Note: Descriptions are shown in the official language in which they were submitted.
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CEREBLON LIGANDS AND BIFUNCTIONAL COMPOUNDS
COMPRISING THE SAME
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present disclosure is an International Application claiming
priority to U.S. Non-
Provisional Application No. 15/953108, filed 13 April 2018, which is a
Continuation-in-Part of
U.S. Non-Provisional Application No. 14/686,640, filed 14 April 2015, that
claims priority to
U.S. Provisional Application No. 61/979,351, filed 14 April 2014, and a
Continuation-in-Part of
U.S. Non-Provisional Application No. 14/792,414, filed 6 July 2015, that
claims priority to U.S.
Provisional Application No. 61/979,351, filed 14 April 2014, and U.S.
Provisional Application
No. 62/171,090, filed 4 June 2015, all of which are incorporated herein by
reference in their
entirety.
INCORPORATION BY REFERENCE
[0002] U.S. Patent Application Serial No. 15/230,354, filed on August 5,
2016, published as
U.S. Patent Application Publication No. 2017/0065719; and U.S. Patent
Application Serial No.
15/801,243, filed on 1 November 2017; and U.S. Patent Application 15/206,497
filed 11 July
2016; and U.S. Patent Application 15/209,648 filed 13 July 2016; and U.S.
Patent Application
Serial No. 15/730,728, filed on October 11, 2017; U.S. Patent Application
Serial No. 15/829,541,
filed on December 1, 2017; U.S. Patent Application Serial No. 15/881,318,
filed on January 26,
2018; and U.S. Patent Application Serial No. 14/686,640, filed on April 14,
2015, published as
U.S. Patent Application Publication No. 2015/0291562; and U.S. Patent
Application Serial No.
14/792,414, filed on July 6, 2015, published as U.S. Patent Application
Publication No.
2016/0058872; and U.S. Patent Application Serial No. 14/371,956, filed on July
11, 2014,
published as U.S. Patent Application Publication No. 2014/0356322; and U.S.
Patent Application
Serial No. 15/074,820, filed on March 18, 2016, published as U.S. Patent
Application
Publication No. 2016/0272639; and U.S. Patent Application Serial No.
15/885,671, filed on 31
January 2018, are incorporated herein by reference in their entirety.
Furthermore, all references
cited herein are incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
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[0003] The description provides imide-based compounds, including
bifunctional compounds
comprising the same, and associated methods of use. The bifunctional compounds
are useful as
modulators of targeted ubiquitination, especially with respect to a variety of
polypeptides and
other proteins, which are degraded and/or otherwise inhibited by bifunctional
compounds
according to the present disclosure.
BACKGROUND
[0004] Most small molecule drugs bind enzymes or receptors in tight and
well-defined
pockets. On the other hand, protein-protein interactions are notoriously
difficult to target using
small molecules due to their large contact surfaces and the shallow grooves or
flat interfaces
involved. E3 ubiquitin ligases (of which hundreds are known in humans) confer
substrate
specificity for ubiquitination, and therefore, are more attractive therapeutic
targets than general
proteasome inhibitors due to their specificity for certain protein substrates.
The development of
ligands of E3 ligases has proven challenging, in part due to the fact that
they must disrupt
protein-protein interactions. However, recent developments have provided
specific ligands
which bind to these ligases. For example, since the discovery of nutlins, the
first small molecule
E3 ligase inhibitors, additional compounds have been reported that target E3
ligases but the field
remains underdeveloped.
[0005] One E3 ligase with therapeutic potential is the von Hippel-Lindau
(VHL) tumor
suppressor. VHL comprises the substrate recognition subunit/E3 ligase complex
VCB, which
includes elongins B and C, and a complex including Cullin-2 and Rbxl. The
primary substrate of
VHL is Hypoxia Inducible Factor la (HIF-1a), a transcription factor that
upregulates genes such
as the pro-angiogenic growth factor VEGF and the red blood cell inducing
cytokine
erythropoietin in response to low oxygen levels. We generated the first small
molecule ligands of
Von Hippel Lindau (VHL) to the substrate recognition subunit of the E3 ligase,
VCB, an
important target in cancer, chronic anemia and ischemia, and obtained crystal
structures
confirming that the compound mimics the binding mode of the transcription
factor HIF-1 a, the
major substrate of VHL.
[0006] Cereblon is a protein that in humans is encoded by the CRBN gene.
CRBN orthologs
are highly conserved from plants to humans, which underscores its
physiological importance.
Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein
1 (DDB1),
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Cullin-4A (CUL4A), and regulator of cullins 1 (ROC). This complex
ubiquitinates a number of
other proteins. Through a mechanism which has not been completely elucidated,
cereblon
ubquitination of target proteins results in increased levels of fibroblast
growth factor 8 (FGF8)
and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of
developmental
processes, such as limb and auditory vesicle formation. The net result is that
this ubiquitin ligase
complex is important for limb outgrowth in embryos. In the absence of
cereblon, DDB1 forms a
complex with DDB2 that functions as a DNA damage-binding protein.
[0007] Thalidomide, which has been approved for the treatment of a number
of
immunological indications, has also been approved for the treatment of certain
neoplastic
diseases, including multiple myeloma. In addition to multiple myeloma,
thalidomide and several
of its analogs are also currently under investigation for use in treating a
variety of other types of
cancer. While the precise mechanism of thalidomide's anti-tumor activity is
still emerging, it is
known to inhibit angiogenesis. Recent literature discussing the biology of the
imides includes Lu
et al Science 343, 305 (2014) and Kronke et al Science 343, 301 (2014).
[0008] Significantly, thalidomide and its analogs e.g. pomolinamiode and
lenalinomide, are
known to bind cereblon. These agents bind to cereblon, altering the
specificity of the complex to
induce the ubiquitination and degradation of Ikaros (IKZF1) and Aiolos
(IKZF3), transcription
factors essential for multiple myeloma growth. Indeed, higher expression of
cereblon has been
linked to an increase in efficacy of imide drugs in the treatment of multiple
myeloma.
[0009] An ongoing need exists in the art for effective treatments for
disease, especially
hyperplasias and cancers, such as multiple myeloma. However, non-specific
effects, and the
inability to target and modulate certain classes of proteins altogether, such
as transcription
factors, remain as obstacles to the development of effective anti-cancer
agents. As such, small
molecule therapeutic agents that leverage or potentiate cereblon's substrate
specificity and, at the
same time, are "tunable" such that a wide range of protein classes can be
targetted and
modulated with specificity would be very useful as a therapeutic.
BRIEF SUMMARY OF THE INVENTION
[0010] The present disclosure describes bifunctional compounds which
function to recruit
endogenous proteins to an E3 Ubiquitin Ligase for degradation, and methods of
using the same.
In particular, the present disclosure provides bifunctional or proteolysis
targeting chimeric
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(PROTAC) compounds, which find utility as modulators of targeted
ubiquitination of a variety
of polypeptides and other proteins, which are then degraded and/or otherwise
inhibited by the
bifunctional compounds as described herein. An advantage of the compounds
provided herein is
that a broad range of pharmacological activities is possible, consistent with
the
degradation/inhibition of targeted polypeptides from virtually any protein
class or family. 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,
such as cancer, e.g.,
multiple myeloma.
[0011] As such, in one aspect the disclosure provides novel imide-based
compounds as
described herein.
[0012] In an additional aspect, the disclosure provides bifunctional or
PROTAC compounds,
which comprise an E3 Ubiquitin Ligase binding moiety (i.e., a ligand for an E3
Ubiquitin Ligase
or "ULM" group), and a moiety that binds a target protein (i.e., a
protein/polypeptide targeting
ligand or "PTM" group) such that the target protein/polypeptide is placed in
proximity to the
ubiquitin ligase to effect degradation (and inhibition) of that protein. In a
preferred embodiment,
the ULM is a cereblon E3 Ubiquitin Ligase binding moiety (i.e., a "CLM"). For
example, the
structure of the bifunctional compound can be depicted as:
PTM _________________________ CLM
[0013] The respective positions of the PTM and CLM moieties as well as
their number as
illustrated herein is provided by way of example only and is not intended to
limit the compounds
in any way. As would be understood by the skilled artisan, the bifunctional
compounds as
described herein can be synthesized such that the number and position of the
respective
functional moieties can be varied as desired.
[0014] In certain embodiments, the bifunctional compound further comprises
a chemical
linker ("L"). In this example, the structure of the bifunctional compound can
be depicted as:
PTM L CLM
where PTM is a protein/polypeptide targeting moiety, L is a linker, and CLM is
a cereblon E3
ubiquitin ligase binding moiety.
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[0015] In certain preferred embodiments, the E3 Ubiquitin Ligase is
cereblon. As such, in
certain additional embodiments, the CLM of the bifunctional compound comprises
chemistries
such as imide, amide, thioamide, thioimide derived moieties. In additional
embodiments, the
CLM comprises a phthalimido group or an analog or derivative thereof. In still
additional
embodiments, the CLM comprises a phthalimido-glutarimide group or an analog or
derivative
thereof In still other embodiments, the CLM comprises a member of the group
consisting of
thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.
[0016] In certain embodiments, the compounds as described herein comprise
multiple CLMs,
multiple PTMs, multiple chemical linkers or a combination thereof.
[0017] In any aspect or embodiment described herein, the ULM
(ubiquitination ligase
modulator) can be Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety
(VLM), or a
cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2
homolog
(MDM2) E3 ubiquitin ligase binding moiety (MLM), or an IAP E3 ubiquitin ligase
binding
moiety (i.e., a "ILM"). In any aspect or embodiments described herein, the
bifunctional
compound includes at least one additional E3 ligase binding moiety selected
from the group
consisting of VLM, VLM', CLM, CLM', MLM, MLM', ILM, ILM', or a combination
thereof
For example, there can be at least 1, 2, 3, 4, or 5 additional E3 ligase
binding moieties.
[0018] In an additional aspect, the description provides therapeutic
compositions comprising
an effective amount of a compound as described herein or salt form thereof,
and a
pharmaceutically acceptable carrier. The therapeutic compositions modulate
protein degradation
in a patient or subject, for example, an animal such as a human, and can be
used for treating or
ameliorating disease states or conditions which are modulated through the
degraded protein. In
certain embodiments, the therapeutic compositions as described herein may be
used to effectuate
the degradation of proteins of interest for the treatment or amelioration of a
disease, e.g., cancer.
In yet another aspect, the present disclosure provides a method of
ubiquitinating/ degrading a
target protein in a cell. In certain embodiments, the method comprises
administering a
bifunctional compound as described herein comprising an CLM and a PTM,
preferably linked
through a linker moiety, as otherwise described herein, wherein the CLM is
coupled to the PTM
and wherein the CLM recognizes a ubiquitin pathway protein (e.g., an ubiquitin
ligase,
preferably an E3 ubiquitin ligase such as, e.g., cereblon) and the PTM
recognizes the target
protein such that degradation of the target protein will occur when the target
protein is placed in
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proximity to the ubiquitin ligase, thus resulting in degradation/inhibition of
the effects of the
target protein and the control of protein levels. The control of protein
levels afforded by the
present disclosure provides treatment of a disease state or condition, which
is modulated through
the target protein by lowering the level of that protein in the cells of a
patient.
[0019] In an additional aspect, the description provides a method for
assessing (i.e.,
determining and/or measuring) a CLM's binding affinity. In certain
embodiments, the method
comprises providing a test agent or compound of interest, for example, an
agent or compound
having an imide moiety, e.g., a phthalimido group, phthalimido-glutarimide
group, derivatized
thalidomide, derivatized lenalidomide or derivatized pomalidomide, and
comparing the cereblon
binding affinity and/or inhibitory activity of the test agent or compound as
compared to an agent
or compound known to bind and/or inhibit the activity of cereblon.
[0020] In still another aspect, the description provides methods for
treating or emeliorating a
disease, disorder or symptom thereof in a subject or a patient, e.g., an
animal such as a human,
comprising administering to a subject in need thereof a composition comprising
an effective
amount, e.g., a therapeutically effective amount, of a compound as described
herein or salt form
thereof, and a pharmaceutically acceptable carrier, wherein the composition is
effective for
treating or ameliorating the disease or disorder or symptom thereof in the
subject.
[0021] In another aspect, the description provides methods for identifying
the effects of the
degradation of proteins of interest in a biological system using compounds
according to the
present disclosure.
[0022] 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
disclosure 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 disclosure. 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.
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BRIEF DESCRIPTION OF THE DRAWINGS
[0023] The accompanying drawings, which are incorporated into and form a
part of the
specification, illustrate several embodiments of the present disclosure 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:
[0024] Figure 1A and 1B. Illustration of general principle for PROTAC
function. (A)
Exemplary PROTACs comprise a protein targeting moiety (PTM; darkly shaded
rectangle), a
ubiquitin ligase binding moiety (ULM; lightly shaded triangle), and optionally
a linker moiety (L;
black line) coupling or tethering the PTM to the ULM. (B) Illustrates the
functional use of the
PROTACs as described herein. Briefly, the ULM recognizes and binds to a
specific E3 Ubiquitin
Ligase, and the PTM binds and recruits a target protein bringing it into close
proximity to the 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.
DETAILED DESCRIPTION
[0025] The following is a detailed description provided to aid those
skilled in the art in
practicing the present disclosure. 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.
[0026] Presently described are compositions and methods that relate to the
surprising and
unexpected discovery that an E3 Ubiquitin Ligase protein, e.g., cereblon,
ubiquitinates a target
protein once it and the target protein are placed in proximity by a
bifunctional or chimeric
construct that binds the E3 Ubiquitin Ligase protein and the target protein.
Accordingly the
present disclosure provides such compounds and compositions comprising an E3
Ubiquintin
Ligase binding moiety ("ULM") coupled to a protein target binding moiety
("PTM"), which
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result in the ubiquitination of a chosen target protein, which leads to
degradation of the target
protein by the proteasome (see Figures 1A and 1B). The present disclosure also
provides a
library of compositions and the use thereof
[0027] In certain aspects, the present disclosure provides compounds which
comprise a
ligand, e.g., a small molecule ligand (i.e., having a molecular weight of
below 2,000, 1,000, 500,
or 200 Daltons), which is capable of binding to a ubiquitin ligase, such as
TAP, VHL, MDM2, or
cereblon. The compounds also comprise a moiety that is capable of binding to
target protein, in
such a way that the target protein is placed in proximity to the ubiquitin
ligase to effect
degradation (and/or inhibition) of that protein. Small molecule can mean, in
addition to the
above, that the molecule is non-peptidyl, that is, it is not generally
considered a peptide, e.g.,
comprises fewer than 4, 3, or 2 amino acids. In accordance with the present
description, the
PTM, ULM or PROTAC molecule can be a small molecule.
[0028] 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
belongs. The terminology used in the description is for describing particular
embodiments only
and is not intended to be limiting of the invention.
[0029] 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.
[0030] 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.
[0031] 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
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unless the context clearly indicates otherwise. By way of example, "an
element" means one
element or more than one element.
[0032] 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.
[0033] 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
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."
[0034] 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.
[0035] 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
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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);
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.
[0036] 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.
[0037] The terms "co-administration" and "co-administering" or "combination
therapy" 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.
[0038] 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
(enantiomers) and other
stereoisomers (diastereomers) thereof, as well as pharmaceutically acceptable
salts and
derivatives, including prodrug and/or deuterated forms thereof where
applicable, in context.
Deuterated small molecules contemplated are those in which one or more of the
hydrogen atoms
contained in the drug molecule have been replaced by deuterium.
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[0039] 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. 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 or understood within the context of the compound shown and well-
known rules for
valence interactions.
[0040] 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. For
example, cereblon is an E3 Ubiquitin Ligase 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.
[0041] The term "patient" or "subject" is used throughout the specification
to describe an
animal, preferably a human or a domesticated animal, to whom treatment,
including prophylactic
treatment, with the compositions according to the present disclosure is
provided. For treatment of
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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
disclosure, the term patient refers to a human patient unless otherwise stated
or implied from the
context of the use of the term.
[0042] The term "effective" is used to describe an amount of a compound,
composition or
component which, when used within the context of its intended use, effects an
intended result.
The term effective subsumes all other effective amount or effective
concentration terms, which
are otherwise described or used in the present application.
Compounds and Compositions
[0043] In one aspect, the description provides compounds comprising an E3
Ubiquitin
Ligase binding moiety ("ULM") that is a cereblon E3 Ubiquitin Ligase binding
moiety ("CLM").
In one embodiment, the CLM is coupled to a chemical linker (L) according to
the structure:
(I) L-CLM
wherein L is a chemical linker group and CLM is a cereblon E3 Ubiquitin Ligase
binding moiety.
The number and/or relative positions of the moieties in the compounds
illustrated herein is
provided by way of example only. As would be understood by the skilled
artisan, compounds as
described herein can be synthesized with any desired number and/or relative
position of the
respective functional moieties.
[0044] The terms ULM and CLM are used in their inclusive sense unless the
context
indicates otherwise. For example, the term ULM is inclusive of all ULMs,
including those that
bind cereblon (i.e., CLMs). Further, the term CLM is inclusive of all possible
cereblon E3
Ubiquitin Ligase binding moieties.
[0045] In another aspect, the present disclosure provides bifunctional or
multifunctional
PROTAC compounds useful for regulating protein activity by inducing the
degradation of a
target protein. In certain embodiments, the compound comprises a CLM coupled,
e.g., linked
covalently, directly or indirectly, to a moiety that binds a target protein
(i.e., protein targeting
moiety or "PTM"). In certain embodiments, the CLM and PTM are joined or
coupled via a
chemical linker (L). The CLM recognizes the cereblon E3 ubiquitin ligase and
the PTM
recognizes a target protein and the interaction of the respective moieties
with their targets
12
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facilitates the degradation of the target protein by placing the target
protein in proximity to the
ubiquitin ligase protein. An exemplary bifunctional compound can be depicted
as:
(II) PTM-CLM
[0046] In certain embodiments, the bifunctional compound further comprises
a chemical
linker ("L"). For example, the bifunctional compound can be depicted as:
(III) PTM-L-CLM
wherein PTM is a protein/polypeptide targeting moiety, L is a linker, and CLM
is a cereblon E3
ligase binding moiety.
[0047] In certain embodiments, the compounds as described herein comprise
multiple PTMs
(targeting the same or different protein targets), multiple CLMs, one or more
ULMs (i.e.,
moieties that bind specifically to another E3 Ubiquitin Ligase, e.g., VHL) or
a combination
thereof In any of the aspects of embodiments described herein, the PTMs, CLMs,
and ULMs
can be coupled directly or via one or more chemical linkers or a combination
thereof In
additional embodiments, where a compound has multiple ULMs, the ULMs can be
for the same
E3 Ubiquintin Ligase or each respective ULM can bind specifically to a
different E3 Ubiquitin
Ligase. In still further embodiments, where a compound has multiple PTMs, the
PTMs can bind
the same target protein or each respective PTM can bind specifically to a
different target protein.
[0048] In another embodiment, the description provides a compound which
comprises a
plurality of CLMs coupled directly or via a chemical linker moiety (L). For
example, a
compound having two CLMs can be depicted as:
(IV) CLM-CLM or
(V) CLM-L-CLM
[0049] In certain embodiments, where the compound comprises multiple CLMs,
the CLMs
are identical. In additional embodiments, the compound comprising a plurality
of CLMs further
comprises at least one PTM coupled to a CLM directly or via a chemical linker
(L) or both. In
certain additional embodiments, the compound comprising a plurality of CLMs
further
comprises multiple PTMs. In still additional embodiments, the PTMs are the
same or, optionally,
different. In still further embodiments, wherein the PTMs are different the
respective PTMs may
bind the same protein target or bind specifically to a different protein
target.
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[0050] In additional embodiments, the description provides a compound
comprising at least
two different CLMs coupled directly or via a chemical linker (L) or both. For
example, such a
compound having two different CLMs can be depicted as:
(VI) CLM-CLM' or
(VII) CLM-L-CLM'
wherein CLM' indicates a cereblon E3 Ubiquitin Ligase binding moiety that is
structurally
different from CLM. In certain embodiments, the compound may comprise a
plurality of CLMs
and/or a plurality of CLM' s. In further embodiments, the compound comprising
at least two
different CLMs, a plurality of CLMs, and/or a plurality of CLM's further
comprises at least one
PTM coupled to a CLM or a CLM' directly or via a chemical linker or both. In
any of the
embodiments described herein, a compound comprising at least two different
CLMs can further
comprise multiple PTMs. In still additional embodiments, the PTMs are the same
or, optionally,
different. In still further embodiments, wherein the PTMs are different the
respective PTMs may
bind the same protein target or bind specifically to a different protein
target. In still further
embodiments, the PTM itself is a ULM or CLM (or ULM' or CLM').
[0051] In a preferred embodiment, the CLM comprises a moiety that is a
ligand of the
cereblon E3 Ubiquitin Ligase (CRBN). In certain embodiments, the CLM comprises
a
chemotype from the "imide" class of of molecules. In certain additional
embodiments, the CLM
comprises a phthalimido group or an analog or derivative thereof.
In still additional
embodiments, the CLM comprises a phthalimido-glutarimide group or an analog or
derivative
thereof In still other embodiments, the CLM comprises a member of the group
consisting of
thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.
[0052] In additional embodiments, the description provides the compounds as
described
herein including their enantiomers, diastereomers, solvates and polymorphs,
including
pharmaceutically acceptable salt forms thereof, e.g., acid and base salt
forms.
[0053] Exemplary Cereblon Binding and/or Inhibiting Compounds
[0054] In one aspect the description provides compounds useful for binding
and/or inhibiting
cereblon E3 Ubiquitin Ligase binding moiety. In certain embodiments, the
compound has a
chemical structure that includes at least one of (e.g., the compound has a
chemical structure
selected from the group consisting of):
14
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[0055] Neo-imide Compounds
[0056] In one aspect the description provides compounds useful for binding
and/or inhibiting
cereblon. In certain embodiments, the compound is selected from the group
consisting of
chemical structures:
X x G X X G
Q
%AZ ______________________ N/ Q3 (;/4
N/
Q(¨I(
4.,......s,........ ej,(
-"--
II N __________ Z II N __________ Z
A
1¨ Q2 ce."\,/ \ _______ )
N
Rn \G' Rn Rn R'
(al) (b)
G
I
X )(N z
X X G
C;14 ____________________ N
Q3 ........`..."-= --........< / Q(Q4NI-I.P1')c
II N ) __ Z I I Rn
V ====----_ w/
A _______________________ N
Rn X G' Rn
(c) (dl)
G
I
X xN z
X X
Q
ci(C)4N sispr.\( crr 4,........s......... ..j,(
I I Rn I I WW1 Z
Cl/ ------....1
Qi
Qi N A
Rn
RnQ/
Rn
(e) (0
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X )(
X X
Q4
c)
Rn
A ______ z
Qi Qi
Rn
RnQ2/ RnQ2/ (a2) (d2)
II
___________________________ N/
Rn
Q3
Q2/NawlACI) .. Z
Qi
Rn
(a3)
wherein:
W of Formulas (a) through (e) is independently selected from the group CH2,
CHR, C=0,
SO2, NH, cyclopropyl group, cyclobutyl group, and N-alkyl;
W3 is selected from C or N;
each X of Formulas (a) through (e) is absent or independently selected from
the group 0 and
S.
Y of Formulas (a) through (e) is independently selected from the group CH2, -
C=CR', NH,
N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, 0, and S;
each Z of Formulas (a) through (e) is absent or independently selected from
the group 0 and
S, except that both X and Z cannot be absent,
G and G'of Formulas (a) through (e) are independently selected from the group
H, alkyl
(linear, branched, optionally substituted), OH, R'OCOOR, R'OCONRR", CH2-
heterocyclyl optionally substituted with R', and benzyl optionally substituted
with R';
Q1 ¨ Q4 of Formulas (a) through (e) represent a carbon C substituted with a
group
independently selected from R', N or N-oxide;
A of Formulas (a) through (e) is independently selected from the group H,
alkyl (linear,
branched, optionally substituted), cycloalkyl, Cl and F;
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R of Formulas (a) through (e) comprises, but is not limited to: -CONR'R", -
OR', -NR'R", -
SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, (-CR'0),,R", -aryl, -hetaryl, -
alkyl
(linear, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -
P(0)(OR')R", -
P(0)R'R", -0P(0)(OR')R", -0P(0)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'
SO2NR'R", -
NR' CONR' R", -CONR' COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-
CN)R", -NR'C(=C-NO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -
CR'=CR'R", -CCR', -S(C=0)(C=N-R')R", -SF5 and -0CF3
R' and R" of Formulas (a) through (e) are independently selected from a bond,
H, alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=0)R, heterocyclyl, each of
which is
optionally substituted;
n' of Formulas (a) through (e) is an integer from 1-10 (e.g., 1-4);
of Formulas (a) through (e) represents a bond that may be stereospecific ((R)
or (S)) or
non-stereospecific;
represents a single bond or a double bond;
represents a bond that may be stereospecific ((R) or (S)) or non-
stereospecific; and
Rn comprises 1-4 independent functional groups, optionally substituted linear
or branched
alkyl (e.g., a C1-C6 linear or branched alkyl optionally substituted with one
or more
halogen, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally
substituted aryl (e.g., an optionally substituted C5 -C7 aryl), optionally
substituted alkyl-
aryl (e.g., an alkyl-aryl comprising at least one of an optionally substituted
C1-C6 alkyl,
an optionally substituted C5-C7 aryl, or combinations thereof), optionally
substituted
alkoxyl group (e.g., a methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy;
wherein
the alkoxyl may be substituted with one or more halogen, alkyl, haloalky,
fluoroalkyl,
cycloalkyl (e.g., a C3 -C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted
ON1:0)/Nc
(e.g., optionally substituted with one or more
halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3 -C6 cycloalkyl),
or aryl (e.g.,
0
C5-C7 aryl)), optionally substituted
(e.g., optionally
17
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substituted with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl
(e.g., a C3-
C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms; and
each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6,
[0057] Exemplary CLMs
[0058] In any of the compounds described herein, the CLM comprises a
chemical structure
selected from the group:
X x G X X G
Q
jvvk _____________________ / \ /
C14...........1( Q;.....= 4...,..
Q3
I I / N __________ Z II N _____ N
Qt ____________________________________________________________ ) z
C/ I A 1¨ Q2 ...**---...1
Qi N
Rn \G' R Rn Rn '
(al) (b)
G
I
X x N z
X X G
(:14 ............1( \ __ 1.1 /
Q3 Q(C)4N'isPrc
I I i sõ,., N Q/) z I 1 Rn
Rn
Q2/
Qi
x/ \G' Qi Y Z
Rn
(c) (dl)
G
I
N
X z Q3 cl4X Xr
Q(Q4N'Is$')c
I I Rn
Rn
Q/ Qi
Qi N A
Rn
Rn
(e) (0
18
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X x N
X X
N
I
RnQ2/ A Rn I I I Rn z
Qi c1
Rn
Q2/
(a2) (d2)
(:)4
Q3
auk __________________________ Z
A
Qi
Rn
RnQ2/
(a3)
wherein:
W of Formulas (a) through (f) is independently selected from the group CH2,
CHR, C=0,
SO2, NH, N, optionally substituted cyclopropyl group, optionally substituted
cyclobutyl
group, and N-alkyl;
W3 is selected from C or N;
each X of Formulas (a) through (f) is absent or independently selected from
the group 0 and
S;
Y of Formulas (a) through (f) is independently selected from the group CH2, -
C=CR', NH,
N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, 0, and S;
each Z of Formulas (a) through (f) is absent or independently selected from
the group 0 and
S, except that both X and Z cannot be absent;
G and G' of Formulas (a) through (f) are independently selected from the group
H, alkyl
(linear, branched), OH, R' OCOOR, R' OCONRR", CH2-heterocycly1 optionally
substituted with R', and benzyl optionally substituted with R';
Q1 ¨ Q4 of Formulas (a) through (f) represent a carbon C substituted with a
group
independently selected from R', N or N-oxide;
A of Formulas (a) through (f) is independently selected from the group H,
alkyl (linear,
branched, optionally substituted), cycloalkyl, Cl and F;
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R of Formulas (a) through (f) comprises, but is not limited to: -CONR'R", -
OR', -NR'R", -
SR', -S 02R' , -S 02NR' R", -CR' R"-, -CR' NR' R" -, (-CR' 0),,R", -aryl, -
hetaryl, -alkyl
(linear, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -
P(0)(OR')R", -
P(0)R'R", -0P(0)(OR')R", -0P(0)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'
SO2NR'R", -
NR'CONR'R", -CONR' C OR" , -NR' C(=N-CN)NR' R", -C(=N-CN)NR' R", -NR' C(=N-
CN)R", -NR' C(=C-NO2)NR'R", - S 02NR' COR", -NO2, -CO2R', -C(C=N-OR' )R", -
CR' =CR' R", -CCR', -S(C=0)(C=N-R')R", -SF5 and -0CF3
R' and R" of Formulas (a) through (f) are independently selected from a bond,
H, alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=0)R, heterocyclyl, each of
which is
optionally substituted;
n' of Formulas (a) through (f) is an integer from 1-10 (e.g., 1-4);
represents a single bond or a double bond;
¨ of Formulas (a) through (f) represents a bond that may be stereospecific
((R) or (S)) or
non-stereospecific;
Rn comprises 1-4 independent functional groups, optionally substituted linear
or branched
alkyl (e.g., a C1-C6 linear or branched alkyl optionally substituted with one
or more
halogen, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally
substituted aryl (e.g., an optionally substituted C5-C7 aryl), optionally
substituted alkyl-
aryl (e.g., an alkyl-aryl comprising at least one of an optionally substituted
C1-C6 alkyl,
an optionally substituted C5-C7 aryl, or combinations thereof), optionally
substituted
alkoxyl group (e.g., a methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy;
wherein
the alkoxyl may be substituted with one or more halogen, alkyl, haloalky,
fluoroalkyl,
cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally
substituted
OhM:0)(
(e.g., optionally substituted with one or more
halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl),
or aryl (e.g.,
)1):
C5-C7 aryl)), optionally substituted
(e.g., optionally
CA 03095912 2020-10-01
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substituted with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl
(e.g., a C3 -
C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms; and
each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6.
[0059] In any aspect or embodiment described herein, each of the X and Z of
the 6-member
monocyclic cyloalkyl or monocyclic heterocycloalkyl of the CLM are each
independently absent,
0 or S, except that both X and Z cannot be absent. In any aspect or embodiment
described
herein, X on the middle ring is selected from 0 and S, and each of the X and Z
of the 6-member
monocyclic cyloalkyl or monocyclic heterocycloalkyl of the CLM are each
independently absent,
0 or S, except that both X and Z cannot be absent.
[0060] In certain embodiments described herein, the CLM or ULM comprises a
chemical
structure selected from the group:
0
NH
jK1 j:
_________________________________________________________ 0
w
R n
Formula (g)
wherein:
W of Formula (g) is independently selected from the group CH2, C=0, NH, and N-
alkyl;
R of Formula (g) is independently selected from a H, methyl, alkyl (e.g., a or
C1-C6 alkyl
(linear, branched, optionally substituted));
¨ of Formula (g) represents a bond that may be stereospecific ((R) or (S)) or
non-
stereospecific; and
Rn comprises 1-4 independent functional groups, optionally substituted linear
or branched
alkyl (e.g., a C1-C6 linear or branched alkyl optionally substituted with one
or more
halogen, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally
substituted aryl (e.g., an optionally substituted C5-C7 aryl), optionally
substituted alkyl-
aryl (e.g., an alkyl-aryl comprising at least one of an optionally substituted
C1-C6 alkyl,
an optionally substituted C5-C7 aryl, or combinations thereof), optionally
substituted
alkoxyl group (e.g., a methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy;
wherein
21
CA 03095912 2020-10-01
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the alkoxyl may be substituted with one or more halogen, alkyl, haloalky,
fluoroalkyl,
cycloalkyl (e.g., a C3 -C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted
00)/c
(e.g., optionally substituted with one or more
halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3 -C6 cycloalkyl),
or aryl (e.g.,
)1):
C5-C7 aryl)), optionally substituted
(e.g., optionally
substituted with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl
(e.g., a C3-
C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms.
[0061]
In any of the embodiments described herein, the W, X, Y, Z, G, G', R, R', R",
Q1 -
Q4, A, and Rn of Formulas (a) through (g) can independently be covalently
coupled to a linker
and/or a linker to which is attached one or more PTM, ULM, CLM or CLM' groups.
[0062]
More specifically, non-limiting examples of CLMs include those shown below as
well as those "hybrid" molecules that arise from the combination of 1 or more
of the different
features shown in the molecules below.
22
CA 03095912 2020-10-01
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PCT/US2019/026570
O 0 0 0 0 0
-,......."\.õ. __ NH =,..õ,.../\.õ __ NH NH
,../ _____ , 0 _____ .,.......(N
1 0
NM
) 1
/ / 0
Rn 0 Rn 0 Rn 0
O 0 0 0 0 S
,...õ..,N, .jK. __ ...... NH ___________ ,........".õ._ NH
,.........õ,.... JK. NH
y.,......,\.(N1111.'"
0 0 1
,../...,N ____________________________________________________________ 0
Alk Al
Rn 0 Rn 0 Rn 0
O 0 0 0 0 0
,.........õ., __ NH ,.......õ,.....,./(µ NH
.õ,.õ,.NH
1 N ______ 0
Rn'
N 0 yl ...........<N
S
y"---..õ/
Rn Rn S Rn 0
0 0
..,.) o 0 o
N.,,., .,.:.,,......K ______________________________________________ NH
N ______________ NH N ...,/.= _______ NH
N 0 y N t/ 0
R n/1
Rn N
0
O Rn 0
O 0 0 0 0 0
\N
________________ NH ____________________ NH NH
1/ N
N ___________________________________________ 0 Rn RII/
0
N 0
".-....--\(
Rn n
0 0
_________________________________________________________________ NH
N ____________________________________________________________
Rn 0 Rn 0 Rn 0
O 0
____________________ . O 0 0 0 H
N _______________________________________________________________ N __
N " 0
.........-=:;,_........ ___________________ NH /
1\/ 0
/K N y
Rn 0 Rn Rn
23
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PCT/US2019/026570
o o ,................. o?.
,.......--........___<. NH _____________ \,..... NH __________ \,,,
NH
1 ) 0 y N
) 0 1 N ______ )
__ S
/.-----JN ____ \
\ -----.....<
\ _______________________________________________________________________ NH
__________________ NH \ __ NH
Rn Rn S Rn 0
0 0 0
...,..,,..õ,,,( 0
N õ,,..,N......,, __ \
NH
__________________ NH N =,.../. _________ NH
1 N ______ \ ) __ 0 N /1
N.,....<N \ ) 0
/< NH
NH \ __ NH
Rn 0
Rn 0 Rn 0
O 0 0 0 0 0
N...,. ....õ....õ( NH (N ________________ NH
N ______________________________ NH
N ______ 0
Nõ,./...,,... \ ) 0 1,/,..,
\ _______________________________________________________________________ )
NH _______________________ NH NH
Rn Rn Rn
0 0 0
,...,.............õ0 0. N/OH 0 0
NH
0
y
N \ ) S
1 N \ )
Rn'
........< __ \ \ NH NH
__________________ NH
Rn Rn S Rn 0
O 0 0 0 . ..,,....,/,
__________________ NH ___________________ N
NH
...õ...-N...... _____.< ..õ,./....,.... J.K.
1
N ______ \ ) S
__________________ NH __________________ NH __________________________ NH
Rn Rn 0 Rn 0
24
CZ
O um 0 0 uN 0
/ 0
um
HN ____ S HN ....,..../ )..õ,..,.../.,,,,../ 0 .. -IN
/VI
I )____.....
0 __ ( N ( _____ N
I 0
N __________________________________
HN __ \ )1......., HN
0 0 0 0
0 0
0 0 um 0 0 um 0
um
HN ______________________ HN __
HN __
)\----/I ).-
------/I
)\---...../
I 0 _______________________ ( N 0 __ K
I
0 __ ( ____ N
),.....,. ,,...,.,H
__________________________________________________________________________
N)....,____.,
)/......-- /N __ \ HN
N
/
0 0 0 0
HO 0 0
O 0 um /0 0
um 0 0
um
HN __ =
HN _____________ y........5.,,,e,N,../
/
0 -IN
).-------,/N
\ I 0
..)
N 0 __ ( N
i
)7_,...õ........s... ) ''''-"N HN )rN
HN __ \ HN __ \ N
O 0 0 0 0 0
O 0 um 0
0 um
0 0 um
HN HN __ \----*--N/ )\ HN / )\---
**/
),
N
1
0 __ ( N),,,j1
) 0 HN HN )rN
)rN
HN __ \ __ N \
O 0 0 0
0 0
O 0 um 0 S um 0
um
HN _____________________________________________________ HN
HN
Y"---./1 7.-------/I
S __ K
N.....-11 0 K
HN _________________________________ N I 0 __ ( i __ N
I
)r..---
).[..,----
HN __
HN _________________________________________________ \
O 0 0 0 \O 0
0 0 um 0 0 um 0 0
um
4IV
HN IV .......,......,,,,../.
HN : ___________ N/1
)\----*---/
1 0 ?
( ...iiiiIN
0 __ ( ____ N
HN 0 __ (
1 I
.,.....z.õ../ ),....---
HN __ )r,----
HN __ \ HN __ \
\0
S 0 0 0 0
O 0 um 0 0
um
S um
...IIIIIN
UN __
N
0 __ ( ___ N0.-'*-- 1 0 __ KHHNN
'-'....
HN __
)---- .- .. ......'.2 HN
O 0 0 0
0 0
OLS9Z0/6IOZSI1/IDcl 918661/610Z OM
TO-OT-OZOZ ZT6S600 VD
CA 03095912 2020-10-01
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H H H
O
ON(3 0 (3NC) S N
N N 'ss' rNµNNµ
YO
/0 /0
Rn Rn H Rn
0.NO
0 ONHC) 0 0 SNHC)
Alk Alk
YO O O
Rn H Rn' H Rn Y
0 0 0NC) ON 0 C)NHS
N N rN
Rn', H 1/s 0
Rn Rn/
0 (3NC) 0 (31'1HC) 0 C)N1HC)
N
I NN (NN
N../0
t/0
Rn H
0 ONO Rn Rn
0 C3NHC) 0 (3NHC)
NN N KNN
Rn
/0 II
Rn Rn
H
H
0 ONO
0 (3N1HC)
NNN N.,..,.,,...,N.,,,,....=
YNO 1/10
H
Rn
1 Rn Rn OH
I N
0 N
0 C)C)
N rN N
O
S0 tO
RI Rn/ Rn/
26
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
el
H H
0 .,N 0 0 0...,,,., N .0 0 0..,...,õN,,
N N N
..,..,,,.0
0 1.0
Rn Rn Rn/
H
0 N 0
0
1/
0
Rn
H
0,..., N e.,.....0
0
0 0 0
N
I N ---\ 0 N
___________________________________________________________________ NH
Rn
Rn Rn 0 0 0
Qn0
0 0 0 0
R Rn \
N 0 Nd: /....---/K N H
,
H N H 1 _,... IN __ 0
0 0 R/
0 0
0 0
õ_.,.../K NH j=K NH
O 1/ N 0
\ "-----j
Rn Rn
0 00o
27
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
F
O 0
____________________ NH F 0
0 0
ly_....._.1 0 NH 0
Rn N
0 R/
oRn-------/
0
O 0 0 0
____________________________________________________ NH
____________________ NH
N __________ 1 N 0
7N/ _____________ /
Rn Rn
O 0
____________________ NH 0 0
____________________________________________________ NH
N ______________________________________________________ 0
Rn 0
0
O 0 0 0
\-NI, >
\ ___________________________________________________ NH
Rn 0 Rn 0
O 0
\\ 0 0
____________________________________________________ NH
0
Rny 0------_------_<
Rn7 0< 28
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
H
N
0 o o
0 0
N N N ______ NH
I...._..__<
0
Rn\/
Rn1/ 0
0 0 X
N ,._...JK NI" ./( ( _____ NH
Rn 0 Rn
H
0 N o o
N
N
Rn
29
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
O _________________________________ o 0 0\ NH 0 0
NH
...... _________ NH
N _________________________________ 0 NIIII.... 0
0
Rn Rn Rn
O 0 0 0 0 S
\ ),\
\ __ NH
________________ NH ______________________ NH
NIIin... ______________________________________ 0 N ______ 0
AI k- Alk
Rn Rn Rn
O 0 S 0 \ 0 0
________________ NH
____________________________________________ NH ___________________ NH
N __________________ 0 N _______ 0 N _________ S
Rn Rn Rn
0 0
0) 0 0
cN.......,oN
________________ NH
_____________________ 0 N =---....--(
N ______________________________________ >
\ __________________________________________ NH
_______________________________________________ 1 N.....
N _________________________________________________________________ NH
___________________________________________________________________________ 0
Rn
RI Rn 0
O 0 \ OH
_________________ NI 0 0 0
N 0 \
r........õ
____________________________________________ NH
N/N.....---K
____________________________________________________________________ NH
N ___________________ 0
11 N N __________ 0
N..,/,..,=-=
Rn 0 Rn Rn
O 0 0 0 0 \
________________ N/
NH
( __________________________________________ NI 0
N ________________________________ 0 _______________________ N __ N
Rn Rn Rn
O 0
______________________ = 0 0
N
\ ________________________________________________ /N ____ NH
________________________________________________________________ 0
N __________________ 0
S
02
Rn Rn
1
Liu
uN k)
HN ______________________________________________________________ S
HN
0 __ K :(! Nil
\ ________________________ N
S HN _______________________________ HN __ \
\ID \ 0 0
0
um
um HN __
HN 0 __ ( N
S _______________ K \ N
HN
* 0 0
0 0
um um
um
HN ___________________ HN ______________________ HN ___________ N
___________________________________ Nrµi
) 0 __ K ) __ N
0 __ RN ___________________ HN ______________________ HN __
1
)...........-........,..,... .......,N
N \
\ µ
0 0 0 0 0 0
um
um
um
HN __________ N HN ______________________ HN __
0 _______ N I 0 K :! _____ N1/./
. 0 __ K __ N),..........
1
HN __
0 N N HN __
HN
0 y............=........õ.....õ,..
0 \
0 0 N
0
um
um um
(HN ______________________________________________________
HN _____________________________
HN __
\ _________ N N 0 ________ N
N ________________________________________________________
HN __
S HN / \
\
0 S
0 HO 0 0
0
OLS9Z0/6IOZSI1LIDcl 918661/610Z OM
TO-OT-OZOZ ZT6S600 VD
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
0 0
O 0 0 0
______________________________________________________________________ NH
...3 ______________ NH NH
N ____________________________________________________________________ ) __ 0
N ) 0 ___ Minn. ) 0
______________________________________________________________________ NH
__________________ NH ____________________ NH
Rn S
Rn 0 Rn 0
O 0 0 0 0 S
\
\ _________________ NH ____________________ NH ______________________ NH
N ) 0 ___ Won. ) 0
N ) __ 0
7Ai; ______________ NH AR __ NH ____________________ NH
Rn 0 Rn 0 Rn 0
O 0\ S 0 0 0\
__________________ NH _____________________ NH
______________________________________________________________________ NH
N ) 0 ____ N ) 0 _____ N __ )
S
__________________ NH _____________________ NH
Rn ___________________________________________________________________ NH
Rn 0 0 Rn 0
0 0\
0 0 0 0
N
........../(N N
? _________________ NH
)
__________________ NH __ 0 N''..-----j(
,s..........::õ..,.......N NH
_______________________________________________ 1 N.:.............õ..K
NH
N? N ___________ )
Rn 0 NH __ 0
Rn 0 Rn 0/
N 0 0 0 0 0
_________________ NH ,N,....JK ? ____ NH N
______________________________________________________________________ NH
N
N ________________ ) __ 0
I I N ________ I N __
) _________________________________________________________________________ 0
/ NA1:7-...... j
O NH ____ NH ______________
/....,".........././ NH
02
Rn 0 Rn 0 Rn 0
O 0\ 0 0
N/ 0 9?NH
): N/PH
__________________ NH
N ) 0 ____ N ) 0 ______ N __ )
0
__________________ NH ____________________ NH
Rn
/ Rn 0 Rn 0
O 0 0 0
____________________________________________________ =
NH N
) ____________________ 0 N __
________________________________________ NH 0
NH
Rn 0 Rn 0
32
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
H H H
0
0
0 N 0 N
S
Rn Rn Rn
H H H
0 0 OT NO
S 0
O N 0 0 N
NNN
00.
N N =
Alk Alk
OH H
Rn H Rn
I 0 S
O Rn
N oN o
0 0 0 N
0
N N
N
Rn
Rn
0 [41 0 H
O Rn 0 N 0 0
0
0 0 N
(N. N N NN
NI? ,,,&,., (....
'N
H
Rn 0 0
0 ==,/'==,,,,,,,, Rn H Rn H
0 N 0 N 0 0
0 0
NN
1 II
N N ../..;,
Rn
Rn Rn
1 0 C) 0 H
N
0
0
0
0 O. N
NN NN
N
Rn Rn
Rn
33
CA 03095912 2020-10-01
WO 2019/199816
PCT/US2019/026570
I.
H H
0
N N
No
0 ,;) 0 o
N N N
Rn Rn Rn
H
0 N 0
0
Rn
N _______________________________________________ 0 0
0
Rn
\ ____________________ NH
Rn(-N HN 0 (-N) HN _____________ 0
/0 0\ ___________________________________ N 0 0
N/ ) _______ < NH
R2/ HN 0 / ) ____ < ______
Rn -N HN _____________________________________________ \
f( NH
0
0
/ )<1 ______________
\ NH
Rnk=N HN _________________ 0
[0063] The term "independently" is used herein to indicate that the
variable, which is
independently applied, varies independently from application to application.
[0064] 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-C6,
alternatively a Ci-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,
34
CA 03095912 2020-10-01
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isopropyl, 2-m ethyl propyl , cyclopropyl, cycl opropyl m ethyl, cyclobutyl,
cycl op entyl, cycl op en-
tylethyl, cyclohexylethyl and cyclohexyl, among others. In certain
embodiments, the alkyl group
is end-capped with a halogen group (At, Br, Cl, F, or I). In certain preferred
embodiments,
compounds according to the present disclosure 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 distal end which results in covalent
binding of the compound
containing such a moiety to the protein.
[0065] The term "Alkoxy" refers to an alkyl group singularly bonded to
oxygen.
[0066] The term "Alkenyl" refers to linear, branch-chained or cyclic C2-C10
(preferably C2-
C6) hydrocarbon radicals containing at least one C=C bond.
[0067] The term "Alkynyl" refers to linear, branch-chained or cyclic C2-C10
(preferably C2-
C6) hydrocarbon radicals containing at least one CC bond.
[0068] The term "alkylene" when used, refers to a ¨(CH2),- 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 C1-C6 alkyl group
(including a
cyclopropyl group or a t-butyl 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, 13-alanine, arginine, asparagine,
aspartic acid,
cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine,
histidine, isoleucine, lysine,
leucine, methionine, proline, serine, threonine, valine, tryptophan or
tyrosine.
[0069] 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
CA 03095912 2020-10-01
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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.
