
...7( e'S 4.25-4.06 (m, 4H), 3.92-3.78 (m, 3 H), 3.75-3.60
(m, 811). 2.43 (s, 3H) , 2.20-2.10 (m, 1
i
0-
it 5...0
H). 2.10-2.01 (m. 1 H), 1.52 (s, 6H). 1.00 (s, 9H); LC-MS (E.S*): m/z 1009.12
[Min, tR =
2.16 min (3.6 minute run).
Prepared from ABM-3, L-5, and ULM-1
, -1/4. 0
.--A, -(j µ \---=0 4 R (2S,4R)-1-[(2S)-2-
(22R,3R)-3-{212-(4-(3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-
FF1,., ,Ni _4:1 ---
O I ' d imethy1-4-oxo-2-sulfanylideneimidazolidin
-1-y1) phenoxy)ethoxy]ethoxy } bu tan-2-
22 1-- yl]oxy}acetamido)-3,3-dimetbylbutanoy1]4-hydmxy-N-
([4-(4-methy1-
1,3-thiazol-5-yl)phenyl]methyllpyrrolidine-2-carboxamide
0 H .õOH IH NMR (400 MHz, CD30D) 8 8.81 - 8.94 (m, 1 H), 8.17 (d, J = 7.43
Hz, 2 H), 8.01 (d, J
= 8.61 Hz, 1 H). 7.73 - 7.89 (n, 1 H), 7.37 - 7.57 (m, 3 H), 7.21 - 7.36(m,
211), 7.01 -
o H 7.17 (m, 2 H), 5.48 -5.54 (m, 1 H), 3.36- 4.88 (m, 20 II), 3.20-
3.29 (m, 2 H), 2.43 - 2.52
S, li (m, 2 H), 2.16 - 2.30 (m, 1 H), 2.03 - 2.16 (m, 1 H), 1.52 - 1.59
(tn. 3 F), 1.39 (d,./ = 4.30
N
Hz, 911), 1.11 - 1.21 (in, 311), 1.06(s, 311); Mass (ES*): nez 1036.47 [MI-1]
Prepared from ABM-3, L-6, and ULM-1
N s (2S.4R)-1-[(2S)-2-12-(2-([(2R.3R)-312-(4-{344-
cyano-3-(trifluoromethyl)pheny11-5,5-
F pNA'N * \---,o
F
O...f.' dimethy1-4-oxo-2-sulfanylideneimidazolidin-l-yl}phenoxperboxy]butan-
2-
ylloxy }ethoxy)acetamido1-3,3-dimethylbutanoyl]-4-hydroxy-N4 [4-(4-methy1-1,3-
thiazol-
23 ) 5-yl)phenyllmethyl}pyrrolidine-2-carboxamide
0 111 NMR 1400 MHz, CD30D) 6 8.86 (s, 111), 8.12 - 8.17 (m, 2 H), 7.98
(dd, J = 8.22,
1 96 H7 1 H) 7 39 - 7 48 (m 4 1-1) 7 24 - 7 30 (m 2 H) 7 03 - 7 08 (m 2 H) 4
70 (s 1
H), 4.58 - 4.63 (n, 2 H), 4.55 (d, J = 15.65 Hz, 2 H), 4.50 (br. s., 1 H),
4.15 (d, J = 4.30
0
0 NH Hz, 211), 4.02 (d, J= 7.83 Hz, 111), 3.88- 3.94(m, 2 H), 3.71 -
3.75 (m, 211), 3.63- 3.68
S 11,
cC / \W' (m, 2 H), 3.56 - 3.61 (m, 1 H), 3.47 - 3.52 (m, 1 H). 2.44 - 2.50
(m, 3 1-1), 2.19 - 2.25 (m, 1
N- H), 2.06 - 2.11 (m, 111), 1.53 (s, 6 11), 1.35
(d, J = 6.65 Hz, 3 H), 1.11 (d, J = 6.26 Hz, 6
H). 1.01 - 1.07 (n, 9 H); Mass (ES): iWz 1036.47
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Structure Compound name and Analytical data
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Prepared from ABM-3, L-7, and ULM-1
F ,
(2S,4R)-1-[(2S)-2-(2-144444-(344-cyanc-3-(trilluoromethyl)phenyl]-5,5-dimethyl-
4-
. v.v, =trN.c.-1..
oxo-2-sulfanylideneimidazolidin -1 -y1} phenoxy)butoxy]butoxy )acetamido)-3,3-
1:34 dimethylbutanoy11-4-hydroxy-N-([4-(4-methyl-1,3-
thiazol-5-
14
Aphenyl]methyl}pyrrolidine-2-carboxamide
1H NMR 1400MHz, CD:10D): 8 8.90(s, 1H), 8.17-8.15 (d, J = 8.4Hz, 2H), 8.01-
8.01 (d, J
H õoil = 1.6Hz, 1H), 7.49-7.42 (m, 4H), 7.30-7.27 (d,
J= 11.6Hz, 2H), 7.06-7.04(d, J = 8.8Hz,
cp.N( 2H),4.71 (s, 1I-1), 4.61-4.54 (m, 311), 4.38-
4.34 (m, 1H), 4.07-4.04 (m, 2H), 3.40-3.95(m,
4....s.raiN
2H), 3.91-3.83 (m, 2H), 3.61-3.58 (m, 2H), 3.52-3.50 (m, 4H), 2.50 (s, 3H),
2.05-2.14(m,
1H), 2.20-2.30 (m, 1H), 1.89-1.86 (in, 211), 1.79-1.723 (m, 6H), 1.56 (s,
611), 1.06 (s, 9H);
if-Ms (EV): ',Liz 1020.30 [MI-1], IR =4.06 min (5.6 minute run).
Prepared from ABM-16, L-7, and ULM-3
(2S,4R)-1-[(2S)-2-(2-{444-(4-{3-(4-cyano-3-(trifluoromerbyl)pheny1)-5,5-
dimerbyl-4-
Nc ....tcy-NyN ,...q. oxo-2-sullanylideneiniidazolidin-1 -y1} -2-
fluoroptienoxy)bu toxy]bu toxy } aceta If I id0-3,3-
S '..."
F3C r Cr- \ -- \ ' diinedrylbutanoyi]-4-hydroxy-N-[(1S)-144-(4-methyl-
1,3-tbiazol-5-
25 yl)pbenynethyl]pyrrolidine-2-carboxamide
oklt...1 ( 1H NMR (300 MHz, CD30D): 68.88 (s, Ili), 8.17-8.14 (d, J= 7.5
Hz, 211), 8.00-7.97 (d.
J = 8.4 Hz, 111), 7.46-7.39 (m, 4H), 7.27-7.12 (m, 3H), 5.01-4.86 (m, 1H),
4.69 (s, 1H),
NS
A) 0-4 A 4.60-4.55 (t. J = 7.5 Hz, 1H). 4.44 (m,
1H), 4.19-4.17 (t, J = 6.0 Hz, 2H), 3.98-3.97 (d, 1..
541). J= 2.7 Hz, 211), 3.87-336 (m, 211), 3.61-3.49 (m, 611), 2.48 (s,
311), 2.17 (m, 111), 2.00-
NH 'OH
1.89 (m, 3H), 1.84-1.75 (m, 2H), L74-1.71 (m. 4H), 1.58 (s, 6H). L52-1.49 (m,
3H), 1.04
(s, 911); Mass (ES*): m/z 1052.20 [MH]
0, \
-sis---t ¨ Prepared from ABM-16, L-7, and ULM-3
KII.N 4
(2S,4R)-1-[(2S)-2-(2- (444-14-(344-cyano-3-(trifluommethyl)pheny1]-5,5-
dimethyl-4-
0
Isi----'1..I1 S F oxo-2-sulfanylideneimidazolidin-l-y1}-2-
fluorophenoxy)butoxy]butoxy)acetamido)-3,3-
F"µF
\---1 dimethylbutanoy11-4-hydroxy-N-{ (4-(4-methy1-1,3-
thiazol-5-
26
yl )phenyl] methyl }pyrrolidine-2-carboxamide
11-1 NMR (400 MHz, CD30D): 8 8.88 (s, 1 H), 8.17-8.15 (m, 2 H), 8.00-7.99 (d,
J = 6.4
Hz, 1 II), 7.49-7.42 (m, 4 II), 7.23-7.13(m, 3 II), 4.71 (s, 1 H), 4.61-4.52
(m, 3 H), 4.38-
HN
,?---A/ 434
(m, 1 H). 4.00-3.83 (m, 3 H), 3.61-3.49 (m, 6 H), 2.4.9 Is, 3 1-1), 2.30-2.10
(m, 2 H).
IIP
Of ,N
.\.3 1.92-1.89(m, 2 H), 1.79-1.73 (m, 6 H), 1.72 (s, 6 H), 1.05(s, 9 H); LC-
MS (ES*): m/z
NH
''OH 1038.50[MH1, tR = 3.05 min (5.0 minute run).
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Structure Compound name and Analytical data
#
0......z
NC
Prepared from ABM-16. L-8, and ULM-1
4 N--
-FP r '' (2S,4R)-1-[(2S)-2-(24 344 -(4- ( 344-cyano-3-
(trilluoromethyl)pheny1]-5,5-dimethyl-4-
oxo-2-sulfanylideneimidazolidin-l-y1}-2-fluorophenoxy)butoxylpropoxy
}acetamido)-3,3-
dimethylbutanoy11-4-hydroxy-N- { [4-(4-methy1-1,3-thiazol-5-
17 yl)phenyl]rnethyl}pyrrolidine-2-carboxamide
IH NMR (300 MHz, CD30D): &8.87(s, 1H), 8.10 (d, ./ = 8.6 Hz, 2H). 7.93 (m,
1H). 7.37
H (in, 4H), 7.11 (in, 3H). 4.83-4.48 (in, 5H),
4.12 (in, 2H), 3.94 (n, 2H) , 3.78 (m, 2H), 3.50
(m, 611), 2.44 (s, 3/1), 2.05 (n, 211), 1.73 (n, 611), 1.52 (s, 611), 1.00 (s,
911); LC-MS
0
)4
(FS): miz 1024.10 [M11'], IR = 2.79 min (5.6 minute run).
H H
1
Q"--(-- Prepared from ABM-3, L-8, and ULM-1
NC-9-44 IS (2S,4R)-1-[(2S)-2-(2-(344-(4-(344-cyano-3-
(trilluoromethyl)pheny1]-5,5-dimethyl-4-
F3 = oxo-2-sul fanylideneim idaz,o1 idin. 1 -y1)
phenoxy)butoxy] propoxy } acetami do)-3,3-
dimethylbutanoy11-4-hydroxy-N- {[4-(4-methy1-1,3-thiazol-5-
28 =
yl)phenyl]methyl)pyrrolidine-2-earboxamide
Ill NMR (300 MHz, CD30D) 68.88 (s, 111), 8.14 (in, 211), 7.97 (m, 111), 7.49-
7.41 (m,
=
4H), 7.26 (n, 2H), 7.02 (n, 2H), 4.70 (s, 1H), 4.61-4.52 (n, 3H), 4.38-4.33
(n, 1H), 4.03
=
NFI
>3:............õ.0
H (t, J= 6.3 Hz, 2H), 3.98 (s, 2H), 3.86-3.82 (rn,
2H), 3.68-3.51 on, 611), 2.48 (s, 311), 2.23-
2.09 (n, 211), 1.93-1.73 (n, 611), 1.55 (s, 611), 1.02 (s, 911); LC-MS (ES):
miz 1006.50
H [MH*.), IR = 2.81 min (5.6 minute run).
o
No i* iss)L1.¨ Prepared from ABM-3, L-8, and ULM-8
Fsc rN * (2S,4R)-1-[(2S)-2-(2-{344-(4-(3-14-cyano-3-
(trifluoromethyl)phenyl]-5,5-dimethyl-4-
oxo-2-sulfanylideneimidamlidin-1-yl}phenoxy)butoxy]propoxy}acetamido)-3-
o methylbutanoy1]-4-hydroxy-N-( [4-(4-methyl-1,3-thiazol-5-
yl)phenyl]methyl}pyrrolidine-
2-caiboxamide
29
IH NMR (400 MHz, CD30D): 5 8.88 (s, 1H), 8.17 (d, J = 8.8 Hz, 211), 8.01 (in,
1H),7.47
Cro (m, 4H), 7.30 (d, ./ = 8.8 Hz., 2H), 7.06 (d../
= 8.8 Hz., 2H), 4.66 (m, 1H),4.61 (in, 1H),
4.54 (m, 2H). 4.42 (m, 1H). 4.08 (m, 2H). 4.01 (m, 2H), 3.85 (n, 2H), 3.67 (n,
2H), 3.61
Hisk_i
n.-.-
h--= \ ' ni (n, 211), 3.56 On, 211), 2.50 (s, 311), 2.25
(in, 1/1), 2.16 (n, 211), 1.93 (n, 411), 1.78 (m,
%4 -.-(3 2H), 1.56 (s, 6H), 1.03 (in, 3H), 0.96(m, 3H); le-
MS (ES*): m'z 992.55 [M111, tR = 3.39
--NH '''()H nun' (5.6 minute run).
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Structure Compound name and Analytical data
#
Q., !
7-t- Prepared from ABM-4, L-8, and ULM-1
(25,4R)-1 4(25)-242- ( 34444- ( 316-cyano-5-(trifluoromethyl)pyridin-3-y1]-5,5-
dimethyl-
S
F3C 'C-').'O--\_\_
4-oxo-2-sullanylideneimidazolidin-l-yllplienoxy)butoxy]propoxy } ace tainido)-
3,3-
dimethylbutanoyll-4-hydroxy-N-{ (4-(4-methy1-1,3-thiawl-5-
c
HNµ..." yl)phenyflmethyl}pyrrolidine-2-carboxamide
1H NMR (300 MHz, CD30D) 8 9.15-9.10 (m, 1H), 8.80 (s, 1H), 8.66-8.62 (m, 1H),
7.45-
V) 7.36 (in, 41-1), 7.25-7.18 (m, 2H), 7.02-6.92
(m, 21-1), 4.70-4.62 (rn, 11-1), 4.60-4.44 (m,
--f-
r ),) 0..c.
(y. i."..13H 3H), 4.35-4.26 (m. 1H), 4.10-3.90 (m, 4H), 3.89-3.69 (m, 211),
3.65-3.40 (m, 6H), 2.44 (s.
4H), 2.20-2.01 (m, 2H), 1.88-1.60 (m, 611). 1.52 (s, 611), 1.00 (s, 9H); LC-MS
(ES): in,z
1007.30 [M/1], tR=1.71 min (3.0 minute run).
0 1 Prepared from ABM-1, L-8, and ULM-1
µ
(25,4R)-1-[(2S)-2-(243-(4-f 443-(3-chloro-4-cyanepheny1)-5,5-dimedv1-4-oxo-2-
NC 4* Nitl..0_0.,\ _
sulfanylideneimidazolidin-1-yl]phenoxy }butoxy)propoxylacera mid } -3,3-
C ¨\--O
dimethylbutanoy1]-4-hydroxy-N-([4-(4-methy1-1,3-thiazol-5-
yl)phenyl]methyl)pyrrolidine-2-carboxamide
31 Cr 11-1 NMR (300 MHz, CD30D) 68.87 (s, 1H), 7.97(d,
J= 8.4 Hz. 111). 7.87 (s. 111), 7.66
FIN\ .../ (m, 1H), 7.49 (m, 411), 7.28 (m, 211), 7.05 (m,
211), 4.71 (s, 111), 4.59 (in. 311), 4.38 (m,
N14'S
r ....Ut 111), 4.07 (m, 4I1), 3.987 (m, 2H), 3.68 (m,
611), 2.48 (s, 3H), 2.27 (m, 211), 1.93 (m, 611),
* 5
'"Oi-i 1.54 (s, 6H),1.03 (s. 9H). LC-MS (ES): m/z 486.40 (M/2H], ri? = 2.21
min (3.6 minute
--Nli
run).
_p_NIL4._ Prepared from ABM-5, L-8, and ULM-1
C
N ),...N
-0 g -...":- . 0), 0 (25,4R)-1-[(25)-2-{ 2-1344- (443-(4-cyano-3-
methoxypheny1)-5,5-dimethy1-4-oxo-2-
--\_._ sulfanylideneimidazolidin-l-yl)phenoxy } butoxy)pmpoxy]acetamido
} -3,3-
\,...?
o dimethylbutanoy1:1-4-hydroxy-N-([4-(4-methyl-1,3-
thiazol-5-
yl)phenyl]methyl)pyrrolidine-2-earboxamide
Cr
HNµ../ 'll NMR (400 MHz, CD30D): 8 8.89 (s, 111), 7.75
(d, J = 8A Hz, 111), 7.49-7.42(m, 411),
32
7.37 (s, 1H), 7.27 (d,./ = 8.8 Hz, 2H), 7.18-7.15 (m, 1H), 7.06-7.04 (m, 2H),
4.88 (s, 1H),
rsi4,
..'/ '''' 4.59-4.46 (in, 31-1), 4.38-4.35 (m, 11-1), 4.07-
4.00 (m, 21-1), 3.99-3.87 On, 51-1), 3.88-3.76
0.--4
4, 5.õ0:-
(m, 211), 3.68-3.60 (m, 211), 3.59-3.55 (m, 211), 3.54-3.53 (m, 211), 2.49 (s,
311), 2.28-2.19
'OH
NH
(m, 111), 2.14-2.05 (m, 111), 1.93-1.86 (m, 411), 1.80-1.78 (m, 211). 1.54 (s.
611), 1.04 (s.
911); LC-MS (ES): nez 968.35 [M11], tR = 2.57 min (5.6 minute run).
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Structure Compound name and Analytical data
#
Prepared from ABM-3, L-8, and ULM-2
N= 41 Hi, (2S,4R)-1-[(2S)-2-(2-{344-(4-(3-14-cyano-3-
(nifluoromethyl)phenyl]-5,5-dimethyl-4-
F3c r
S liti oxo-2-sulfanylideneimidamlidin-1-
yllphenoxy)butoxy]propoxy } acetami do)-3,3-
0--\...
dimethylbutanoyi]-4-hydroxy-N-} [4-(1,3-thiazol-5-yl)phenyl]methyl
1pyrrolidine-2-
- \--0 carboxamide
I H NMR (400 MHz, CD30D): 8 8.94 (s, 1H), 8.16 (d, J = 8.8 Hz. 3H), 8.00 (d,J
= 1.6 Hz.
33 p 1H), 7.61 (d, J = 8.0 Hz, 21-1), 7.44 (d, J= 8.0
Hz, 2/I), 7.28 (d,J = 8.8 Hz, 2I1), 7.04 (d, .1
oz) = 8.8 Hz, 2H), 4.71 (s, 1H), 4.61-4.51 (m, 3H), 4.37-4.33 (m, 1H), 4.07-
4.03 (m, 2H),
le\ H/\. .1 ...)(. 4.01-3.96 (m, 2H), 3.88-3.82 (m,
1H), 3.81-3.77 (rn, 1H), 3.69-3.3.62 (rn, 2H), 3.61-3.55
¨
0 (m, 2I1), 3.54-3.53 (m, 2I1), 2.28-2.19 (m,
111), 2.14-2.05 (m, III), 1.96-1.84 (m, 41-1),
. 0).....0 1.80-1.74 (in, 2H), 1.56 (s, 6H), 1.06 (s. 9H); LC-MS (ES*): miz
496.85 1MH/21, itz =
1.60 min (3.0 minute run).
0
Ner¨cy_d1--1,_
Prepared from ABM-3, L-8, and ULM-4
F3C r-------\,
_-k (2S,4R)-1-[(2S)-2-(24 344441 344-cyano-3-
(trilluoromethyl)pheny1]-5,5-dimethyl-4-
e- \ oxo-2-sul fanylideneim idaml idin- 1 -
yllphenoxy)butoxy]propoxy }acetamido)-3,3-
-A.-0 dimethylbutanoy11-4-hydroxy-N-{ [4 -(1,3-oxazol-
5-yl)phenyl]methyl )pyoolidine-2-
carboxamide
'H NMR (400 MHz, CD3OD) 8 8.24(s, 1H), 8.17 (d, J = 8.0 Hz, 2H), 8.01 (dd, J =
8Ø
o
34
r-41 1.6 Hz, 1H), 7.70 (d,J= 8.0 Hz., 2H), 7.49-7.45
(m, 3H), 7.29 (d,./ = 8.8 Hz, 2H), 7.06 (d,
oiii2).7( ,./3.= 8(.8 ,H:1-2H2),.
4.7,2(s, 1H) 4 . 4.619.3511(m, 3H).4.371nt(, 1H), 4.08-.3.383(n1,1 6H),
3.69-
54
Pt...4_
) 0 ,
( , 6
), ( 6) 6õ 6 0 ( (s 9
, ),
s
\ , (EV): iniz 976.45 [MI-1], IR = 1.69 min (3.0
minute run).
'OH
NH
0
NZ.: ill NKA.
Prepared from ABM-3, L-8, and ULM-5
F F F s)--N (2S,4R)-1 -[( 2S)-24 2- ( 344-14- (344-cyano-3-
(trifl uommethyl)pheny1]-5,5-dimethy1-4-
' *
oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)butoxy]propoxy}acetamido)-3,3-
0-11õ
dimethylbutanoyli-4-bydroxy-N-{(4-(4-methyl-1,3-oxazol-5-
y1 )phenyl] methyl }pyrrolidine-2-carboxamide
35 I H NMR (400 MHz, CD3OD) 8 8.16-8.14 (d, J = 8.8
Hz, 3 H), 7.98-7.98 (d, J = 2.0 Hz, 1
I-1), 7.61-7.59 (d, J = 8.4 Hz, 211), 7.49-7.47 (d, J = 8.4 Hz, 2 II), 7.29-
7.27 (d, J= 8.8
0
....C) Hz, 2 H), 7.05-7.03 (d../ = 8.8 Hz, 2 H), 4.71-4.52 (m. 4 H), 4.37-
4.34 (m, 1 H),4.07-
HN 3.99 on, 4 H), 3.87-3.82 (rn, 2 H), 3.68-3.53
(m, 6 H), 2.41 (s, 3 H), 2.21-2.00 on, 2 H),
,..'-'=
N 0
1.93-1.76 (m, 6 H), 1.55 (s, 6 H), 1.05 (s. 9 H); 1.12-MS (F-S1): ma" 990.60
[M1-11, tR =
I
i) '-') <\ 0)....0 3.50 nun (56 minute run).
\ /
--NH 'TM
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Structure Compound name and Analytical data
#
)r-N Prepared from ABM-1, L-8, and ULM-9
CI S *
(2S,4R)-1-[(2S)-2-{ 2-1344- (443-(3-chloro-4-cyanopheny1)-5.5-dirnethyl-4-oxo-
2-
=
-.\-I sulfanylideneimidazolidin-1-yl]phenoxy
}butoxy)propoxy]acetamido }-3-methylbutanoy1]-
4-hydroxy-N-( [441,3 -tli iazol-5-yl)phenyl] methyl }pyrrolidine-2-carboxamide
11-1 NMR (400 MHz, CD30D): 8 8.89(s. 1H), 8.12 (s, 1H), 7.90 (d, J = 8.4 Hz,
1H), 7.82
(s, 1H), 7.62-7.56 (in. 3H), 7.40 (d,J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz,
2H). 7.00 (s, 2H).
(0 4.61-4.52 (m, III), 4.51-4.40 (m, 2/1), 4.39-4.36 (m, 1/1), 4.03-3.95
(m, 411), 3.78-3.74
36 14.4\s I-1'k .1 ...<
(m, 2H), 3.63-3.27 Im, 7H), 2.23-1.98 (m, 3H), 1.89-1.71 (m, 6H), 1.50 (s,
6H), 0.97 (d, J
0
µ I-- --- = 6.6 Hz, 3H),0.89 (d, J = 6.6 Hz, 3H); LC-MS
(ES*): nil: 944.25 [MH], tR = 1.51 mi
Z.
n
NH 40H
\ / DN
(3.0 minute run).
.
13..... ),./....
N),¨N Prepared from ABM-1. L-8, and ULM-1
(2S,4R)-1 -[( 2S)-2- ( 243-(4-{443-(5-chloro-6-cyanopyridi n-3-y1)-5,5-
dimethy1-4-oxo-2-
0 sulfanylideneimidazolidin-1-yl]phenoxy
}butoxy)propoxy]acetamido } -3,3-
dimethylbutanoyl] -4-hydroxy-N- { [4-(4-methy1-1,3-thiazol-5-
yl )phenyl] methyl }pyrrolidine-2-carboxamide
37
11-1 NMR (400 MHz, C133013): 8 8.87-8.86(m, 2 H). 8.44 (s, 1 H), 7.49-7.42 (m.
4 H),
)ro 7.29-7.27 (d, J = 8.8 Hz, 2 II), 7.06-7.04 (d, J
= 8.8 Hz, 2 H), 4.72 (s, 1 H), 4.59-4.52
N' HN\ j (m, 3 H), 4.39-4.35 (m, 1 H), 4.08-3.99 (m,
4 H), 3.96-3.83 (m, 2 H), 3.68-3.59 (m, 6 H).
¨ 0=U\ 2.50(s, 3 H), 2.15-2.05 (m, 2 H), 1.92-1.88
(in, 6 H), 1.56(s, 6 H), 1.04 (s, 9 H); LC-MS
. 0)...0I -
H (ES'): nez 973.30 NM, IR = 1.58 min (3.0 minute run).
NH
Prepared from ABM-1, L-8, and ULM-5
Oa 1i
N= . -NF--
c. s I- (2S,4R)-1-[(2S)-2-(213-(4-(443-(3-chloro-4-
cyanopheny1)-5,5-dimethyl-4-oxo-2-
e40,
sulfanylideneimidazolidiu-1-yl]phenoxy }butoxy)propoxy]acetamido } -3,3-
zIo dimethylbutanoy1]-4-hydroxy-N-([4-14-methy1-1,3-
oxam1-5-
yl)phenyllmethyl}pyrrolidine-2-carboxamide
38 ' II NMR (400 MHz., CD30D) 8 8.20 (s, 1 H), 7.97-
7.95 (d, J= 8.4 F17., 1 H), 7.87 (s, 1 H),
\r 7.66-7.59 (m, 3 H), 7.49-7.47 (d, J = 8.4 Hz, 2
H), 7.28-7.26 (d, J = 9.2 Hz, 2 H), 7.05-
HI,L.1 7.03 (d, J = 8.8 Hz, 211), 4.71 (s, 1 II), 4.57-4.52 (m, 3 II), 4.38-
4.34 (m, 1I-I), 4.07-3.99
N4'0 0 ( fµ (m, 4 H), 3.87-3.80 (m, 2 H). 3.67-3.53
(m. 6 H), 2.42 (s, 1 H), 2.20-2.00 (m, 2 H), 1.93-
r ar. N
5..-0=NDH 1.77 (in, 6 H), 1.54 (s, 6 H), 1.06 (s, 9 H); LC-MS (ES*); mil-
956.30 [MI-1], tR = 1.56 min
\IIIE NH
(3.0 minute run).
159
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Structure Compound name and Analytical data
#
Prepared from ABM-1, L-8, and ULM-10
(2S,4R)-1-[(2S)-2-(213-(4-{443-(3-chloro-4-cyanopheny1)-5,5-dimethyl-4-oxo-2-
sulfanylideneimidazolidin-1-yl]phenoxy } butox y)propoxy)acetam ido } -3-
methylbutanoyl ] -
yr.
4-hydroxy-NI [4-(4-methy1-1,3-oxazol-5-yl)phenyl]methyl } pyrroi idine-2-
carboxamide
r\r-s, -N,,,,N-C1.0
39 No-----' g - -- \-- \...c
0
)c 'H NMR (400 MHz, CD3OD) 8 8.15 (s, 1 H), 7.97-
7.95 (d, J = 8.4 Hz, 1 H), 7.87(s, 1 H),
7.66-7.60 (m, 3 H), 7.48-7.45 (d,J= 8.4 Hz, 2 Ii), 7.28-7.26 (d, J = 9.2 Hz, 2
I-1), 7.06-
7.03 (d. .1 = 9.2 Hz, 2 H). 4.66-4.41 (m, 5 H), 4.07-3.99 (m, 4 H), 3.85-3.83
(m, 2 I-1).
No,* HN/ 3.66-3.53 (in, 6 H), 2.41 (s, 3 H), 2.25-2.00 (m, 3 H), 1.93-
1.77 (in, 6 I-1), 1.53 (s, 6 H),
¨ (:1 1.03-1.02 (d, J=5.8 Hz, 3 II), 0.95-0.93(d,
J=6.8 Hz, 3 H); LC-MS (ES'): Int 942.30
* 0)...(4)
[MH1, tR= 1.50 min (3.0 minute run).
NH
1--- )L-1--
i ...-Nsn. Prepared from ABM-20, L-8, and ULM-1
F ( F g 1 (25.4R)-1-[(2S)-2-[2-(3-(4-[(5-(344-cyano-3-
(trifluommethyl)phenyl]-5,5-dimethyl-4-
F
oxo-2-sulfanylideneimidazolidin-l-yl}pyridin-2-yl)oxylbutoxy
}propoxy)acetatilido}-3,3-
\_,.
e dimethylbutanoy11-4-hydroxy-N-{ [4-(4-methy1-1,3-
thiazol-5-
yl )phenyl] methyl }pyrrolidine-2-carboxamide
40 0 1H NMR (300 MHz, CD30D):88.81 (s, 1 H), 8.16-
8.03 (in, 3 H), 8.00-7.90 (m, 1 H), 7.70-
co 7.60 (m, 1I-I). 7.51-7.30 (m, 41-1), 6.91-
6.80(m, III), 4.67 (s, 1 H), 4.60-4.40(m, 4 I-1),
N.4\
..... S 14 4.32-4.21 (m, 3 H), 3.89-3.70(m, 4 H), 3.65-3.40 (m, 6 H),
2.41 (s, 3 H), 2.23-2.01 (in, 2
-- O'?(' H), 1.90-1.62 (m, 6 I-1), 1.55 (s, 6 H), 1.02(s, 9 H); LC-MS
(ES): m,'z, 1007.35 [MFI1, i p
=1.58 min (3.0 minute run).
tH
q Prepared from ABM-21. L-8, and ULM-1
Y-----
(25,4R)-1 -[(2S)-2- [ 21344 - (443-(3-chloro-4-cyanopheny1)-5,5-dimethy1-4-oxo-
2-
c) y
S Yko.. sulfanylideneimidazolidin-l-y1]-2-fluorophenoxy
} butoxy)propoxy] acetamido } -3,3-
CI
F \¨\_ dimethylbutanoy1]-4-hydroxy-N-{ [444-methyl-I ,3-thiaz.o1-5-
0
yl)phenyl]rnethyl}pyrrolidine-2-carboxamide
41
IH NMR (400 MHz, CD30D): 8 8.88 (s. 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.88(s.
1H), 7.66-
7.64 (m, 1H), 7.48-7.39 (m, 4H), 7.22-7.19 (m, 2H), 7.14 (s, 1H), 4.71 (s,
1H), 4.59-4.47
(m, 31-1),4.36 (d, J = 15.61-h, 1I-1), 4.14 (t, J= 6.4 Hz, 2/1), 4.00 (d,J =
3.6 Hz, 2/1), 3.87-
-1. 01-IN
. 3.78 (m, 2H), 3.67-3.54 (in. 6H), 2.45 (s. 3H), 2.26-2.21 (m, 1H).
2.13-2.04 (m, 1H), 1.93-
q1.89 (m, 4H), 1.83-1.74 (m, 2H), 1.55 (s, 6H), 1.04 (s, 9H); LC-MS (ES*); miz
990.35
-N/14 \¨j-tm [MF11. IR = 1.59 min (3.0 minute run).
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Structure Compound name and Analytical data
#
(1._ 1
N ..,_...p--Nrp i-
Prepared from ABM-22, L-8, and ULM-1
¨ '-':- _. ess,,..,
s ',, 1 (2S,4R)-14(2S)-2-(243-(4-(443-(4-cyano-3-
methoxypheny1)-5,5-dimethyl-4-oxo-2-
F 0¨\_\_0
sulfanylideneimidazolidin-1-y11-2-fluorophenoxy}butoxy)propoxy]acetamido}-3.3-
dimethylbutanoy1]-4-hydroxy-N-([4-(4-methy1-1,3-thiazol-5-
yl)phenyl]methyl)pyrrolidine-2-carboxamide
42 1H NMR (400 MHz, CD30D) 8 8.98 (s, 1 H), 7.77-
7.75 (d, J= 8.4 Hz, 2 H), 7.49-7.42(m.
4 H), 7.36-7(s, 1 H), 7.21-7.14 (in, 4 H), 4.71 (s, 1 H), 4.59-4.52 (m, 3 H),
4.39-4.35(m,
/1- 4
I-IN
\.;0 1H), 4.16-4.13(m, 2H), 4.00-
3..98(m, 511), 3.99-3.83 (m, 2 H), 3.68-3.667, 2H), 2.50
0
Ntrobii 9 H),
(s. ) . 1
( ) . ( ) . ( ) . ( --
). 0 (
LC-MS (ES): m/z 986.45 [M1-1], IR = 1.65 min (3.0 minute run).
0.0) Prepared from ABM-8, L-8, and ULM-1
Nr- fh iN 4 (2S,4R)-14(2S)-2-(2-{344-(4-(344-cyano-3-
(trifluoromethylwhenyl]-4-oxo-2-
F
0-N.. sulfanylidene-8-oxa-1,3-diazaspiro[4.5]decan-1-
yl}phenoxy)butoxylpropoxy}acetamido)-
\-0
3,3-dimethylbutanoyl] -4-hydroxy-N-{ [444-methyl-I ,3-thiazol-5-
y1whenyl]methyl)pyrrolidine-2-carboxamide
43
IFI NMR (400 MHz, CD30D) 8 8.98-8.83 (s, 1 H), 8.18-8.16 (d../ = 8.4 Hz., 2
H). 8.01-
N'S i-12% ."( x 7.99 (in, 1 H), 7.49-7.42(m, 4 H), 7.42-
7.2A (d, J= 8.4 Hz, 2 H), 7.08-7.06 (d, J= 8.4 Hz,
l..410 2 H), 4.80 (s, 1 H), 4.72 (s, 1 H), 4.59-4.34(m, 3
H), 4.20-4.08 (m, 6 H), 3.99-3.87 (m, 4
z
= 0 N
\ / )....Ø H), 3.67-3.56 (m, 6 H). 2.49 (s, 3 H),
2.21-1.87 (m, 12 H), 1.05 (s, 9 H); LC-MS (ES*):
H 1DH nez 1048.45 [MW], IR = 1.73 min (3.0 minute
run).
0
,--4--- Prepared from ABM-21, L-8, and ULM-5
(2S,4R)-1-[(2S)-2-(243-(4-(443-(3-chloro-4-cyanopheny1)-5,5-climethyl-4-oxo-2-
. ¨ CI ¨ 'Sr. It sulfanylideneimidazolidin-1-y1)-2-fluorophenoxy
} butoxy)pmpmy]acetamido) -3,3-
0.--\_
F dimethylbutanoy1:1-4-hydroxy-N-([4-(4-methyl-1,3-
oxazol-5-
yl)phenyllmethyl)pyrrolidine-2-carboxamide
44 'll NMR (400 MHz, CD30D): 68.15 (s, 111), 7.96
(d, J= 8.4 Hz, III), 7.87 (s, 1I1), 7.66-
7.60 (m, 3H), 7.48 (d,J = 8.4 Hz, 2H), 7.24-7.14(m, 3H),4.71 (s, 1H), 4.61-
4.52 (m. 3H),
N ---N S=O 4.38-4.33 (m, 1H), 4.14 (in, 2H), 4.00 (d, J =
4.0 Hz, 3H), 3.88-3.82 (m, 2H), 3.68-3.54
HN
.....i\/ (m, 6H), 2.42 (s, 3H), 2.27-2.18 (m, 1H), 2.13-2.04 (m, 1H), 1.93-
1.89 Im, 4H), 1.88-1.80
6:-/ 00 N (m, 2H), 1.55 (s, GH). 1.06(s. 9H); LC-MS (ES*):
mil. 974.25 (MW], tR = 1.57 min (3.0
minute run).
H .'OH
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Structure Compound name and Analytical data
#
o .
Prepared from ABM-21. L-8, and ULM-4
rd.-_2"-y--
1:¨
(2S,4R)-1-[(2S)-2-(243-(4-f 443-(3-chloro-4-cyanopheny1)-5,5-climethyl-4-oxo-2-
'.¨
C s Y'o sulfanylideneimidazolidin-l-y1]-2-fluorcrphenoxy }
butoxy)propoxy] acetamido } -3,3-
- dimethylbutanoy1]-4-hydroxy-N-{ [4-(1,3-oxazol-5-
yl)phenyl) methyl J pyrrolidine-2-
o carboxamide
III NMR (400 MHz, CD30D): 8 8.24(s, 111), 7.96 (d, J = 8.4 Hz, III), 7.87 (s,
1H), 7.70-
p 7.7.64 (m, 3H), 7.49-7.40 (m, 3H), 7.22 (d, J =
8.4 Hz, 2H), 7.14 (d, J= 8.0 Hz., 1H), 4.71
N'=0 (21 (s, 111), 4.60-4.51 (in, 3H), 4.38-4.34 (m,
111), 4.18-4.11 (in, 2H), 4.00-3.96 (m, 211),
--
--... HN
)...,/ 3.92-3.76 (m, 211), 3.68-3.55 (m, 611), 2.27-
2.21 (m, 111), 2.18-2.06 (m, 1I1), 1.95-1.86
10 O I / \ (m, 4H). 1.83-1.72 (m, 2H). 1.55 (s. 6H),
1.06(s, 9H); LC-MS (ES*): ttilz 960.30 [MI-11.
iR = 1.54 min (3.0 minute run).
'OH
0 1
N.= / \ ).--F. Prepared from ABM-21. L-8, and ULM-2
- -- -N)r-N-r (2S,4R)-1-[(2S)-2-(243-(4-f 443-(3-chloro-4-
cyanopheny1)-5,5-climethyl-4-oxo-2-
CI S y
F ,..
0 sulfanylideneimidazolidin-1-y1]-2-fluorcrphenoxy
}butoxy)propoxylacetamido} -3,3-
dimethylbutanoy11-4-hydroxy-N-{ (4-(1,3-thiazol-5-yl)phenyll methyl
}pyrrolidine-2-
carboxamide
IH NMR (400 MHz, CD30D): 8 8.94 (s, 111), 8.15 (s, 111), 7.96 (d, J = 8.4 Hz,
111), 7.87
... (s, 1H),7.66-7.6J (m, 3H), 7.44 (d, J= 8.4 Hz,
2H), 7.19-7.12 (m, 3H), 4.71 (s, 1H),4.60-
HN 0
46 1µ11- 4.51 (in, 3H). 4.38-4.34 (m. 111), 4.17-4.11 (n,
211), 3.99-3.94 (m, 2H), 3.88-3.75 (m,
10 Iµ.....e 11
twr. ..) )7( 2I1), 3.71-3.55 (m, 6I1), 2.37-2.20 (m, 111), 2.13-2.06 (m, 1I1),
1.94-1.89 (m, 411), 1.80-
1.77 On, 2H), 1.55 (s, 6H), 1.03 (s, 9H); If-Ms (FS):
976.25 (MW). 4 = 1.57 min
N' \-1-J., (3.0 minute run).
H 'OH
O.......L
N"-=--1:1)--- 4 IV¨
r '' Prepared from ABM-23, L-8, and ULM-4
F. s µ9,..so
F=(2S.4R)-1-R2S)-2-(2-(344-(4-(316-cyano-5-(trifluoromethyl)pyridin-3-y1J-5.5-
dimethyl-
F =
F 4-oxo-2-sulfanylideneimidazolidin-1-y1}-2-
fluorophenoxy)butoxylpropoxy}acetamido)-
3,3-dimethylbutanoy11-4-hydroxy-N-([4-(1,3-oxazol-5-
yl)phenyl]methylipyrrolidine-2-
carboxamide
47 0 'H NMR (300 MHz, CD300) 69.16 (s, 1 H), 8.67 (s,
1 H). 8.23 (s, 1 H), 7.69-7.66 (d, J
= 8.1 Hz, 211), 7.48-7.43 (m, 311), 7.22-7.15 (m, 311), 4.70 (s, 1 H), 4.60-
4.49 (in, 311),
--, HN
)....../ 4.36-4.31 (n, 1 H). 4.16-4.12 (n, 2 H), 3.99 (m,
2 H), 3.86-3.81 (m, 2 H). 3.67-3.53 (n, 6
H). 2.22-2.08 (m. 2 H), 1.95-1.75 (m, 6 II). 1.57(s, 6 II). 1.04 (s, 9 II); LC-
MS (ES*): ttilz
995.10 [M}1, tR = 2.26 min (3.6 minute run).
?-7----).
bH
õ.
.õ
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Structure Compound name and Analytical data
#
(:::\yN -
(trifluoromethyl)pyridin-3-y1]-5,5-dimethyl-
\ r--
F S ---
_)-
F (P2r.:.:4aRred).1f-rolainsA)-2B-72-.2313:1L4-
844,-73idit6TLM.cya-n10.5
F X
4-oxo-2-sulfanylideneimidazolidin-1-y1}-2-fluorophenoxy)butoxy]propoxy
lacetaniido)-
3,3-dimethylbutanoy1]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-
y1)phenyl]methyl)pyrrolidine-2-carboxamide
48 IHNMR (300 MHz, CD301.)) 6 9.16 (s, 1 H), 8.87
(s. 1 H), 8.67(s, 1 H), 7.4-7.40 (in, 4
--0
N'S FiN II), 7.24-7.12 (m, 3 /I), 4.70 (s, 1 II), 4.62-4.46 (m, 3
11),4.38-4.32 (m, 1 H), 4.15-4.09
...... 0,-7( (m, 2 H), 3.99 (s, 2 H), 3.90-3.78 (m, 2
H), 3.67-3.52 (m, 6 H), 2.47 (s, 3 H), 2.27-2.17
\ / Ot.ii..1
)---4.
(in, 1 H), 2.16-2.06(m, 1 I-1), 1.94-1.83 (in, 4 H), 1.82-1.71 (rn, 2 H),
1.57(s, 6 H), 1.04 (s,
48 \--)''OH 9 H); LC-MS (ES'): nez 1025.30 [MIII, IR = 2.27 min, (3.6 minute
run)
0\1 1
N= 13¨N/-1--
N
.,,, Prepared from ABM-22, L-8, and 1.1M-4
---0 s ck
(2S.4R)-1-[(25)-2-(213-(4-{443-(4-cyano-3-methoxyphenyl)-5,5-dimethyl-4-oxo-2-
F 0.--\...\... s
ulfany licleneimidazolidin-l-y1]-2-fluorophenoxylbutoxy)propoxy)acetamido} -
3,3-
dimethylbutanoy11-4-hydroxy-N-f [4-(1,3-oxazol-5-yl)phenyl]methyl}pyrrolidine-
2-
<c
carboxamide
49 0 'H NMR (400 MHz, CD30D) 6 8.25 (s, 1H), 7.77
(d, J = 8.0 Hz, 1H), 7.70(d, J = 8.4 Hz,
NI% 211), 7.50 (m, 311), 7.36 (m, 111), 724 (m, 41-1), 4.71 (s, 1I1),
4.60 (m, 31-1), 437 (m, 1I-1),
HN 4.16 (in, 2H), 4.01 (in. 5H), 3.88 (m, 1H).3.83 (m, 1H). 3.69 (m, 6H),
2.28 (m, 1H), 2.14
* o''( (rn, 1H), 1.94 (m, 4H), 1.81 (m, 2H), 1.56 (s, 6H), L06 (in, 9H); LC-MS
(ES*): ni/z
)1...ciiq...)
956.45 [MHI, IR = 2.17 min (3.6 minute run).
N
H 'OH
0
i
),--N Pmpared from ABM-21, L-8, and ULM-11
01 g *
(2SAR)-1-[(2S)-2-(2-[3-(4-(443-(3-chlom-4-cyanopheny1)-5,5-dimethyl-4-oxo-2-
F 4 A.... SUE fanylideneimidazolidin-l-y1]-2-fluorophenoxylbutoxyjpropox
y I acetamido } -3,3-
dinlethylbutanoyl]-4-hydroxy-N1 [4-(1-methyl-1H-pyrazol-5-
e\_.
? yl)pbenyl]methyl)pyrrolidine-2-carboxamide
IH NMR (300 MHz. CD30D) 6 7.96-7.93 (d, J = 8.1 Hz, 1 H), 7.86 (s, 1 H),7.65-
7.61(d,
50 0 J . 9.6 Hz, 111), 7.50-7.41 (m,5 H), 7.23-7.10
(m, 31-1), 634 (s, 1 H), 431 (s, 1H),
4.61-4.46 (m, 3 H), 4.41-4.34 (m, 1 I-I), 4.18-4.09 (m, 2 H), 3.98 (s, 2 H),
3.90-339 (m, 5
inH), 3.66-3.51 (in, 6 H), 2.28-2.16 (in, 1 H), 2.14-2.01 (in, 1 H), 1.93-1.83
(m, 4 H), 1.81-
/
O'7< 132 (m, 2 II), 1.54 (s, 61-I), L04 (s, 9 II); LC-MS (ES): miz, 973.35
[MI-I'], /R = L55
,
(.. .N,....
min, (3 minute run)
-411---\---1.
'OH
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Ex
Structure Compound name and Analytical data
Prepared from ABM-9, L-8, and ULM-1
(2S,4R)-1-[(2S)-2-(2-1344-(4-(344-cyano-3-(trilluoromethyl)phenyl]-8-methyl-4-
oxo-2-
sulfanylidene-1,3,8-triazaspim[4.5]decan-1-y1) phenoxy)butoxy)pmpoxy
}acetamido)-3,3-
dimethylbutanoy11-4-hydroxy-N-( [4-(4-methy1-1,3-thiazol-5-
51 yl)phenyl] methyl }pyrrolidine-2-carboxamide
NMR (300 MHz, CD30D):68.81 (s, 111), 8.16-8.03 (m, 21-1), 8.00-7.90 (m, 1 /I),
7.50-
7.30 (m. 4 H), 7.23-7.15 (m, 2H), 7.05-6.90 (m, 2 H), 4.67 (s, 1 H), 4.60-4.30
(m, 4 H).
4.12-3.91 (m, 4 H), 3.80-3.70 (m, 2 H), 3.65-3.40 (in, 6 H), 2.80-2.61 (m, 4
H), 2.41 (s, 3
H), 2.25-2.11 (m, 6 H), 2.10-1.60 (m, 9 H), 1.02 (s, 9 FI); LC-MS (ES"): nez,
531.35
H [M/2+H], 4 =1.86 min (3.6 minute run).
Prepared from ABM-3. L-9, and ULM-1
:
(2S,4R)-1-[(2S)-2-(2- [44344- 3-[4-cyano-3-(tri fluoromethyl)pheny1]-5,5-
dimethyl-4-
iN-0¨
/
NC10 0 oxo-2-sulfanylideneimidazolidin-1-
yllphenoxy)propoxy]butoxy }acetamido)-3,3-
,
52 F3 dimethylbutanoy1J-4-hydroxy-N-{14-(4-methyl-
1,3-thiazol-5-
yl)phenylimethyl}pyrrolidine-2-carboxamide
11-1 NMR (300 MHz, CD3OD) 6 8.83 (s, 1H), 8.12-8.10(m, 2H), 7.96 (d, J = 8.1
Hz, 1H),
1-117(te'S 7.44-7.37 (m, 411), 7.25 (d, J = 8.7 Hz, 211),
7.02 (d, J= 83 Hz, 211), 4.66-4.29 (m, 5I1),
;)
o,....0 4.09-3.78 (m, GH), 3.60-3.47 (m, 6H), 2.44 (s, 3H), 2.19-1.97 (m,
4H). 1.70-1.63 (m. 4H),
.40H 1.50 (s, 6H), 1.00 (s, 9H), LC-MS (ES'): m/z 1006.30 [M
= L71 min (3.0 minute
run).
Q._ Prepared from ABM-16, L-9, and UL11-1
(2S,4R )-1-[(2S)-2 -(2- [ 44344- { 314-cyano-3-(tri fluoromethyl )phenyI)-5,5-
di methyl-4-
w s 0?
F
F oxo-2-sulfanylideneimidazolidin-1-y1 } -2-
fluorophenoxy)propox y] butoxy } acetamido)-3,3-
di i tethylbutanoyll -4-hydroxy-N-I [4-(4 -methy1-1,3-thiazol-5 -
F F
0
53 o yl)pbenyl]methyl ) pyrrolidi ne-2-cattmamide
N'IN
'H NMR (400 MHz, CD3OD) 6 8.98 (s, 1 H), 8.17-8.15 (d, J = 8.4 Hz, 211), 8.01-
7.99 (m,
s
01-7( 1 Ii), 7.49-7.42 (m, 4 II), 7.42-7.20 (m, 3 /I), 4.80 (s, 1 Ii), 4.71-
4.70 (d, J = 2.8 Ilz, II-!),
( 0 N 4.59-4.51 (m. 4 H), 4.38-4.20 (m, 4 H), 3.99-3.87 (m, 2 H),
3.65-3.52 (m, 6 H). 2.50 (s. 3
¨NH "O(4 H), 2.10-2.05 (m, 4 H), 1.72 (rn, 4 H),
1.56 (s, 6 H), 1.03 (s, 9 H); LC-MS (ES"): m/z
1025.50 [MI-11, 4 = 3.50 min (5.6 minute run).
10536] Example 54: (2S,4R)-1-0S)-2-(2-(6-(4-(3-(4-cyano-3-
(trilluoromethyl)pheny1)-5,5-
dimethyl-4-oxa-2-thioxaimidazolidin-l-yl)phenoxyjhexa-2,4-diynyloxy)acetamido)-
3,3-
dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-
carboxamide:
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y_
N-0-0 _____________________________________________________
j---0 K2CO3, ABM-3
Ts ¨ ¨
\ .................. J Step 1 -NCI) S
L-1 CF3 BJ
HQ
)c_S.14
Fiztsi 0 0
N N 1110= __ 0 0
Step 2 p- ULM-1 IN
S
NC Step 3
CF3 BK
HQ
0 (31¨NH 0 0
N N
NC Example 54 S
CF3
=
[0537] Step 1: Synthesis of tert-butyl 2-{[6-(4-13-[4-cyano-3-
(trifluoromethyl)phenyl]-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-y1)phenoxy)hexa-2,4-diyn-1-
yl]oxy)acetate (BJ)
[0538] This material was synthesized according to a similar procedure
described in reaction step
1 for the synthesis of Example 1. LC-MS (ES+): m/z 634.05 [MNal, tR = 1.26 min
(2.0 minute
run).
[0539] Step 2: Synthesis of 2-{ [6-(4-(3-[4-cyano-3-(trifluoromethyl)pheny1]-
5,5-dimethyl-4-
oxo-2-sulfanylideneimidazolidin-1-yl)phenoxy)hexa-2,4-diyn-l-yl]oxy)acetic
acid (BK)
[0540] This material was synthesized according to a similar procedure
described in reaction step
2 for the synthesis of example 1. LC-MS (ES+): miz 556.10 [MF11, tR = 1.54 min
(2.6 minute
run).
[0541] Step 3: Synthesis of (25,4R)-1-I (25)-2-(2-{ [6-(4-(344-cyano-3-
(trifluoromethyl)phenylj -5,5 -dimethyl -4-oxo-2-sulfanylideneimidazolidi n-l-
yl phenox y)hexa-
2,4-di yn-l-yl]ox y ) acetamido)-3,3-dimethylbutanoy1J-4-hydroxy-N-{ [4-(4-
methyl-1,3-thi azol-5-
yl)phenyll meth yl ) pyrrol idine-2-carbox amide (Example 54)
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[0542] This material was synthesized according to a similar procedure
described in reaction step
3 for the synthesis of Example 1. 11-1 NMR (400 MHz, CD30D): 5 8.88 (s. 1H),
8.15 (d, J= 8.4
Hz, 2H), 8.00 (d, J. 1.6 Hz, 1H), 7.49-7.43 (m, 4H), 7.34 (d, J. 8.8 Hz, 2H),
7.14 (d, ./=8.8 Hz,
2H). 4.93 (s, 2H). 4.71 (s, 1H). 4.60-4.34 (m, 6H), 4.08 (s, 2H), 3.90-3.80
(m. 2H), 2.49 (s, 3H),
2.25-2.22 (m, 1H), 2.13-2.05 (m, 1H), 1.56 (s, 6H), 1.03 (s, 9H); LC-MS (ES):
rmiz 968.45
[MH-1, tR = 1.67 min (3.0 minute run).
[0543] Table 3. Exemplary Compounds.
Ex
Structure Compound name and Analytical data
#
55.s.so Prepared from ABM-3, L-II, and ULM-1
NC..a.N)v
(2S,4R)-1-[(2S)-2-(3-{ [6-(4- ( 3 44-cyano-3-(trifluoromethyl)phenyl j -5,5 -
dimethyl-4-oxo-
r,c
se-isl\ 2-sulfanylideneimidazolidin-1-yllphenoxy)hexa-
2,4-diyn-l-yl]oxy Ipmpanamido)-3,3-
\ dimethylbutanoy11-4-hydroxy-N-([4-(4-methy1-1,3-
thiazol-5-
yl)phenyl] methyl ) pyirolidine-2-carboxamide
'Il NMR (400 MHz, CD30D): 8 8.88(s, 1/1), 8.16 (d, J = 8.8 Hz, 2/1), 7.99
(d,J= 1.6 Hz,
\--)--M 1H), 7.49-7.42 (m, 4H), 7.33 Id, .1= 8.8 Hz, 2H), 7.14 Id, .1 = 8.8
Hz, 2H), 4.93 (s, 2H),
if- 0 4.66 (s, 111), 4.60-4.38 (m, 311), 4.38-4.27
(in, 3H), 3.92-3.80 (m, 4H), 2.63-2.59 (in, 1H),
rIla.,
..t_
NH '"OH
2.58-2.49 (m, 411), 2.26-2.18 (m, III), 2.13-2.05 (m, 111), 1.56 (s, 6/1),
1.03 (s, 911); LC-
MS (ES*): miz 982.40 [M1-1], IR = 3.35 min (5.6 minute nin).
56 Prepared from ABM-3, L-12, and ULM-1
(2S,4R )-1-[(2S)-2-(4- ([644 - ( 3 44-cyano-3-(trifluoromethyl)phenyll -5,5 -
dimethy1-4-oxo-
FeC. N.0
2 -sulfanylideneimidazolidin -1 -yi ) phenoxy)hexa-2,4-diyn- 1 -yl]oxy
Ibutzia;nido)-3.3-
dimethylbutanoy1]-4-hydroxy-N-1[4-(4-methyl-1,3-thiazol-5-
y0phenyl]methylIpyrrolidine-2-carboxamide
"""\--c f). 'H NMR (400 MHz, CD30D): 5 8.88(s, 1H), 8.16 (d,./ = 8.8 Hz.
2H), 7.99 (d,./ = 1.6 H7,
..,,,
0 NH 1H), 7.49-7.42 (m, 41-1), 7.35 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8
Hz, 2H), 4.93 (s, 2H),
2
4.63 (s, 1I-1), 4.59-4.51 (m, 311), 4.38-4.27 (d, J = 12.4 Hz, 1I-1), 4.25 (s,
211), 3.93-3.79
ii63()C1) (in, 2H). 3.53 (t. J = 6.0 Hz, 2H). 2.50 (s,
3H), 2.49-2.33 (m, 2H), 2.26-2.18 (m, 1H),
2.13-2.05 (in, 111), 1.90-1.86 (m, 211), 1.57 (s, 6H), 1.02 (s, 911); LC-MS
(ES'): miz
996.40 [MI-1], IR= 3.41 min (5.6 minute run).
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Ex
Structure Compound name and Analytical data
#
57 N _ Prepared from ABM-16. 1.40, and ULM-I
F 4 Yy, (2S,4R)-1-[(2S)-2-I 2- ( [6-(4- (3-(4-cyano-3-
(tri fluoromethyl)pheny1)-5,5 -dimethy1-4-oxo-
F ;-hi
2-suanylidenei If I idazolidin-1-y1}-2-fluorophenoxy)hexa-2,4-diyn-1-yl]oxy
}acetamido)-
0 ll
--F
3,3-dimethylbutanoy11-4-hydroxy-N-(14-(4-methyl-
o
1,3-thiazol-5-yl)phenyl)methyl)pyrrolidine-2-carboxamide
\\.0 'H NMR (400 MHz, CD301.3): 8 8.88 (s, 1H), 8.16
(d, J = 8.0 Hz, 2H), 8.00 (d, .1 = 1 2
Hz, 1I-1), 7.49-7.43 (m, 411), 7.36-7.29 (m, 2H), 7.19 (d,J = 8.0 Hz, 1I1),
5.03 (s, 2I1), 4.71 \...1:44 x41
= (2,1H), 4.61-4.42 (m, 3H), 4.41-4.33 (m, 3H), 4.09 (s, 2H), 3.90-3.80 (m,
2H), 2.49 (s.
o 3H), 2.27-2.15 (rn, 1H), 2.12-2.06 (rn, 1H), 1.56
(s, 611), 1.03 (s, 9H); LC-MS (ES): treZ
NH
986.30 [Mtn, tR = 1.58 min (3.0 minute run).
(s_re2rj
N
0 -c
58 ,i Prepared 1E01 H ABM-1, L-10, and LIM-1
,-i...)ti__
(2S,4R)-1-[(2S)-2-(2-[(6- (413-(3-chloro-4-cyanopheny1)-5,5-dinlethyl-4-oxo-2-
su I fanyl ideneimidazolidin-l-Aphenoxylhexa-2,4-diyn-l-y1)oxy]acetamido ) -
3,3-
?
dimethylbutanoy11-4-hydroxy-N-([4-(4-methyl-1,3-thiazol-5-
\0 o yl)phenyt]methyl}pyrrolidine-2-carboxamide
OH
'Il NMR (400 MHz, CD30D): 5 8.88(s, 1/I), 7.96(d, J= 8.4 Hz, 1I-1), 7.87 (s,
111), 7.66-
0 H 7.64(m, 1H), 7.49-7.43 (m, 4H), 7.33 (d, J =
8.8 Hz, 111). 7.14 (d, J = 9.2 Hz, 1H), 4.94
(s, 211), 4.71 (s, 111), 4.61-4.42 (m, 311), 4.41-4.29 (m, 311), 4.09 (s,
211), 3.92-3.86 (m,
C-KCrj 1I1), 3.82-3.77 (m, 1I1), 2.49 (s, 311), 2.27-2.18 (m, 111), 2.12-
2.06 (m, 111), 1.52 (s, 6I1),
1.01 (s, 911). LC-MS (ES'): miz 934.20 [MHI, IR = 1.54 min (3.0 minute run).
õ
59 4 N;( Prepared from ABM-1, L-10, and ULM-5
c.1 8)-N
0
o (25,4R)-1-[(2S)-2-(2-[(6-(4-[3-(3-chloro-4-cyanopheny1)-5,5-dimethyl-4-
oxo-2-
suIfanylideneimidazoiidin-1-yl]phenoxy } he xa-2,4-diyn-1-yl)oxy]ace tamido } -
3,3-
dimethylbutanoy1]-4-hydmxy-N-{ [4-14-methyl-1,3-ox az,o1-5-
yl)phenynmethyl}pyrrolidine-2-carboxamide
S41\\_o o 'H NMR (400 MHz, CD30D): 8 8.15 (s. 1H), 7.95 (d, J = 8.4 Hz,
1H), 7.87 (s. 111), 7.66-
11 s...4
PI
7.58(m, 311), 7.49-7.47 (m, 2H), 7.35-7.31 (in, 2H), 7.14 (d,J = 8.8 Hz, 211),
4.94 (s, 211),
0 NH 4.71 (s, 111), 4.63-4.57 (m, 3I1), 4.41-4.28
(m, 311), 4.09 (s, 2I1), 3.90-3.86 (m, 111), 3.82-
3.77 (in. 1H). 2.42 (s, 311), 2.27-2.20 (in, 1H), 2.12-2.02 (m, 1H), 1.55 (s,
611), 1.03 (s.
....Cri
9H); LC-MS (ES): nez 918.25 [MW], tR = 1.51 min (3.0 minute run).
60 1.14--CO,L
Prepared from ABM-21, L-10, and 1.7LM-4
O (2S,4R)-1-[(25)-2-(2-[(6-(413-(3-chloro-4-
cyanopheny1)-5,5-dimethyl-4-oxo-2-
s N
sunny! idenei midazolidin-l-y1]-2-fluoroplrenoxylhexa-2,4-diyn-1 -yl)oxy]
acetami do ) -
F 3,3-dimethylbutanoy1:1-4-hydroxy-N-{ [4-(1,3-
oxazol-5-yl)phenyl]methyl )pyrrolidine-2-
0 . elHvviarboxanRiide
= = ( MHz, CD3OD): 8 8.23 (s, 1H), 7.94
(d, J = 8.1 Hz, 1H), 7.86 (s, 1H),7.70-
N Z 7.63(m, 3H), 7.49-7.43 Im, 3H). 7.36-7.21 (m. 2H), 7.18-7.12(m, 1H),
5.12(s. 211), 4.71
o
o Is, 1H), 4.61-4.47 (m, 3H), 4.44-4.29 (m, 311), 4.09 (s, 2H), 3.89-3.79
(in. 211), 2.22-2.18
(m, 1I1), 2.12-2.06 (m, 1I1), 1.55 (s,611), 1.02 (s, 91-1); LC-MS (ES): Int
922.15 [MI-11,
t8= 2.53 min (5.0 minute run).
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Ex
Structure Compound name and Analytical data
#
61 NT-p.. j.,/... Prepared from ARM-16.1.-10, and U1.M--1
1,1).44
(2S,4R)-1 -[( 2S)-24 2- ( [6-(4-(3-(4-cyano- ; - (rri fluoromedly 1 )pheny1)-
5,5-dimediy1-4-0KO-
F r S
2 -su Ilanylideneimidazolidin -1 -y1) -2-fluuroplienoxy)hexa-2,4-dlyn-1-yl]oxy
}acetamido)-
F
3,3-dimethylbutanoyll -4-hydroxy -N- (14-(1,3-oxazol-5-
\\ ....0 yl)phenyrimethyl}pyrrolidine-2-carboxamide
C;IN IH NMR (300 MHz., CD301.3): 8 8.23 (s, 1H). 8.15
(d.../ = 7.5 Hz, 2H). 7.98 (d.../= 9.0 Hz,
H
111), 7.71 (d, J. 7.8 Hz, 2/1), 7.49-7.40 (m, 3H), 7.36-7.21 (m, 211), 7.18-
7.12 (m, 1H),
3
0 H
5.02 (s, 2H), 4.71 (s, 1H), 4.59-4.47 (m, 3H), 4.44-4.29 (m, 3H), 4.09 (s,
2H), 3.89-3.74
(..y
(in, 2H), 2.22-2.18 (rn, 1H), 2.12-2.01 (m, 1H), 1.57 (s, 611), 1.04 (s, 914);
LC-MS (ES*): 1)
miz 956.20 [MIT], tR = 2.60 min (5.0 minute tun).
[0544] Example 62: (2S,4R)-1-((S)-2-tert-butyl-16-(4-(3-(4-cyano-3-
(trifluorom ethyl)pheny1)-5,5-d i methy l-4-oxo-2- thioxoimid azol id in- 1 -y
1)pheny1)-4,13-dioxo-
6,9-dioxa-3,12-diazahexadeca ne)-4-hydroxy-N-(4-(4-methylthiazol-5-
yl)benzyl)pyrrolidine-
2-carboxamide:
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F 0
F-A¨F
1-13 0
9
OH Step 1
ABM-12
F 0
F
NaOH
isfr- *
k C)""*Or0'''' Step 2
0
BL
HQ
"
HZ 0 10
--/
ULM-
BM 0 Step 3
St/ HQ
N N
N :1 o3
1y
iti s,
H 0
Example 62
[0545] Step 1: Synthesis of ethyl 2-(2-{2-[4-(4-{3-[4-cyano-3-
(trifluoromethyl)pheny1]-5,5-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-l-y1 ) phenyl)bu tanamido]ethoxy )
ethoxy)acetate
(BL)
10546] To a stirred solution of 4-(4-1344-cyano-3-(trifluoromethyl)phenyl]-5,5-
dimethyl-4-oxo-
2-sulfanylideneimidazolidin-1-yl}phenyl)butanoic acid (ABM-12, 417 mg, 0.88
mmol) in N,N-
dimethylformamide (10 mL) was added HATU (669 mg, 1.76 mmol), D1EA (454 mg,
3.51
mmol) and ethyl 242-(2-aminoethoxy)ethoxy]acetate hydrochloride (L-13, 400 mg,
1.76 mmol)
at 0 C . The resulting solution was stirred at 0 C for 30 minutes, and then
it was warmed up to
room temperature and stirred at room temperature for 15 hours. A mixture of
water/ice (1: 1, 50
mL) was added to the reaction, the resulting mixture was extracted with ethyl
acetate (100 mL x
3). The organic layers were combined, washed with saturated aqueous solution
of sodium
chloride (20 mL x 2), dried over anhydrous sodium sulfate and then
concentrated under reduced
pressure to give a crude residue, which was purified by flash silica gel
chromatography (eluent:
ethyl acetate/petroleum ether (v:v = 1:1) to give BL (yield: 35%) as a yellow
solid. LC-MS (ES):
nez 649.15[MH1, 1R = 1.05 inin (2.0 minute run).
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[0547] Step 2: Synthesis of 2-(2-(2-[4-(4-13-[4-cyano-3-
(trifluoromethyl)phenyl]-5,5-dimethyl-
4-oxo-2-sulfanylideneimidazolidin-1-y1}phenyl)butanamido]ethoxy}ethoxy)acetic
acid (BM)
[0548] To a stirred solution of ethyl 2-(2-12-14-(4-{3-(4-cyano-3-
(trifluoromethyl)pheny1)-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
yl)phenyl)butanamidoiethoxy)ethoxy)acetate
(BL, 200 mg, 0.31 mmol) in methanol (10 mL) was added a solution of NaOH (123
mg, 3.08
mmol) in water (10 mL) at room temperature. The resulting solution was then
heated to 50 C
and stirred at this temperature for 2 hours. The bulk of organic solvent was
removed under
reduced pressure. To the remaining residue was added aqueous hydrogen chloride
(1 M) to adjust
the pH to -3. The resulting mixture was extracted with ethyl acetate (50 mL x
2), the organic
layers were combined, washed with saturated aqueous solution of sodium
chloride (20 mL x 2),
dried over anhydrous sodium sulfate and then concentrated under reduced
pressure followed by
high vacuum pump to give BM (yield: 78%) as a yellow solid. LC-MS (ES): nvi
621.20 [MHI,
= 0.96 min (2.0 minute run).
[0549] Step 3: Synthesis of (2S,4R)-1-[(2S)-242-(2-(2-[4-(4-13-[4-cyano-3-
(trifluoromethypphenyl)-5.5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
y1)phenyl)butanamido]ethoxy}ethoxy)acetamido]-3.3-dimethylbutanoyl]-4-hydroxy-
N-{ [4-(4-
methy1-1,3-thiazol-5-y1)phenyl]methyl }pyrrolidine-2-carboxamide (Example 62)
[0550] To a stirred solution of 2-(2-{244-(4-{344-cyano-3-
(trifluoromethyl)pheny1)-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
y1)phenyl)butanamido]ethoxy)ethoxy)acetic acid
(BM, 200 mg, 0.32 mmol) in N,N-dimethylformamide (20 mL) was added HATU (245
mg, 0.64
mmol), DIEA (166 mg, 1.28 mmol) and (2S,4R)-1-K2S)-2-amino-3,3-
dimethylbutanoyli-4-
hydroxy-N-{ (4-(4-methyl-1,3-thiazol-5-yl)phenylimethyl)pyrrolidine-2-
carboxamide
hydrochloride (ULM-1, 226 mg, 0.48 mmol) at 0 C. The resulting solution was
stirred at 0 C
for 30 min, and then it was warmed up to room temperature and stirred at room
temperature for
15 hours. A mixture of water/ice (1: 1, 50 mL) was added to the reaction, the
resulting mixture
was extracted with ethyl acetate (100 mL x 3). The organic layers were
combined, washed with
saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous
sodium sulfate and
then concentrated under reduced pressure to give a crude residue, which was
purified by Prep-
HPLC to give Example 62 (yield: 6%) as a yellow solid. 11-1 NMR (400MHz.
CD30D): 8.89 (s.
1H), 8.18-8.16 (d, ./ = 8.4 Hz, 2H), 8.01-7.99 (d, J - 8.0 Hz, 1H), 7.47-
7.41(m, 4H), 7.38-7.36
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(d, J ¨ 8.4 Hz, 2H), 7.30-7.28 (d, 8.4 Hz, 2H), 4.87 (s, 1H), 4.78-4.60 (m,
3H), 4.39-4.35
(d, J = 15.2 Hz, 1H), 4.04-3.98 (m, 2H), 3.98-3.85 (m, 2H), 3.72-3.60(m, 7H),
3.50-3.49(m,
1H), 2.71-2.69 (m, 2H), 2.49 (s, 3H), 2.45-2.28 (m, 3H), 2.25-2.10 (m, 1H),
2.10-1.95 (m, 2H),
1.58 (s, 6H), 1.09 (s, 9H); LC-MS (ES): m/z 1033.50 [MH1, 1R = 3.06 min (5.6
minute run).
[0551] Examples 63-65 were synthesized according to similar procedure
described for synthesis
of example 62, by using corresponding starting materials and intermediates.
[0552] Table 4. Exemplary Compounds.
Ex
Structure Compound name and Analytical data
63 oV
Prepared from ABM-12, L-14. and ULM-1
NC)C,
kl 12S,4R)-1-[(2S)-242-( (544444 344-cyano-3-
(trifluommethyl)phenyl]-5,5-dimethyl-4-
oxo-2-sullanylideneimidazolidin-l-y1}plienyl)butaniunido]pentyl oxy)acetamido]
-3,3-
dimethylbutanoy1]-4-hydroxy-NI [4-(4-methyl-1,3-thiazol-5-
\
yl)phenyl)methyl ) pyrrolidi ne-2-catboxamide
Hr4 IHNMR (400 MHz. DMS0):68.98 (s. 1H), 8.60 (m,
1H), 8.40 (d.../ = 8.0 liz, 1H), 8.30(s,
N 0 1H), 8.10 (d, J= 8.0 Hz, 1/1), 7.79 (m, 111), 7.40 (m, 41-1),
7.36 (m, 3I1), 7.29 (d, J= 8.0
'OH
*I NH Hz, 2H), 5.16 (m, 1H), 4.57 (d,./ = 9.2 Hz, 1H),
4.45 (m, 4H), 3.92 (m, 2H), 3.66 (m, 2H),
3.48 (m, 2H), 3.07 (m, 2H), 2.64 (m, 211), 2.51 (in, 3H), 2.14 (in, 311), 1.90
(in, 3H), 1.57
(m, 211), 1.50 (s, 611), 1.44 (m, 211),1.36 (m, 211), 0.94 (s, 9/1): LC-MS
(ES*): mir. 516.65
[M+2] /2. tk =2.55 min. (50 minute run).
64
Prepared from ABM-12, L-15, and ULM-1
F3cV11+-0---5rN/
(2S,4R)-1-[(2S)-242-(2-{214-(44 344-cyano-3-(tri fluommethyl)phenyl] -5,5-di
methyl-4-
NC
1.)), oxo-2-sulfanylideneimidazolidin-1-yl}pheny1)-N-
1Y methylbutanamido]ethoxy ietboxy)acetainido]-3,3-dimethylbutanoyl]-4-
hydroxy-N1 [4-
(4-methy1-1,3-thiazol-5-y1)phenyl]methyl Ipyrrolidine-2-carboxamide
HNoris 11-1NMR (300 MHz, CD30D) 68.87 (s, 111), 8.17-
8.14 (d, J = 8.4 Hz, 211), 8.01-7.98(d, .1
= 8.7 Hz, 111), 7.47-7.31 (m, 611), 7.28-7.13 (d, J = 8.1 Ilz, 21-1), 4.71 (s,
111), 4.61-4.51
NH (m. 3H). 4.38-4.33(d. J -15.2 Hz, 111), 4.04-4.02
(m, 211), 3.86-3.81(m, 2H), 3.69-3.60
(in, 711), 3.59-3.52 (m, 111), 3.10 (s, 211), 2.97 (s, 111), 2.75-2.73 (in,
211), 2.46 (s, 311),
2.46-2.41 (m, 211), 2.38-2.23 (m, 111), 2.21-2.09 (m, 1H), 1.99-1.91 (m, 211),
1.55 (s, 6H),
1.02 (s. 9H); LC-MS (ES*): tn4.- 1047.80 [Min, tR = 2.09 min (3.6 minute run).