[0070] 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 sub stitutents, preferably up
to three substituents,
often 1 or 2 substituents on a moiety in a compound according to the present
disclosure 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 (CI\T), 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, Ci-Cio ,
more preferably, Ci-C6), aryl (especially phenyl and substituted phenyl for
example benzyl or
benzoyl), alkoxy group (preferably, Ci-C6 alkyl or aryl, including phenyl and
substituted phenyl),
thioether (Ci-C6 alkyl or aryl), acyl (preferably, Ci-C6 acyl), ester or
thioester (preferably, Ci-C6
alkyl or aryl) including alkylene 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,
Ci-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 Ci-C6
dialkyl amine which
alkyl groups may be substituted with one or two hydroxyl groups) or an
optionally substituted ¨
N(Co-C6 alkyl)C(0)(0-Ci-C6 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
Ci-C6 alkyl groups), alkanol (preferably, Ci-C6 alkyl or aryl), or alkanoic
acid (preferably, Ci-C6
alkyl or aryl). Substituents according to the present disclosure may include,
for example ¨
SiRisubRzsubR3sub groups where each of Rib and R2sub is as otherwise described
herein and R3sub
is H or a Ci-C6 alkyl group, preferably Rlsub, R2sub, R3sub in this context is
a Ci-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)m- or alternatively an optionally substituted -(OCH2)m-, -(OCH2CH2)m- or -
(CH2CH20)m-
group, which may be substituted with any one or more of the above-described
substituents.
36
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
Alkylene groups -(CH2)m- or -(CH2),- 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 C i-C6 (preferably Ci-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 sidechain 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 Cl-C6 alkyl groups,
preferably Ci-C4 alkyl
group, most often methyl or 0-methyl groups or a sidechain of an amino acid as
otherwise
described herein. In the present disclosure, a moiety in a molecule may be
optionally substituted
with up to five substituents, preferably up to three substituents. Most often,
in the present
disclosure, moieties which are substituted are substituted with one or two
substituents.
[0071] The term "substituted" (each substituent being independent of any
other substituent)
shall also mean within its context of use Cl-C6 alkyl, Cl-C6 alkoxy, halogen,
amido,
carboxamido, sulfone, including sulfonamide, keto, carboxy, Cl-C6 ester
(oxyester or
carbonylester), Ci-C6 keto, urethane -0-C(0)-NRisubR2sub or ¨N(Risub)-C(0)-0-
Risub, nitro,
cyano and amine (especially including a Cl-C6 alkylene-NRisubR2sub, a mono- or
di- Cl-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, -(CH2)m- (here, m and n are in context, 1, 2, 3, 4, 5 or 6), -S-, -S(0)-,
SO2- or ¨NH-C(0)-
NH-, -(CH2)o0H, -(CH2)nSH, -(CH2)oC 00H, C -C6 alkyl, -(CH2)n0-(Ci-C6 alkyl), -
(CH2)nC(0)-
(Ci-C6 alkyl), -(CH2)n0C(0)-(Ci-C6 alkyl), -(CH2)nC(0)0-(Ci-C6 alkyl), -
(CH2)nNHC(0)-Risub,
-(CH2)nC(0)-N-R¨isubR2sub, -(0 CH2)n0H, -(CH20)oC 0 OH, C -C6 alkyl, -(0CH2)n0-
(C1-C6 alkyl),
-(CH20)nC(0)-(Ci-C6 alkyl), -(OCH2)nNHC(0)-Risub, -(CH20)oC(0)-NRisubR2sub, -
S (0)2-Rs, -
S(0)-Rs (Rs is Ci -C6 alkyl or a ¨(CH2)m-NRisubR2sub group), NO2, CN or
halogen (F, Cl, Br, I,
preferably F or Cl), depending on the context of the use of the substituent.
Rlsub and R2sub are
each, within context, H or a Ci-C6 alkyl group (which may be optionally
substituted with one or
two hydroxyl groups or 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
37
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
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 Ci-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 0-C(0)-NR1sublt2sub group where Rlsub and R2sub 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.
[0072] 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 disclosure 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, pyrimidine, phenanthroline, phenacene,
oxadiazole,
benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-
containing
aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing
aromatic
38
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WO 2019/199816 PCT/US2019/026570
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, i sothiazole, benzoxazole,
benzothiazole, benzothiadiazole,
phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,
imidazothiazole, thienofuran,
furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and
oxazole, among
others, all of which may be optionally substituted.
[0073] 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)n0H, -(CH2)n-O-(C1-C6)alkyl, -
(CH2)n-0-(CH2)o-
(C1-C6)alkyl, -(CH2)n-C(0)(Co-C6) alkyl, -(CH2)n-C(0)0(Co-C6)alkyl, -(CH2)n-
OC(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, CO groups,
OH, COOH, Ci-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 PTM 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
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
39
CA 03095912 2020-10-01
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indole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), an optionally
substituted quinoline,
and combinations thereof.
[0074] "Carboxyl" denotes the group --C(0)0R, where 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.
[0075] 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 -(CH2)m-O-
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:
Sc (0
R HET0 RH ET
"Zz N )22,
LURE
RURE
0
0
RHET
RHET RHET
N
0
RH ET
yC
wherein
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
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(Ci-C6 alkyl) (preferably substituted with one or two
hydroxyl
groups or up to three halo groups) or an optionally substituted acetylenic
group ¨CC-Ra
where Ra is H or a Ci-C6 alkyl group (preferably Cl-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-(C i-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);
R' is H, a C1-C6 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, where RYc is H, OH, 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(Ci-C6 alkyl)
(preferably substituted
with one or two hydroxyl groups or up to three halo groups) or an optionally
substituted
acetylenic group ¨CC-Ra where Ra is H or a Ci-C6 alkyl group (preferably Ci-C3
alkyl).
[0076]
The term "Heterocycle" refers to a cyclic group which contains at least one
heteroatom, e.g., N, 0 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 heteroaryl groups are described hereinabove.
[0077]
Exemplary heterocyclics include: azetidinyl, benzimidazolyl, 1,4-
benzodioxanyl,
13-benzodioxo1yl, benzoxazolyi, benzothiazolyl, benzothienyl,
dihydroimidazolyl,
dihydropyranyl, dihydrofuranyl, di oxa,nyl, dioxolanyl, ethyleneurea, 1,3-
dioxolane, 1,3-dioxane,
1,4-dioxane, fury!, homopiperidinyl, irnidazolyl, imidazolinyl,
imidazolidinyl, indolinyl, indolyl,
isothiazolidinyl, isothiazolyl, isoxazoli dinyl,
isoxazolyl, morpholinyl,
naphthyridinyi, oxazolidinyl, oxazolyl, pyri done, 2-pyrroli done, pyridine,
piperazinylõ N-
41
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methylpiperazinyl, piperidinyi, phthalimide, succinimide, pyrazinyl,
pyrazolinyl,
pyri m d in yl, pyrrolidinvi, pyrroli nyl , pyrTolyl, qui nol My!, tetra
hydrofuranyl, tetrahydropyranyl ,
tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene,
oxane, oxetanyl,
oxathiolanyl, thiane among others.
[0078] Heterocyclic groups can be optionally substituted with a member
selected from the
group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl,
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, aryl oxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, ¨SO-alkyl, ¨SO-substituted alkyl, ¨SOaryl,
¨SO-
heteroaryl, ¨S02-alkyl, ¨S02-substituted alkyl, ¨S02-aryl, oxo (=0), and -S02-
heteroaryl.
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, morpholino, 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).
[0079] 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,
42
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whereas these generic substituent groups have meanings which are identical
with definitions of
the corresponding groups as defined in this legend.
[0080] 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.
[0081] The term "lower alkyl" refers to methyl, ethyl or propyl
[0082] The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.
[0083] More specifically, non-limiting examples of CLMs include those shown
below as
well as "hybrid" molecules or compounds that arise from combining 1 or more
featrues of the
following compounds:
43
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0 0 0 0
Rn _._.A NH r_____ __ NH
[z 1 N ______ 0 Rn-----r- w __ N\ ____ 0
Z'S/
0 R1
(V) (w)
eN 0 0
Rn
I
.õ.(,...., ______________________________ NH
,......---...,
N NH 7¨ __ N 0
Rn----'--
\----
0
R1
R1
(X) (y)
0 0 H
0 NH 0 N 0
71 __________________ \ ?
Rn-----c 1 CN N
W
I,
R1 ,\
R- N
(Z) (aa)
0
N_ NH
0 N\
R1
Rn-----kc /
(ab)
44
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H
0 0 ,N,0
N_ NH
R3¨ N 0
Rn¨ 1
N.\
0
(ac) (ad)
o\ N io , ,z
NH
R3 N \ N 0 Rn \
N 0
/ NH
0 0
(ae) (af)
N, 0
Rn--C
HN 0
NH
0
(ag)
CA 03095912 2020-10-01
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0 R5
0 0
NH
/1 .........w/N R6 (lij
1 N __________ 0
L _ /
R' 1:)2
Rn
0 R2 0
...... j< NH
N\
_________________________________________________________ NH
__________________________________ 0
1 N __ / -7.-----
______________________________________________________________ 0
y-----....."
R'
Rn R1
R4 0
Oy<R4 0 0
N
______________________________ NH N __
HN¨___.<
N _________________________________ 0
0
N 0
RV
H 0
Ozrs:
0 0
) _______________________________ NH N 7
.........--/K
1 NACH2)¨N
y-------.1 \ 0
HO
0
Rn
RI
HO
wherein:
W is independently selected from the group CH2, CHR, C=0, SO2, NH, and N-
alkyl;
Rl is selected from the group absent, H, CH, CN, C1-C3 alkyl;
R2 is H or a C1-C3 alkyl;
R3 is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
R4 is methyl or ethyl;
R5 is H or halo;
R6 is H or halo;
46
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R of the CLM is H;
R' is H or an attachment point for a PTM, a PTM', a chemical linker group (L),
a ULM, a
CLM, a CLM',
Q1 and Q2 are each independently C or N substituted with a group independently
selected
from H or C1-C3 alkyl;
is a single or double bond; and
Rn comprises a functional group or an atom.
[0084] In any of the embodiments described herein, the W, le, R2, Ql, Qz,
Q3, Q4, and Rn
can independently be covalently coupled to a linker and/or a linker to which
is attached one or
more PTM, ULM, ULM', CLM or CLM' groups.
[0085] In any of the embodiments described herein, the 10, R2, Ql, Qz, Q3,
Q4, and Rn can
independently be covalently coupled to a linker and/or a linker to which is
attached one or more
PTM, ULM, ULM', CLM or CLM' groups.
[0086] In any of the embodiments described herein, the Ql, Qz, Q3, Q4, and
Rn can
independently be covalently coupled to a linker and/or a linker to which is
attached one or more
PTM, ULM, ULM', CLM or CLM' groups.
[0087] In any aspect or embodiment described herein, Itr, is modified to be
covalently joined
to the linker group (L), a PTM, a ULM, a second CLM having the same chemical
structure as the
CLM, a CLM', a second linker, or any multiple or combination thereof
[0088] Exemplary Linkers
[0089] In certain embodiments, the compounds as described herein include
one or more
CLMs chemically linked or coupled to one or more PTMs (e.g., PTM and/or PTM'),
ULMs (e.g.,
ULM, ULM', and/or CLM') via a chemical linker (L). In certain embodiments, the
linker group
L is a group comprising one or more covalently connected structural units
(e.g., -ALi (AL)q- or ¨
(AL)q-), wherein Ai is a group coupled to PTM, and Aq is a group coupled to at
least one of a
ULM, a ULM', a CLM, a CLM', or a combination thereof. In certain embodiments,
AL1 links a
CLM or CLM' directly to another ULM, PTM, or combination thereof. In other
embodiments,
AL1 links a CLM or CLM' indirectly to another ULM, PTM, or combination thereof
through Aq.
[0090] In any aspect or embodiment described herein, the linker group L is
a bond or a
chemical linker group represented by the formula ¨(AL)q-, wherein A is a
chemical moiety and q
is an integer from 1-100, and wherein L is covalently bound to the PTM and the
ULM, and
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provides for sufficient binding of the PTM to the protein target and the ULM
to an E3 ubiquitin
ligase to result in target protein ubiquitination.
[0091] In certain embodiments, the linker group is -(AL)q-, wherein
-(AL)q- is a group which is connected to at least one of a ULM moiety, a PTM
moiety, or a
combination thereof;
q of the linker is an integer greater than or equal to 1;
each AL is independently selected from the group consisting of a bond,
CRL1RL2, 0, 5, SO,
SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3S02NRIA, CO,
CRL1=CRL2, CC, SiRL1RL2, Ll,
" P(0)ORL1, N1L3C(=NCN)NRIA, NR13-
u(=NCN),
NRL3C(=CNO2)NRIA, C3-11cycloalkyl optionally substituted with 0-6 RL1 and/or
RL2
groups, C5-13 spirocycloalkyl optionally substituted with 0-9 RL1 and/or RL2
groups, C3-
llheterocyclyl optionally substituted with 0-6 RL1 and/or RL2 groups, C5-13
spiroheterocycloalkyl optionally substituted with 0-8 RL1 and/or RL2 groups,
aryl
optionally substituted with 0-6 RL1 and/or RL2 groups, heteroaryl optionally
substituted
with 0-6 RL1 and/or RL2 groups, where RL1 or RL2, each independently are
optionally
linked to other groups to form cycloalkyl and/or heterocyclyl moiety,
optionally
substituted with 0-4 RL5 groups; and
RL2, RL3, RIA and rs L5
are, each independently, H, halo, C1-8a1ky1, 0C1-8a1ky1, SC1-8a1ky1,
NHC 1-8 alkyl, N(C 1-8 alky1)2, C3-11cycloalkyl, aryl, heteroaryl, C3-
iiheterocyclyl, OC1-
8cyc10a1ky1, SC1-8cycloalkyl, NHC1-8cycloalkyl, N(C1-8cycloalky1)2, N(C1-
8cycloalkyl)(Ci-
8alkyl), OH, NH2, SH, SO2C1-8alkyl, P(0)(0C1-8alkyl)(C1-8alkyl), P(0)(0C1-
8alky1)2, CC-Ci-
8alkyl, CCH, CH=CH(C1.8alkyl), C(C1.8alky1)=CH(C1.8alkyl),
C(C1.8alky1)=C(Ci.8alky1)2,
Si(OH)3, Si(C1-8alky1)3, Si(OH)(Ci_8alkyl)2, COC1-8alkyl, CO2H, halogen, CN,
CF3, CHF2,
CH2F, NO2, SF5, SO2NHC1-8alkyl, 502N(C1-8a1ky1)2, SONHC1-8a1ky1, SON(C1-
8a1ky1)2,
CONHC1-8alkyl, CON(C1-8alky1)2, N(C1-8alkyl)CONH(C1-8alkyl), N(Ci_8alkyl)CON(C
1-
8 alky1)2, NHCONH(C1.8alkyl), NHCON(C 1-8 alky1)2, NHCONH2, N(C 1-8
alkyl)S02NH(Ci_
8alkyl), N(C1-8alkyl) SO2N(C1-8alky1)2, NH SO2NH(C1-8alkyl), NH SO2N(C1-
8alky1)2, NH
SO2NH2.
[0092] In certain embodiments, q of the linker is an integer greater than
or equal to 0. In
certain embodiments, q is an integer greater than or equal to 1.
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CA 03095912 2020-10-01
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[0093]
In certain embodiments, e.g., where q is greater than 2, ALq is a group which
is
connected to a ULM or ULM' moiety (such as CLM or CLM'), and AL1 and ALq are
connected
via structural units of the linker (L).
[0094]
In certain embodiments, e.g., where q of the linker is 2, ALq is a group which
is
connected to AL1 and to a ULM or a ULM' moiety (such as CLM or CLM').
[0095]
In certain embodiments, e.g., where q of the linker is 1, the structure of the
linker
group L is ¨AL1¨, and AL1 is a group which is connected to a ULM or ULM'
moiety (such as
CLM or CLM') and a PTM moiety.
[0096]
In certain embodiments, the linker (L) comprises a group represented by a
general
structure selected from the group consisting of:
-NR(CH2)n-(lower alkyl)-, -NR(CH2)n-(lower alkoxyl)-, -NR(CH2)n-(lower
alkoxyl)-OCH2-,
-NR(CH2)n-(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2)n-(cycloalkyl)-(lower
alkyl)-
OCH2-, -NR(CH2)n-(hetero cycloalkyl)-, -NR(CH2CH20)n-(lower alkyl)-0-CH2-, -
NR(CH2CH20)n-(hetero cycloalkyl)-0-CH2-, -NR(CH2CH20)n-Aryl-0-CH2-, -
NR(CH2CH20)n-(hetero aryl)-0-CH2-, -NR(CH2CH20)n-(cyclo alkyl)-0-(hetero ary1)-
0-
CH2-, -NR(CH2CH20),-(cyclo alkyl)-0-Aryl-0-CH2-, -NR(CH2CH20)n-(lower alkyl)-
NH-Ary1-0-CH2-, -NR(CH2CH20)n-(lower al kyl)-0-Aryl -CH2, -NR(CH2CH20)n-
cycloalky1-0-Aryl-, -NR(CH2CH20)n-cycloalky1-0-(heteroaryl)l-, -
NR(CH2CH2)n-
(cycloalkyl)-0-(heterocycle)-CH2, -NR(CH2CH2)n-(heterocycle)-(heterocycle)-
CH2, -
N(R1R2)-(heterocycle)-CH2; where
n of the linker can be 0 to 10;
R of the linker can be H, lower alkyl;
R1 and R2 of the linker can form a ring with the connecting N.
[0097]
In certain embodiments, the AL group is represented by a general structure
selected
from the group consisting of:
-N(R)-(CH2)m-0(CH2)n-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-OCH2-,
-0-(CH2)m-0(CH2)n-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-OCH2-,
-0-(CH2)m-0(CH2)n-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-0-;
-N(R)-(CH2)m-0(CH2)n-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-0-;
-(CH2)m-0(CH2)n-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-0-;
-(CH2)m-0(CH2)n-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-OCH2-;
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.1"-N
N-(CH2)n-NH
=
-r(CF12)m-N N-(CH2)n-0/(.
µ,
=-:-(CH2)m0(CH2)n-N N-(CH2)o-NfH
=
(
-4-(CH2)m0(CF12)n-N N-(CF12)o-0/.
-4-(CH2)m0(CH2)n-NNN--(CH2)o-NH'
- -(CH2)m0(CH2)n-N/KN-(CH2)o-0(µ
,
(CH2)m-: -i-N\ 0
, ;
_____ 0
(NCH2)m-:-
H2)m
\
_______________________ ,N-(CH2)m-H ; 0(CH2)m 1 ;
/
'0=<h) ; (CH2)m ;
,
r-- r -
/ / 0
N N
0 ___ /
-
/ N
____ N\
0 ___ / 0
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tsJ
H )-0(CH2)õ,0(CH2),O(CH2)p0(CH2)q0CH2
X
-:-NH =
0(CH2)m0(0H2),O(CH2)p0(0H2)q0CH2
-:-NH =
0(CH2)m0(0H2),O(CH2)p0(CH2)q0CH2
-I-NH =
A o(cH2)õ0(cH2)no(cH2)po(cH2)gocH2
-:-NH =
0(CH2),,O(CH2),OCH2
0(CH2),,O(CH2),OCH2
X ;and
1-N
N--(CH2),õOCH2
-14 ; wherein
m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6; 7,
8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, or 20;
when the number is zero, there is no N-0 or 0-0 bond
R of the linker is H, methyl and ethyl;
X of the linker is H and F
1-N
N---(CH2),,,OCH2
¨14
where m of the linker can be 2, 3, 4, 5;
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, N /N WC)) =;,1
H
H H
%
-/N \()e\C)-/
H H
0()0()(),
H H
%
%/N1(300C)0(
H H
H
= 0
0
H
,
>:. "\N Xs
0
H µss0 NH
0 0
H f
.',../,,/ ,..,...S.,,,,.õ.,.....''.,..,.,..,...,.. 0
,...õ,.....,............,,,,,,.,, Ns:),,,,
= 0 .
0
\
¨ N \N¨ ¨ ¨ N ..", N ¨ k
_ ¨0 ____________________________________ / __ N N
\ _____________________________________________________________________ 0¨ -
52
CA 03095912 2020-10-01
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/
H
N1()0()e%<
H H
N 00 C Of),
, N %'N OC)1
H H H
'/NIC)C3C) \''( 'iNIN %000'`
H H
0
0 õ0
;''N S C'µr ;'/Ni S (:/.µr ,/Ni =)SC);,r
H H H
1/N1C)()µrõ---,.,,,,,.>
/ N
H H H
, 1
-:-N-0/ \-0/-7
-,1=N 0 H
H
-; HN - \
-\ ...
HN.--0".0\__/0"
,'µ ,'µ , H
,
r N
OC)4(
H H , N
H
,
;INIC)N1- r:y
H - H
H
0
'
. NO'C' \
-'=1 *
1 1 . N .- 0,...1 N
- r- \
-1-NH 'H \ ___ 1 , 0 1, =N
,..../
H s )
,\
H
N /-0¨ \_ /71- '
-1-NH 0 H
1
0
\ -_( \ I _____________________________________________ :
AN -\_ r:¨ :-
_______ / 0 1-1>N
N -01K/ o
--/ \ N 4n :
\ _____________________________________________________ /
53
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...r...õõØ..,.......^-,00.......,N:1-,
,
H
o
2-2E-
,
Oey'L'L
0 = 0 ;
,
OH
0
OeY41.1. ,Lz1, 0 0 j'ccss
0 ; ;
0 0
0
0
0 0
0 cr
. ;
\.
'LLL. 0
H 0
C) C)(µ\
cs' = 0 = 'N-
55' =
0 0 0
H 1 1
51 = l'- 51 = l'-
cc'
0 0
,.v....--,..õ,0.......õ....--,.0,---.1.rih.
0
''1=,5--(s . 0 = 0
,
0 0 0
54
cc
0
-11-r N
Hss- 0 N
N e iN
"1-r 0 N
CN¨µ10
0
. . 0
ON
IsV 1 0
-/
N.,.._,z.,_õ_,,,,,,,,..____,),
0 N 0
, ,
N¨N,
, z
...._ o..4 ¨ /
0
0
c c c c
=
0 ...--..,,....0
N -^,.....,.0 Isl,,
fly.0 1
NO 0 0 1r I
0 I / 0 N ,,
c c c
=
0 0\ 0
.fre I = iy0(3 = 6r0
I /
N
I
N ,
c c c
= ,i.r0 0 0
= /Y0
= 0 /Y0
ty
0 0 0
/ N
N I I
IN
\
c c c
0
r NX
0 ....0C 0-00-0 irON-)
Y
o
,
= o t ,
.7.,,y,0,-,.., N,
0
c c c
= 0
= -65-6H0.1',- = ss-60-1.Lz-
OLS9Z0/6IOZSI1LIDcl 918661/610Z OM
TO-OT-OZOZ ZT6S600 VD
CA 03095912 2020-10-01
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HO
0 0 N 0
\ NZN j4 -csss Nj-Los,r
= 0
=
/¨
0 / __ \\ C----1)C -/-1
/¨ /-0 5
( \i-Nr-\N-/ N'o
\/ . 1-N N-f
\/ . 1-N N-f
\/
5 /--\
1-N N-CN-;µ I-Nr-\N-CN-i-
,
56
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40 0 .,/,N ,..õ,...,,,,,,.0
H H H i 1
\ X
-)r0,
(N ()s` %/;=1 >1=1()N
H H 1 i H
X&% .
)( X = H, F
H H
'N = 10 \'i
N ¨:-
H
,,,
N \ / 0
H . /
.,
, / >N
k H
0
H
H
`Ai 0 Isl ;(N \/() 0 \ \ _ s)J\J 0 0
H I
0 0
(rq()
H =
H
z
0 0 - N
:A N MC))r.") N 0 ,Ow
H H I 1 i I
N Y,%
X X
. ,
H
/%
X H E 1
N (:), - N (:);,'
H /
N N
=,:N 0
' \- 0 \-µ
H H
X X
ro\_:_ HN / 0\ r0\_:
N N
1 1-
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-1-NH * N /--\7\r:- , -1-NH * N) \-Or
/ ________________________________________________ ,
:_ * /-
\ - ,
\-0 Nl -1-NH r:-
\_/ \-0
, 0
-1-NH * /- 0 -1-NH , -
1-NH ,
N N 0-
\ ,/-:-
\__/
i
i I
0 _:- -1-NH
\ _ / K-) _ p-\
-:-N H 0 - \ , -:-N H
_ -
_ - - \ \ ________ / I \ / __ -
,
nµµ
1 (-
H
\ _ ________________ _ nµ
,\Nõ._õõ--,,,._õ,--,õ0,---:-...õ..... N Ors1
H
0,.;v
\ H
µ1110 s H 0, '
0/ \ 0 ; \lµi c,/\) z N
N
, / , /
1-1N i=-=<>"0-d FIN
' .'<>"0-(_
X N
X = H, F X
'
"0-µ j¨\_
1 N 1
1 1 1
* ,. 1411"0-.10 * - ,
1
X 1.....0, / \
, N ...tii110 L-
H
N-
s0"-\ r---\ N----=\ : / ! 01 '
so._,
N, __ x._
\ \---
___, N
N...._./ N
-7. N
58
CA 03095912 2020-10-01
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r, ,,_
HN-0"1 ift 0 HN""0-11%.31
--it-, 1 \ 0
..0, = , µ 0 ,O, , µ , 0 ....0,,,10
HN
HN ' H!si i-a_fµ ilk
N - ;I-
-V
X
0...õ.õ,---.:......õ, `,,-- --/N....---,,,.,õ0,...õ,-...,-
HN'"0"-al 44, //sil 1 H i 1 X X
,(, , , ie. .
,,CN'Cro
H N 1'0-'1 0 //sN
' H 411, \ , H 410 \ /
-\--
0 ' 0 '
X
H H
0
/ HN o 0 I
0 0 '
_.._ = , % 0.3._
' /
HN....0-.0 fik or%C -HN-.....C. _IN * ,'` HN- \ \-
--/L -
4k / HN N A HN N \,,(
14N. , .0 = o-)
N ,, r-----N N 1._ /----A N
-/' N N /
V.....,./N
0
/--\¨K \N/
--N N ' --NXN¨(
N¨i --NN¨ \ ,i
\__/ / I
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(1
--NN --NN -;-NXN-( /N - '- +NXN-(
/ /
;--
0 -\__
N - \ HO HQ
I/-\ ,
-:-N N-\ / I /--\
I /-- N \ _____________________________________________________________ \O-/N
-:-N N 0-' N -:-N \/ N \/ \/
0-µ__ .
__________________________________________ - --
I /--\ /
o)ra
I /--\
HN ,
-:-N N- j \ -:-N N
\- NI N ,-- µ.
\-/ 0
I /--\
-:-N N-µ / .VINCI\---\ ,
-:-N N
\- N t. 0-:- \__/
0 = -
: N
/--\ -,-N -{ - -KiV
HN
/ N
0
'sr-
.'
:-
\,
'I1N-CN-µ j-Ori lrIN-CN-µ )H-
N N N
i
/--\ -/ 1 \ FIN-ON
"i 0-/'' HN'Ll N I
- i= - 0--\ =
,,, N
õO
HN )(1`11 H
N,--N.......õ-----.)\----N,,Ox
,
7- F F
where each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, 6.
[0098] In any aspect or embodiment described herein, the AL group is
selected from the
group consisting of:
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-
-%
0--- J
Nr----N ,/.. .
i-----\ ' , NN/--\N :_
µ.....
\¨/I
/---N r---\¨ \ .1 ----D
,,,
= P---rs N\.. N N .
,..,../N ---0....- = ,, sz<0 --X- \.-.---
D....._ `', - N-0 ,
N / 6 s ' N / m
= \
ro
' N
sNN ,0N , 7õ......_7"-N\ i
N-7-14 NJ' N.,
, ',I-0 N-1-
'
0 N
, 0
N N ,Ly---NN_, #
N,,,,
.,, .-,
N , -
/----NN---)
, 0--T-N----\___ /---\ ,
.....0--/ c,N , :', N N--,-
, -
,/
0
.,Trj1 = =,\ON7' N
,
=õ, N;, c, N ,H, N
7\)
"m
rN' --,LeNi NN
, Ø___7"-N
.ON
N
õ
µ--------rsi ,N,,'
--.-1=I=,
ON /-----\
, 0----/--"\___Jss,0---/---N," --NON .
o
o
rs, W
s-N WI N Isl 41111 .
H = H = H )
abh
\.
0 4 VI 0 .
H = il
0
0
WI 0,zy-yµ'11_ 4 0 0,..,00,1
cs's
N N
H ; H ;
61
Z9
0
H =
/ ..,.... 0
0 N 0
c c
= 0 t 0 = H
.2,)=LO Nõ-
,..,....,,,, ,O..õ.õ......Nsf ,
\-'-'1H H
N ..õ......eN..,../
0
c c c
= H = H = H
--,.. N 0 N /
, . yo ,. %,,
0 ,).0
0
c c c
= = H
sr-....,õ---.....õ---.....õ-N-.
/ / (:) NH sss, s=cslo0 0 N
0 0
= :is' = / H = 0
H
H ..----..,õ,..0 ...---..õ..----...,õõN
r0 0 ,=
,,),
0 0 0,,N,," '21
0.,,.õ,..-...õ..0,,
ssr
c c
/ H = sso
rµls ISH
o
H
N
c c
= ,s H = sss'
ss-,.r 0 0c) N sss y00
0
0 0
lc
,
c c
H
= sss'YO 0 N
0
scr'
H sy-.Ø-
-..,....--..0,-..õ,---..Ø.....,..*-..N
N
0
=
t 0 t 0
-µ,..,-L.,Ø,,,,..---..,,,...0õ.......õ--...õ,,õ0 0 H
.v.k.õ,.Ø,,...õ.--õ.õ..õ.0õ..õ,-...,...õ,=0 0
H
N N
A
=
c c
= H = H
ssy. N
0 /
000 d
ly--0--00 0 Nscs'
0 0 J
OLS9Z0/6IOZSI1LIDcl
918661/610Z OM
TO-OT-OZOZ ZT6S600 VD
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0
0 ..,=, H I F
µ 0
0 0 0.,)1.,"
O'r /, I.1
N ,sss . H
H = N
0 H = cy."......=== -..."-\,-. =...)1`y .
)
0 /....11.---i0iN...,,i
/ 0 N
N U 4 N.õ
L.Aey\- H
'''sNO oThrµ
H 0 ; 0 ; 0 ;
,s0 N 0
4 e0. U 0 4.N.----
..,...õ..0õ,..õ... ....^:,* oy\
H
0 ; F pr = ,...
----
0
;
0
0
0 0
4.-N=-=-====.õ."-ty.-,....õ,0.,),õ 4... ...---..õ....",0,....õ,0õõ),õ
H = I = F F =
) )
0
0 0 [1 0 /
()..,.....õ--,....õ.01), ,,,,N,l,
4N 0
H i / . 0 =-.. N
.
H
1.1
; H =
)
0 0 0
Ms/ 0 ,re ifi
H H E l
F - F 4111"vr = H =
IssrN \ 0 0 0 0 N ,0 N
4.......--,,,,,... \.
0 rs..o= . pi 0 , H
0 = H
0 ;
0 0
H1 1 0
v ros
1%!"--\
\--'0^-eyµ 4 0
eCIA 0
H S
F ; H = 0 ; F =
) )
0 0 0
0 / 0
,Cr 0 0 'Fr)n' 0 / 4f....,r,00,-,111 ,,
...Øõ0.,0õ..}...õN1õ..,s
/
= H = H =
)
0
/ e0.
Isl 00 0
0 ,0
/ = 4isil.0' I. O\ 4N 0'0
\ 0 /
N 6
H = H 0 osr .
411Irr F =
)
O 0
4
/ 0 0 4, ,ztz. r====TO s F =
f.
N
H E
N .
F F =
) )
0
/ 0
Isl! * 0 /
H = r / csr',N \ -N 0
H 1 H \ 4Niss=Cr 0 0 lel \
F; rµ,1, .
\ 0
/
Theijr0 0 0,),,,, ,.,
H 1 tr=-. N ..---....õ.0 0 0 4 N
0 0
H H E
H
F = F r-'''. = rrrr =
, ,
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0
cs(Nic) 0 '''L
0 0 0 H osN...rjr 0
/
H H
H e'r = F ; F ; F =
)
.õ0
jõ,s,s, i, NiEj a _,,rL 4
4 * '1=11
N N H ; H = H and H N )
wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5 , or 6.
[0099] In any aspect or embodiment described herein, AL group is selected
from the group
consisting of:
N
=
=C)'=/.'NLD5j.N't
=.õ.%. 0 ......õ..--..õ-----.....,-----. N'..", µµ,0 ./...
0 H
H ; = .
.,,O, , a
.õ0 . o Nats N.µ 0 0 ..."...f,..f. N ;%
0
. H = H ;
. µt,
t
'-':c= 41 ON-t`
H H
= ; ;
t;0 N o ,i0
0 Ne%
. ...-
- -0 0 il.'
,
-i õ.....)
`,, 0 N1
cN 0 N
iX
is
i = ; ,
. i
Ø,õ.......--.. N .."..1
i ' N
c.N 0 N N 0 N
IX i)
/ 0, = / 0 /
,'= . ; = .
64
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Is N Is N
N 0 N c.NNON1
i)
_....._
% ;'µ =
,.
=I
_.= N" 1 0 N
H
c.N ./, . . / = ; ;
)()N
c.N
c.N1 (:),0N1µ.):
00()), .
H =
s'isN-1
c.N (y-0.-N:,- -,0ONµ..
H
H = ;1'0C)0;µ
;
i'N
c.N N F F
F F
00-µ`
F F ; =
; ;
µµ,ON
l'N
cN c.N NL
U
ON1)% Oi\N-N`
H F F H
F F = =
; ;
./ N
,
' U N
e.(*N-N`
H I . cN (y-
y= ,v
F F
;1'0N1)` 0 `
H F F
; F F ; ;
/
N"1 iN
cN (:)/(= ,v
c.N (1)A/' v
0' ' N `
F F F F H
=
; ;
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N
cN r=L.
k)
e=y=
' N
ON NC`
H . H ;
OH OH
0 s
OH
OH H
OH
; 0 =
0 H ;
0 ; 0
0
H ; =
0 0
H . H .
0
H = µC)`0'()'-0C) =
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0
N
H ;
_______________ / __ \ ''
/N ( \A\ S/ )m N/ __ \ __ (
,'= s'isµ \ __ / n
m \ ___ n
________ / ___ \
N ( \./0),(\ %/ix
\ k ) m ON (4\
- -N ______ N
/ \ (0 o \ (
\/)\(vi = ) _
1
\ _______ / /In ( ______ / n
n
\ (/ ______ 0)( \ S N/ __ \ __ 0 ________ s
- -N/ ________ N i N (\
\/ 0 \/ m
\
\ ..s/
i(s%( ''')
N/ \ t
___________________________ N k O i ss _________ / O N
(/ s
n ______ \ / m n ____________________________ m
- -N/ ______ \N (/ _____ 0) (- - \ ,(/(3 \ A ____ N/ __ \ N __
i,s, \ __ / \/
/ m n
o
\ / o
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= H =
N
$0))sµs= ''' /hko) `,=
m / 0
1'1,(,,,//''N rk/
m
n n n
0
o1,/ rs,
or'-'' -\-N.........µ.......................n)/
m
0
\ so,. N 0 .43.2.2..=(= \ .00.
N......................H....../ ........A74'''''
.." \ = .=== = i ==
m' m' s
m n
0 0 0
: / \ t / \
1(
NFLIJI \ /--- ¨
--.¨N N¨ ¨ 1 / \
N ( //m \rs, ( 4m
1 \ / -;-N.
t \ ____ / (N m ¨1¨N
1 \ / 1 \ /
¨i--( \ __________________ 0 NH ._< \ ¨
N¨ ¨ \ 1
N k 4 --1¨ \ N¨am \N (C
______________ \( / r-
r-
________________________ , 0
/ \ /
N N ln ___________ N N ( )n
0 ___ /) \ ______ / / \ _____ /
0 ( )
-.I m =-, i im
0 0
I I
N/T1----
\,/
/.,, V........./N n H
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_CC c
_io __/\N¨
0
i
k / m
0-- 0--
/ \ / \
0 S
/K1 N\ /N - n (cµin N\ /N¨ -
,
0 ___________________________
/
e " "n-N
0- 0-
/'
0
N N._____ / m
__No---
e in N N'
N/ eõN.,
M
SE)' 5n N'2N e'S :n jA
N'5(
e " "n-N
'21
M rn M
N ;1/4 n
0
k¨ 1m \ m
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,,, \
t (\f( ) N 0\ V,'= NH--õ
Nõ1.....r.õ,,.
0
/N
o
i \
V-
foV) \ / (
N \
N 0 0 s/ ss, 0('=eC
___________________ \4\(\0\/)
\ \
m o
P n \ 10
/ \ \ H
\s((0v) N\ /N ( \/0 0 N¨ ¨ , ,
..../ õss.ss.s. =,,,,:
',,/
o n n
P n
\
\
% 0
N \...:s s' N
N s
i
i n n
.(,)N -.....,....,...,.N
m m
\\...- / \
N ( 'KC) \ - 41 N N ( (:) \
ss
iss.
)s s)O y ......---\
¨
\, o7 \
-...,
o/
41 N / \N¨ Na m
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µLe<1 N N132C, F F
,
s,
:),,,,s 0,,,f,.,.1.,,,,..N.,õ,,........v..õõ,--õ,,s i N õ%.,,.õ,,,,,
= 0
\ ../
N.õ....,....õ,õ,
,.
n m M m n
h 0 OHN\is
,...*"......'\.N,, \
n %
= 0 = 0
1 m \ ¨0¨ ,s
, .
¨ m n
m n
/ is( CF3
OH N s
isTOX. \ sO N = 0 n , =
m n
m n
N N is(
I 0
= 0
\ ,-
'''' 0 ____ ON _____ /(/) nN\ /N
- ¨0 / \ ¨ ____
N., j¨ \_ N Ai
\ / ,2/\ .. 0
= N
s,'
N N_
( n\ __ / N\____r/N 1,
... =
,/,..o n
...<2(..s..1."..1 . N / m
¨
, rS
N / -,s, e N132c, '4A/ Nµ2k, Ok7
,, n N
, . n OH
'' \o 0 M = m
F m n .. 7..... , Nõ,õ,0õ,.õ.
s 'm
.,
i Nr.-...-..\ , ss:AN N eNk='=/
= 0
n
H
=,õ,%.õ,õ,õ,,,,t,...rnõN,,,(,..,r,,.
M
N
---N n
' N
n
C\ N i
N
N
H
\(\--)¨ -
f \
µ4 :1/4 , o
m
n
F
.)= OkIN =,/
.õ,....õ.õ,õ/Ã3õN.,.õ,..õ=,õ. \ 0
N =
M
N
m n
71
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.----D- _.... s
N N
k / 1
n
N / "---
,
...,,,,õ......õ,N,' _ ¨N
N.-----D___
,''
I / i 0
N
\
m 0 '
N '''
\ N
H n
..
,
NH2
0 ________ / __ N N __ \ _____ \s/
m
)d m N N _____ n 0 __ r
---
2/ ) m NO0-0 0\ z
A
/ \ )n
____________ N N __
0 ( /c \ / \o
`, / m
HO
% \,= r\N
,'
NON
' = P 0----- ,
\- NI \ j n P '
()%c r A)N\ j
m n
m
0
HO
µ ,
' r\N r------\N %_
__µ -.. ' ..¨ni
µ \.... j
m n
X
N ii:' N =
\(0.,,(.....9
m
1 n
.,'
/
' 0
72
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\ H ,
KNr.
z /
z , Y
./
' \ m H
/ P
:Nf-D---I
rrµn ii'N1 rN1\
NI7
\N, ,Nlis,
\ /Ill
NHN
m ,NI, ,N1/ m
H
nH 4 OH NI-''<
N,>,N, Nsse m
"s'. rNI\C,
NI, \N, ,N1,/,
\ im 0
N 1-g
ii i'hN /*L-\
1\1/ m NI/ c)/----/--NN-ii_
\/
N .(,/ro NH ,, ,,
i ('N /
V
= m r 0
73
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1
1 ''µON
rN1)-0-:- ( N1)10.---1-
I I
N
0 ___________________________________________________________________ /
=,..7-..õ....;====-,-
N,y NV"
m
1 Y
,
N,> ,
' 0 n
m
CN\ '
m
ss INT ,
...= , ri\T-' ----:.---
n
/-----\ ,
n0.---N 1\1-µ
N 1 7.--=,..,,,N \J
-)-N N-:-
C7 )6_0_0, in \__,
(N\ ,N
N,> m
m
....õ- ,\-
sci----Nr--\N¨s_11--(---N\
\____,
N._....../N----/)
f--N ______ \ , ) , r------\ r---\N,
'
,...
p--7 0---c_ - - so-A__ r-N\__J N-o, =
m /.
n
,.
1 NN 'N..2\- %."01`rN"-.-..-y----..N .- `
N
\ ) n
µ,0 ` 0
-s Nad=;\
\ 4}.... r-\ , oti-N'N ¨N.2,, n
N."; ';'s
N \._. j
CF3
N 1
, 1-00¨
N N-:-
\__/
NI --...N.,.: m L.N/
. ,
74
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õ
. % Em n 0 P
% 0 0 0 /
H
N21'
.,\(,: ,,,4...............A,,... , ,
H ,
m m n
H ,
12.
m n o P
H ,
N /
\ /
i
m n o
. \
;,, 0 E)or \ 7(,), r N
\ 0 0 0 0
m n 0 P
H ,
\ (0 0 0 N %(
m n o m 0
H
\ 0 0) 02. 02.
fr
m n m n 0
H
N (,,r
m n 0 P q
H %
N % (1,,\
m n 0 P
1
%)0 N
m n 0 P
CA 03095912 2020-10-01
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N/s='õ
II Nait...,
n
, N
,./
o
V7 o m
m
,./
" o
m
_
nO p0 0
.,....i Ix
...,/
,
m N
m
n
ho -
,
m \Oo 11 N \ N C µ
\ ________________________________________ /
/,..
\ 1.1 o'''''' _ ¨ 41 NI \ N - ¨
/ N _______________ /
-'- \
_
_
n ,
n \
¨_
/
N
1,-
N
m m ¨ N / ., \
¨
)
N i \ N i ,.:- -,,
/ -...
,
1
- 11 o N¨ - _ . ,
/
..-ff
=..,
\ ..-
n
m
\s/
0 s
,
',.
\
\ n r
m m
0
ON
,
m
o.....1 ,l'
m
,
,
,
,
0 N \ 0 rH> N
=
/ m
76
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- / \
\ __ / ' m
N
m
\
/ \ , i= \
______________________________________________________ /.=
2' / , ___ ¨ ii N
\ )
N 1
\ __ /
\
. ()). <= \
'N '
_ N ______________________ ON¨ ¨ _ 41, N/ \ 0
\ __ /
m
0
\ N
, 4i, / ______ \ \ ,N
0 . , m
: . N , _____ , __
' N
\ ____________ / \ _______ N" __ N \ ! \
\ /
m
1 1
s 0 CIO 0 0 '
0
0
c,(,), \
\
1110 / m
77
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----(k
m o
------------------------------------------------------------ 0
) m
sn
/ \ __ ON¨ci-i'l) ex ....\-- N...................+K_____NH¨ ¨
\ ___ / . n .." =s, m ,",
2/ ) m N N¨ ¨
¨ ¨Nk\¨ -
-0
m n
--/
A \ / ___ N N __ \
--, N¨ ¨ 0
0
\ N
/
2,) m N N __ n / __ N/ \ __ /
0
0 _______________________ 0
--,/ N
'
/ __________________ \ / N
/ \ ______________________________________________________________ /
/
N N / __ N\ /N
0 _____________ / \/ 0
1 A
/ \ / n
/ \
/ __ \ /1
0 0 /On \ /1¨ ¨
N ___________________________________________________________
--,/
/---
0
> ___________________ N, m
N¨:¨
)) N/ \N /
6) N ) (in
--,/
cs-
78
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; ____________________________________________________ 0
ki-
N (/ ) N/ ) N M /
)) N \¨ -
n \ /
¨ ¨0
r \n
0
0
1 / \ :-
i
\''/\ /,='' --I---N N---IK2n I
I \
/
o
/ \ 0I"' -,1-/''
N\ /N ()(n N \ > __ ./n
2(-1 13¨h1C¨N/ ) __ NHC
0 0
/ __________________ 0
N/ V
N44/---
0 )
0
N \ / n __________ N
/'= c's
/ \ )(¨NH N/ NH
)c\i N\ /N \, n ,, N =/ `.
C 0 kr
N N
0 -41---H
0
79
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/ \ =
(
0-(-)
0 __ kn \ N/
N N- ¨ N iell \ /
\ __________ / \\....s.......//N,1 N
\ _____________________________________________ (
N- ¨ õf 0
\N ____________ f
) / '
N/
\N _____________________________________________________________ n
N __ icµn \ / n N/
`=,/ le
N\N / / _
...1
,,-.¨
F-'
NI) im _______________________________________ \ ¨ i
`=,/ _ _ /
/--,
N/ )-0fr )n =
\ ,=.
/ \ 0
N N- ¨ 0 m N
ie \ ____________________________________________________ (
(N _________________________________________________________ Wn
1
Ot) N/Nrs-1-
\........../N
a H
4 H 0 __
/--,
1 ________ 0 \ \ )( 1 In -1,-, Z...----A
-1 / V
-r-N/ \ 0
\ /N \, n N¨ - 1¨N N
\ /
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\
o.,,..,,,,=,..,..,.,,,,,õ0,>c
\ ,-0 ' 0
..µ
,\(:
m h)H \ 0õ,,,,,,,.=,,,.,...,,,,,.. s,s
n
0...'
\
,,..0
Nd=r
Otli i 0
0 NW0X
I 0
hrs''0
m m m
NW0<s =
n \ 0
N.,L)Ci
/ \
I 0 1 n m
2( 00 NU' '
N =
, 0 n
0...j
=
N =
0
0 oo
,./
0
s /CP
N0
N = : 0
,-=== 1 0
X
70 =
I ...%,1,..1/,-õ,.,,,A0
N...õ,..õ=,,,, n n
0
0...4
N = 1\
=,,
, N 0 I
07(17ro
0(3C\N i n n
0
,
....
l'OLI:l 0 ;
\
n
m 0
I--0 ,.
0,),:,'
0,%(.....õ,n,0õ.y.,..,,N '7:''= 0 I N, i
-i,
m H
-i---0
81
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s/
\ A
CI:3r)N 0-õON..sil_
N
\ A \
1
ON
\ A
'So
'SS
i . '-'-=C Ili
0 00)<
n
1 (0¨ -
ONO)
0IN n
N
\\ rN
n
\ Th::\
, 1 000)(
n
IN 0---f-
n I n
\ A\i
, 1
, I 0
ON 0
)ç0
1
0".)
n
n 0,
\ 0,,,ca, .õ...,'
1 \
\
ON \ A Os
n
' N
1
ON n
0)% )ç
(\
n
ON
0
= 0
0 '
n
ON
k.0 \\10\
/ --%
\ A
m
2%.r
\[:*/
I
0
\ ,0
1
0
0
0
0
82
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,....:3..> n
\ / ..,--
<0,-""\(Ly=-0/
I / n
n
ON 0 \ N
.,,,....0
1
O N ....../ ../:,
/
0 0 \ N
m
n
..\..õ0 N ...,/ ..õ.....a.,
1
ON ...:.µ,...0
1, \iiii FsC
,...../ ../".
_..,....= n
0.....,....ro,/
0 = 0 \ N \
m
ss(s C' I
,
0
..i
..../
=
0
0 \ N
m
ON ../:-.= 0
_.../
F F
0 0
),
Y: 1
\ / N
M
\.....õ0,.... .=,/
.,
...../
,=.--
ON
n
0 \ N M
\ ......õ0õ...õ.a..... ,,,/
1 F,C
ON 0
\ 0 1 = /
I
= s '`...va..,,
.,
,....,,... IN \
0
0
n
\ 0 1 = /
o
I
.....,,,...=====,,,, õN
'
0()4
NC
\ Oc\
1
ON
83
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o sõ,
,,,
F F n
j2,:r 0
F a 0 '
F F
7:27-0
r
0 0/
= /
0-------
' 0
SS CF
I 0
7' N
ON
0
I FsC
0
u 0
7,=0w0 õ
sNi- w, 0-0
1
.555 , 0 0
0
= OZ000N1 i
0 s
I
i 0
/ 0 0
I
0 ' ,I0'(=))0)0
= \ 0 0 m M
n
=
,N
i
84
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CF3
0 \
,m m
n
n
,Th n
m m
n
% 0
% OH 00
m 0 /
/.
m
n
.;
0/,......õõ(
m m
n
ss( 0
0
\ .=
N \
0
:-..,
, 0
0
, 0
0
/ õ,/,=,..õ0. N.,....-N
0
,
CA 03095912 2020-10-01
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)27,,..0õ....