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Ex
Structure Compound name and Analytical data
it
65 00/
Prepared from ABM-12, L-16, and ULM-1
NCA,001- (2S,4R)-1-[(2S)-2424 (544444 344-cyano-
34trifluoromethyl)pheny11-5.5-dimethy1-4-
0 Is oxo-2-sulfanylideneimidazolidin-l-yllphenyl )-N-
niethylbutanamido]pentyl )oxy)acetamido]-3.3-dimethylbutanoy1]-4-hydroxy-N-{
[444-
nlethy1-1,3-thiazol-5-3,1)plienylimethyllpyrrolidine-2-earboxamide
HN Lr IIINMR (400 MHz, DMSO) 8 8.98 (s, 1H), 8.60 (s,
1/I), 8.40 (d, J = 8.0 Hz, III), 8.30 (s,
1H), 8.10 (d, J= 8.0 Hz, 1H), 7.46-7.27 (m, 9H), 5.15 (s, 1H), 4.57-4.55 (m,
1H), 4.47-
N9" 0
Okr,..ON =NDH 4.23 (rn, 4H). 3.92-3.85 (m, 21-1), 3.68-3.59 (m, 21-1), 3.47
(s, 2H). 3.29-3.20 (m, 21-1), 2.91-
ipr NH 2.64 (m, 511), 2.44 (s, 3I1), 2.33-2.30 (m, 211),
2.09-2.03 (m, III), 1.95-1.81 (m, 311), 1.59-
1.46 (m, 10H), 1.30-1.24 (m, 2H), 0.94 (s. 9H); Mass (ES*): WI, 1045.40 [MW]
[0553] Example 66: 2-(2-(4'43-(4-cyano-3-(trifluoromethyl)pheny1)-5,5-dimethyl-
4-oxo-2-
t hioxaimidazolidin-1-yl)biphenyl-4-yloxy)ethoxy)ethyl (S)-1-((28,4R)-4-
hydroxy-2-(4-(4-
methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-y1)-3,3-dimethy1-1-oxobutan-2-
ylcarbamate:
F F q
L-18 F
N= = N t N
HO0,..."¨"cas N=
10
Step 1 1
ABM-14 OH BN 111)11
HQ
0, v --kr-k
F 0 0
NH
Step 2 NiN
0
ULM-1 S S
Example 66
[0554] Step 1: Synthesis of 4-[3-(4-{ 4-[2-(2-
hydroxyethoxy)ethoxy]phenyl}pheny1)-4,4-
dimethy1-5-oxo-2-sulfanylideneimidazolidin-1-y1]-2-
(trifluoromethyDbenzonitrile (BN)
[0555] To a stirred solution of 4-1344-(4-hydroxyphenyl)pheny1]-4,4-dimethy1-5-
oxo-2-
sulfanylideneimidazolidin-l-y1}-2-(trifluoromethypbenzonitrile (ABM-14, 610.5
mg, 1.27 mmol)
in N,N-dimethylformarnide (10 mL) was added K2CO3 (318.46 mg, 2.29 mmol) and 2-
{2-[(4-
methylbenzenesulfonyl)oxy]ethoxy}ethan-1-ol (L-18, 300 mg, 1.15 mmol) at room
temperature.
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The resulting mixture was then stirred at 80 C for 2 hours in an oil bath, LC-
MS indicated
formation of the desired product. The reaction mixture was cooled down to room
temperature,
water (20mL) was added and the resulting mixture was extracted with ethyl
acetate (100 mL x 2).
The organic layers were combined, washed with saturated aqueous solution of
sodium chloride
(20 mL), dried over anhydrous sodium sulfate and then concentrated under
reduced pressure to
give a crude residue, which was purified by a flash silica gel chromatography
(eluent: ethyl
acetate/petroleum ether (v:v = 7:3) to give BN (yield: 66%) as a light yellow
oil. LC-MS (ES):
m/z 570, [MHI, tR = 1.60 min (2.0 minute run).
[0556] Step 2: synthesis of 2-12-[4-(4-{344-cyano-3-(trifluoromethyl)pheny1}-
5,5-dimethy1-4-
oxo-2-sulfanylideneimidazolidin-l-yl}phenyl)phenoxyJethoxy}ethyl N-R2S)-1-
[(25,4R)-4-
hydroxy-2-(([4-(4-methy1-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-
y1}-3,3-
dimethy1-1-oxobutan-2-yl}carbamate (Example 66)
[0557] To a stirred solution of 4-[3-(4-1442-(2-
hydroxyethoxy)ethoxy]phenyl}pheny1)-4,4-
dimethyl-5-oxo-2-sulfanylideneimidazolidin-l-y1}-2-
(trifluoromethypbenzonitrile (200 mg, 0.35
mmol) in dichloromethane (10 mL) was added triethylamine (106.5 mg, 1.05
mmol), followed by
triphosgene (36.5 mg, 0.12 mmol) which was added slowly in 30 minutes at 0 C.
To this mixture
was then added (25,4R)-1-[(25)-2-amino-3,3-dimethylbutanoy1]-4-hydroxy-N-([4-
(4-methy1-1,3-
thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (ULM-1,
196.9 mg, 0.42
mmol) at 0 C. The resulting mixture was then warmed up to room temperature
and stirred at
room temperature for 2 hours. Water (20mL) was added to the reaction and the
resulting mixture
was extracted with dichloromethane (50 mL x 3). The organic layers were
combined, washed
with saturated aqueous solution of sodium chloride (20 mL), dried over
anhydrous sodium sulfate
and then concentrated under reduced pressure to give a crude residue, which
was purified by
Prep-HPLC to give Example 66 (yield: 6%) as a white solid. 1H-NMR (400MHz,
CD30D): 8
8.88 (s, 1 H), 8.20-8.17 (m, 2 H), 8.04-8.02 (d, J= 8.0 Hz, 1 H), 7.77-7.72
(m, 2 H), 7.65-7.59 (m,
2 H), 7.48-7.42 (m, 6 H), 7.08-7.06 (d, J. 8.4 Hz, 2 H), 4.61-4.53 (m, 1 H),
4.47-4.44 (s, 1 H),
4.38-4.34 (m, 2 H). 4.25-4.20 (m, 4 H). 3.92-3.90 (m, 3 H). 3.82-3.79 (m, 3
H). 2.48 (s, 3 H),
2.26-2.21 (m, 1 H), 2.13-1.09 (m, 1 H), 1.61 (s, 6 H), 1.30 (s, 1 H), 1.04 (s,
9 H); LC-MS (ES):
nez 1026.40 [MF11, 1R = 2.23 min (3.0 minute run).
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[0558] Example 67: (28,4R)-1-08)-2-(2-(2-(2-(4'-(3-(4-cyana-3-
(trifluoromethyppheny1)-
5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-y1)biphenyl-4-
yloxy)ethoxy)ethoxy)acetamido)-
3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyppyrrolidine-2-
earboxamide:
F F L-19
F tsj N
Nr-
S Step 1
ABM-14
F F
F F 0µ0
N= N NaOH
401
Step 2 N= -Nil'
I
BO = .,/.Ø--..,..000OEt BP
HQ
CIH
F F
Step 3 µN--0 NH oe
ULM-1 cy.'"
1\17 S 0
Example 67 S
N
[0559] Step 1: Synthesis of ethyl 2-(2-{2-[4-(4-13-[4-cyano-3-
(trifluoromethyl)pheny1]-5,5-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
y1}phenyl)phenoxy]ethoxy}ethoxy)acetate (BO)
[0560] To a stirred solution of 4-{3-[4-(4-hydroxyphenyl)pheny1]-4,4-dimethyl-
5-oxo-2-
sulfanylideneimidazolidin-1-y1}-2-(trifluoromethypbenzonitrile (ABM-14, 300
mg, 0.62 mmol)
in N,N-dimethylformamide (10 mL) was added K2CO3 (172 mg, 1.24 mmol) and ethyl
2-(2-{2-
[(4-methylbenzenesulfonyl)oxy]ethoxy}ethoxy)acetate (L-19, 237.4 mg, 0.69
mmol). The
resulting mixture was stirred at 80 C in an oil bath for 2 hours. The
reaction was cooled down to
room temperature, water (50mL) was added and the resulting mixture was
extracted with ethyl
acetate (100 mL x 2). The organic layers were combined, washed with saturated
aqueous solution
of sodium chloride (30 mL x 3), dried over anhydrous sodium sulfate and then
concentrated under
reduced pressure to give a crude residue, which was purified by a flash silica
gel chromatography
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(eluent: ethyl acetate/petroleum ether (v:v = 3:7)) to give BO (yield: 48%) as
light yellow oil. LC-
MS (17S+): m/z 656, [MHI, IR = 1.19 inin (2.0 minute run).
(0561) Step 2: Synthesis of 2-(2-{2-[4-(4-{344-cyano-3-(trifluoromethyppheny1)-
5,5-dimethyl-
4-oxo-2-sulfanylideneimidazolidin-l-yl}phenyl)phenoxy]ethoxy}ethoxy)acetic
acid (BP)
[0562] To a stirred solution of ethyl 2-(2-{244-(4-13-[4-cyano-3-
(trifluoromethyl)pheny1]-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
y1)phenyl)phenoxy]ethoxy}ethoxy)acetate (BO,
198 mg, 0.30 mmol) in ethanol (5 mL) was added a solution of sodium hydroxide
(36.3 mg, 0.91
mmol) in water (2 mL) at room temperature. The resulting solution was stirred
overnight at room
temperature, the bulk of organic solvent was then removed under reduced
pressure. To the
remaining aqueous residue was added hydrogen chloride in water (IN) to adjust
the pH to -5.0,
and the resulting mixture was extracted with ethyl acetate (250 mL x 2). The
organic layers were
combined, dried over anhydrous sodium sulfate and concentrated under reduced
pressure
followed by high vacuum pump to give BP (yield: 99%) as a light yellow oil. LC-
MS (E51"): m/z
628, [MH+), 1R = 1.08 inin (2.0 minute run).
[0563] Step 3: Synthesis of (25,4R)-1-[(25)-2-(2-(2-12-[4-(4-(344-cyano-3-
(trifluoromethyl)pheny1:1-5,5-dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
y1}phenyl)phenoxylethoxy)ethoxy)acetamido:1-3,3-dimethylbutanoy1J-4-hydroxy-N-
{ [4-(4-
methyl-1,3-thiazol-5-yl)phenyl]methyl)pyrrolidine-2-carboxamide (Example 67)
[0564] To a stirred solution of 2-(2-{244-(4-{344-cyano-3-
(trifluoromethypphenyl)-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
yl}phenyl)phenoxy]ethoxylethoxy)acetic acid
(BP, 190 mg, 0.30 mmol) in N,N-dimethylformainide (10 inL) was added HATU
(149.7 mg, 0.39
mmol), D1EA (156.4 mg, 1.21 mmol) and (2S,4R)-1-[(25)-2-amino-3,3-
dimethylbutanoy1]-4-
hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-
carboxamide
hydrochloride (ULM-1, 183.9 mg, 0.39 mmol). The resulting solution was stirred
at room
temperature for 2 hours. Water (50mL) was added and the resulting mixture was
extracted with
ethyl acetate (100 mL x 2). The organic layers were combined, washed with
saturated aqueous
solution of sodium chloride (25 mL x 3), dried over anhydrous sodium sulfate
and then
concentrated under reduced pressure to give a crude residue, which was
purified Prep-HPLC to
give Example 67 (yield: 17%) as a white solid. 11-1-NMR (400MHz, CD30D): 5
8.82 (s, 1 H),
8.19-8.16 (d, J=9.0 Hz, 2 H), 8.02-8.00 (d, J=8.1 Hz, 1 H), 7.72-7.69 (d,
J=8.1 Hz, 2 H), 7.61-
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7.55 (m, 2 H), 7.46-7.37 (m, 6 H),7.08-7.01 (m, 2 H), 4.71(s, 1 H), 4.61-4.51
(m, 1 H), 4.47 (s, 2
H), 4.38-4.31 (m, 1 H), 4.23-4.20 (m, 2 H), 4.01(s, 2 H), 3.96-3.78 (m, 4 H),
3.63 (s, 4 H), 2.43
(s, 3H), 2.27-2.20 (m,1 H), 2.13-2.04 (m, 1 H), 1.61 (s, 6 H), 1.04 (s, 9 H);
LC-MS (ES): m/z
1040.10 [MHI, iR= 2.26 mm (3.0 minute run).
[0565] Examples 74 and 76 were synthesized according to similar procedure
described for
synthesis of Example 66, by using corresponding starting materials and
intermediates. Examples
68-73, 75, 77-79 were synthesized according to similar procedure described for
synthesis of
Example 67, by using corresponding starting materials and intermediates.
[0566] Table 5. Exemplary Compounds.
Ex # 1Structure Compound name and Analytical data
Prepared from ABM-14, L-20, and ULM-1
(2S,4R)-14(2S)-243-(2-{ 244441 3-I4-cyano-3-(ui fluoromethyl)phenyll -5,5 -
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
yl phenyl)phenoxylethoxy } ethoxy)propanamido] -3,3-
dimetbylbutanoy1J-4-hydroxy-N-f [4-(4-methy1-1.3-thiazol-5-
,OH yl)phenyl]methyl Ipyrrolidine-2-carboxamide
IHNMR (400 MHz, CD300) 8 8.87 (s, 1H). 8.21-8.17 (m. 2H), 8.04 (d, J= 8.0
NH Hz, III), 7.76 (d, J = 8.4 Hz, 2/1), 7.63
(d, J. 8.8 Hz, 211), 7.49-7.41 (m, 611),
7.07 (d, J = 8.8 Hz, 2H), 4.67 (s, 1H), 4.61-4.51 (m, 3H), 4.37-4.33 (m, 1H),
4.20-4.18 (in, 2H), 3.92-3.66 (in, 10H), 2.62-2.45 (m, 5H), 2.26-2.17 (m, 1H),
68
2.14-2.05 (m, 1H), 1.61 (s, 6H),1.05 (s, 9H); LC-MS (ES): mlz. 1054.50 NM,
tit =2.20 mm (3.6 minute run).
Prepared from ABM-14, L-21, and ULM-1
(2S,4R)-1-[(2S)-2-(544-(4-{344-cyano-3-(trifluoromethyl)phenyll-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
pH yl }phenyl Vhenoxy]pentanamido } -3,3-di
methylbutanoyl I -4-hydmxy-N-
methyl-1,3 -thiazol-5-yl)phenyll methyl I pyrrolidine-2-carboxamide
0 NH
11-1 NMR (400 MHz, CD30D): 8 8.90 (s, 1H), 8.20-8.18 (d, J = 8.4 F17., 2H),
8.04-8.02 (d, J= 7.6 Hz, 1H), 7.77-7.74 (d,J = 8.4 Hz, 2H), 7.63-7.61 (d, J=
8.4
/ \ Hz 211) 7 50-7 48 (m 211) 7.50-7.41 (m,
411), 7.06-7.04 (d, J = 8.811z, 2/1),
s....jN 4.67(s. 111), 4.61-4.52 (m. 3H), 4.39-4.35 (m, 111), 4.08-4.07 (m,
2H), 3.95-3.93
69
(m, 1H), 3.85-3.81 (m, 111), 2.48 (s, 311), 2.41-2.37 (in, 2H), 2.23-2.21 (m,
111),
0 F 2.14-2.10 (m, 1H), 1.86-1.85 (tn. 4H), 1.62 (s, 6H),
1.06 (s, 911); LC-MS (ES):
itilz 994.40 IM1-11, IR = 1.71 min (3.0 minute run).
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Ex # Structure Compound name and Analytical data
Prepared from ABM-14, L-22, and ULM-1
(2S,4R)-1-[(2S)-2-(3-(244-(4-{314-cyano-3-(trifluoromethyl)pheny1]-5,5-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
pH yl }phenyl)phenoxy]ethoxy }propanamido)-3,3-
I dimethylbutanoy11-4-hydroxy-N-([4-(4-metliy1-
1,3-thiazol-5-
0 0
0 0 NH yOphenyl]methyl)pyrrolidine-2-earboxamide
0 .---= IHNMR (400 MHz, CD30D) 88.85 (s, 111), 8.21-
8.17 (in, 2H), 8.04 (d, J = 8.0
1
-..
0 ..-- Hz, tH), 7.74 (d, J = 8.4 Hz, 2H), 7.61
(4, .1= 8.4 Hz, 2H), 7.49-7.39 (m, 6H),
N
¨ ,,kS S-4 7.08 (d, J = 8.8 Hz, 2H), 4.68 (s, 1H), 4.59-
4.51 (n, 3H), 4.37 (s. 1H),4.23-4.20
70 "L ,N * 7:2N
. (m, 211), 3.93-3.80 (m, 611), 2.63-2.45 (m, 211), 2.45
(s, 311), 2.23-2.06 (in, 2/1),
0 F F 1.62 (s. 6H), 1.05 (s. 9H);
F
LC-MS (ES): miz 1010.30 [MW], IR = 1.68 min (3.0 minute run).
Prepared from ABM-14, L-23. and ULM-1
(2S,4R)-1-[(2S)-242-( ( 544-14- ( 3 44-cyano-3-(trifl uommethyl)phenyl] -5,5-
dimetliy1-4-oxo-2-sulfany lidenei in idazolidin- 1 -
y1 }phenyl)phenoxy]pentyl}oxy)acetainidoj-3.3-
dimethylbutanoyl]-4-hydmxy-N-([4-(4-methy1-1,3-thiazol-5-
y0phenyl]rnethyl}pyrrolidine-2-carboxiunide
11-1 NMR (400 MHz, CD30D): 68.84 (s, 1 H), 8.19-8.17 (d, J - 8.4 Hz, 2H),
0 i,1-;
=-...-^-.....----...--0-.}... .....hir 8.04-8.02 (d, J - 8.4 Hz, 1H), 7.73-
7.71 (d, J = 8.4 Hz, 2H). 7.59-7.57 (d, J -
N. =
0 8.4 Hz, 211), 7.49-7.38 (m, 611), 7.02-7.00(d, J = 8.4 Hz, 211),
4.72(s, 111),
0 NH
: 4.59-4.46 I'm, 3H), 4.37-4.33 (d, J - 10.6
Hz, 1H), 4.08-4.06 (n. 211). 4.05-
/\
s µ..-... I. ..., 4.00 (n, 211), 3.98-3.83 (in, 2H), 3.64-3.61
(in, 211), 2.49 (s, 3H), 2.29-2.21 On,
71 C,¨
--r¨ ¨N N
111), 2.11-2.01 (m, 111), 1.90-1.86 (m, 211), 1.78-1.75 (m, 211), 1.66-1.62
On,
ki --
8-8
0 F- --F 2H), 1.61(s, 6H), 1.06 (s, 9H)
p
LC-MS (ES*): /fez 1038.38 [M11], tR = 1.68 min (3.0 minute run).
Prepared from ABM-14, L-24, and ULM-1
(2S,4R)-1-[(2S)-213-({544-(4-{3-[4-cyano-3-(trifluoromethyl)ptienyi)-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
yllphenyl)phenoxy]pentyl } oxy)propanamido] -3,3-
dimethylbu tanoyl] -4-hydroxy -N- [ [4-(4-methy1-1,3-thiazol-5-
yl)phenyl]methyl)pyrrolidine-2-carboxamide
0 ..... pH IH NMR (400 MHz. CD301.3): 8 8.84 (s, 1 H).
8.19-8.17 (d, J - 8.4 Hz, 2H),
;.,.---..õ---.._,--Ø.--...õ.....k 8.04-8.02(d, J = 8.4 Hz, 1H), 7.73-7.71
(d, J = 8.4 Hz, 2H), 7.59-7.57(d, J=
N H 1,2
0
,--i-
i \ NH 8.4 Hz, 2H), 749-7.38 (m, 6H), 7.02-7.00 (d,
J - 8.4 Hz, 2H), 4.72 (s, 1H),
4.59-4.46 (in, 311), 4.37-4.33 (d, .1 - 10.6 Hz, 111), 4.08-4.06 (m, 2H), 4.05-
,t1.-__ s ' ...- N 4.00 On, 211), 3.98-3.83 (in, 211),
3.64-3.61 On, 211), 2.49 (s, 31-1), 2.29-2.21 On,
s_s /
AI: -'_ftc":=N
1H), 2.11-2.01 (n, 1H), 1.90-1.86 (m, 211), 1.78-1.75 (n. 211), 1.66-1.62 (n,
72
F---F 211), 1.61(s, GH), 1.06 (s, 911); LC-MS (ES*): m,'z 1052.39
[MW]. tR= 1.81 min
F
(3.0 minute run).
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Ex # Structure Compound name and Analytical data
F
F = 0 Prepared from ABM-24, L-29. and ULM-1
)
Nz--.=:-. / \N -Kr:
:--=
... (25,4R)-1-[(25 )-2 4242- { 24444- { 3-(4-
cyano-3-(tri fluoromerhyl)pheny1)-5,5 -
f--..,.'== dimethy1-4-oxo-2-sullanylideneimidamlidin-1-
y1)-2-
N
fluorophenyl)phenoxy]ethoxy}ethoxy)acetainido:1-3.3-dimethylbutanoy1]-4-
0 hydroxy-N-([4-(4-methy1-1,3-thiazol-5-
yl)phenyl]metbyl)pyrrolidine-2-
L1-7 carboxamide
73
`0 Ill NMR (400 MHz, CD30D): 8 8.89 (s, 111),
8.20-8.18 (d, J = 8.4 Hz, 211),
0 8.04-8.02 (d, J = 8.4 Hz, 1H), 7.62 -7.59
Im, 1H), 7.59-7.57 (m, 2H), 7.49-
FIN / 7.40(m, 211), 7.40-7.30 (m, 211), 7.30-7.10
(m, 211), 7.08-7.06 (d, J = 8.4 Hz,
0=r7\ 2/1), 4.720- 111), 4.62-4.60 (m, 31-1), 4.37-
4.34 (d,J = 15.2 Hz, 1H), 4.25-4.23
/t.. 0...__I ,...z)
(m, 2H), 4.13-4.09 (m, 2H), 3.97-3.92 (m, 4H), 3.89-3.79(m, 4H), 2.46(s, 3H),
\..
\ / '"OH
NH 2.24-2.22(m, 1H), 2.14-2.12(m, 111), 1.63
(s, 611), 1.06 (s, 9H); LC-MS (ES*):
in,: 1058.35 [MHI, 4 = 1.47 min (4.6 minute run).
F
:..Z.F."..... 0
Prepared from ABM-14, L-25, and ULM-1
N:----. / ---1' KL., 5-14-(4-(314-cyano-3-
(trifluoromethyl)pheny1J-5.5-dimethy1-4-oxo-2-
N T
--N sulfanylidenei midazolidin -1-y1)
phenyl)phenoxy]pentyl N-[(25)-1-[(25,4R )-4-
S
hydroxy-2-({ [4-(4-methyl-1,3-thiazol-5-
74 Aphenyl] methyl }carbamoyl)pyrrolidin-1-y1]-
3,3-dimethy1-1-oxobutan-2-
0¨\....7
yllcarbamate
IF1 NMR (300 MHz, CD30D): 8 8.87 (s, 1H), 8.18-8.15 (d, J = 10.2 Hz, 211),
8.02-8.00 (d, J = 8.1 Hz, 111), 7.75-7.73 (d, J = 8.4 Hz, 211), 7.63-7.60 (d,
J =
0 8.4 Hz, 211), 7.47-7.40 (m, 611), 7.04-7.01 (d, J = 8.7 Hz, 211) , 4.61-
4.51 (m,
N'- X--z0
HN 3H), 4.37-4.32 (in, 2H), 4.16-4.02 (in, 411). 3.92-3.78 (m, 211), 2.47
(s, 3H),
0 .--,X 2.26-2.11 (m, 111), 2.10-2.07 (in, 111),
L86-1.80 (in, 211), 1.76-1.64 (in, 211),
lit0t....../N,1 1.60 (m. 811), 1.03 (s. 9H) ; LC-MS (ES'):
miz 1023.82 [Mil, 4 = 2.36 min
NI---J)31.i (3.6 minute run)
Prepared from ABM-14, L-26. and ULM-1
F
NaLZ(2S,4R)-1-[(2S)-2-(2-{4-14-(4- ( 3-14-cyano-3-(trifluoromethyl)phenytj-s
,5-
-t.
e-14' y dimethy1-4-oxo-2-sullanylideneimidazolidin-1-
i-NC.71.0zo yl}pllenyl)phenoxy]butoxy}acetarnitki)-3,3-
$
dimethylbutanoy1]-4-hydmxy-N-( E4-4-methyl-1,3-tbiazol-5-
yl)phenyll methyl }pyrrolidine-2-carboxamide
7 'H
114 NMR (400 MHz, 0.33013): 8 8.83 (s, 1H), 8.19-8.17 (d, J = 8.4 Hz, 211),
8.04-8.02 (d, J = 9.6 Hz, 111), 7.75-7.72 (d, J = 8.4 Hz, 211), 7.60-7.58 (d,
J =
8.4Hz, 2H), 7.59-7.39 (m, 6H), 7.04-7.02 (d, J = 8.8 Hz, 2H) , 4.88 (s, 1H),
4.71-
4.41 (in. 3H), 4.37-4.32 (d. J = 15.2Hz, 111), 4.11-4.09 (in. 2H), 4.084.01(m,
).../<
211), 3.98-3.90 (m, 1/1), 3.90-3.83 (m, 111), 3.69-3.66 (m, 211), 2A4 (s,
311),
0
N 1- 2.25-2.23 (m, 111), 2.12-2.10 (m,1H), 1.98-
1.90 (m, 211). 1.90-1.84 Im, 2H), 44,1
H H 1.60 (s, 611), 1.03 (s, 911); LC-MS (ES*):
in/z 1024.10 [MH], IR = 2.33 min
(4.6 minute run)
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Ex # Structure Compound name and Analytical data
Prepared from ABM-24, L-1.8. and ULM-1
2-{214-(4-(344-cyano-3-(trifluommethyl)plienyl]-5,5-dimethyl-4-oxo-2-
sulfanylideneimidazolidin-l-yl }-2-fluorophenyl)phenoxy]ethoxy }ethyl N -[(
2S)-
F- F
1..
1-[(2S,4R)-4-hydroxy-2-(([4-(4-methyl-1,3-thiazol-5-
yl)phenyl]methyl )carbamoyl)pyrrolidin-l-y1]-3,3-dimethyl-l-oxobutan-2-
1 yl]carbamate
P``-'0-7
76
`.0
(µ' Ill NMR (400 MHz, CD30D): 5 8.88 (s, 1H),
8.20-8.18 (d, J = 9.6 Hz, 211),
8.04-8.02 (d, J - 8.4 Hz, 1H), 7.69-7.63(m, 1H), 7.58-7.56 (d,./ - 8.0 Hz,
2H),
HN,,....1 7.48-7.42 (m, 4H), 7.34-7.30 (m, 211), 7.10-
7.08 (d, J = 8.8 Hz, 211), 4.61-4.57
;0/ (m, 311), 4.53-4.47 (m, 211), 4.38-4.21 (m,
4/1), 3.93-3.90 (m, 311), 3.84-3.78
¨
Kw 01 NH .,
VH (m, 3H), 2.48 (s. 3 H), 2.26-2.17 (m, 1H). 2.11-2.07 (m, 1H), 1.63 (s, 6H),
1.02
Ili
(s, 9H) ; LC-MS (ES*): mil, 1044.33 [M111, tR= 2.21 min. (3.6 minute run).
0 Prepared from ABM-14, L-27, and ULM-1
L.A
NC-_(>_N' (2S,4R)-1-[(2S)-2-(2-[ 314441 344-cyano-3-
(trifluoromethyl)pheny11-5,5-
F3C S , )r-NN--:N1
al dimethy1-4-oxo-2-sulfanylidetteimidazolidin-
1-
yl}phenyl)phenoxylpropoxy }aeetamido)-3,3-
0-N.7 dimethylbutanoy1]-4-hydroxy-N-([4-(4-methyl-
1,3-thiazol-5-
yl)phenyl]methyl)pyrrolidine-2-carboxamide
77 0\
0 111 NMR (300 MHz, CD30D): 5 8.83 (s, 1H),
8.19-8.16 (4, J = 9.0 Hz, 2H),
N#µ=S NIL/ 8.03-8.01 (d, J = 8.1 Hz, 1H), 7.75-7.72
(d, J = 8.7 Hz. 2H), 7.72-7.69(d, J=
)---r.. 0 ==(I 8.711z, 2I-1), 7.63-7.36(m, 6/1), 7.08-7.05
(d, J = 8.7 Hz, 211), 4.72(s, 111), 4.62-
/ 4.51 (m, 3H), 4.36-4.31 (d, J= 15.3Hz, 1H),
4.22-4.19 (m, 2H), 4.04-3.98 (m,
Nill \ ...'''OH 2H), 3.91-3.76 (m, 411). 2.43 (s, 3H), 2.21-2.10 (in, 4H),
1.60 (s, 6H), 1.02 (s,
9/1); Mass (ES): m/z 1010.30 [MIll
0 Prepared from ABM-14, L-28, and ULM-1
NC 4 1,i))r1< (2S,4R)-1-[(2S)-2-(2-(244-(4-{314-cyano-3-
(trifluoromethyt)phenyl]-5,5-
F3C S * dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
* yl)phenyl)phenoxy]ethoxy }acetainido)-3,3-
dimethylbutanoy11-4-hydroxy-N4 [4-(4-methy1-1,3-thiazol-5-
LI
0 yl)phenyl]methyl)pyrrolidine-2-earboxamide
78 111 NMR (300 MHz, CD30D): 5 8.79 (s, 1H),
8.71-8.69 (in, 1H), 8.19-8.16 (d, J
0=Z =9.0 Hz, 2H), 8.03-8.01 (d, J = 8.4 Hz, 1H),
7.77-7.75 (d,J = 4.8 Hz, 1H), 7.77-
N^s NH
.).---- 4... 0 N 7.75 (d,./ = 4.8 Hz, 111). 7.72-7.64 (m.
4H), 7.55-7.45 (m, 4H), 7.17-7.14 (d,
2...4X J = 8.7 Hz, 211), 4.78-4.75 (d, J = 6.6 Hz,
111), 4.75-4.62 (m, 211), 4.55-4.52
/ \ 0
N)170, On, 1H), 4.28-4.26 (m, 3H), 4.14 (5, 2H),
3.98-3.95 (m, 2H), 3.88-3.84 (m,
'OH 2H), 2.38 (s, 3H), 2.29-2.110m, 111), 2.11-2.01(m, 1H), 1.60 (s, 611),
1.04 (s,
911); LC-MS (ES'): m/z 996.33 [M/11, IR = 2.92 min (5.0 minute run).
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Ex # Structure Compound name and Analytical data
0
NC * N,KK Prepared from ABM-24, L-19, and ULM-3
---N (2S,4R )-1-[(2S)-212-( 2- (244-14- (344-
cyano-3-(trifl uommethyl)pheny1]-5.5-
F3C S * dimethy1-4-oxo-2-sulfanylideneimidazolidin-l-
y1 } -2-
F * fluorophenyl)phenoxy]ethoxy
)ethoxy)acetamido]-3,3-dimethylbutanoy1]-4-
hydmxy-N-R1S)-144-(4-methy1-1,3-thiazol-5-y1)phenyflethyl ] pyrrolidine-2-
79
carboxamide
LO
4µ) 111 NMR (400 MHz, CD30D): 8 8.76 (s, 1/1),
8.08-8.06 (d, J = 9.6114 2/1),
7.91-7.89 (d, J=7.2 Hz, 1H), 7.56-7.53(m, 1H), 7.45-7.42 Id, ./ = 9.2 Hz, 2H),
0
0:--- 7.33-7.29 (in, 4H), 7.22-7.20 (m, 2H). 6.99-
6.97 (d, J = 8.8 Hz, 2H), 4.95-4.93
N'SNS
NH (m, 111), 4.60(s, 1/1), 4.50-4.47 (m, 111),
4.45-4.34 (m, 1113,4.16-4.14 (m, 211),
¨
0)-7( 3.98-3.97 (m, 2H), 3.83-3.81 (m. 2H). 3.77-
3.74 (m, 1H), 3.67-3.63 (m, 5H),
41 N
¨0 2.36 (s, 3H), 2.12-2.10 (m, 1H), 1.89-1.85
(m, 1H). 1.51 (s, 61-1), 1.37-1.36 (in,
¨NH '',0H 3H) , 0.93 (s, 9H): LC-MS (ES): va/z
1072.4 [MW], IR = 1.46 min (4.6 minute
run).
105671 Example 80: (2S,4R)-1-((S)-2-(243-(24444-(3-(4-cyano-3-
(trifluoromethyl)pheny1)-
5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-y1)phenyl)piperidin-1-
yl)ethoxy)propoxy)acetamido)-3,3-dirnethylbutanoyl)-4-hydroxy-N-(4-(4-
methylthiazol-5-
yl)benzyppyrrolidine-2-carboxamide:
OH
:.=
HO, H 0
N
NH
Step 1 0
S \,..---N *
ULM-1 BO S
\
pH
:
0
ss ir
K2CO3, DMF (^..N.-,......,0õ..,.,,..,,,O.,.õ,-K.,N
N
H
Step 2 1 0 0
ABM-25 NC
Ilif NI''N Example 80
F30
Cri¨ S
N 1
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[0568] Step 1: synthesis of (2S,4R)-1-[(2S)-3,3-dimethy1-2-[2-(3-{2-[(4-
methylbenzenesulfonyl)
oxy]ethoxy}propoxy)acetamido]butanoy1]-4-hydroxy-N-1[4-(4-methyl-1,3-thiazol-5-
yl)phenyl]methyl}pyffolidine-2-carboxamide (BQ)
[0569] To a stirred solution of 2-(3-{2-[(4-
methylbenzenesulfonypoxylethoxy}propoxy)acetic
acid (L-17, 300 mg, 0.90 mmol) in N,N-dimethylformamide (5 mL) was added EDCI
(350 mg,
1.83 mmol), HOBt (240 mg, 1.78 mmol) and D1EA (350 mg, 2.71 mmol) at room
temperature.
The resulting solution was stirred at room temperature for 10 minutes. Then to
the solution was
added (25,4R)-1-[(25)-2-amino-3,3-dimethylbutanoy1]-4-hydroxy-N-{[4-(4-methyl-
1,3-thiazol-5-
yl)phenyl]methyl}pyrrolidine-2-carboxamide (ULM-1, 390 mg, 0.91 mmol), and the
resulting
solution was stirred at room temperature for 1 hour. Water (30mL) was added
and the resulting
mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were
combined, washed
with saturated aqueous solution of sodium chloride (30 mL), dried over
anhydrous sodium sulfate
and then concentrated under reduced pressure to give a crude residue, which
was purified by a
flash silica gel chromatography (eluent: dichloromethane/methanol (v:v = 10:1)
to give BQ
(yield: 64%) as a yellow solid. LC-MS (ES): ink 745.35 [MHI, tR = 0.96 min
(2.0 minute run).
[0570] Step 2: Synthesis of (2S,4R)-1-[(2S)-242-(3-(2-[4-(4-13-[4-cyano-3-
(trifluoromethypphenyl] -5.5 -dimethy1-4-oxo-2-sulfanylideneimidazolidin-l-y1
}phenyl)piperidin-
l-yflethoxy}propoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-( [4-(4-
methy1-1.3-thiazol-
5-yl)phenyl]methyl)pyrrolidine-2-carboxamide (Exampl 80)
[0571] To a stirred solution of 4-(4,4-dimethy1-5-oxo-3-[4-(piperidin-4-
yl)phenyl]-2-
sulfanylideneimidazolidin-1-y1}-2-(trifluoromethypbenzonitrile (ABM-25, 150
mg, 0.32 mmol),
(25,4R)-1-[(25)-3,3-dimethy1-242-(3-12-[(4-methylbenzenesulfonyl)
oxy]ethoxy}propoxy)acetamido]butanoy1]-4-hydroxy-N-([4-(4-methy1-1,3-thiazol-5-
yflphenyl]methyl}pyrrolidine-2-carboxamide (BQ, 236 mg, 0.32 mmol) in N,N-
dimethylformamide (5 mL) was added potassium carbonate (131 mg. 0.95 mmol).
The resulting
mixture was stirred at 60 C overnight. The reaction mixture was cooled to
room temperature,
water (20mL) was added and the resulting mixture was extracted with ethyl
acetate (30 mL x 3).
The organic layers were combined, washed with saturated aqueous solution of
sodium chloride
(20 mL), dried over anhydrous sodium sulfate and then concentrated under
reduced pressure to
give a crude residue, which was purified by Prep-HPLC to give Example 80
(yield: 7%) as a
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white solid. 1H NMR (300 MHz, CD30D): 8 8.91 (s, 1H), 8.15 (d, J=4.5 Hz, 2H),
8.02 (d, J=
4.5 Hz, 1H), 7.40(m, 7H), 4.45 (d, J= 12.0 Hz, 1H), 4.45 (m, 4H), 4.02 (d, J=
3.9 Hz, 2H), 3.70
(m, 10H), 3.38 (m, 2H), 3.11 (m, 3H), 2.48 (s, 3H), 2.26 (m, 8H), 1.54 (s,
6H), 1.03 (s, 9H); LC-
MS (ES): mrz 1045.35 [MHI, tR = 2.74 min (5.6 minute run).