,....% ./
\ ,,,.......... õ,,......,,,,,, N...,...
'I0 \,.......,..,.N
1
)2(o
)::::r.0,,........,..
' o2 \, = ss(
..' C) =
v
' c / 0 ==,,.,.....õ,,N
I
0õ........ *....,,,,, N NC
i's. /Lir
ss
=\
= 0 \,,..õ........,,N
C) =
0===' = v
0 /
`,=
/ \
......Li,,O,,....õ
x
1 v
õ
0 F3C
1 , = = x
0 \
>( N
, 0 0 '10 \,,..õ....,,,N
õ,.,,,,,,,,=== .. ,.,,,,,,,i''''''''' '''''''''''''''''./.'/
1
\
e%
N., F3C
1 )7:r 0
= 0 \ .,,..... N 0
n
fj,õ0.,........,...,,,,,,,....
ssc, 0 ,
0 = 1."./
i'==
,...,,,,\.,,.....74.,N
= 0 ..õ.......,,,,,N
NC
HO v
x
0 \
X / 0 0. \...,......,...,N
0 \
..,/
= 0 \,,....,...,.N
CN
o
x\ .='
.,'=
0 \
0 \ v
v , \
\,........,,,, N õ.............õ, N...,...
1
0,õ..,........,,,,,,,... N.,,,,,,..,,,,='
)(
= 0 \,......,õõ N ,.......õ,,,,õ 0 õ,..........,,, \
,...Ø.),;=:
1
N
86
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=. 0
0A,
,
0F3 \ 0
0 =
0
1 =
...õ,,,,,,,,0 == /
0?µ=
\ 0
,==
CF3
..õõzr,..õ,
= ,
. OA
7'0 N,...õ..,.........'' ' 0
I 0
,,, ,0)---A."==,0........."µõ,.......õ0õ,õ,.,..,, µ /
CF, \
\ ,
= 0 \
0
,,,õ...,,,N = 0
\
.,
/ V \
/ \
=,,,,,...,,.;õ,=,N / ', 0...,..7.-----'' %
0 -...s....
F F ---__
= ,
= OA.
= ,
V\
=,,,õ.õ,.õN
1
NCN
1
87
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,-A-
.,,,,ON" = N .
-7L-0
= 0
NW02(\ F3C,...,..,.N)cc
n
/-0
NWO2r\
- / ( __ N\/
\ , ¨N\
NWO )
n
.
N \ A Th10 \
\
,,=\ '',.\:II,õ
n
m
=I\N \ 0
..,
0 \
õ,..,..N.,,...,.,.. 0 =
0 ,.=\ '`,,C1,õ
n
0
--h0
0 /
--- \
,,,,(.7.N.,......
0
n
\,(00 N 0
x,
0 = 0
0
\ 0
)! NO
HO n
0 =,,,,..,,,,,N''''', ,, .....*==,,......,,,õ
0
\ 0
Nt=rNO ,
x
0 0 .
0 =
,.=
,,,,,,..,,,,,''''''''''N ,,=,'
0,,,.,..,,,,
88
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N N
r
N =,...,..,......N
' \ 0 =
n P
N N
r
\ 0
s N ,( N
((<0).1.....r.,.... \
\
n P
N N
r
N N
\
n
,
0 / -V., NO\ / i __ 0
o
NO
41% o
n \ : '=/,_
0 o
NH2
, ______ N Ni----)
0 a
\H 1 OWO
I
I ,
0=
i
N
N N
r
ss>,(0,1,,rsi,N -.,..,,..,,,,N 0),(,.< =<,,
m
n P
89
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H .
..,--
N N '
,
N N .
H
m
0
H
N N N
N H '
m
N 0 11:11\o
, 0
H
NN NMO%\
m
1 0 o
/'\ N
, 0
H
N N 0
N
m
1 0o
N
i 0
.,..,õ0.,,N....,,. Nµ 1 0
\/"/\o/\
N N N X
H
N
N o
N N
N
H
>0 rN
N)00000,vZ 4µ0.'10N
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/ 0 0011,,, µ): ***T-1
0N.)
:`0WoWN\..
OWOWO %.<
0 .
/...,..7,0Ø/.. µ,/Ø---,...Ø,=-=-=..õ.õ.0
,)/0W0W0µs.4"---1 / CF3 N.,'
'
\ ,
\-0 /.\\
/
.µ =i----\ I
N , wherein each m, n, o, p, q, and r is
independently 0, 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[0100] In
any aspect or embodiment described herein, the AL group is selected from the
group consisting of:
/1/¨\¨ /--\ 0
r--\_ /--\ _/¨ \ /--\_ /--\ _r0 0- -
\__/
0 0- - = , 0 0 µ = ' 0 0
y y ;
,/- /-\ /-0\ /0-\ ,/ /-\ /-\ /-0\ /O-\ /-\
, "-0
0-I \-0 = I \-0 0-I ______________________ \-0 0- - =
y y
ii--\
rs ,, _______________ \ ___________ i ,o . ,,--\_,.i . ,, \ ,,,. ,,,--\
- - . , o--.
, , u , , ________ \-, ,
NH , ________________________________________________________ HN---
/¨\ ¨0/-1\-1N--- = ''' \-00¨/¨ 1 \ = ' \-00¨r
\__/
, , ;
,/, __ \ /¨\ /¨ 0\ /0 ¨\ / / _____ \ /¨\ /¨ 0\ /0 ¨\ /¨\
\-0 0¨/ \ __ NH = ' \-0 0¨/ _______________ \-0 HN--- =
, ,
= /
/, __ \ /¨\ /-0\ /0¨\ 1-NH __ . -- -- = 1=
\-0 0¨/ __ \-0 0 __ / µ =
, , ,
-- 4. - = -- = µµ . ---0¨/¨\---
. --
, , , ;
-- . di. -- . o -- r¨ . /Th
0-µ -- * o/¨\---
,
o
= ______________ 0/ \ /
; , 41 µµ -- . o¨µ 0--
,
\ . -- lik
, ;
¨\__,,, =
\__,/ _ _ .
0¨,'
, , , ;
91
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- * 0-- . -- = /--\ 0
0 0-- -- = 0/ 0-/- µ'
, ; ,
= 0/0 -/-0 \__/0- - . cr-\0 j- 0\__/0 -\_ di
= 00-/-0\ /o¨\ /--\ --
o /--\o¨ '
\¨o o-- = /
; .
,
. 0/0-1-- -- . d \¨di -- . 0/ \¨o/---
; ; ;
o--
* 0/ \ ________ / . 0/¨\ /¨\0-- --
\-0
; ; ;
__ . 0¨\ o-- o o-- = \_1
/ - - \
, ; ;
# d \-0/¨`0-- -- = 0/ _______________ `0¨/ \¨di -- * 0/--\0-1 \o--
o
. Cl ¨Cl \¨cc" -- # 0/ \ _________________ / ¨\¨di --
, ;
--\N-/ \O-- -- \N-/ \¨di -- ____ \N¨/ \-1 ¨
/ _________________________________ / __ / .
, _________________________________ ; __ ,
/-0 o- ___________________________ /¨o i¨o o
-- \N-1 \¨/ _______________________________________________ -- \N-1 \ / \ <
\N¨/¨ \ / \o--
_________________________________________________ /
; ; ;
/--\
-- = 0 N-
0- -
\_d, ___/ ______________________ \N_ro\ __ ro\__/
N
-\ _____________________________ / .
, ,
,
-- = Or-\N-\
( = 0/ \ ______________________________ N/¨\N--- -- * /¨\
NN---
\__/ = \__/ =
, , ,
__ = Nr-\N-/-0\ /0-- __ = 0 / ___________ \
\ __________________________________________ /0 II
92
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01
/--\
= = (r\ /¨N\ /N---
; .
,
/--\ /
N N--- /¨ ¨N )---
. 0/0¨/¨ \__/
= 4. 0 0_/\
, ;
N-
r,
0,N -- = N/--\N¨/ \O--
; \/ ;
07Th ._
0---./---\
__ = 0 0_ ., SO .-----...õ..0 0 0.õ..s,õ,---,0,..--.õ_,õ.0,_
IIP
¨ , 0
¨0 ,
/¨......õ7--0
0
._ 0 /--\ /
N N--- N\ >
¨K \N¨/¨ \__/ < \N¨/¨
00 5 - / . ____ /
; , ;
Ni
-- < \NJ _________ ( /\N¨
¨ ¨ < \N ) 0\
-- N--- \N¨( \N--- ; \ /--\ )
NH
/ / ___________ / ____ / = ' '0 0 \
=
; ; , ,
HN---
/\ j-0\ ,/¨\_0/¨\0_/-0 0
\/¨ri
0 0 \
0 = 0 =
ip
,,,¨\_0/¨\ o /
0_/¨o\ /¨\ ___________________ \
\¨o HN--- .
,
0
R
/¨ j¨NH
,,, __ \ ¨0 /¨ 0¨/ /0¨\ ¨0/¨\ i ___ NH __ =
0 0 \
\ 0 ' =
HN---
41 0/¨\0¨/-0
\ ,,
\\ = 00_r 0 \ __ /0¨> N/H/
0 = 0/ =
93
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0
. 'l< 00¨/¨ \¨/O¨\ \¨ /
0 HN---
;
0
-- 0/¨\0¨/¨
,
0\ /O¨\ ¨0 /¨\0 jµ= N,I-,1 = 0/ \ HP¨
. \
0 =
= 0 HN---
\ _____________ /
\\
0 = 0
II ¨>/¨ NiFli -- ll . 0/ Ni
, i
0 0
, ;
0 0
-- = 0 i
1¨r4E1 -- HN--- -- = l<
0/ /
\-0HN---
; ; ;
0 0
-- = 0/0 ¨/ ./ ______________________________ = 0¨\ / l<
\-0 HN---
; =
,
_______________ 0
= d \ / ¨¨N111-1' - - * d \-0/
NH
O 0 =
__ = 0/0 ¨/ ¨rs11-1/ - - * 0¨\ /0¨>/_ ,,
NH
O ; 0 =
,
0
4. 0 0 0¨\ /
N/11 = \¨ 0 N/H _ _ =
O 0 / /<
0 HN---
=
; , ,
0
HN---
, /--\ ¨NH
\
-- / NH -- \ /
-- = 0 _________________________________________________
)\=
0 ; 0 =
, ,
0 0 0
4. 0¨>\¨N-1
' . -- \ ___________________ / NH
s' . - [
- . 0/--\ IN---
, , ;
p p p
\
---0¨/¨\¨/ o HN--- -- = /-1-1N- . =
\ __ / 0\ / ___ ''c
_________________________________________________________________________ / HN-
--
, , ;
0 0
II 0¨/ HN--- --
; \ ________________ ;
94
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0 0
NH
= ________________ 07--\0_/ _______________________ \ci j-Nt,i . 0/ \_0/-\0
; .
,
0 0
/--\
NH
-- * 0 /-\ J \ -- * 0/-\0-/
\-0/ O HN---
; .
,
p p
= o/ \-0/ \-0 HN--- --\-0 HN---
0 ip
0 HN---
--<--< \N ________________________________________ / \Oi-Ns1-1 < \N_/ \_ /
0 HN---
____ / 0 = _____ / _____________________ /
; .
, ,
7-0 0
N/F1 -- < \N-f \-/ -)7 ____________________________ NH
/ 0 / 0 =
; ,
0
0 /-0\ HN---
__< \N_F \ ____ 7 __________ / __ \ /-0\ / ___ \oi-r
/ \O = \ ____ 7 .
, ,
_________________________ 0
\ 0 __ ,_0 0-) N.
--/
\N-r()\-/ \-0/ 1- N
N---
/ --< / \/ H
/ 0 =
fp, rn \N
4Ik 0
HN-- HN--
--
'--- = 0 =
0
CZ\
= _____________ 0/ \ __ N/-\N il-N-,1 -- 0
0 N
\__/ ; =
,
/ ____________________ \ /--\
= ______ -- ___ 0/--\ /-N\ /N->/_ /
NH -- 11 7-\ 7-N
0 0-/ NH
0= cr
, ;
,--\
N N
= ____________________ Cr-N/\ __________________________ ) -141-1/ -- \N-/-
\__/ )/ N/FI
0 / 0 =
CA 03095912 2020-10-01
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\N¨rN / \
-- /\__)
¨141-1 - - < \-71-¨N/H/
/ 0 ; / 0 . \.N
, HN
N. =
,
,,
- - < \N¨K \N 0
/ / '1 _______________ N1,1-I ,--\ r0.\ H N - ,, \
\
NH __ 4. i) .
0 0
, , , ;
0 /5) o o
,/ __ \ __ / 'i ,--\ N--- ¨1=1-1
' 0 HN--- = ' H = ,' \ _______ 0
, , ` ; ,
0 ).( j_N- __ --0 0 N-0
* 0--(3 ,
0
' ; , ,
0
-
N-o '' 0 N-R
tt.,)-- - - -
O OC)
; ;
1$ 0 N-0 N-0
N-N/= o,,,,.--\
0---
_,
, ;
., 0
1$0 N-0 N
-- 0()
=
, .
,
-. 0 '. 0
) _ IL.,)..N--() _
O0 0
= 0 =
, ,
O 0 N-0 1*0 N-0
..õ---N0
__ .--N .----.__ _,
,$ N-0 N-0 ,$0 N-0
NNONA.._ _
-- Os-- . -- .
N-C) * 0 N-0
\----N I / --
-- OONA___
101 OC)
; .
,
N-C) N
0
-- 0
c=0)--
O0
, ;
-. 0
N- 0 N. \-"C)
09---
OWO c:)/\/\/\
96
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õ 0
- 0
-0 ' N, \--0
OC)()il')- - 00()-- -
õ 0
N-0 -- -- * Nil¨N-0N -
O()C)
. =
, ,
.0
_-
N
-- = N/Th ji
. - * NON ---N-0\.....-\_
, ;
õ *r\l NM i"----\N
/ fat N\_j --\--\__k\ 1-
)_0
N . - - õ .
W top
r--\
gilL N N-\_.-0 N---0 õ N/
--
\---/
L.szN,f--/o
õ . -0 N-0
z ,_..,p_ / __ 410
Nr N/
\N r=
N-0 N-0
- . N / / -, _ . . Nj---\-- \____\_,
- V
4. Nr: iNi N-0 1----\
0---\___, __ * N\_JN---\--\--OUs 7-O _ s
.-
/- \ /0- - /¨\ /-0 0-\
--0 0- - = --0 0¨/-0 ' \ = --0 0 = - -0 0
\__/ \-0 =
, , , ,
/--\ /-0\ /0¨\ /¨\ /--\ /¨\ /¨(:)\
i---
--0 ________________ 0-7 \-0 0-- =
¨0 0-7 \-7 \-0 0-7 ` = - -0 .
, , ,
/ \¨ ii µµ ¨/-- = ¨0 =
/ \ __________________________ P /¨\ __ / \ -/--\ _____ /--\
, , , -0 0 O ; 0 0--;
--0 / \_ai \_,/ . --0 o-'
\_ ,/ /¨\ /-0\
0 = ¨0 0-7
1/4) , L , ,
-0/ \-0/¨\ r()% /--\ / __________ \ /-0\ /
\ /0¨\ /-0µ
`; 0 0¨/ 0-7 ` = 0 \ __ / \ .
, ,
--0/¨\ ____________________________________ /--\0¨rS /\ j¨O\ / ____ \ /--\
_/ \ _/ \
\ = 0 0 0-- = --0 0 0 0--
=
, ,,
97
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_/ \_ /--\ 0
/ \ _______________________ / -\_ /--\ 0 \ /
- -0 0 0 0-- = - -0 0 0 = 0
, , ,
/--\
--0/-\ /--\0-/ 0-- 00O";--
- -N N---.
; ,
/\ I'
/-\ / __ \ /-\ _/ __ \_ / /-\ -0 0- -
--N N ` --N N 0-- --N N 0 --N N
\__/ = , \__/ , = \__/ = \__/
, ;
/--\
/-\ /-N\ 7- p-\ /-\ /C 9\ / ________________________________ \ /-\
--N N , \-N N-/ " \-0 \-N N---
\__/ ; , \__/ \/ =
,
/- ________________________________ /- 0\ 0%
-\--/-\-N N--- - -N N __________ i / ` - -N N" `
\/ , = \ , / = \__/
;
/--\ /--\
--N N
-
/ ______________________ \0\
N -0 \ __ N ___ N i /- _ -N N 0 0- -
\ ________________ \__/ = \__/ -\ /- \__/ = \ =
--N r-\ N \ / \ /O-\ 7-n - - , . -\_0/ \ /- . --N\
/--\ /--\ /--\ b---\ r-NN---
\___0\
--N\ 7-\ /-N\ ,N--- . - -0\ /-N\ 7-\ p--.
\ .
___________________ ' , _______________ ' , ,
________________ /-\ J-0 J _________ N\I-1 0 0' µ 0 0 \/
.H N
- -0,
µ = -0 0 0 = 0
, , , ;
0 0
- /-\ /-0\ /O-\ HN
/ ________________________ */ = - _______________________________ NH /-0\ /O-\
/-\ j \
-0 /-\0' _______ \-0 0 =
, ,
/
/2-\ /-\ /-0\ /0-\ /-\ NH --0 - -0 -NI/H
Oi- µ` = 0 = 0 =
, , ,
\ /o-\ / -NH
- -0 0 HN--- = - -0 0-/ FIN-- = - -0 HN---
= 0 =
,
ho
41-1/ 00J 1' NH 0 ,/-\-/-)-N H/ /
/<
/
0 ; 0 , 0 = - -0 H N--- =
,-NH µ0-/ \-/ -1\11-11 µ0-/ \O-/ Nii
H
--0/-\ 0 0
; , ;
98
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o
1
\o¨/ \-0/ _____ N/1-1 \o¨/ \¨/() ____ / / NH _____ /--\ / \ )\¨Nti
o ; o = --o 0¨, o
, ;
o o o
/ ___________________ \ /¨\ )\¨N-I /-\ /-0\ -
N1\1-1 /-\ /- j-N-,1
--0 \-0 0 ' = -0 0-/ ` -0 0 =
, , ,
o o o
/¨\ - ro\ \-1\ip / _____ \ 0 NH / ____________________ \ /-\ -N-
, ; µ1
= __________________________________________________________________ -0 \-0- \
=
,
O h0 0
j-\_)-NP /¨ _/¨\_ i ______________________ '<
--0 0 \ = - - 0 0
0 HN--- = --0/ \_0/ \-0/ HN--- =
, ,
,
/9 /9
- ______ -0/\ \ i ¨\ / \ µ / / \
\-0 HN--- = '0¨, \¨/ ¨
\¨o HN--- =
, ,
O 0
µ ./ \\_ / \
0-/ \ / -0 \ /-0 HN--- = 0-' O-
/ \ /-0 HN--- =
, ,
O 0
/ \
/ __________________ < \ /-0\ / \ /
\-0 HN--- = 0-/ 0 ________ / HN--- =
, ,
/0 o
µµ /-0\ ro\ / ______ < µµ /¨o\_ jo¨\ /-4
o¨/ _____________________________________________ / HN- = 0-/ HN--- =
, ,
/9 /9
\\0_/ \__/ ¨\ _______ /--' \ _/ \_(r\ ______ /--µ
HN- = 0 HN--- =
, ,
O 0 /-\
µµ _/ µµ _FC) N N
0 \ __ X
\\
0 HN--- = 0 HN--- = \-
0 =
, ,
,
O 0
/--\ / ______________ \ i-N-1 _____ /--\ / \ / - -N/-\N-/ \-- /1 NH
--N N / 0 _____________________________ ` --N N / \-0 HN---
\__/
= \__/ = 0
, ,
;
/-\ /-0\ 0-\ / /-\ /-0\ O\ HN
/ ---
--N N-/ -NH --N N-/ r
µ
0 =
, ,
0 0
/--\ rO\ / _______ \ j-Np /--\ /¨o\ / _________ \ / __ ./
--N N¨/ / o _______ µ --N N / \-0 HN---
\__/ = \__/
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0
HN,' HN/
/¨\ /-0\__/0¨\_0/ __ Eti_ p..../....._N/Th _._./. , \¨Np¨\ / )
0
--N N¨ __
,
\_..__/N
0
\ =
, ,
0
0 Isif /--\
/ ___ \ /--\ ¨1µ1, E1 7. \ HN-_ /¨\ /¨N NH
N ,
N N ¨/
- _____________________________________________________________________ _0
\__/ 0
, , ;
/--\
/¨N\ /N¨>/_ / /--\ j¨NI
/\ )
- -0 0¨' NH - -0 0 ¨1=11-1/
0 ; 0 =
,
/--\
/¨N\ / /N¨)i_ /--\ /¨
/\ )
- -N N NH - -N N ¨NH
0
, ;
/--\ _/ _________ ( \iN / 0 - -N/¨\N¨( \N
--N ____________________________________ N ¨)i¨N/H 'INI N
\¨/ / -¨ / NH
\/ 0 . N HN
-, = 0 =
, , ,
N-0 N-0
,o- - _ ,,_ - -
= .
() ,
N
N-C)
I / -- -- ,,0
''03()ff- = ,'(:) 0 =
, ; ,
N '1-/ _ .)11
,,001-(..,, ¨ ' (y.\.(:) = ''00
; , ;
n J.).. __
1)> ", _
1,t.,)-- - -
,o,...--.......,...= . , ,%.,...........õ,--...0 . , - 0 0
.
, , ,
,
ii tt.,.)_N-C) _ )---
,,O.,,..õ---..,.,,,,--._
0" ,
' . ,C)0
, ;
I /
_,.0o0 --
= ''0 --
, ,
N-C) N-
- -= Q---
0
.
, ,
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N-C) N-R
09- --
¨ . ',,-,/\./\/" .
-= ,oõ----õ,õ..0õ,..õõ----...,,,,,Ø...õ,..4õ,,,- - -
- -
, u ;
1., /\ N -0 `,N1 ___ NN )--- - -N N U
\/ ' N ---
; , =
, ;
N-0
r-NN ---\____., _ 'NII'Th N-0 r--\ N-0
- -N -.- - - - N\___-/N
; ; ,
N-0 N
, , ,
,
'N N-C) NN N-0
/
I / --
;
rfsi 0 N-0 rNi-xõ, N-0
, -NN.e..) N"--N----j\--- , -NN....) O'NA---
; ;
-- /\ __________________________________________ N-0
r--NN --.N...---Neõ..0 _...
N
\ ____ / N- \ ; and --NN. .
[0101] In additional embodiments, the linker (L) comprises a structure
selected from, but
not limited to the structure shown below, where a dashed line indicates the
attachment point to
the PTM or ULM moieties:
ofL1 )4i
0_2
(yL1 )0_2
. 0
or ,
wherein:
WL1 and WL2 are each independently absent, a 4-8 membered ring with 0-4
heteroatoms,
optionally substituted with RQ, each RQ is independently a H, halo, OH, CN,
CF3, Ci-C6
alkyl (linear, branched, optionally substituted), Ci-C6 alkoxy (linear,
branched, optionally
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substituted), or 2 RQ groups taken together with the atom they are attached
to, form a 4-8
membered ring system containing 0-4 heteroatoms;
YL1 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-C6 alkoxy (linear,
branched,
optionally substituted);
n is 0-10; and
a dashed line indicates the attachment point to the PTM or ULM moieties.
[0102] In additional embodiments, the linker (L) comprises a structure
selected from, but
not limited to the structure shown below, where a dashed line indicates the
attachment point to
the PTM or ULM moieties:
(RQ)0-
(yLl
)0-2 6
QL 4I
/4111) 11/
or
IDQ
(yLl )0_2
41111L )0-6 CIO
wherein:
WL1 and WL2 are each independently absent, aryl, heteroaryl, cyclic,
heterocyclic, C1-6 alkyl
and optionally one or more C atoms are replaced with 0, C1-6 alkene and
optionally one
or more C atoms are replaced with 0, C1.6 alkyne and optionally one or more C
atoms are
replaced with 0, bicyclic, biaryl, biheteroaryl,or biheterocyclic, each
optionally
substituted with RQ, each RQ is independently a H, halo, OH, CN, CF3,
hydroxyl, nitro, C
CH, C2-6 alkenyl, C2-6 alkynyl, Ci-C6 alkyl (linear, branched, optionally
substituted),
Ci-C6 alkoxy (linear, branched, optionally substituted), 0C1-3a1ky1
(optionally substituted
by 1 or more ¨F), OH, NH2, NRY1RY2, 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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YL1 is each independently a bond, NRyLi, 0, 5, NRYL2, cRYL1RYL2,
C=S, SO, SO2, Cl-
C6 alkyl (linear, branched, optionally substituted) and optionally one or more
C atoms are
replaced with 0; Ci-C6 alkoxy (linear, branched, optionally substituted);
QL is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms,
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);
RyLl, R' are each independently H, OH, C1-6 alkyl (linear, branched,
optionally substituted
by 1 or more halo, C1.6 alkoxyl), or R1, R2 together with the atom they are
attached to,
form a 3-8 membered ring system containing 0-2 heteroatoms);
n is 0-10; and
a dashed line indicates the attachment point to the PTM or ULM moieties.
[0103] 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.
[0104] In any of the embodiments of the compounds described herein, the
linker group may
be any suitable moiety as described herein. In one embodiment, the linker is a
substituted or
unsubstituted polyethylene glycol group ranging in size from about 1 to about
12 ethylene glycol
units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene
glycol units,
between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene
glycol units.
[0105] In another embodiment, the present disclosure is directed to a
compound which
comprises a PTM group, which binds to a target protein or polypeptide, which
is ubiquitinated
by an ubiquitin ligase and is chemically linked directly to the ULM group
(such as CLM) or
through a linker moiety L, or PTM is alternatively a ULM' group (such as CLM')
which is also a
ubiquitin ligase binding moiety, which may be the same or different than the
ULM group as
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described above and is linked directly to the ULM group directly or through
the linker moiety;
and L is a linker moiety as described above which may be present or absent and
which
chemically (covalently) links ULM to PTM, or a pharmaceutically acceptable
salt, enantiomer,
stereoisomer, solvate or polymorph thereof.
[0106]
In certain embodiments, the linker group L is a group comprising one or more
covalently connected structural units independently selected from the group
consisting of:
X
0
*
0 R1 RI
- - *N)L*
,N
141 0
The X is selected from the group consisting of 0, N, S, S(0) and SO2; n is
integer from 1 to 5;
0:0 *
RH- is hydrogen or alkyl, *
is a mono- or bicyclic aryl or heteroaryl optionally
substituted with 1-3 substituents selected from alkyl, halogen, haloalkyl,
hydroxy, alkoxy or
0 *
cyano; *
is a mono- or bicyclic cycloalkyl or a heterocycloalkyl optionally
substituted with 1-3 substituents selected from alkyl, halogen, haloalkyl,
hydroxy, alkoxy or
cyano; and the phenyl ring fragment can be optionally substituted with 1, 2 or
3 substituents
selected from the grou consisting of alkyl, halogen, haloalkyl, hydroxy,
alkoxy and cyano. In an
embodiment, the linker group L comprises up to 10 covalently connected
structural units, as
described above.
[0107]
Although the ULM group and PTM group may be covalently linked to the linker
group through any group which is appropriate and stable to the chemistry of
the linker, in
preferred aspects of the present dislcosure, the linker is independently
covalently bonded to the
ULM group and the PTM group preferably through an amide, ester, thioester,
keto group,
carbamate (urethane), carbon or ether, each of which groups may be inserted
anywhere on the
ULM group and PTM group to provide maximum binding of the ULM group on the
ubiquitin
ligase and the PTM group on the target protein to be degraded. (It is noted
that in certain aspects
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where the PTM group is a ULM group, the target protein for degradation may be
the ubiquitin
ligase itself). In certain preferred aspects, the linker may be linked to an
optionally substituted
alkyl, alkylene, alkene or alkyne group, an aryl group or a heterocyclic group
on the ULM and/or
PTM groups.
[0108] 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.
[0109] In certain embodiments, the linker (L) is selected from the group
consisting of:
`N, Oey4It.
OH
0
I
0 = csjs =
0 0
,111.01ijL00).=,55s
sr. .
0
Ojoss
0 ;
0 0
e =
0 0
0 H
N 0 j.-csss
e = = '1/4
0 0 0
41( N j= . N 0 ,/
0 0
o
= O\;r 0 0 =
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0 0 0
cr =
0 0
0 = rcr =
\>"-- 0 0
o
: N (;="---t),
¨
kõ4 A
=
\
;
= 0 ;and
0.
0
't
[0110] In additional embodiments, the linker group is optionally substituted
(poly)ethyleneglycol haying 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.
[0111] In any of the embodiments of the compounds described herein, the
linker group may
be any suitable moiety as described herein. In one embodiment, the linker is a
substituted or
unsubstituted polyethylene glycol group ranging in size from about 1 to about
12 ethylene glycol
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units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene
glycol units,
between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene
glycol units.
[0112] .. Although the CLM (or ULM) group and PTM group may be covalently
linked to the
linker group through any group which is appropriate and stable to the
chemistry of the linker, in
preferred aspects of the present disclosure, the linker is independently
covalently bonded to the
CLM group and the PTM group preferably through an amide, ester, thioester,
keto group,
carbamate (urethane), carbon or ether, each of which groups may be inserted
anywhere on the
CLM group and PTM group to provide maximum binding of the CLM group on the
ubiquitin
ligase and the PTM group on the target protein to be degraded. (It is noted
that in certain aspects
where the PTM group is a ULM group, the target protein for degradation may be
the ubiquitin
ligase itself). In certain preferred aspects, the linker may be linked to an
optionally substituted
alkyl, alkylene, alkene or alkyne group, an aryl group or a heterocyclic group
on the CLM and/or
PTM groups.
[0113] In certain embodiments, "L" can be linear chains with linear atoms
from 4 to 24, the
carbon atom in the linear chain can be substituted with oxygen, nitrogen,
amide, fluorinated
carbon, etc., such as the following:
I' N\'µ
0 0
0 0
N
0
N 0 0
N
N 0 0 01\11r
N 0
0 0
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,,,,N..---..õ.õ,,O.õ,..õ,=-=-=.,0,---...,,,,,O.,./. 'i, 0 0 õ,
H H
0 0
, n ,
N)--,'-
i
H H H H ,
, .
, . ,
,, -
i N 0 0 = %1=100-\ s
H H
H
,
- \
H H
0 ,
, . . ,
'/-1\10N '''N N"µ=
H H H H
II' N C)N
H H H H ,or
H
H H H
F F F F F\ IF H
H F F H H .
[0114] In certain embodiments, "L" can be nonlinear chains, and can be
aliphatic or aromatic
or heteroaromatic cyclic moieties, some examples of "L" include but not be
limited to the
following:
--
HN 4. 0-X-Y-h HN = 0-X-y--
F
N¨
HN 11 0-X-Y-h 1
¨\ ¨0-X-Y-:-
F
--µc - -'c-
HN = 0-X-Y-h HN-0-0-X-YH-
N
- - N-
1 _ -
Y.,' \ ¨)-0-X-Y-:- = / 1
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F
= õ
-7-N . ,X--y ' , lip A--y' s 1 404 o'X-=µ?(
0 7-N 7-N
0
H H H
F
--.. = ,
X y . -.ys /=
X-- %
7-N =si-N Y
0'X 0'
-,I-N 0 0' - s''
H H H
711 illp,
n-- y ' = -,'''N
-:
--1, Ilp
-N - i--\
0
',.. s
0 . /
--:-N 1110 N/--\ N¨/._ 1 N-----N_
, H -;--NH Y ,
0 0
,
NH-X-Y O-X-Y
\,,' µ
wherein:
'X" in above structures can be linear chain with atoms ranging from 2 to 14,
and the
mentioned chain can contain heteroatoms such as oxygen; and
"Y" in above structures can be 0, N, S(0),, (n=0, 1, 2).
[0115] Exemplary PTMs
[0116] In preferred aspects of the present disclosure, the PTM group is a
group, which binds
to target proteins. Targets of the PTM group are numerous in kind and are
selected from proteins
that are expressed in a cell such that at least a portion of the sequences is
found in the cell and
may bind to a PTM group. The term "protein" includes oligopeptides and
polypeptide sequences
of sufficient length that they can bind to a PTM group according to the
present disclosure. Any
protein in a eukaryotic system or a microbial system, including a virus,
bacteria or fungus, as
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otherwise described herein, are targets for ubiquitination mediated by the
compounds according
to the present disclosure. Preferably, the target protein is a eukaryotic
protein. In certain aspects,
the protein binding moiety is a haloalkane (preferably a C i-Cio alkyl group
which is substituted
with at least one halo group, preferably a halo group at the distal end of the
alkyl group, i.e.,
away from the linker or CLM group), which may covalently bind to a
dehalogenase enzyme in a
patient or subject or in a diagnostic assay.
[0117] PTM groups according to the present disclosure include, for example,
include any
moiety which binds to a protein specifically (binds to a target protein) and
includes the following
non-limiting examples of small molecule target protein moieties: Hsp90
inhibitors, kinase
inhibitors, androgen receptor inhibitors, HDM2 & MDM2 inhibitors, compounds
targeting
Human BET Bromodomain-containing proteins, HDAC inhibitors, human lysine
methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone
receptor compounds,
immunosuppressive compounds, and compounds targeting the aryl hydrocarbon
receptor (AHR),
among numerous others. The compositions described below exemplify some of the
members of
these nine types of small molecule target protein binding moieties. Such small
molecule target
protein binding moieties also include pharmaceutically acceptable salts,
enantiomers, solvates
and polymorphs of these compositions, as well as other small molecules that
may target a protein
of interest. These binding moieties are linked to the ubiquitin ligase binding
moiety preferably
through a linker in order to present a target protein (to which the protein
target moiety is bound)
in proximity to the ubiquitin ligase for ubiquitination and degradation.
[0118] Any protein, which can bind to a protein target moiety or PTM group
and acted on or
degraded by a ubiquitin ligase is a target protein according to the present
disclosure. In general,
target proteins may include, for example, structural proteins, receptors,
enzymes, cell surface
proteins, proteins pertinent to the integrated function of a cell, including
proteins involved in
catalytic activity, aromatase activity, motor activity, helicase activity,
metabolic processes
(anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis,
proteins with kinase
activity, oxidoreductase activity, transferase activity, hydrolase activity,
lyase activity, isomerase
activity, ligase activity, enzyme regulator activity, signal transducer
activity, structural molecule
activity, binding activity (protein, lipid carbohydrate), receptor activity,
cell motility, membrane
fusion, cell communication, regulation of biological processes, development,
cell differentiation,
response to stimulus, behavioral proteins, cell adhesion proteins, proteins
involved in cell death,
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proteins involved in transport (including protein transporter activity,
nuclear transport, ion
transporter activity, channel transporter activity, carrier activity, permease
activity, secretion
activity, electron transporter activity, pathogenesis, chaperone regulator
activity, nucleic acid
binding activity, transcription regulator activity, extracellular organization
and biogenesis
activity, translation regulator activity. Proteins of interest can include
proteins from eurkaryotes
and prokaryotes including humans as targets for drug therapy, other animals,
including
domesticated animals, microbials for the determination of targets for
antibiotics and other
antimicrobials and plants, and even viruses, among numerous others.
[0119] In still other embodiments, the PTM group is a haloalkyl group,
wherein said alkyl
group generally ranges in size from about 1 or 2 carbons to about 12 carbons
in length, often
about 2 to 10 carbons in length, often about 3 carbons to about 8 carbons in
length, more often
about 4 carbons to about 6 carbons in length. The haloalkyl groups are
generally linear alkyl
groups (although branched-chain alkyl groups may also be used) and are end-
capped with at least
one halogen group, preferably a single halogen group, often a single chloride
group. Haloalkyl
PT, groups for use in the present disclosure are preferably represented by the
chemical structure
¨(CH2),-Halo where v is any integer from 2 to about 12, often about 3 to about
8, more often
about 4 to about 6. Halo may be any halogen, but is preferably Cl or Br, more
often Cl.
[0120] In another embodiment, the present disclosure provides a library of
compounds. The
library comprises more than one compound wherein each composition has a
formula of A-B,
wherein A is a ubiquitin pathway protein binding moiety (preferably, an E3
ubiquitin ligase
moiety as otherwise disclosed herein) and B is a protein binding member of a
molecular library,
wherein A is coupled (preferably, through a linker moiety) to B, and wherein
the ubiquitin
pathway protein binding moiety recognizes an ubiquitin pathway protein, in
particular, an E3
ubiquitin ligase, such as cereblon. In a particular embodiment, the library
contains a specific
cereblon E3 ubiquitin ligase binding moiety bound to random target protein
binding elements
(e.g., a chemical compound library). As such, the target protein is not
determined in advance and
the method can be used to determine the activity of a putative protein binding
element and its
pharmacological value as a target upon degradation by ubiquitin ligase.
[0121] The present disclosure may be used to treat a number of disease
states and/or
conditions, including any disease state and/or condition in which proteins are
dysregulated and
where a patient would benefit from the degradation of proteins.
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[0122] In an additional aspect, the description provides therapeutic
compositions comprising
an effective amount of a compound as described herein or salt form thereof,
and a
pharmaceutically acceptable carrier, additive or excipient, and optionally an
additional bioactive
agent. The therapeutic compositions modulate protein degradation in a patient
or subject, for
example, an animal such as a human, and can be used for treating or
ameliorating disease states
or conditions which are modulated through the degraded protein. In certain
embodiments, the
therapeutic compositions as described herein may be used to effectuate the
degradation of
proteins of interest for the treatment or amelioration of a disease, e.g.,
cancer (such as prostate
cancer) and Kennedy's Disease. In certain additional embodiments, the disease
is prostate
cancer.
[0123] In alternative aspects, the present disclosure relates to a method
for treating a disease
state or ameliorating the symptoms of a disease or condition in a subject in
need thereof 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, e.g.,
a therapeutically
effective amount, of at least one compound as described hereinabove,
optionally in combination
with a pharmaceutically acceptable carrier, additive or excipient, and
optionally an additional
bioactive agent, wherein the composition is effective for treating or
ameliorating the disease or
disorder or symptom thereof in the subject. The method according to the
present disclosure 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.
The disease state
or condition may be a disease caused by a microbial agent or other exogenous
agent such as a
virus, bacteria, fungus, protozoa or other microbe or may be a disease state,
which is caused by
overexpression of a protein, which leads to a disease state and/or condition.
[0124] In another aspect, the description provides methods for identifying
the effects of the
degradation of proteins of interest in a biological system using compounds
according to the
present disclosure.
[0125] The term "target protein" is used to describe a protein or
polypeptide, which is a
target for binding to a compound according to the present disclosure and
degradation by
ubiquitin ligase hereunder. Such small molecule target protein binding
moieties also include
pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of
these compositions,
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as well as other small molecules that may target a protein of interest. These
binding moieties are
linked to CLM or ULM groups through linker groups L.
[0126] Target proteins which may be bound to the protein target moiety and
degraded by the
ligase to which the ubiquitin ligase binding moiety is bound include any
protein or peptide,
including fragments thereof, analogues thereof, and/or homologues thereof
Target proteins
include proteins and peptides having any biological function or activity
including structural,
regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage,
transportation,
and signal transduction. In certain embodiments, the target proteins include
structural proteins,
receptors, enzymes, cell surface proteins, proteins pertinent to the
integrated function of a cell,
including proteins involved in catalytic activity, aromatase activity, motor
activity, helicase
activity, metabolic processes (anabolism and catabolism), antioxidant
activity, proteolysis,
biosynthesis, proteins with kinase activity, oxidoreductase activity,
transferase activity,
hydrolase activity, lyase activity, isomerase activity, ligase activity,
enzyme regulator activity,
signal transducer activity, structural molecule activity, binding activity
(protein, lipid
carbohydrate), receptor activity, cell motility, membrane fusion, cell
communication, regulation
of biological processes, development, cell differentiation, response to
stimulus, behavioral
proteins, cell adhesion proteins, proteins involved in cell death, proteins
involved in transport
(including protein transporter activity, nuclear transport, ion transporter
activity, channel
transporter activity, carrier activity, permease activity, secretion activity,
electron transporter
activity, pathogenesis, chaperone regulator activity, nucleic acid binding
activity, transcription
regulator activity, extracellular organization and biogenesis activity,
translation regulator activity.
Proteins of interest can include proteins from eukaryotes and prokaryotes,
including microbes,
viruses, fungi and parasites, including humans, microbes, viruses, fungi and
parasites, among
numerous others, as targets for drug therapy, other animals, including
domesticated animals,
microbials for the determination of targets for antibiotics and other
antimicrobials and plants, and
even viruses, among numerous others.
[0127] More specifically, a number of drug targets for human therapeutics
represent protein
targets to which protein target moiety may be bound and incorporated into
compounds according
to the present disclosure. These include proteins which may be used to restore
function in
numerous polygenic diseases, including for example B7.1 and B7, TINFR1m,
TNFR2, NADPH
oxidase, Bc1113ax and other partners in the apotosis pathway, C5a receptor,
HMG-CoA reductase,
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PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII,
PDEIII,
squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-
oxygenase 1,
cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq,
histamine receptors,
5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine
nucleoside phosphorylase,
GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine
receptors,
JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza,
neuramimidase,
hepatitis B reverse transcriptase, sodium channel, multi drug resistance
(MDR), protein P-
glycoprotein (and MRP), tyrosine kinases, CD23, CD124, tyrosine kinase p56
lck, CD4, CD5,
IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4
integrin,
selectins, CD40/CD4OL, newokinins and receptors, inosine monophosphate
dehydrogenase, p38
MAP Kinase, Ras1Raf1MEWERK pathway, interleukin-1 converting enzyme, caspase,
HCV,
N53 protease, HCV N53 RNA helicase, glycinamide ribonucleotide formyl
transferase,
rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease,
cytomegalovirus (CMV)
protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular
endothelial growth
factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid
transport inhibitor, 5
alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline
reuptake receptor,
endothelin receptors, neuropeptide Y and receptor, estrogen receptors,
androgen receptors (AR),
adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors
(P2Y1, P2Y2,
P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyl transferase, TrkA a
receptor for
NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin
receptor, Her-21
neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor
tyrosine kinase.
Additional protein targets include, for example, ecdysone 20-monooxygenase,
ion channel of the
GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium
channel protein,
calcium release channel, and chloride channels. Still further target proteins
include Acetyl-CoA
carboxylase, adenylosuccinate synthetase,
protoporphyrinogen oxidase, and
enolpyruvylshikimate-phosphate synthase.
[0128]
Haloalkane dehalogenase enzymes are another target of specific compounds
according to the present disclosure. Compounds according to the present
disclosure which
contain chloroalkane peptide binding moieties (C i-C12 often about C2-C10
alkyl halo groups) may
be used to inhibit and/or degrade haloalkane dehalogenase enzymes which are
used in fusion
proteins or related dioagnostic proteins as described in PCT/U52012/063401
filed December 6,
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2011 and published as WO 2012/078559 on June 14, 2012, the contents of which
is incorporated
by reference herein.
[0129] These various protein targets may be used in screens that identify
compound moieties
which bind to the protein and by incorporation of the moiety into compounds
according to the
present disclosure, the level of activity of the protein may be altered for
therapeutic end result.
[0130] The term "protein target moiety" or PTM is used to describe a small
molecule which
binds to a target protein or other protein or polypeptide of interest and
places/presents that
protein or polypeptide in proximity to an ubiquitin ligase such that
degradation of the protein or
polypeptide by ubiquitin ligase may occur. Non-limiting examples of small
molecule target
protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2
inhibitors,
compounds targeting Human BET Bromodomain-containing proteins, HDAC
inhibitors, human
lysine methyltransferase inhibitors, angiogenesis inhibitors,
immunosuppressive compounds, and
compounds targeting the aryl hydrocarbon receptor (AHR), among numerous
others. The
compositions described below exemplify some of the members of these nine types
of small
molecule target protein.
[0131] Exemplary protein target moieties according to the present
disclosure include,
haloalkane halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2
inhibitors,
compounds targeting Human BET Bromodomain-containing proteins, HDAC
inhibitors, human
lysine methyltransferase inhibitors, angiogenesis inhibitors,
immunosuppressive compounds, and
compounds targeting the aryl hydrocarbon receptor (AHR).
[0132] The compositions described below exemplify some of the members of
these types of
small molecule target protein binding moieties. Such small molecule target
protein binding
moieties also include pharmaceutically acceptable salts, enantiomers, solvates
and polymorphs of
these compositions, as well as other small molecules that may target a protein
of interest.
References which are cited hereinbelow are incorporated by reference herein in
their entirety.
[0133] I. Heat Shock Protein 90 (HSP90) Inhibitors:
[0134] HSP90 inhibitors as used herein include, but are not limited to:
[0135] 1. The HSP90 inhibitors identified in Vallee, et at., "Tricyclic
Series of Heat Shock
Protein 90 (HSP90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-
C]Pyridines as Potent
Inhibitors of the HSP90 Molecular Chaperone (2011) IMed.Chem. 54: 7206,
including YKB
(N-[4-(3H-imidazo[4,5 -C]Pyri din-2-y1)-9H-Fluoren-9-yl] -succinami de):
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0
HN
N H2
Se. 0
N¨
N H
N
[0136]
derivatized where a linker group L or a ¨(L-CLM)
group is attached, for example, via the terminal amide group;
[0137]
2. The HSP90 inhibitor p54 (modified) (8-[(2,4-dimethylphenyl)sulfany1]-3]pent-
4-
yn-1-y1-3H-purin-6-amine):
N H2
N N
N N
[0138]
derivatized where a linker group L or a ¨(L-CLM)
group is attached, for example, via the terminal acetylene group;
[0139]
3. The HSP90 inhibitors (modified) identified in Brough, et at., "4,5-
Diarylisoxazole
HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of
Cancer",
vol: 51, pag:196 (2008), including the compound 2GJ (542,4-dihydroxy-5-(1-
methylethyl)pheny1]-n-ethy1-444-(morpholin-4-ylmethyl)phenyl]isoxazole-3-
carboxamide)
having the structure:
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co
0
N
HO / H
0" N
[0140] OH derivatized, where a linker group L or a
¨(L-CLM)
group is attached, for example, via the amide group (at the amine or at the
alkyl group on the
amine);
[0141] 4. The HSP90 inhibitors (modified) identified in Wright, et at.,
Structure-Activity
Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, Chem Biol.
2004
Jun;11(6):775-85, including the HSP90 inhibitor PU3 having the structure:
N H2
N
0
¨0 0¨
[0142] derivatized where a linker group L or ¨(L-CLM)
is
attached, for example, via the butyl group; and
[0143] 5. The HSP90 inhibitor geldanamycin
((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-
hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethy1-3,20,22-tri oxo-2-az abi
cycl o [16.3 .1]
(derivatized) or any of its derivatives (e.g. 17-alkylamino-17-
desmethoxygeldanamycin ("17-
AAG") or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin ("17-DMAG"))
(derivatized, where a linker group L or a¨(L-CLM) group is attached, for
example, via the amide
group).