[0572] Example 81 was synthesized according to similar procedure described for
synthesis of
Example 80, by using corresponding starting materials and intermediates.
[0573] Example 81: (2S,4R)-14(S)-2-(2-(4-(2-(4-(4-(3-(4-cyano-3-
(trifluoromethyl)pheny1)-
5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-y1)phenyl)piperidin-l-
yOethoxy)butoxy)acetamido)-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-
methylthiazol-5-
yl)benzyppyrrolidine-2-carboxamide
Nc-p-Ne
F3 6
041--N11 =1..õ
r co,
[0574] N NH
[0575] NMR (300 MHz, DMS0): 8 8.98 (s, 1H), 8.63-8.61 (m, 1H), 8.40-8.37
(m, 1H),
8.37-8.34 (m, 1H), 8.11-8.01(m, 1H), 7.44-7.40 (m, 3H), 7.37-7.32 (m, 6H),
4.57-4.54 (d, J= 9.6
Hz, 1H), 4.47-4.45 (m, 2H), 4.45-4.44 (m, 2I-1), 4.39-4.37 (in, 1H), 3.92 (s,
2H), 3.71-3.65 (m,
2H), 3.58-3.47 (m, 5H), 3.45-3.40 (m, 4H), 2.99-2.95 (m, 2H), 2.51 (s, 3H),
2.12-2.02 (m, 3H),
1.93-1.90 (m, 1H), 1.90-1.79 (m, 3H), 1.77-1.71 (m, 5H), 1.67-1.61 (m, 6H),
0.94 (s, 9H); Mass
(ES): tn/z 1059.44 [MH+].
[0576] Example 82: (2S,4R)-N-(2-(2-(2-(2-(4-(3-(4-cyano-3-
(trifluoromethyl)pheny1)-5,5-
dimethyl-4-oxo-2-thioxoimidazolldin-1-y1)phenoxy)ethoxy)ethoxy)ethoxy)-4-(4-
methylthiazol-5-y1)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-
yl)butanoyl)pyrrolidine-2-carboxamide:
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L-30 F F
Oa
K2CO3
N¨=N N Ag20, Ki TsCi
r
Step 1 Step 2
411-1' OH
ABM-3 BR
F F 010
F F 0 N= = N174 M.T=CS
N= 411 N N r rtµ
Step 3
00 ULM-12 0i..)
" i 0
EIS 81* s
N=1 \
F F 0
OH
TFA N)LI.Nr
kJ' XI Step 4 N= 40 N
0 ,
= 0 ..*
Example 82 (N,0
[0577] Step 1: Synthesis of 4-[3-(4-(2-1:2-(2-
hydroxyethoxy)ethoxylethoxy)phenyl)-4,4-
dimethyl-5-oxo-2-sulfanylideneimidazolidin-l-y1]-2-
(trifluoromethyDbenzonitrile (BR)
[0578] To a stirred solution of 413-(4-hydroxypheny1)-4,4-dimethy1-5-oxo-2-
sulfanylideneimidazolidin-1-y1]-2-(trifluoromethyDbenzonitrile (ABM-3, 405 mg,
1.00 mmol) in
CH3CN (20 mL) was added potassium carbonate (276 mg, 1.98 mmol) and 2-(2-12-
[(4-
methylbenzenesulfonyfloxy]ethoxylethoxy)ethan-l-ol (L-30, 456 mg, 1.50 mmol)
at room
temperature. The resulting mixture was then heated to 80 C and stirred at
this temperature
overnight. LC-MS indicated formation of the desired product. The reaction
mixture was cooled
to room temperature, concentrated under vacuum to give a crude residue, which
was purified by a
flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v =
1:1)) to give BR
(yield: 91%) of as a brown oil.
[0579] Step 2: Synthesis of 2-(2-[2-(4-(344-cyano-3-(trifluoromethyl)pheny1}-
5,5-dimethyl-4-
oxo-2-sulfanylideneimidazolidin-l-y1 } phenoxy)ethoxy]ethoxy }ethyl 4-
methylbenzene-1-
sulfonate (BS)
[0580] To a stirred solution of 4-13-(4-{2-(2-(2-
hydroxyethoxy)ethoxy)ethoxy}phenyl)-4,4-
dimethyl-5-oxo-2-sulfanylideneimidazolidin-1 -y1J-2-
(trifluoromethypbenzonitrile (BR, 490 mg,
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0.91 mmol) in dichloromethane (10 mL) was added tosyl chloride (190 mg, 1.00
mmol),
potassium iodide (30.2 mg) and silver oxide (314 mg) at room temperature. The
resulting mixture
was then stirred at 30 C for 6h, LC-MS indicated formation of the desired
product. The
inorganic salts were removed from the reaction by filtration, the solution
phase was concentrated
under vacuum to give a crude residue, which was purified by a flash silica gel
chromatography
(eluent: ethyl acetate/petroleum ether (v:v = 1:3)) to give BS (yield: 60%) of
as a light yellow
solid.
[0581] Step 3: Synthesis of (25,4R)-4-(tert-butoxy)-N-{ [242121244-f 3-[4-
cyano-3-
(tiifluoromethyl )phenyl] -5,5 -di meth y1-4-oxo-2-sulfan ylideneimidazolidin-
1-
yl) phenoxy)ethoxy]ethoxy )ethoxy)-4-(4-methyl-1,3-thiazol-5-y1)phenyl)methyl
) -1-1 (2S )-3-
methy1-2-(1-oxo-2,3-dihydro-1H-i soindo1-2-yl)butanoyflpyrrolidine-2-
carboxamide (BT)
[0582] To a stirred solution of 2-{ 24244- ( 3-[4-cyano-3-
(trifluoromethyl)pheny1]-5,5-dimethyl-
4-oxo-2-sulfanylideneimidazolidin- I -y1) phenoxy)ethoxy]ethoxy }ethyl 4-
methylbenzene-1-
sulfonate (BS, 207 mg, 0.30 mmol) and (2S,4R)-4-(tert-butoxy)-N-{[2-hydroxy-4-
(4-methy1-1,3-
thiazol-5-yl)phenylimethyl )-1-[(25)-3-methy1-2-(1-oxo-2,3-dihydro-IH-isoindol-
2-
yl)butanoyflpyrrolidine-2-carboxamide (ULM-12, 181 mg, 0.30 mmol) in N,N-
dimethylformamide (2 mL) was added potassium carbonate (83 mg, 0.60 mmol) at
room
temperature. The resulting mixture was then heated to 80 C and stirred at the
same temperature
overnight, and LC-MS indicated formation of the desired product. The reaction
was then cooled
to room temperature, diluted by water (10 mL) and then extracted with ethyl
acetate (20 mL x 3).
The organic layers were combined, dried over anhydrous sodium sulfate and
concentrated under
reduced pressure to give a crude residue, which was purified by a flash silica
gel chromatography
(eluent: ethyl acetate/petroleum ether (v:v = 1: 1) to give BT (yield: 54%) as
a white solid.
[0583] Step 4: Synthesis of (25,4R)-N-{ [2-(2-{ 2-[2-(4- (344-cyano-3-
(trifluoromethyl)pheny1]-
5,5-dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-y1
}phenoxy)ethoxy]ethoxy}ethoxy)-4-(4-
meth y1-1,3 -thiazol-5-y1)phenyl)methyl -4 -hydroxy-1-[(25)-3-methy1-2-(1-oxo-
2,3-dihydro-1H-
isoindo1-2-y1)butanoyl]pyrrolidine-2-carboxamide (Example 82)
[0584] To a stirred solution of (2S,4R)-4-(tert-butoxy)-N-{[2-(2-{2-[2-(4-13-
[4-cyano-3-
(trifluoromethyl)pheny1]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
yllphenoxy)ethoxy]ethoxy }ethoxy)-4-(4-methy1-1,3-thiazol-5-yl)phenyl)methyl I
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methyl-2-(1-oxo-2,3-dihydro-1H-isoindo1-2-y1)butanoyl]pyrrolidine-2-
carboxamide (BT, 180 mg,
0.16 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL)
at room
temperature. The resulting solution was stirred room temperature for 6 hours,
LC-MS indicated
formation of the desired product. Saturated aq. solution of sodium bicarbonate
was added to the
reaction to neutralize the trifluoroacetic acid. Organic layer was separated,
the aqueous layer was
extracted with of dichloromethane (10 mL x 2). The organic layers combined,
dried over
anhydrous sodium sulfate and concentrated under reduced pressure to give a
crude residue, which
was purified by Pre-H PLC to give Example 82 (yield: 31%) as a white solid. 11-
1 NMR
(400MHz, CD30D): 8 8.90 (s, 1 H), 8.40-8.38 (d, J = 8.0Hz, 2 H), 8.29 (s, 1
H), 8.09-8.07 (d, J
= 8.4 Hz, 1 H), 7.72-7.70 (d, J = 7.6Hz, 1 H), 7.62-7.61 (d, J = 4.0Hz, 2 H),
7.50-7.40(m, 1H),
7.35-7.33 (d, ./ 7.6Hz, 1H), 7.27-7.25 (d, J ¨8.8Hz, 2 H), 7.10-7.06 (m, 3H),
7.05-7.00 (m,
1H), 5.09(5, 1H), 4.72-4.69 (d, J =10.8 Hz, 1H), 4.61 -4.41 (m, 2H), 4.41 -
4.31 (m, 2H), 4.31 -
4.21 (m, 2H), 4.21 -4.11 (m, 2H), 4.11 -4.01 (m, 2H), 3.82-3.71 (m, 5H), 3.69-
3.61 (m, 5H),
2.51 (m, 3H), 2.47-2.25 (m, 1 H), 2.10-2.00 (m, 1H), 2.00-1.95 (m, 1H), 1.48
(s, 6 H), 0.97- 0.96
(d, J ¨ 6.4Hz, 3H), 0.74-0.72 (d, J = 6.4Hz, 3H);
LC-MS (ES): ribiz 1068.20 [MH1, tR = 1.59
min (3.0 minute run).
[0585] Examples 83-85 were synthesized according to similar procedure
described for synthesis
of Example 82, by using corresponding starting materials and intermediates.
[0586] Table 6. Exemplary Compounds.
Ex
Structure Compound name and Analytical data
Prepared from ABM-3, L-30, and ULM-13
(2S,4R)-N-([2-(2-(242-(4-(314-cyano-3-(trifluoromethyl)pheny11-5,5-
Nz. Airk
N N (11-W-
F dimethy1-4-oxo-2-sullanylidenciinidazolidin-
1-
F
y1)phenoxpethoxy)ethoxy)etboxy)-4-(4-methy1-1.3-
?: 0
thiazol-5-yl)phenyllmethyl}-1-[(2S)-2-(6-fluoro-1-oxo-2,3-dihydro-111-
83
isomdo1-2-y1)-3-
N \ methylbutanoy1]-4-hydroxypyrrolidine-2-
carboxamide
LS NH
NMR (400MHz, CD30D): 6 8.89 (s, 1H), 8.17-8.15 (d, J = 8.0 Hz, 2H),
101 Y---NDõ.0ii 8.00-7.98 (d, J=8.4 Hz, 111), 7.60-7.56
(m, 1/1), 7.49-7.37 (m, 3/1), 7.28-7.26
(d, J=8.8 Hz, 2H), 7.08-7.05 (m, 4H), 4.90-7.83 (in. 1H). 4.59-4.46 (in, 6H),
4.26-4.25 (in, 2H), 417-4.15 (in, 2H), 3.98-3.86 (m, 6H), 3.79-3.77 (in, 4 H),
2.51 (s. 3H), 2.50-2.49(m, 1H), 2.25-2.15 (m, 1H), 2.01-2.00(m, 1H), 1.54 (s,
6 H), 1.07-1.06 (d. J = 6.8Hz, 3H), 0.85-0.83 (d, J = 6.8Hz, 3H); LC-MS
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Ex
Structure Compound name and Analytical data
#
(ES'). tti/z 1086 60 NH'', th, r 2.24 min (3.6 minute run).
N.
Prepared from ABM-3, L-30, and ULM-14 -..
S (2S,4R)-1-[(2S)-2-(7-cyano-1-oxo-2,3-dihydro-
1H-isoindo1-2-y1)-3-
F F IP Nril\ N . '0 .. methylbutanoyl] -N-1[2-(2-(
24244 -1314-cyano-3-(trifluoromethyl)phenyl] -
i
F (?--A
-.) 5,5-dimethy1-4-oxo-2-
sulfanylideneimidazolidin-1-
yl }phenoxy)ethoxy]erhoxy }ethoxy)-4-(4-methyl-1,3-
84 ) thiazol-5-y1whenyl]methyl)-4-
hydroxypyrrolidine-2-carboxamide
N
H NMR (400MHz, CD30D): 8 8.89 (s, 1H), 8.17-8.15 (d, J =7.2Hz. 2H),
t _.__ __\µ 0
8.01-7.98 (d, J =8.4Hz, 1H), 7.98-7.76(m, 3H), 7.44-7.42 (m, 1H), 7.29-7.25
c 5
S µ / NH (m, 2H), 7.08-7.04 (m, 4H), 4.87-7.85 (m,
1H), 4.69-4.41 (m, 6H), 4.25-4.23
C) (m, 2H), 4.22-4.16 (m, 2H), 4.10-4.00 (m,
1H), 3.94-3.87 (m, 5H), 3.79-3.77
0 -.
* N---.)LN (m, 4/1), 2.51 (s, 311), 2.50-2.49 (m,
III), 2.23-2.13 (m, III), 2.05-2.00 (m,
N6 0 1-N OH 1H), 1.54 (s, 6H), 1.10-1.07(d, J =
6.8Hz, 3H), 0.88-0.86 Id, J - 6.8Hz, 3H);
LC-MS (ES*): miz 1093.00 [MH*], tR = 2.22 min (3.6 minute run).
Prepared from ABM-3, L-31, and ULM-12
(2S,4R)-N-( [2-(2-{[(2R,3R)-342-(4-(314-cyano-3-(trilluoromethyl)pheny1]-
0 5,5 -di methy1-4-oxo-2-sulfanylideneimidazolidin-l-yl }
phenoxy)ethoxy] bu tan-
2-yfloxy}ethoxy)-4-(4-methyl-1,3-thiazol-5-yl)phenyllmethyl}-4-hydroxy-I-
ON -'-
N-µs [(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-
isoindo1-2-y1)butanoyl]pyrrolidine-2-
0 .,
F F .
1 carboxamide
F t. 0 11-1 NMR (400 MHz, CD300) 80.82 (d, J = 6.65
Hz, 3 H), 1.05 (d, J = 6.65
ii
N
,-",
i NH Hz, 3 H), 1.15 (t,J = 5.48 Hz, 6 H), 1.44 -
1.56 (rn, 6 H), 1.98 - 2.10 (rn, 2 H),
00H 2.14 - 2.24 (m, 1 H), 2.37 - 2.52 (m, 4 H),
3.52 - 3.62 (tn. 2 H), 3.89 (td, J =
T 10.76, 4.70 Hz. 3 H). 3.93 - 4.01 (m, 3 H),
4.09 (br. s.. 2 H). 4.16 - 4.24 (m, 2
.).
"
41 N 0 I ,."-
II), 4.44 - 4.67 (m, 6 H), 4.84 (d,J= 10.96 Hz, 1 /1), 6.95 - 7.08 (m, 4 H),
7.19
- 7.30 (m, 2 Fp, 7.43 (d,./ = 7.43 Hz, 1 H), 7.46 - 7.51 (m, 1 H), 7.52 -7.63
(m,
211), 7.78 (d, J = 7.43 Hz, 1 H), 7.97 (d, J = 7.83 Hz, 1 H), 8.08 - 8.17 (m,
2
II), 8.43 (t,J = 5.87 Hz, 111), 8.87 (s, III); Mass (ES*): miz 1096.37 [MI-I']
[0587] Synthesis of example 86.
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arys...1 sr
02N abh
(HOV8-0--NO2
r
Slop 2
0
fr,,C
1-1 14214
N7.7.
p.I1 2 -.... TMSCN, 2=
Step 3 Step 4 1 S Steps
0
1
LOHMN
00 NA \-/ ewe e frsi, r.,4 ro -.-
step 7
%MC
CF,
110,
pig
OH
Hcl
- --N
HATU. DIPEA 0 HIA
Nekr Step 8 CP, Example 86
cF2
tk
[0588] Step 1: Synthesis of tert-butyl 3-{2-[(5-bromopyridin-2-
yDoxy]ethoxy)propanoate:
Br
[0589] To a stirred solution of 5-bromopyridin-2-ol (3.0 g, 17.24 mmol), tert-
butyl 3-(2-
hydroxyethoxy)propanoate (3.3 g, 17.19 mmol) and triphenylphosphine (6.8 g,
25.81 mmol) in
tetrahydrofuran (120.0 mL) was added diethyl diazene-1,2-dicarboxylate (4.49
g, 25.78 mmol)
dropwise at 0 under an atmosphere of nitrogen. The resulting solution was
stirred overnight at
room temperature. The reaction mixture was concentrated under reduced pressure
to give a crude
residue, which was purified by silica gel flash chromatography (eluent: ethyl
acetate/petroleum
ether, v/v =1/3) to provide the titled product (yield: 50%) as colorless oil.
[0590] Step 2: Synthesis of tert-butyl 3-(2- ( [5-(4-nitrophenyl)pyridin-2-
yl]oxy}ethoxy)propanoate:
o2N
I
0
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[0591] To a stirred mixture of tert-butyl 3-12-[(5-bromopyridin-2-
yDoxy]ethoxy}propanoate (3.0
g, 8.67 mmol) and (4-nitrophenyl)boronic acid (1.5 g, 8.87 mmol) in a mixed
solvent of dioxane
(90.0 mL) and water (9.0 mL) was added potassium carbonate (2.4 g, 17.36 mmol)
and Pd(PPh3)4
(450.0 mg, 0.39 mmol) under an atmosphere of nitrogen. The resulting mixture
was stirred for 12
hours at 100 C. The bulk of solvent was removed under reduced pressure, and
the resulting
aqueous residue was extracted with ethyl acetate (100 mL x 2). The organic
layers were
combined, washed with brine (70 mL x 2), dried over anhydrous sodium sulfate,
and concentrated
under reduced pressure to give a crude residue which was purified by silica
gel flash
chromatography (eluent: ethyl acetate/petroleum ether, v/v =1/5) to provide
the titled product
(yield: 83%) a yellow solid. Mass (ES): m/z 389.00 [MH+].
[0592] Step 3: Synthesis of tert-butyl 3-(2- ( (5-(4-aminophenyppyridin-2-
yl]oxy)ethoxy)propanoate:
H2N
I
[0593] To a stirred solution of tert-butyl 3-(2-1[5-(4-nitrophenyppyridin-2-
yl]oxylethoxy)propanoate (2.8 g, 7.21 mmol) in ethanol (200.0 mL) under an
atmosphere of
nitrogen was added palladium on carbon (1.5 g) at room temperature. The
reaction mixture was
then charge with hydrogen gas and stirred at room temperature for 12 hours.
The solids were
removed by filtration and the solution phase was concentrated under reduced
pressure to give a
crude residue which was purified by silica gel flash chromatography (eluent:
ethyl
acetate/petroleum ether, v/v=1/3) to provide the titled product (yield: 89%) a
yellow oil. LC-MS
(ES): viz 358.97 [MH-].
[0594] Example 86 was synthesized from tert-butyl 3421 [5-(4-
aminophenyl)pyridin-2-
yl]oxy}ethoxy)propanoate, according to chemistry highlighted above (steps 4-
8), utilizing similar
procedures described for the similar chemistry carried out for the synthesis
of examples 67, 75,
103, by using corresponding starting materials and intermediates.
[0595] Example 90 was synthesized according to similar procedures described
for the synthesis
of examples 86, by using corresponding starting materials and intermediates.
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[0596] Examples 88, 91-92 were synthesized according to similar procedures
described for the
synthesis of examples 80, 75, 103, by using corresponding starting materials
and intermediates.
[0597] Examples 87, 89, 93-102, 104-134, 136-142, 146-149 were synthesized
according to
similar procedures described for the synthesis of examples 75, by using
corresponding starting
materials and intermediates.
[0598] Table 7. Exemplary Compounds.
Ex # Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-243-(2-{ [5 -(4 - 344-cyano-3-(trifluoromethyl)phenyl] -5,5-
dimethy1-4-oxo-2-sullanylide neimidazolidin-l-yllphenyl)pyridin-2-
HN 0 yl)oxy }ethoxy)propanamido]-3.3-
dimethylbutanoy1)-4-hydmxy-NI [4-(4-
XL LN medv1-1,3-thiazol-5-
5/1)phenyl]methyl)pyrrolidine-2-carboxamide
86
'H NMR (300 MHz, CD30D):68.80 (s, 1 H), 8.36-8.30 (m, 1 H), 8.17-8.10 On,
2 H). 7.96-7.88(m, 2 H), 7.71-7.65 (tn. 2H), 7.46-7.26 (m, 6 H), 6.88-6.80 (m,
VS/
1 H), 4.64-4.35 (in, 6 H), 4.30-4.21 (in. 1 H), 3.89-3.65 (m, 8 H), 3.60-3.35
(m,5 H), 2.23-1.98 (m, 2 I1), 1.55 (s, 6 I1), 1.02 (s, 9 H); LC-MS (ES*): m/z
Cit.0
1011.20 [MW]
!Ai ______ (2S,4R)-1-[(2S)-243-(2-{ [6-(4-(344-cyano-3-
(trifluoromethyl)pheny11-5,5-
14 dimethy1-4-oxo-2-sullanylide nennidazolidin-
l-yllphenyl)pyridin-3-
HN at ynoxy }ethoxy)propanwnido 1-3.3-
dimethylbutanoy1]-4-hydroxy-N-{[4-(4-
XL ) methy1-1,3-thiazol-5-5/1)phenyl]methyl)pyrrolidine-2-
carboxamide
IH NMR (300 MHz, CD30D):68.80 (s, 1 H), 8.36-8.30 (m, 1 H), 8.17-8.10 (m,
87 2 H), 8.07-7.92(m, 3 II), 7.81-7.75 (m, 1H),
7.46-7.26 (m, 7 H), 4.61 (s, 1 H),
\... 4.54-4.50 (m, 1 H), 4.49-4.40 (m, 2H). 4.33-4.28 (m, 1 H),
4.26-4.15 (m, 2 H),
* 3.89-3.65 (m, 6 H), 2.64-2.40(m, 2 H). 2.38 (s, 3 H), 2.20-
2.10 (m, 1 H),
1.19-1.95 (m, 111), 1.55 (s, 611), 1.01 (s, 911); LC-MS (ES*):
1011.20
I Fa [MW]
HQ
(2S,4R)-1-[(2S)-2-(544-(4-(443-(3-chloro-4-cyanopheny1)-5,5-dimethyl-4-
oxo-2-sulfanylideneimidazolidin-1-yl]phenyl}phenyl)piperazin-1-
A110k
Q yl)pentanamido J -3,3-dimethylbutanoy1]-4-
hydmxy-N-{ [4-(1,3-oxazol-5-
yl)phenyl] methyl }pyrrolidine-2-carboxamide
88
0/ 1H NMR (400 MHz, DMS0): 68.51-8.58 (in, 1H), 8.42 (s, 1H), 8.20 (d,
J =
8.4 Hz, 1I1), 8.05 (s, 1I1), 7.87 (d, J =9.3 Hz, III), 7.73-7.79(m, 3I1), 7.60-
-
7.65 (m, 5H). 7.38-7.44 (in, 4H), 7.05 (d, J = 9.0 Hz, 2H), 5.13 (m, 1H), 4.58
(d, J =9.3 Hz, 1H), 4.36-4.45 (m, 3H), 4.23(m, 1H), 3.68 (in, 2H), 3.31 (s,
2H), 3.21 (m, 4H), 2.53 (s, 2H), 2.27-2.34(m, 3H), 2.17-2.19 (m, 1H), 2.07
(m, 1H), 1.89 (m, 1H), 1.52 (m, 10H), 0.96 (s. 9H); LC-MS (ES*); miz 998.30
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Ex if Structure Compound name and Analytical data
NO, H
(2S,4R)-1-[(2S)-2-(2-{4-[(6-(443-(3-ctiloro-4-cyanopheny1)-5,5-dimethyl-4-
.4c).t:
oxo-2 -sulfanylideneimidazolidin -1-yl] phenyl } pyrid in-3-
)4II
0%,..NN o yl)oxy]butoxy }acetamido)-3,3-dimethylbutanoy11-4-hydroxy-N4
[441,3-
o) cLN ocazol-5-yl)phenyl]methyl Ipyrrolidine-2-
carboxamide
69
I
'H NMR (300 MHz, CD30D):88.38 (s, 1 H), 8.21 (s, 1 H). 8.10-7.95 (m, 3 H),
7.90 (s, 111), 7.89-7.80 (m, 1 H), 7.71-7.60 (m, 3 H), 7.55-7.40 (m, 611),
4.70
(m, 1 H), 4.63-4.45 (m, 3 H), 4.40-4.30 (m, 1 H), 4.22-4.13 (m, 2 H), 4.10-
3.92
oolst2ft's (m, 2 H), 3.90-3.79 (m, 2 H), 3.70 -3.60 (in, 211), 2.30-
2.21 (rn, 1 H), 2.14-
2.00 (m, 111), 2.00-1.90 (m, 211), 1.90-1.80 (m, 2/1), 1.58 (s, 611), 1.01 (s,
9
(t=IN-s 1 H); LC-MS (ES*): m/z, 961.20 [MI-11
"S. m (2S,4R)-1-[(2S)-2-(2-(4-1(5-(443-(3-chloro-4-cyanopheny1)-5,5-
dimethyl-4-
oxo-2-sulfanylideneimidazolidin-1-yl] phenyl }pyridin-2-
).NH
yl)oxy]butoxy }acetamido)-3,3-dimethylbutanoy1]-4-hydroxy-N-{ [441,3-
oxazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide
90 'H NMR (300 MHz, CD30D):88.42 (s, 1 H), 8.21
(s, 1 H), 8.00-7.95 (m, 211),
i 7.90 (s, 1 H), 7.79-7.71 (m, 2 H), 7.70-7.61
(m, 3 H), 7.55-7.40 (m, 5 H), 6.90
(d.J = 6.6 Hz, 1 H). 4.70 (m, 1 H), 4.63-4.45 (m,3 H), 4.42-4.30 (m, 311),
ot"-'"s 4.10-3.96 (m, 2 /I), 3.90-3.85 (m, 1 H), 3.84-3.76 (m, 1
H), 3.70-3.60 (m, 2
C
I-I), 2.30-2.21 (m, 1 H), 2.14-2.00 (m, 1 H), 2.00-1.90 (m, 2 H), 1.90-1.80
(m, .4,1:scI 211), 1.58 (s, 6 1-1), 1.01 (s, 9 H); LC-MS (ES+): m/z, 961.20
[MHI
(2S,4R)-1-[(2S)-2-(444-(4-(443-(3-chloro-4-cyanopheny1)-5,5-dimethyl-4-
Hq oxo-2 -sulfanylideneimidazolidin -1-yl] phenyl }phenyl)piperidin-l-
yl]butanamido) -3,3 -dimethylbutanoy11-4-hydroxy-N- ( [4-(1,3-ozazol-5-
yl)phenyl]methyl}pyrrolidine-2-carboxamide
91
o)(/
NS 1H NMR (400 MHz, CD30D) 8 8.23 (s, 1H), 7.99 (d,J= 8.0 Hz.
1H), 7.91 (s.
1/1), 7.80 (d, J = 8.8 Hz, 21-1), 7.69-7.63(m, 5/1), 7.49-7.45 (m, 5I1), 7.39
(d,J
= 8.4 Hz, 2H), 4.67 (s, 1H), 4.60-4.52 (m, 3H),4.38 (d,J= 15.6 Hz, 1H), 3.95-
3.91 (m, 111), 3.88-3.81 (m, 111), 3.17-3.15 (m, 211), 2.66-2.61 (rn, 111),
2.54-
521.=CI 2.45 (m, 2I1), 2.38-2.31 (m, 2I-1), 2.29-2.15 (m, 31-1),
2.13-2.06 (m, 1I1), 1.88-
N
1.85 (in. 6H), 1.61 (s. 6H), 1.08 (s. 9H); LC-MS (ES): miz 983.45 [MW]
4? (2S,4R)-1-[(2S)-2-(2-(2-14-(4-(443-(3-chloro-4-cyanopheny1)-5,5-
dimethyl-4-
g oxo-2-sulfanylideneimidazolidin-1 -yl]phenyl
}plienyl)piperidin-1-
yflethoxy}acetamido)-3,3-dimethylbutanoy11-4-hydroxy-N-([4-(1,3-oxazol-5-
1.94 yl)phenyl]methyl}pyrrolidine-2-carboxamide
92
4 i H NMR (400 MHz, CD30D) 8 8.19 (s, 1H),
7.99 (d, J= 8.4 Hz, 1H),7.91 (s,
ir 111). 7.77-7.73 (m, 211), 7.69-7.52(m. 5H), 7.45-7.43 I m,
511). 7.36 (d, J= 8.4
= f4).S Hz, 2H). 4.73 (s, 1H). 4.61-4.49 (m, 311), 4.36-4.32 (m.
1H),4.13-4.01 (m,
2I1), 3.91-3.77 (m, 4I4), 3.21-3.12 (m, 211), 2.78 (t, J= 5.2 Hz, 211), 2.68-
2.61
51ci
(m, 1H), 2.37-2.30 (m, 2H), 2.28-2.19 (m, 1H), 2.14-2.05 (m, 111), 1.92-1.88
190
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Ex if Structure Compound name and Analytical data
(m, 4H), 1.60 (s, 6H), 1.08 (s, 9H); LC-MS (ES'): mlz 999.65 [MI41
(2S,4R)-1-1(2S)-2-(2-{444-(4.-{344-cyano-3-(trifluoromethyl)phenyl]-5,5-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
yl}phenyl)phenoxy]butoxy }acetamido)-3-methylbutanoy1)-4-hydmxy-N-( [4-
_ NW" (4-methyl-1,3-thiazol-5-
yl)phenyl]methyl}pyrrolidine-2-carboxamide
N
sr:N
1H NMR (400 MHz, CD301.)) o ppm 8.83 (s. 1 H,) 8.67 (t, J= 6.06 Hz, 1 II),
ro 0
8.18 (d, J = 1.96 Hz, 1 H),8.15 (d, J= 8.22 Hz, 111), 8.00 (dd, J = 8.22, 1.96
93
!Le) Hz, 1 H),7.69 - 7.74 (m, 2 H), 7.64 (d, J=
9.00 Hz, 1 H), 7.54 - 7.60 (m, 2 H),
7.37 - 7.46 (m, 6 H), 6.96 - 7.02 (m, 2 H), 4.63 - 4.69 (m, 1H), 4.55 - 4.61
(m,
7-N
0 h, II-I), 4.48 - 4.55 (m, 2 11), 4.34 - 4.41
(m,1 II), 4.04 - 4.10 (m, 2 II), 3.98
4.03 (m, 2 H), 3.83 - 3.88 (m, 1 H), 3.77 - 3.82 (m, 1 H), 3.64 (t, J= 6.26
Hz., 2
F;
H),2.42 -2.47 (m,3 H),2.25 (dd, J= 13.30, 7.83 Hz, 1 11), 2.14 (dd, J=
13.30, 6.65 Hz, 1 11), 2.07 (ddd,J = 13.30, 9.00,4.30 Hz, 1I1), 1.89 - 1.97
(m,
2H), 1.81- 1.89 (m, 2 H). 1.59 (s, 6 H), 1.01 (d, J= 6.65 Hz, 3 H). 0.91 (d,
J=
6.26 Hz, 311); LC-MS (ES*): nez 1010.36 [MW]
H04.
(2S,4R)-1-1(2S)-2-{244-(4-(4-13-(3-chloro-4-cyanopheny1)-5,5-dimethyl-4-
o
oxo-2-sulfanylideneimidazolidin-1-yflphenyl }phenoxy)butoxy)acetamido}-
0
3,3-dimethylbutanoy1]-4-hydroxy-N-1[4-(1,3-oxazol-5-
0)
Aphenyl]methyl}pyrrolidine-2-calboxamide
94 IH NMR (300 MHz, CD30D):88.14 (s, 1 H),8.00-
7.9J (m, 1 H), 7.90-7.80 (m,
1 H), 7.71-7.60 (m, 511). 7.59-7.51 (m, 211), 7.45-7.30 (m. 5 H), 7.05-6.94
(m,
)1/ 2 II), 4.67 (s, 1 H), 4.55-4.50(m, 111), 4.49-4.40(m, 2 H),
4.31-3.25 (m, 1 II),
4.10-4.00(m, 2H), 3.99-3.96 (m, 2 F1). 3.90 -3.70 (m, 211), 3.65-3.55 (m, 2
11), 2.22-2.13 (m, 1 H), 2.14-2.00 (m, 1 H), 2.00-1.72 (m, 4 1-1), 1.56 (s, 6
1-1),
1.01 (s, 9 H): LC-MS (ES.): ml:, 960.30 [M1-1]
CS
191
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Ex It Structure Compound name and Analytical data
( 2S,4R)-1-[(2S)-2-(2- (41444- ( 344-cyano-3-(tri fluommethyl)phenyl] -5,5-
dimethy1-4-ozo-2-sulfanylideneimidazolidin-1-
0 yliphenyl)phenoxy]butoxy}acetamido)-3,3-dimetliylbutanoyl]-4-
hydroxy-N-
*.44
RIS)-1-(4-(4-methy1-1,3-thiazol-5-yl)phenyl ] ethyl] pyrrolidine-2-cathozamide
(.)-)
95 1I4 NMR (300 MHz, CD30D): 5 8.86 (s,
1H),8.18-8.15 (d, J = 9.0 Hz, 21-1),
8.03-7.99 (m, 1H), 7.76-7.71 (d, J = 14.4 Hz, 2H), 7.64-7.59 (d, J = 15.3 Hz.
211), 7.45-7.39 (rn, 611), 7.07-7.04 (d, J = 8.7 Hz, 2H) ,5.01-4.99 (rn, 111),
4.70
(s, 1H), 4.61-4.55 (m, 1H), 4.45 (s, 1H), 4.13-4.08 (m, 2H), 4.03-3.96 (m,
2H),
3.84-3.80 (m, 1H), 3.78-3.76 (m, 1H). 3.68-3.64 (in, 2H), 2.47 (s, 3H), 2.22-
2.15 (m, 111) ,1.99-1.85 (m, 51-1), 1.60 (s, 61-1), 1.51-1.48 (d,J = 6.911z,
311),
F; 1.05 (s, 9H) ; IC-MS (ES'): m/z. 1038.50 [M1-
11
1111
(2S,4R)-1-[(2S)-2-(2- (414 -(4- ( 344 -cyano-3-(trifluoromethyl)phenyll -5,5-
I t
Cr-ki(llocrL1-) dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
04,r,rm 41.)
cri yl)phenyl)phenozyibutozy}acetamido)-3,3-dimethylbutanoyl]-4-
hydrozy-N-
cLS ( [4-(1,3-ox.azol-5-yl)phenyl]methyl
)pyrrolidine-2-carboxamide
rj)
96 1.1-1NMR (300 MHz, CD30D): 88.23-8.15 (m,
311) ,8.03-7.99 (d,J= 9.9 Hz,
111), 7.73-7.65 (rn, 411), 7.60-7.57 (d, J = 8.7Hz, 211), 7.46-7.41 (m, 511),
7.05-
7.00 (d,J =12.6 Hz, 2H) , 4.71 (s, 1H), 4.61-4.50 (m, 3H), 4.36-4.31 (d, J
"r)s =15.6 Hz. 1H), 4.10-4.08 (m, 411), 4.03-
3.82(m, 211), 3.68-3.64 (t, J= 7.3Hz,
211), 2.22-2.10 (m, 111), 2.10-2.02 (m, 111), 1.98-1.85 (m, 4I1), 1.60 (s,
6I1),
1.05 (s, 911) ; IC-MS (ES'): m/z. 994.65 (M1-11)
Ng, ___________________________________________________
(2S,4R)-1-[(2S)-2-(2-(414-(4-(344-cyano-3-(trifluoromethyl)phenyl]-5,5-
0),M
dimethy1-4-ozo-2-sulfanylideneimidazolidin-1-
oym yllphenyl)phenozy]butozy }acetamido)-3,3-dimethylbutanoy1]-4-
hydrozy-N-
or) I [4-(4-methy1-1,3-mazol-5-
yl)phenyl]methyllpyrrolidine-2-carboxamide
gfj 1H NMR (300 MHz, CD301.)): 5 8.18-8.15 (d. J-
9.3 Hz, 2H), 8.08(s. 1H),
97
8.03-7.99 (d, J= 9.9 Ilz,111), 7.73-7.70 (d, J=8.4 Hz, 21-1), 7.61-7.56 (m,
4/1),
7.49-7.41 (m, 411), 7.02-7.00 (d, J=8.7 Hz, 2H) , 4.71(s, IH), 4.61-4.52 (m,
311), 4.37-4.11 (d, J= 15.6 Hz, 211), 4.11-4.07 (in, 411), 3.96-3.82 (rn,
211),
3.68-3.64 (t, J=6.0 Hz, 21-1), 2.36 (s, 31-1), 2:23-2.14 (m, III), 2.14-2.09
(m,
111). 1.98-1.84 (m, 4H), 1.60 (s, GH), 1.05 (s, 911); LC-MS (ES*): m/z
1008.20 [MW]
192
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Ex if Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-2-(2-(414-(4-(344-cyano-3-(trifluoromethyl)phenyl]-5,5-
ni
dimethy1-4-oxo-2-sulfanylideneirnidazolidin-1-
yliphenyl)phenoxy]butoxy}acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-
0or/H
([4-(1,3-thiazol-5-y0phenyl]methyl }pyrrolidine-2-carboxamide
NMR (300 MHz, CD30D): &8.89(s, 111), 8.18-8.15 (d, J= 9.0 Hz, 21-1),
98
ci(j¨ 8.10(s, 1H). 8.03-7.99 (d, J=12.0 Hz. 1H),
7.73-7.70 (d, J=8.4 Hz, 2H). 7.62-
7.56 (m, 411), 7.44-7.41(rn, 411), 7.05-7.00 (d, J=14.1 Hz, 2H) ,4.71 (s,
111),
k1s 4.61-4.51 (m, 3H), 4.35-4.30 (m, 1H). 4.12-
4.08 (m, 2H), 4.08-4.03 (m, 2H),
3.95-3.82 (m, 2H), 3.68-3.64 (t, J=6.0 Hz, 2H), 2.22-2.20 (in. 1H), 2.13-
2.08(m, 1I1), 1.98-1.84 (m,411), 1.60 (s, 611), 1.04 (s, 911); LC-MS (ES):
m/z.
1010.30 [MW]
(2S,4R)-1-1(2S)-2-(2-(413-(4-(344-cyano-3-(trifluoromethyl)pheny11-5,5-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
yl iphenyl)phenoxy]butoxy }acetamido)-3,3-dirnethylbutanoyl]-4-hydroxy-N-
sr:h (14-(4-methy1-1,3-thiazol-5-
yl)phenytimethyl}pyrrolidine-2-carboxamide
,O)
99 L,ç H NMR (400 MHz, CD-,0D): 5 8.82 (s, 1H),
8.20 (d, J= 5.4 Hz, 2H), 8.02(d,
J= 8.0 Hz, 1H). 7.77 (d. J = 5.4 Hz, 2H). 7.52 (m. 4H), 7.44 (m, 3H), 7.24 (d.
J= 8.4 Hz, 2I1), 6.96 (d,J = 8.4 Hz, 111), 4.71 (s, III), 4.56 (m, 31-1), 4.34
(m,
Fc
1H), 4.12 (tn. 2H), 4.00 (m, 211), 3.84(m, 1H), 3.72 (m, 1H), 3.67(m, 211),
2.45 (s, 311), 2.24 (in, 111), 2.10 (m, Ili), 1.90 (m, 4H), 1.61 (s, 611),
1.03 (s,
9I1); LC-MS (ES*): nez 1024.35 [MI1]
HQ
C (2S,4R)-1-1(2S)-2-(2 [4 (4 (4 [3 ( chloro-4-
eyanophony1)-5,5-dimethyl-4-
)c-LO
oxo-2-sulfanylideneimidazolidin-l-y1)-3-
= NH µ4",--(
fluorophenyllphenoxy)butoxylacetamido}-3,3-diniethylbutanoy11-4-hydroxy-
=
[4-(4-methy1-1,3-oxazol-5-y0phenylimethyl}pyrrolidine-2-carboxamide
=
100
4 IH NMR (400 MHz, DMA")) 5 8.61 (s, 1H), 8.29 (s, 1H), 8.21
(d, = 8.4 Hz,
111), 8.08 (s, 111), 7.78-7.64 (rn, 511), 7.53-7.42 (m, 611), 7.04 (m, J= 8.8
Hz,
4.4411P
21-1), 5.16 (s, 1/1), 4.58 (d, J= 9.6 Hz, 1I-1), 4.57-4.27 (m, 4/1), 4.20 lt,
J = 6.8
F Hz, 2H). 3.91 (s, 2H). 3.68-3.53 (m, 411),
2.33 (s, 311), 2.07 (s, 111), 1.90-1.72
(m, 5H), 1.60 (s, 3H), 1.48 (s, 3H), 0.95 (s, 9H); LC-MS (ES'): in/r. 992.30
[MW]
I 93
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Ex if Structure Compound name and Analytical data
FIN i'l ' (2S,4R)-1-[(2S)-2-(2-f 414-(4-(3-[4-cyano-3-
(trifluoromethyl)pheny1]-5,5-
1-10...CrA0 o_iiN dimethy1-4-oxo-2-sulfanylideneimidazolidin-
1-
. roN
yl}phenyl)phenoxy]butoxy}acetamido)-3,3-dimethylbutanoy11-4-hydroxy-N-
NH
1-.0 R1S)-114-(4-methy1-1,3-oxazol-5-
1)pheny1lethy1]pyrrolidine-2-carboxamide
ro
101 =.1 i H NMR (400 MHz, CD30D): 5 8.19-8.14 (m,
3H), 8.03-8.01 (d, J=8.4 Hz,
#11 1H), 7.77-7.73 (d. J=16.0 HZ, 2H), 7.64-7.60
(m, 4H), 7.45-7.42 (m, 4H), 7.07-
.)P 7.05 (d. J=8.4 Hz, 2H) . 5.01-5.00(m, 1H),
4.71(s, 1H). 4.61-4.56 (m. 1H),
4.45 (s, III), 4.13-4.10 (m, 211), 4.07-4.01 (m, 211), 3.88-3.85 (m, III),
3.78-
3 .75 (m, 1H). 3.69-3.66 (t, J= 12.0Hz, 2H), 2.40(s, 3H), 2.21-2.19 (in,
F)41 1H) ,2.00-1.86 (m, 5H), 1.61 (s,611), 1.51-
1.49 (d, J= 7.2 Hz, 3H), 1.06(s,
F 911) ; LC-MS (ES*): m/z 1022.45 [MI-1]
1.1
(2S.4R)-1-[(2S)-2-(2-(414-(5-(3-[4-cyano-3-(trifluoromethyl)pheny1]-5,5-
1'4 dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
ylipyridin-2-
-i--S 6 -Ni;
S yl >phenoxy]butoxy }acetamido)-3,3-
dimethylbutanoy1)-4-hydmxy-N-{ [444-
0 methyl-1,3-thiazol-5-yl)phenyllmethyl
}pyrrolidine-2-carboxamide
...)--)
e,v/¨
102 -
)-...) I Ii NMR (400 MHz, CD30D): 5 8.96 (s, 1H),
8.62 (rn, 2H), 8.42 (d, J = 8.4 Hz,
-1 ),.....N 1H), 8.33(s, 1H), 8.12(m, 4H), 7.89 (m, 1H),
7.44 (m, 5H), 7.07 Id, .1= 8.8
0.,7-N
rt== Hz, 2H), 5.17 (m, 1H). 4.59 (d..1= 9.6 Hz,
1H), 4.41-4.48 (m, 1H), 4.38 (m.
RI_ P, )' ::' )
21-1), 4.29 (m, 111), 4.07-4.10 (m, 21-1), 3.97 (m, 2I1), 3.55-3.67 (in, 41-
1), 2.45
I
(s, 3H), 2.08 (m, 1H), 1.81-1.91 I m, 3H), 1.72-1.77 (m, 2H), 1.58 Is, 6H),
0.95
(s, 9H), LC-MS (ES*): nez 1025.55 [MW]
HQ
(2S,4R)-1-[(2S)-242-(4-( [4-(4-(344-cyano-3-(trifluoromethyl)phenyl]-5,5-
H dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
C
yl}phenyl)phenyliamino}butoxy)acetamido]-3,3-dimethylbutanoy11-4-
ol..-NH N i hydroxy-N-( [4-(4-methy1-1,3-thiazol-5-
yl)phenyl]methyllpyrrolidine-2-
o-i
carboxamide
103 NH
/ µ
ill NMR (300 MHz, CD30D) 68.71 (s, 1I4), 8.18-8.15 (d, J . 8.4 Hz, 2/1),
8.03-8.00 (d, J = 7.8 Hz, 1H), 7.68-7.66 (d, J= 8.4 Hz, 2H), 7.47-7.35(m,
As
N 811), 6.74-6.71 (d, J= 8.7 Hz, 2H), 4.72(s,
1H), 4.62-4.50 (in, 3H), 4.37-4.32
(d, J = 15.2 Hz, 111), 4.00-3.98(m, 211), 3.94-3.79(m, 2I4), 3.64-3.61 (m,
211),
3.21-3.11 (m, 2H), 2.48 (s, 3H), 2.28-2.21 (m, 1H). 2.09-2.05 (m, 1H), 1.93-
r: CF's
1.89 (in, 4H), 1.59 (s, 6H), 1.01 (s, 9H); LC-MS (ES*): /fez 1023.30 [MH]
194
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Ex if Structure Compound name and Analytical data
HQ ( 2S,4R )4 -[(2S)-2-(2- (41444- ( 344-cyano-
3-(tri fluoromethyl)phenyl] -5,5-
_k_cril dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
Oy..NH 0 '.1 yliphenyl)phenoxy]butoxy}acetamido)-3,3-
dirnetliylbutanoyl]-4-hydroxy-N-
rf5) ....t.N ( [4-(1-methyl-1H-imidaml-5 -
yl)phenyl]merhyllpyrrol idine-2-carboxamide
= 1H NMR (300 MHz, CD30D): 08.18-8.15 (d, J= 9.0 Hz, 21-1), 8.02-7.99 (d,J
104
. = 10.2 Hz, 1H), 7.73-7.70 (d, J=8.4 Hz, 2H),
7.59-7.56 (d, J=8.7 Hz, 2H),
\ ill 7.50-7.39 (m, 711), 7.03-7.00 (d, J=8.7 Hz,
211), 6.30(s, 111), 4.71 (s, 111),
Z
4.624.50(m, 3H), 4.39-4.33 (d, J= 15.2 Hz, 1H),4.114.08 (m, 211), 4.08-4.00
(m, 2H), 3.87-3.80(m, 5H). 3.68-3.64 (t, J.0 Hz, 2H), 2.25-2.15 (m, 1H).
Filif
2.10-2.00 (m, 1/1), 1.97-1.84 (m, 411), 1.60 (s, 611), 1.04 (s, 911); LC-MS
(ES'): mfr. 1007.50 [MI-1]
(2S,4R)-N-( [4-(4-chloro-1,3-oxazol-5-yl)phenyl] methyl ) -1-[(2S)-2-(2- (414-
Ho
1 (4-(3-[4-cyano-3-(trifluoromethyl)phenyl]-
5,5-dimethy1-4-oxo-2-
_k: N--Nrk SU Ifanylideueilnidazolidin-lid }phenyllphenoxy]butoxy
}acetiunido)-3,3-
.
..N.-1 ;=====1)
dimethylbutanoy1]-4-hydroxypyrrolidine-2-carboxamide
f
6' '1-1NMR (400 MHz, CD-,0D): 8 8.63-8.66 (m,
111), 8.53 (s, 111), 8.41 (d, 1 =
105 (;) 8.4 Hz, 1H), 8.32(s, 1H), 8.12 (d, J =8.8
Hz, 111), 7.80 (d, J = 8.0 Hz, 211).
, 0
411' 7.75 (d, J =8.4 Hz, 2H), 7.67 (d, J =8.4 Hz,
2Ii), 7.50 (m, 511), 7.04 (d, J =8.8
V e Hz, 2H), 5.17(m, 111), 4.59(d. J = 8.4 Hz,
1H), 4.48 (n, 2H), 4.39 (m, 111),
F$-C)
4.32 (m, 111), 4.08 (m, 211), 3.97 (m, 211), 3.55-3.67 (m, 411), 2.06-2.08 (m,
il N Hi), 1.81-1.91 (m, 311), 1.72-1.77 (m, 211),
1.55 (s, 611), 0.95 (s, 911): LC-MS
(ES'): in.,z 1028.50 IMH1
HQ
....\c4c:13 IsH (2S,4R)-1-[(2S)-2-(244-(4-(4-[3-(3-chloro-4-cyanopheny1)-
5,5-dimethyl-4-
?,1oxo-2-sulfanylideneimidazolidin-l-y1]-3-
fluorophenyllphenoxy kutoxy]acetamido 1 -3,3-di methylbutanoyl] -4-hydrox y-
N-( [4-(1,3-oxazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide
=
=
106
411 1H NMR (400 MHz, CD30D) 8 8.20 (s, 1H), 8.00
(d, J= 8.4 Hz, 1H), 7.90 (s,
IP 1H), 7.70-7.44 (m, 11H), 7.05 (d,J = 8.8 HZ,
2H), 4.72 (s,
3H). 4.37-4.33 (m, 111), 4.14-4.02 (m. 4H), 3.98-3.84 (m, 2H). 3.67 (t. J= 6.4
Hz, 211), 2.24-2.22 (m, 1I4), 2.12-2.09 (m, 1I-1), 1.99-1.86 (m, 411), 1.66
(s,
3H), 1.54 (s. 3H), 1.06 (s. 9H); LC-MS (ES): mit 978.25 (MH')
N
195
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Ex if Structure Compound name and Analytical data
rick
( 2S,4R )-1-[(2S)-2-{ 2-14-(4-14-13-(3-chlom-4-cyanopheny1)-5,5-dimethyl-4-
oxo-2-sulfanylideneimidazolidin-l-y1]-3-
y0 vN ,HiCivigli
fluorophenyl }phenoxy)butoxy]acetamido} -3,3-dimethylbutattoy1]-4-hydroxy-
NI [4-(4-methy1-1,3-thiazol-5-yl)phenyl]methyl }pyrrolidine-2-
/ sµ,..N carboxamide
107
..,..? 1H NMR (400 MHz, DMSO) 8 8.96 (s. 1H), 8.61
(m, 1H), 8.20 (d, J= 8.4 Hz,
111), 8.19 (s, 111), 7.78-7.64 (m, 511), 7.70-7.37 (m, 6H), 7.03 (m, J=8.8 Hz,
oi-i:La F 2H), 5.16 (s, 1H), 4.57 (d, J= 9.6 Hz., 1H),
4.57-4.27 (m, 4H), 4.08 (t, J = 6.8
Hz, 211). 3.96(s, 211). 3.66-3.55 (m, 4H), 2.43 (s, 3H), 2.16 (m, 111). 1.92-
1.75
CIil (m, 5/1), 1.60 (s, 3/1), 1.48 (s, 311), 0.93
(s, 9H): LC-MS (ES'): nez 1008.50
(M1-11)
HQ (2S,4R)-1-1(2S)-2-12-14-(4-(4-[3-(3-chloro-4-
cyanophenyl)-5,5-dimethyl-4-
H oxo-2-sulfanylideueimidazolidin-l-yI]-3-
_Aci....4ibiri
fluorophenyl}phenoxykutoxy]acetamido}-3,3-dimethylbutanoyl]-4-hydroxy-
r¨rj t'N N-114-(1,3-thiazol-5-yl)phenylimethyl}pyrrolidine-2-carboxamide
108
fiCe 'H NMR (400 MHz, DMSO) 69.04 (s, Ili), 8.61-
8.56 (m, 111), 8.27 (s, 111),
8.21 (d,J = 8.4 Hz, IH), 8.08 (s, IH), 7.78-7.36 (m, 11H), 7.06 (d,./ = 8.4
Hz,
omttit F
211). 5.16(s, 111). 4.58-4.56 (m, 111), 4.47-4.22 (m. 4H), 4.09-4.06(m, 211).
eig? 3.96 (s, 211), 3.66-3.55 (m, 4/1), 2.07-2.04
(m, 111), 1.89-1.72 (m, 511), L60 (s,
3H), 1.48 (s. 3H), 0.95 (s. 9H); ir-Ms (ES): nez 994.50 (MH')
(2S,4R)-1-1(2S)-2-12-14-(4-(4-[3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-
Hs
Qi l oxo-2-sulfanylideneimidazol1din-1-y1]-2-
il
fluorophenyl}phenoxykutoxy]acetamido}-3,3-dimethylbutanoyl]-4-hydroxy-
N-114-(1,3-oxazol-5-y1)phenyllmethyl}pyrrolidine-2-carboxattlide
i 4
rj '14
'H NMR (300 MHz, CD30D): 68.23 (s, 111), 8.19-7.99 (d, J = 5.9 Hz, 111),
109 0
4 7.96(s, III), 7.78-7.61 (m, 411), 7.58-7.51
(m, 211), 7.47-7.46 (m, 211), 7.46-
= * p 7.41 (m, 311). 731-7.29 (m, 2H), 7.05-
7.02 (d. J= 8.7Hz, 1H). 4.71(s, 111),
ONIS 4.61-431 (m, 311), 4.36-4.31 (d, J = 15.2
Hz, 111), 4.13-4.11 (m, 211), 4.09-
r.--.-
4.01 (m, 2H), 3.96-3.79 (m, 2H), 3.69-3.65 (t,./ = 6.0 Hz, 2H), 2.23-2.20 (m,
Z CI 111), 2.13-2.09 (m, 111), 1.96-1.87 (m,
411), 1.60(s, 611), 1.03 (s, 911) ; LC-MS
(ES*): m/z 978.25 [M}1
196
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Ex It Structure Compound name and Analytical data
HQ. ( 2S,4R )-1-[(2S)-2-{ 24444- (4-(3-(3-chlom-
4-ganophenyl)-5,5-dimethyl-4-
H
..k.1 N oxo-2 -sulfanylideneimidazolidin -1-yl]
phenyl }phenoxy)butoxy]acetamido } -
0 NH
3,3-dimethylbutanoy1]-4-hydroxy-N-I [4-(4-methy1-1,3-oxazol-5-
D (.....
. yl)phenyl]methyl }pyrrolidine-2-carboxamide
110 .
I14 NMR (300 MHz, CD30D): 68.08 (s, 1I-1), 7.77-7.72 (in, 3I1), 7.69-7.56 (m,
4H),7.48-7.39 (m, 5H), 7.19-7.17 (d,J = 6.3Hz, 1H), 7.02-6.99 (d, J = 9.0 Hz,
4,1 IP 211), 4.71 (s, 111), 4.61-4.52 (rn, 311),
4.36-4.31 (in, 1H), 4.11-4.08 (in, 211),
NS 4.03-4.01 (m, 5H), 3.95-3.82 (m, 2H). 3.68-3.64(m, 2H),
2.36 (s, 3H), 2.22-
C;5(c 2.09(m, 1H). 2.09-2.01(m, 1H), 1.95-1.84
(m. 4H), 1.58 (s, 6H), 1.04 (s, 9H);
Nc. j LC-MS (ES*): m/z 974.30 IMIll
, .
HQ
(2S,4R)-1-[(2S)-2-124444-(4-[3-(3-chloro-4-cyanoplieny1)-5,5-dimediyi-4-
oxo-2-sulfanylidencimidazolidin-1-yl]phenyllphenoxy)butoxyjacctamido}-
6
(:)....NH ) 3,3-dimethylbutanoy11-4-hydroxy-N-([4-(1,3-
thiazol-5-
Qj
yl)phenyl]methyllpyrrolidine-2-carboxamide
7
111 $,.....N
1H NMR (300 MHz, CD30D): 5 8.89 (s, 1H), 8.10(s, 1H), 7.98-7.95 (d, J =
clip 8.4 Hz, 111), 7.89-7.88 (d, J= L8 Hz, 111),
7.72-7.56 On, 7H), 7.44-7.39 on,
,...i _.. / 4H), 7.03-7.00 (d, J= 8.7 Hz, 211) , 4.70
(s, 111), 4.61-4.50 (n, 3H),4.35-430
,-.C.
s., N- -I.s (d,./ = 15.2 Hz, 1H), 4.12-4.03 (m, 214),
4.01-3.95 (n, 211), 3.86-3.82 (in. 2H),
Ski 3.68-3.64 (m, 2Ii), 2.22-2.18 (m, 1I-1),
2.12-2.08 (m, III), 1.98-1.85 (m, 4H),
1.58 (s, 6H), 1.04 (s, 9H) ; ir-Ms (ES): m/z 976.20 [MH1
(2S,4R)-1-[(2S)-2- ( 244 -(4 - (4-[3-(3-chloro-4-cyanopheny1)-5,5-dimethy1-4-
NC'n. XI
oxo-2-su Ifanyl ideneimidavalidin-1-yl] phenyl }phenoxy)butoxy]acetamidol-
3,3-dimethylbutanoy1]-4-hydroxy-N-([4-(4-methyl-1,3-thiazfal-5-
S
Aphenyl]methyl}pyrrolidine-2-carboxamide
112
01.1. IH NMR (300 MHz, CD30D): 68.81 (s, 1H), 7.98-7.95 (d, J=8.4 Hz,
111),
7.89-7.88 (d, J=1.8 Hz, 1H), 7.73-7.64 (m, 3H), 7.58-7.56 (d, J=8.7 Hz, 211),
ITO 7.48-7.38 (m, 6H), 7.02-6.99(d, J = 8.7Hz,
2H), 4.71 (s, 111), 4.62-4.51 (in,
HNik
311), 4.36-4.31 (m, 114), 4A1-4.07 (m, 2I1), 4.02-4.00 (d, J=5.4 Hz, 2I1),
3.87-
P
0 N =,OH
NII
3.82(m, 2H), 3.68-3.64 (t, J5.0 Hz, 2H), 2A4 (s, 3H), 2.23-2.10 (m, 1H),
ri
, ,,,µ,...,14FE 2.09-2.00 (n, 111), 1.97-1.84 (m,
411), 158(s,611), 1.04 (s, 9H) ; LC-MS
(ES): m/z 99030 IMH1
197
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Ex It Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-2-(2-(4-14-(4-(344-cyano-3-(trifluoromethyl)phenyfl-5,5-
Nclia-Nk
F3C s).-N _ dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
y1)-3-
11 fluorophenyl)phenoxy)butoxy Jacetamido)-3,3-
dimethylbutanoyl.)-4-hydroxy-
I N-f [4-(1,3-oxazol-5-yl)phenyl]methyl
}pyrrolidine-2-carboxamide
113
110 1H NMR (300 MHz, DMSO) 88.62-8.56 (m, 1H),
8.41 (s, 1H), 8.39 (s, 1H),
8.350- III), 8.15 (d, J = 8.4 Hz, III), 7.76-7.63 (m, 711), 7.51-7.38 (m, 41-
1),
HN xi(
7.06 (d, J = 8.7 Hz, 2H), 5.15 (d, J = 3.3 Hz, 1H), 4.58-4.26 (m. 5H),4.09-
4.05
ro
(m, 2H), 3.96(s, 2H), 3.66-3.56 (rn, 4H), 2.12-2.04 (in, 1H), 1.93-1.73 (m,
Oo,,p= .0H
5H), 1.60 (s, 3H), 1.50 (s, 3H), 0.95 (s, 9H); ir-ms (Es+): nez 1012.30 [M1-
1']
(2S,4R)-1-[(2S)-2-(2-( 314-44-(344-eyano-3-(trifluoromethyl)pheny1:1-5,5-
1 1 diniethy1-4-oxo-2-sulfanylideneinlidazolidin-1-
NC-P-Nc2- yliphenyl)phenoxy]phenoxy}acetafflido)-3,3-dimedlylbutanoyl]-
4-hydroxy-N-
F3C S no,
( [444-methy1-1,3-thiazol -5-yl)ptieny I .) methyl } pyrrolidine-2-carboxamide
1 ja
114 .-
11-1 NMR (300 MHz, CD30D):88.81 (s, 1 H), 8.14-8.05 (tn. 2 H), 8.00-7.95 (rn,
Hikoix.i-
1 H). 7.75-7.69 (in, 2 H), 7.65-7.59 (in, 2 H), 7.44-7.20 (m, 7 H), 7.10-7.00
(in,
_ tr).,OH
rS 211), 6.80-6.78 (m, 11-I), 6.75-6.55 (m, 2
H), 4.68 (s, 1 /I), 4.60-4.40 (m, 5 11),
Nrts0CrH 4.30-4.20(m, 1 H), 3.90-3.65 (tn. 2 F1),
2.40(s. 3 H), 2.25-2.21 I'm, 1 H), 2.14-
2.00 (m, 1 H), 1.55 (s, 6 H), 0.99 (s, 9 H); LC-MS (ES): ,n/z, 1044.30 [MH]
HO,
:(2S,4R)-1-[(2S)-2- (24444- (443-(4-eyano-3-methoxypheny1)-5,5 -dimethyl.-4-
N
>k1"4"0 8 oxo-2-sulfanylideneimidazolidin-l-yliphenyl
}phenoxy)butoxylacetamido } -
Oy.NH 3,3-dimethylbutanoy11-4-hydroxy-N-1[4-(4-
methyl-1,3-oxazol-5-
rj5 (LN yl)phenyl]methyl}pyrrolidine-2-carboxamide
115 0
1H NMR (300 MHz, CD30D): 8 8.08 (s, 1H), 7.76-7.69 (m, 3H>,7.60-7.55 (d,
0 J=15.9 Hz, 4H), 7.48-7.37 (m, 5H), 7.19-7.16 (d, J=9.9 Hz,
1H), 7.02-6.99(d,
49 J= 8.7 Hz, 21-1), 4.71(s, 1I-1),4.61-4.51 (m, 31-1), 4.36-
4.31 (m, 111),4.10-4.00
0-'4NS (m, 7H), 3.98-3.82 (m, 2H), 3.67-3.63 (t, J= 6.0 Hz, 2H),
2.35 (s, 3H), 2.22-
4:1)
CN 2.12 (m, 1H), 2.12-2.09 (rn, 1H), 1.97-1.84
(in, 4H), 1.58(s, 6H), 1.04(s,
91-I); LC-MS (ES.): ink 971.45 [M11']
(2S,4R)-1-[(2S)-2-(2- (41444- (344-cyano-34 trifl uoromethyl )phenyl]-5,5-
dimethy1-4-oxo-2-sulfanyl ide ne ill iidazolidin-l-y11-3-
F1C --tµl
8 F. fit fluorophenyllphenoxy)butoxy Jacetamido)-3,3-Mmethylbutanoy11-
4-hydroxy-
N- f [4-(4-methy1-1,3-oxazol-5-yl)phenyl]methyl)pyrrolidine-2-catboxamide
46'
=..1
116
--1.. 1/1 NMR (400 MHz, DMSO) 6 8.66-8.61 (m,
III), 8.42 (d, J = 8.0 Hz, III),
9.,r0 8.35 (s, 1H), 8.29(s, 1H), 8.15 (d, ./ = 8.4
Hz, 1H), 7.76-7.64 (m, 4H), 7.53-
Htsy(1 7.40 (in, 6H), 7.05 (d, J= 8.8 Hz, 2H), 5.160- 1H), 4.58-4.27 (in,
5H), 4.09-
0 :?1,D 'OH 4.06 (m, 211), 3.96 (s, 211), 3.66-3.55 (m,
411), 2.33 (s, 311), 2.07-2.02 (m, 1H),
Nr 0
1.94-1.73 (m, 5H), 1.61 (s, 3H), 1.50 (s, 3H), 0.95 (s, 9H); LC-MS (ES): m/z
1026.30 [MW]
198
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Ex if Structure Compound name and Analytical data
( 2S,4R )-1-[(2S)-2-(2-{414-(4-(344-cyano-3-(trifluoromethyl)phenyl]-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-y1) -3-
F3Cv Q
fluorophenyl)phenoxy]butoxy)acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-
eN,
S [441,3 -thi azol-5-yl)phenyl) methyl )
pyrmlidine-2-carboxamide
117 NMR (400 MHz, DMSO) 69.04 (s, 1H), 8.60
(s, 1H), 8.42-8.35 (m, 211),
8.27(s, 1H), 8.14 (d, J = 8.0 Hz, 2H), 7.75-7.67 (m, 3H), 7.66 (d. J = 8.0 Hz,
OH 1H),7.59 (m, J = 8.4 Hz, 2H), 7A8 (t, J= 8.4
Hz, 1H),741-7.36 (m, 3H), 7.05
H1+01(s2.
(d. J = 8.8 Hz, 2H). 5.19 (s, 1H). 4.57 (d, J = 9.2 Hz, 1H). 4.58-4A4 (m,
NH
1H).4.42-4.34(m, 2H), 4.35-4.33(m, 1H), 4.08 (s, 2H), 3.96 (s. 2H), 3.66-3.55
(m, 4113,2.10-2.02 (m, 111), 1.89-1.72 (m, 511), 1.61 (s, 31-1), 1.50 (s, 31-
1), 0.95
(s, 9H); LC-MS (ES): ?W.:. 1028.30 [WI,
(25,4R)-1-1(2S)-2-(2-{414-(4-{344-cyano-3-(trifluoromethyl)pheny11-5,5-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-y1} -3-
NC-2-NN
fluorophenyl)phenoxy]butoxy)acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-
F3C S
N-{(4-(4-methy1-1,3-thiazol-5-yl)phenytimethyl}pyrrolidine-2-carboxamide
0
118 1H NMR (400 MHz, DM50) 68.96 (s. 1H), 8.61
(s. 1H), 8.42-8.35 I'm, 2H),
8.15 (d,J= 1.6 Hz, 2H), 7.76-7.64 (m, 4H), 7.51-7.39(m, 6H), 7.04 (d,J= 8.8
Hz, 211), 5.17 (s, 1I-1), 4.57 (d, J = 9.6 Hz, 1I-1), 4.56-4.38 (m, 311), 4.36-
4.27(m, 1H). 4.08 (s, 2H), 3.96 (s, 2H), 3.66-3.55 (m, 4H), 2.45(s, 3H), 2.10-
rSj ,NH
N..e,-
2.02 (m, 1H), 1.93-1.84 (m, 1H),1.84-1.82(m, 214),1.75-1.73(m, 2H), 1.61 (s,
3H), 1.50 (s, 3H), 0.94 (s, 9H); LC-MS (ES*): nit 1042.25 [M111
( 2S,4R )-1-[(2S)-2-(2- {41444- (744-cyano-3 -(tri fluoromethyl)phenyl] -8-oxo-
6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-
0,
N yl }phenyl)phenoxy]butoxy }acetamido)-3,3-
dimethylbutanoy11-4-hydroxy-N -
r10 ([4-(4-methy1-1,3-oxazol-5-
yl)phenyl)methyl)pyrrolidine-2-carboxamide
NMR (300 MHz, CD30D): 58.17-8.15 (d, J = 8.1 Hz, 21-1), 8.09 (s, Ill),
119 \-0 8.02-8.00 (d, = 8.7 Hz, 1H), 7.78-7.75 (d,
J= 8.4 Hz, 2H), 7.62-7.57 (m, 4H),
HN,OH4- 7.49-7.43 (m, 411), 7.04-7.01 (d, J = 8.7Hz,
211), 4.71 (s, 111), 4.62-4.53 (m,
31-1), 4.37-4.32(d, J. 15.3 11z, 111), 4.12-4.11 (m, 21-1), 4.09-4.01(m, 211),
3.96-
3.82 (m, 2H). 3.69-3.65 (m, 2H), 2.80-2.55 (m. 4H), 2.41 (s, 3H), 2.23-2.21
(m, 1H), 2.15-2.10 (m, 2H), 1.98-1.88 (m, 4H), 1.70-1.66(m, 111), 1.03(s,
9H); ir-rvis (ES): m/z 1020.35 [MH]
199
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Ex if Structure Compound name and Analytical data
( 2S,4R )-1-[(2S)-2-(2- {41444- (744-cyano-3-(tri fluorometbyl)phenyl] -8-oxo-
ait
F 11/4, IC
F F Y,/ % 6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-
yl}pbenylvbenoxy]butoxy}acetamido)-3,3-dirnetliylbutanoyl]-4-bydroxy-N-
thl
( [4-(4-metby1-1,3-thiazol-5-yl)phenyl] methyl } pyrrolidi ne-2-carboxamide
120
NMR (300 MHz, CD30D): 5 8.82 (s, 1I-1), 8.17-8.15 (d, J = 7.8 Hz, 21-1),
8.02-8.00 (d, J=8.1 Hz. 1H),7.78-7.75 (d. J = 8.4 Hz, 2H), 7.61-7.59 (d, J =
Cr 8.4 Hz, 2H), 7.48-7.42 (m, 6H), 7.04-7.01
(d,J = 8.7 Hz, 2H), 4.71 (s, 1H),
HNolk.
4.62-4.51 (m, 3H), 4.47-4.321d, J = 15.9 Hz, 1H), 4.12-4.10 (m, 2H), 4.08-
.p.OH
H 4.01(m, 2H). 3.96-3.82 (in, 2H), 3.69-3.65
(in. 2H), 2.80-2.55 (m, 4H). 2.48 (s,
311), 2.23-2.21 (m, 111), 2.14-2.10 (m, 111), 1.98-1.89 (m, 411), 1.70-1.66
(m,
1H), 1.03 (s. 9H); tr-ms (Es.): rn/z 1036.25 [MW]
(2S,4R)-1-1(2S)-2-( 21444- { 4-13-(3-chloro-4-cyanopheny1)-5,5-dimethy1-4-
NC-0..N9.4, oxo-2-sulfanylideneimidazolidin-1-Aphenyl }-3-
CI fluorophenoxy)butoxy]acetamido}-3,3-
dimethylbutanoy1]-4-hydroxy-N-f [4-
S
(1.3-oxazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide
121 1H NMR (300 MHz, CD-,0D):58.14 (s, 1 H),
8.00-7.91 (m, 1 H), 7.90-7.80 (m,
1 H), 731-7.58 (m, 5 H). 7.50-7.41 (m, 6 H), 6.90-6.71 (in. 2 H), 4.67 (s. 1
H),
HN1)4. 4.58-4.41 (m, 3 H), 4.30-4.22 (m, 1 I-1),
4.12-4.01 (m, 2 11), 3.99-3.94 (m, 2 11),
3.90 -3.70 (m, 2 H), 3.65-3.55 (m, 2 H), 2.22-2.13 (m, 1 H), 2.14-2.00 (m, 1
NH H), 2.00-1.72 (m, 4 H), 1.56(s, 6H), 1.01
(s,9 H); LC-MS (ES*): ,n',97830
[Mull
(2S,4R)-1-[(2S)-2-(2-{414-(4-(344-cyano-3-(trifluorometbyl)phenyl]-5,5-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
yl}phenyl)phenoxy]butoxy}acetamido)-3,3-dimethylbutanoylj-4-hydroxy-N-
F
S
( [4-(1H-pyrazol-5-yl)phenylimethyl } pyrrolidine-2-carboxamide
14 NMR (400 MHz, CD30D): 8.25-8.15 (m, 211), 8.05-8.00 (s, 1 14), 738-7.70
122
-1-101 (m, 4 H), 7.70-7.58 (tn. 3 H), 7.48-7.39 m,4
H). 7.08-7.00 (m, 2 HI, 6.69-
-T 6.60, (s, 1 H), 4.95-4.85 (s, 1 H), 4.65-
4.58 (s, 1 H), 4.554.49 (rn, 2 H), 4.40-
4 .30 (s, 1 11),4.15-4.08(m,2 11),4.05-4.00(m,2 1-1),3.90-3.85 (s, 111), 3.82--
3.75
(s, 1 H), 330-3.60 (m. 2 H), 2.28-2.20 (s, 1 H), 2.15-2.05 (s, 1 H). 1.98-1.89
II 144?-0¨/N11
(m, 4 H), 1.63-1.59 (m, 6 H)1.10-1.00(n,9 H); LC-MS (ES*): ner. 993.35
[MW]
200
CA 03069544 2020-01-09
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Ex if Structure Compound name and Analytical data
(25,4R)-1-((2S)-2-{2-[4-(4-{4-13-(3-chloro-4-cyano-2-fluoropheuyl)-5,5-
NC
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
C11.*f F yl]phenyllphenoxy)butoxy]acetamido} -3,3-
dimethylbutanoyl]-4-hydroxy-N-
s
([4-(1,3-oxazol-5-yl)phenyl]methyl Ipyrrolidine-2-carboxamide
123 0 14 NMR (400 MHz, CD30D) 68.21 (s, 114), 7.88-
7.87 (d, J = 1.6/1z, 1/1),
7.86-7.73 (m, 3H), 7.69-7.67 (d. J = 8.4 Hz, 2H). 7.61-7.59 (d, J=8.4 Hz.