[0144] II. Kinase and Phosphatase Inhibitors:
[0145] Kinase inhibitors as used herein include, but are not limited to:
[0146] 1. Erlotinib Derivative Tyrosine Kinase Inhibitor:
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HN
R,0 'N
0
where R is a linker group L or a ¨(L-CLM) group attached, for example, via the
ether group;
[0147] 2. The kinase inhibitor sunitinib (derivatized):
N
0
[0148] H
derivatized where R is a linker group L or a ¨(L-CLM)
group attached, for example, to the pyrrole moiety;
[0149] 3. Kinase Inhibitor sorafenib (derivatized):
0
CI
I N
CF3 = N N
[0150] H H
derivatized where R is a linker
group L or a ¨(L-CLM) group attached, for example, to the amide moiety;
[0151] 4. The kinase inhibitor desatinib (derivatized):
CI
= NH
rs 11
¨ NH
N R derivatized where R is a linker group Lor
a¨(L-CLM)
attached, for example, to the pyrimidine;
[0152] 5. The kinase inhibitor lapatinib (derivatized):
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CI
0 10
0
g---
HN I \ HN
N 0
[0153] N derivatized where a linker group L or
a¨(L-
CLM) group is attached, for example, via the terminal methyl of the sulfonyl
methyl group;
[0154] 6. The kinase inhibitor U09-CX-5279 (derivatized):
N N __
N
HO
N NH
0
[0155] rs '1c
3 derivatized where a linker group L or a ¨(L-CLM)
group is attached, for example, via the amine (aniline), carboxylic acid or
amine alpha to
cyclopropyl group, or cyclopropyl group;
[0156] 7. The kinase inhibitors identified in Millan, et at., Design and
Synthesis of Inhaled
P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease,
IMED.CHEA1
vol:54, pag:7797 (2011), including the kinase inhibitors YlW and Y1X
(Derivatized) having the
structures:
0
N
H H
/
N¨N
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[0157] YIX(1-ethyl-3 -(24 [3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-
6-
yl]sulfanylIbenzyl)urea, derivatized where a linker group L or a¨(L-CLM) group
is attached, for
example, via the ipropyl group;
= k.
0 N-11\
HN AN
s
YIW
H-pyrazol-5-y1)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-
yl]sulfanyllbenzyl)urea
derivatized where a linker group L or a ¨(L-CLM) group is attached, for
example, preferably via
either the i-propyl group or the t-butyl group;
[0158] 8. The kinase inhibitors identified in Schenkel, et at., Discovery
of Potent and
Highly Selective Thienopyridine Janus Kinase 2 Inhibitors I Med. Chem., 2011,
54 (24),
pp 8440-8450, including the compounds 6TP and OTP (Derivatized) having the
structures:
HN 0
s
N s-NH
0
NH2
6TP
4-amino-2-[4-(tert-butylsulfamoy0phenyI]-N-methylthieno[3,2-c]pyridine-7-
carboxamide
Thienopyridine 19
derivatized where a linker group L or a ¨(L-CLM) group is attached, for
example, via the
terminal methyl group bound to amide moiety;
HN 0
S
1 N 0
N
N H2
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OTP
4-amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-
carboxamide
Thienopyridine 8
derivatized where a linker group L or a ¨(L-CLM)group is attached, for
example, via the
terminal methyl group bound to the amide moiety;
[0159] 9. The kinase inhibitors identified in Van Eis, et at., "2,6-
Naphthyridines as potent
and selective inhibitors of the novel protein kinase C isozymes", Biorg. Med.
Chem. Lett.2011
Dec 15;21(24):7367-72, including the kinase inhibitor 07U having the
structure:
N H2
H N
N
N
N
07U
2-methyl-N-1-43-(pyridin-4-y1)-2,6-naphthyridin-1-yl]propane-1,2-diamine
derivatized where a linker group L or a ¨(L-CLM)group is attached, for
example, via the
secondary amine or terminal amino group;
[0160] 10. The kinase inhibitors identified in Lountos, et at., "Structural
Characterization of
Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer
Therapy",
ISTRUCT.BIOL. vol:176, pag:292 (2011), including the kinase inhibitor YCF
having the
structure:
H H
N N N N
HO- r 'N 0 NOH
N H2
NN
NH
[0161] H H
derivatized where
a linker group L or a ¨(L-CLM) group is attached, for example, via either of
the terminal
hydroxyl groups;
[0162] 11. The kinase inhibitors identified in Lountos, et at., "Structural
Characterization of
Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer
Therapy",
ISTRUCT.BIOL. vol:176, pag:292 (2011), including the kinase inhibitors XK9 and
NXP
(derivatized) having the structures:
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HN pH
)¨NH
NO2 N¨NH
/
N HN
wl 0
X1(9
N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]pheny1)-7-nitro-1H-
indole-2-carboxamide ;
NH
0
=
---N
NH
HN-
NH2
NXP
[0163] N-{4-[(1E)-N-CARBAM I M IDOYLETHANEHYDRAZONOYL]PHENYL)-1H-INDOLE-3-
CARBOXAM IDE
derivatized where a linker group L or a ¨(L-CLM) group is attached, for
example, via the
terminal hydroxyl group (XK9) or the hydrazone group (NXP);
[0164] 12.
The kinase inhibitor afatinib (derivatized) (N44-[(3-chloro-4-
fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazoliny1]-
4(dimethylamino)-2-
butenamide) (Derivatized where a linker group L or a ¨(L-CLM) group is
attached, for example,
via the aliphatic amine group);
[0165] 13.
The kinase inhibitor fostamatinib (derivatized) ([6-({5-fluoro-2-[(3,4,5-
trimethoxyphenyl)amino]pyrimidin-4-ylIamino)-2,2-dimethy1-3-oxo-2,3-dihydro-4H-
pyrido[3,2-b]-1,4-oxazin-4-yl]methyl disodium phosphate hexahydrate)
(Derivatized where a
linker group L or a ¨(L-CLM) group is attached, for example, via a methoxy
group);
[0166] 14. The kinase inhibitor gefitinib (derivatized) (N-(3-chloro-4-
fluoro-pheny1)-7-
methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine):
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HN CI
R,0 'N
[0167] 0 N
derivatized where a linker group L or a ¨(L-CLM)
group is attached, for example, via a methoxy or ether group;
[0168] 15.
The kinase inhibitor lenvatinib (derivatized) (4-[3-chloro-4-
(cyclopropylcarbamoylamino)phenoxy] -7-methoxy-quinoline-6-carb oxami de)
(derivatized
where a linker group L or a ¨(L-CLM) group is attached, for example, via the
cyclopropyl
group);
[0169] 16. The kinase inhibitor vandetanib (derivatized) (N-(4-bromo-2-
fluoropheny1)-6-
methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (derivatized
where a linker
group L or a ¨(L-CLM) group is attached, for example, via the methoxy or
hydroxyl group);
[0170] 17. The kinase inhibitor vemurafenib (derivatized) (propane-l-
sulfonic acid {345-
(4-chl oropheny1)-1H-pyrrol o [2,3 -1)] pyri dine-3 -carbonyl] -2,4-difluoro-
phenyl }-ami de),
derivatized where a linker group L or a ¨(L-CLM) group is attached, for
example, via the
sulfonyl propyl group;
[0171] 18. The kinase inhibitor Gleevec (derivatized):
HN
[0172] OR
derivatized where R as a linker group L or a¨(L-CLM)
group is attached, for example, via the amide group or via the aniline amine
group;
[0173] 19. The kinase inhibitor pazopanib (derivatized) (VEGFR3 inhibitor):
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R
NH
N
II I N¨
[0174] I
derivatized where R is a linker group L or a -
(L-CLM) group attached, for example, to the phenyl moiety or via the aniline
amine group;
[0175] 20. The kinase inhibitor AT-9283 (Derivatized) Aurora Kinase
Inhibitor
0 p.
HN H
R N
N-NH
[0176] H
where R is a linker group L or a -(L-CLM) group
attached, for example, to the phenyl moiety);
[0177] 21. The kinase inhibitor TAE684 (derivatized) ALK inhibitor
I
0 HNNNH
,\\s/ 0
¨
[0178] R
where R is a linker group L or a -(L-CLM) group
attached, for example, to the phenyl moiety);
[0179] 22. The kinase inhibitor nilotanib (derivatized) Abl inhibitor:
HN
/ NH
0
= 1/,
[0180] F3C
derivatized where R is a linker group L
or a -(L-CLM) group attached, for example, to the phenyl moiety or the aniline
amine group;
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[0181] 23. Kinase Inhibitor NVP-BSK805 (derivatized) JAK2 Inhibitor
0
N
F 0 F
N
NJ/ NR
.---IN-R
[0182] N
derivatized where R is a linker group L or a ¨(L-
CLM) group attached, for example, to the phenyl moiety or the diazole group;
[0183] 24. Kinase Inhibitor crizotinib Derivatized Alk Inhibitor
R
IV
NIO
I
ILNH2
0
CI 0 CI
[0184] F
derivatized where R is a linker group L or a ¨(L-CLM) group
attached, for example, to the phenyl moiety or the diazole group;
[0185] 25. Kinase Inhibitor JNJ FMS (derivatized) Inhibitor
0 HN,Co
R 0 NO
I
NNN
a[0186] H
derivatized where R is a linker group L or a ¨
(L-CLM) group attached, for example, to the phenyl moiety;
[0187] 26. The kinase inhibitor foretinib (derivatized) Met Inhibitor
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RNXN
0 0
0
0
R,
[0188] 0 N
derivatized where R is a linker
group L or a ¨(L-CLM)group attached, for example, to the phenyl moiety or a
hydroxyl or ether
group on the quinoline moiety;
[0189] 27. The allosteric Protein Tyrosine Phosphatase Inhibitor PTP1B
(derivatized):
0
HN
f- 0 0
\//
S N 401 0 0
H \\i/
iSCN
0
OH
[0190] Br
derivatized where a
linker group L or a ¨(L-CLM) group is attached, for example, at R, as
indicated;
[0191] 28. The inhibitor of SHP-2 Domain of Tyrosine Phosphatase
(derivatized):
OMe
0
HN
I
[0192]
derivatized where a linker group L or a ¨(L-CLM)
group is attached, for example, at R;
[0193] 29. The inhibitor (derivatized) of BRaf (BRaf
v o6 oE)/mEK:
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o
ci 0
I F
N N
[0194] H
derivatized where a linker group L or a¨
(L-CLM) group is attached, for example, at R;
[0195] 30. Inhibitor (derivatized) of Tyrosine Kinase ABL
Me
HN NH
NR
N 0
N)
N
[0196]
derivatized where a linker group
L or a¨(L-CLM) group is attached, for example, at R;
[0197] 31. The kinase inhibitor OSI-027 (derivatized) mTORC1/2 inhibitor
NH2 \ NH
N
z
/11
[0198]
derivatized where a linker group L or a¨(L-CLM) group is
attached, for example, at R;
[0199] 32. The kinase inhibitor OSI-930 (derivatized) c-Kit/KDR inhibitor
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411, OCF3
HN
cs
NH
[0200] R¨o
derivatized where a linker group L or a¨(L-CLM)
group is attached, for example, at R; and
[0201] 33. The kinase inhibitor OSI-906 (derivatized) IGF1R/IR inhibitor
NI-12
N
N
[0202] R
derivatized where a linker group L or a¨(L-CLM)
group is attached, for example, at R.
[0203] Wherein, in any of the embodiments described in sections I-XVII, "R"
designates a
site for attachment of a linker group L or a ¨(L-CLM)group on the piperazine
moiety.
[0204] III. HDM2/1VIDM2 Inhibitors:
[0205] HDM2/MDM2 inhibitors as used herein include, but are not limited to:
[0206] 1. The HDM2/MDM2 inhibitors identified in Vassilev, et at., In vivo
activation of
the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303,
pag:844-848
(2004), and Schneekloth, et at., Targeted intracellular protein degradation
induced by a small
molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008)
5904-5908,
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including (or additionally) the compounds nutlin-3, nutlin-2, and nutlin-1
(derivatized) as
described below, as well as all derivatives and analogs thereof:
CI
0 410
OiNN
FINN --;>1 ""14.' CI
0 11.))
(derivatized where a linker group L or a ¨(L-CLM)group is attached, for
example, at the
methoxy group or as a hydroxyl group);
Br
0 41li
N N
HONN Br
(37
0
(derivatized where a linker group L or a ¨(L-CLM) group is attached, for
example, at the
methoxy group or hydroxyl group);
CI
0 441,
r-NNAN--\
o
ci
0
0
(derivatized where a linker group L or a ¨(L-CLM) group is attached, for
example, via the
methoxy group or as a hydroxyl group); and
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[0207] 2. Trans-44odo-4'-Boranyl-Chalcone
0
I B4OH
OH
[0208] (derivatized where a linker group L or a a linker group L or a¨(L-
CLM) group is
attached, for example, via a hydroxy group).
[0209] IV. Compounds Targeting Human BET Bromodomain-containing proteins:
[0210] In certain embodiments, "PTM" can be ligands binding to Bromo- and
Extra-terminal
(BET) proteins BRD2, BRD3 and BRD4. Compounds targeting Human BET Bromodomain-
containing proteins include, but are not limited to the compounds associated
with the targets as
described below, where "R" or "linker" designates a site for linker group L or
a¨(L-CLM) group
attachment, for example:
[0211] 1. JQ1, Filippakopoulos et al. Selective inhibition of BET
bromodomains. Nature
(2010):
S S
z NN z N
N
N 0
N N
ci 0 0
X= CI, Br, F, H,
R S
bond, or a chemical
moiety coupling the
`jk\ CLM to the PTM N
N/ 0
¨N1Z.',/7'-'0
R R = H, a lower alkyl, X = CI, Br, F,
H
a bond, or a chemcial
moiety coupling the
CLM to the PTM
X x
¨N
coNH2
¨
¨N '',/)LLinker X = CI, Br, F, H Linker¨N N X = CI, Br,
F, H
X X
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¨N
N'03 0
Linker¨N X = CI, Br, F, H
X , Linker
,
or
X
\ 0
N
= H
Linker
X = H, F
=
[0212]
2. I-BET, Nicodeme et al. Supression of Inflammation by a Synthetic Histone
Mimic.
Nature (2010). Chung et al. Discovery and Characterization of Small Molecule
Inhibitors of the
BET Family Bromodomains. J. Med Chem. (2011):
N)N
110 N
N
N NN _P,
CI 0
0
\\)--=N X = CI, Br, F, H,
bond, or a chemical
Ni=I 0
moiety coupling the
CLM to the PTM
NH
R R = H, a lower alkyl,
a bond, or a chemcial
moiety coupling the
X CLM to the PTM
[0213]
3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-
lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761-6770.
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R
HO HO
. / 9 / I)-<I:9
-- N 11
0 0,
\_
R
[0214] 4. I-BET151, Dawson et al. Inhibition of BET Recruitment to
Chromatin as an
Efective Treatment for MLL-fusion Leukemia. Nature (2011):
Linker
R
Nip
NI \
N
0 R 0
H
N----µ N
0 NH 0 N /0
N/ I N
N/ i N /
N\ 1 N
b b 0 ,
N? Linker
N---<
0 N
/
/
N N \ I
0
[0215] 5. Carbazole type (US 2015/0256700)
0 0
NH2 NH2
0 \ 0 \
I I
1 ¨Linker 1 ¨R
N N
[ . i Linker
0216]
\X
[0217] 6. Pyrrolopyridone type (US 2015/0148342)
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TIN/
Linker _N'R
N ----Linker
F
0 F
0
F F
H 0
H 0
[0218]
[0219] 7. Tetrahydroquinoline type (WO 2015/074064)
0 ¨N
\srq¨R
Linker
[0220]o
[0221] 8. Triazolopyrazine type (WO 2015/067770)
N I N
IS (IN
lµrj
N
Linker
'Linker
[0222] 0--
[0223] 9. Pyridone type (WO 2015/022332)
¨N (No
LinkerYN
[0224]
[0225] 10. Quinazolinone type (WO 2015/015318)
0
-TLinker
NH
[0226] 0
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[0227] 11. Dihydropyridopyrazinone type (WO 2015/011084)
N
H N N
ON
N -Linker
O
[0228]
[0229] (Where R or L or linker, in each instance, designates a site for
attachment, for
example, of a linker group L or a ¨(L-CLM) group).
[0230] In any aspect or embodiment described herein, the claimed structure
the PTM may be
composed of tricyclic diazepine or tricyclic azepine as a BET/BRD4 targeting
moiety (PTM-a),
where the dashed lines indicate the linker connection trajectory and three
sites are defined to
which linkers may be attached:
Zi
õ,
Y\1
N _____________________
XY3
4110 ,/(C'
)\
PTM-a
wherein:
A and B are independently an aromatic ring, a heteroaromatic ring, a 5-
membered
carbocyclic, a 6-membered carbocyclic, a 5-membered heterocyclic, a 6-membered
heterocyclic, a thiophene, a pyrrole, a pyrazole, a pyridine, a pyrimidine, a
pyrazine,
optionally substituted by alkyl, aloxy, halogen, nitrile or another aromatic
or
heteroaromatic ring, where A is fused to the central azepine (Y1=C) or
diazepine (Y1 =
N) moiety;
Yl, Y2, and Y3 and Y4 can be carbon, nitrogen or oxygen for to form a fused 5-
membered
aromatic ring as triazole or isoxazole; and
Z1 is methyl, or lower alkyl group.
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[0231] The fragment of PTM-a as BET/BRD4 targeting moiety is described in
the literature
(WO 2016/069578; W02014/001356; W02016/050821; WO 2015/195863; WO
2014/128111).
[0232] In any aspect or embodiment described herein comprising the
structure CLM-L-PTM-
a, PTM-a can be represented by the following general structures, where dashed
line indicates a
possible linker connection point. In structure PTM-aa through PTM-ai, the
substitution pattern of
X and Y can be mono- or bis-substitution.
N
I / N
N __________________ X = Cl, F, Br, H, CN, methyl, acetylene, methoxy
-
X PTM-aa
_N
N 0
N X = Cl, F, Br, H, CN, methyl, acetylene, methoxy
\ /
PTM-ab
X
/ N
0 X = Cl, F, Br, H, CN, methyl, methoxy, acetylene
N
I/ Y: mono- or di-substitution, Y = Me, OMe, N-
methypyrazole/imidazole
X
PTM-ac
¨N
Y
0
X = Cl, F, Br, H, CN, methyl, methoxy, acetylene
'
(Z Y: mono- or di-substitution, Y = Me, OMe, N-methylpyrazole/imidazole
/
X PTM-ad
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_N
N
0 x = Cl, F, Br, H, CN, methyl, methoxy,
acetylene
Ni
R = lower alkyl, aryl, substituted aryl
/
X
PTM-ae
/ N
= 1-N 0
N __________________________ R = lower alkyl, aryl, substituted aryl
PTM-af
Y
N
\ / 0 Y: mono- or di-substitution, Y = Me, OMe, N-
methylpyrazole/imidazole
R = lower alkyl, aryl, substituted aryl
1104
PTM-ag
N
N
0
N ____________________ X = Cl, F, Br, H, CN, methyl, acetylene, methoxy
X PTM-ah
N N
0
N ____________________ X = Cl, F, Br, H, CN, methyl, acetylene, methoxy
-
PTM-al
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[0233] In any
aspect or embodiment described herein, the structures of PTM-a as the
BET/BRD4 targeting moiety includes, wherein the dashed line indicates the
connection point
between the BET/BRD4 targeting moiety and the linkers:
S S
) S'------N )-----=N
/ / N i I
N / N
0 CI F 0 i
1.---;N 0 .:-.-.=-N )----:-N
.....1 0 _...1 0
'',, __________________________________________________
- - \
PTM-al PTM-a2 PTM-a3
S S
1/ N 1 )-----N 1 /N 1
...._r-N 0 i / N 1
.....r.N 0
0
\--
- \
NC
PTM-a4 PTM-a5 PTM-a6
S S S
)'-----N )-----=--N
1 / N 1 ).=---N
/ / N 1
_ _./.---N 0 )------N )---=-N
0 ,/ 0
1 --
N - \ - N - \ NN - \
PTM-a7 PTM-a8 PTM-a9
N 1 N 1 0 Nril
õ..)--=:-.N 0 )---;--N )---=--N
.....1 .....1 0
0 N t 0 N , ________ 0 , 0 N , __ <,
CI F
PTM-a10 PTM-all PTM-a12
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104
N 1 )'----'N
N 1
)------N );---N -----N
0
,i N '',, 0
--\ - \
0 NC
PTM-a13 PTM-a14 PTM-a15
)------=N1
/0 /110 N)j =N
.--:-=N CI )--=-N );---N
0 ____________ 0 N ,-/ '',, ,/ , CI 0 N / '',,
- \
--\ CI
PTM-a16 PTM-a17 PTM-a18
-11 _N -N
, 0 , 0
/ x 0 0
/ N 0 / N 0
N),,2'/
`
F CI
CI
PTM-a19 PTM-a20 PTM-a21
_N _N
-11 , 6 , 0
0 0 / N 0 / N 0
/ x N ''''
N , ` ---')./`
NC // PTM-a23 PTM-a24
PTM-a22
, 0 , 0 0
/ N / N 0 /
''')/`
-0 CI CI
PTM-a25 PTM-a26 PTM-a27
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-N
_N
N
\ ---N \ 6
---- 0
N \ )...-.,...N N \ Nb 0
N 1
N i
CI
-N
--\
CI
PTM-a28 PTM-a29 PTM-a30
1 S ),.. S ), 0
I / N li 1 ---N )''''''N
I.---N 0 / N i N i
_7--N 0 )_.=--N
N '',, .
N '',, _____________________________________________________ i
NI' '',, (:)
,A, N HN .
PTM-a31 PTM-a32 HN
PTM-a33
\ b N-
I
0 , b 0 , b
/ i -:
0 / x ..N 7
.. / N 0
=
- A J
-N
H H H
PTM-a34 PTM-a35 PTM-a36
[0234] V. HDAC Inhibitors:
[0235] HDAC Inhibitors (deriyatized) include, but are not limited to:
[0236] 1. Finnin, M. S. et al. Structures of Histone Deacetylase Homologue
Bound to the
TSA and SAHA Inhibitors. Nature 40, 188-193 (1999).
0
H
0 R,N N
H 'OH
0
HN N 'OH 0
0 0
R
(Deriyatized where "R" designates a site for attachment, for example, of a
linker group L or a ¨
(L-CLM) group); and
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[0237] 2. Compounds as defined by formula (I) of PCT W00222577
("DEACETYLASE
INHIBITORS") (Derivatized where a linker group L or a ¨(L-CLM) group is
attached, for
example, via the hydroxyl group);
[0238] VI. Human Lysine Methyltransferase Inhibitors:
[0239] Human Lysine Methyltransferase inhibitors include, but are not
limited to:
[0240] 1. Chang et al. Structural Basis for G9a-Like protein Lysine
Methyltransferase
Inhibition by BIX-1294. Nat. Struct. Biol. (2009) 16(3) 312.
nN¨R
0 NyNN......1
0 0
HN HN
N
[0241] (Derivatized where "R" designates a site for attachment, for
example, of a linker
group L or a ¨(L-CLM) group);
[0242] 2. Liu, F. et al Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline
as a Potent
and Selective Inhibitor of Histone Methyltransferase G9a. J. Med. Chem. (2009)
52(24) 7950.
nN¨ I nN¨R
0 NyN/ N Ny N
N
HN HN
[0243] (Derivatized where "R" designates a potential site for attachment,
for example, of a
linker group L or a ¨(L-CLM) group);
[0244] 3. Azaciti dine (derivatized) (4-amino-1-0 -D -rib ofuranosyl-1,3,5 -
tri azin-2(11/)-one)
(Derivatized where a linker group L or a ¨(L-CLM) group is attached, for
example, via the
hydroxy or amino groups); and
[0245] 4. Decitabine (derivatized) (4-amino-1-(2-deoxy-b -D-erythro-
pentofuranosyl)-1, 3,
5-triazin-2(11/)-one) (Derivatized where a linker group L or a ¨(L-CLM) group
is attached, for
example, via either of the hydroxy groups or at the amino group).
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[0246] VII. Angiogenesis Inhibitors:
[0247] Angiogenesis inhibitors include, but are not limited to:
[0248] 1. GA-1 (derivatized) and derivatives and analogs thereof, having
the structure(s)
and binding to linkers as described in Sakamoto, et at., Development of
Protacs to target cancer-
promoting proteins for ubiquitination and degradation, Mot Cell Proteomics
2003
Dec;2(12):1350-8;
[0249] 2. Estradiol (derivatized), which may be bound to a linker group L
or a ¨(L-CLM)
group as is generally described in Rodriguez-Gonzalez, et at., Targeting
steroid hormone
receptors for ubiquitination and degradation in breast and prostate cancer,
Oncogene (2008) 27,
7201-7211;
[0250] 3. Estradiol, testosterone (derivatized) and related derivatives,
including but not
limited to DHT and derivatives and analogs thereof, having the structure(s)
and binding to a
linker group L or a ¨(L-CLM) group as generally described in Sakamoto, et at.,
Development of
Protacs to target cancer-promoting proteins for ubiquitination and
degradation, Mot Cell
Proteomics 2003 Dec; 2(12):1350-8; and
[0251] 4. Ovalicin, fumagillin (derivatized), and derivatives and analogs
thereof, having the
structure(s) and binding to a linker group L or a ¨(L-CLM) group as is
generally described in
Sakamoto, et al., Protacs: chimeric molecules that target proteins to the Skpl-
Cullin-F box
complex for ubiquitination and degradation Proc Natl Acad Sci USA. 2001 Jul
17;98(15):8554-9
and United States Patent No. 7,208,157.
[0252] VIII. Immunosuppressive Compounds:
[0253] Immunosuppressive compounds include, but are not limited to:
[0254] 1. AP21998 (derivatized), having the structure(s) and binding to a
linker group L or
a ¨(L-CLM) group as is generally described in Schneekloth, et at., Chemical
Genetic Control of
Protein Levels: Selective in Vivo Targeted Degradation, I AM CHEM. SOC. 2004,
126, 3748-
3754;
[0255] 2. Glucocorticoids (e.g., hydrocortisone,
predni sone, predni sol one, and
methylprednisolone) (Derivatized where a linker group L or a ¨(L-CLM) group is
to bound, e.g.
to any of the hydroxyls) and beclometasone dipropionate (Derivatized where a
linker group or a
¨(L-CLM) is bound, e.g. to a proprionate);
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[0256] 3. Methotrexate (Derivatized where a linker group or a ¨(L-CLM)
group can be
bound, e.g. to either of the terminal hydroxyls);
[0257] 4. Ciclosporin (Derivatized where a linker group or a ¨(L-CLM) group
can be
bound, e.g. at any of the butyl groups);
[0258] 5. Tacrolimus (FK-506) and rapamycin (Derivatized where a linker
group L or a ¨
(L-CLM) group can be bound, e.g. at one of the methoxy groups); and
[0259] 6. Actinomycins (Derivatized where a linker group L or a ¨(L-CLM)
group can be
bound, e.g. at one of the isopropyl groups).
[0260] IX. Compounds targeting the aryl hydrocarbon receptor (AHR):
[0261] Compounds targeting the aryl hydrocarbon receptor (AHR) include, but
are not
limited to:
[0262] 1. Apigenin (Derivatized in a way which binds to a linker group L or
a ¨(L-CLM)
group as is generally illustrated in Lee, et al., Targeted Degradation of the
Aryl Hydrocarbon
Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem
Volume
8, Issue 17, pages 2058-2062, November 23, 2007); and
[0263] 2. SR1 and LGC006 (derivatized such that a linker group L or a ¨(L-
CLM) is
bound), as described in Boitano, et at., Aryl Hydrocarbon Receptor Antagonists
Promote the
Expansion of Human Hematopoietic Stem Cells, Science 10 September 2010: Vol.
329 no. 5997
pp. 1345-1348.
[0264] X. Compounds targeting RAF Receptor (Kinase):
0
H N
0
,
\ F
N "
[0265] PLX4032
[0266] (Derivatized where "R" designates a site for linker group L or ¨(L-
CLM) group
attachment, for example).
[0267] Any protein, which can bind to a protein target moiety or PTM group
and acted on or
degraded by an ubiquitin ligase (e.g., RAF) is a target protein according to
the present disclosure.
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[0268] In any aspect or embodiment described herein, the PTM targets and/or
binds RAF
(i.e., a Raf or BRaf targeting moiety). For example, in any aspect or
embodiment described
herein, the PTM may comprise a chemical group selected from the group of
chemical structures
consisting of PTM-Ia or PTM-Ib:
RPTM1
z=pTm
WPTM-3 %%=
RPTM2 =
= tiw
PTM RPTM3
VpTMI
ZpTm
RPTM4
HO/ PTM-Ia or
IRPTM1
s,
npTM
RpTM2 WPTM: sls
1 I i,YPTM¨RPTM3
ZpTiv1
XpTM35 RpTM4
0
RRpTM5
z .,,XpTM38
0
npTm36 %."'"
xp-rm37
PTM-Ib
wherein:
double dotted bonds are aromaric bonds;
VPTM, WPTM, XPTM, YPTM, ZPTM is one of the following combinations: C, CH, N,
N, C; C, N,
N, CH, C; C, 0, C, CH, C; C, S, C, CH, C; C, CH, C, 0, C; C, CH, C, S, C; C,
CH, N,
CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, C; C,
CH, C,
N, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N, N, C;
XpTM35, XPTM36, XPTM37, and XPTM38 are independently selected from CH and N;
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RpTmi is covalently joined to a ULM, a chemical linker group (L), a CLM, an
ILM, a VLM,
MLM, a ULM', a CLM', a ILM', a VLM', a MLM', or combination thereof;
RpTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-M2,
wherein M1 is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
RPTM3 is absent, hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl,
OCH3, NHCH3 or
M1-CH2-CH2-M2, wherein M1 is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic
alkyl, aryl or heterocycle;
RpTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-M2,
wherein M1 is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle; and
RPTM5 is selected from the group consisting of
F
F
c> /N
------------------------------ ( )14
---------------------------- F/ -------- F
F
/
Z/ HO HO HO
HO
[0269] In any aspect or embodiment described herein, the PTM may comprise a
chemical
group selected from the group of chemical structures consisting of PTM-IIa or
PTM-IIb:
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RPTM5a RPTM6a RPTM8
\ 0 RPTM7 I
XPTM3 PR TM9
RPTM6 APIM2 APTM4
RPTM6b v 1 11
APTM1 XPTM5
/
1 XPTM6
I RPTM10
N N RPTM1 1
H
PTM-IIa or
RPTM6a
RPTM5a RPTM8
\ 0 RPTM7
RPTM9
RPTM6 N
1
XPTM1 N
1
RPTM6b / RPTM10
N N RPTM1 1
H
PTM-IIb ,
wherein:
XPTM1, XPTM2, XPTM3, XPTM4, XPTM5, and XpTm6 are independently selected from
CH or N;
RPTM5a is selected from the group consisting of: bond, optionally substituted
amine,
optionally substituted amide (e.g., optionally substituted with an alkyl,
methyl, ethyl,
RPTM5 0
\s,
A----NH
0' \ .- -
propyl, or butyl group), H, ---Cõ -NEIC(0)RpTm5;
RPTM5 is selected from the group consisting of
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/N
\N
F
0 ------------- F Ing=--ON ---- F F -------------- ON
F
N/\
\/N
/
7/
HO HO HO
\
HO
RpTM6a and RPTM6b are each independently selected from hydrogen, halogen, or
optionally
substituted Ci-C6 alkyl (linear, branched, optionally substituted);
RPTM6 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-
CH2-M2,
wherein M1 is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
RPTM7 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-
CH2-M2,
wherein M1 is CH2, 0 or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
RpTMS, RPTM9 or RPTM10 are independently selected from the group consisting of
absent,
hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl,
ethyl, OCH3,
NHCH3 or M1-CH2-CH2-M2, wherein M1 is CH2, 0 and NH, and M2 is hydrogen,
alkyl,
cyclic alkyl, aryl or heterocycle;
RPTM11 is absent, hydrogen, halogen, methyl, ethyl, OCH3, NH CH3 or M1-CH2-CH2-
M2,
wherein M1 is CH2, 0 or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
and
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at least one of RPTM8, RPTM9 or RPTM10 is modified to be covalently joined to
a ULM, a
chemical linker group (L), a CLM, an ILM, a VLM, MLM, a ULM', a CLM', a ILM',
a
VLM', a MLM', or combination thereof
[0270] In certain embodiments, the PTM may comprise a chemical group
selected from the
group of chemical structures consisting of:
RPTM5 a
NH
01 RpTM6a RpTM8
0 RpTM7
XpTry.!! RPTM9
RpTm6 XPTM2 XPTM4
I I
XPTM...5
RpTM6b
XpTm6 RPTM1 0
RpTM11
or
RpTM5 0
NH
01 RpThisa RpTma
0 RpTm7
N R pTM9
RpTm6
,
RpTM6b npTM1 N
rxpTM1 0
RpTM11
wherein RPTM5, RPT1v16a, RPT1v16b, RPTM6, RPTM7, RPTM8, RPTM9, RPTM10, RPTM11
are as described
herein.
[0271] In some embodiments, when RPTM9 is the covalently joined position,
RpTm7 and RpTmg
can be connected together via a covalent bond in a way to form a bicyclic
group with the ring to
which RpTm7 and RpTmg are attached.
[0272] In other embodiments, when RPTM8 is the covalently joined position,
RPTM9 and
RpTmlo can be connected together via a covalent bond in a way to form a
bicyclic group with the
ring to which RpTm9 and RPTM10 are attached.
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[0273] In further embodiments, when RPTM10 is the covalently joined
position, RPTM8 and
RpTM9 can be connected together via a covalent bond in a way to form a
bicyclic group with the
ring to which RpTm8 and RpTm9 are attached.
[0274] In any aspect or embodiment described herein, the PTM may comprise a
chemical
group selected from the group of chemical structures consisting of PTM-III:
XPTM16
az<OX
XPTM15
RPTM13
RPTM14
XPTM10 RPTM12
v v
N 0%ss XPTM17 0 RPTM17 "PTM1 T
^PTM9
RPTM18
ym
-PTM20 Xp-r Xp-
rmg N
RPTM16 XPTM12 XPTM7
"PTM19
x
PTM13 RPTM19 XPTM18
RPTM15
0
RPTM20
RPTM21
PTM-III
wherein:
XpTm7, XpTM8, XPTM9, XPTM10, XPTM11, XPTM12, XPTM13, XPTM14, XPTM15, XPTM16,
XPTM17,
XpTM18, XPTM19, XPTM20 are independently CH or N;
RpTm12, RPTM13, RPTM14, RPTM15, RPTM16, RPTM17, RPTM18, RPTM19 are
independently selected
from the group consisting of absent, hydrogen, halogen, aryl, heteroaryl,
cycloalkyl,
heterocycle, methyl, ethyl, other alkyl, OCH3, NHCH3 or M1-CH2-CH2-M2, wherein
M1
is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
RpTm2o is a small group containing less than four non-hydrogen atoms;
RpTm21 is selected from the group consisting of trifluoromethyl, chloro,
bromo, fluoro, methyl,
ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, OCH3, NHCH3, dimethylamino or M1-CH2-CH2-M2, wherein M1 is CH2, 0
or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; and
at least one of RPTM12, RPTM13 and RPTM16 is modified to be covalently joined
to a ULM, a
chemical linker group (L), a CLM, an ILM, a VLM, MLM, a ULM', a CLM', a ILM',
a
VLM', a MLM', or combination thereof
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[0275] In some embodiments, when RPTM12 is the covalently joined position,
RPTM13 and
RpTm14 can be connected together via a covalent bond in a way to form a
bicyclic group with the
ring to which RPTM13 and RPTA414 are attached; and/or RPTM15 and RPTM16 can be
connected
together via a covalent bond in a way to form a bicyclic group with the ring
to which RpTm15 and
RpTM16 are attached.
[0276] In other embodiments, when RPTM13 is the covalently joined position,
RPTM12 and
RpTm16 can be connected together via a covalent bond in a way to form a
bicyclic group with the
ring to which RPTM12 and RPTA416 are attached; and/or RPTM15 and RPTM16 can be
connected
together via a covalent bond in a way to form a bicyclic group with the ring
to which RpTm15 and
RpTM16 are attached.
[0277] In further embodiments, when RPTM16 is the covalently joined
position, RPTM12 and
RpTm13 can be connected together via a covalent bond in a way to form a
bicyclic group with the
ring to which RpTm12 and RPTA413 are attached; and/or RPTM13 and RPTM14 can be
connected
together via a covalent bond in a way to form a bicyclic group with the ring
to which RpTm13 and
RpTM14 are attached.
[0278] In any aspect or embodiment described herein, the PTM may comprise a
chemical
group selected from the group of chemical structures consisting of PTM-IVa or
PTM-IVb:
RpTm22
7/1 NH
f RPTM25a RPTM26 x N
O
RpTM25
y v
¨PTM21 "PTM23
x N XpTM27
X N
PTM28 p
¨PTM22
D ¨PTM28
sPTM27
RPTM29
RPTM25b XPTM26 RPTM30
XPTM24% II xpTm134.--- Xpi-m33
XPTM25
PTM24
XpTM31
R
RPTM2/ x 3 -PTM30
D RPTM32
'PTM31
PTM-IVa or
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RPTM22 0
V
,-- ------ NH
RPTM26 N
0 RPTM25a
.0======'
RPTM25 y ,,PTM29, NI
x
/ \ v \
IXPTM27
XPTM21 ^PTM23
\ N / ^
¨PTM22 vPTM28 NR -------
0, / PTM28
-----
"PTM27
RPTM29
RPMT25b XPTM26 RPTM30 /
XPTM24 \ /
v PTM I= xpTM33
^34
XPTM25
PTM24
N XPTM32------- R
/ /
p
----- XPTM31
"PTM23 XPTM30
\
m PTM /
"
RPTM32
31
PTM-Wb ,
wherein:
XPTM21, XPTM22, XPTM23, XPTM24, XPTM25, XPTM26, XPTM27, XPTM28, XPTM29,
XPTM30, XPTM31,
XPTM32, XPTM33, XPTM34 are independently CH or N;
RpTm22 is selected from the group consisting of
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/N
\N
F
0 ------------- F Ing=--ON ---- F F -------------- ON
F
N/\
\/N
/
7/
HO HO HO
\
HO
RpT1v125a and RPTM25b are each independently selected from hydrogen, halogen,
or C i-C6 alkyl
(linear, branched, optionally substituted);
RpTM23, RPTM24, RPTM28, RPTM29, RPTM30, RPTM31, RPTM32 are independently
selected from the
group consisting of absent, bond, hydrogen, halogen, aryl (optionally
substituted),
heteroaryl (optionally substituted), cycloalkyl (optionally substituted),
heterocycle
(optionally substituted), methyl, ethyl (optionally substituted), other alkyl
(linear,
branched, optionally substituted), OCH3, NHCH3 or M1-CH2-CH2-M2, wherein M1 is
CH2, 0 and NH, and M2 is hydrogen, alkyl (linear, branched, optionally
substituted),
cyclic alkyl (optionally substituted), aryl (optionally substituted)or
heterocycle
(optionally substituted); and
RpTm25 is absent, hydrogen, halogen, Ci-C6 alkyl (linear, branched, optionally
substituted),
OCH3, NHCH3 or SCH3;
RPTM26 is absent, hydrogen, halogen, Ci-C6 alkyl (linear, branched, optionally
substituted),
OCH3, NHCH3 or SCH3;
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RpTM27 is selected from the group consisting of absent, hydrogen, halogen, Ci-
C6 alkyl (linear,
branched, optionally substituted), OCH3, NHCH3 or SCH3; and
at least one of RPTM24, RPTM29, RPTM32 is modified to be covalently joined to
a ULM, a
chemical linker group (L), a CLM, an ILM, a VLM, MLM, a ULM', a CLM', a ILM',
a
VLM', a MLM', or combination thereof
[0279] In some embodiments, when RPTM24 is the covalently joined position,
RPTM31 and
RpTM32 can be connected together via a covalent bond in a way to form a
bicyclic group with the
ring to which RpTA431 and RPTM32 are attached; or RPTM29 and RPTM30 can be
connected together
via a covalent bond in a way to form a bicyclic group with the ring to which
RPTM29 and RPTM30
are attached.
[0280] In other embodiments, when RPTM29 is the covalently joined position,
RPTM24 and
RpTM32 can be connected together via a covalent bond in a way to form a
bicyclic group with the
ring to which RpTm24 and RPTm32 are attached; and/or RPTM31 and RPTM32 can be
connected
together via a covalent bond in a way to form a bicyclic group with the ring
to which RpTm3i and
RpTM32 are attached.
[0281] In further embodiments, when RPTM32 is the covalently joined
position, RPTM24 and
RpTM29 can be connected together via a covalent bond in a way to form a
bicyclic group with the
ring to which RpTm24 and RPTm29 are attached; and/or RPTM29 and RPTM30 can be
connected
together via a covalent bond in a way to form a bicyclic group with the ring
to which RpTm29 and
RpTM30 are attached.
[0282] In any aspect or embodiments described herein, the PTM is selected
from the group
consisting of chemical structures PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6,
PTM-7, and
PTM-8:
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F\0
N__.µµ
/
/ k
/ F
- N
HO 0
N N 0 ,-
---
N
N N
H
PTM-1
PTM-2
P
NH WI ,-
0 F N.,-....,.(16' 0
0 * --
NH I "
F / 1 N N 0
' F H
N N F F
H
PTM-3 PTM-4
Nz-..-_ \
9
co H F \ / N
i-NH
\S1-41 0 F
N -
40-
N
F \
N
I , '
IN N
H
PTM-5 PTM-6
Nz.:-._\
\ N
i I 0, H F
I,
\ P S/-N /
\--/ 41k, N
--- I
N 1 F N\/
N I
PTM-7 PTM-8
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6 NH F 0
NH F
0
C C"
I
N N N
PTM-9 PTM-10
[0283] XI. Compounds Targeting FKBP:
Me0
Me0
0"1-1N,R
0- 0
0
Me0 OMe
[0284] OMe
[0285] (Derivatized where "R" designates a site for a linker group L or a
¨(L-CLM) group
attachment, for example).
[0286] XII. Compounds Targeting Androgen Receptor (AR)
[0287] 1. RU59063 Ligand (derivatized) of Androgen Rceptor
NC
S
F3C Nj(
¨ 0
[0288] µIR
[0289] (Derivatized where "R" designates a site for a linker group L or a
¨(L-CLM) group
attachment, for example).
[0290] 2. SARM Ligand (derivatized) of Androgen Receptor
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F3C
0
02N
N H
111 ).7---10---NEi 0 it R
[0291] 0
[0292] (Derivatized where "R" designates a site for a linker group L or
a¨(L-CLM) group
attachment, for example).
[0293] 3. Androgen Receptor Ligand DHT (derivatized)
0
0-d<
N_R
[0294] 0
[0295] (Derivatized where "R" designates a site for a linker group L or ¨(L-
CLM) group
attachment, for example).
[0296] 4. MDV3100 Ligand (derivatized)
R
NC
Nk I' -NI
F3C
[0297] 0
[0298] 5. ARN-509 Ligand (derivatized)
R
NC
Nk r
F3C
[0299] 0
[0300] 6. Hexahydrobenzisoxazoles
N R
F3C
[0301] NC
[0302] 7. Tetramethylcyclobutanes
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R
CI 034/
."N
NC
[0303]
[0304] 8. In any aspect or embodiment described herein, the PTM is 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, some of which are
described above.
Those of ordinary skill in the art would appreciate that these androgen
receptor binding
compounds could be potentially used as an androgen binding moiety (ABM) 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, I Med. Chem. 2012, 55, 6316 ¨ 6327 A. Pepe et. al, I
Med. Chem. 2013,
56, 8280 ¨ 8297; M. E. Jung et al, I Med. Chem. 2010, 53, 2779-2796, which are
incorporated
by reference herein
[0305] In any aspect or embodiment described herein, the ABM comprises a
structure
selected from, but not limited to the structures shown below, wherein a dashed
line indicates the
attachment point of a linker moiety or a ULM, such as a CLM:
y2 o 2
R
Ni)rrisi
ABM-a
(RQ)o-6
05
Y3 4
Y
ri
ABM-b
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yl 3
Y ,Ra
--
0 N
Rb
ABM-c ; and
(Rz)km1
n,w2
k
ABMA
wherein:
Wl is aryl, heteroaryl, bicyclic, or biheterocyclic, each independently
substituted by 1 or
more H, halo, hydroxyl, nitro, CN, CCH, C1-6 alkyl (linear, branched,
optionally
substituted; for example, optionally substituted by 1 or more halo, C1-6
alkoxyl), C1-6
alkoxyl (linear, branched, optionally substituted; for example, optionally
substituted by 1
or more halo), C2-6 alkenyl, C2-6 alkynyl, or CF3;
Y1, Y2 are each independently NRY1, 0, S;
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRY1RY2, C=0, C=S, SO, SO2,
heteroaryl, or aryl;
Q is a 3-6 membered ring with 0-4 heteroatoms, optionally substituted with 0-6
RQ, each
RQ,is independently H, C1-6 alkyl (linear, branched, optionally substituted;
for example,
optionally substituted by 1 or more halo, C1-6 alkoxyl), halogen, C1-6 alkoxy,
or 2 RQ
groups taken together with the atom they are attached to, form a 3-8 membered
ring
system containing 0-2 heteroatoms);
Rl, R2, Ra, Rb, Ryl, _tc ¨Y2
are each independently H, C1-6 alkyl (linear, branched, optionally
substituted; for example, optionally substituted by 1 or more halo, C1-6
alkoxyl), halogen,
C1-6 alkoxy, cyclic, heterocyclic, or Rl, 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, C1-6 heteroalkyl, 0, aryl, heteroaryl, alicyclic,
heterocyclic,
biheterocyclic, biaryl, or biheteroaryl, each optionally substituted by 1-10
Rw2;
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each Rw2 is independently H, halo, C1-6 alkyl (linear, branched, optionally
substituted; for
example, optionally substituted by 1 or more F), -0Rw2A , C3-6 cycloalkyl, C4-
6
cycloheteroalkyl, C1-6 alicyclic (optionally substituted), heterocyclic
(optionally
substituted), aryl (optionally substituted), or heteroaryl (optionally
substituted), bicyclic
hereoaryl or aryl, 0C1-3a1ky1 (optionally substituted), OH, NH2, NRY1RY2, CN;
and
Rw2A is H, C1-6 alkyl (linear, branched), or C1-6 heteroalkyl (linear,
branched), each optionally
substituted by a cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl,
halo, or 0C1-
3alkyl.
[0306] In any aspect or embodiment described herein, the W2 is covalently
coupled to one or
more ULM or CLM groups, or a linker to which is attached one or more ULM or
CLM groups as
described herein.
(R23)0-4
[0307] In any aspect or embodiment described herein, Wl is 1 or
(R23)0-3
¨R22
¨N ,
wherein each R22 is independently halo, H, optionally substituted alkyl,
haloalkyl, cyano, or nitro; and each R23 is independently H, halo, CF3,
optionally substituted
alkyl, alkoxy,haloalkyl, cyano, or nitro.
[0308] In any aspect or embodiment described herein, Wl is selected from
the group
consisting of:
CF3 CF3 F CI
= CN = NO2 CN = CN 411 CN
CI
OMe F CI CI CF3
c--
CN = CN F CN _______ -- SCN S-CN
. ;
and
CN
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[0309] In any aspect or embodiment described herein, the ABM comprises a
structure
selected from the following structures shown below, where a \ indicates tha
attachment
point of a linker or a ULM:
N&-k
N
03 04_4
N
)(3
RQ2 Y3
RQ
RQ
RQ
RQ3 RQ4_4
y5 N
RQ2 Y3
RQ
RQ
, and
RQ
Y3
RQ2 Y3
RQ
RQ
wherein:
RQ2 is a H, halogen, CH3 or cF3;
RQ3 is H, halo, hydroxyl, nitro, CN, CCH, 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, or CF3;
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRY1RY2, C=0, heteroaryl,
or aryl,
RY2 are each independently H, or C1-6 alkyl (linear, branched, optionally
substituted by 1
or more halo, C1-6 alkoxyl, cyclic, or heterocyclic); and
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RQ each independently is H, Ci-C6 alkyl (linear, branched, optionally
substituted by 1 or
more halo, or C1-6 alkoxyl), or two RQ together with the atom they are
attached to, form a
3-8 membered ring system containing 0-2 heteroatoms.