0
f.) 21-1), 7.48-7.43 (rn, 5H), 7.05-7.02 (d, J = 8.8 Hz, 21-1), 4.88 (s,
1H), 4.73-4.59
HN
(m, 3H), 4.52-4.37 (d, J=15.2 Hz, 1H), 4.08-4.02 (m, 2H), 3.98-3.82 (in, 2H).
d'N").01-1
4-0 04¨ 3.89-3.88(m, 1H), 3.84-3.83(m, 1H). 3.69-
3.66 (t, J = 6.0 Hz, 2H), 2.23-2.20
Ns's '')-0,..AN (m, 1113,2.13-2.04 (m, 111), 1.97-1.88 (m,414), 1.62 (s, 61-
1), 1.04 (s, 91-1); LC-
MS (FS'): nez 978.26[MH]
(2S,4R)-1-1(2S)-2- ( 24444- (4-17-(3-chloro-4-cyanopheny1)-8-oxo-6-
CI
sullanylidene-5,7-diazaspiro[3.4]octan-5-
yl]phenyllphenoxy)butoxy]acetamido) -3,3-dimethylbutanoyl] -4-hydroxy-N-
qk(14-(1.3-oxazol-5-y1)phenyllmethyl}pyrrolidine-2-carboxamide
110,
õ\cp
124 1H NMR (400 MHz, CD-,0D) 5 8.18 (s, 1H),
7.99-7.96 (d, J = 8.4Hz, 1H), 7.89
(s. 1H), 7.79-7.77 (d, J= 8.4Hz, 211), 7.67-7.61 (m. 5H), 7.48-7.43 (m, 5H),
HN 7.06-7.04 (d, J= 8.8 Hz, 21-1), 4.88 (s, 1/1), 4.73-4.59 (m, 311),
4.52-4.37 (d, J
00 isp = 15.2 Hz, 1H), 4.14-4.11 m, 211). 4.05-4.02(m, 211), 3.99-3.83 (tn.
2H),
5---0NH 3.70-3.67(t, J= 6.0 Hz, 211), 2.66-2.62 (m, 411), 2.13-2.00 (m,
311), 1.98-1.88
(m, 4/1), 1.80-1.70 (m, 111), 1.04 (s, 911); LC-MS (ES): nez 972.25[MI1]
( 2S,4R )-1-[(2S)-2- ( 24444- (4-(3-(4-cyano-3-methylpheny1)-5,5 -ditnethy1-4-
oxo-2-su phenyllphenoxy)butoxy]
acetiunido 1-
e-N 3,3-dimethylbutanoy/J-4-hydroxy-N-([4-(1,3-
oxazol-5-
S
yl)phenyl]methyl }pyrrolidine-2-carlx)xamide
4.\
125 14 NMR (400 MHz, DMSO) 68.60 (t, J = 6.0 Hz,
111), 8.40 (s, 111), 7.97 (d,J
(t.,e0 =8.0 Hz, 111), 7.79 (d, J= 8.4 Hz, 2H), 7.67-7.63 (m, 611), 7.54 (d,
J = 8.4 Hz,
=OH 111), 7.44-7.39 (m, 511), 7.05 (d, J= 8.8 Hz, 211), 5.16(s, 111), 4.58-
4.56 (m,
1/1), 4.47-4.26 (m, 4113,4.08-4.05 (m, 211), 3.97 (s, 211), 3.66-3.57 (m, 41-
1),
NH
2.56 (s. 3H), 2.06-2.02 (m, 1H), 1.93-1.72 (m, 511). 1.52 (s, 611). 0.93 (s,
9H);
LC-MS (ES*): miz 940.30 [MI-11
201
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Ex if Structure Compound name and Analytical data
F (2S,4R)-1-[(2S)-2- ( 244 -(4 - (44344 -cyano-
3-fluoropheny1)-5,5 -dimethy1-4-
NC-6-1,1134-- oxo-2 -sulfanylideueimidazolidin -1-yl] phenyl
}phenoxy)butoxy]acetamido)-
__ NI
t -0, 3,3-climerhylbutanoy1]-4-hydroxy-N- ([4-0 ,3-
oxazol-5-
a..., yOphenyl]methyl}pyrrolidine-2-carboxamide
126
-"VS....? 'H NMR (400 MHz, DMSO) 8 8.60 (t, J = 6.0
Hz, 1H), 8.40(s, 1H), 8.15 (d, J
HN- ,OH = 8.0 Hz, 111), 7.85-7.78 (m, 31-1), 7.67-
7.63 (m, 611), 7.43-7.39(m, 511), 7.05
00P (d...1= 8.8 Hz, 2H). 5.16 (s, 1H). 4.58-4.56
(m, 1H), 4.47-4.26(m, 4H), 4.08-
65_021H
N 4.05 (m, 2H), 3.97 (s, 2H), 3.66-3.55 (m,
4H), 2.06-2.02(m, 1H), 1.93-1.72
(m, 5H), 1.53 (s, 6H), 0.95 (s, 9H); LC-MS (FS): nez 944.50 [MI-1]
(2S,4R)-1-[(2S)-2-(2-(413-(4-(344-cyano-3-(trifluoromethyl)pheny11-5,5-
0 dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
4..
yl)phenyl)phenoxy)phenoxy)acetamido)-3,3-dimethylbutanoy1]-4-hydroxy-N-
F3c r
NC-2-Ne S .-, -...
.1 1 ( [4-(4 -methy1-1,3-thiazol-5-y1)pheny 1]
methyl Ipyrrolidiue-2-carboxamide
..,e
127 H 'H NMR (300 MHz, CD30D):68.81 (s, 1 1-0,
8.14-8.05 (m, 2 H), 8.00-7.95 (m,
1:?..?11.k. 1I-I), 7.75-7.69 (m, 211), 755-7.32(m, 8 II), 7.20-7.15 (m, 1
11), 7.10-7.00 (m,
op" 1-1 4 H), 6.99-6.85 (m, 1 H), 4.68 (s, 1 H),
4.65-4.60 (m, 2 H), 4.63-4.55 (m, 1 H),
0.
1,.?--0....,NH 4.50-440(m, 211), 4.30-4.20 (m, 1 H), 3.90-3.80 (m, 1H),
3.75-3.65 (m, 1 H),
2.40(s, 311), 2.25-2.21 (m, 1 113,2.14-2.00 (m, 111), 1.55 (s,6 II), 0.99 (s,9
H); Le-ms (ES): m,'z, 1044.30 [M1-1]
(2S,4R)-1-1(2S)-242-(3-(14-(4-(3-14-cyano-3-(trifluoromethyl)phelly1:1-5,5-
jr (Th H chmethvi-4-oxo-2-sulfanvhdeneimidazolidin-1-
. -
yl)phenyl)phenylimetboxy}propoxy)acetamidol-3,3-dimethylbutanoy11-4-
Yhydroxy-N-( [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pprolidine-2-
J carboxamide
128
'H NMR (400 MHz, CD30D): 68.85 (s, 111), 8.20 (m, 211), 8.02 (d, J = 8.4
Hz, 111), 7.80 (d, J= 7.6 Hz, 211), 7.66 (d, J= 8.0 Hz, 211), 7.48 (m, 611),
739
c
j,-0 -
(m, 2113,4.71 (s, 1113,4.61 (m, 511), 4.34(m, 1H), 4.01 (in. 2H), 3.84 (m,
2H).
F
A 3.72 (m, 411), 2.45 (s, 311), 2.25 (m, 1H),
2.12 (m, 111), 1.97(m, 211), 1.62(s,
6H), 1.02 (s, 9H); ir-rvis (ES): nez 1024.20 [MF1']
(2S,4R)-1-[(2S)-2-(2- (4-14-(4-(344-cyano-3-(trifluoromethyl)pheny1]-5,5-
HQ dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
y1}phenyl)phenoxy]-3-
o 24S:i.1-11 hydroxybutoxy}acetamido)-33-
dimethylbutanoy1)-4-hydmxy-N-([4-(4-
) NH 0 ,
Clj- '\ methyl-1,3-thiazol-5-
5/1)phenyl]methyl)pyoolidine-2-carboxamide
r-,
(21or-bH
129 6rt
1., ... 'H NMR (400 MHz, CD30D) 68.82 (s, 111), 8.20
(m, 211), 8.03 (m, 111), 7.74
0 -
(m, 211), 7.60 (m, 2/1), 7.48 (m, 61-1), 7.07 (m, 211), 4.74 (m, 1 /1), 4.60-
4.53 (m,
,.'% 3H).4.37 (in. 1H),421 (m, 111), 4.08
(m,411), 3.92-3.88 (m, 111), 3.83-3.75
F3C ;:i?,
(m, 3H), 2.49 (s, 3H), 2.26 (m, 1H), 2.14 (m, 2H), 1.87(m, 1H), 1.62 (s, 6H),
1.03 (s, 91); 1_C-MS (ES): /Mr. 1040.25 [MW]
202
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Ex if Structure Compound name and Analytical data
( 2S,4R )-1-[(2S)-2-{ 2-[(2R)-414-(4- ( 344-cyano-3-(tri fluorometbyl)phenyl] -
HQ
5,5-dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-y1 1phenyl)phenoxy1-2-
hydroxybutoxy]acetamido}-3,3-dimethylbutanoy1]-4-hydroxy-N-f [4-(4-
o
o.--' J methyl-1,3-thiazol-5-yl)phenyl]methyl
}pyrrolidine-2-carboxamide
/-1
130 Ill NMR (400 MHz, CD30D): 5 8.81 (s, 1H),
8.18 (d, J = 8.4 Hz, 211), 8.04 (d,
J=8.4 Hz, 1H). 7.71 (s, ./ = 8.4 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.44 (m,
614), 7.02 (d, J = 8.8 Hz, 2H), 4.71 (s, 1H), 4.56 (in, 3H), 4.33 (m, 111),
4.17
(m, 2H), 4.05 (m, 3H), 3.75 (m, 2H), 3.65(m. 2H), 2.44(s. 3H), 2.22 (m, 1H),
2.08 (m, 2H). 1.90 (m, 1H), 1.60 (s, 6H), 1.05 (s, 9H); LC-MS (ES*): trth
1040.20 [M}1
(2S,4R)-1-[(2S)-2-{ 2-[(2S)-4-[4-(4-(314-cyano-3-
(irifluoromethyl)pheny1]-5,5-dimethyl-4-oxo-2-
, sulfanylideneimidavandin-l-
yl)phenyl)phenoxy]-2-
P
o ) hydroxybutoxylacetamido)-3,3-
dimethylbutanoy1]-4-hydroxy-N-( [444-
9 'HQ -
methy1-1,3-thiazol-5-Aphenyl]methyl}pyrrolidine-2-carboxamide
a`-1-j
131 f"--(
'H NMR (400 MHz, CD30D): 5 8.84 (s, 1H), 8.18 (d, J= 8.4 Hz, 2H), 8.04(d,
J= 8.4 Hz, 1H), 7.71 (s, J = 8.4 Hz, 2H), 7.57 (d, J= 8.8 Hz, 2H),7.44 (m,
6H), 7.02 (d, J= 8.8 Hz., 2H), 4.71 (s, 1H), 4.56 (tn. 3H), 4.33 (m, 1H), 4.17
(.. 2H), 4.05 (in, 3H), 3.90 (m, 1H), 3.83 (in. 1H), 3.60 (m, 2H), 2.44 (s,
3H),
2.22 (m, 111), 2.08 (m, 211), 1.90 (m, 111), 1.60 (s, 611), 1.05 (s, 911); LC-
MS
m/z 1040.20 [ME],
(2S,4R)-1-1(2S)-2-( 214-(4-(443-(3-chloro-4-cyanopheny1)-5,5-dimethyl-4-
HQ
oxo-2-sulfanylideneimidazolidin-1-yl)phenyl }phenoxy)butoxy)acetamido}-
, `=7 õ
3,3-dimethylbutanoyl] -4 -hydroxy-N-R1S)-144-(1,3-oxazol-5-
Aphenyflethyljpyrrolidine-2-carboxamide
132 7.;1/4(
'H NMR (300 MHz, CD30D): 5 8.22 (s, 1H), 7.97-7.95(d, ./ ¨ 84 Hz, 1H),
7.89-7.88 (d,J=1.8Hz, 1H), 7.75-7.58 (m, 7H), 7.47(s, 1H), 7.43-7.38(m, 4H),
!JD
4- 7.06-7.01 (d, J=14.1 Hz, 211) ,5.00 (m,
111), 4.69 (s, 111), 4.61-4.55(m, 1H),
cps*1õ,8
4.44(s, 1H), 4.13-4.09 U. J=6.0 Hz, 2H). 4.02-4.00 (d, Hz.
2H), 3.87-
3.76 (in, 2H), 3.68-3.64 (in, 2H), 2.19-2.16(m, 1H) ,2.03-1.84 (in, 5H), 1.58
(s,
re 611), 1.49-1.47(d, J=6.9 Hz, 311) 1.04(s,
911); LC-MS (ES'): m/z 974.20,
976.20 (M11+1
203
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Ex It Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-2- ( 244 -(4 - (443-(5-chloro-4-cyano-2-fluoropheny1)-5,5 -
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
NC yl)phenyl } phenoxy)butoxy)acetamido)-3,3-
dimethylbutanoy1)-4-hydroxy-N-
0i rola
( [4-(1,3-oxazol-5-yl)phenyl]methyl )pyrrolidine-2-carboxamide
133
\-CLe 1H NMR (300 MHz, CD30D) 88.23 (s, 111), 8.18-
7.94 (m, 2H), 7.74-7.65 (m,
N- H 61-1), 7.50-7.40(m, 511), 7.04-7.01 (d,J =
8.71-1z, 21-1), 4.71 (s, II-1), 4.60-4.56
(m, 3H), 4.53-4.34 (d, J = 15.2Hz, 1H), 4.12-4.08 (m. 2H), 4.08-4.01 (m, 2H).
ta<50)---1.11.1 3.96-3.82(m, 211), 3.69-3.65 (m, 2H), 2.23-
2.20 (m, 1H), 2.13-2.04(m, 1H),
1.98-1.85 (m, 4H), 1.59 (s, 6H), 1.05 (s, 9H); le-MS (ES'): miz 978.26[MH1
(2S,4R)-1-[(2S)-2-(2-(414-(4-(344-cyano-3-(trifluoromethyl)pheny11-5,5-
H
Hop dimethy1-4-oxo-2-su Ifanylidenei midazolidin
- 1 -y1) pheny1)-2-
'- ,N
methylphenoxy]butoxy }acetamido)-3,3-dimethylbutanoy1]-4-hydroxy-N4 [4-
0,7,NH c")
(4-methy1-1,3-thiazol-5-y1)phenyl]methyl }pyrrolidine-2-carboxamide
134 ,r-NA NMR (400 MHz, DM50): 6 8.96(s, 1113,8.61
(m, 1H), 8.42(d, J =7.6 Hz,
I I-1), 8.33 (s, II-1), 8.13 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, 211),
7.43 (d, J
= 10.4 Hz, 7H), 7.19 (d, J = 8.0 Hz, 1H), 6.83-6.89 (m, 2H), 5.17 (m, 1H),
4.59
' N
0 N S (d, J =9.6 Hz, 111), 4.40-4.48 (m, 111),
4.37-4.38 (in, 211), 4.25-4.29(m, Ili),
F r 4.02-4.05 (m, 2113,3.97 (s, 2113,3.55-3.69
(m, 411), 2.45 (s, 311), 2.25 (s, 311),
2.05-2.10 (m, 111), 1.91-1.93 (m. 1H), 1.81-1.84 (m, 211). 1.72-1.75 (m, 211),
1.55 (s, 611), 0.95 (s, 911): LC-MS (ES*): int 1038.35 [MW]
(2S,4R)-1-[(2S)-242-(3-([4-(4-(344-cyano-3-(trifluoromethyl)pheny11-5,5-
dintethyl-4-oxo-2-sulfanylideneimidazolidin-1-
NC-Wv,
yl ) phenyl )phenyl)carbarnoyl) propoxy)acetamido] -3,3-dimethylbutanoyl] -4-
F3C k'44
S 44,-) hydroxy-N-( [4-(4-methyl-1,3-oxazol-5-
yl)phenyl]methyl }pyrrolidine-2-
carbox amide
HNq
135
1/1 NMR (400 MHz, CD30D) 68.19-8.16 (d, J = 12.41-1z, 21-1), 8.13 (s,
8.04-8.01(d. J = 10.8Hz, 111). 7.78-7.75 (d, J = 11.2Hz, 211), 7.75-7.60(m,
0 N)OH 611), 7.57-7.44 (m, 411), 4.87 (s, 111),
4.73-4.57 (m, 311), 4.52-4.37 (d, J = 15.2
tsitiLdS4 Hz, 1H), 4.10-4.05 (m, 2H), 3.96-3.83 (n,
2H). 3.70-3.66(m, 2H), 2.59-2.54
(t, J = 9.6 Hz. 2H), 2.36(s. 3H), 2.24-2.22 (m, 111). 2.17-2.04 (m, 311), 1.05
(s,
61-1), 1.03 (s, 91-1); LC-MS (ES`): tntz 1021.25[mi1'l
204
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Ex if Structure Compound name and Analytical data
HQ __________________________________________________________________________
e- (2S,4R)-1-[(2S)-2-(2-1414-(4-(344-cyano-3-
(trifluoromethyl)pbenyl]-5,5-
-415:01 dimethy1-4-oxo-2-sulfanylideneimidazolidin-l-y1}pheny1)-3-
.401 0
methylphenoxylbutoxy}acetamido)-3,3-dimethylbutanoy1]-4-hydroxy-N-([4-
)-- (4-methyl-1,3-thiazol-5-
yl)phenyl]methyl}pyrrolidine-2-carboxamide
r' --N
136
d
,-( \ ,H NMR (400 MHz, CD30D): 8 8.80(s, 1H), 8.15-8.18 (m. 2H), 7.99-
8.02 (in,
1H), 7.72 (d, J = 8.4 Hz, 211), 7.38-7.47 (m, 8H), 6.98 (d, J = 8.8 Hz, 1H),
4.70
o---/ ......
N 0 (s, 1H),4.50-4.60 (m, 3H), 4.31-4.34 (m,
1H), 3.96-4.11 (m, 4H), 3.81-3.87
F4-6 (m, 2H), 3.65-3.68 (m, 2H), 2.43 (s, 3H),
2.26 (m, 4H), 2.09 (m, 1H), 1.87-
F I
A 1.98 (m, 411), 1.59 (s, 611), 1.04 (s, 911);
LC-MS (ES`): miz, 1038.40 [M/I]
1 (2S,4R)-I -R2S)-2-(2-{414-(4-{344-cyano-3-
(trifluoromethyl)pheny11-5,5-
NC-0.FsC dimettly1-4-oxo-2-sulfanylideneimidazolidin-
l-y1}-3-
-' 11.Nr
SF-- (-
fluorophenyl)phenoxy]butoxy )acetamido)-3,3-dimetliylbutanoyl]-4-hydroxy-
N-R 1 S)-144-(4-metby1-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-
carboxamide
C401
137
Ili NMR (400 MHz, DMSO) 88.99 (s, Ili), 8.46-8.40 (rn, 211), 8.36 (s, 111),
AO
LO; 8.15 (d, J = 8.0 Hz, III), 7.78-7.67 (m,
4I1), 7.45-7.35 (m, 61-1), 7.09 (d, J= 8.8
HN/o
Hz, 2H), 5.15 (s, 1H), 4.93-4.89 (m, 1H), 4.57 (d, J= 9.6 Hz, 1H), 4.46-4.39
Iri.1,000TI,P H (m, 111), 4.30(s, 111), 4.11-4.08 (rn, 211),
3.96 (s, 211), 3.60-3.56 (m, 411), 2.46
NH (s, 3H), 2.07-2.03 (m, 1H), 1.84-1.74 (m,
5H), 1.62 (s, 3H), 1.50 (s, 3H), 1.38
(d,./ = 6.8 Hz, 3H), 0.95 (s, 9H); LC-MS (ES): tn/2,- 1056.30 [MH]
, ___________________________________________________________________________
(2S,4R)-1-[(2S)-2-(2-{414-(4-(344-cyano-3-(trifluorometliy1)plieny11-5,5-
dimettly1-4-oxo-2-sulfanylideneimidazolidin-l-y1}-3-
NC-0_1,13,/ fluorophenyl)phenoxy]butoxy Jacetamido)-3,3-
dimethylbutanoy1]-4-hydroxy-
I: .0 ry..., N-RIS)-114-(4-merhyl-1,3-oxazol-5-yl)phenyl]
ethyl] pyrrolidine-2-
Cao-Z carboxamide
0-i
138 1 'H NMR (400 MHz, DMSO) 8 8.46-8.40 (m, 21-
1), 8.36 (s, 11-1), 8.31 (s, 11-1),
-NO 8.15 (d,J = 8.4 Hz, 1H), 7.78-7.67 (m. 4H),
7.57-7.48 (m, 311), 7.40-7.35 (m,
HN.t" OH
311). 7.09 (d, J= 8.4 Hz, 211), 5.15(s, 111), 4.93-4.89 (m, 1H), 4.57 (d, J=
9.2
0 .p.
Hz, III), 4.46-4.40 (m, 111), 4.28 (s, 1I1), 4.11-4.07 (m,211), 3.96 (s, 211),
3.59-
Ni7---001 NH 3.56(m. 4H), 2.35 (s. 3H), 2.07-2.03 (m,
111), 1.84-1.73 (m, 511), 1.62 (s, 311).
1.51 (s,311), 1.39 (d, J= 6.4 Hz, 311), 0.95 (s, 9H); LC-MS (ES*): nez 1040.25
1M111
205
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Ex if Structure Compound name and Analytical data
( 2S,4R)-1-[(2S)-2-(2- {41444- [ 344-cyano-3-(tri fluoromethyl)phenyl] -5,5-
F r
N4:). 9 ,
dimethy1-4-oxo-2-sulfanylideneimidazolidin- 1 -yl}pheny1)-2-
N metlioxyphenoxy]butoxy facetamido)-3,3-
dimethylbutanoy1]-4-hydroxy-NI
dr- [4-
(4-merhyl-l3-thiazol-5-y1)phenyl]methyl}pyrrolidine-2-carboxamide
139
01.1.
'll NMR (400 MHz, DMSO) 68.96 (s, 111), 8.61 (s, 111), 8.41 (d, J= 8.4 Hz,
(t_to 1H), 8.33(s, 1H), 8.11 (d, J= 8.0 Hz, 1H),7.83 (d, J = 8.4 Hz, 2H),
7.45-7.40
HNik" (in, 711),7.30-7.23 (m, 211), 7.06 (d, J =
8.4 Hz, 1H), 5.17 (s, 1H), 4.57 (d, J =
o ..p.43H 9.2 Hz, 1H), 4.46-4.36 (m, 3H),
4.30-4.28 (m, 1H), 4.06-4.03 (m, 2H), 3.96 (s,
o
2H). 3.86 (s, 3H). 3.67-3.56 (m, 4H), 2.44 (s, 3H), 2.08 (s, 1H), 1.85-1.75
(in.
511), 1.55 (s, 6H), 0.95 (s, 9H); LC-MS (ES*): Int 1054.25 [M11]
(2S,4R)-1-[(2S)-2-(2-1414-(4-(3-[4-cyano-3-(trifluoromethyl)pheny1]-5,5-
9" dimethy1-4-oxo-2-sulfanylideneimidazolidin-l-
ylipheny1)-3-
methoxyphenoxy]butoxy }acetanlido)-3.3-dimethylbutanoy1]-4-hydroxy-N-( [4-
o
).-NH Or)
r-P- S--1 (4-methy1-1,3-thiazol-5-y1)phenyl]methyl}pyrrolidine-2-
carboxamide
140 'H NMR (400 MHz, DMSO) 5 8.96 (s, 1H),8.61
(s, 1H),8.41 (d, J = 8.4 Hz,
1H), 8.33 (s, 1H), 8.12 (d,./ = 1.6 Hz, 1H), 7.64 (d,./ = 8.4 Hz, 2H), 7.43-
7.37
N s (m, 7H), 7.28 (d, J = 8.4 Hz, 1H), 6.68-6.61
(m. 2H), 5.17 (s. 1H), 4.57 (d, J =
9.6 Hz, 111), 4.46-4.36 (m, 311), 4.30-4.28 (m, 114), 4.06-4.03 (m, 211), 3.96
(s,
211). 3.86(s, 311). 3.67-3.56 (m, 4H), 2.44 Is, 3H), 2.08 Is, 1H), 1.85-1.75
(tn.
5H), 1.56 (s, 6H), 0.95 (s, 9H), LC-MS (ES): m/z 1054.25 [MH1
(2S,4R)-1-[(2S)-2-(2-1[(4S)-444-(4-1344-cyano-3-trifluommethyl)phenyll-
m9 5,5-dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
õ
yl }phenyl)phenoxy]pentyl]oxyJacetarnido)-3,3-dimethylbutanoy1]-4-hydroxy-
5.-N.H b Or"\ N-1[4-(4-methy1-1,3-thiazol-5-
y1)phenyl]methyl}pyrrolidine-2-carboxamide
I
(2S,4R)-1-[(2S)-2-(2-{[(4R)-444-(4-1314-cyano-3-(trilluoromethyl)phenyl]-
, 0_
5,5-dimethy1-4-oxo-2-sulfanylideneimidazolidin-l-
os yl J phenyl )phenoxy)pentyl]oxy }acetamido)-
3,3-dimethylbutanoy1]-4-hydroxy-
T. N-1 [4-(4-methy1-1,3-thiazol-5-
yl)phenyl]methyl pyrrolidine-2-carboxamide
F. 6
141, e r
142 H9 1H NMR (400 MHz, CD30D) 5 8.84 (s, 1H), 8.19-
8.17 (d, J = 8.0Hz, 2H),
õ 4 8.04-8.02 (d, J= 8.411z, 7.75-7.73 (d, J = 8.411z,
2H), 7.60-7.58 (d,J =
2,
C5--N.H 8.4Hz, 2H), 7.49-7.41 (m, 6H), 7.03-7.01 (d,
J = 8.8Hz., 211). 4.87(s, 111).
P- 4.73-4.58 (m, 4H), 4.50-4.39 (d, J = 15.2 Hz, 1H), 4.02-4.00(m,
211),
_
3.88 (m, 111), 3.84-3.83 (m, 111), 3.64-3.62 (m, 211), 2.46 (s, 311), 2.25-
2.23
(m, 1H), 2.13-2.11 (m. 1H), 1.86-1.78 (m, 4H), 1.62(s, 6H). 1.37-1.34 (m, 3H).
CL?I 1.12 (s, 9H): LC-MS (ES*): m/z 1038.15[MH]
irks
1H NMR (400 MHz, CD30D) 5 8.84 (s, 1H), 8.19-8.17 (d, J= 8.0Hz, 2H),
Fr
8.04-8.02 (d, J= 8.411z, 111), 7.75-7.73 (d, J= 8.411z, 211), 7.60-7.58 (d, J
=
8.4Hz, 2H), 7.49-7.41 Im, 6H), 7.03-7.01 (d,./ = 8.8Hz, 2H), 4.87 (s, 1H),
206
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Ex if Structure Compound name and Analytical data
4.73-4.58 (m, 411), 4.50-4.39 (d, J = 15.2 Hz, III), 4.02-4.00(m, 211), 3.91-
3.88 (m, 1H). 3.84-3.83 (in, 1H), 3.64-3.62 (m. 2H), 2.46 (s, 3H), 2.25-2.23
(m, 111), 2.13-2.11 (m, 1H), 1.86-1.78 (m, 4H), 1.62(s, 6H), 1.37-1.34 (m,
311),
1.12 (s, 9H); 1..C.-MS (ES.): 1038.15[MH1
(2S,4R )-1-[(2S)-2-[2-(4- { [4-(4 -1344-cyano-3-(trillucrromethyl)phenyl]-5,5-
d i methy1-4-oxo-2-sulfanylideneimidazolidin -1-
HQ.
Fro)itp yi) phenyl )phenyl)amino J butoxy)acetamido)-
3,3-dimerhylbutanoyl] -4-
I lydroxy-N-RIS)-114-(4-methyl-1,3-oxazol-5-y1)phenyl] ethyl]pyrrolidine-2-
carboxamide
=
tiHr
143 'H NMR (400 MHz, CD30D) 5 8.20-8.17 (m,
3II), 8.03-8.01 (d, J = 8.1Hz,
1H). 7.73-7.71 (d, = 8.4Hz. 2H), 7.70-7.67 (d,J = 8.4Hz, 2H), 7.63-7.61 (d,
= 8.4114 211), 7.52-7.40 (rn, 41-1), 6.78-6.76 (d, J = 8.4Hz, 2H), 5.02-
5.00(m,
0'414.3..s 111), 4.87 (s, 111), 4.62-4.60 (m, 111),
4.58-4.56 (m, 1I1), 4.07-4.00 (m, 2I1),
3.88-3.85 (m, 1H), 3.78-3.77 (in, 1H), 3.65-3.63 (m, 2H). 3.23-3.22 (m, 2H),
2.41 (s, 3H), 2.24-2.22 (m, 111), 1.97-1.96 (m, 111), 1.80-1.70 (rn, 4H), 1.61
(s,
611). 1.49-1.48 (d, =4.4Hz. 3H), 1.04 (s. 9H); IC-MS (ES): in/z.
1021.25[MH1
(2S,4R)-1-[(2S)-242-( { 515 -(4- (344-cyano-3-(trifluoromethyl)phenyl] -5,5-
dimethy1-4-oxo-2-sulfanylideneimidazolid in-1-y1) phenyl)pyfidin -2-
NC
yllpentyl}oxy)acetamido]-3,3-dimethylbutanoy1]-4-hydroxy-N-([4-(4-methyl-
S
1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide
144 11-1 NMR (400 MHz, CD30D): ö9.01 (s, 1 H),
8.89(s, 1 H), 8.72-8.70 (m, 1
o. pH H), 8.21-8.18 (m, 211), 8.04-7.96 (m, 4 H),
7.65-7.47 (m, 2 H),7.46-7.38 (m, 4
H), 4.731s, 1 H), 4.63-4.50 (m, 3 H),4.41-4.37 m, 1 H), 4.05-3.99 (m, 2 H),
0
0 3.89-3.85 (m, 1 H), 3.85-3.84m (m, 1 H),
3.63-3.60 (m, 2H), 3.14-3.10(m, 2
H), 2.45 (s, 3 H),2.30-2.28 (m, 1 /0, 2.15-2.03 (m, 1 H),1.94-1.93 (m, 211),
S
. 1.78-1.76 (m, 2 H), 1.63-1.59 (m, 8 I-1).
1.01 (s, 9 H); LC-MS (ES'): miz
N
1023.45[MH1
207
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Ex if Structure Compound name and Analytical data
( 2S,4R )4 -[(2S)-2-1.2-( 41 [444- (344-cyano-3-(tri fluoromethyl)phenyl] -5,5-
89 dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-
icSb.--4ot ' yliphenyl)phenyl]amino)butoxy)acetamido]-3,3-
dimethylbutanoy1]-4-
hydroxy-N-[(1S)-114-(4-methy1-1,3-thiazol-5-yl)phenyl]ethyl)pyrrolidine-2-
:_f
r" carboxamide
145
1jisiH
1H NMR (300 MHz, CD30D) 8 8.95 (s, 1H), 8.19-8.16 (d, J = 8.7Hz, 2H),
8.03-8.00(d, J= 8.1Hz, 111), 7.87-7.82 (rn, 4H), 7.53-7.37 (m, 8H), 5.01-4.99
o tr..k.s
F (m, 1H), 4.87 (s, 1H), 4.70-4.68 I m, 1H), 4.56-4.54 (m,
1H), 4.08-4.05 (m,
,
2H). 3.83-3.80 (in, 2H), 3.70-3.59 (in. 2H), 3.52-3.47 (m, 2H). 2.48 (s, 31-
1).
2.24-2.22 (m, 1/1), 1.98-1.89 (m, 511), 1.61 (s, 611), 1.61-1.60 (in, 1I-1),
1.56-
1.54(m, 2H), 1.03 (s, 9H); ir-ms (ES*): m/z 1037.10[MH1
Hy,....., (25,4R)-1-1(2S)-2-(2-{414-(4-{344-cyano-3-
(trifluorometbyl)pheny1]-5,5-
4-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1-y1) -3-
--b11 i
te
or t4i.i 0 0 (....,\ j fluorophenyl)phenoxy]butanamtdolacetamido)-
3,3-dimethylbutanoyl]-4-
H hydroxy-N-( [4-(4-methyl-1.3-thiazol-5-
yl)phenyl]methyl}pyrrolidine-2-
N
r% t- .C'--
.- carboxamide
146
er-Ci 'H NMR (400 MHz, CD300) 8 8.87 (s. 1H), 8.19
(m, 2H), 8.05 (in, 1H), 7.64
Oa (d, J= 8.8 Hz, 2/1), 7.59 (m, 2H), 7.49 (m, 3/1), 7.41
(in, 2/1), 7.04 (d, J= 8.8
irj....s F
Hz, 2H), 4.88 (s, 1H), 4.66 (n, 3H), 4.38 (m, 1H), 4.11 (m, 2H), 3.92 (m, 3H),
r
F3ci -N, 3.80 (m,1H), 2.54 (m, 2H), 2.47 (s, 311), 2.23-2.09 (in,
4H), 1.68 (s, 311), 1.57
d (s, 311), 1.05 (s, 911); LC-MS (ES*): m/z 1055.10 [MI41
H9
.. (25,4R)-1-[(2S)-2-(2-{[(2S)-544-(4-1344-
cyano-3-(trifluoroiliettly lyplienylj-
' 1 H
_. k: 5,5-dimethy1-4-oxo-2-
sulfanylideneimidazolidin-1-yl}phenyl)phenoxy]pentan-
o, i''''
s\-5 2-ylloxy}acetamido)-3,3-dimethylbutanoy1]-4-
hydroxy-N-(14-(4-methyl-1,3-
e
thiazol-5-yl)phenyl]methyllpyrrolidt ne-2-carboxiunide
6-14
0
(1
(2S,4R)-1-[(2S)-2-(2-([(2R)-544-(4-1344-cyano-3-(trifluoromethyl)phenyl]-
, .._, 5,5 -di methy1-4-oxo-2-su
Ifanylideneimidazolidin-l-y1) phenyl)phenoxy]pentan-
N
. N s 2-yfloxy}acetamido)-3,3-dimethylbutanoy11-4-
hydroxy-N-([4-(4-methyl-1,3-
.--,
thiazol-5-Aphenyl]methyl}pyrrolidine-2-carboxamide
147, i
N
148 19
CI H 1H NMR (400 MHz, CD301.)): 5 8.88 (s, 1H) ,
8.18-8.15 (in, 2H), 8.02-8.00 (d,
- ----4`4. -14µ. J= 8.4 Hz, 1/1), 7.72-7.70 (d, J= 8.8 Hz,
211), 7.58-7.55 (d, J= 8.8 Hz, 211),
13NH,0
7.47-7.38(m , 6H), 7.01-6.99 (d,J = 4.8 Hz, 2H), 4.86 (s, 1H), 4.58-4.50 (m,
9")
,..r4s si.-...__ 31-1), 4.35-4.31 (m, 1H), 4.09-4.05 (m, 3H), 3.86-
3.81 (in, 311), 3.71-3.61 (m,
: 1/1), 2.47 (s, 3/1), 2.37-2.23 (m, 1113,2.11-
2.09 (m, 111), 2.02-1.87 (m, 211),
= 1.84-1.68 (m, 2H), 1.59 (s, 6H), 1.26 (s, 3H), 1.02 (s, 9H); LC-MS (EV.):
m/z
dlik 1038.10 [MW]
= 0 ,
04.6 'H NMR (400 MHz, CD30D): 8 8.88 (s, 1H) .
8.18-8.15 (m, 2H), 8.02-8.00 (d,
0 4 J= 8.4 Hz, 1H), 7.72-7.70 (d, J = 8.8 Hz, 2H), 7.58-7.55
(d, J= 8.8 Hz, 2H),
....._
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Ex It Structure Compound name and Analytical data
7.47-7.38 (m .611), 7.01-6.99 (d,J = 4.8 Hz, 211), 4.87 (s, 111), 4.70-4.50(m,
3H). 4.36-4.32 (in, 1H), 4.09-4.00 (in. 4H), 3.86-3.81 (m, 3H). 2.47 (s, 3H).