[0310] In any aspect or embodiment described herein, each RQ is
independently H or CH3. In
another embodiment RQ3 is CN.
[0311] In any aspect or embodiment described herein, the ABM comprises a
structure
selected from the following structures shown below, where a \-= indicates the
attachment
point of a linker or a ULM:
R(33 y4
Y5
R(32 Y3
03
RQ2 Y3
X
RQ3 y4
)(5X X
Y3
, and
RQ3 y4
y5,(2Z21
RQ2 Y3
wherein:
RQ2 is a H, halogen, CN, CH3 or CF3; and
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RQ3 is H, halo, hydroxyl, nitro, CN, CCH, 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, or CF3; .
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRY1RY2, C=0, heteroaryl,
or aryl; and
RY2 are each independently H or C1-6 alkyl (linear, branched, optionally
substituted by 1
or more halo, C1-6 alkoxyl, cyclic, or heterocyclic); and
X is N or C.
[0312] In any aspect or embodiment described herein, RQ3 is a CN.
[0313] In any aspect or embodiment described herein, the ABM comprises a
structure shown
below, where a dashed line indicates the attachment point of a linker moiety
or a ULM or a CLM:
R1
R2 R2 Ri
CI? --------------------------------------
R 1
R I
Y3
R2
R 1
R2 R1
wherein:
(R23)0-3
(R23)0-4
)¨R22 R22
W' is
or ¨N
each R22 is independently H or -CN;
each R23 is independently H, halo, Ci-C6 alkyl (linear, branched, optionally
substituted), Cl-
C6 alkoxy, or ¨CF3;
Y3 is a bond or 0;
Y4 is a bond or NH;
Y5 is a bond, C=0, Ci-C6 heteroaryl, or Ci-C6 aryl;
R', R2, are each independently H, or Ci-C6 alkyl (linear or branched,
optionally substituted;
for example, optionally substituted by 1 or more halo, or C1-6 alkoxyl);
W2 is a bond, C1-6 aryl, C1-6 heteroaryl, C1-6 alicyclic, or C1-6
heterocyclic, biheterocyclic,
biaryl, or biheteroaryl, each optionally substituted by 1-10 Rw2; and
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each Rw2 is independently H, or halo; and
,,,,---.- represents a bond that may be stereospecific ((R) or (S)) or non-
stereospecific
[0314] In any aspect or embodiment described herein, the W2 is covalently
coupled to one or
more ULM or CLM groups, or a linker to which is attached one or more ULM or
CLM groups as
described herein
[0315] In any aspect or embodiment described herein, W' is selected from
the group
consisting of:
CI C F3
C F3 F CI
1 . CN 1 li CN 1 . CN ----CS--CN -----CS--CN
N N .
, ,
[0316] In any aspect or embodiment described herein, W2 is selected from
the group
, /-------\ .................. r --ks __ ., ., 7---\ ., s
..,,, \ te \ , .. ,,,--s, .t.
.i...,, -- !si ...i , .., 4, N 14 ----'i
:i--,N
consisting of: .' 1 \----1 ' \*:¨.4 ' \L, N \-
-1 = e \ \--- 14 ' .
1 , ,
. ..................................... ,õ ,
,' '= ; '
--;.s.,, ,õ=2= -'-- ;.'.
1
1 ''
.,
----;-, e,' = 5
7 7 7
N.,....õ.....
..............".õNõ..........õ...õN,,..,............"
1 I
)
..........õN.......
I
1 N
7 ; and
,
[0317] In any aspect or embodiment described herein, the ABM comprises a
structure
selected from, but not limited to the structures shown below, where a dashed
line indicates the
attachment point of a linker moiety or a ULM:
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y2
N
yl CO
ABM-a
wherein:
(R23)0-4 (R23)0-3
wl is
or -N
each R22 is independently H or -CN;
each R23 is independently H, halo, or ¨CF3;
yl, y2 are each independently 0 or S;
R', R2, are each independently H or a methyl group;
W2 is a bond, C1-6 aryl, or heteroaryl, 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_
3a1ky1 (optionally substituted by 1 or more ¨F).
[0318] In any of the embodiments described herein, the W2 is covalently
coupled to one or
more ULM or CLM groups, or a linker to which is attached one or more ULM or
CLM groups as
described herein.
[0319] In certain additional embodiments, Wl is selected from the group
consisting of:
CI
CF3 CI
41/ CN CN CN
= ; and
,C F3
[0320] In any aspect or embodiment described herein, W2 is selected from
the group
/
consisting of:
and \
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[0321] In any aspect or embodiment described herein, ABM is selected from
the group
consisting of:
S ci
o 0 II
N
N= 411 NH--- N¨ / \ NH---- 1 = Nj< ____________________________
N ____________________________________________________ \ ---=N
F
F ¨ 7...-NN,,,,
S S
F F F F
0
0
)Y 4. d -1 0
NC NC . N N N
F 10
F3C t 02N __3C Se N"---(¨N
µ
110
\ C) F3C t .
oA =
C) = F =
,
0\\_ i 0
NC
0\v i
NC . NIL(
__d-IN
NC 41 Ni NT eN
i to
\. F t 40 \ CI S 10
C) = (:) = C)µ =
0 0\\_ i F %_ 1
NC N)\--Ir
N \
NC 41 N1-1- NCI "-}-Nil
. ,N
F3C S
40 \ F3C
___________________________________________________________ s 40
Me0 t 10
''2?_ 0 \
CI = F C) =
0\\_ i
(/ 0\\_ i
NC . Ni n NC . Nil,- NC 40 Ni 1
e
CI S
\ F3C SeNn t .
Me0
0,
N (3, . F = F =
, ,
0)LQC, 0).\,;)7 Csv i
NC . N
)r-N NC . N)r-N NC 411 Ni-r
)7-
g 40 , F30
F30 g .
\ F30 s 0
0- =
/ ;
0
0,_ ,
NC * N)(
0\\_ i
NC .N1-1¨ NC . Ni -1¨ eN
eN eN
F3 s
F3C s F3 s
F N
OA ; OA =
s,,,s
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0 0- 0 0:e.\-
NH
NH
NV /
CI 0 0
NA N
CI OC\
N¨
H ---r\I
Oi\:z" NH
V
0 : N
NH CI 0
NV
CI 0 0
NA NA
H H
0,
0 NH 0
NV NH
CI 0
NV ... f,
1-3 0 0
NA
oA. ; H =
N
0
::
0 :: 0:_
N
NH 0 NH 0 NH
V V
V CI 0 0 CF3 0 0
CI 0 0 N
OA = 1 = / =
0
N= 411 NH---- 0
N1)\--4---
F 7.--N N=
S F
S
F F
F F
F
L'k
N1
(:) =
H ;
0
N ,
N= / \ N)-4---
F --- sN
I
N,,...,::::.
FF N.,õ........... õN
tzaz. a o o
CY =
;
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/2k
H 1
NµZr 0
0
.,,......õNõ....õ.,,,,õ.=
N
1
CI 0
c)=( H 0
CI IN1
; .
7
0
1110 "'NH N1.....,
I
LININ
0
N csSS . a o o
;
0 --....?
1
NI.....
__NH
14IN
0
0
CI 0
= N
;
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H rr\ N'µ N\L HN---(N
\ I-V
.,.NIN
H 0 0 /0o 0 0
0 0 0
0
0
CI 0
0 CI 0
Cl 0 CI 0
II a II II II
N N N N
II
N
,N N.
Th rsrU
H H 1 H 1
0 ..ØANre
0 F
0 F
0 0 0 0
0
CI 0
0 CI 0 CI 0
CI
II II
A
N II N
N
7-
7_1')N
H
N* H N'r
1 /1
cro)L.
N n-/
0 N
0 -..1 '"N N
0
0
CI, CI,
0 0 0
II II a a a
N N II II II
N N N
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-
\ 1\l' \ 1
H rY\ H
W hi e H I H N-4,, .
CioNre
0 0 0? 0
0
40 40 40
C . CI 40 CI CI CI
I I I I I I I
I I
N N N N I I
N
F
,N,2% µ
H N' 1
H I N,
Cr=N 09 N OAN F
Crrr
1 a
II II II II
N N N N
.7-
NN/2'= --
i 0
H I
N k * \
OC).'
rN ,IL H rY ko-1
cr.N =N
,0 \
40 = 0,
= 0
c 40 ci
1
II II 40 . 40
N N Cl CI CI
I I I I I I
N N N .
[0322] In any aspect or embodiment described herein, the ABM comprises the
structure:
(Fr44
WI )
ABM-b
,
wherein:
W1 is aryl, or heteroaryl, each independently substituted by 1 or more H,
halo, hydroxyl,
nitro, CN, CCH, 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, or CF3;
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRY1RY2, C=0, C=S, SO, SO2,
heteroaryl, or aryl;
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Q is a 4 membered alicyclic ring with 0-2 heteroatoms, 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, C1-6 alkyl (linear, branched, optionally
substituted by 1 or
more halo, C1-6 alkoxyl);
W2 is a bond, C1-6 alkyl, C1-6 heteroalkyl, 0, C1.6 alicyclic, heterocyclic,
aryl, biheterocyclic,
biaryl, or biheteroaryl, or heteroaryl, each optionally substituted by 1, 2 or
3 Rw2; and
each Rw2is independently H, halo, C1.6 alkyl (linear, branched, optionally
substituted by 1 or
more F), C16 heteroalkyl (linear, branched, optionally substituted), -0Rw2A
0C1.3a1ky1
(optionally substituted by 1 or more ¨F), C3-6 cycloalkyl, C4-6
cycloheteroalkyl (optionally
substituted), C1.6 alkyl (optionally substituted), C1-6 alicyclic (optionally
substituted),
heterocyclic (optionally substituted), aryl (optionally substituted),
heteroaryl (optionally
substituted), bicyclic hereoaryl (optionally substituted), bicyclic aryl, OH,
NH2, NRY1RY2,
or CN; and
Rw2A is H, C1-6 alkyl (linear, branched), or C1-6 heteroalkyl (linear,
branched), each optionally
substituted by a cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl,
halo, or 0C1-
3alkyl.
[0323] In any aspect or embodiment described herein, the description
provides an androgen
receptor bindingcompound comprising a structure of:
(R)04
va )
w' )
ABM-e
wherein:
Wl is aryl, heteroarylõ bicyclic, or biheterocyclic, each independently
substituted by 1 or
more H, halo, hydroxyl, nitro, CN, CCH, 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, or CF3;
Y1, Y2 are each independently NRY1, 0, or S;
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Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRY1RY2, C=0, C=S, SO, SO2,
heteroaryl, or aryl;
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, 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);
Rl, R2, Ra, Rb, Ryl, ¨Y2
are each independently H, C1-6 alkyl (linear, branched, optionally
substituted by 1 or more halo, C1.6 alkoxyl), or le, 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, C1-6 heteroalkyl, 0, C1.6 alicyclic, heterocyclic,
aryl, biheterocyclic,
biaryl, or biheteroaryl, or heteroaryl, each optionally substituted by 1, 2 or
3 Rw2;
each Rw2 is independently H, halo, C1.6 alkyl (linear, branched, optionally
substituted by 1 or
more F), C1-6 heteroalkyl (linear, branched, optionally substituted), -0Rw2A,
0C1.3a1ky1
(optionally substituted by 1 or more ¨F), C3-6 cycloalkyl, C4-6
cycloheteroalkyl, C1-6 alkyl
(optionally substituted), C1-6 alicyclic (optionally substituted),
heterocyclic (optionally
substituted), aryl (optionally substituted), or heteroaryl (optionally
substituted), bicyclic
hereoaryl or aryl, OH, NH2, NRY1RY2, CN; and
Rw2A is H, C1-6 alkyl (linear, branched), or C1-6 heteroalkyl (linear,
branched), each optionally
substituted by a cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl,
halo, or 0C1-
3alkyl.
[0324] In any aspect or embodiment described herein, an androgen receptor
binding moiety
has a structure of:
,
03 \
õ \1. Q,1 4
(WI
ABM-e
wherein:
(R23)0-4 (R23)0-3
/ I \
___________________________ )¨R22
1-(I)-R22
wl is
or -N
each R22 is independently H or -CN;
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each R23 is independently H, halo, or ¨CF3;
Y3 is a bond or 0;
Q is a 4 member ring, optionally substituted with 0-4 RQ, each RQ is
independently H or
methyl;
Y4 is a bond or NH;
Y5 is a bond, a C=0, or a C=S; and
each W2 is independently a bond, C1-6 aryl or heteroaryl, each optionally
substituted by 1, 2
or 3 Rw2, each Rw2 is independently H, halo, a 6 member alicyclic ring with 1
or 2
heteroatoms or a 5 member aromatic ring with 1 or 2 or 3 heteroatoms
[0325] In any aspect or embodiment described herein, W2 is selected from
the group
,
N N a%--4 ..=; N N
\--4/ t;1 consisting of
7 7
: N
;and F
[0326] In any aspect or embodiment described herein, the W2 is covalently
coupled to one or
more ULM or CLM groups, or a linker to which is attached one or more ULM or
CLM groups as
described herein
[0327] In any aspect or embodiment described herein, W' is selected from
the group
CF3 F CI CI
CN = CN 411 CN S-CN
consisting of:
Me CF
OMe
CN CN
and
[0328] In any aspect or embodiment described herein, an androgen binding
moiety has a
structure of:
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v3, -vv2 ,
w:5"
Ak3fik,,.d
wherein:
W' is aryl, independently substituted by 1 or more halo, CN;
Y3 are each independently a bond, NRY2, CRY1RY2, C=0;
Q is a 5 membered aromatic ring with 1 or 2 heteroatoms;
RY2 are each independently H, C1-6 alkyl (linear, branched);
W2 is a bond, aryl, or heteroaryl, 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_
3a1ky1 (optionally substituted by 1 or more -F).
[0329] In any aspect or embodiment described herein, the W2 is covalently
coupled to one or
more ULM or CLM groups, or a linker to which is attached one or more ULM or
CLM groups as
described herein.
(R23)04
/ I \
14- }R22
= [0330] In any aspect or embodiment described herein, Wl is
wherein each R22 is independently halo or CN; and
each R23 is independently H or halo.
[0331] In any aspect or embodiment described herein, Wl is selected from
the group
consisting of:
CI
CI CI
CN
411 CN CN CN
; and
N ....
[0332] In any aspect or embodiment described herein, Q is
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N
[0333] In any aspect or embodiment described herein, W2 is
[0334] In any aspect or embodiment described herein, (Y3)0.5 is
[0335] In any aspect or embodiment described herein, the ABM comprises a
structure
selected from, but not limited to the structures shown below, where a dashed
line indicates the
attachment point of a linker moiety or a ULM, such as a CLM:
R2
N
y2 Ri 2
N
Y3
y5
ABM-a R2
ON
NH
0
wherein:
(R23)0-4 (R23)0-3
wl is
or -N
each R22 is independently H or -CN;
each R23 is independently H, halo, or ¨CF3;
Y1, y2 are each independently 0 or S;
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRY1RY2, C=0, C=S, SO, or
SO2;;
R', R2, are each independently H or a methyl group;
W2 is a bond, C1.6 aryl, or heteroaryl, each optionally substituted by 1, 2 or
3 Rw2; and
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each Rw2is independently H, halo, C1-6 alkyl (optionally substituted by 1 or
more F), C3-6
cycloalkyl, C4-6 cycloheteroalkyl, 0C1.3alkyl (optionally substituted by 1 or
more ¨F).
[0336] In any aspect or embodiment described herein, the W2 is covalently
coupled to one or
more ULM or CLM groups, or a linker to which is attached one or more ULM or
CLM groups as
described herein.
[0337] In any aspect or embodiment described herein, Wl is selected from
the group
consisting of:
CI C F3
C F3 CI
CN CN = CN
CN
and
[0338] In any aspect or embodiment described herein, W2 is selected from
the group
\ '
0
.===
\µ. =
/ consisting of: -------------------------- N
> =
wi
\
and
[0339] In any aspect or embodiment described herein, the ABM comprises a
structure shown
below, where a dashed line indicates the attachment point of a linker moiety
or a ULM or a CLM:
R1
R2 R2 RI
(Y5)1-2
Ri
Ri
Y3
R2
Ri
R2 R1
wherein:
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(R23)0-3
(R23)0-4
/ I \
/ I \
14- -Y R22 14- R22
W1 is ¨ or N
¨
each R22 is independently H or -CN;
each R23 is independently H, halo, or ¨CF3;
Y3 is a bond or 0;
Y4 is a bond or NH;
Y5 is a bond, C=0, Ci-C6 heteroaryl, or Ci-C6 aryl;
R', R2, are each independently H, or Ci-C6 alkyl (linear or branched,
optionally substituted
by 1 or more halo, or C1-6 alkoxyl);
W2 is a bond, C1-6 aryl, C1-6 heteroaryl, C1-6 alicyclic, or C1-6
heterocyclic, each optionally
substituted by 1-10 Rw2; and
each Rw2is independently H, or halo; and
[0340] represents a bond that may be stereospecific ((R) or (S)) or non-
stereospecific
[0341] In any of the embodiments described herein, the W2 is covalently
coupled to one or
more ULM or CLM groups, or a linker to which is attached one or more ULM or
CLM groups as
described herein
[0342] In certain additional embodiments, Wl is selected from the group
consisting of:
CI C F3
C F3 CI
= CNi CN CN
t¨CS--CN
[0343] In certain additional embodiments, W2 is selected from the group
consisting of:
N
j Nµ_11 N / N . .
/\24
/-\2µ
N
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N ssiN
kN
; and
[0344] In certain embodiments, the androgen receptor binding compound of
ABM is selected
from the group consisting of:
trans-2-Chloro-4- [3 -amino-2,2,4,4-tetramethylcycl obutoxy]benzonitrile;
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 - chl oro-4- cyanophenoxy)-2,2,4,4-tetramethyl cycl
butyl] carb amate;
trans 4-Amino-N- [3 -(3 - chl oro-4- cyanophenoxy)-2,2,4,4-tetramethyl cycl
obutyl]b enzami de;
trans 5-Amino-N- [3 -(3 -chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutyl]pyrazine-2-
carboxamide;
trans 2-Amino-N- [3 -(3 - chl oro-4- cyanophenoxy)-2,2,4,4-tetramethyl cycl
obutyl]pyrimi dine- 5 -
carboxamide;
4-Methoxy-N- [( 1 r, 3 r)-3 -(3 - chl oro-4- cyanophenoxy)-2,2,4,4-tetram
ethyl cycl obutyl]b enzami de;
trans 1 -(2-Hydroxyethyl)-N- [3 -(3 - chl oro-4- cyanophenoxy)-2,2,4,4-
tetramethyl cycl butyl] - 1H-
pyrazole-4-carb oxamide;
trans 6-Amino-N- [3 -(3 - chl oro-4- cyanophenoxy)-2,2,4,4-tetramethyl cycl
obutyl]pyri dine-3 -
carboxamide;
trans 4-[(5 -Hydroxypentyl)amino] -N-[3 -(3 - chl oro-4-cyanophenoxy)-2,2,4,4-
tetramethyl cy clobutyl]b enz ami de; and
trans tert-Butyl 2415 -[(4- [3 -(3 - chl oro-4- cyanophenoxy)-2,2,4,4-
tetramethyl cycl butyl] carb amoyl Iphenyl)aminopentyl oxy)acetate; and
N-(( 1 r, 3 r)-3 -(4-cyanophenoxy)-2,2,4,4-tetramethyl cyclobuty1)-4-methylb
enz ami de.
[0345] XIII. Compounds Targeting Estrogen Receptor (ER) ICI-182780
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[0346] 1. Estrogen Receptor Ligand
OH
N R
[0347] HO
[0348] (Derivatized where "R" designates a site for linker group L or ¨(L-
CLM) group
attachment).
[0349] In any embodiment or aspect described herein, the PTM may be
represented by the
Formula PTM-I:
XPTM1-4._.2\--
RPTMF-f- X
PTM2
Xpi-m
RPTM2¨ / I
PTM-I
wherein:
XpTm iS 0 or C=0;
each of XpTmi and XPTM2 is independently selected from N or CH;
RpTmi is independently selected from OH, 0(C0)RpTm, 0-lower alkyl, wherein
RpTm is an
alkyl or aryl group in the ester;
at least one RPTM2, each independently selected from H, OH, halogen, CN, CF3,
S02-alkyl,
0-lower alkyl;
at least one RPTM3, each independently selected from H, halogen; and
the dashed line indicates the site of attachment of at least one linker, CLM,
CLM', PTM, PTM', or a
combination thereof.
[0350] In any embodiment or aspect described herein, the PTM may be
represented by the
Formula PTM-I:
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XPTM1µr
RPTM3--f-
Xpi-m
RPTM2¨ / I
------RPTM 1
PTM-I
wherein:
XpTm iS 0 or C=0;
each of Xpmu and XPTM2 is independently selected from N or CH;
RpThu is independently selected from OH, 0(C0)RpTm, 0-lower alkyl, wherein
RpTm is an
alkyl or aryl group in the ester;
each RPTM2 is independently selected from H, OH, halogen, CN, CF3, S02-alkyl,
0-lower
alkyl;
each RpTm3 is independently selected from H, halogen;
the PTM-I comprises as least one RPTM2, at least one RPTM3, or a combination
thereof on the
respective rings; and
the dashed line indicates the site of attachment of at least one linker, CLM,
CLM', PTM, PTM', or a
combination thereof.
[0351] In any embodiment or aspect described herein, PTM-I has at least one
of: two RPTM2, two
RpTM3, or a combination thereof.
[0352] In any embodiment or aspect described herein, the PTM may be
represented by the
Formula PTM-II:
XPTM1----;\
\
RPTM3
RPTM4 Xpi-m
\
\ \
RPTM2¨
-----RPTM 1
PTM-II
wherein:
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XpTm S 0 or C=0;
each of XpTmi and XPTM2 is independently selected from N or CH;
RpTmi is independently selected from OH, 0(C0)RpTm, 0-lower alkyl, wherein
RpTm is an
alkyl or aryl group in the ester;
RpTm2 and RPTM4 are independently selected from H, OH, halogen, CN, CF3, S02-
alkyl, 0-
lower alkyl;
RpTm3 and RPTM5 are independently selected from H, halogen; and
the dashed line indicates the site of attachment of at least one linker, CLM,
CLM', PTM, PTM', or a
combination thereof.
[0353] In aspect or embodiment described herein, 0(C0)RpTm functions as a
prodrug of the
corresponding phenol in Formula PTM-I or PTM-II.
[0354] In any embodiment or aspect described herein, the 0-lower alkyl of PTM-
I or PTM-II an
alkyl chain with carbon number 1 to 3.
[0355] In aspect or embodiment described herein, the present disclosure
provides a compound or
PTM of Formula (IpTm):
RPTM4 XpTm
RPTM
APTM
RPTM3
XPTM
JJ.RPTM2
Formula (Ipmr)
wherein:
each XpTM is independently CH, N;
indicates the site of attachment of at least one linker, CLM, CLM', PTM, PTM',
or a
combination thereof;
each RPTM1 is independently OH, halogen, O(CO)RPTM, where RPTM is alkyl or
cycloalkyl group with
1 to 6 carbons or aryl groups, substitution can be mono-, di- or tri-
substituted;
each RpTm2 is independently H, halogen, CN, CF3, alkoxy, substitution can be
mono- or di-
substitution; and
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each RpTm3 is independently H, halogen, substitution can be mono- or di-
substitution.
[0356] In any aspect or embodiment described herein, the PTM is represented
by the Formula (IIpTm):
RPTM1--
JJ
RPTM3
Formula (IIpmT)
wherein:
XpTm is CH, N;
indicates the site of attachment of at least one linker, CLM, CLM', PTM, PTM',
ULM, an ILM,
a VLM, MLM, a ULM', a ILM', a VLM', a MLM', or a combination thereof;
each RpTmi is independently OH, halogen (e.g., F);
each RpTm2 is independently H, halogen (e.g., F), CF3, substitution can be
mono- or di-substitution;
and
each RpTm3 is independently halogen (e.g. F), substitution can be mono- or di-
substitution.
[0357] In certain embodiments, at least one of:
XpTm of Formula (IIPTM) is CH;
RpTmi of Formula (IIPTM) is OH;
RpTm2 of Formula (IIpTm)is H;
each RpTm3 of Formula (IIPTM) is independently H or F; or
a combination thereof
[0358] XIV. Compounds Targeting Thyroid Hormone Receptor (TR)
[0359] 1. Thyroid Hormone Receptor Ligand (derivatized)
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cor0H
m0m0
0
101
NR
[0360] 0
[0361] (Derivatized where "R" designates a site for linker group L or ¨(L-
CLM) group
attachment and MOMO indicates a methoxymethoxy group).
[0362] XV. Compounds targeting HIV Protease
[0363] 1. Inhibitor of HIV Protease (derivatized)
Ph
0 0
N 0
0 PhOH
[0364]
[0365] (Derivatized where "R" designates a site for linker group L or¨(L-
CLM) group
attachment). See, I Med. Chem. 2010, 53, 521-538.
[0366] 2. Inhibitor of HIV Protease
OH
0C
1\1(N 0
S-
\\(:)
Ph0 0
RN
[0367]
[0368] (Derivatized where "R" designates a potential site for linker group
L or ¨(L-CLM)
group attachment). See, I Med. Chem. 2010, 53, 521-538.
[0369] XVI. Compounds targeting HIV Integrase
[0370] 1. Inhibitor of HIV Integrase (derivatized)
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Me0
I OH
F 0 0
[0371] CI
[0372] (Derivatized where "R" designates a site for linker group L or ¨(L-
CLM) group
attachment). See, I Med. Chem. 2010, 53, 6466.
[0373] 2. Inhibitor of HIV Integrase (derivatized)
?.iii
Me0
0,R
F 0 0
[0374] CI
[0375] 3. Inhibitor of HIV integrase Isetntress (derivatized)
0
R_e )H
NH
\O
[0376] 0 0
[0377] (Derivatized where "R" designates a site for linker group L or ¨(L-
CLM) group
attachment). See, I Med. Chem. 2010, 53, 6466.
[0378] XVII. Compounds targeting HCV Protease
[0379] 1. Inhibitors of HCV Protease (derivatized)
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NH
S¨\(
N
N
I
0
Me0
tBu NS_ -
0 CO 2H
NH 2
[0380] R-
103811 (Derivatized where "R" designates a site for linker group L or ¨(L-
CLM) group
attachment).
[0382] XVIII. Compounds targeting Acyl-protein Thioesterase-1 and -2 (APT!
and
APT2)
[0383] 1. Inhibitor of APT1 and APT2 (derivatized)
Me2N
S\NO=C)
N¨N
s.=
[0384] 0
[0385] (Derivatized where "R" designates a site for linker group L or ¨(L-
CLM) group
attachment). See, Angew. Chem. Int. Ed. 2011, 50, 9838 ¨9842, where L is a
linker group as
otherwise described herein and said CLM group is as otherwise described herein
such that ¨(L-
CLM) binds the CLM group to a PTMgroup as otherwise described herein.
[0386] VIV. Compound targeting Tau Protein
[0387] In any aspect or embodiment described herein, the PTM may include a
Tau protein
binding moieties. For example, the PTM may be represented by Formula I,
Formula II, Formula
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III, Formula IV, Formula V, Formula VI, Formula, VII, Formula, VIII, Formula
IX, Formula X,
or Formula XI:
CO B 0 LPTM D A B
LpTM D
I II
0 B 0 LPTM D 0 A B
LPTM D 0
III IV
A LPTM B
LPTM - LPTM D
V
co_ LPTM B 0 LPTM A B LPTM -,LPTM D
VI VII
D - LPTM - A LPTM BLpTm - 0 LPTM co
VIII
0 B
LpTm -= LPTM fla - LPTM D
X
IX
0
A - LPTM - D - LPTM - B - LPTM -
XI
,
wherein:
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A, B, C, D, E, and F are independently selected from an optionally substituted
5- or 6-
membered aryl or heteroaryl ring, an optionally substituted 4- to 7-membered
cycloalkyl
or a heterocycloalkyl, where contact between circles indicates ring fusion;
and
LpTm is selected from a bond, an alkyl, an alkenyl or an alkynyl, optionally
interrupted by one
or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one
or more
functional groups selected from the groups -0-, -S-,Tm- (where RipTm is
selected
from H or alkyl), -N=N-, -S(0)-, -SO2-, -C(0)-, -NHC(0)-, -C(0)NH-, -NHS02-, -
NHC(0)NH-, -NHC(0)0-, or -0C(0)NH-, wherein the said functional group are
optionally located at either end of the linker.
[0388] In any aspect or embodiment described herein, aryl and heteroaryl
rings of A, B, C, D,
E, and F of PTM are optionally substituted with 1-3 substituents each
independently selected
from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy,
amino, alkylamino,
dialkylamino, acylamino, trifluoromethyl, and cyano, wherein the said alkyl
and alkenyl groups
are further optionally substituted.
[0389] In any aspect or embodiment described herein, the rings of at least
one of A, B, C, F,
or a combination thereof is selected from optionally substituted 5- or 6-
membered aryl or
heteroaryl rings;
[0390] In any aspect or embodiment described herein, the PTM has the
chemical structure of
Formula I, wherein:
A, B and C rings are independently 5- or 6- membered fused aryl or heteroaryl
rings;
LpTm is selected from a bond or an alkyl, and
D is selected from a 6-membered aryl, heteroaryl or heterocycloalkyl,
wherein A, B, C and D are optionally substituted with alkyl, haloalkyl,
halogen, hydroxyl,
alkoxy, amino, alkylamino, dialkylamino or cyano.
[0391] In any aspect or embodiment described herein, The PTM has the
chemical structure
of Formula I, wherein:
A and C are a phenyl or a 6-membered heteroaryl ring;
B is a 5-membered heteroaryl ring;
LpTm is a bond; and
D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl ring;
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wherein each A, B, C and D is optionally independently substituted with alkyl,
haloalkyl,
halogen, hydroxyl, alkoxy, amino, dialkylamino or cyano, and wherein a
nitrogen atom
of any of the A, B, C and D rings is not directly connected to a heteroatom or
to a carbon
atom, to which another heteroatom is directly attached.
[0392] In any aspect or embodiment described herein, the PTM has the
chemical structure of
Formula III or IV, wherein A, B and C are 5- or 6- membered fused aryl or
heteroaryl rings,
LpTm is selected from a bond or an alkyl, and D and E are 5- or 6-membered
fused aryl or
heteroaryl rings, wherein A, B, C, D and E are optionally substituted with
alkyl, haloalkyl,
halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino or cyano.
[0393] In any aspect or embodiment described herein, the PTM is represented
by following
chemical structure:
HN 0
NH2
N N = \NH
0 I S
R6 N
0
\ I
0 NH
R4 OH
=
0
41 R6 OH ,¨NH 0 ¨
N S N
NH
1
N
R5 0
rsV N
Me0 s
[10 4. NH R6
01
CDN
CN
R1, N CN
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N
\
0 N\ \
1101 \
R6 \ R6
S S s \ RI * N:R1 \ / NI
R2 N µR2
N
0 N\
\ R6 0 \ \ R6
N R1 N \ R1
tR3 \ 4J N'
R2 N R2
0 N R6
RI
0 \ \
NI, * '
R3 N Ri
sR2 N IV 9 NI
R' sR2
R6
N N R6
\ 1 )¨ N R1
0 11--µ--C+¨ 'IR 0 0 _Ct)_ I
\ / N N N \ / Ns
R3 N sR2 IR3 N R2
R10 0
F F
N
R1
N H
N N
N \ /
%R3 N
* F ,
wherein:
R', R2 and R3 are independently selected from H, methyl, ethyl, 2-fluoroethyl
and 2,2,2-
trifluoroethyl;
R4 and R5 are independently selected from H, methyl, ethyl and halogen; and
R6 is 1 to 2 substituents independently selected from H, methyl, ethyl and
halogen,
wherein the PTM is coupled to a ULM via L.
[0394] In any of the aspects or embodiments described herein, the PTM is
covalently
coupled to one or more ULM (VLM or CLM) groups, or a linker to which is
attached one or
more ULM (VLM or CLM) groups as described herein.
[0395] In any aspect or embodiment described herein, PTM is represented by
chemical
structure:
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R7
N_ R8 ¨N R8 R8
R7 / R9 R7
N N N
R7
R8 R8 R7/ N_
\ / N
N R9 R7 / 1 R9 1
I
R9
Fil
R I ail I
N ¨ R8 N
N
N_ N¨
N_ R8
R7 i 1 N R9 R7 -Q¨N R9 R7 / R9
141 R8 I 8 I N /
N R N 141 1
\ N
N¨ R8
R7 / R9
N / ,
gi I
N
R8 ¨N R8 N¨ R8
R7 * N Rio
R7 --Ct- N Rio
R7 --Q-- N Rio
:76õ, A ,....d
N N 0 N N 0 N N N
R7 R7
R8 R8
N..n_
Rio R
(---' N .
A N ....C,i
N N N N N 0
R8 R8 N_ R8
_N
R7 * N"'"Xl Rio
R7 Rio
R7 --- N Rio
...4õ. .,õ.
N N Nõ24.1 6'"- .N-241 Isr-1.- = N ."211
c., NH c., NH c. NH
R7 R7
R8 R8
NA
.nn.
Rio (-----' N Rio
N
N N N 1µ1"-L 1%....1.'.-" N
NH LISIH
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R8 R9 R8
OH
R7 R7
N
N N
R9
RI, ri RI, ri
R2 R2
R8 F R8
0,.0 ,
R7 -R- 0 F
R7
N
N
R9 R9
RI,1%.1 RI,
ri
R2 R2
R8 OH R8 N
R
70r,D,
R- R9
\ 1 Iµl
I R9 - ,,,
\ N \ / im-Ri
i'll
R2 R7
N_ R8
R7---C4r1 /1 Rlo ( ,
1 R7/ I Rlo
N Nr Nii N N N
R1 c.NH R1
N¨ R8 N¨ R8
R8
R7.---µ / 1 R10 R7 / I R10 R9
N
,
R1 R1 LNH N N , \ / R i
.
R7
N
(/ \ eµ.___N R8
R7-- ,./.,R8
Q. R8 I , R7 ¨ ._,L)
7' N
R --- N N N NO
R9 O
......-..k. ,..
N N 1 \ 141 gi
- N
N R9 R-
,
wherein:
Rl, R2 and le are independently selected from H, optionally substituted alkyl,
methyl, ethyl,
2-fluoroethyl and 2,2,2-trifluoroethyl; and
R7, R8 , R9 and Rl are 1 to 8 substituents independently selected from H,
optionally
substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino,
aceylamino,
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trifluoromethyl or cyano, and wherein the PTM is coupled to a ULM (VLM or CLM)
via
L.
[0396] In any aspect or embodiment described herein, PTM is represented by
chemical
structure:
N..... N._ N._
H / I
I
NN I
N N
F
N N F N
I / I
..-F N I c..-F N N
F F F
\ / F
N N N
I
N OH N OH N OH
F
N / , N ,
/ I
...-F NI OH s====F NI OH N OH
F F F
N.__
\
\ /
N
N OH N OH N OH
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H
I / I
I
N F N F N F
F
N F
F c=--F I
N F / I
N F
F F
N
N-
\ / F
N F N F N F
* ja * ja = N )
..,.. -1... õ.=
N N NO N N Na F
N N Ng F
F
F F
N N ja Na N NNO * N
A., ,..
N N NQ
F
F
F F
F
F .
N F *
N
F N(=N*" NO NI.:1'N'' NO
N N aN N Na N N Na
OH F OH
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f-N
/-N
N'
---N
J-NNH
[0397] In any aspect or embodiment described herein, the linker attachment
point to PTM is
as indicated by the dotted line:
R7 N.__ R7 R8 R9
R10 R9 R7
R9
I
; RI Me2N
N
Z = N, CH
N N
rsr...LN Na N0-Th
cN;Z
N
Me2N
[0398] Therapeutic Compositions
[0399] Pharmaceutical compositions comprising combinations of an effective
amount of at
least one bifunctional compound as described herein, 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
disclosure.
[0400] The present disclosure includes, where applicable, the compositions
comprising the
pharmaceutically acceptable salts, in particular, acid or base addition salts
of compounds as
described herein. The acids which are used to prepare the pharmaceutically
acceptable acid
addition salts of the aforementioned base compounds useful according to this
aspect are those
which form non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable
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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 -toluene sul fonate and p am oate [i . e., 1,1 '-m ethyl
en e-b i s-(2-hydroxy-3
naphthoate)]salts, among numerous others.
[0401] Pharmaceutically acceptable base addition salts may also be used to
produce
pharmaceutically acceptable salt forms of the compounds or derivatives
according to the present
disclosure. 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.
[0402] The compounds as described herein may, in accordance with the
disclosure, 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 used to enhance
bioavailability of the
compounds from an oral route of administration. The most effective dosage form
will depend
upon the pharmacokinetics of the particular agent chosen as well as the
severity of disease in the
patient. Administration of compounds according to the present disclosure as
sprays, mists, or
aerosols for intra-nasal, intra-tracheal or pulmonary administration may also
be used. The
present disclosure therefore also is directed to pharmaceutical compositions
comprising an
effective amount of compound as described herein, optionally in combination
with a
pharmaceutically acceptable carrier, additive or excipient. Compounds
according to the present
disclosureion may be administered in immediate release, intermediate release
or sustained or
controlled release forms. Sustained or controlled release forms are preferably
administered
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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.
[0403] The compositions as described herein 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 carboxymethyl cellulose, polyacrylates, waxes, polyethylene-
polyoxypropylene-block
polymers, polyethylene glycol and wool fat.
[0404] The compositions as described herein may be administered orally,
parenterally, by
inhalation spray, topically, rectally, nasally, buccally, vaginally or via an
implanted reservoir.
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.
[0405] 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
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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.
[0406] 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.
[0407] 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.
[0408] The pharmaceutical compositions as described herein 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.
[0409] 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
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.
[0410] 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,
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sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-
octyldodecanol,
benzyl alcohol and water.
[0411] 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.
[0412] The pharmaceutical compositions as described herein 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.
[0413] The amount of compound in a pharmaceutical composition as described
herein 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.
Preferably, the
compositions should be formulated to contain between about 0.05 milligram to
about 750
milligrams or more, more preferably about 1 milligram to about 600 milligrams,
and even more
preferably about 10 milligrams to about 500 milligrams of active ingredient,
alone or in
combination with at least one other compound according to the present
disclosure.
[0414] 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.
[0415] A patient or subject in need of therapy using compounds according to
the methods
described herein can be treated by administering to the patient (subject) an
effective amount of
the compound according to the present disclosure including pharmaceutically
acceptable salts,
solvates or polymorphs, thereof optionally in a pharmaceutically acceptable
carrier or diluent,
either alone, or in combination with other known erythopoiesis stimulating
agents as otherwise
identified herein.
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[0416] These 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, or by aerosol form.
[0417] 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 mg 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.
[0418] 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.
[0419] 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 [tM.
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.
[0420] 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.
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[0421] 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
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 can be included as part
of the composition.
[0422] 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.
[0423] 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.
[0424] The active compound or pharmaceutically acceptable salts thereof can
also be mixed
with other active materials that do not impair the desired action, or with
materials that
supplement the desired action, such as erythropoietin stimulating agents,
including EPO and
darbapoietin alfa, among others. In certain preferred aspects of the
invention, one or more
compounds according to the present disclosure are coadministered with another
bioactive agent,
such as an erythropoietin stimulating agent or a would healing agent,
including an antibiotic, as
otherwise described herein.
[0425] 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
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sodium chloride or dextrose. The parental preparation can be enclosed in
ampoules, disposable
syringes or multiple dose vials made of glass or plastic.
[0426] If administered intravenously, preferred carriers are physiological
saline or phosphate
buffered saline (PBS).
[0427] 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 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.
[0428] Liposomal 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.
[0429] Therapeutic Methods
[0430] In an additional aspect, the description provides therapeutic
compositions comprising
an effective amount of a compound as described herein or salt form thereof,
and a
pharmaceutically acceptable carrier. The therapeutic compositions modulate
protein degradation
in a patient or subject, for example, an animal such as a human, and can be
used for treating or
ameliorating disease states or conditions which are modulated through the
degraded protein.
[0431] 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 disclosure are set forth
hereinabove.
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[0432] The description provides therapeutic compositions as described
herein for
effectuating the degradation of proteins of interest for the treatment or
amelioration of a disease,
e.g., cancer. In certain additional embodiments, the disease is multiple
myeloma. As such, in
another aspect, the description provides a method of ubiquitinating/ degrading
a target protein in
a cell. In certain embodiments, the method comprises administering a
bifunctional compound as
described herein comprising, e.g., a CLM and a PTM, preferably linked through
a linker moiety,
as otherwise described herein, wherein the CLM is coupled to the PTM and
wherein the CLM
recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, preferably
an E3 ubiquitin
ligase such as, e.g., cereblon) and the PTM recognizes the target protein such
that degradation of
the target protein will occur when the target protein is placed in proximity
to the ubiquitin ligase,
thus resulting in degradation/inhibition of the effects of the target protein
and the control of
protein levels. The control of protein levels afforded by the present
disclosure provides treatment
of a disease state or condition, which is modulated through the target protein
by lowering the
level of that protein in the cell, e.g., cell of a patient. In certain
embodiments, the method
comprises administering an effective amount of a compound as described herein,
optionally
including a pharamaceutically acceptable excipient, carrier, adjuvant, another
bioactive agent or
combination thereof.
[0433] In additional embodiments, the description provides methods for
treating or
emeliorating a disease, disorder or symptom thereof in a subject or a patient,
e.g., an animal such
as a human, comprising administering to a subject in need thereof a
composition comprising an
effective amount, e.g., a therapeutically effective amount, of a compound as
described herein or
salt form thereof, and a pharmaceutically acceptable excipient, carrier,
adjuvant, another
bioactive agent or combination thereof, wherein the composition is effective
for treating or
ameliorating the disease or disorder or symptom thereof in the subject.
[0434] In another aspect, the description provides methods for identifying
the effects of the
degradation of proteins of interest in a biological system using compounds
according to the
present disclosure.
[0435] In another embodiment, the present disclosure is directed to a
method of treating a
human patient in need for a disease state or condition modulated through a
protein where the
degradation of that protein will produce a therapeutic effect in that patient,
the method
comprising administering to a patient in need an effective amount of a
compound according to
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the present disclosure, optionally in combination with another bioactive
agent. The disease state
or condition may be a disease caused by a microbial agent or other exogenous
agent such as a
virus, bacteria, fungus, protozoa or other microbe or may be a disease state,
which is caused by
overexpression of a protein, which leads to a disease state and/or condition
[0436] The term "disease state or condition" is used to describe any
disease state or
condition wherein protein dysregulation (i.e., the amount of protein expressed
in a patient is
elevated) occurs and where degradation of one or more proteins in a patient
may provide
beneficial therapy or relief of symptoms to a patient in need thereof In
certain instances, the
disease state or condition may be cured.
[0437] Disease states of conditions which may be treated using compounds
according to the
present disclosure include, for example, asthma, autoimmune diseases such as
multiple sclerosis,
various cancers, 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.
[0438] Further disease states or conditions which may be treated by
compounds according to
the present disclosure include Alzheimer's disease, Amyotrophic lateral
sclerosis (Lou Gehrig's
disease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention
deficit hyperactivity
disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic
obstructive pulmonary
disease, Crohn's disease, Coronary heart disease, Dementia, Depression,
Diabetes mellitus type 1,
Diabetes mellitus type 2, Epilepsy, Guillain¨Barre syndrome, Irritable bowel
syndrome, Lupus,
Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity,
Obsessive¨compulsive
disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid
arthritis, Sarcoidosis,
Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome,
Vasculitis.
[0439] Still additional disease states or conditions which can be treated
by compounds
according to the present disclosure include aceruloplasminemia,
Achondrogenesis type II,
achondroplasia, Acrocephaly, Gaucher disease type 2, acute intermittent
porphyria, Canavan
disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency,
adenylosuccinate lyase
deficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA
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dehydratase deficiency, Alkaptonuria, Alexander disease, Alkaptonuric
ochronosis, alpha 1-
antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic
lateral sclerosis
Alstrom syndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratase
deficiency,
Anderson-Fabry disease, androgen insensitivity syndrome, Anemia Angiokeratoma
Corporis
Diffusum, Angiomatosis retinae (von Hippel¨Lindau disease) Apert syndrome,
Arachnodactyly
(Marfan syndrome), Stickler syndrome, Arthrochalasis multiplex congenital
(Ehlers¨Danlos
syndrome#arthrochalasia type) ataxia telangiectasia, Rett syndrome, primary
pulmonary
hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson
cutis gyrata
syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia,
Bilateral
Acoustic Neurofibromatosis (neurofibromatosis type II), factor V Leiden
thrombophilia, Bloch-
Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked
sideroblastic anemia,
Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous
sclerosis), prion
disease, Birt¨Hogg¨Dube syndrome, Brittle bone disease (osteogenesis
imperfecta), Broad
Thumb-Hallux syndrome (Rubinstein-Taybi syndrome), Bronze Diabetes/Bronzed
Cirrhosis
(hemochromatosis), Bulbospinal muscular atrophy (Kennedy's disease), Burger-
Grutz syndrome
(lipoprotein lipase deficiency), CGD Chronic granulomatous disorder,
Campomelic dysplasia,
biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cri du chat, CAVD
(congenital
absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP
(congenital
erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism,
Chondrodystrophy
syndrome (achondroplasia), otospondylomegaepiphyseal dysplasia, Lesch-Nyhan
syndrome,
galactosemia, Ehlers¨Danlos syndrome, Thanatophoric dysplasia, Coffin-Lowry
syndrome,
Cockayne syndrome, (familial adenomatous polyposis), Congenital erythropoietic
porphyria,
Congenital heart disease,
Methemoglobinemia/Congenital m ethaem ogl ob inaemi a,
achondroplasia, X-linked sideroblastic anemia, Connective tissue disease,
Conotruncal anomaly
face syndrome, Cooley's Anemia (beta-thalassemia), Copper storage disease
(Wilson's disease),
Copper transport disease (Menkes disease), hereditary coproporphyria, Cowden
syndrome,
Craniofacial dysarthrosis (Crouzon syndrome), Creutzfeldt-Jakob disease (prion
disease),
Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome
(myotonic
dystrophy), Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,
spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,
Duchenne and Becker
types (DBMD), Usher syndrome, Degenerative nerve diseases including de Grouchy
syndrome
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and Dejerine-Sottas syndrome, developmental disabilities, distal spinal
muscular atrophy, type V,
androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbe
disease), Di George's
syndrome, Dihydrotestosterone receptor deficiency, androgen insensitivity
syndrome, Down
syndrome, Dwarfism, erythropoietic protoporphyria Erythroid 5-aminolevulinate
synthetase
deficiency, Erythropoietic porphyria, erythropoietic protoporphyria,
erythropoietic uroporphyria,
Friedreich's ataxiaõ familial paroxysmal polyserositis, porphyria cutanea
tarda, familial pressure
sensitive neuropathy, primary pulmonary hypertension (PPH), Fibrocystic
disease of the
pancreas, fragile X syndrome, galactosemia, genetic brain disorders, Giant
cell hepatitis
(Neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthoma
elasticum),
Gunther disease (congenital erythropoietic porphyria), haemochromatosis,
Hallgren syndrome,
sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-
Lindau disease
(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria
syndrome
(progeria), Hyperandrogenism, Hypochondroplasia, Hypochromic anemia, Immune
system
disorders, including X-linked severe combined immunodeficiency, Insley-Astley
syndrome,
Kennedy's syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan
syndrome,
Jackson-Weiss syndrome, Kidney diseases, including hyperoxaluria,
Klinefelter's syndrome,
Kniest dysplasia, Lacunar dementia,Langer-Saldino achondrogenesis, ataxia
telangiectasia,
Lynch syndrome, Lysyl-hydroxylase deficiency, Machado-Joseph disease,
Metabolic disorders,
including Kniest dysplasia, Marfan syndrome, Movement disorders, Mowat-Wilson
syndrome,
cystic fibrosis, Muenke syndrome, Multiple neurofibromatosis, Nance-Insley
syndrome, Nance-
Sweeney chondrodysplasia, Niemann¨Pick disease, Noack syndrome (Pfeiffer
syndrome),
Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystic kidney disease,
polyostotic
fibrous dysplasia (McCune¨Albright syndrome), Peutz-Jeghers syndrome, Prader-
Labhart-Willi
syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan
syndrome),
primary pulmonary hypertension, primary senile degenerative dementia, prion
disease, progeria
(Hutchinson Gilford Progeria Syndrome), progressive chorea, chronic hereditary
(Huntington)
(Huntington's disease), progressive muscular atrophy, spinal muscular atrophy,
propionic
acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial
hypertension, PXE
(pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen disease
(neurofibromatosis
type I), Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rett
syndrome, RFALS type
3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe
achondroplasia with
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developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome,
sarcoma,
breast, leukemia, and adrenal gland (SBLA) syndrome, sclerosis tuberose
(tuberous sclerosis),
SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SED Strudwick
(spondyloepimetaphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal
dysplasia
congenita) SEMD, Strudwick type (spondyloepimetaphyseal dysplasia, Strudwick
type),
Shprintzen syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome,
South-
African genetic porphyria (variegate porphyria), infantile-onset ascending
hereditary spastic
paralysis, Speech and communication disorders, sphingolipidosis, Tay-Sachs
disease,
spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity
syndrome,
tetrahydrobiopterin deficiency, beta-thalassemia, Thyroid disease, Tomaculous
neuropathy
(hereditary neuropathy with liability to pressure palsies), Treacher Collins
syndrome, Triplo X
syndrome ( triple X syndrome), Trisomy 21 (Down syndrome), Trisomy X, VHL
syndrome (von
Hippel-Lindau disease), Vision impairment and blindness (Alstrom syndrome),
Vrolik disease,
Waardenburg syndrome, Warburg Sjo Fledelius Syndrome, Weissenbacher-Zweymuller
syndrome, Wolf¨Hirschhorn syndrome, Wolff Periodic disease, Weissenbacher-
Zweymuller
syndrome and Xeroderma pigmentosum, among others.
[0440] The term "neoplasia" or "cancer" is used throughout the
specification to refer to the
pathological process that results in the formation and growth of a cancerous
or malignant
neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often
more rapidly than
normal and continues to grow after the stimuli that initiated the new growth
cease. Malignant
neoplasms show partial or complete lack of structural organization and
functional coordination
with the normal tissue and most invade surrounding tissues, metastasize to
several sites, and are
likely to recur after attempted removal and to cause the death of the patient
unless adequately
treated. As used herein, the term neoplasia is used to describe all cancerous
disease states and
embraces or encompasses the pathological process associated with malignant
hematogenous,
ascitic and solid tumors. Exemplary cancers which may be treated by the
present compounds
either alone or in combination with at least one additional anti-cancer agent
include 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
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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 and
teratocarcinomas. Additional cancers which may be treated using compounds
according to the
present disclosure include, for example, T-lineage Acute lymphoblastic
Leukemia (T-ALL), T-
lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-
cell Leukemia,
Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell
ALL,
Philadelphia chromosome positive ALL and Philadelphia chromosome positive
CIVIL.
[0441] The term "bioactive agent" is used to describe an agent, other than
a compound
according to the present disclosure, 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,
antiviral agents, especially including anti-HIV agents and anti-HCV agents,
antimicrobial agents,
antifungal agents, etc.
[0442] The term "additional anti-cancer agent" is used to describe an anti-
cancer agent,
which may be combined with compounds according to the present disclosure 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, 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 inhibitor, an AKT inhibitor, an mTORC1/2
inhibitor, a
JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase
inhibitor, a Map
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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, IL13-PE38QQR, INO 1001, 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, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-
pyrrolo[2,3-
d]pyrimidin-5-yl)ethyl]benzoy1]-, di sodium 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)- indolyl-quinolone,
vatalanib, AG-013736,
AVE-0005, 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, levami sole, lomustine,
mechlorethamine, melphalan,
6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone,
nilutamide,
octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,
procarbazine, raltitrexed,
rituximab, 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,
EM1D121974,
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interleukin-12, IM862, angiostatin, vitaxin, droloxifene, 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 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.
[0443] The term "anti-HIV agent" or "additional anti-HIV agent" includes,
for example,
nucleoside reverse transcriptase inhibitors (NRTI), other non-nucloeoside
reverse transcriptase
inhibitors (i.e., those which are not representative of the present
disclosure), protease inhibitors,
fusion inhibitors, among others, exemplary compounds of which may include, for
example, 3TC
(Lamivudine), AZT (Zidovudine), (-)-FTC, ddI (Didanosine), ddC (zalcitabine),
abacavir (ABC),
tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C,
NVP
(Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate),
RTV
(Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV
(Amprenavir), LPV
(Lopinavir), fusion inhibitors such as T20, among others, fuseon and mixtures
thereof, including
anti-HIV compounds presently in clinical trials or in development.
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[0444]
Other anti-HIV agents which may be used in coadministration with compounds
according to the present disclosure include, for example, other NNRTI' s
(i.e., other than the
NNRTI' s according to the present disclosure) may be selected from the group
consisting of
nevirapine (BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781
(N-[4-
chloro-3 -(3 -m ethy1-2-butenyl oxy)phenyl] -2m ethyl3 -furan carb othi ami
de), etravirine (TMC 125),
Trovirdine (Ly300046.HC1), MKC-442 (emivirine, coactinon), HI-236, HI-240, HI-
280, HI-281,
rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II
(Methyl
3' ,3 ' -di chl oro-4 ' ,4"-dim ethoxy-5 ' ,5"-bi s(methoxycarbony1)-6,6-
diphenylhexenoate), Methyl 3 -
Brom o-5-(1-5-b rom o-4-m ethoxy-3 -(methoxycarbonyl)phenyl)hept-l-eny1)-2-
methoxybenzoate
(Alkenyl di arylm ethane analog, Adam
analog), (5-chloro-3-(phenylsulfiny1)-2' -
indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), Capravirine (AG-1549, S-
1153),
atevirdine (U-87201E), aurin tricarboxylic acid (SD-095345), 1-[(6-cyano-2-
indolyl)carbonyl]-
443 -(i sopropylamino)-2-pyridinyl]piperazine, 1-
[5-[ [N-(m ethyl)m ethyl sulfonylamino] -2-
indolyl carb ony1-443 -(i sopropyl amino)-2-pyri dinyl] piperazine, i-[3 -
(Ethyl amino)-2-[pyri diny1]-
4- [(5-hydroxy-2-indolyl)carb onyl]piperazine, 1
-[(6-F ormy1-2-indolyl)carb onyl] -443-
(i sopropyl amino)-2-pyri dinyl] pip erazine, 1 -[ [5-(Methyl sulfonyl oxy)-24
ndoyl y)c arb onyl] -443 -
(i sopropylamino)-2-pyridinyl]piperazine, U8 8204E, Bis(2-nitrophenyl)sulfone
(NSC 633001),
Calanolide A (NSC675451), Calanolide B, 6-Benzy1-5-methy1-2-
(cyclohexyloxy)pyrimidin-4-
one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet
(Foscavir),
HEPT (1- [(2-Hydroxyethoxy)m ethyl] -6-(phenylthio)thymine),
HEPT-M (1-[(2-
Hydroxyethoxy)m ethyl] -6-(3 -m ethylphenyl)thi o)thymine),
HEPT-S (1-[(2-
Hydroxyethoxy)m ethyl] -6-(phenylthi o)-2-thi othymine), Inophyllum
P, L-737,126,
Michellamine A (N5C650898), Michellamine B (N5C649324), Michellamine F,
Dim ethylb enzy1)-1- [(2-hydroxyethoxy)m ethyl] -5-i sopropyluracil, 6-
(3 ,5-Dim ethylb enzy1)-1-
(ethyoxym ethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), Oltipraz (4-
Methy1-5-
(pyraziny1)-3H-1,2-dithiol e-3 -thi one), N-
{2-(2-Chloro-6-fluorophenethy1]-N' -(2-
thi azol yl)thi ourea (PETT Cl, F derivative), N-{2-(2,6-Difluorophenethy1]-N'
4245-
b rom opyri dy1)]thi ourea {PETT
derivative), N- {2-(2,6-Difluorophenethy1]-N' 4245-
methylpyridylAthiourea {PETT Pyridyl derivative), N-[2-(3-Fluorofuranyl)ethy1]-
N'42-(5-
chloropyridyl)]thiourea, N-[2-(2-Fluoro-6-ethoxyphen ethyl)] -N' - [2-(5-b rom
opyri dy1)]thi ourea,
N-(2-Phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697,639, L-697,593, L-
697,661, 3-[2-
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(4,7-Difluorob enzoxaz ol-2-yl)ethylI-5-ethyl -6-methyl (pypri din-2(1H)-thi
one (2-Pyridinone
Derivative), 3 -[[(2-Methoxy-5,6-dimethy1-3 -pyri dyl)m ethyl] amine] -5-ethyl
-6-m ethyl (pypri din-
2(1H)-thione, R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-
2720, Suramin
Sodium, TBZ (Thiazolobenzimidazole, NSC 625487), Thiazoloisoindo1-5-one,
(+)(R)-9b-(3,5-
Dimethylpheny1-2,3-dihydrothiazolo[2,3-a]isoindo1-5(9bH)-one, Tivirapine
(R86183), UC-38
and UC-84, among others.
[0445] 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
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 disclosure.
[0446] The term "pharmaceutically acceptable derivative" is used throughout
the
specification to describe any pharmaceutically acceptable prodrug form (such
as an ester, amide
other prodrug group), which, upon administration to a patient, provides
directly or indirectly the
present compound or an active metabolite of the present compound.
[0447] General Synthetic Approach
[0448] The synthetic realization and optimization of the bifunctional
molecules as described
herein may be approached in a step-wise or modular fashion. For example,
identification of
compounds that bind to the target molecules can involve high or medium
throughput screening
campaigns if no suitable ligands are immediately available. It is not unusual
for initial ligands to
require iterative design and optimization cycles to improve suboptimal aspects
as identified by
data from suitable in vitro and pharmacological and/or ADMET assays. Part of
the
optimization/SAR campaign would be to probe positions of the ligand that are
tolerant of
substitution and that might be suitable places on which to attach the linker
chemistry previously
referred to herein. Where crystallographic or NMR structural data are
available, these can be
used to focus such a synthetic effort.
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[0449] In a very analogous way one can identify and optimize ligands for an
E3 Ligase, i.e.
ULMs/CLMs.
[0450] With PTMs and ULMs (e.g. CLMs) in hand one skilled in the art can
use known
synthetic methods for their combination with or without a linker moiety.
Linker moieties can be
synthesized with a range of compositions, lengths and flexibility and
functionalized such that the
PTM and ULM groups can be attached sequentially to distal ends of the linker.
Thus a library of
bifunctional molecules can be realized and profiled in in vitro and in vivo
pharmacological and
ADMET/PK studies. As with the PTM and ULM groups, the final bifunctional
molecules can be
subject to iterative design and optimization cycles in order to identify
molecules with desirable
properties.
[0451] Abbreviations:
ACN: acetonitrile
AcOH, acetic acid
ADDP: 1,1'-(azodicarbonyl)dipiperidine
aq., aqueous
BAST: N,N-bis(2-methoxyethyl)aminosulfur trifluoride
BINAP, 2,2'-bis(diphenylphosphino)- I , I '-binaphthalene
Boc, tert-butoxycarbonyl
Boc20, di-tert-butyl decarbonate
BOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
BPO: benzoyl peroxide
Cbz: Carbonylbezyloxy
CDC13, deuteriochloroform
CD30D, deuteriomethanol
CH3CN, acetonitrile
CH3OH, methanol
CsF, cesium fluoride
Cs2CO3, cesium carbonate
Cu(OAc)2, copper (II) acetate
Cy2NMe, dicyclohexylmethylamine
DAST: diethylaminosulfur trifluoride
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DBE: 1,2-dibromoethane
DCM: dichloromethane
DEAD: diethyl azodicarboxylate
DIAD: diisopropyl azodicarboxylate
DIBAL: disiobutylaluminium hydride
DIEA or DIPEA: diisopropylethylamine
DMA: N,N-dimethylacetamide
DMAP, N,N-dimethylaminopyridine
DMF: N,N-dimethylformamide
DMP: Dess-Martin periodinane
DMSO, dimethylsulfoxide
DMSO-d6, hexadeuterodimethyl sulfoxide
EA: ethyl acetate
EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
Et2NH, diethylamine
Et0Ac or EA, ethyl acetate
HC1, hydrochloric acid
H20, water
HBTU: N,N,N'N'-tetramethy1-0-(1H-benzotriazol-1-y1)uronium hexafluorophosphate
HMDS: bis9trimethylsilyl)amine
HMPA: hexamethylphosphoramide
HPLC, high performance liquid chromatography
MX, 2-iodoxybenzoic acid
KOAc, potassium acetate
LCMS, liquid chromatography / mass spectrometry
LDA: lithium diisopropylamide
Li0H, lithium hydroxide
MCPBA: meta-chloroperoxybenzoic acid
Me0H, methanol
MsCl: methanesulfonyl chloride
M.W: microwave
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N2, nitrogen
NaH, sodium hydride
NaBH3CN, sodium cyanoborohydride
NaBH(0Ac)3, sodium triacetoxyborohydride
NaCl, sodium chloride
NaHCO3, sodium bicarbonate
NaI, sodium iodide
Na2SO4, sodium sulfate
NB S: N-bromosuccinimide
n-BuLi, n-butyllithium
NH3, ammonia
N1H4C1, ammonium chloride
NH201-111C1, hydroxylamine hydrochloride
NMP, N-methylpyrrolidone
NMR, nuclear magnetic resonance
02, oxygen
PCC: pyridinium chlorochromate
Pd-118 or Pd(dtpf)C12: 1,1'-bis(di-tert-butylphosphino)ferrocene
dichloropalladium
Pd(aMPhos)C12, bis(di-tert-buty1(4-
dimethylaminophenyl)phosphine)dichloropalladium(II)
Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium
Pd(dppf)C12: 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium
Pd(dba)2: bis(dibenzylideneacetone)palladium
Pd(OH)2, palladium hydroxide
Pd(PPh3)4, tetrakis(triphenylphosphine)palladium(0)
PE, petroleum ether
Ph3P, triphenylphosphine
PPTS: pyridium p-tolunesulfonate
PTSA: p-toluenesulfonic acid
Py, pyridine
PyBOP, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
rt, room temperature
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RuPhos-Pd-G3 : XPhos-Pd-G3 : [(2-dicyclohexylphosphino-2', 6 '-dii sopropoxy-
1,11-bipheny1)-2-
(2'-amino-1,1'-bipheny1)] palladium(II) methanesulfonate
RuPhos-Pd-G2: Chloro[(2-dicyclohexylphosphino-21,61-diisopropoxy-1,11-
bipheny1)-2-(2'-
amino-1,1 '-biphenyl)] palladium(II)
SFC: supercritical fluid chromatography
TBAF, tetra-n-butylammonium fluoride
TBDPSC1, tert-butyldiphenylsilyl chloride
TB S, tert-butyldimethylsilyl
tBuOK, potassium tert-butoxide
[tBu3PH]BF4, tri-tert-butyl phosphonium tetrafluoroborate
t-BuXPhos-Pd-G3 : [(2-di-tert-butylphosphino-2',4',6'-triisopropy1-1,11-
bipheny1)-2-(2'-amino-
1,1'-bipheny1)] palladium(II) methanesulfonate
TEA: trimethylamine
TFA: trifluoroacetic acid
TLC: thin layer chromatography
TMP: 2,2,6,6-tetramethylpiperidine
TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide
TMSOTf, trimethylsilyl trifluoromethanesulfonate
TosC1 or TsCl: p-toluenesulfonyl chloride
TsCl, p-toluenesufonyl chloride
Ts0H: p-toluenesulfonic acid
XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
XPhos: 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl
XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',4',6'-triisopropy1-1,11-bipheny1)-2-
(2'-amino-1,1'-
biphenyl)] palladium(II) methanesulfonate
12354-85-7: bis(pentamethylcyclopentadienylrhodium dichloride)
[0452] A. Exemplary Synthetic Schemes for Exemplary Estrogen Receptor
Binding
Moiety Based Compounds
[0453] Synthetic scheme A-1, A-2 through A-5, A-6, and A-7 described the
routes used in
the preparation of CRBN ligands, as well as CRBN ligands with partial linker
moieties
connected.
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[0454] General synthetic scheme A-1 to prepare intermediate.
L/ L/\ OH L/\ OH
\OH LOH LO
F )\ )\ )\
X Y O NaNO2, HBr, CuBr N Dess-Martin
0 N
H V
X N Pd/C, H2
K2CO3DMF
_)...
0
Y THE X N Y H20, 0-
100 C X v.-
Y
,
NO2 0 0
NO2 NH2 Br Br
0
0 o' 'o
)
/1 __
L 0 '13¨BPf LO OTf L I0
L)0
_________________ / I o"o ________ I bn, O.
o
I
N pyridinium
tribromide
______ o
Ts0H Pd(dppf)Cl2, KOAc N Pd(dppf)C12, K2CO3
N ' N a...).- X
Y
Y ____________________________________________________________________ N.-
trimethoxymethane x Y dioxane, 100 C X
X Y
0 0 dioxane/H20, 100 C TEA, DCM, 0-25 C, 2h
uII
Bn,0
Br ,B,
0 0
Br
..õ...,,,I......, Bn,
0
0 \ 0
0
0
L/L0 LO LO
L 0
I I I
I
N
N
Pd(dppf)Cl2, K2CO3 N Pd/C, H2 chiral SFC
separation N X Y
_____________ 0 X Y X Y ______ X [10 Y +
THF/Et0H
dioxane/H20, 100 C
phenylboronic acid
. 101
Bn
, , .
HO
, HO
0 HO
X and Y = H, F; L = (CH2)n where n = 0, 1, 2
[0455] General synthetic scheme A-2 to prepare intermediate.
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--... --..
\ (s-NH 0 0 0 0
0 OH Br----.'Br \.0 0
Boe.N.'") 110 o NaOH
OH
110 0 ________________________________ o
pd(oAc), (0.1 eq), K2HPO4 (3 eq) 0 DIPEA, DMSO r'N H20, Me0H/THF rN
OH
F
dioxane, 140 C, 10 h F 120 C, 12 h Boc__NJ
Boe N J
0
\ \
0 0
\0 0 _tr:/ai 0
0
H2N 0 HATU, DIEA
Mn02
HCI OH NH
_,
)
OH __________________________________ 101 H 0 N¨N¨ 0
DCM, 25 C, 1h (...., rN N...,....õ---õ, DMF
N 0 Na0Ac, NaBH3CN rN
Boo' N J H AcOH, Me0H Boo'0 N J ." .....
N 0 Boc,Nj
H
HCl/Dioxane 1
\
0
0 0
HCI r----\
/ N N t1FLI
HN \_.... j
0
[0456] General synthetic scheme A-
3 to prepare intermediate.
0 o 0
o 0 Br,A,,,L,0
H2SO4 0 F F (3 NaOH is OH
0 OH _________________ 411) 0.---
______________________________________________________________ ....-
F 0 F 0
F OH Me0H, 85 C, 20 h F OH K2CO3, DMF
THF/Me0H/H20
F.J. F
80 C, 12h F F
F
F F
J r"NH F 0 0
0 F.-1'0 OHFO---1\
0 Boc'N'')
_________ V.- CH3CH21, K2CO3 0
..-"*.
AgOAc, cat:12354-85-7 DIPEA DMSO 120 C 12h r -N
-----
1-methylnaphthalene F DMF, 20 C, 1 h , , ,F ..-
--
100 C, 12 h Boe
F F
F 0
...i. F 0 ...--1 H2N.,...zi
F 0 0 F.-.1'0 0 0
0
0s04(2% eq), Na104 (3 eq) o DIPEA
__________ ).- 0 _______ 1r N
0
THF, H20, 20 C ---N 0 DCM, Me0H
Na0Ac, NaBH3CN
r-----N N.,,...zi DMF r-N
, ________
i---
'N
Boc
Boc,N) 0 Boc", F
.1.0 HCl/dioxane F 0 0
_____ )...-
\¨NH
dioxane
_ __
N 0
HCI r-----N
HN j
[0457] General synthetic scheme A-
4 to prepare intermediate.
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r'NH
0 0 0
0 NIS Cu20, NaOH CH31, K2003
Boc'N'-')
________________________ V. 0 _______________________ 0 _____________ =
Br 0 V.-
0 0
trifluoromethanesulfonic acid Br H20, DMF, 80 C Br
acetone Br 1.1
I OH o,
o
L
o o o
NaOH 40 OH NH
OH CIFI-12N¨,
I.
) 0 ).-
OH Mn02 COOH 0
r-N =THE, H2OH0 r-N r-
DCM v- ---N __ 0 ,....
Na0Ac, NaBH3CN, rN 101 11 JLNH
Boc'Nj 0 Boc'Nj 0
Boo'Nj (:) H Me0H
BoeNj 0
0
00 00
NH _\¨NH
HATU el N¨'\¨ 0 0 N o
_______ > HCl/dioxane (.N
DIP, DMF r-N ____________ _,,..
Boc'Nj (:) dioxane HNJ 0
HCI
o 0
r....' NH 0
0
Br
BrBr-..Ø.-0 Boe NaOH N.--"--1
0 OH
1.1 0 __________ =-= 0 = 0 0 ___ =
OH
Br
K2CO3, DMF XPhos-Pd-G3, Cs2CO3, r-N Me0H, THE,
H20 Boc
r-N
OH ()(:) dioxane, 90 C,16 h BocNj 00.---
20 C, 2 h
'Nj 0,.....,..--Ø-,
o
0 00
_t_rfazi COOH
_tNH
Mn02 ,... OH CIH H N 0
lel 14 HATU, DIEA 0 N ,;)
0 , 0 = 2 (3
DCM, 20 C, 2 h (-NI r-N NH
DMF, 20 C, 1 h r-ri
Boo 'Nõ...) 0......,,,-,, ,..- Na0Ac, NaBH3CN Boc,NI,) 0..õ..--...0
Boo'N
0..õ..--,...0,--
0 Me0H, 20 C, 2 h 0
1
00
NH
HCl/dioxane lel N¨t o
DCM __ I.- r,N
HNJ 0.,......--.Ø.,
HCI
[0458] General synthetic scheme A-5 to prepare intermediate.
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O o o o
0 0 Br¨--O..0
0 v.- liFie
__________________________________________ a 0 NaOH OH
1
OH
Br K2CsCO3, KI Br Pd(dppf)C12, KCO3, THF,
H2O, 20 C, lh
OH DMF, 100 C, 1h 0(3(:)1)ioxane, H2O, 70 C, 3h
0O,..,
0
H2Nr OH
0
0 H2N . 0,
H 0 NH2
HATU,DIEA
Mn02 N'' NH2
OH _________ a ).
DCM, 20 C, 1h ,0 NaBH3CN, AcOH (:),õ.,,.----,0.----
..,,.0 DMF, 20 C, 1h
Me0H, 20 C, 12.5h
0
0..õ--..Ø.---.õ.Ø., 0 0 ,-0.õ..---.Ø0
0 )7
õ.-----õ
0 NH2 0 NH2
tO tO Cbz-N,-
--\
NaB03.4H20, BH3-Me2S jTiN. TosCI, DMAP, TEA
N.,= pH
HO ______________________________________ a Ts0
___________________________ ).-
THF, 0-20 C, 3hi0 0 0 ¨C) DCM, 25 C, 12h ¨C) DIPEA,
ACN, 60 C, 24h
0 )\ ,.Ø....õ,.--,0,-.õ.0 0 )\
0 Y--
0 )\-0
00
00
N...
N
Cbz---C\N /----\N
r--"` 0 N÷.t....N/t HN
Cbz¨N 0 H2N 0 Pd/C, H2, 15
Psi \....., 0
X benzensulfonic acid
J-0
0 ACN, 80 C, 12h 0 DMF, 20
C, 2 h 0
? ri rl
--0 ...-0
[0459] General synthetic scheme A-6 to prepare intermediate.
o o 0 0
r 0/
N NH )?L
/ Boo' Ti(i-PrO)4 Br
0
---- N
0 NH (:) o
______________________________________________________________________ v...
F N /N--)
DIPEA, DMSO (--___N .20, EtMgBr N NaH, DMF, 30 C, 12h
`
NJ
Boc
Boc
0 0 / NI-13-1-120/Me0H 0 0
0 (1) 50 C, 15 h
N r rN 0
N
HNi....)
\\ ,an
0
Boc 0 03.0 eq
,N / (2) s
\\
0
MeCN, 90 C, 2h
[0460] General synthetic scheme A-7 to prepare intermediate.
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i
i N2H4.H20 r--- \N-Boc Boc
I N----\
/L CD! HN\--/ \ __--,N1 tI \
)1, ____ D. N F 20 C, 12 hr N __ ,NH2 MeCN, 50 C, 12h Iµ1.-
._.\KNH
H
0 c____
RuPhos-Pd-G2, t-BuONa N
t-Amyl-OH, 90 C, 16h
(----- Ni
o .=\
H
N
_t NH
k,_i I/
Br 0 0 HN 0 0
Boc N/Th N NH , HCl/Dioxane N
______ ).- NsN.\¨NE-0
L..../N---Cf sN w _],,,_
tBuOK, MeCN, 12 hr
100 C N---i DCM HCI N-_..\K
0 0
[0461] Synthetic schemes A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-
16, and A-17,
described the routes used in the preparation of representative chimeric
compounds claimed in
this application.
[0462] General synthetic scheme A-8 to prepare claimed compounds.
HO NTho7-0
N
\ 0
HN N
NaCNH3, HOAc, Me0H
0
N
/-- _____________________ _
.---- N
0\ +
1
1 HCI
0 N 0 N Y
/ \ 'E) H R
1- HO
HN¨
y=-.../NR s=_).,
0
n = 0, 2, 3, 4
0..---H
R = H, F; Y = CH, N
tv7rN
HO
o7-----0
N
HN N NaCNH3, HOAc, Me0H
\__/
0
)
+ ..---
1 0
N
to HCI 0 ,, ' -14- 0
HO
HN
Y=>R )--H
0
0 n = 0, 2, 3, 4
R = H, F; Y = CH, N
[0463] General synthetic scheme A-9 to prepare claimed compounds.
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H2N
o o H2N 0 H2N
N"
..---'13F3 k' 0 0 NaB03.4H20, BH3-Me2S
0 TosCI, DMAP, TEA
0
__________________________ op
= C..-----Nr .
Pd(dppf)Cl2, K2CO3 N's. ON,..... THE, 0-15 C, 3h N.
=DCM, 0-15 C, 2h
,
0 nx--- dioxane, H20, 70 C, 3 h 0 IN
HO 0
Br
0 H2N
(--Ni 00
0 NH2
;_ cuz-N'---1 Benzenesulfonic acid
Cbz¨N
= 0
N, . = ________________ x...- _____________________ )..-
KI, DIPEA, CH3CN --0 CH3CN
Tos0 0
0 )\-___ Cbz¨N\ j
0
0...f....AH H2,
Pd/C
HO
THF/Et0H
0,V1s1/----N 0
HO IN ___p 0
N,.....ti HN N
NH
0
Me0H, DCE, AcOH, NaBH3CN 0
[0464] General synthetic scheme A-10 to prepare claimed compounds.
o 0
)r(:) (i) TMSCHN2, AC9N Brr.)Le
CI
(2) HBr/AcOH, ACN
0 0
0
Bn'0 OH 0
Bn'0 Or0 F
F
BrL0'
0 0 DAST Bn'o
K2CO3, acetone DCE
0'Bn
CIH.HN/"...-"\
N *
0 1
LiAIH
o oF F 0
Bn-0 4
THF
Bn'0
0 F
__Iz1H
F N 0 (1) chiral SFC
/-----\
N\____71 * 0 Na0Ac, NaBH3CN, AcOH, Me0H (2) PCC, DCM F
0
0
N
\----tF1
1 Pd/C, H2
0
OH
HO THF
0
0
i N .
0
[0465] General synthetic scheme A-11 to prepare claimed compounds.
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\
0 o 0
0 ONa
0 0 0
0----- N HCI III( HO OH ---------
=00< D NaBH4
_ .
]...
Me0H
)=)=)L, ), 0
0 Ts0H, toluene 0
0 ' NaOH, Me0H, reflux \
Na0 0
--0
0 0
HO-00<c):
0 TsCI
DCM, TEA ..-- Ts0-00< :
0
Brr
F THF 0,,ciz: Bn--
0 0,Qi:L
OH
Bn,.,0
0\
Ts0¨00< D
0 0---/ HCI (1 M)
_)õ..
0
_______________________ D.-
Cs2CO3, DMF F F
00
0o r-\N
N...,OLIFI
r----.N ill N....t.:/t j\-,:f2r_N\_j
HO HN j 0
0 0 0
HCI 0
Pdie, H2
NaBH3CN, Na0Ac, Me0H/DCM
THF
F
F
HO
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[0466] General synthetic scheme A-12 to prepare claimed compounds.
F F
OH
F F F 0 )5(IFI<._ 0¨ 0 /t-Bu
X 0 F
.,sµ_...,õ2c..V...I<FF ..,\\s
0 \\ F HN
F
0 F F F o¨ ip
0 F F F X X
)...
K2CO3,THF, MeCN t-BuONa, Pd(OAc)2 = \
1110
XPhos
t-Bu ,c:1 toluene, 90 C 0
411 /
t-Bu
'0
HO
li X
00
HO (-N An Ntnyai 0
= . \/ ) \N
w
H2s04(2m) = x HN.,) HCI
________________________ 0 ________________________ 41 N
l...-
THF = . 11 ) _______ 1/ Na0Ac, NaBH3CN, Me0H, DCM
\
. o X = H, F
N 0
0 ).r0
I HNr¨ \ -I N * N..,1E1
Na0Ac, NaBH3CN, Me0H, DCM \¨
HCI 0 -,...r. NH
0
0
X
HO N
0
N 0
0
J1-1
X = H, F
o
[0467] General synthetic scheme A-13 to prepare claimed compounds.
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r.---.õõ..OH CbzCI ... OH DMP /0 CH(0Me)3 0¨ H2, Pd/C
0,
HN, Na2CO3, DCM, H2O ("-j--/ DCM, r7
TsOH, Me01-1 (ro¨ Me0H, TrIF HNO::),
CbiN N
N Cbi
FFF Cbi
/
F+FF
aS g F F .
o
o 0
- -
0,_ Bn
0
- 0
HO Nra
1-(N) Pd/C, H2 (50 psi)
=
_____
t-BuOK, Pd(0A02 ND_____ / Me0H, THF m chiral SFC
C separation HO +
XPhos 0
N- 0 /
toluene, 90 C 0
\
Bn-0Q,cY
OH oN
HO OH
000
N_(!y1H0
H2SO4 (2,ID r'N
THF,70 C 70 C Na._\... HN,> HCI
N, ).-
-0
Na0Ac, HOAc, Me0H, DCM NcD
,0 0
Na0Ac, HOAc, r-NN . ....,/6,
ON Me0H, DCM HN,___, N o NH N"--
HCI 0 c-N
0
IW
HO
0 0
N 0
NO--\--Nr-\\__JN * rµi-NH
o 0
NH
[0468] General synthetic scheme A-14 to prepare claimed compounds.
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t-BuO so 0 OH
OL(I)
OBn OH
IW
OTs
0)Lir Pd/C, H2 )\_if TosCI, KOH
o, fl'
0 "- 0) jili rs ts" ru
A,
7-0 THF, Et0H ,--.0
/ THF
/-0 l..0S2%.-J3, LJIVIr
t-BuO
OH ...0,..OH
0 0 CfL-1
AlLiH4 SFC separation
-).-
cg
THF _____________________ )..-
t-BuO 00 H
t-BuO t-BuO
40 (N N--1:1C
.,0,..,OH iii
0 aih. 0 0
r-^N N......7 '
N,)
oir-r/
HCI
Dess-Martin
DCM Na0Ac, NaCNBH3
DCM/ Me0H, rt, 12 h
t- t-BuO
BuO
t-BuO
N\ IV .
N`)LNH
HCl/dioxane HO
).- 0
DCM
[0469] General synthetic scheme A-15 to prepare claimed compounds.
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OH r70Tos
TosCI, TEA,
DCM
Bn¨cFr Bn-0)-1/
Iiin
0 0
OH /Er OTos /0'OH
/Cr
o o/Cr
0
Bn'-0 Ph 0
H2, Pd/C, 15 psi
_________________________ a- __________ w- Swern oxidation
Cs2CO3, DMF, 80 C, 16h Me01-1/THF, __________________________
DCM, r.t., 6 h
t-BuO
t-BuO t-BuO t-BuO
):i./.2...e.,...õ..- 0
0\¨OH
0 0 0 0
DIBAL-H m-CPBA LIAIH4 DMP
DCM, -78 C DCM, r.t. , 16 h DCM
THF
t-BuO t-BuO t-BuO t-BuO
---0
0
\
N- 0
--.0 o o (_\=F, 0 ,----N 40 -----:\,.
_ti.iõ j=ri NN, õ,/ OH N N
0 .
o 0 H J:!--/-
- \--/
,..--N 1.1 N N
HN ,I 0 n
____________________________ 0 HCl/dioxane 0 N
0
___________________________________________________ 10- H
DCM, TEA, NaBH(OAc)3
t-BuO
HO
*0
[0470] General synthetic scheme A-16 to prepare claimed compounds.
"1---
0 40 I. OH
= ----k--
0 0,XL:: CI
N
NaBF14, CaCl2
_______________ v.- HO.,....0õ.:: õOH SOCl2 I*
N isr CI
0 0 Me0H, 0-20 C, 16 h THF,80 C,4h
Cs2CO3, ACN, 90 C, 3h
H HO
0 N 0 0
H H
iini- \N * 0 C:)::T0
o- 0\ __el 0)'1'1\110
N TFA
_q_
N /- \
TEA, KI, DMF, 13,16h N N THF, 20 C, 3h .. N .. N
\__/ 0
0- 0-
[0471] General synthetic scheme A-17 to prepare claimed compounds.
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o
Bn0 " OH
JO
j:j)Le õEr0H
y2-0 IW LiAIH4, THF Dess-Martin
_________________________________________________________ J.-
DCM, 0 C to r.t, 1 h
Cs2CO3, DMF,16h 0 C, 1 h
Tos¨O
Bn0 Bn0
Bn0 0
0 HO Br
Br
* Br 0
0 7 110 m-CPBA ). LiBr, AcOH/THF
o- Dess-Martin ,
DCM, 00C to rt, 16 h
n-BuLi, -60 C, 2 h
Bn0
Bn0 Bn0
Bn0
---0 0 _c"-Nr0
HN,i'
\
1
o o dr NH 0 N,---\ N 0
l 0 0
Nj \_____/
Pd/C, H2, 50 psi N yTh
______________ I.
ACN/DMSO, DIEA, 70 C, 2 h DMF/THF, 6 h a- HO
O'''''N".-0
H
0
Bn0
[0472] Exemplary Synthesis of Exemplary Compound 2: 3-{5-14-(5-{4-1(1R,25)-
6-
hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenoxy}pentyl)piperazin-1-
y11-7-
methoxy-1-oxo-2,3-dihydro-111-isoindol-2-yllpiperidine-2,6-dione
[0473] Step 1: Preparation of 5-bromopentanal
DMSO
oxalyldichloride
Br¨OH ________________________ ). BrO
TEA
[0474] To a solution of oxalyl dichloride (9.12 g, 72 mmol, 6 mL, 4.00 eq)
in
dichloromethane (50 mL) was added a solution of dimethylsulfoxide (5.61 g, 72
mmol, 4.00 eq)
in dichloromethane (10 mL) at -70 C over 30 min, and then 5-bromopentan-1-ol
(3.00 g, 18
mmol, 1.00 eq) was added at below -60 C. The resulting mixture was stirred at
-70 C for 1 hr.
Thin-layer chromatography (petroleum ether: ethyl acetate = 10:1) showed the
reaction was
complete. Triethylamine (14.54 g, 144 mmol, 20 mL, 8.00 eq) was added into the
mixture and
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the reaction was stirred at -60 C for 30 min. The mixture was poured into
water (20 mL) and
stirred for 1 min. The aqueous phase was extracted with dichloromethane (20 mL
x 3). The
combined organic phase was washed with brine (20 mL x 2), dried with anhydrous
sodium
sulfate, filtered and concentrated in vacuum. The residue was directly used
for the next step
without further purification. 5-bromopentanal (2.80 g, 17 mmol, 94% yield) was
obtained as a
colorless oil.
[0475] Step 2: Preparation of 5-bromo-1,1-dimethoxypentane
trimethoxymethane
BrO _______________________________
methanol BrO
[0476] To a solution of 5-bromopentanal (2.80 g, 16.97 mmol, 1.00 eq) in
methanol (50 mL)
was added trimethoxymethane (9.00 g, 85 mmol, 9 mL, 5.00 eq) and 4-
methylbenzenesulfonic
acid hydrate (161 mg, 0.85 mmol, 0.05 eq) at 25 C. The resulting mixture was
stirred at 25 C
for 16 hr. Thin-layer chromatography (petroleum ether: ethyl acetate =10:1)
showed a major new
spot. The mixture was poured into water (40 mL) and stirred for 1 min. The
aqueous phase was
extracted with ethyl acetate (30 mL x 3). The combined organic phase was
washed with brine
(20 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in
vacuum. The
residue was purified by silica gel column chromatography (petroleum ether:
ethyl acetate =15:1).
5-Bromo-1,1-dimethoxy-pentane (3.50 g, 16.58 mmol, 97% yield) was obtain as a
colorless oil.
1H Wit (400MHz, CDC13) 6 4.37 (t, J=5.6 Hz, 1H), 3.41 (s, 2H), 3.33 (s, 6H),
1.95- 1.84 (m,
2H), 1.67- 1.59 (m, 2H), 1.54- 1.45 (m, 2H).
[0477] Step 3: Preparation of (1R,25)-6-benzyloxy-144-(5,5-
dimethoxypentoxy)pheny1]-2-
phenyl-tetralin
Bn
OH
0
Bre
CS2CO3, DMF, 100 C, 1h 0
Bn,=
0 0\
[0478] To a solution of 4-[(1R,25)-6-benzyloxy-2-phenyl-tetralin-1-
yl]phenol (500 mg, 1.23
mmol, 1.00 eq) in dimethylformamide (5 mL) was added cesium carbonate (1.2 g,
3.69 mmol,
3.00 eq) and 5-bromo-1,1-dimethoxy-pentane (390 mg, 1.84 mmol, 1.50 eq). The
mixture was
stirred at 100 C for 1 hour. The reaction mixture was diluted with water (30
mL) and extracted
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with ethyl acetate (15 mL x 2). The combined organic phase was washed with
saturated brine (15
mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in
vacuum. The residue
was purified by silica gel column chromatography (petroleum ether: ethyl
acetate = 50:1 to 10:1)
to give (1R,2S)-6-benzyloxy-144-(5,5-dimethoxypentoxy)pheny1]-2-phenyl-
tetralin (500 mg,
0.93 mmol, 76% yield) as a white solid. LC/MS (ESI) m/z: 559.2 [M+23]
NMR (400MHz,
CDC13) 6 7.49 - 7.45 (m, 2H), 7.44 - 7.38 (m, 2H), 7.37 -7.31 (m, 1H), 7.21 -
7.13 (m, 3H), 6.90
- 6.85 (m, 2H), 6.82 (dd, J=2.0, 7.2 Hz, 2H), 6.76 (dd, J=2.4, 8.4 Hz, 1H),
6.53 (d, J=8.8 Hz, 2H),
6.32 (d, J=8.8 Hz, 2H), 5.07 (s, 2H), 4.38 (t, J=5.6 Hz, 1H), 4.25 (d, J=4.8
Hz, 1H), 3.84 (t,
J=6.4 Hz, 2H), 3.41 -3.28 (m, 7H), 3.17 - 2.99 (m, 2H), 2.28 -2.13 (m, 1H),
1.87- 1.71 (m, 3H),
1.69 - 1.60 (m, 2H), 1.54 - 1.42 (m, 2H).
[0479] Step 4: Preparation of (1R,25)-1-[4-(5,5-dimethoxypentoxy)pheny1]- 2-
phenyl-
tetralin-6-ol
Bn
HO
0
Pd/C, H2 git
qt,
Me0H, THF, 25 C, 12 h =
0
[0480] To a solution of (1R,25)-6-benzyloxy-1-[4-(5,5-
dimethoxypentoxy)pheny1]-2-phenyl-
tetralin (500 mg, 0.93 mmol, 1.00 eq) in methanol (20 mL) and tetrahydrofuran
(20 mL) was
added palladium on carbon (200 mg, 10% purity) under nitrogen atmosphere. The
suspension
was degassed and purged with hydrogen 3 times. The mixture was stirred under
hydrogen (15
psi) at 25 C for 12 h. The reaction mixture was filtered and the filter was
concentrated to give
(1R,25)-144-(5,5-dimethoxypentoxy)pheny1]-2-phenyl-tetralin-6-ol (420 mg,
crude) as a white
solid. LC/MS (ESI) m/z: 469.1 [M+23]
[0481] Step 5: Preparation of 544-[(1R,25)-6-hydroxy-2-phenyl-tetralin-1-
yl]
phenoxy]pentanal
HO HO
0
H2SO4 (2 M) 416, 0
= 4f* \-0 THF, 70 C, 0.5 h
411i
0
gli
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[0482] To a solution of (1R,2S)-1-[4-(5,5-dimethoxypentoxy)pheny1]-2-phenyl-
tetralin-6-ol
(420 mg, 0.94 mmol, 1.00 eq) in tetrahydrofuran (75 mL) was added sulfuric
acid (2 M in water,
18 mL, 40.00 eq). The mixture was stirred at 70 C for 0.5 h. Thin layer
chromatography
(petroleum ether: ethyl acetate = 3:1) showed the reaction was completed and a
new spot formed.
The reaction mixture was diluted with water (40 mL) and extracted with ethyl
acetate (20 mL x
2). The combined organic phase was washed with saturated sodium bicarbonate
(15 mL) and
saturated brine (20 mL x 2), dried with anhydrous sodium sulfate, filtered and
concentrated in
vacuum to give 5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]
pentanal (370 mg, 0.92
mmol, 98% yield) as a white solid.
[0483] Step 6: Preparation of tert-butyl 4-(7-methoxy-1-oxo-1,3-
dihydroisobenzofuran-5-
yl)piperazine-1-carboxylate
r NH 0 0
0
Boc
_____________________________ )P. 0
0
DIPEA, NMP, 90 C
Boc,N
[0484] To a mixture of 5-fluoro-7-methoxy-3H-isobenzofuran-1-one (1 g, 5.49
mmol, 1 eq)
and tert-butyl piperazine-l-carboxylate (2.05 g, 10.98 mmol, 2 eq) in 1-
methylpyrrolidin-2-one
(6 mL) was added N-ethyl-N-isopropylpropan-2-amine (2.84 g, 21.96 mmol, 3.83
mL, 4 eq) in
one portion. The mixture was stirred at 100 C for 12 hours. TLC (ethyl
acetate/petroleum ether
= 1/1, Rf = 0.1) indicated a new spot formed. The reaction mixture was diluted
with water (20
mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers
were washed
with water (15 mL), dried over sodium sulfate, filtered and concentrated under
reduced pressure.
The residue was purified by silica gel chromatography (petroleum ether/ethyl
acetate = 10/1 to
1:1). Tert-butyl 4-(7-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-
carboxylate (1 g, 2.87
mmol, 52% yield) was obtained as a yellow solid. LC/MS (ESI) m/z: 349.3 [M+1]
+; 1-H NMR
(400MHz, CDC13) 6 6.38 (s, 1H), 6.30 (s, 1H), 5.13 (s, 2H), 3.99 (s, 3H), 3.62-
3.59 (m, 4H),
3.42-3.35 (m, 4H), 1.48 (s, 9H).
[0485] Step 7: Preparation of 4-(4-(tert-butoxycarbonyl)piperazin-1-y1)-2-
(hydroxymethyl)-
6-methoxybenzoic acid
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0 0 0
0 NaOH OH
OH
H20, Me0H/THF
Bocrqj
Bocrsij
[0486] To a mixture of tert-butyl 4-(7-methoxy-1-oxo-3H-i sob enz ofuran-5 -
yl)pi p erazi ne-1-
carboxylate (1 g, 2.87 mmol, 1 eq) in methyl alcohol (10 mL) and
tetrahydrofuran (10 mL) was
added the solution of sodium hydroxide (459 mg, 11.48 mmol, 4 eq) in water (2
mL). The
mixture was stirred at 20 C for 1 h. TLC (ethyl acetate/petroleum ether =
1/1, Rf = 0) indicated a
new spot formed. The reaction mixture was concentrated under reduced pressure
to remove
solvent. The residue was diluted with water (20 mL) and extracted with ethyl
acetate (30 mL x 2).
The aqueous phase was adjusted to pH value to 4 ¨ 5 with hydrochloric acid
(1.5 N), then
filtered and the solid was collected. The solid was used for the next step
without further
purification. 4 -(4- Tert-butoxycarb onylpi p erazi n-l-y1)-2-(hydroxym
ethyl)-6-m ethoxy-b enzoi c
acid (700 mg, 1.68 mmol, 58% yield, 88% purity) was obtained as a white solid.