2.37-2.23 (m, 1H),2.11-2.09 (in, 1H), 2.00-1.85 (in, 2H), 1.84-1.68 (m, 211),
158 (s, 6H). 1.23 (s, 3H).1.01 (s, 91-1): IC-MS (ES.): m/z 1038.10 [MI-1]
(2S,41t )-1-[(2S)-2-(2- {414441 344-cyano-3-(trifluoromethyl)phenyll -5,5-
(?.H
dimethy1-4-oxo-2-sulfanylideneimidazolidin-1 -yl)phenyl)-3-
fluorophenoxy]butoxy }acer.amido)-3.3-dimethylbucanoy1)-4-hydmxy-N-{ [4-
0
(:)-2 (4-illedly1-1,3-thiazol-5-y1)phenyl]methyl}pyrrolidine-2-
earboxamide
149 tN
NMR (400 MHz, CD301)): 8.80 (s, 1H).8.18-8.12 (m,2
8.00-7.95 (s, 1
II), 7.65-7.60 (m, 2 /0, 7.45-7.35 (m, 7 11), 6.88-6.72 (m, 2 I-1), 4.65 (s,
111),
-s 4.6J-452(s, 1 H), 4.50-4.35 (m, 2 H), 4.32-
4.22(s, J H), 4.18-4.02 (m, 2 H),
4.00-3.94 (m, 2 H),3.95-3.75 (m, 2 H), 334-3.55 (in, 2 H),2.40 (m, 3 H), 2.28-
2.15(s, 111), 2.14-2.01 (s, 1 H),2.00-1.72 (m, 4 11),1.68-1.48 (m, 6 /1),
1.00(m,
9 I I ): LC-MS (ES miz 1042.05 [MW]
[0599] Examples 135, 143-145 were synthesized according to similar procedures
described for
the synthesis of examples 103, by using corresponding starting materials and
intermediates.
[0600] Synthesis of example 103:
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(Boc),ci. K2co, - , 2 t4c)Cic:
H2N¨e1-0¨NH2 ________________ H2N--/ \ / NHBoo TMSCN 1
SteP 1 Step 2
,,NCS
rd j
r4C---tv FIN
cF, HO
NHSoc - * NH2
DMAP ,... 14...1( Step 4 N..,/
170Ac, Nal:FTA(0A :':5
Step 3 p $ , = NNS Step 5
NC NC
CF3 CF3
0
0 1 __
gpN.,-.....--,.Ø....kcy)K. ¨7.1 3
.
N,I 1 H
NC 40 s
NC cir 3
CF3
HN- pH
N,...--....õ..-.,_,,0õ..)1jtii.
/ 1,4Ha '=:',N 10/ N-i H
NH
HC1 S 0
HATU, CHPIEA. DMI, NC
CF3 Example 103
s 1110
Step 7
t-k .
[0601] Step 1: Synthesis of tert-butyl N44-(4-aminophenyl)phenyflcarbamate:
H2N NHEloc
=
[0602] To a stirred solution of 4-(4-aminophenyDaniline (15.0 g, 81.42 mmol)
in a mixed
solvent of N,N-dimethylformainide / tetrahydrofuran /water (v/v/v = 100/300/50
mL) was added
potassium carbonate (9.5 g, 68.74 mmol) and di-tert-butyl dicarbonate (13.67
g, 62.63 mmol) at
room temperature. The resulting mixtire was stirred for 5h at room
temperature. The reaction was
then diluted by water (500 mL) and extracted with ethyl acetate (200 mL x 3).
The organic layers
were combined, washed with brine (50 mL x 2), dried over anhydrous sodium
sulfate, and
concentrated under reduced pressure to give a crude residue which was purified
by silica gel flash
chromatography (eluent: ethyl acetate/petroleum ether, v:v = 1:2) to provide
the titled product
(yield: 97%) as a yellow solid.
[0603] Step 2: Synthesis of tert-butyl N-(4- (44(1 -cyano-l-
methylethyDamino]phenyl I phenyl)carbamate:
1-iN N H Elm;
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[0604] To a stirred solution of tert-butyl N44-(4-aminophenyl)phenyl]carbamate
(7.0 g, 24.62
mmol) in acetone (100 mL) under an atmosphere of nitrogen was added
trimethylsilanecarbonitrile (4.9 g, 49.49 mmol) drop wise at 0 C, followed by
addition of iodine
(630.0 mg, 2.48 mmol) in several batches at 0 C. The resulting mixture was
stirred for 15h at
room temperature. The reaction was then quenched by the addition of water (100
mL), and the
resulting solution was extracted with ethyl acetate (100 mL x 2). The organic
layers were
combined, washed with brine (70 mL x 2), dried over anhydrous sodium sulfate,
and concentrated
under reduced pressure to give a crude residue which was purified by silica
gel flash
chromatography (eluent: ethyl acetate/petroleum ether, v:v = 1:3) to provide
the titled product
(yield: 87%) as a yellow solid. Mass (ES): m/z 352.20 [MI-11.
[0605] Step 3: Synthesis of tert-butyl N-[4-(4-13-[4-cyano-3-
(trifluoromethyl)pheny1]-4-imino-
5,5-dimethyl-2-sulfanylideneimidazolidin-1-y1}phenyl)phenyl]carbamate:
HN
Y\C: 111 NHBoc
1
NC
F3
=
[0606] To a stirred solution of tert-butyl N-(4-14-1(1-cyano-l-
methylethypaminoJphenyl )phenyl)carbamate (3.1 g, 8.82 inmol) in toluene (40.0
mL) was added
4-dimethylaminopyridine (1.6 g, 13.10 mmol) and 4-isothiocyanato-2-
(trifluoromethyl)benzonitrile (2.0 g, 8.76 mmol) at room temperature under an
atmosphere of
nitrogen. The resulting solution was stirred for 12h at 100 C in an oil bath.
The reaction mixture
was then concentrated under reduced pressure to give a crude residue which was
purified by silica
gel flash chromatography (eluent: ethyl acetate/petroleum ether, v:v = 1:1) to
provide the titled
product (yield: 36%) as a yellow solid. Mass (ES+): m/z 580.30 [MH+].
[0607] Step 4: Synthesis of 4-{344-(4-aminophenyl)pheny1)-4,4-dimethyl-5-oxo-2-
sulfanylideneimidazolidin-1-y1)-2-(trifluoromethypbenzoninile:
0,,\(
4 N =NH2
S
NC
CF3
21.1
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[0608] To a stirred solution of tert-butyl N14-(4-(344-cyano-3-
(trifluoromethyl)pheny1]-4-
imino-5,5-dimethyl-2-sulfanylideneimidazolidin-l-yl}phenyl)phenyl]carbamate
(2.0 g) in
methanol (20 mL) was added hydrogen chloride (3 N solution in water, 5 mL) at
room
temperature. The resulting solution was stirred for 2 h at 70 C in an oil
bath. The reaction mixture
was then concentrated under reduced pressure to remove the bulk of methanol.
To the resulting
aqueous mixture was added sodium bicarbonate (sat. aqueous solution) to adjust
the pH to - 8,
and the resulting mixture was extracted with ethyl acetate (80 mL x 3). The
organic layers were
combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate,
and concentrated
under reduced pressure to give a crude residue which was purified by silica
gel flash
chromatography (eluent: ethyl acetate/petroleum ether, v:v = 1:2) to provide
the titled product
(yield: 45%) as a yellow solid. Mass (ES): m/z 481.15 {MM.
[0609] Step 5: Synthesis of tert-butyl2-(4-( [4-(4-13-(4-cyano-3-
(trifluoromethyl)pheny1:1-5,5-
dimethy1-4-oxo-2-sulfanylideneimidazolidin-l-y1 )phenyl)phenylJamino )butox
y)acetate:
N vir
N-1( \W/ H
õ9: S
NC
CF3
=
[0610] To a stirred solution of 4-1344-(4-aminophenyl)pheny1]-4,4-dimethy1-5-
oxo-2-
sulfanylideneimidazolidin-1-y1}-2-(trifluoromethypbenzonitrile (200.0 mg, 0.42
mmol) in
dichloromethane (10 mL) was added acetic acid (0.01 mL) and tert-butyl 2-(4-
oxobutoxy)acetate
(93.0 mg, 0.46 mmol) at room temperature. The resulting mixture was stirred
for 10 min at room
temperature, then to the mixture was added sodium triacetoxyborohydride (124.0
mg, 0.59
mmol). The resulting mixture was stirred overnight at room temperature. The
reaction mixture
was diluted by water (30 mL), extracted with dichloromethane (20 mL x 3). The
organic layers
were combined, washed with brine (20 mL x 2), dried over anhydrous sodium
sulfate, and
concentrated under reduced pressure to give a crude residue which was purified
by silica gel flash
chromatography (eluent: ethyl acetate/petroleum ether, v:v = 1:2) to provide
the titled product
(yield: 36%). Mass (ES): m/z 667.20(MH1.
[0611] Step 6: Synthesis of 2-(4- ( (4-(4-13-[4-cyano-3-
(trifluoromethyl)phenyl]-5,5-dimethy1-4-
oxo-2-sulfanylideneimidazolidin-1-y1)phenyl)phenyl]amino}butoxy)acetic acid:
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rL,eN._ H
)0;
NC 1
CF3
=
[0612] To a stirred solution of tert-butyl 2-(4-1[4-(4-1344-cyano-3-
(trifluoromethyl)phenyl]-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl)phenyl)phenyl]amino }
butoxy)acetate (100.0
mg, 0.15 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.0
mL) at room
temperature. The resulting solution was stirred for 2h at room temperature.
The reaction mixture
was then concentrated under reduced pressure to give a crude material (yield:
99% based on
crude) which was used for next step reaction without any further purification.
Mass (ES): miz
611.10[MH1
[0613] Step 7: Synthesis of example 103.
[0614] This compound was synthesized from 2-(4-{[4-(4-{344-cyano-3-
(trifluoromethyl)pheny1]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-
yl}phenyl)phenyl]amino)butoxy)acetic acid and (25,4R)-1-[(2S)-2-amino-3,3-
dimethylbutanoy1]-
4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl)pyrrolidine-2-
carboxamide
hydrochloride, according to similar procedures in the last step (amide
coupling) described for the
synthesis of example 75.
[0615] Synthesis of tert-butyl 2-(4-oxobutoxy) acetate:
0
0--j< DMP
[0616] To a stirred solution of tert-butyl 2-(4-hydroxybutoxy)acetate (1.0 g,
4.90 mmol) in
dichloromethane (10 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-
benziodoxo1-3(1H)-one
(2.7 g, 6.37 mmol) at room temperature. The resulting mixture was stirred for
12h at room
temperature. The reaction mixture was then diluted with water (20 mL),
extracted with ethyl
acetate (20 mL x 3). The organic layers were combined, washed with brine (20
mL x 2), dried
over anhydrous sodium sulfate, and concentrated under reduced pressure to give
a crude residue
which was purified by silica gel flash chromatography (eluent: ethyl
acetate/petroleum ether, v/v
= 1:2) to provide the titled product (yield: 50%) as colorless oil. 11-1 NMR
(3(X) MHz, CD30D) 8
9.68 (s, 1H), 3.95 (s, 2H), 3.48-3.45 (m, 2H), 2.51-2.50 (m, 2H), 1.81-1.63
(m, 2H), 1.42 (s, 9H).
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[0617] Table 8. Exemplary Compounds.
Ex # S tructure Compound name and Analytical data
-)/
H
(2S,4R)-1-[(2S)-3,3-dimethyl-2-(21 [5 -(4- { [trans-3-(3-chloro-4-
cyanophenoxy)-
N 2,2,4,4-
tetramethylcyclobutyl]carbamoyl)phenoxy)pentyl]oxy)acetamido)butanoy1)-
5.-NH 4-hydroxy-N-( [441,3 -thiazol-5 -yl)phenyl]
methyllpyrrolidine-2-carboxamide
ofj
150 'H NMR (400 MHz, CDCI3): 60.95 (s,911), 1.22 (s,
6H), 1.27 (s, 6H), 1.56-1.58 (m,
a) 2H), 1.68-1.70 (m, 2H), 1.83-1.86 (tn. 2H), 2.11-2.12 On,
1H), 2.54 (br, 1H),3.52-
3.63 (m, 3H). 3.91-4.16 (in, 7H), 4.28-4.54(m. 5H), 4.70-4.71 (m, 1H). 6.19
(d,J =
0.z< 6.8 Hz, 111), 6.80-6.97 (m, 41-1), 7.17 (d, J = 8A Hz, 11-1),
7.32 (d, J = 6.8 Hz, 211),
7.48-7.58 (m, 3H), 7.72-7.74 (m, 2H), 8.03-8.10 (m, 2H), 8.78 (br, 1H); LC-MS:
6cis.=
(ES): ink 94 L20 [M+1-1]
N
(2S,4R)-1412S)-3,3-dimetby1-2-(24 [544- ( [trans-3-(3-chlom-4-cyanophenoxy)-
14c4 2,2,4,4-
tetramethylcyclobutyl]carbamoyl}phenoxy)pentylloxy}acetamido)butanoyll-
--ZOHN 4-hydroxy-N1 [4-(4-methyl-1,3-thiazol-5-
yl)phenyl]methyl }pyrrolidine-2-
H carboxamide
151 'H NMR (400 MHz. CDCI3) 8 8.67 (s. IH), 7.72 (d, J
= 9.0 Hz, 2H), 7.57 (d, J =8.6
Hz, 111), 731-7.38 (m, 41-1), 7.20 (d, J = 9.0 Hz, 11-1), 6.97 (d, J = 2.3
Ilz, 1I1), 6.92(d,
Ht4 J = 8.6 Hz, I H), 6.81 (dd, J = 2.5, 8.8 Hz, 1H), 6.19 (d, J
= 8.2 Hz, 1H). 4.72 (t..1=
7.8 Hz, 1H), 4.47-4.58 (in, 3H), 4.31-4.41 (m, 111), 3.87-4.18 (in, 7H), 3.73
(a, 1H),
3.58 (br. s., 2H), 3.54 (t, J = 6.5 Hz, 2H), 3.48 (s, 1H), 2.4.6-2.55 (m, 3H),
2.08-2.17
(m, IH), L80-1.88 (m. 2H), 1.65-1.74 (m, 2H), 1.53-1.61 (m, 2H), 1.46 (s, 1H).
1.26
(br. s., 6I1), 1.22 (s, 6I1), 0.95 (s, 9I1). LC-MS (ES*): Int 955.42 [MI1]
(2S,4R)-1-[(2S)-3,3-dimethy1-2-(21 [544- ( I trans- 3-(3-chloro-4-
cyanophenoxy)-
2,2,4,4-tetramethylcyclobutyl.icatbamoyl}pbenoxy)pentylloxy}acetamdo)butanoyll-
H0,?..1
4-hydroxy-N-([4-(4-methy1-1,3-oxazol-5-yt)phenyl]methyl}pyrrolidine-2-
.9x4oHN carboxamide
'H NMR (400 MHz, CDCI3) 8 7.85 (s, IH), 7.72 (d, J = 8.6 Hz, 2H), 7.57 (d, J =
8.6
Nwri
152 Hz, 1H). 7.52 (d, J = 8.2 Hz. 2H), 735 (d, J = 8.2
Hz, 3H), 7.20 (d, J =8.6 Hz, 1H).
51 6.97 (d, J = 2.7 Hz, 1H), 6.92 (d, J =8.6 Hz,
211), 6.81 (dd, J = 2.3, 8.6 Hz, 1H),6.20
1-1 ;3 (d, J = 7.8 H7., 1H), 4.70 (t, .1= 7.8 Hz., 1H). 4.48-
4.56 (m, 3H), 4.34 Idd, J = 5.3, 15.1
6 Hz, 1H), 4.12-4.16 (m, IH), 4.04-4.09(m, 2H). 4.01 (t..1= 6.3
Hz, 2H), 3.85-3.97 (m,
211), 3.63 (dd, J = 3.3, 11.2 Hz, I H), 3.53 (t, J = 6.5 Hz, 21-1), 2.49 (ddd,
J = 4.7, 8.0,
C: N
13.1 Hz, 211), 2.41 0-311), 2.12 (dd, .1= 8.2, 133 Hz, 1H), 1.80-1.86 (m, 2H),
1.65-
1.72 (in, 211), 1.53-1.60 (m, 211), 1.26-1.28 (m, 611), L22 (s, 611), 096 (s,
911). LC-
MS (ES'): tniz 940.44 [mill,
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Ex # Structure Compound name and Analytical data
(2S,412)-1-[(2S)-3,3-dimethy1-2-(2- [5-(4- [trans-3-(3-chloro-4-cyanophenoxy)-
HQ 2,2,4,4-
tetramethyleyelobutyl]carbamoyl}phenoxy)pentylioxy )acetamido)butanoy1]-
4-hydroxy-N-( [4-(1,3-oxazol-5-yl)phenyl] methyllpyrrolidine-2-carboxam ide
0¨\qi Feslir
H
IH NMR (400 MHz, CDCI3) 8 7.91 (s, 1H), 7.72 (d, = 9.0 Hz, 2H), 7.54-7.57 (m,
153 211), 7.34 (s, 311), 7.21 (d, J = 8.6 Hz, 111),
6.96 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 9.0
Hz, 2H), 6.81 Idd, J = 2.5, 8.8 Hz, 11-1), 6.21 (d, J = 7.8 Hz, 1H), 4.69 (t,
.1= 8.0 Hzõ
1- 1H), 4.48-4.55 (m, 311), 4.32 (dd, J = 5.3, 15.1 Hz, 1H), 4.15
(d, J = 7.8 Hz, 1H),
3.98-4.08 (m, 4H), 3.84-3.97 (m, 211), 3.63 (dd, J = 3.5, 11.3 Hz, 111), 3.53
(t, J = 6.3
(C Hz, 2H). 2.40-2.57 (m, 4H), 2.11 (dd, J = 8.0, 13.5
Hz, 1H), 1.79-1.88 (m. 2H), 1.64-
,1-'61
1.73 (m, 2H), 1.51-1.60 (m, 2H), 1.27(s, 611), 1.22 (s,611), 0.96 (s, 91-1).
LC-MS
(ES.): in,: 926.42 [MHI
(2S,4R)-1412S)-3,3-dimeday1-2-(24 [544- ( [trans--3-[4-cyano-3-
(trifluoromethyl)phenoxy]-2,2,4,4-
HQ
tetramedlykyclobutyl]carbamoyl}phenoxy)pentylloxy}acetamido)butanoyl]-4-
hydroxy-N-{[4-(4-methy1-1,3-oxazol-5-y1)phenyl]methyl }pyrnolidine-2-
carboxamide
N=f
154 111 NMR (300 MHz, CD30D): 8 8.10 (s, 1 H),7.90-7.83
(m, 1 H), 7.80-7.71 on, 211),
7.60-7.52 (m, 2 H), 7.49-7.541 (m, 2 H). 7.32 (s, 1 H), 7.23-7.19 (m, 1 H),
7.00-6.89
= (m, 2 H), 4.67 (s, 1 H), 4.60-4.40 (m, 3 H), 4.354.25 (m, 2 H), 4.15-4.10
(m, 1 H),
1.09-3.98 (m, 2 H), 3.97-3.90 (m, 211), 3.85-3.70 (m, 211), 3.63-3.49 (m,
211), 2.40
(s. 3 H), 2.25-2.10 (m, 1 H). 2.09-2.00 (m, 111), 1.89-1.79 (m. 2 H),1.80-
1.45(m, 4H),
1.33-1.14 (m, 1211), 1.01 (s, 911); LC-MS (ES*): miz, 973.35 [MW]
(2S,4R)-1-[(2S)-3,3-dimethy1-2-(2-([5-(4-( ftrans-314-cyano-3-
Ho H (trifluoromethyl)phenoxy]-2,2,4,4-
Cr:31 'IN'
retramethylcyclobutyl]carbamoyl}phenoxy)pentyl]oxyJacetamido)butanoyl]-4-
o,r. H
hydroxy-N-( [4-(4-methy1-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-
carboxamide
rJ
155 IHNMR (300 MHz, CD30D): 8 8.84 Is, 1 H), 7.90-7.84
(m, 1 H), 7.80-7.70(m, 211),
7.45-7.32 (m, 4 /1), 7.26-7.22 (m, 111), 7.28-7.20(m, 1 II), 7.00-6.89 (m, 2
11), 4.67
LNH (S. 1 H),4.60-4.50(m, 1 H). 4.46-4.40 (m, 1 H), 4.27-4.20 (m. 2
H), 4.13 (s. 1 H),
4.15-4.00 (m, 211), 3.99-3.95 (m, 211), 3.90-3.80 (m, 211), 3.59-3.51 (m,
211), 2.40
F30
(s, 3 H), 2.25-2.10 (m, 1 H),2.11-2.00 (tn. 1 H), 1.85-1.75 (m, 2 H), 1.70-
1.50 (m, 4
H), 1.33-1.14 (m, 1211), 1.01 (s, 911); LC-MS (ES*): in/z, 989.30 [MH1]
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Ex # Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-3,3-dimetbA-2-(2-( [544- [trans--3-(3-chlom-4-cyanophenoxy)-
2,2,4,4-tetramethylcyclobutyl]carbamoyl }phenoxy)pentyl]oxy
}acetanlido)butanoyll-
HQ
= N-31 :.c 4-hydroxy-N-R1S)-144-(4 -me thy1-1,3-
oxazol-5-y1)phe nyl] ethyl] pyrrolidine-2-
carboxamide
ccAH'o
156 'H NMR (300 MHz. CD30D): 8 8.14(s, 1 H),7.85-7.80
(m, 2 H), 7.78-7.72(m, 1 H),
7.65-7.55 (m, 2 H), 7.47-7.40 (m, 21-1), 7.15-7.10(m, III), 7.15-6.95 (m,
311), 5.03-
,4_ NH
4.94 (m, 1 H). 4.67 (s, 1 H).4.60-4.50 (in, 1 H), 4.46-4.40 (m, 1 10, 4.27-
4.25 (m, 1
H), 4.15-4.00 (m, 3 H), 3.99-3.95 (m, 2 H), 3.90-3.80 (m, 1 H), 3.79-3.80 (m,
1 H),
3.63-3.49 (m, 2 H), 2.40 (s, 3 H), 2.25-2.10 (tn. 1 H),2.09-1.80 (m, 3 H),
1.79-1.50
(m,4 H), 1.48-1.46 (m, 3 1), 1.33-1.14 (m, 12 H). 1.01 (s, 9 H): LC-MS (ES*):
ttilz,
953.35 [MIll
(2S,4R)-1-[(2S)-3,3-dimethy1-2-(2-([5-(4-( itrans-3-(3-chloro-4-cyanophenoxy)-
HQ 2,2,4,4-tetrame thylcyclobutyl] carbamoyllphe
noxy)pentyl] oxy }acetamido)butanoy1]-
, 4-hydroxy-N-RIS)-114-(4-methyl-1,3-thiazol-5-
y0phenyl]edlyl]pyrrolidine-2-
-=%.4,, o
01..14H s' carbomunide
r_
157 ,.0 'H NMR (400 MHz, CD30D): 8 8.90 (s, 1 H. 7.85-
7.00(m, 3 H), 7.50-7.39 (m, 4 H),
7.15-7.10(s, 111), 7.05-6.95 (m, 3 11), 5.05-4.98 (m, 1 10,4.70 (s, 111), 4.65-
4.52
o 1- (m, 1 H), 4.48-4.40 (m, 1 H), 4.30 (s, 1 H), 4.15-
4.10 (m, 3 H), 4.00 (tn. 2 H), 4.02-
3.70(m, 2 H),3.70-3.58 (m, 211), 2.50 (in, 3 H), 2.45-2.35 (rn, 1 H), 2.28-
2.15 (m, 1
H),2.08-1.82 (m, 4 H),1.80-1.45 (m,7 II), 1.39-1.20 (m, 12 II),1.10-1.00 (m,
9H):
LC-MS (ES*): itez 969.50 (MH1
S-10
1,Tjf11`
8:11HA13 6 6
Ik1='
,J
(2S,410-1-[(2S)-3,3-dimeday1-2-(2-(1(210-6-(4-j[trans-3-(3-chloro-4-
cyanophenoxy)-
o.õ),...3
2,2,4,4-tetramethykyclobutyl]carbamoyl }phenoxy)hexan-2-
a 1-- yl]oxy } acetamido)butanoy1]-4-hydroxy-N-{ [4-(4-
methy1-1,3-thiazol-5-
158 :
cr-(1) yl)phenyl]methyl}pyrrolidine-2-carboxamide
, ,
159 HQ.
/ C-41 (2S,4R)-1-R2S)-3,3-dimethy1-2-(2-{[(2S)-6-(4-(
[trans-3-(3-chloro-4-cyanophenoxy)-
'I,
ro.5.1A1 ci 2,2,4,4-tetramethylcyclobutyl]cathamoyl}phenoxy)hexan-2-
--e's y0oxylacetamido)butanoy1]-4-hydroxy-N-f [4-(4-methy1-1,3-thiazol-5-
rf 14='
y0pheny methyl}pyrrolidine-2-carboxamide
(
ci
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Ex # Structure Compound name
and Analytical data
(2S,4R)-1412S)-3,3-di methA-2-(2- ( [ (5 S)-5-(4- { [trans-3-(3-chloro-4-
cyanophenoxy)-
no. 2,2,4,4-
tetramethylcyclobutyl]carbamoyl}phenoxy)hexylioxy}acetamido)butanoy1:1-4-
/-1 0
, = *S. -I hydroxy-N-( [4-(4-methy1-1,3-thiazol-5-y1)phenyl] methyllpyrrol
id ine-2-carboxamide
3 (1
y H 4,-
,_J -..j'S
N=1 (2S,4R)-1-[(2S)-3,3-dirnethyl-2-(2-1[(5R)-5-(41 [trans-3-(3-chloro-4-
cyanophenoxy)-
, ;
. 8 2.2,4,4-tetramethylcyclobutyl]carbamoyl
}phenoxy)hexyl]oxy }acernmido)butannyl]-4-
,' ,.
o.., '',/ hydroxy-N-([4-(4-methy1-1,3-thiazol-5-
yl)phenyl]methyl}pyrrolidine-2-carboxamide
_1 NH
'LI
cr-r-
,--, 'H NMR (300 MHz, CD3OD): 8 8.88 (s, 111), 7.75-7.67 (m, 3 H),
7.44-7.36 (rn, 4 1-1),
1)'''
160, c k;
Pv 7.09(s, 1 H), 6.96-6.91 (m, 3 H), 4.84 (s, 1 H), 4.66-4.47
(m, 4 H), 4.36-4.31 I'm, 1
161 HO H), 4.26 (s, 1 H), 4.24 (s, 1 H), 4.10 (s, 1
H),3.93-3.91 (m, 2 H), 3.83-5.78 (m, 2 H),
1) 6 3.55-3.51 (m,2 H),2.43 (s, 3 H), 2.12-2.10 (m, 1 H), 2.09-1.95 (m, 1
H), 1.67-1.62
...0: ---s (m, 6 H), J.30-1.28(m, 9H), 1.18 (s, 6 H),
1.00 (s, 9 H); LC-MS (FS'): miz 969.10
te
, r [MHI
,y8--
..M-1 IFINMR (300 MHz. CD30D): 8 8.88 (s, 1H), 7.75-7.67(m, 3 H),
7.44-7.36 (m, 4 H),
7.10(s, 1 1-1), 6.96-6.91 (m, 3 H), 4.66 (s, 1 H), 4.58-4.48 (m, 4 H), 4.35-
4.03(m, 1
CI H), 4.24 (s, 1 H), 4.10 (s, 1 H), 3.92-3.86 (m,
211), 3.83-5.55 (m, 2 II), 3.53-3.51 (m,
N 2 H). 2.43 (s, 3 H). 2.20-2.10 (m, 1 H),2.09-2.01 (m, 1 II),
1.67-1.62 (m, 6 H), 1.30
(s, 9 H), 1.19 (s, 6 H),1.00 (s, 9 H); LC-MS (ES*): /fez 969.15 [MH]
[0618] Synthesis of example 150:
HQ PH
t(711 IP j
W
O
- Me0 lip ..,-..../^.../..0,:it 43...NH
LJOH
H 0
1,1H2
HATU. DIPEADMF 0 THF, H20
HO 2-..
S Step 1
\/
N '
9H
OH
C % 0
43....
N = C)."*--N-0--.(3'.- jH
...._*, NC NH
HO H 0_e ' HAW 0
, DIPEA,DMF
\ /
<c....")
Step 3 NC Example 150
..F.:
r
r-----
[0619] Step 1: Synthesis of methyl 4- { [5-(1[(2S)-1-[(2S,4R)-4-hydroxy-2-(1[4-
(1,3-thiazol-5-
yflphenyl]methyl}carbamoyflpyrrolidin-l-y1]-3,3-dimethyl-l-oxobutan-2-
yl]carbamoyl}methoxy)pentyl]oxy }benzoate:
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9H
0
Me ip ooJNS
[0620] To a stirred solution of 2-(15-14-
(methoxycarbonyl)phenoxy]pentyl}oxy)acetic acid (200
mg), (2S,4R)-1-{(2S)-2-amino-3,3-dimethylbutanoy1J-4-hydroxy-N-I [4-(1,3-
thiazol-5-
yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrogen chloride salt (149 mg,
0.32 mmol), N-
ethyl-N-isopropylpropan-2-amine (185 mg, 1.44 mmol) in anhydrous N,N-
dimethylformamide (5
mL) was added HATU (2-(7-aza-1H-benzotriazole-1-y1)-1,1,3,3-tetramethyluronium
hexafluorophosphate ) (203 mg, 0.54 mmol) at 0 C. The resulting mixture was
allowed to warm
up to room temperature and stirred at room temperature for 20 min. TLC and LC-
MS showed
formation of the desired product. The mixture was partitioned between ethyl
acetate (100 mL) and
water (50 mL). The organic layer was collected, washed with brine (50 mL),
dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to give a crude
residue which was
purified by silica gel flash chromatography (eluent 2% methanol in methylene
dichloride) to
afford the titled product (yield 25%, 2 steps) as a white solid. Mass: (ES):
m/z 695.30 [M+H+].
[0621] Step 2: Synthesis of 4-1[5-({[(2S)-1-[(25,4R)-4-hydroxy-2-({[4-(1,3-
thiazol-5-
yl)phenylimethyl ) carbamoyl)pyrrolidin-l-y11-3,3-dimethyl-1-oxobutan-2-
yl]carbamoyl}methoxy)pentyl]oxy }benzoic acid:
OH
0 11
HO 0 0 OC)'`)Cilli) NH IP \S
¨N
0
=
[0622] To a stirred solution of methyl 4-{ [5-({ [(25)-1-[(2S,4R)-4-hydroxy-2-
({ [4-(13-thiazol-5-
yflphenyl]methyl}carbamoyl)pyrrolidin-l-y1]-3,3-dimethyl-l-oxobutan-2-
yl]carbamoyl}methoxy)pentyl]oxy}benzoate (150 mg, 0.22 mmol) in a mixed
solvents of
tetrahydrofuran (4 mL)-water (2 mL)-methanol (1 ml) was added lithium
hydroxide monohydrate
(36 mg, 0.86 mmol) at room temperature. The resulting mixture was stirred at
35 C overnight.
TLC and LC-MS showed formation of the desired product. The reaction mixture
was acidified
with aqueous HC1 (3N) to pH =3-4 and extracted with methylene dichloride (50
mL x 2). The
organic layers were combined, washed with brine, dried over Na2SO4 and
concentrated to afford
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the titled product (110 mg, crude) as a white solid which was used for next
step without further
purification. Mass: (ES): m/z 681.20 [M+Hl.
[0623] Step 3: Synthesis of exmaple 150:
?H
CI
NC
[0624] To a stirred mixture of 4- { [5-(1[(2S)-1-[(25,4R)-4-hydroxy-2-({ [4-(i
,3-thiazol-5-
yl)phenyl]methyl}carbamoyl)pyrrolidin-l-y1]-3,3-dimethyl-l-oxobutan-2-
ylicarbamoyl }methoxy)pentylioxy }benzoic acid (110 mg, 0.16 mmol), 2-chloro-
44trans-3-
amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile hydrogen chloride salt (50
mg, 0.16 mmol),
N-ethyl-N-isopropylpropan-2-amine (77 mg, 0.64 mmol) in anhydrous N,N-
dimethylformamide
(4 mL) was added HATU ((2-(7-Aza-1H-benzotriazole-1-y1)-1,1,3,3-
tetramethyluronium
hexafluorophosphate )) (68 mg, 0.18 mmol) at 0 C. The resulting mixture was
allowed to warm
up to room temperature and stirred at room temperature for 20 min. TLC and LC-
MS showed
formation of the desired product. The reaction mixture was partitioned between
ethyl acetate (100
mL) and water (40 mL). The organic phase was separated, washed with brine
(50mL), dried over
anhydrous sodium sulfate, and concentrated under reduced pressure to give a
crude residue which
was purified by preparative TLC (eluent: 5% methanol in methylene dichloride)
to afford the
titled product (yield 25%, 2 steps) as a white solid.
[0625] Synthesis of 24(5-14-(methoxycarbonyl)phenoxylpentylioxy)acetic acid
IEWCH2C0:48u
BnOW Pd/C, N
C.N2 a"....-"O'sy()) T4C13
µ01-1 _______________
Step 1 I- Step2
''s J)Lri 0
odit T FA lip
Ts0Wei 1 ....................... '4! -.0 ir/
K7co, 0
Step4 St4p5
10626] Step 1: Synthesis of tert-butyl 2- { [5-(benzyloxy)pentyl]oxy)acetate:
BnOW0'.%).r 1<
0 I
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[0627] To a stirred mixture of 5-(benzyloxy)pentan-1-ol (10 g, 51.5 mmol),
tert-butyl 2-
bromoacetate (40.2 g, 206 mmol) and tetrabutyl ammonium chloride (14.2 g, 51.5
mmol) in
methylene dichloride (60 mL) was added sodium hydroxide (40 ml, 35% in water)
at room
temperature, and the resulting mixture was stirred at room temperature for 16
hours. The reaction
mixture was then partitioned between methylene dichloride (200 mL) and water
(100 mL). The
organic layer was collected and washed with brine (50 mL), dried over
anhydrous sodium sulfate,
and concentrated under reduced pressure to give a crude residue which was
purified by silica gel
flash chromatography (eluent: 5% ethyl acetate in hexane) to afford tert-butyl
2-1[5-
(benzyloxy)pentyl]oxy}acetate (yield 31.6%) as light yellow oil. LC-MS: (ES):
ink 331.10
[M+Nal, NMR (400 MHz, CDC13): 5 1.48 (s, 9H), 1.63-1.67 (m, 6H), 3.46-3.53 (m,
4H),
4.10 (s, 2H), 4.50 (s, 2H), 7.28-7.34 (m, 5H).
106281 Step 2: Synthesis of tert-butyl 2-[(5-hydroxypentypoxy]acetate:
Howo^l-r I<
=
[0629] To a stirred solution of tert-butyl 2-{[5-(benzyloxy)pentyl]oxy)acetate
(5 g, 16.2 mmol)
in ethanol (100 nil) under a nitrogen atmosphere was added palladium on carbon
(10%, 600 mg)
at room temperature. The resulting mixture was stirred at 50 C overnight under
hydrogen
atmosphere (hydrogen balloon). TLC showed formation of desired product.
Palladium on carbon
was removed through filtration and washed with ethyl acetate (50 mL). The
filtrate was
concentrated under reduced pressure to afford tert-butyl 2-[(5-
hydroxypentypoxy]acetate (2.5 g,
crude) as colorless oil which was used in next step without further
purification.
10630] Step 3: Synthesis of tert-butyl 2-({5-[(4-
methylbenzenesulfonyl)oxy]pentylioxy)acetate:
Tsowo^el<
[0631] To a stirred solution of tert-butyl 2-[(5-hydroxypentypoxy]acetate (2.5
g, crude) and
triethylamine (3.5 g, 34.5 mmol) in anhydrous methylene dichloride (50 mL) was
added a
solution of 4-toluenesulfonyl chloride (2.7 g, 13.8 mmol) in anhydrous
methylene dichloride (8
mL) drop wise at 0 C. The reaction mixture was allowed to warm up to room
temperature and
stirred at room temperature overnight. TLC showed formation of desired
product. The mixture
was quenched with aqueous solution of potassium carbonate (1N, 50 mL) at room
temperature
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and extracted with ethyl acetate (50 mL x 3). The organic layers were
combined, washed with
brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under
reduced pressure to
give a crude residue which was purified by silica gel flash chromatography
(eluent: 1% methanol
in methylene dichloride) to afford tert-butyl 2-(15-[(4-
methylbenzenesulfonyl)oxylpentyl }oxy)acetate (yield 35.1%) as colorless oil.
Mass: (ES+): mh
395.10 [MNal.
10632] Step 4: Synthesis of methyl 4-(f 5-[2-(tert-butoxy)-2-
oxoethoxy]pentyl}oxy)benzoate:
dirb
9%.
o .