LC/MS (ESI)
m/z: 367.3 [M+1]
[0487] Step 8: Preparation of 4-(4-(tert-butoxycarbonyl)piperazin-1-y1) -2-
formy1-6-
methoxybenzoic acid
0 0 0 0
OH mn02 OH
OH
Me0H, 60 C NO
BocN
BocNj
[0488] To a mixture of 4-(4-tert-butoxycarbonylpiperazin-1-y1)-2-
(hydroxymethyl)-6-
methoxy-benzoic acid (650 mg, 1.77 mmol, 1 eq) and in methyl alcohol (20 mL)
was added
manganese dioxide (1.54 g, 17.74 mmol, 10 eq) in one portion at 20 C under
nitrogen. The
mixture was stirred at 50 C for 12 hours. LC/MS showed the reaction was
completed and
desired product was formed. The reaction mixture was filtered and the solution
was concentrated
under vacuum. The reaction was used for the next step without further
purification. 4-(4-Tert-
butoxycarbonylpiperazin-1-y1)-2-formy1-6-methoxy-benzoic acid (600 mg, 1.65
mmol, 92%
yield) was obtained as a yellow solid. LC/MS (ESI) m/z: 365.3 [M+1]
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[0489] Step 9: Preparation of 4-(4-(tert-butoxycarb
onyl)piperazin-l-y1)-2-(((2, 6-
dioxopiperidin-3-yl)amino)methyl)-6-methoxybenzoic acid
0 0 0 0
H2NIANH
OH HCI or 0
rNNa0Ac, Me0H, NaBH3CNj.' NNNH
Bocrqj
Boc
[0490] To a mixture of 4-(4-tert-butoxycarbonylpiperazin-1-y1)-2-formy1-6-
methoxy-benzoic
acid (600 mg, 1.65 mmol, 1 eq) and 3-aminopiperidine-2,6-dione (407 mg, 2.47
mmol, 1.5 eq,
HC1) in methyl alcohol (10 mL) was added sodium acetate (203 mg, 2.47 mmol,
1.5 eq) and
sodium cyanoborohydride (310 mg, 4.94 mmol, 3 eq) in one portion at 20 C. The
mixture was
stirred at 20 C for 2 h. LC/MS showed the reaction was completed and desired
product was
formed. The reaction mixture was concentrated under vacuum. The residue was
purified by
reverse phase flash silica gel chromatography (120 g SepaFlash silica gel
column, eluent of
0-60% acetonitrile in water with a flow rate of 30 mL/min). 4-(4-Tert-
butoxycarbonylpiperazin-
1-y1)-2-[[(2,6-dioxo-3-piperidyl)amino]methy1]-6-methoxy-benzoic acid (300 mg,
0.63 mmol,
38% yield) was obtained as a white solid. LC/MS (ESI) m/z: 477.4 [M+1]
[0491] Step 10: Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-y1)-7-
methoxy-1-
oxoisoindolin-5-yl)piperazine-1-carboxylate
0 0 0 00
_tNH
RH 0 EDCI, TEA N
NtN.JLNH HOBT, DCM"." rN
Boc,N)
L oCs Boc'N
[0492] To a mixture of 4-(4-tert-butoxycarbonylpiperazin-1-y1)-2-[[(2,6-
dioxo-3-
piperidyl)amino]methyl]-6-methoxy-benzoic acid (300 mg, 0.63 mmol, 1 eq) in
dichloromethane
(10 mL) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
(181 mg,
0.94 mmol, 1.5 eq), N-hydroxybenzotrizole (128 mg, 0.94 mmol, 1.5 eq), and
triethylamine (191
mg, 1.89 mmol, 3 eq). The mixture was stirred at 20 C for 1 h. LC/MS showed
the reaction was
completed and desired product was formed. The reaction mixture was quenched by
addition of
water (15 mL), and then extracted with dichloromethane (40 mL x 2). The
combined organic
layers were washed with brine (10 mL), dried over sodium sulfate, filtered and
concentrated
under reduced pressure. The residue was purified by preparative TLC
(dichloromethane: methyl
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CA 03095912 2020-10-01
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alcohol = 10:1, Rf = 0.60). Tert-butyl 442-(2,6-dioxo-3-piperidy1)-7-methoxy-1-
oxo-isoindolin-
5-yl]piperazine-1-carboxylate (260 mg, 0.57 mmol, 90% yield) was obtained as a
white solid.
LC/MS (ESI) m/z: 459.4 [M+1]
[0493] Step 11: Preparation of 3-(7-methoxy-1-oxo-5-(piperazin-1-
yl)isoindolin-2-y1)
piperidine-2,6-dione
NH NH
)_o HCl/dioxane
20 C
H
Boc N)'N)
[0494] To a mixture of tert-butyl 442-(2,6-dioxo-3-piperidy1)-7-methoxy-1-
oxo-isoindolin-
5-yl]piperazine-1-carboxylate (300 mg, 0.65 mmol, 1 eq) in dioxane (10 mL) was
added
hydrogen chloride/dioxane (4 M, 17 mL, 105.81 eq) in one portion. The mixture
was stirred at
20 C for 2 h. The reaction mixture was concentrated under reduced pressure to
remove solvent.
The residue was used for the next step without further purification. 3-(7-
Methoxy-1-oxo-5-
piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (216 mg, 0.55 mmol, 83%
yield, HC1 salt)
was obtained as a white solid. LC/MS (ESI) m/z: 359.2 [M+1] +; 1-H-NMR
(400MHz, Me0D) 6:
6.72 (s, 1H), 6.60 (s, 1H), 5.08-5.04 (m, 1H), 4.36-4.35 (m, 2H), 3.92 (s,
3H), 3.66-3.65 (m, 5H),
3.38-3.35 (m, 4H), 2.89-2.78 (m, 1H), 2.77-2.67 (m, 1H), 2.45-2.42 (m, 1H),
2.14-2.14 (m, 1H).
[0495] Step 12: Preparation of 3- {544-(5-{4-[(1R,25)-6-hydroxy-2-pheny1-
1,2,3,4-
tetrahydronaphthalen-l-yl]phenoxy}pentyl)piperazin-l-y1]-7-methoxy-l-oxo-2,3-
dihydro-1H-
isoindo1-2-ylIpiperidine-2,6-dione (Exemplary Compound 2)
o o
_t
N 0
NH
HO 00
HN,) HO 0 NO
NaBH3CN, Na0Ac, AcOH, Me0H, DCM
[0496] To a mixture of 3-(7-methoxy-l-oxo-5-piperazin-l-yl-isoindolin-2-
yl)piperidine-2,6-
dione hydrochloride (89 mg, 0.23 mmol) in methyl alcohol (5 mL) and
dichloromethane (1 mL)
was added sodium acetate (102 mg, 1.25 mmol, 5 eq) in one portion at 20 C.
The mixture was
stirred at 20 C for 1 h, then 5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-
yl]phenoxy]pentanal
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(100 mg, 0.25 mmol, 1 eq) was added to the reaction mixture and stirred for 1
h. Sodium
cyanoborohydride (31 mg, 0.50 mmol, 2 eq) and acetic acid (0.05 mL) was added
to the reaction
mixture. The resulting solution was stirred at 20 C for 5 h. LC/MS showed the
reaction was
completed and desired product was formed. The reaction mixture was
concentrated under
reduced pressure to remove solvent. The residue was purified by preparative
HPLC (column:
Phenomenex Synergi C18 150 x 25 x 10 um; mobile phase: [water(0.05%HC1)-
acetonitrile];
B%: 35%-55%, 7.8
min). 3 45444544-[(1R,25)-6-Hydroxy-2-phenyl-tetralin-1-
yl]phenoxy]pentyl]piperazin-1-y1]-7-methoxy-1-oxo-i soindolin-2-yl]piperidine-
2,6-dione (109.9
mg, 0.14 mmol, 56% yield, 100% purity, HC1 salt) was obtained as a white
solid. LC/MS (ESI)
m/z: 743.7 [M+1] +; 1-H-NMR (400MHz, DMSO-d6) 6 10.93 (s, 1H), 10.56-10.43 (m,
1H), 9.18-
9.13 (m, 1H), 7.16-7.13 (m, 3H), 6.84-6.83 (d, J= 6.4Hz, 2H), 6.69 (s, 1H),
6.62-6.61 (m, 2H),
6.55-6.52 (m, 3H), 6.28-6.26 (d, J= 8.4Hz, 2H), 4.99-4.97 (m, 1H), 4.29-4.25
(m, 1H), 4.23-4.18
(m, 1H), 4.17-4.15 (m, 1H), 4.06-4.00 (m, 2H), 3.85-3.83 (m, 5H), 3.56-3.53
(m, 1H), 3.34-3.33
(m, 4H), 3.10-3.02 (m, 4H), 3.00-2.85 (m, 2H), 2.60-2.58 (m, 3H), 2.16-2.08
(m, 1H), 1.91-1.88
(m, 1H), 1.76-1.69 (m, 5H), 1.43-1.41 (m, 2H).
[0497] Exemplary Synthesis of Exemplary Compound 3: 3-15-14-15-14-1(1R,25)-
6-
hydroxy-2-phenyl-tetralin-l-yll
phenoxy]pentyllpiperazin-l-y11-4-methoxy-l-oxo-
isoindolin-2-yl]piperidine-2,6-dione
[0498] Step 1: Preparation of 5-bromo-4-iodo-3H-isobenzofuran-1-one
0
0
NIS
0
0
Br trifluoromethanesulfonic acid Br
[0499] To a solution of 5-bromo-3H-isobenzofuran-1-one (50 g, 234.71 mmol,
1 eq) in
trifluoromethanesulfonic acid (680 g, 4.53 mol, 400 mL, 19.30 eq) was added 1-
iodopyrrolidine-
2,5-dione (55.45 g, 246.45 mmol, 1.05 eq) at 0 C in portions. The mixture was
allowed to warm
to 15 C and held for 16 h. TLC (petroleum ether: ethyl acetate = 5:1) showed
no starting
material remained and two new spots (Rf = 0.4, 0.5) formed. The reaction
mixture was poured
into ice-water (1 L) and yellow solid precipitated. The mixture was filtered
and the filter cake
was washed with water. The filter cake was dissolved in ethyl acetate (500 mL)
and the resulting
orange solution was dried over sodium sulfate. The mixture was filtered and
the filtrate was
concentrated to afford a yellow solid. The residue was triturated with ethyl
acetate (50 mL),
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filtered and washed with ethyl acetate (10 mL x 2). 5-Bromo-4-iodo-3H-
isobenzofuran-1-one (40
g, 118.02 mmol, 50% yield) was obtained as a yellow solid. 1-H NMR (400MHz,
CDC13) 6 7.83
(d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 5.10 (s, 2H).
[0500] Step 2: Preparation of 5-bromo-4-hydroxy-3H-isobenzofuran-1-one
0 0
Cu2O, NaOH
0 ________________________________ I 0
Br H20, DMA, 80 C Br
OH
[0501] To a mixture of 5-bromo-4-iodo-3H-isobenzofuran-1-one (40 g, 118.02
mmol, 1 eq),
sodium hydroxide (23.60 g, 590.10 mmol, 5 eq) in water (400 mL) and N,N-
dimethylacetamide
(200 mL) was added cuprous oxide (3.38 g, 23.60 mmol, 2.4 mL, 0.2 eq). The
reaction mixture
was heated to 80 C and held for 16 h. TLC (petroleum ether : ethyl acetate =
1:1, Rf = 0.3)
showed the reaction was completed. The reaction mixture was poured into 1N
hydrochloride
solution (400 mL) and extracted with ethyl acetate (400 mL x 2). The combined
organic layers
were concentrated and dissolved in ethyl acetate (500 mL), washed with
saturated aqueous
sodium bicarbonate (150 mL), brine (150 mL) and then dried over sodium
sulfate. The mixture
was filtered and the filtrate was concentrated to afford a residue. The
residue was triturated with
ethyl acetate (20 mL), filtered and washed with ethyl acetate (10 mL) to give
a solid. The filtrate
was further concentrated and triturated with ethyl acetate. 5-Bromo-4-hydroxy-
3H-
isobenzofuran-1-one (14.5 g, 60.15 mmol, 50% yield, 95% purity) was obtained
as a white solid.
1-H NMR (400MHz, DMSO) 6 10.90 (s, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.23 (d, J =
8.0 Hz, 1H),
5.35 (s, 2H).
[0502] Step 3: Preparation of 5-bromo-4-methoxy-3H-isobenzofuran-1-one
0 0
CH3I, K2CO3
ii I 0 I Ii0
Br acetone Br
OH
[0503] To a mixture of 5-bromo-4-hydroxy-3H-isobenzofuran-1-one (3 g, 13.10
mmol, 1 eq)
in acetone (20 mL) was added iodomethane (17.5 g, 123.29 mmol, 7.7 mL, 9.41
eq) and
potassium carbonate (5.43 g, 39.30 mmol, 3 eq). The mixture was stirred at 20
C for 15 h. TLC
(ethyl acetate: petroleum ether = 1:3, Rf = 0.37) indicated reaction was
completed. The reaction
mixture was quenched by addition of water (10 mL), and then extracted with
ethyl acetate (20
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mL x 2). The combined organic layers were washed with saturated sodium
bicarbonate (10 mL x
2), dried over sodium sulfate, filtered and concentrated under reduced
pressure. 5-Bromo-4-
methoxy-3H-isobenzofuran-1-one (2.9 g, 11.93 mmol, 91% yield) was obtained as
a yellow solid.
1-H NMR (400MHz, CDC13) 6 7.72 (d, J= 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H),
5.44 (s, 2H),
4.00 (s, 3H).
[0504] Step 4: Preparation of tert-butyl 4-(4-methoxy-1-oxo-3H-
isobenzofuran -5-y1)
piperazine-l-carboxylate
r'NH 0
BoeNI
0
Br Pd2(dba)3, XantPhos
C)
potassium phosphate
Boc'N
dioxane, 100 C
[0505] A vial was charged with 5-bromo-4-methoxy-3H-isobenzofuran-1-one
(500 mg, 2.06
mmol, 1 eq), tert-butyl piperazine-l-carboxylate (383 mg, 2.06 mmol, 1 eq),
tris(dibenzylideneacetone)dipalladium(0) (188 mg, 0.20 mmol, 0.1 eq), XantPhos
(119 mg, 0.20
mmol, 0.1 eq), potassium phosphate (873 mg, 4.11 mmol, 2 eq) and dioxane (5
mL). The
mixture was purged with nitrogen and heated to 100 C for 16 h. TLC (ethyl
acetate: petroleum
ether = 1:3) showed reaction was complete. The mixture was diluted with ethyl
acetate (30 mL)
and washed with water (30 mL). The aqueous layer was extracted with ethyl
acetate (15 mL x 3).
The organic layer was washed with brine (30 mL) and dried over sodium sulfate.
The crude was
purified by silica gel chromatography (ethyl acetate : petroleum ether = 1:20
to 1:6). Tert-butyl
4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (700 mg,
2.01 mmol, 97%
yield) was obtained as a yellow solid. LC/MS (ESI) m/z: 349.2 [M+1]
[0506] Step 5: Preparation of 4-(4-tert-butoxycarbonylpiperazin-1-y1)-2-
(hydroxylmethyl)-
3-methoxy-benzoic acid
0 0
1u10 NaOH OH
OH
THF, H20
Boc'N
Boc'N
[0507] To a solution of tert-butyl 4-(4-methoxy-1-oxo-3H-isobenzofuran-5-
yl)piperazine-1-
carboxylate (700 mg, 2.01 mmol, 1 eq) in tetrahydrofuran (4 mL) and water (4
mL) was added
sodium hydroxide (401 mg, 10.05 mmol, 5 eq). The mixture was stirred at 20 C
for 16 h. TLC
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(ethyl acetate: petroleum ether = 1:2) showed reaction was complete. The
mixture was adjusted
to pH = 4 with aqueous hydrochloric acid (1 M) and extracted with ethyl
acetate (10 ml x 3). The
organic layer was washed with brine (20 mL) and dried over sodium sulfate. The
crude material
was not further purified. 4-(4-Tert-butoxycarbonylpiperazin-1-y1)-2-
(hydroxymethyl) -3-
methoxy-benzoic acid (700 mg, crude) was obtained as a yellow solid.
[0508] Step 6: Preparation of 4-(4-(tert-butoxycarbonyl)piperazin-1-y1)-2-
formy1-3-
methoxybenzoic acid
0 0
I*LOH mn02 OH
OH
DCM ,0
Boc'N) 0
Boc'N) 0
[0509] To a solution of 4-(4-tert-butoxycarbonylpiperazin-1-y1)-2-
(hydroxymethyl)-3-
methoxy -benzoic acid (700 mg, 1.91 mmol, 1 eq) in dichloromethane (10 mL) was
added
manganese dioxide (2.49 g, 28.66 mmol, 15 eq). The mixture was stirred at 20
C for 1 h. TLC
(dichloromethane: methanol = 20:1) showed reaction was complete. The mixture
was diluted
with dichloromethane (10 mL) and filtered through a pad of Celite. The
filtrate was concentrated
in vacuum. The crude product was purified by silica gel column chromatography
(dichloromethane: methanol = 100:1to 60:1). 4-(4-(Tert-
butoxycarbonyl)piperazin-1-y1)-2-
formy1-3-methoxybenzoic acid (300 mg, 0.82 mmol, 43% yield) was obtained as a
pale yellow
solid.
[0510] Step 7: Preparation of 4-(4-tert-butoxycarbonylpiperazin-1-y1)-2 -
[[(2,6-dioxo -3-
piperidyl)amino]methy1]-3-methoxy-benzoic acid
0 0
CIH H2N
. 0
OH pH o
j-L
,0 ________________________________
Na0Ac, NaBH3CN, N NH
Boc'N) 0 Me0H
Boc'N) 0
[0511] To a mixture of 3-aminopiperidine-2,6-dione (135 mg, 0.82 mmol, 1
eq, HC1 salt) in
methanol (2 mL) and dichloromethane (4 mL) was added sodium acetate (270 mg,
3.29 mmol, 4
eq). The mixture was stirred at 20 C for 10 min, then 4-(4-tert-
butoxycarbonylpiperazin-1-y1) -
2-formy1-3-methoxy-benzoic acid (300 mg, 0.82 mmol, 1 eq) was added and the
mixture was
stirred for 10 min. Sodium cyanoborohydride (103 mg, 1.65 mmol, 2 eq) was
added and the
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mixture was further stirred for 40 min. LCMS showed reaction was complete. The
mixture was
adjusted to pH = 4-5 with aqueous hydrochloric acid solution (1 M) and
extracted with ethyl
acetate (10 mL x 3). The organic layer was dried over sodium sulfate. The
crude product was not
further purified. 4-(4-Tert-butoxycarbonylpiperazin-1-y1)-2-[[(2,6-dioxo-3-
piperidyl)amino]methyl]-3-methoxy-benzoic acid (400 mg, crude) was obtained as
a white solid.
LC/MS (ESI) m/z: 477.1 [M+1]
[0512] Step 8: Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidy1)-4-
methoxy-1-oxo-
isoindolin-5-yl]piperazine-1-carboxylate
0 00
RH 0 HATU
Nj=NH DIPEA, DMF
Boc,N) 0 \/ Boc'N) 0
0
[0513] To a solution of 4-(4-tert-butoxycarbonylpiperazin-1-y1)-2-[[(2,6-
dioxo-3-
piperidyl)amino] methyl]-3-methoxy-benzoic acid (400 mg, 0.84 mmol, 1 eq) in
dimethylformamide (5 mL) was added o-(7-azabenzotriazol-1-y1)-N,N,N',N'-
tetramethyluronium
hexafluorophosphate (383 mg, 1.01 mmol, 1.2 eq). The solution was stirred for
10min, then N,N-
diisopropylethylamine (325 mg, 2.52 mmol, 3 eq) was added. The solution was
stirred at 20 C
for 20 min. LCMS showed reaction was complete. The solution was diluted with
ethyl acetate
(40 mL) and washed with water (30 mL x 5) and brine (40 mL). The organic layer
was dried
over sodium sulfate. Tert-butyl 4-[2-(2,6-dioxo-3-piperidy1)-4-methoxy-1-oxo-
isoindolin-5-yl]
piperazine-l-carbo xylate (400 mg, crude) was obtained as a pale yellow solid.
LC/MS (ESI)
m/z: 459.1 [M+1]
[0514] Step 9: Preparation of 3-(4-methoxy-1-oxo-5-piperazin-1-yl-
isoindolin -2-y1)
piperidine-2,6-dione
00 00
NH NH
N HCl/dioxane
dioxane
Boc,N 0 HN.) 0
HCI
[0515] To a mixture of tert-butyl 442-(2,6-dioxo-3-piperidy1)-4-methoxy-1-
oxo¨isoindolin-
5-yl] piperazine-l-carboxylate (400 mg, 0.87 mmol, 1 eq) in dioxane (2 mL) was
added
hydrochloric acid in dioxane (4 M, 4 mL, 18.34 eq). The mixture was stirred at
20 C for 10 min
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and solvent was removed under vacuum. 3-(4-Methoxy-1-oxo-5-piperazin-1-yl-
isoindolin-2-
yl)piperidine-2,6-dione (350 mg, crude, HC1 salt) was obtained as a white
solid. LC/MS (ESI)
m/z: 359.1 [M+1]
[0516]
Step 10: Preparation of 345444544-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-l-yl]
phenoxy]pentyl]piperazin-l-y1]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine -
2,6-dione
(Exemplary Compound 3)
HO 00 H
oo
0
HNTh t 40
0
0 _________________________________________________________ 0-
N
0 AcONa, NaBH3CN, Me0H
HCI
NH
0 HO
[0517]
To a mixture of 3 -(4-methoxy-1-oxo-5-piperazin-1-yl-i soindolin-2-
yl)piperidine-2,6-
dione (100 mg, 0.25 mmol, 1 eq, HC1 salt) in dichloromethane (4 mL) and
methanol (1 mL) was
added sodium acetate (83 mg, 1.01 mmol, 4 eq). The mixture was stirred at 20
C for 10 min.
Then 544-[(1R,25)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal (101 mg,
0.25 mmol,
1.00 eq) was added and the mixture was stirred for 10 min. Sodium
cyanoborohydride (31 mg,
0.51 mmol, 2 eq) was added to the mixture and stirring was kept for 40 min.
LCMS and TLC
(dichloromethane: methanol = 10:1) showed reaction was complete. Solvent was
removed under
vacuum. The crude product was purified by prep-TLC (dichloromethane: methanol
= 10:1). 3-[5-
[4- [544-[(1R,2 S)-6-Hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-1-
y1]-4-methoxy-
1-oxo-isoindolin-2-yl]piperidine-2,6-dione (55 mg, 0.07 mmol, 29% yield, 99%
purity) was
obtained as a white solid. LC/MS (ESI) m/z: 743.3 [M+1] +; 1-H-NMIt (400MHz,
DMSO-d6) 6
10.96 (s, 1H), 9.12 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.25 - 6.98 (m, 4H), 6.83
(d, J=6.8 Hz, 2H),
6.72 - 6.43 (m, 5H), 6.26 (d, J=8.6 Hz, 2H), 5.06 (dd, J=5.0, 13.2 Hz, 1H),
4.56 -4.11 (m, 3H),
3.94 - 3.70 (m, 5H), 3.30 - 3.25 (m, 1H), 3.21 - 2.77 (m, 8H), 2.64-2.55 (m,
5H), 2.46 - 2.26 (m,
2H), 2.16- 1.94 (m, 2H), 1.80- 1.22 (m, 7H).
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[0518] B. Exemplary Synthetic Schemes for Exemplary Androgen Receptor
Binding
Moiety Based Compounds
[0519] General Synthetic Scheme B-1
r-
0 r-OH rOH -0
0 0 HN 0 NL.
Dess-Martin 0 NI
.
DIEA, DMF, 100 C *) DCM, rt, overnight
0
F
0 0
H
/--\ 0 H (:)
II,.0
0
HN N 0 OLN ,.(3
TFA \__/ 0
N .)-LNH N
0 4N HCI 0
0 ________________________________________________ ...
. 0
NaBH(OAc)3, DCM, rt N Dioxane
(-:_il
c:)
HO
X0
0 .
11 )/N
\ _______________________________________ 0 N0 . _7
HCI
0#_
NC '''NH2
I. 0#
CI 0 0 0
0
N 0
fi
________________ NC 'N 40 _tNH
HATU, DIEA, DMF CI r-N
N 0
[0520] General Synthetic Scheme B-2
o 0 Boc,N 0
so
KMn04, NaOH
Br Br OH H2SO4 Br o RuPhosPd, Cs2CO3 N
e
CN o 0
H20/dioxane OH Me0H, 70 C, 20 h PhMe, reflux, 16 h
0 0 0
100 C, 20 h 0 0 0 0
Boc,N 0 Boc,N HN Th 0 0
NaOH N
OH DIEA, CD! N 0 0
_tNH TFA
JJIrOH N N
Ni_tNH
0
0
Me0H/H20, rt CH3CN, 70 C DCM ,rt, 3 h 0
0
0 0 0
,o
[0521] Exemplary Synthetic Scheme for Exemplary Compound 32:
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CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
o 0 Boc,N 0
0
Br a
KMn04, NaOH Br OH H2SO4 Br o--- RuPhosPd, Cs2CO3
____________________________________________________________ . o
W
______________ ,.-
0 i CN o
H20/dioxane OH Me0H, 70 C, 20 h PhMe, reflux, 16
h
0 0 0 0 0
100 C, 20 h 0 0
TEA
Boc,N,-,....1
HN 0 0
NaOH N
OH DIEA, CD .,N1 0 0
rzt TFA N ti:1E1
N _____________ . N 0
MeOH/H20, rt J:ILIOH CH3CN, 70 C t:0DCM ,rt, 3
h
0 0
00
1rN
0 0
H 1 ,IONN tNIE1
N N,N
NC a (-...
0 H 1
NC am
CI WI Oss. 0
_________________________ . 0 0
CI Wi O's.
NaBH(OAc)3, DCM, rt, 1h
[0522] 1. Synthesis of 5-bromo-3-methoxybenzene-1,2-dicarboxylic acid
[0523] Into a 100-mL round-bottom flask, was placed 4-bromo-2-methoxy-6-
methylbenzonitrile (800 mg, 3.54 mmol, 1.00 equiv), water (10 mL), sodium
hydroxide (708 mg,
17.70 mmol, 5.00 equiv), KMn04 (1.12 g, 7.09 mmol, 2.00 equiv). The resulting
solution was
stirred for 16 h at 100 C in an oil bath. The solids were filtered out. The pH
value of the solution
was adjusted to 3 with hydrogen chloride (2 mol/L). The resulting solution was
extracted with
dichloromethane (15 mL x 3) and the aqueous layers combined. The resulting
solution was
extracted with ethyl acetate / methanol = 10:1 (15 mL x 3) and the organic
layers combined and
dried in an oven under reduced pressure, concentrated under vacuum. This
resulted in 330 mg
(34%) of 5-bromo-3-methoxybenzene-1,2-dicarboxylic acid as a white solid.
[0524] 2. Synthesis of 1,2-dimethyl 5-bromo-3-methoxybenzene-1,2-
dicarboxylate
[0525] Into a 100-mL round-bottom flask, was placed 5-bromo-3-
methoxybenzene-1,2-
dicarboxylic acid (330 mg, 1.20 mmol, 1.00 equiv), methanol (20 mL), sulfuric
acid (5 mL). The
resulting solution was stirred for 16 h at 70 C in an oil bath. The resulting
solution was diluted
with water (40 mL). The pH value of the solution was adjusted to 8 with sodium
carbonate. The
resulting solution was extracted with ethyl acetate (30 mL x 3) and the
organic layers combined
and dried over anhydrous sodium sulfate and concentrated under vacuum. The
residue was
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applied onto a silica gel column with ethyl acetate/petroleum ether (1:10).
This resulted in 340
mg (93%) of 1,2-dimethyl 5-bromo-3-methoxybenzene-1,2-dicarboxylate as a white
solid.
[0526] LC-MS (ES+): m/z 302.85 [MH+], tR = 0.906 min (2.0 minute run).
[0527] 3. Synthesis of 1,2-dimethy1-5-14-1(tert-butoxy)carbonyllpiperazin-1-
y11-3-
methoxybenzene-1,2-dicarboxylate
[0528] Into a 100-mL round-bottom flask, was placed 1,2-dimethyl 5-bromo-3-
methoxybenzene-1,2-dicarboxylate (300 mg, 0.99 mmol, 1.00 equiv), tert-butyl
piperazine-l-
carboxylate (277 mg, 1.49 mmol, 1.50 equiv), RuphosPd (39 mg, 0.05 mmol, 0.05
equiv),
Cs2CO3 (978 mg, 3.00 mmol, 3.00 equiv), toluene (15 mL). The resulting
solution was stirred for
12 h at 100 C in an oil bath. The resulting solution was diluted with water
(30 mL). The resulting
solution was extracted with ethyl acetate (30 mL x 3) and the organic layers
combined and dried
over anhydrous sodium sulfate and concentrated under vacuum. The residue was
applied onto a
silica gel column with dichloromethane/ethyl acetate (10:1). This resulted in
340 mg (84%) of
1,2-dimethyl 5-[4-[(tert-butoxy)carbonyl]piperazin-1-y1]-3-methoxybenzene-1,2-
dicarboxylate
as light yellow oil.
[0529] LC-MS (ES+): m/z 409.05 [MH+], tR = 0.963 min (2.0 minute run).
[0530] 4. Synthesis of 5-14-1(tert-butoxy)carbonyllpiperazin-1-y11-3-
methoxybenzene-
1,2-dicarboxylic acid
[0531] Into a 100-mL round-bottom flask, was placed 1,2-dimethyl 544-[(tert-
butoxy)carbonyl]piperazin-1-y1]-3-methoxybenzene-1,2-dicarboxylate (340 mg,
0.83 mmol, 1.00
equiv), methanol/H20/THF (8 mL), sodiumol (100 mg, 2.50 mmol, 3.00 equiv). The
resulting
solution was stirred for 12 h at 25 C The resulting solution was diluted with
water (30 mL). The
pH value of the solution was adjusted to 8 with hydrogen chloride (2 mol/L).
citric acid
monohydrate was employed to adjust the pH to 3. The resulting solution was
extracted with ethyl
acetate (30 mL x 3) and the organic layers combined and dried over anhydrous
sodium sulfate
and concentrated under vacuum. This resulted in 300 mg (95%) of 544-[(tert-
butoxy)carbonyl]piperazin-1-y1]-3-methoxybenzene-1,2-dicarboxylic acid as
colorless oil.
[0532] LC-MS (ES+): m/z 306.95 [MH+], tR = 0.853 min (2.0 minute run).
[0533] 5. Synthesis of tert-buty1-4-12-(2,6-dioxopiperidin-3-y1)-7-methoxy-
1,3-dioxo-2,3-
dihydro-1H-isoindo1-5-y11piperazine-1-carboxylate
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[0534] Into a 100-mL round-bottom flask, was placed tert-butyl 4-(7-methoxy-
1,3-dioxo-1,3-
dihydro-2-benzofuran-5-yl)piperazine-1-carboxylate (260 mg, 0.72 mmol, 1.00
equiv), 3-
aminopiperidine-2,6-dione hydrochloride (153.6 mg, 0.93 mmol, 1.30 equiv),
pyridine (10 mL).
The resulting solution was stirred for 4 h at 120 C in an oil bath. The
resulting solution was
diluted with water (30 mL). The resulting solution was extracted with ethyl
acetate (30 mL x 3)
and the organic layers combined and dried over anhydrous sodium sulfate and
concentrated
under vacuum. The residue was applied onto a silica gel column with
dichloromethane/methanol
(100:1). This resulted in 280 mg (83%) of tert-butyl 442-(2,6-dioxopiperidin-3-
y1)-7-methoxy-
1,3-dioxo-2,3-dihydro-1H-isoindo1-5-yl]piperazine-1-carboxylate as a yellow
solid.
[0535] LC-MS (ES+): m/z 417.05 [MH+], tR = 0.852 min (2.0 minute run).
[0536] 6. Synthesis of 2-(2,6-dioxopiperidin-3-y1)-4-methoxy-6-(piperazin-1-
yl)isoindoline-1,3-dione
[0537] Into a 50-mL round-bottom flask, was placed tert-butyl 442-(2,6-
dioxopiperidin-3-
y1)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindo1-5-yl]piperazine-1-carboxylate
(270 mg, 0.57
mmol, 1 equiv), dichloromethane (6 mL, 0.07 mmol, 0.124 equiv), TFA (2 mL,
0.02 mmol,
0.031 equiv). The resulting solution was stirred for 2 hr at 25 C. The
resulting mixture was
concentrated to give 2-(2,6-dioxopiperidin-3-y1)-4-methoxy-6-(piperazin-1-
yl)isoindoline-1,3-
dione as a brown oil.
[0538] LC-MS (ES+): m/z 373.05 [MH+], tR = 0.155 min (2.0 minute run).
[0539] 7. Synthesis of 6-14-(14-12-(2,6-dioxopiperidin-3-y1)-7-methoxy-1,3-
dioxo-2,3-
dihydro-1H-isoindo1-5-yllpiperazin-1-yllmethyl)piperidin-1-y11-N-1(1r,40-4-(3-
chloro-4-
cyanophenoxy)cyclohexyllpyridazine-3-carboxamide
[0540] Into a 100-mL round-bottom flask, was placed 2,2,2-
trifluoroacetaldehyde;
dioxopiperidin-3-y1)-4-methoxy-6-(piperazin-1-y1)-2,3-dihydro-1H-isoindole-1,3-
dione (130 mg,
0.28 mmol, 1.078 equiv), dichloromethane (10 mL, 0.12 mmol), 6-(4-
formylpiperidin-1-y1)-N-
R1r,40-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (120 mg,
0.26 mmol,
1 equiv), NaBH(OAc)3 (163.4 mg, 0.77 mmol, 3.006 equiv). The resulting
solution was stirred
for 2 hr at 25 C. The resulting solution was diluted with dichloromethane (30
mL). The
resulting mixture was washed with H20 (30 mL x 3). The mixture was dried over
anhydrous
sodium sulfate and concentrated under vacuum. The resulting mixture was
concentrated under
vacuum. The residue was applied onto a silica gel column with
dichloromethane/ethyl acetate
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(3:1). The crude product was purified by Prep-HPLC with the following
conditions: Column,
)(Bridge Prep C18 OBD Column, 5um,19*150mm; mobile phase, Water (10 mmol/L
NH4HCO3)
and acetonitrile (43% Phase B up to 65% in 8 min); Detector, uv. This resulted
in 70 mg
(33.11%) of 644-([442-(2,6-dioxopiperidin-3-y1)-7-methoxy-1,3-dioxo-2,3-
dihydro-1H-
isoindo1-5-yl]piperazin-1-yl]methyl)piperidin-1-y1]-N-R1r,4r)-4-(3-chloro-4-
cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide as a yellow solid.
[0541] 1H NMR (400 MHz, DMSO-d6) 6 11.04(s, 1H), 8.57 (d, J= 8.4Hz, 1H),
7.87-7.79
(m, 2H), 7.39-7.32 (m, 2H), 7.15-7.12 (m, 1H), 6.96 (s, 1H), 6.68 (s, 1H),
5.04-4.98 (m, 1H),
4.50-4.47 (m, 3H), 4.93-3.85 (m, 4H), 3.35-3.33 (m, 5H), 3.07 ¨2.81 (m, 3H),
2.51 (s, 3H),
2.27 ¨22.1 (m, 2H), 2.09 ¨2.01 (m, 2H), 2.00¨ 1.49(m, 11H), 1.23¨ 1.11(m, 3H);
LC-MS
(ES+): m/z 824.25/826.25 [MH+], tR = 182 min (3.0 minute run).
[0542] Chemical Formula: C42H46C1N907 [823.32/825.32]
[0543] Total H count from HNMR data: 46.
[0544] Exemplary Synthesis of Exemplary Compound 34
ci 0 0 0 0
NH
/INIH
Nj
rac-N-((1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-4-(4-
((4-(2'-(2,6-
dioxopiperidin-3-y1)-3'-oxospiro[cyclopropane-1,1'-isoindolinl-6'-y1)piperazin-
1-
y1)methyl)piperidin-1-y1)benzamide
[0545] Synthetic scheme:
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CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
0
0 0 1.s0012,70.c...
HO OH 2.I3r2,70 C ? 0
3.Me0H,0 C Br I
0 0 elL.-"M"-IL'o d
0 (-NH
&....,..,) ,
ith.. 0 TiO-PrO)4 NH I Br I N
F0
DIEA, DMSO r----N -IP- . .N THF, EtMgBr r----N NaH,
DMF, 30 C, 12 h BoeN."--) id
Boo' N --*--) >101N,..] 0
0 0 0 0 0 0
0 0
IOH iNH2 NiOH
till
Na0H,THF N Urea, NMP N
_,..._ (---N _._ r-N + rrii + N 0
Me0H, H20 ,N,...) 0H 160 C, 2 h
Boc,N, j (----N
Boc OH Boc--N----.2 NH'
o o o
o o oH
_L
OH H
N IH ardioxane N¨LN:1 0
(---N
MeCN, C 90 , 3 h r---N
r.---N
Boc'N'") NH2 HN,)
BoeN.---)
0
0 o
CI N 111 OHO,
0 0
NH
110 11 NaBH , DC C, 12.5 h N*
0 CI (Ac0)2 TEA, E, 30 Na.....,N01
[0546] Step 1: Synthesis of dimethyl 2-bromopentanedioate
o o i.soci2,7o c
HO OH 2.Br2,70 C 0
I 0
I
3.Me0H,0 C Br
[0547] To a solution of glutaric acid (30 g, 227.07 mmol, 1 eq) in
chloroform (90 mL) was
added thionyl chloride (59 g, 499.56 mmol, 36 mL, 2.2 eq). The mixture was
stirred at 70 C for
1 h. Liquid bromine (36.29 g, 227.07 mmol, 1 eq) was added into the mixture
dropwise. The
mixture was stirred at 70 C for 12 h. The mixture was cooled to 0 C and
methanol (58 g, 1.82
mol, 73 mL, 8 eq) was added into the mixture drop wise at 0 C. LCMS detected
the desired
product. The mixture was extracted with ethyl acetate (150 mL x 3) and washed
with saturated
aqueous sodium bicarbonate (200 mL). The organic layer was dried over
anhydrous sodium
sulfate and concentrated. The residue was purified with Flash C18 column
chromatography
(acetonitrile: water = 1:0 to 1:1). Dimethyl 2-bromopentanedioate (4g+20 g
(crude), 16.73 mmol,
7% yield) was obtained as a yellow oil.
[0548] LCMS: MS (ESI) m/z: 241.0 [M+1] +.
[0549] Chemical Formula: C7HilBr04, Molecular Weight: 239.06
243
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[0550] '11 NMR: (400 MHz, DCC13) 6: 4.39 - 4.36 (m, 1H), 3.78 (s, 3H), 3.72
(s, 3H), 2.56 -
2.49 (m, 2H), 2.44 - 2.34 (m, 1H), 2.33 - 2.23 (m, 1H).
[0551] Total H count from HNMR data: 11.
[0552] Step 2: Synthesis of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)
phenyl)piperazine-l-carboxylate
rNH
Boc'N'')
DIEA, DMSO
N
BocN -
[0553] To a solution of methyl 2-cyano-4-fluoro-benzoate (10 g, 55.82 mmol,
1 eq), tert-
butyl piperazine-l-carboxylate (12.48 g, 66.98 mmol, 1.2 eq) in
dimethylsulfoxide (100 mL) was
added diisopropylethylamine (28.86 g, 223.28 mmol, 4 eq). The reaction mixture
was stirred at
120 C for 12 h. Thin layer chromatography (petroleum ether: Ethyl acetate =
3:1) showed
methyl 2-cyano-4-fluoro-benzoate was consumed, and desired product was
detected. The
mixture was poured into water (50 mL), and filtered. The filtrate was dried
under vacuum. The
residue was purified with silica gel column chromatography (petroleum ether:
ethyl acetate =
10:1 to 3:1). Tert-butyl 4-(3-cyano-4-methoxycarbonyl-phenyl)piperazine-1-
carboxylate (18 g,
52.11 mmol, 93% yield) was obtained as a yellow solid.
[0554] Chemical Formula: C18H23N304, Molecular Weight: 345.39
[0555] Step 3: Synthesis of tert-butyl 4-(1'-oxospiro[cyclopropane-1,3'-
isoindolinel-5'-
y1)piperazine-1-carboxylate
0 Ti(i-PrO)4 NH
THF, EtMgBr
Boc,Nj >.0yNj
[0556] To a solution of tert-butyl 4-(3-cyano-4-methoxycarbonyl-
phenyl)piperazine-1-
carboxylate (18 g, 52.11 mmol, 1 eq) in tetrahydrofuran (200 mL) was added
tetraisopropyl
titanate (17.77 g, 62.54 mmol, 1.2 eq) and a solution of ethyl magnesium
bromide in
tetrahydrofuran (2 M, 52.11 mL, 2 eq) at 0 C. The mixture was stirred at 25
C for 1 h. Thin
layer chromatography (petroleum ether: ethyl acetate = 1:1) showed tert-butyl
4-(3-cyano-4-
methoxycarbonyl-phenyl)piperazine-1-carboxylate was consumed, and desired
product was
detected. The mixture was added into saturated aqueous ammonuim chloride (150
mL). The
244
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mixture was extracted with ethyl acetate (100 mL x 3). The organic layer was
dried over sodium
sulfate and concentrated. The residue was triturated with ethyl acetate (30
mL) and filtered. Tert-
butyl 4-(1'-oxospiro[cyclopropane-1,3'-isoindoline]-5'-yl)piperazine-1-
carboxylate (6 g, 17.47
mmol, 33% yield) was obtained as a yellow solid.
[0557] Chemical Formula: C19H2503N3, Molecular Weight: 343.42
[0558] NMR: (400 MHz, CDC13) 6: 7.75 ¨ 7.73 (d, J=8.8 Hz, 1H), 6.97 ¨ 6.95
(d, J=8.8
Hz, 1H), 6.94 ¨ 6.85 (m, 1H), 6.41 (s, 1H), 3.61 - 3.58 (t, J=4.8 Hz, 4H),
3.28 - 3.25 (t, J=4.8 Hz,
4H), 1.56 (s, 2H), 1.49 (s, 9H), 1.38 ¨ 1.36 (m, 2H).
[0559] Total H count from HNMR data: 25.
[0560] Step 4: Synthesis of dimethyl 2-16'-(4-tert-butoxycarbonylpiperazin-
1-y1)-3'-oxo-
Spiro Icyclopropane-1,1'-isoindoline1-2'-y11pentanedioate
0 0 0 o
0)CYL0
NH Br I
NaH, DMF, 30 C, 12 h
Boc,Nj
>0yNj
0
0 0
[0561] 20 batches in parallel:
[0562] To a solution of tert-butyl 4-(1'-oxospiro[cyclopropane-1,3'-
isoindoline]-5'-
yl)piperazine-1- carboxylate (100 mg, 0.29 mmol, 1 eq) and dimethyl 2-
bromopentanedioate
(104 mg, 0.44 mmol, 1.5 eq) in dimethylformamide (2 mL) was added sodium
hydride (35 mg,
0.88 mmol, 60% in mineral oil, 3 eq). The mixture was stirred at 30 C for 12
h. Thin layer
cromatography (petroleum ether: ethyl acetate = 1:1) showed 30% of the tert-
butyl 4-(1'-
oxospiro[cyclopropane-1,3'-isoindoline]-5'-yl)piperazine-1-carboxylate was
consumed. The 20
reaction mixtures were poured into 50 mL of brine, and extracted with ethyl
acetate (30 mL x 2),
the combined organic layers were dried over anhydrous sodium sulfate, filtered
and concentrated
in vacuum. The residue was purified by silica gel column chromatography
(petroleum ether/
ethyl acetate=3/1 to 1/1). Dimethyl 2-[6'-(4-tert-butoxycarbonylpiperazin-1-
y1)-3'-oxo-
spiro[cyclopropane-1,1'-isoindoline]-2'-yl]pentanedioate (200 mg, 0.40 mmol,
10% yield
corrected for recovered starting material) was obtained as a yellow oil. Also
isolated was tert-
butyl 4-(1'-oxospiro[cyclopropane-1,3'-isoindoline]-5'-yl)piperazine-1-
carboxylate (675 mg).
[0563] Chemical Formula: C26H35N307, Molecular Weight: 501.57
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[0564] Step 5: Synthesis of 2-16'-(4-tert-butoxycarbonylpiperazin-l-y1)-3'-
oxo-
Spiro Icyclopropane-1,1'-isoindoline1-2'-y11pentanedioic acid
o o o o
Na0H,THF
rN (N
0H, H20 N)
BoeN 0 Me Boe OH
0
[0565] To a solution of dimethyl 246'-(4-tert-butoxycarbonylpiperazin-1-y1)-
3'-oxo-spiro
[cyclopropane-1,1'-isoindoline]-2'-yl]pentanedioate (800 mg, 1.59 mmol, 1 eq)
in
tetrahydrofuran (5 mL) and methanol (5 mL) was added a solution of sodium
hydroxide (255 mg,
6.38 mmol, 4 eq) in water (3 mL). The mixture was stirred at 25 C for 2 hr.
LCMS showed the
reaction was completed and desired MS was detected. The mixture together with
the other batch
was poured into 20 mL water, and adjusted the pH to 3.0 with 2.0 N
hydrochloride acid, then
extracted with ethyl acetate (30 mL x 3). The combined organic layers were
dried over
anhydrous sodium sulfate, then concentrated in vacuum. 246'-(4-tert-
butoxycarbonylpiperazin-1-
y1)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]pentanedioic acid (740
mg, 1.56 mmol,
97% yield) as an off-white solid was obtained, which was directly used for the
next step without
further purification.
[0566] LCMS: MS (ESI) m/z: 474.3[M+1]
[0567] Chemical Formula: C24H31N307, Molecular Weight: 473.52
[0568] Step 6: Synthesis of 5-amino-4-16'-(4-tert-butoxycarbonylpiperazin-l-
y1)-3'-oxo-
spiro[cyclopropane-1,1'-isoindolinel-2'-y11-5-oxo-pentanoic acid; 5-amino-2-
16'-(4-tert-
butoxycarbonylpiperazin-l-y1)-3'-oxo-spiro[cyclopropane-1,1'-isoindolinel-2'-
y11-5-oxo-
pentanoic acid and tert-butyl 4-12'-(2,6-dioxo-3-piperidy1)-1 '-oxo-
spiro[cyclopropane-1,3'-
isoindolinel-5'-yllpiperazine-1-carboxylate
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00 00 00
iNH2
iON
Urea, NMP
160 C, 2 ____________________ ho-
Boc, N)
Boc'N OH Boc'rsi) OH
NH2
0 0 0
00
NH
Boc-N)
[0569] A mixture of 246'-(4-tert-butoxycarbonylpiperazin-l-y1)-3'-oxo-
spiro[cyclopropane-
1,1'-isoindoline]-2'-yl]pentanedioic acid (400 mg, 0.85 mmol, 1 eq) and urea
(253 mg, 4.22
mmol, 5 eq) in 1-methyl-2-pyrrolidinone (4 mL) was heated to 160 C and
stirred at 160 C for 2
hours. LCMS showed two peaks with desired MS signals. The mixture together
with the other
batch was filtered. The filtrate was further purified by Semi-preparative
reverse phase HPLC
(column: Boston Green ODS 150*30 5 um; mobile phase: [water (0.225% formic
acid)-
acetonitrile]; B%: 35%-45%, 10 min). 2 isomeric mono-amides 5-amino-446'-(4-
tert-
butoxycarbonylpiperazin-1-y1)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-
y1]-5-oxo-
pentanoic acid and 5-amino-2-[6'-(4-tert-butoxycarbonylpiperazin-1-y1)-3'-oxo-
spiro[cyclopropane-1,1'-isoindoline]-2'-y1]-5-oxo-pentanoic acid were obtained
(170 mg, 0.36
mmol, 42% yield and 90 mg, 0.19 mmol, 22% yield respectively. It was not
conclusively
established which of the 2 isomeres corresponds to which structure.) Also
isolated was tert-butyl
442'-(2,6-dioxo-3-piperidy1)-1'-oxo-spiro[cyclopropane -1,3'-isoindoline]-5'-
yl]piperazine-1-
carboxylate (90 mg, 0.20 mmol, 23% yield) as an off-white solid.
[0570] LCMS: mono-amide product 1: MS (ESI) m/z: 473.1[M+1] +, Mono-amide
product
2: MS (ESI) m/z: 473.1[M+1] Imide product 3: MS (ESI) m/z: 455.1[M+1]
[0571] Chemical Formula mono-amide product 1: C24H32N406, Molecular Weight:
472.53.
[0572] Chemical Formula mono-amide product 2: C24H32N406, Molecular Weight:
472.53.
[0573] Chemical Formula Imide product: C24H30N405, Molecular Weight:
454.52.