[0633] To a stirred mixture of tert-butyl 2-({5-[(4-
methylbenzenesulfonyl)oxylpentyl }oxy)acetate (1.0g, 2.7 mmol) and potassium
carbonate (266
mg, 1.6 mmol) in acetonitrile (15 mL) was added methyl 4-hydroxybenzoate (500
mg, 3.29
mmol) at room temperature. The resulting mixture was refluxed overnight. TLC
showed
formation of desired product. The reaction mixture was cooled to room
temperature, and
partitioned between ethyl acetate (150 mL) and water (50 mL). The organic
layer was washed
with washed with brine (50 mL), dried over anhydrous sodium sulfate, and
concentrated under
reduced pressure to give a crude residue which was purified by silica gel
flash chromatography
(eluent 10% ethyl acetate in hexane) to afford methyl 4-(f 542-(tert-butoxy)-2-
oxoethoxy]pentyl}oxy)benzoate (yield 33%) as colorless oil. Mass (ES+): m/z
353.10 [M+Na];
NMR (400 MHz, CDC13): 5 1.48 (s, 9H), 1.55-1.61 (m, 2H), 1.68-1.72 (m, 2H),
1.80-1.87 (m,
2H), 3.55 (t, J. 6.4 Hz, 2H), 3.88 (s, 3H), 3.96 (s, 2H), 4.02 (t, J. 6.4 Hz,
2H), 6.89 (d, J. 9.2
Hz, 2H), 7.97 (d, J= 9.2 Hz, 21-1).
[0634] Step 5: Synthesis of 2-(f 5(4-
(methoxycarbonyl)phenoxy]pentyl}oxy)acetic acid:
¨o o .
10635] To a stirred solution of methyl 4-({5[2-(tert-butoxy)-2-
oxoethoxy]pentyl}oxy)benzoate
(300 mg, 0.85 mmol) in DCM (4 mL) was added and TFA (2 ml) at room
temperature, the
resulting solution was stirred at room temperature for 1 hour. TLC showed
formation of the
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WO 2019/023553 PCT/US2018/044051
desired product. The solvent was evaporated to afford 2-({5-[4-
(methoxycarbonyl)phenoxy]pentyl}oxy)acetic acid (200 mg, crude) as yellow oil
which was used
in next step without further purification.
[0636] Examples 151-157 were synthesized according to similar procedure
described for
synthesis of example 150, by using corresponding starting materials and
intermediates.
[0637] Table 9. Exemplary Compounds.
Ex # Structure Compound name and Analytical data
(2S.4R)-1-[(2S)-3,3-dimethyl-2-(2- (244441 [trans-3-(3-chloro-4-eyanophenox y
)-
2,2,4,4-
0 htetramethNyle;lo(b1u3tythl]c, arbial5noyil)hpheni7
tby)butiolxy]ethrodx.y }ac2etamia do)bu.tande
162 oy1]-4-
yd
'H NMR (400 MHz, CDC13): 5 0.95 (s, 9H), 1.22 (s, 6H), 1.27 (s, 6H), 1.74-1.80
(m,
,
4H), 2.09-2.14(m, 1H), 2.53-2.60 (m, 1H), 3.54-3.69 (m, 8H), 3.99-4.05 (m,
5H),
t?
4.12-4.16 (m, 211), 4.28-4.33 (m, 1H),4.46-4.58 (m, 311), 4.72 (t, J = 8.0 Hz,
111), 6.20
(d, J = 8.0Hz, 1H), 6.79-6.97 (m, 4H), 7.26-7.33 (m, 3H), 7.49 (d, J = 8.0 Hz,
2H), 7.57
(d, J = 8.8 Hz, 111), 7.72 (d, J = 8.4 Hz, 2H), 8.03(s, 1H), 8.78 (s, 1H). LC-
MS: (ES*):
CI N
m/z 971.20 [MI-111
(2S.4R)-1-[(2S)-3,3-dimethyl-2-(244-(4-(1trans-3-(3-chloro-4-cyanophenoxy)-
2,24-
tetramethylcyclobutyl]carbamoyl Iphenoxy)butoxy]acetamidolbutanoy1)-4-hydroxy-
N-
",...c 1(4-(4-methy1-1,3-thiazol-5-yl)phenynmethyl)pyrrolidine-2-
carboxamide
=ro
I If NMR (400 MHz, CD30D) 5 ppm 8.85 (s, 1 H),7.75 -7.81 (m, 211), 7.72 (d, J
=
ro
9.00 Hz, 1 II), 7.44 - 7.50 (m, 2 II), 7.38 - 7.43 (m, 211), 7.13 (d, J = 2.35
Hz, 111),
163
6.94- 7.02 (m, 3 H). 4.70 (s, 1 H). 4.54 - 4.61 (m, 2 H), 4.48 - 4.54 (m, 2
H), 4.36 (d,
\r-
F4:44 = 15.65 Hz, 1 H), 4.28 (s, 1 H), 4.14 (s, 1 H),
4.10 (t, J = 6.06 Hz, 2 H), 4.01 (d, J =
o
,õy4""C
Ner.) 7.43 Hz, 2 H). 3.85- 3.90 (m, 1 H), 3.77- 3.84(m. 1
H), 3.64 (t, J= 6.26 Hz, 2 H).
2.45(s, 3 H), 2.24 (dd, J= 13.30, 7.43 Hz, 1 1-1), 2.09 (ddd, J = 13.21, 9.10,
4.30 Hz, 1
11), 1.89- 1.98 (m, 211), 1.80- 1.88 (m, 211), 1.28 (s, 611). 1.22 (s, 6 1-1),
0.99 - 1.06
lm, 9 H): IC-MS (ES'): trv:.- 941.41 [MH1
222
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Ex # Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-3,3-dimethyl-2-(244-(4-( Itrans-3-(3-chlom-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobutylicarbamoyl }phenoxy)butoxy]acetamido}butanoy1]-4-hydroxy-
N-
HO:{ [4-(4-metiv1-1,3-oxazol-5-yl)phenyl]methyl }pyrrolidine-2-carboxamide
164 rz:74 11-1NMR (400 MHz, CD301.3) 6 ppm 8.12(s, 1 H), 7.75 -
7.81 (m, 2 H), 7.72 (d, J =
9.00 Hz, 1 H), 7.56 - 7.64(m, 2 H), 7.47 (d,J= 8.61 Hz, 2 H), 7.13 (d, J =
2.35 Hz, 1
H). 6.95 - 7.03 (m, 3 H), 4.70(s, 1 H), 4.56- 4.61 (m, 1 H). 4.55 (s, 1 H).
4.46 - 4.53
(m, 2 H), 4.35 (d, J= 15.65 Hz, 1 H), 4.28 (s, 1 H), 4.12 - 4.15 (m, 1 H),
4.06 - 4.12
Ht"
l< (m, 2 II), 3.98 - 4.03 (m, 2 H), 3.85 - 3.92 (m, 1
H), 3.78 - 3.84 (m, 111), 3.65 (t, J.
6.06 Hz., 2 H), 2.38 (s, 3 H), 2.19 - 2.28 (m, 1 H), 2.08 (ddd, J = 1330,
9.19, 4.50 Hz, 1
H), 1.91 - 1.98 (m, 2H), 1.82- 1.89 (in, 2H), 1.28 (s, 6H), 1.22 (s, 6 H),
1.04 (s, 9 H);
N
tr-ms (ES): Int 925.43 [MI1]
NO. H (2S,4R)-1-[(2S)-3,3-dimethy1-2-1244-(4-(Brans-344-cyano-3-
Q").
.4., Lc, 0 õ--). (trifluoromethyl)phenoxyl-2,2,4,4=-
tetramethylcyclobutyl]carbamoyl)phenoxy)butoxylacetamido)butanoy11-4-hydroxy-N-
- ( [4-(4-methy1-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-
carboxiunide
165
1 11-INMR (300 MHz, CD300): 6 8.88 (s, 1H), 7.75-7.67 (m, 3 H),
7.447.36 (m, 4 H),
.
7.09(s, 1 H), 6.96-6.91 (m, 3 H), 4.84 (s, 1 H), 4.66-4.47 (m, 4 H), 4.36-
4.31(m, 1
--i--
H), 4.26(s. 1 H), 4.24(s. 1 H), 4.10(s. 1 H), 3.93-3.91 (m, 2 H). 3.8.3-
5.78(m, 2 FEL
3.55-3.51 (m, 2 H),2.43 (s, 3 H), 2.12-2.10 (m, 1 H), 2.09-1.95 (m, 1 H), 1.67-
1.62(m,
i-..\
F,C .,
'
N 6 /I), 1.30-1.28 (m. 9 H), 1.18(s. 6 H), 1.00(s. 9 H); LC-MS
(ES): m/z 969.10 [MH1
õ
HQ. (25,4R)-1-[(2S)-3,3-dimethy1-2-(244-(44 [trans-344-cyano-3-
o m (tetritralflun7thiny rrior.4. le:7101)bpuhmeniolexy]-a2m,20,4v,14)-
phenox
y)butoxylacetamido)butauoy11-4-hydroxy-N-
-,N,.., ([4-(4-methyl-1,3-oxazol-5-
yl)phenyl]methyl)pyrrolidine-2-carboxamide
166 . 11-INMR (400 MHz, CD3OD):8.09 (s, 1H),7.89 (d, 1 1-
1), 7.80-7.70 (m, 2 H), 7.69-7.50
...L e(c) (m, 211), 7.49-7.40 (m, 2 H),7.32 (s, 1 H), 7.28-
7.08 (m, 1 H), 7.00-6.82 (m, 211),
H 4.72(s, I H), 4.60-4.40 (m, 3 H), 4.39-4.20 (m, 2
H), 4.19-4.00 (m, 3 H), 3.99-3.95
o'114-
(in, 2 H),3.92-3.70 (m, 2 H),3.69-3.53 (m, 2 H), 2.40-2.32 (in, 3 H), 2.30-
2.18 (m, 1
F3Cil H),2.15-2.01 (m, 1 H), 2.00-1.60 (m, 4 H),J.35-1.28
(m, 6 H),1.25-1.15 (m, 6 H),1.03-
1.00(m, 9 H); LC-MS (ES): m,'z 959.60 (MH1.
Ho, H
( 2S,4 R )- l -R2S)-3,3-dimethyl-212-[4-(4-{ (nuns -3-(3-ch lom-4-
cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]carbamoyl)phenoxy)butoxylacetamido)butanoy11-4-hydroxy-N-
vo o (,
y1S)-144-(4-methy1-1,3-thiazol-5-yl)phenyllethyl]pyrrolidine-2-carboxamide
o)
ii 'H NMR (400 MHz, CD30D): 8.82 (s, 1H),7.81-7.75 (m,2 H), 7.74-7.62
(s, 1 H), 7.6J-
1677.53 (m, 2 H), 7.49-7.35 (m, 2 H), 7.19-7.10 (s, 1 H), 7.08-6.80(m, 3 H),
5.08-4.91
o.( (m, 111), 4.65 (s, III), 4.60-4.59(m, 1I-I), 4.45-4.36 (m, 1
/0,4.22 (s, 111), 4.11-4.05
---\.-r:: (m, 3 H),4.01-3.96 (m, 2 H), 3.95-3.70 (m, 2 H).
3.69-3.45 (m, 2 H), 2.40-2.35 (m, 3
c( %
H), 2.21-2.04 (s, 1 H),2.00-1.70 (m, 4 H),1.60-1.40 (m, 3 1-1), 1.21-1.12 (m,
12H),
ciqT4 1.00-0.95(m, 9 H): IC-MS (ES'): tw'z 478.45 [(14/2)H1
223
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Ex # Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-3,3-dimethy1-2-( 21444- ( [trans-3-(3-chloro-4-cyanophenoxy)-
2,2.4,4-
.0 .
tetramethylcyclobutyl)carbamoyl)phenoxy)butoxy]acetamido)butanoy1]-4-hydmxy-N-
,..õ-I ,
[(1S)-114-(4-methy1-1,3-oxazol-5-yl)phenyflethyl]pyrrolidine-2-carbomunide
'H NMR (400 MHz, CD3OD): 8.82 (s, 1H),7.81-7.75 (rn,2 H), 7.74-7.62 (s, 1 H),
7.61-
168 . 0
(1.
,..../ 7.53 (m, 2 H), 7.49-7.35 (m, 2 H), 7.19-7.10 (s, 1
H), 7.08-6.80 (m, 311), 5.08-4.91
G
4...rpH
(in.! H), 4.65 (s. 1 H), 4.60-4.59(m, 1 H). 4.45-4.36 (m, 1 H),4.22 (s, 1 H),
4.11-4.05
ah (in, 3 H),4.01-3.96 (m, 2 H), 3.95-3.70 (in, 2 H),
3.69-3.45 (in, 2 H), 2.40-2.35 (m, 3
ct'N
t H), 2.21-2.04 (s, 1 H),2.00-1.70 (m, 4 H),1.60-1.40
(m, 3 H), 1.21-1.12(m. 1211),
1.00-0.95(m, 9 H); LC-MS (ES*): in/z 478.45 [MH1
I 2S,4R)-N-[ (4-chlorophenyl)methyl)-1-[(2S)-3,3-dimethy1-2- ( 244444 [ tra n
s-3 43-
ChlOr0-4-CyallOphCnOXV-2,2,4,4-
HN
110,==Q='44D1c
teiramethylcyclobutyl]carbamoyl)phenoxy)butoxy]acetamido)butanoyl]-4-
1
hydroxypyrrolidine-2-carboxamide
--)--C::
169 o-rf
'H NMR (400 MHz, CD30D) 8 ppm 7.80 (d, J= 8.61 Hz, 2 H), 7.72 (d, J= 9.00 Hz,
1
' cr4t3
H), 7.24 - 7.37 (m. 4 H), 7.13 (d,./ = 2.35 Hz. 1 H), 6.94 - 7.04 (m, 3 H).
4.69 (s, 1 H),
4.54 (dd,J= 8.80, 7.63 Ilz, 1 H), 4.43 - 4.51 (m, 2 II), 4.24 - 4.32 (m, 2
II), 4.08 .4.16
utt--:05
ci c?C.
- (m, 3 H, 3.95 - 4.06 (m, 2 H), 3.84 - 3.90 (m, 1 H),
3.76- 3.83 (m, 1 H), 3.65 (t, J=
6.26 Hz, 2 H), 2.21 (dd, J= 13.11, 7.63 Hz, 1 H), 2.06 (ddd, J= 13.30, 9.19,
4.50 Hz, 1
N
H), 1.90- 1.98 (m, 211), 1.80- 1.89 (m, 211), 1.28 (s, 611), 1.22(s, 6 II),
0.95 -1.15
(m, 9 H); LC-MS (ES'). nit 878.28[14W]
(2S,4R)-N-[(4-cyanophenyOmethy1]-1-[(2S )-3,3-dimethy1-24 2-4444- ( (trans-3-
( .1-
HN chloro-4-cyanophenoxy)-2,2.4,4-
HO. tetramethylcyclobutylicarbamoyl}phenoxy)butoxy]acetamido}butanoy1]-4
=
...)
H hydmxypyrrolidine-2-carboxamide
170 0--rr 'H NMR (400 MHz, CD30D) 8 ppm 7.80 Id, J= 8.61 Hz, 2
H), 7.72 Id, J= 8.61 Hz,!
H), 7.64 (d,./ = 8.22 Hz. 2 H), 7.54 (d, J = 8.22 Hz. 2 H), 7.13 (d, J = 2.35
Hz. 1 H),
Ht4===
6.94- 7.05 (n, 3!-!), 4.69 (s, II-!), 4.49- 4.62(m, 4 II), 4.34 (d, J = 16.04
Ilz, 111),
wc:rx)r):3 C 4.29(s. 1 H), 4.08 - 4.17 (m, 3 H), 3.95 - 4.06 (m, 2
H), 3.85 - 3.91 On, 1 H), 3.80 (dd,
J= 11.15, 3.72 Hz, 1 H), 3.65 (t, J= 6.06 Hz, 2 H), 223 (dd, J= 13.11, 7.63
Hz, 1 H),
2.06 (ddd, J= 13.11, 9.19, 4.30 Hz, 1 H), 1.90- 1.99 (m, 2 H), 1.8!- 1.90 (m,
2 II),
224
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Ex # Structure Compound name and Analytical data
1.28 (s, 611). 1.22 (s, 6 11), 0.92- 1.18 (m, 911); LC-MS (ES*): in/z 869.32
[MH1
HQ . j.. (2S,4R)-1-[(2S)-3,3-dimethy1-2-12-[4-(4-( [trans-3-
(3-chlom-4-cyanophenoxy)-2,2,4,4-
c .-
tetramethylcyclobutyl]carbamoyl }pheinoxy)butoxy]acetamido}butanoy1]-4-hydroxy-
N-
0-Y
[(1R)-144-(4-medv1-1,3-thiazol-5-yl)phenyllethyllpyrrolidine-2-carboxamide
¨rs
/
r- .----1 'H NMR (400 MHz, CD301.3) 6 8.85(s, 1H), 7.79 (m, 3H), 7.58
(d, ./ = 8.4 Hz, 2H),
r"
171 rY 7.42(d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 7.01 (m,
3H), 5.00 (in, 111), 4.69 (m, 2H), 4.53 (s,
1H), 4.30 (s, 1H), 4.16 (s, 1H), 4.13 (m, 2H), 4.01 (s, 2H), 3.91-3.85 (m,
1H), 3.85-
.4.
3.78 (m, 1H),3.65 (m, 2H), 2.46(s, 3H), 2.30-2.19(m, 1H), 2.18-2.05 (m,
1H),1.99-
9 µ-
n 1.92 (m, 211), 1.89-1.82 (m, 211),1.53 (m, 311), 1.30 (s,
611), 1.24 (s, 611), 0.92 (s, 911);
= 1
V,1 Mass (ES'): /fez 955.45 [MW]
[0638] Synthesis of example 163:
H9.
H9
/
Cillr M
o )-0H oeCro\....\....µ ...k.r..4.0 0
11.....
Ne0H
' -...-= a. 0 0). NH
Step 2
S Step 1
S
6N
6N
149. Htl.
H 110 St, N
II-t2 N a
...V44r40.1..N s'.*
0
$ii..... Example 163 s
toN
[0639] Step 1: synthesis of methyl 4-[4-(( [(2S)-1-[(2S,4R)-4-hydroxy-2-(( [4-
(4-methy1-1,3-thiazol-5-
yl)phenyl]methyl)carbamoyppyrrolidin-1-y1]-3,3-dimethy1-1-oxobutan-2-
yllcarbamoylimethoxy)butoxy]benzoate
225
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HO
H
--O qt,
o d
0"s¨NH 0 114
:
106401 To a stirred solution of 2-{4[4-(methoxycarbonyl)phenoxy]butoxy }acetic
acid (22.0 mg, 77.9
pniol) and (2S,4R)-1-[(2S)-2-amino-3.3-dimethylbutanoy1]-4-hydroxy-N-[(1S)-144-
(4-methyl-1,3-thiazol-
5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (36.3 mg, 77.9 pmol)
in methylene
chloride (2.0 mL) was added 0-(benzotriazol-1-y1)-N,N,NcNi-tetramethyluronium
tetrafluoroborate (25.0
mg, 77.9 pmol) and diisopropylethylamine (40.5 pL, 233 pmol) at room
temperature. The reaction mixture
was stirred at room temperature for 30 minutes, LC-MS indicated formation of
the desired product. The
reaction mixture was concentrated under reduced pressure. The crude material
was purified by flash silica
gel chromatography on a Teledyne Combifiash ISCO (gradient eluent:
Heptane/Acetone (v:v = 100:0 to
0:100)) to give the titled product (yield: 78%) as a white solid. LC-MS (ES4):
miz 695.3138 1MH1.
[0641] Step 2: Synthesis of 444-(1[(25)-1-[(2S,4R)-4-hydroxy-2-(([4-(4-methy1-
1,3-thiazol-5-
ypphenyl]methyl )carbamoyppyrrolidin-l-y1]-3,3-dimethyl-l-oxobutan-2-
yl]carbamoyl)methoxy)butoxy]benzoic acid:
Hs
HO 4, 0
0 Qy
[0642] To a stirred solution of methyl 4-[4-({[(2S)-1-[(2SAR)-4-hydroxy-2-(([4-
(4-methy1-1,3-thiazol-
5-yl)phenyl]methyl)carbamoyppyrrolidin-1-y1]-3,3-dimethy1-1-oxobutan-2-
yl]carbamoylimethoxy)butoxy]benzoate (42.4 mg, 61.0 pmol) in methanol (2.0 mL)
was added 1 M
NaOH in water (0.5 mL, 12.5 mmol) at room temperature. The reaction mixture
was stirred at room
temperature for 16 hours. LC-MS indicated formation of the desired product.
The reaction mixture was
quenched with 1.0 M aqueous HCI and then concentrated under reduced pressure
to remove the methanol.
The aqueous residue was extracted with Et0Ac (15 mL x 2). The organic layer
was washed with brine (5
mL), dried over Na2SO4, filtered and concentrated under reduced pressure to
give the titled product (yield:
82%) as a white solid. The material was used in next step without any further
purification. Mass (ES): miz
681.2986 [MH].
[0643] Step 3: Synthesis of example 163:
226
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[0644] To a stirred solution of 2-chloro-4-[trans-3-amino-2,2.4,4-
tetramethylcyclobutoxy]benzonitrile (13.9 mg, 50.2 pmol) and 4444( [(2S)-1-
[(2S,4R)-4-hydroxy-2-(1[4-
(4-methy1-1,3-thiazol-5-yDpheny1] methyl }carbamoyppyrrolidin-l-yli -3,3-
dimethyl-1-oxobutan-2-
yl]carbamoyl methoxy)butoxy]benzoic acid (34.2 mg, 50.2 pmol) in methylene
chloride (2.0 mL) was
added 0-(benzotriazol-1-y1)-N,N,N',N'-tetramethyluronium tetrafluoroborate
(16.1 mg, 50.2 pmol) and
diisopropylethylamine (26.0 pL, 150 pmol) at room temperature. The reaction
mixture was stirred at room
temperature for 1.5 hours. LC-MS indicated formation of the desired product.
The reaction mixture was
quenched with water (5 mL) and extracted with DCM (15 mL x 3). The organic
layers were combined,
washed with aqueous NaHCO3 (5 mL), brine (5 mL), dried over Na7SO4, filtered
and concentrated under
reduced pressure to give a crude material, which was purified by flash silica
gel chromatography on a
Teledyne Combiflash ISCO (eluent: DCM/Me0H (v:v = 90:10)) to give the titled
product (yield: 39%) as
an off white solid.
[0645] Synthesis of 2-14-[4-(methoxycarbonyl)phenoxy]butoxy }acetic acid:
o OH
TsCI
Step 1 Step2
0 0
0 _______________________________________ ' 0
1 Steps 1
106461 Step 1: synthesis of tert-butyl 2- (4[(4-
methylbenzenesulfonyl)oxylbutoxylacetate:
0
106471 This material was synthesized from tert-butyl 2-(4-
hydroxybutoxy)acetate and 4-toluenesulfonyl
chloride according to similar procedures described above for the synthesis of
tert-butyl 24(5-[(4-
methylbenzenesulfonypoxy}pentyl}oxy)acetate.
[0648] Step 2: synthesis of methyl 4-(4-[2-(tert-butoxy)-2-
oxoethoxy]butoxy!benzoate.
[0649] To a stirred mixture of methyl 4-hydroxybenzoate (27.99 mg, 184.0 pmol)
and tert-butyl 2-14-
}(4-methylbenzenesulfonyl)oxyJbutoxy }acetate in acetonitrile (2.0 mL) was
added potassium
carbonate (34.67 mg, 250.9 pmol) at room temperature. The reaction mixture was
then stirred at 80 C for
16 hours. LC-MS indicated formation of the desired product. The reaction
mixture was concentrated under
reduced pressure to give a crude residue, which was purified by flash silica
gel chromatography on a
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Teledyne Combiflash ISCO (gradient eluent: heptane/acetone (v:v = 100:0 to
50:50)) to give the titled
product (yield: 94%) as a clear oil. Mass (ES): ink 361.16 [M+Na].
10650] Step 3: Synthesis of Synthesis of 2-{4-14-
(methoxycarbonyl)phenoxylbutoxylacetic acid:
[0651] To a stirred solution of methyl 4-{4-12-(tert-butoxy)-2-oxoethoxyl
butoxy }benzoate (53.1 mg, 156
mot) in dichloromethane (1.0 inL) was added nifluoroacetic acid (1.0 mL, 12.9
mrnol) at room
temperature. The reaction mixture was then stirred at room temperature for 30
minutes. LC-MS indicated
formation of the desired product. The reaction mixture was concentrated under
reduced pressure to give
the titled product (yield: 99% based on crude material) as an off white solid.
The crude material was then
used in next step without any further purification. Mass (ES+): raiz 305.10.
[0652] Examples 162, 164-171 were synthesized according to similar procedure
described for
synthesis of example 163, by using corresponding starting materials and
intermediates.
[0653] Table 10. Exemplary Compounds.
Ex
Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-3,3-dimethy1-242-( { 51(44 [tan s-3-(3-chloro-4-cyancrphenoxy)-
2,2,4,4-
tetrametbylcyclobutyl]carbamoyl }phenyl)amino]pentyl }oxy)acetamido]butanoy1]-
4-
ci-o hydroxy-N-([4-(4-metby1-1,3-thiazol-5-
y1)phenyt]methyl}pyrrolidine-2-carboxamide
µ(:).
k-NH IH NMR (400 MHz, CDC13)3 8.68 (s, 1H). 7.63 (d..1= 8.6 Hz, 2H),
7.57 (d, J = 8.6
L o Hz, 1H), 7.35 (q, .1= 8.5 Hz, 411). 6.97 (d, J =
2.3 Hz, 1H),6.81 (dd, J = 2.5. 8.8 Hz,
--v 111), 6.60 (d, J =).0 Hz, 2H). 6.07-6.12 (in, 111),
4.74(s, 1H), 4.50-4.59 (m. 3H),4.37
OH
(d, J = 5.1 Hz, 1H), 4.11-4.17 (m, 2I-1), 3.64 (dd, J = 3.5, 11.31-h, 1I-1),
3.53 (d, J = 7.0
" 'o
Hz, 2H), 3.19 (t, J = 7.0 Hz, 2H), 2.55-2.61 (m, 1H), 2.52(s, 3H), 2.10-2.19
(m, 211).
1.65-1.71 (m,411), 1.50-1.53 (rn, 2H), 1.24-1.33 (m, 9H), 1.22 (s, 6H), 0.96
(s, 9H),
172 0.86-0.91 (m, 31-1). LC-MS (ES.): in& 955.43 [MI-11
(2S,4R)-1-[(2S)-3,3-dimethy1-2-1.24 ( 54(44 [trans-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
11%
tetramethylcyclobutyl] carbamoyl } phenyl* linojpeittyl }
oxy)acetamido]butanoy11-4-
hydroxy-N- ( [4-(4-methy1-1,3-oxazol-5-yl)phenyl]methyl ) pyrrolidine-2 -
carbox amide
x
o NMR (400 MHz, CDC13) 8 7.82 (s, 1I-1), 7.63 (d, J
= 8.6 Hz, 2Ii), 7.53 (d, J = 8.6
Hz, 211), 7.35 (s, 211), 7.18-7.21 (m, 1H), 6.97 (d, J = 2.3 Hz, 111), 6.81
(dd, J = 2.3, 8.6
Alsip
Hz, 1H), 6.59 (d, .1= 8.6 Hz, 2H), 6.08-6.12 (m, 1H), 4.73 t, J = 8.0 Hz.,
1H),4.49-4.60
(m, 3H). 4.32-4.39 (m, 1H), 4.11-4.17 (m. 2H), 3.63 (dd, J = 3.5. 11.3 Hz,
1H), 3.49-
HN-t
b 3.57 (m, 21-1), 3.18 (t, J = 6.8 IIz, 2I1), 2.53-
2.61 (m, 1I-1), 2.42 (s, 31-1), 2.08-2.18 (m,
2H), 1.68 (td, J = 7.2, 14.5 Hz., 4H), 1.50-1.53 (m, 2H), 1.26 Id, J = 0.8
Hz., 9H), 1.22(s,
173 611), 0.96 (s, 9H), 0.86-0.91 (m, 3H). LC-MS (ES):
ink 939.46 [MH1
228
CA 03069544 2020-01-09
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Ex
Structure Compound name and Analytical data
#
(2S,4R)-1-[(2S)-3,3-dimethy1-212-( (5 -[(4- ( [trans-3-(3-chloro-4-
cyanophenoxy)-
2.2.4,4-
KZ
tetramethylcycloburyl]carbamoyl)phenyl)amino]pentyl)oxy)acetamido)butanoy1]-4-
,õ
hydroxy-N-[(1S)-144-(4-methy1-1,3-thiazol-5-y1)phenyflethyllpyrrolidine-2-
Z 0 carboxamide
'H NMR (300 MHz. CD300):68.88 (s. 1 H), 7.80-7.65 (m, 3 H). 7.50-7.33 (m, 4
H),
p
0 7.16(s, 1/1), 7.03-6.93 (m, 1 II), 6.54-6.43 (m, 2
II), 5.02 - 4.95 (m, 1 I-1), 4.67 (s, 1 H),
4.65-4.50(m. 1 H), 4.46-4.40 I m, 1 H), 4.29-4.25 (m, 1 H), 4.20-4.15 (n. 1
H), 4.04-
-9-1 3.90 (rn, 2 H), 3.89-3.85 On, 1 H), 3.80-3.73 (m, 1
H), 3.66-3.52 On, 2H), 3.20-3.10
,..-3.C.
(m, 2 I-1), 2.40 (s, 3 1-1), 2.25-1.95 (m, 1 II), 2.02 -- 1.90 (m, 111), 1.80-
1.68 (m, 4 II),
1.65-1.50 (m, 2 H), 1.49-1.43 (in, 2H), 1.30-1.23 (m, 6H), 1.22-1.15 (m, 6 H).
1.01 (s,
174 9 H); LC-MS (ES*); miz,, 968.40 [MH]
(2S,4R)-1-[(2S)-3,3-dimethy1-2-(2-{4-[(4-( [trans-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
9\! 9=1.0 tetrame thylcyclobutyl] carbamoyl } phe uyl)amino}butoxy } acetam
ido)bu ta noyl] -4-
N o hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-
yl)pheny/]methyl }pyrrolidine-2-carboxamide
_ 11-INMR (300 MHz, CD30D):68.88 (s, 1 H), 7350-7.65 (m, 3 H), 7.50-7.33
(rn, 4 H),
X 7.10-7.05 (m, 111), 6.99-690(m, 111), 634-6.43(m, 2 H), 467(s, 1
H), 460-4.50(m,
3 H), 4.48-4.45 (m, 1 H),4.21 (s, 1 H), 4.13-4.05(m, 1 H), 3.98-3.90 (m, 2 H),
3.88-
II
175 c= 3.70 On, 2 H), 3.66-3.48 (rn, 2 H), 3.20-3.03 On, 2
H), 2.40 (s, 3 H), 2.25-2.12 on, 1
H), 2.09 - 1.99 (m, 1 H), 1.80-1.68 (m, 4 H), l.30-1.10(m. 12 H), 1.01 (s. 9
H); LC-MS
(ES*): in/z, 940.15 [MHI]
(2S,4R)-1-[(2S)-212-( (5-[(2-fluom-4-( [trans-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobutyl]carbamoyl}phenyl)aminolpentyl}oxy)acetarnido]-3,3-
_It r_j) dimethylbutanoy11-4-hydroxy-N-([4-(4-methy1-1,3-thiazol-5-
c, o I*
YIIIVNhenRY1](rneth my1Lpyrrocplid oiDne)-2-carboxamide
I m
l`r :68.86 (s, 1 H), 7.80-7.70 (m, 111), 7.60-7.55 (m, 1 H),
7.50-7.37 (in. 4H), 7.14 (s. 1 H), 7.00-6.93 (m, 1 H). 6.80-6.65 (m, 1 H),4.70
(s, 1 H),
4.65-4.50 (m, 3 H), 440-4.30 (m, 1 H), 4.29-4.25 (m, 1 H), 4.20-4.15 (m, 1 H),
4.04-
/
vc. 3.90 (m, 2 H), 3.89-3.85 (m, 1 H), 3.80-3.73 (m, 1
H), 3.70-3.65 (m, 1 H), 3.60-3.52
(m, 2H). 3.30-3.15(m, 2 H), 2.40 (s, 3 H), 2.25-1.95 (m, 1 H), 2.02- 1.90(m, 1
H).
n.
1.80-1.68 (m,4 II), 1.65-1.50 (m, 21-1), 1.30-1.23 (m, 611), 1.22-1.15 (m, 6
II), 1.01 (s,
176 9 H); IC-MS (ES): ma. 972.10 [MH1
(2S,4R)-1-[(2S)-3,3-dimethy1-2-(2- {41(4- ( Wan s-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcycloburyl)carbamoyl)phenyl)amino]butoxy}aceramido)butanoy1]-4-
)4A0 0 (I-1
hydroxy-N-[(1S)-1-[4-(4-n le thy1-1,3-thiazol-5-y1)phenyl]ethyllpyrrolidine-2-
YNN 'Y
0 ---e'p carboxamide
'H NMR (400 MHz. CD301.)) 6 8.86 (s, 1H), 7.72-7.64 (in. 3H), 744(s. 4H), 7.12
(s.
H
N
e'--,'
111), 6.98 (d,J= 2.4 Hz, 111), 6.64 (d,J= 8.8 Hz, 2H), 5.00 (d, J= 6.8 Ilz,
III), 4.69 (s,
o../.----
1H), 4.62-4.58 (m, 1H), 4.44 (s, 1H), 4.28 (s, 1H), 4.12 (s, 1H), 4.00-3.93
(m, 2H),
o -
;.. = 3.87-3.75 (m, 2H), 3.65-339 (rn, 2H),3.21 (5, 2H),
2.47 (5, 3H), 2.27-2.15 (in, 1H), 1.95
a' 1 (m, II-1), 1.76 (s, 4/1), 1.58-1.49 (m, 3/1), 1.26
(d, J = 9.6 Hz, 12H), 1.02(s, 9H); Mass
177 N
(ES*): in& 955.20 [MH]
229
CA 03069544 2020-01-09
WO 2019/023553 PCT/US2018/044051
Ex
Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-3,3-dimethy1-2-(2-{4-[(41 [trans-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
,
tetramethykyclobutyl]carbamoyl}phenyl)amino]butoxy}acetamido)butanoy1]-4-
hydroxy-N-[(1R)-144-14-methy1-1,3-thiazol-5-yl)phenynethyl]pyrrolidine-2-
H s
9) bej carboxamide
1 11 NMR (400 MHz, DMS0) 68.96 (s, 111), 8.49 (d,J
=7.6 Hz, III), 7.90 (d,J = 8.8
NH Hz, 1F1), 7. 63 Id, J = 8.4 Hz, 2H),7.51 (d, J= 8.0
HZ, 2H), 7.42-7.21 (m, 4H), 7.20 (s,
1H), 7.00 (d, J = 8.8 Hz, 1H), 6.55 (d, J= 8.8 Hz, 2H), 6.19 (s, 1H), 5.16 (s,
1H),4.89
/*I
(s, 114), 4.56-4.47 (m, 211), 4.36-4.40 (m, 211), 4.03 (d,J = 9.2 Hz, III),
3.94 (s, 211),
\
3.67-3.57 (in. 2H), 3.56-3.50 (m, 2H),3.07 (s, 2H), 2.44(s, 3H), 2.08-2.01 (m,
1H),
1.98-1.92(m, 111), 1.64 (m, 4H), 1.38 (d, J= 6.8 Hz, 3H), 1.20 (s, 6H), 1.11
(s, 6H),
178 0.91 (s, 9H); Mass ES'): z 954.15 [Mil].
[0654] Synthesis of example 172:
0
.
Step 2
Step 1 Step 3 lor
pH
0 Q
0
N 0 0 H
Step 4 Stet: 5 =O 0 =-=
HN 0 Step
0
1110
4
pH
=-=.õ,../ =
0
yico * N OH
HO 0 N
HN
Step 7 (i=\.) 0
0
s ioltiN 0
Example
S-
172
I
10655] Step 7: Synthesis of example 172:
[0656] TBTIJ (21.5 mg, 0.067 mmol) was added to a solution of 4-{ (5-(1[(25)-1-
[(2S,4R)-4-hydroxy-2-
( ( [4-(4-methy1-1,3-thiazol-5-yl)phenyl]methyl }carbamoyppyrrolidin-1-y1]-3,3-
dimethyl-l-oxobutan-2-
yl]carbamoyl)methoxy)pentyl]amino)benzoic acid (31 mg, 0.044 mmol), 2-chloro-4-
[trans-3-amino-
2,2,4,4-tetramethylcyclobutoxy]benzonitrile (12.4 mg, 0.044 mrnol) in DMF (3.0
mL) and DIPEA (15.4
p L, 0.089 nunol) at room temperature. The resulting reaction mixture was
stirred at room temperature for
lhr. LC-MS indicated formation of the desired product. The reaction mixture
was diluted with Et0Ac (30
230
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