[0574] Step 7a: Synthesis of 3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane
-1,1'-
isoindoline1-2'-yl)piperidine-2,6-dione from the mono-amide product 1 of step
6
247
CA 03095912 2020-10-01
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N\-1s1F0
NcN
MeCN, 90 C, 3 h
Bocisk) NH2 His)
0
[0575] To a mixture of 5-amino-246'-(4-tert-butoxycarbonylpiperazin-1-y1)-
3'-oxo-spiro
[cyclopropane-1,1'-isoindoline]-2'-y1]-5-oxo-pentanoic acid (190 mg, 0.40
mmol, 1 eq, the first
eluting mono-amide product from above) in acetonitrile (15 mL) was added
benzenesulfonic acid
(114 mg, 0.72 mmol, 1.80 eq) in one portion at 25 C under nitrogen
atmosphere. The mixture
was stirred at 90 C for 3 hours. LCMS showed the product was the main peak.
The mixture was
concentrated in vacuum. The residue was purified by Semi-preparative reverse
phase HPLC
(column: Boston Green ODS 150*30 5 um; mobile phase: [water (0.225% formic
acid)-
acetonitrile]; B%: 1%-27%, 10 min). The product 3-(3'-oxo-6'-piperazin-1-yl-
spiro[cyclopropane-1,1'-isoindoline]- 2'-yl)piperidine-2,6-dione (55 mg, 0.14
mmol, 34% yield,
benzene sulfonate) was obtained as a brown solid.
[0576] LCMS: EW4875-628-P1B, MS (ESI) m/z: 355.1[M+1]
[0577] Chemical Formula: C19H22N403, Molecular Weight: 354.40.
[0578] Step 7b: Synthesis of 3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane
-1,1'-
isoindoline1-2'-yl)piperidine-2,6-dione from the imide product of step 6
0 0
0 0
N 2-0 HCIoxane
DCM r-NN
0
Boc,N) HNxõ)
[0579] To a mixture of tert-butyl 442'-(2,6-dioxo-3-piperidy1)-1'-oxo-
spiro[cyclopropane -
1,3'-isoindoline]-5'-yl]piperazine-l-carboxylate (90 mg, 0.20 mmol, 1 eq) in
dichloromethane (5
mL) was added hydrochloric acid (4 M in dioxane, 2.5 mL, 50 eq) in one portion
at 25 C. The
mixture was stirred at 25 C for 1 hour. LCMS showed the product was the main
peak. The
mixture was concentrated in vacuum. The crude solid The product 3-(3'-oxo-6'-
piperazin-1-yl-
spiro[cyclopropane-1,1'-isoindoline]-2'-yl)piperidine-2,6-dione (70 mg, 0.18
mmol, 90% yield,
hydrochloride) was obtained as a brown solid, which was directly used into the
next step without
further purification.
[0580] LCMS: MS (ESI) m/z: 355.1[M+1]
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CA 03095912 2020-10-01
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PCT/US2019/026570
[0581] Chemical Formula: C19H22N403, Molecular Weight: 354.40
[0582] Step 8: Synthesis of N-13-(3-chloro-4-cyano-phenoxy)-2,2,4,4-
tetramethyl-
cyclobuty11-4-14-114-12'-(2,6-dioxo-3-piperidy1)-r-oxo-spiro[cyclopropane-1,3'-
isoindolinel-
5'-yllpiperazin-1-yllmethyll-1-piperidyllbenzamide
*
rN
=
NaBH(Ac0)3, TEA, DCE, 30 C, 12.5 h 'NH0
Nia.õ01 0
0 (3 CI
[0583] To a solution of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-
cyclobuty1]-4-
(4- formy1-1-piperidyl)benzamide (63 mg, 0.12 mmol, 1 eq) in 1,2-
dichloroethane (3 mL) was
added triethylamine (38 mg, 0.38 mmol, 3 eq) and 3-(3'-oxo-6'-piperazin-1-yl-
spiro[cyclopropane-1,1'-isoindoline]-2'-yl)piperidine-2,6-dione (50 mg, 0.12
mmol, 1 eq,
hydrochloride). The mixture was stirred at 30 C for 30 min. Sodium
triacetoxyborohydride (54
mg, 0.25 mmol, 2 eq) was added, then the mixture was stirred at 30 C for 12
hours. LCMS
showed the reaction was completed and desired MS can be detected. The reaction
mixture was
concentrated under reduced pressure to remove solution. The residue was
purified by Semi-
preparative reverse phase HPLC (column: Phenomenex Synergi C18
150*25*10um;mobile
phase: [water(0.225%FA)-ACN];B%: 40%-70%,10min) to give N43-(3-chloro-4-cyano-
phenoxy)-2,2,4,4-tetramethyl-cyclobuty1]-4-[44[442'-(2,6-dioxo-3-piperidy1)-1'-
oxo-
spiro[cyclopropane-1,3'-isoindoline]-5'-yl]piperazin-1-yl]methy1]-1-
piperidyl]benzamide (17.8
mg, 0.02 mmol, 16% yield, 98% purity) as a white solid.
[0584] LCMS: MS (ESI) m/z: 932.3 [M+1]
[0585] NMR:
(400MHz, DMSO-d6) 6: 10.88 (s, 1H), 8.22 (s, 1H), 7.91 (d, J=8.8 Hz,
1H), 7.74 (d, J=8.8 Hz, 2H), 7.53 - 7.45 (m, 2H), 7.21 (d, J=2.4 Hz, 1H), 6.99
(dd, J=9.2, 17.6
Hz, 4H), 6.73 (s, 1H), 4.33 (s, 1H), 4.06 (d, J=9.2 Hz, 1H), 3.86 (d, J=12.4
Hz, 3H), 3.32 - 3.29
(m, 9H), 2.80 (t, J=12.0 Hz, 3H), 2.59 - 2.54 (m, 4H), 2.22 (d, J=6.8 Hz, 2H),
1.81 (d, J=10.3 Hz,
4H), 1.55 - 1.47 (m, 2H), 1.45 - 1.31 (m, 2H), 1.25 - 1.17 (s, 8H), 1.13 (s,
6H).
[0586] Chemical Formula: C47H54C1N705, Molecular Weight: 832.43.
[0587] Total H count from HNMR data: 54.
[0588] C. Exemplary Synthetic Schemes for Exemplary Androgen Receptor
Binding
Moiety Based Compounds that are Imide Isosteres
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CA 03095912 2020-10-01
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[0589] General Synthetic Scheme C-1
[0590] Synthesis of building block N-((1r,30-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobuty1)-6-(piperazin-1-yl)nicotinamide
CI N)* 0
N H I
NH
[0591] Synthetic Scheme
NH2 HCI
roN,Boc
><
N
0 ci digik
0 Boc HO N __ HO)", N 0
NC
)"1 H
DMA, DIPEA, 130 C, o/n HATU, DIPEA, DCM
CI
65% Boc rt, o/n
86%
CI
CN
CI la 0
NC tW N)"N
HCI, 1,4-dioxanme H
rt, 4 h
100%
[0592] Step 1: Synthesis of 6-(4-(tert-butoxycarbonyl)piperazin-l-
yl)nicotinic acid
0
Boc,N
0 HON
NH
HO N
DMA, DIPEA, 130 C, o/n N,Boc
65%
[0593] 6-Chloronicotinic acid (1.6 g, 10.0 mmol) was dissolved in N,N-
dimethylacetamide
(15 mL), and tert-butyl piperazine-l-carboxylate (1.9 g, 10.0 mmol) and
ethyldiisopropylamine
(2.6 g, 20 mmol) were added thereto, followed by stirring at 130 C overnight.
The reaction
mixture was concentrated under reduced pressure, and to the obtained residue
was added a 1 M
aqueous NaOH solution (10 mL), followed by washing with CHC13 (50 mL). The pH
of the
aqueous layer was adjusted to around 6 to 7 by the addition of 1 M
hydrochloric acid, followed
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CA 03095912 2020-10-01
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by extraction with CHC13 (50 mL x 3). The organic layer was dried over
anhydrous sodium
sulfate and the solvent was concentrated under reduced pressure. The obtained
residue was
purified by silica gel column chromatography (CH2C12/Me0H = 10/1) to give 6-(4-
(tert-
butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g, 65 % yield) as a white
solid.
[0594] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50
mm*4.6
mm*3.51.tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3C1\1] in 1.6 min, then under this condition for 1.4 min, finally changed
to 95% [water + 10
mM NH4HCO3] and 5% [CH3C1\1] in 0.1 min and under this condition for 0.7 min).
Purity is
83.17%, Rt = 1.312 min; MS Calcd.: 307.15; MS Found: 308.2 [M+H]t
[0595] Chemical Formula: C15H211\1304, Molecular Weight: 307.34.
[0596] Step 2: Synthesis of tert-butyl 4-(5-((lr,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine-l-carboxylate
NH2 HCI
>o<
0 CI 0
HO)"1 N CI 401
NC
HATU, DIPEA, DCM NC H
Boc rt, o/n
86%
KN.
Boc
[0597] A mixture of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid
(614 mg, 2.0
mmol), 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile
hydrochloride
(630 mg, 2.0 mmol), 2-(7-Aza-1H-benzotriazole-1-y1)-1,1,3,3-tetramethyluronium
hexafluorophosphate (1.1 g, 3.0 mmol) and ethyldiisopropylamine (516 mg, 4.0
mmol) in
dichloromethane (20 mL) was stirred at room temperature overnight. Water (50
mL) was added
and extracted with dichloromethane (50 mL x 3). Combined organic layers were
washed by brine
(50 mL x 2), dried over anhydrous sodium sulfate. The solvent was concentrated
to give the
residue, which was purified by column chromatography on silica gel (petroleum
ether/ethyl
acetate = 1/1) to give tert-butyl 4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate (977 mg,
86 % yield) as
a white solid.
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CA 03095912 2020-10-01
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[0598] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50
mm*4.6
mm*3.5 pm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min).
Purity is
88.26%, Rt = 2.161 min; MS Calcd.: 567.26; MS Found: 568.3 [M+H]t
[0599] 1-H NMR (400 MHz, DMSO-d6) 61.12 (6H, s), 1.22 (6H, s), 1.43 (9H,
s), 3.42-3.44
(4H, m), 3.60-3.63 (4H, m), 4.02-4.07 (1H, m), 4.31 (1H, s), 6.88 (1H, d, J=
8.8 Hz), 7.00 (1H,
dd, J= 8.4, 2.4 Hz), 7.21 (1H, d, J= 2.4 Hz), 7.65 (1H, d, J= 9.2 Hz), 7.91
(1H, d, J= 8.8 Hz),
7.99 (1H, dd, J= 8.8, 2.4 Hz), 8.64 (1 H, d, J= 2.4 Hz).
[0600] Chemical Formula: C30H38C1N504, Molecular Weight: 568.11.
[0601] Total H count from HNMR data: 38.
[0602] Step 3: Synthesis of N-((lr,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(piperazin-l-y1)nicotinamide hydrochloride
o
N
NC = HCI, 1,4-dioxane N1)"N
H
rt, 4 h
100%
[0603] A mixture of tert-butyl 4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobutyl carbamoyl)pyridin-2-yl)piperazine-1-carboxylate (405 mg,
0.7 mmol) in
HC1/1,4-dioxane (10 mL) was stirred at room temperature for 4 h. The solvent
was removed in
vacuum to give N-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-
(piperazin-1-yl)nicotinamide hydrochloride (353 mg, 100 % yield) as a white
solid.
[0604] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50
mm*4.6
mm*3.5 pm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min).
Rt = 1.791
min; MS Calcd.:467.21; MS Found: 468.3 [M+H]t
[0605] Chemical Formula: C25H31C12N502, Molecular Weight: 504.45
[0606] General Synthetic Scheme C-2
[0607] Synthesis of building block tert-butyl 4-(4-formylpiperidin-1-
yl)benzoate
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0
) 0 = NI/ )
0
[0608] Synthetic scheme:
OH
OH
F r) N
HN
>0
DMSO, 120 C, o/r:- >0
0 0
91.2%
DMP, DCM, ) 0 0
N
rt, 1 h 0
81%
[0609] Step 1: Synthesis of tert-butyl 4-(4-(hydroxymethyl)piperidin-1-
yl)benzoate
OH
OH r)
F r) N
HN
>0
DMSO, 120 C, oin >0
0 0
91.2%
[0610] To a solution of tert-butyl 4-fluorobenzoate (23 g, 0.12 mmol) in
DMSO (100 mL)
was added piperidin-4-ylmethanol (40.5 g, 0.35 mmol). The mixture was heated
to 120 C
overnight under nitrogen. After cooling to room temperature, water (50 mL) was
added to the
reaction mixture, and extracted with ethyl acetate (20 mL x 3). The organic
layer was washed
with brine (15 mL x 3). The combined organic phases were dried over anhydrous
sodium sulfate
and concentrated in vacuo, and purified by CC (PE/EA = 10:1) to give compound
tert-butyl 4-(4-
(hydroxymethyl)piperidin-1-yl)benzoate (31g, 91.2%) as a white solid.
[0611] LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6 mm
x 3.5 [tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 90%
[(total 10mM AcONH4) water/CH3CN=900/100 (v/v)] and 10% [(total 10mM AcONH4)
water/CH3CN=100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN=900/100
(v/v)]
and 90% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 1.6 min, then under
this
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condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4)
water/CH3CN=900/100
(v/v)] and 10% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 0.1 min and
under this
condition for 0.7 min). Purity is 99.57%, Rt = 2.035 min.; MS Calcd.: 291.2;
MS Found: 292.2
[M+H]+.
[0612] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm x 4.6
mm x 3.5
1.tm); Column Temperature: 40 C; Flow Rate: 1.0 mL/min; Mobile Phase: from
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in
10
min, then under this condition for 5 min, finally changed to 95% [water + 10
mM NH4HCO3]
and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity is
93.27%, Rt = 9.542
min.
[0613] .. 1H NMR (400 MHz, CDC13) 6 1.29-1.40 (2H, m), 1.49 (1H, d, J= 5.4
Hz), 1.57 (9H,
s), 1.70-1.75 (1H, m), 1.82 (2H, d, J= 12.8 Hz), 2.80-2.87 (2H, m), 3.53 (2H,
t, J= 5.8 Hz),
3.87-3.90 (2H, m), 6.85 (2H, d, J = 9.2 Hz), 7.84 (2H, d, J= 9.2 Hz).
[0614] Chemical Formula: C17H25NO3, Molecular Weight: 291.39.
[0615] Total H count from HNMR data: 25.
[0616] Step 2: Synthesis of tert-butyl 4-(4-formylpiperidin-1-yl)benzoate
) 0 0 rt, =
/OH DMP, __ 1 DCM,
0
) 0 =
N11-)
h
81%
[0617] To a solution of tert-butyl 4-(4-(hydroxymethyl)piperidin-1-
yl)benzoate (300 mg,
1.03 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (1.31
g, 3.09
mmol) slowly at 0 C. The reaction mixture was stirred at room temperature for
1 h. Then
filtered, and concentrated in vacuo to give compound tert-butyl 4-(4-
formylpiperidin-1-
yl)benzoate (240 mg, 81%) as a pale yellow solid.
[0618] Exemplary Synthesis of Exemplary Compound 46
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H
u
_ ON 0
;-j
N
rNwo
N H N
N
;,s 00' 0 N
N-((1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-6-(4-(5-
((2-(2,6-
dioxopiperidin-3-y1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-
yl)oxy)pentyl)piperazin-1-
yl)nicotinamide
[0619] Synthetic Scheme
>:c.,,
13
0 ---\,...--...:.--
0 0 0 0
101 OH H2SO4(cat.), MeOFI
________ /10 0"-- Cs2CO3, Pd
(Ph3P)4 e
0s04, Nal04 e
.-
0 Br 90 C, 16 h 0
Br DMF/H20=10/1 ,C) MeCN:acetone:F120(1:1:1) 0
.
91% 100 C, 4 h \ r.t, 4 h
0
100% 35%
0
Hij.....)
0 0 0
NH C1-...,_...---
..õ....--0,g,
H2N¨t 0 Ha H H 0 0
N
N 0 Cr 0
0N.,,0 0 U
TEA, AcOH, NaBH3CN 0 ----- BBr3, DCM, -78 C to rt.
C0
K23, DMF, 40 C, o/n N- 0/fl 411*
Me0H, 0-rt, o/n ___________________ . . N
HO
st) 38% 23% 0
59%
(-NH /0
N...
HyCY4 CI
N \ N
N
\\
CI I.1 ;):r ID
,. CI* NON 0 0
N
N
DIEA, KI, CH3CN, 100 C 0`" el¨ ¨\--\\O . N H
o
sealed tube 0
8%
[0620] Step 1: Synthesis of methyl 2-bromo-4-methoxybenzoate
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0 0
OH H2SO4(cat.), Me0H 110
Br 90 C, 16 h so Br
91%
[0621] To a solution of 2-bromo-4-methoxybenzoic acid (5.0 g, 21.7 mmol) in
methanol (50
mL) was added 98% sulfuric acid (0.5 m1). The reaction mixture was heated to
90 C for 16 h
under nitrogen gas, and concentraction under reduced pressure. After cooling
to room
temperature, sodium bicarbonate (2.0 M) was added to adjust PH=8. Thus was
extracted with
ethyl acetate (50 mL x 3). The organic layer was washed with brine (30 mL).
The combined
organic phases were dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo to
give 2-bromo-4-methoxybenzoate (4.8 g, 91%) as yellow oil.
[0622] Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x 4.6 mm
x 3.5
pm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase: from 90%
[(total
10mM AcONH4) water/CH3CN=900/100 (v/v)] and 10% [(total 10mM AcONH4)
water/CH3CN=100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN=900/100
(v/v)]
and 90% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 1.6 min, then under
this
condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4)
water/CH3CN=900/100
(v/v)] and 10% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 0.1 min and
under this
condition for 0.7 min. Purity is 98.94%, Rt = 2.609 min; MS Calcd.: 243.97; MS
Found: 245.0
[M+H]
[0623] Step 2: Synthesis of methyl 2-ally1-4-methoxybenzoate
0,
0 0
0 cs2c 3, pd(Ph3P)4
Br DMF/H20=10/1
100 C, 4 h
100%
[0624] To a solution of methyl 2-bromo-4-methoxybenzoate (3.0 g, 12.3
mmol), cesium
carbonate (12.0 g, 36.9 mmol), 2-ally1-4,4,5,5-tetramethy1-1,3,2-dioxaborolane
(2.98 g, 18.5
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mmol) in N,N-dimethylformamide /water (30.0 mL/3.0 mL) was added
tetrakis(triphenylphosphine)palladium (1.42 g, 1.23 mmol) under nitrogen
atmosphere. The
reaction mixture was heated to 100 C and stirred for 4 h. The resulting
reaction was
concentrated under reduced pressure, and then water (10 mL) was added. The
mixture was
extracted with ethyl acetate (50 mL x 3). The combined organic phase was
washed with brine (20
mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified
by silica gel chromatography column (petroether/ethyl acetate = 4:1) to give
the methyl 2-ally1-
4-methoxybenzoate (2.6 g, 100%) as yellow oil.
[0625] Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm x 4.6 mm
x 3.5
lm); Column Temperature: 40 C; Flow Rate: 1.5 mL/min; Mobile Phase: from 95%
[water +
0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100%
[CH3CN +
0.05 TFA] in 1.5 min, then under this condition for 0.5 min, finally changed
to 95% [water +
0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.1 min and under this condition for
0.5 min.
Purity is 96.85%, Rt = 1.293 min; MS Calcd.: 206.09; MS Found:207.3 [M+H]t
[0626] Step 3: Synthesis of methyl 4-methoxy-2-(2-oxoethyl)benzoate
0 0
0 0504, Na104
0 MeCN:acetone:H20(1 :1 :1)
rt, 4 h
35% 0
[0627] To a solution of methyl 2-ally1-4-methoxybenzoate (1.20 g, 5.83
mmol) and osmium
tetraoxide (5 mg) in acetonitrile, acetone, and water (v: v: v=10 mL: 10 mL:
10 mL) was added
sodium periodate (4.99 g, 23.3 mmol) at 0 C. The mixture was stirred at room
temperature for 4
h. The mixture was filtered through a pad of celite and extracted with ethyl
acetate (20 x 3 mL).
The organic layer was separated, washed with water and brine, dried over
anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by prep-TLC
(petroether/ethyl
acetate = 4:1) to give compound methyl 4-methoxy-2-(2-oxoethyl)benzoate (420
mg, 35%) as
yellow oil.
[0628] LC-MS (Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm x
4.6
mm x 3.5 lm); Column Temperature: 40 C; Flow Rate: 1.5 mL/min; Mobile Phase:
from 95%
[water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and
100%
[CH3CN + 0.05 TFA] in 1.5 min, then under this condition for 0.5 min, finally
changed to
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95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.1 min and under this
condition
for 0.5 min.). Purity is 96.26%, Rt = 1.007 min; MS Calcd.: 208.1; MS Found:
209.3 [M+H]
[0629] Step 4: Synthesis of 3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-
yl)piperidine-
2,6-dione
0
NH
0 HCI
0 ONO
TEA, AcOH, NaBH3CN
Me0H, 0¨rt, o/n
59%
[0630] To a solution of methyl 4-methoxy-2-(2-oxoethyl)benzoate (420 mg,
2.02 mmol) in
methanol (6 mL) was added a solution of 3-aminopiperidine-2,6-dione
hydrochloride (397 mg,
2.42 mmol) and triethylamine (245 mg, 2.24 mmol) in methanol (2 mL). The
reaction mixture
was stirred at room temperature for 1 h, then sodium cyanoborohydride (254 mg,
4.04 mmol)
was added at 0 C. The reaction was stirred at room temperature overnight,
water (10 mL) was
added, and extracted with ethyl acetate (20 mL x 3), washed with water and
brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue was purified
by prep-TLC
(dichloromethane/methanol = 20:1) to give 3-(6-methoxy-l-oxo-3,4-
dihydroisoquinolin-2(1H)-
yl)piperidine-2,6-dione (340 mg, 59%) as a pale yellow solid.
[0631] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm x
3 mm
x 2.5 lm); Column Temperature: 40 C; Flow Rate: 1.5 mL/min; Mobile Phase: from
95%
[water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM NH4HCO3] to 5% [water + 10 mM
NH4HCO3] and 95% [CH3CN + 10 mM NH4HCO3] in 1.5 min, then under this condition
for 0.5
min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM
NH4HCO3]
in 0.1 min and under this condition for 0.5 min.). Purity is 80.84%, Rt =
0.924 min; MS Calcd.:
288.1; MS Found: 289.1 [M+H]
[0632] Step 5: Synthesis of 3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-
yl)piperidine-
2,6-dione
0 N 0
0 0NO
0 )j
BBr3, DCM, -78 C to rt.
o/n
HO
0 38%
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[0633] To a solution of 3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-
yl)piperidine-2,6-
dione (220 mg, 0.76 mmol) in dichloromethane (10 mL) was added boron
tribromide (0.5 mL) in
dichloromethane (2 mL) dropwise at -78 C and stirred overnight at room
temperature. The
reaction mixture was added to water (10 mL) and sodium bicarbonate (20 mL),
then extracted
with dichloromethane/ methanol (30 mL x 5). The organic layer was washed with
brine (10 mL).
The combined organic phases were dried over anhydrous sodium sulfate,
filtered, and
concentrated in vacuo . The residue was purified by prep-TLC (dichloromethane/
methano1=10:1)
to give compound 3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-
2,6-dione (80
mg, 38%) as a yellow solid.
[0634] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm x
3 mm
x 2.5 pm); Column Temperature: 40 C; Flow Rate: 1.5 mL/min; Mobile Phase: from
95%
[water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM NH4HCO3] to 5% [water + 10 mM
NH4HCO3] and 95% [CH3CN + 10 mM NH4HCO3] in 1.5 min, then under this condition
for 0.5
min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM
NH4HCO3]
in 0.1 min and under this condition for 0.5 min.). Purity is 96.22%, Rt =
0.736 min; MS Calcd.:
274.1; MS Found: 275.1 [M+H]
[0635] Step 6: Synthesis of 3-(6-(5-chloropentyloxy)-1-oxo-3,4-
dihydroisoquinolin-2(1H)-
yl)piperidine-2,6-dione
0
ONO
0 N 0
-II0 CIOTs
K2CO3, DMF, 40 C, o/n
HO
23% CI
[0636] To a solution of 3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-
yl)piperidine-2,6-
dione (80 mg, 0.292 mmol) in N,N-dimethylformamide (5.0 mL) was added 5-
chloropentyl 4-
methylbenzenesulfonate (64.5 mg, 0.234 mmol) and potassium carbonate (121 mg,
0.876 mmol).
The mixture was heated to 40 C overnight. After cooling to rt., the reaction
mixture was added
to water (10 mL), and extracted with ethyl acetate (20 mL x 3). The organic
layer was washed
with brine (10 mL x 3). The combined organic phases were dried over anhydrous
sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by prep-TLC
(dichloromethane/
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methano1=10:1) to give 3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-
2(1H)-
yl)piperidine-2,6-dione (25 mg, 23%) as a yellow solid.
[0637] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm x
3 mm
x 2.5 lm); Column Temperature: 40 C; Flow Rate: 1.5 mL/min; Mobile Phase: from
95%
[water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM NH4HCO3] to 5% [water + 10 mM
NH4HCO3] and 95% [CH3CN + 10 mM NH4HCO3] in 1.5 min, then under this condition
for 0.5
min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM
NH4HCO3]
in 0.1 min and under this condition for 0.5 min.). Purity is 93.68%, Rt =
1.263 min; MS Calcd.:
378.1; MS Found: 379.1 [M+H]
[0638] Step 7: Synthesis of N-((lr,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(4-(5-(2-(2,6-dioxopiperidin-3-y1)-1-oxo-1,2,3,4-
tetrahydroisoquinolin-
6-yloxy)pentyl)piperazin-l-y1)nicotinamide
NH
H 0 N 0
0 N 0 N N y
0 1- -r
ci 41-P-P 0". 0 0
DIEA, KI, CH3CN, 100 C ,)
Cl sealed tube a H Ir(
8%
N N
Cl 4111111PF 0
[0639] A solution of 3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-
2(1H)-
yl)piperidine-2,6-dione (25 mg, 0.066 mmol) was dissolved in acetonitrile (2
mL), N-((lr,3r)-3-
(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-6-(piperazin-1-
y1)nicotinamide (31
mg, 0.066 mmol), ethyldiisopropylamine (17 mg, 0.132 mmol), potassium iodide
(2 mg) was
added to the solution. The mixture was heated to 100 C for 16 h under sealed
tube. After cooling
to rt., the reaction mixture was added to water (10 mL), and extracted with
ethyl acetate (10 mL
x 3). The organic layer was washed with brine (10 mL x 3). The combined
organic phases were
dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, then
purified by prep-
HPLC to give compound N-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(4-(5-(2-(2,6-dioxopiperidin-3-y1)-1-oxo-1,2,3,4-
tetrahydroisoquinolin-
6-yloxy)pentyl)piperazin-l-yl)nicotinamide (4.1 mg, 8%) as a white solid.
[0640] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6
mm x 3.5 lm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
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[CH3CN] in 3.0 min, then under this condition for 1.0 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.).
Purity is
87.84%, Rt = 2.923 min; MS Calcd.: 809.4; MS Found: 810.3 [M+H]t
[0641] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm x 4.6
mm x 3.5
lm); Column Temperature: 40 C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95%
[water + 10
mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in
10
min, then under this condition for 5 min, finally changed to 95% [water + 10
mM NH4HCO3]
and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity is
84.56%, Rt = 10.161
min.
[0642] 1H NMIR (400 MHz, DMSO-d6) 6 1.12 (6H, s), 1.21 (6H, s), 1.43-1.54
(4H, m), 1.74-
1.78 (2H, m), 1.88-1.91 (1H, m), 2.30-2.44 (8H, m), 2.90-2.97 (3H, m), 3.42-
3.59 (7H, m), 4.03-
4.07 (3H, m), 4.30 (1H, s), 6.86-6.91 (3H, m), 6.99-7.02 (1H, m), 7.22 (1H, d,
J= 2.4 Hz), 7.64
(1H, d, J= 8.8 Hz), 7.79 (1H, d, J= 8.8 Hz), 7.90-7.97 (2H, m), 8.62 (1H, d,
J= 2.0 Hz), 10.90
(1H, s).
[0643] Chemical Formula: C44H52C1N706, Molecular Weight: 810.38.
[0644] Total H count from HNMR data: 52.
[0645] Exemplary Synthesis of Exemplary Compound 47
0
N
N 0
N
N H
N N
CI = 0):r
[0646] N4(1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-
6-(4-(5-
((2-(2,6-dioxopiperidin-3-y1)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-
yl)oxy)pentyl)piperazin-1-yl)nicotinamide
[0647] Synthetic Scheme
261
CA 0 3 0 95912 2 02 0-10-01
WO 2019/199816
PCT/US2019/026570
0 o o
OH 1). THF, LDA, -78 C,- , 0
0 -01e 0 OH
SOCl2 , 0 0" 1) BBrs, DCM, rt, o/n 01$ OH rt. o/ri ,
0
I 0
Me0H, rt, 1h 1 2) NaOH, Me0H, reflused, 5
h HO
0
I 2). Li0H.H20, DMSO, 120 C, 2 h 0 OH 66% 0 0 61% two steps
0 OH
73% two steps
r'PlH
Hip N'..---)
TsOWCI 0 0 CI 10, o'l 0
1). K2CO3, DMSO, 70 C, oh) la e SOCl2 a e
CIO 'W KI, DIEA
' 'W
2) Li0H.H20, Me0H, 9, o/n Me0H, 9, 2 h __________________ CI C) i
44% two steps 0 OH 62% 0 0 DMSO, 70 C,
0/fl
41%
({ 0
I-12N*
HCI
a, OH0 0
N,J
61,:,.,
0 0 Li0H.H20 r)
HATU, DIEA
CI :L riya'
I _____________________________________________________________ 0
Me0H, rt, 3 h N':..' 0 1-11raN---
i DMF, rt, 30 min
110 ():ir
81%
IIII" ;lir 0
CI
H
HC:7'\IN
0 0,y0.0
r-N-,--0 0. N)'"---)
0
2.5 N NaOH
0 0
I DMSO, rt, 5 min N'::' di rilp
42%
CI WI'
CI IP 0:):rN 0
[0648] Step 1: Synthesis of 2-(carboxymethyl)-4-methoxybenzoic acid
0 0
0 0).LO
OH
40 OH 1). THF, LDA, -78 C,¨ it, o/n
0
0 I
I 2). Li0H.H20, DMSO, 120 C, 2 h 0
OH
73% two steps
[0649] To a solution of of 4-methoxy-2-methylbenzoic acid (5.0 g, 30.1
mmol) in dry
tetrahydrofuran (50 mL) was added lithium diisopropylamide in tetrahydrofuran
(1.0
mol/L)(66.3 mL, 66.3 mmol) at -78 C under nitrogen gas. The mixture was left
to stir for 1 hour
at that temperature and then dimethyl carbonate (2.98 g, 33.1 mmol) was added.
The reaction
mixture was left to stir overnight. Water (200 mL) and ethyl acetate (100 mL)
was added. The
aqueous layer was separated, extracted with ethyl acetate (50 mL x 2) and
neutralized with
hydrochloric acid (1 N) until pH < 4. The mixture was extracted with ethyl
acetate (100 mL x 2).
The combined organic layers were washed with saturated brine (50.0 mL x 2),
dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was
dissolved in
dimethyl sulfoxide (40 mL) and lithium hydroxide hydrate (5.06 g, 120.4 mmol)
was added. The
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mixture was stirred at 120 C for 2 hour, cooled down to room temperature and
poured into ice-
water (200 mL). Hydrochloric acid (1 N) was added until pH < 4. The mixture
was extracted
with ethyl acetate (100 mL x 2). The combined organic layers were washed with
saturated brine
(50.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo to give
2-(carboxymethyl)-4-methoxybenzoic acid (4.6 g, 73% two steps) as a yellow
solid.
[0650] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30
mm*4.6
mm*3.5 lm); Column Temperature: 40 C; Flow Rate: 1.5 mL/min; Mobile Phase:
from 95%
[water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] to 0% [water + 0.1% TFA] and 100%
[CH3CN + 0.1% TFA] in 0.5 min, then under this condition for 1.5 min, finally
changed to 95%
[water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] in 0.1 min and under this
condition for 0.5
min). Purity is 94.6%, Rt = 0.774 min; MS Calcd.: 210.1; MS Found: 233.1
[M+23]+.
[0651] Step 2: Synthesis of methyl 4-methoxy-2-(2-methoxy-2-
oxoethyl)benzoate
0 0
OH
SOCl2
0
Me0H, rt, 1h 0
0 OH 66% 0
[0652] To a solution of (2-(carboxymethyl)-4-methoxybenzoic acid (1.2 g,
5.7 mmol) in
methanol (10.0 mL) was added thionyl chloride (1.7 g, 14.3 mmol) dropwise. The
mixture was
refluxed for 2 hour. The mixture was cooled down to room temperature and then
the solvent was
removed in vacuo to give crude product which was purified by column
chromatography on silica
gel (ethyl acetate/ petroleum ether = 1: 1) to give 4-methoxy-2-(2-methoxy-2-
oxoethyl)benzoate(900 mg, 66%) as a white solid.
[0653] Step 3: Synthesis of 2-(carboxymethyl)-4-hydroxybenzoic acid
0 0
1) BBr3, DCM, rt, o/n OH
0
2) NaOH, Me0H, refluxed, 5 h HO
0 C) 61% two steps 0 OH
[0654] To a solution of 4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate (0.9 g,
3.78 mmol) in
dichloromethane (30 mL) was added boron tribromide (4.7 g, 18.9 mmol) dropwise
under ice-
waer bath. The resulting mixture was allowed to warm to room temperature and
stirred overnight.
Water (100 mL) was added. The organic layer was separated, washed with brine
(50 mL x 2),
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dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to
give a mixture. The
mixture was dissolved in methanol (30 mL) and sodium hydroxide (0.76 g, 18.9
mmol) in water
(4.0 mL) was added. The mixture was refluxed for 5 hour. The solvent was
removed. The residue
was dissolved in water (30 mL). Hydrochloric acid (1 N) was added until pH <
4. The mixture
was extracted with ethyl acetate (50 mL x 2). The combined organic layers were
washed with
saturated brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered,
and concentrated in
vacuo to give 2-(carboxymethyl)-4-hydroxybenzoic acid (0.45 g, 61% two steps)
as a yellow
solid.
[0655] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30
mm*4.6
mm*3.5 pm); Column Temperature: 40 C; Flow Rate: 1.5 mL/min; Mobile Phase:
from 95%
[water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] to 0% [water + 0.1% TFA] and 100%
[CH3CN + 0.1% TFA] in 0.5 min, then under this condition for 1.5 min, finally
changed to 95%
[water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] in 0.1 min and under this
condition for 0.5
min). Purity is 95.2%, Rt = 0.570 min; MS Calcd.: 196.0; MS Found: 197.2 [M+H]
[0656] Step 4: Synthesis of 2-(5-(5-chloropentyloxy)-2-
(methoxycarbonyl)phenyl)acetic acid
0
TsOwCIii I 0
OH
1). K2CO3, DMSO, 70 C, o/n
HO CI 0
2) Li0H.H20, Me0H, rt, o/n
0 OH 44% two steps 0 OH
[0657] The mixture of 2-(carboxymethyl)-4-hydroxybenzoic acid (120 mg, 0.61
mmol),
potassium carbonate (253 mg, 1.83 mmol) and 5-chloropentyl 4-
methylbenzenesulfonate (506
mg, 1.83 mmol) in dimethyl sulfoxide (5 mL) was stirred at 70 C overnight.
The resulting
mixture was allowed to cooled down to room temperature and stirred overnight.
Water (20 mL)
and ethyl acetate (20 mL) was added. The organic layer was separated, washed
with brine (50
mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo to give a
mixture. The mixture was dissolved in methanol (30 mL) and lithium hydroxide
hydrate (128 mg,
3.05 mmol) was added. The mixture was stirred at room temperature overnight.
The solvent was
removed. The residue was dissolved in water (30 mL). Hydrochloric acid (1 N)
was added until
pH < 4. The mixture was extracted with ethyl acetate (20 mL x 2). The combined
organic layers
were washed with saturated brine (10 mL x 2), dried over anhydrous sodium
sulfate, filtered, and
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concentrated in vacuo to give 2-(5-(5-chloropentyloxy)-2-
(methoxycarbonyl)phenyl)acetic acid
(85 mg, 44% two steps) as yellow oil.
[0658] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30
mm*4.6
mm*3.51.tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 90%
[water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95%
[CH3CN] in 0.5 min, then under this condition for 1.5 min, finally changed to
90% [water + 10
mM NH4HCO3] and 10% [CH3CN] in 0.1 min and under this condition for 0.5 min.).
Purity is
69.9%, Rt =0.829 min; MS Calcd.: 314.1; MS Found: 315.1 [M+H]
[0659] Step 5: Synthesis of methyl 4-(5-chloropentyloxy)-2-(2-methoxy-2-
oxoethyl)benzoate
0 0
SOCl2
CI
Me0H, rt, 2 h CI I
0 OH 62% 0
[0660] To a solution of 2-(5-(5-chloropentyloxy)-2-
(methoxycarbonyl)phenyl)acetic acid (85
mg, 0.27 mmol) in methanol (2 mL) was added thionyl chloride (48.3 mg, 0.41
mmol) dropwise.
The mixture was refluxed for 2 hour. The mixture was cooled down to room
temperature and
then the solvent was removed in vacuo to give crude product which was purified
by prep-TLC
(ethyl acetate/ petroleum ether = 1: 1) to give methyl 4-(5-chloropentyloxy)-2-
(2-methoxy-2-
oxoethyl)benzoate (55 mg, 62%) as yellow oil.
[0661] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30
mm*4.6
mm*3.51.tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 90%
[water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95%
[CH3CN] in 0.5 min, then under this condition for 1.5 min, finally changed to
90% [water + 10
mM NH4HCO3] and 10% [CH3CN] in 0.1 min and under this condition for 0.5 min.).
Purity is
72.9%, Rt =1.208 min; MS Calcd.: 328.1; MS Found: 329.2 [M+H]
[0662] Step 6: Synthesis of methyl 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-
methoxy-2-
oxoethyl)benzoate
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o/
N 0
N
HyCr
N N
0 0- N 0
CI 0 0 \ r
KI, DIEA NJ
a
a a- DMSO, 70 C, o/n H N
41%
* 0
0
CI
[0663] The mixture of methyl 4-(5-chloropentyloxy)-2-(2-methoxy-2-
oxoethyl)benzoate (55
mg, 0.17 mmol), ethyldiisopropylamine (65.8 mg, 0.51 mmol), potassium iodide
(28.2 mg, 0.17
mmol) and N-((1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-
6-(piperazin-
l-y1)nicotinamide (78.5 mg, 0.17 mmol) in dimethyl sulfoxide (2 mL) was
stirred at 70 C
overnight. The resulting mixture was allowed to cooled down to room
temperature and stirred
overnight. Water (20 mL) and ethyl acetate (20 mL) was added. The organic
layer was separated,
washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered,
and concentrated
in vacuo to give the crude product which was purified by column and flash
chromatography
(ethyl acetate/ petroleum ether = 1: 1) to give methyl 4-(5-(4-(5-((lr,3r)-3-
(3-chloro-4-
cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-l-
yl)pentyloxy)-
2-(2-methoxy-2-oxoethyl)benzoate (53 mg, 41%) as a white solid.
[0664] Step 7: Synthesis of 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-
methoxy-2-
oxoethyl)benzoic acid
o/ HO
0
0
o 0\
0
0 \
c-N\
Li0H.H20
_pN
Me0H, rt, 3 h
HN 81% HN
*
0 0 =
d \
0
CI
CI
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[0665] The mixture of methyl 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-
methoxy-2-
oxoethyl)benzoate (53 mg, 0.07 mmol) was dissolved in methanol (2 mL) and
lithium hydroxide
hydrate (14.7 mg, 0.35 mmol) was added. The mixture was stirred at room
temperature for 3
hour. The solvent was removed. The residue was dissolved in water (15 mL).
Hydrochloric acid
(1 N) was added until pH < 4. The mixture was extracted with ethyl acetate (15
mL x 2). The
combined organic layers were washed with saturated brine (10 mL x 2), dried
over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to give 4-(5-(4-(5-
((lr,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-l-
yl)pentyloxy)-
2-(2-methoxy-2-oxoethyl)benzoic acid (42 mg, 81%) as a white solid.
[0666] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30
mm*4.6
mm*3.51.tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 90%
[water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95%
[CH3CN] in 0.5 min, then under this condition for 1.5 min, finally changed to
90% [water + 10
mM NH4HCO3] and 10% [CH3CN] in 0.1 min and under this condition for 0.5 min.).
Purity is
75.4%, Rt =1.041 min; MS Calcd.: 745.3; MS Found: 746.2 [M+H]
[0667] Step 8: Synthesis of methyl 2-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-
cyanophenoxy)-
2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-
2-(2,6-
dioxopiperidin-3-ylcarbamoyl)phenyl)acetate
0
ON 0
H2N
OH a_Lal
HN)\)
HCI
0
r-N-wo HATU, DIEA 0
0 0 rNO
N.
\Lrilyal DMF, rt, 30 min
94% Att. 0 0
CI 411Ir 0'. 0
[0668] A solution of 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-
methoxy-2-
oxoethyl)benzoic acid (42 mg, 0.056 mmol), HATU (25.5 mg, 0.067 mmol) and
ethyldiisopropylamine (29.7 mg, 0.23 mmol) in N, N-dimethylformamide (2 mL)
was stirred for
30 min, and then 3-aminopiperidine-2,6-dione hydrochloride (9.2 mg, 0.056
mmol) was added.
The mixture was stirred at room temperature overnight and water (10 mL) was
added. The
mixture was extracted by ethyl acetate (20 mL x 3). The combined organic
layers were washed
with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo .
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The residue was purified by prep-TLC (dichloromethane/ methano1=10:1) to give
methyl 2-(5-
(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobutylcarbamoyl)pyridin-
2-yl)piperazin-1-yl)pentyloxy)-2-(2,6-dioxopiperidin-3-
ylcarbamoyl)phenyl)acetate (45 mg,
94%) as a white solid.
[0669] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30
mm*4.6
mm*3.5 lm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 90%
[water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95%
[CH3C1\1] in 0.5 min, then under this condition for 1.5 min, finally changed
to 90% [water + 10
mM NH4HCO3] and 10% [CH3C1\1] in 0.1 min and under this condition for 0.5
min.). Purity is
77.7%, Rt =1.213 min; MS Calcd.: 855.4; MS Found: 856.3 [M+H]
[0670] Step 9: Synthesis of N-((lr,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(4-(5-(2-(2,6-dioxopiperidin-3-y1)-1,3-dioxo-1,2,3,4-
tetrahydroisoquinolin-6-yloxy)pentyl)piperazin-l-y1)nicotinamide
CI ci
0õ1:t
NH NH
2.5 N NaOH
DMSO, rt, 5 min
N N
42%
0 u 0
0
kij.LNH
0 0
0 0 o
0
NH
0
[0671] A solution of methyl 2-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2,6-
dioxopiperidin-3-
ylcarbamoyl)phenyl)acetate (45 mg, 0.053 mmol) in dimethyl sulfoxide (2 mL)
was added
sodium hydroxide in water (2.5 moL/L, 2 drops). The mixture was stirred at
room temperature
for 5 min. Water (20 mL) and ethyl acetate (20 mL) was added. The organic
layer was separated,
washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered,
and concentrated
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in vacuo to give the crude product which was purified by prep-HPLC to give N-
((lr,30-3-(3-
chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-6-(4-(5-(2-(2,6-
dioxopiperidin-3-y1)-
1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)pentyl)piperazin-l-
y1)nicotinamide (18.5 mg,
42%) as a white solid.
[0672] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50
mm*4.6
mm*3.5 pm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 90%
[(total 10mM AcONH4) water/CH3CN=900/100 (v/v)] and 10% [(total 10mM AcONH4)
water/CH3CN=100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN=900/100
(v/v)]
and 90% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 1.6 min, then under
this
condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4)
water/CH3CN=900/100
(v/v)] and 10% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 0.1 min and
under this
condition for 0.7 min). Purity is 100.0%, Rt = 2.988 min; MS Calcd.:823.4; MS
Found:824.3
[M+H]
[0673] HPLC (Agilent HPLC 1200; Column: L-co1umn2 ODS (150 mm*4.6 mm*5.0
pm);
Column Temperature: 40 C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95%
[water + 0.1%
TFA] and 5% [CH3CN + 0.1% TFA] to 0% [water + 0.1% TFA] and 100% [CH3CN + 0.1%
TFA] in 10 min, then under this condition for 5 min, finally changed to 95%
[water + 0.1% TFA]
and 5% [CH3CN + 0.1% TFA] in 0.1 min and under this condition for 5 min).
Purity is 95.2 %,
Rt = 8.168 min.
[0674] 1H NMR (400 MHz, DMSO-d6) 6 1.12 (6H, s), 1.21 (6H, s), 1.37-1.58
(4H, m), 1.73-
1.81 (2H, m), 1.86-1.91 (1H, m), 2.30-2.37 (2H, m), 2.40-2.46 (2H, m), 2.82-
2.91(1H, m), 3.30-
3.35 (4H, m), 3.55-3.65 (4H, m), 4.03-4.30 (6H, m), 5.54-5.63 (1H, m), 6.87
(1H, d, J= 9.6 Hz),
6.96-7.07 (3H, m), 7.21 (1H, d, J= 2.4 Hz), 7.63 (1H, d, J= 9.6 Hz), 7.90-8.04
(3H, m), 8.62
(1H, d, J= 2.4 Hz), 10.93 (1H, s).
[0675] Chemical Formula: C44H50C1N707, Molecular Weight: 824.36.
[0676] Total H count from HNMR data: 50.
[0677] Exemplary Synthesis of Exemplary Compound 48
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00
N
-1(N NH
r N 0>--N 2-0
N N
HI.N
I. N
N-((lr,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-6-(4-
(54(2-(2,6-
dioxopiperidin-3-y1)-3-oxo-2,3-dihydro-11,2,41triazolo[4,3-alpyridin-7-
y1)oxy)pentyl)piperazin-1-Anicotinamide
[0678] Synthetic Scheme
soi OWI3r
....C-isk
r.) CI N2H4.H20, Et0H 0
\ I 60% NaH, DMF H
HO CI MW, 120 C, 8 h
50 C, o/n 83%
78%
0 0 0 0
NH
CL1ANH Br-ttO ---k 'b-
NH
CM, CH3CN
n, ,N- 0
80 C, 2 h Po 0 0W0 --I'l K2CO3, CH3CN 0 ow-o----N
80 C, o/n
20%
39%
NH
N H N
N
0 0
TMSI, CHCI3, rt, o/n =rill N-t 0 ______ .
79% DIEA, CH3CN, 80 C, o/n
34%
00
(N_A _tNH
0
r-NWIDNIN
N HyfrN
N , N
CI lei
[0679] Step 1: Synthesis of 4-(5-(b enzyl oxy)p entyl oxy)-2-chl oropyri
dine
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CA 03095912 2020-10-01
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OWBr
rj
OWOCI
II
HO 60% NaH, DMF
-
50 C, o/n
78%
[0680] To a solution of 2-chloropyridin-4-ol (1.3 g, 10.0 mmol) in DMF (15
mL) was added
sodium hydride (60% dispersed in mineral oil, 482 mg, 12.0 mmol) at 0 C, and
the mixture was
stirred at room temperature for 30 min. Then ((5-bromopentyloxy)methyl)benzene
(3.1 g, 12.0
mmol) was added to the reaction and the resulted mixture was stirred at 50 C
overnight. When
the reaction was completed (monitored by TLC), water (30 mL) was added. The
resultant
mixture was extracted by ethyl acetate (10 mL x 3) and the combined organic
layers were
washed by brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and
concentrated.
The residue was purified by column chromatography on silica (petroleum/ethyl
acetate = 1/4) to
give 4-(5-(benzyloxy)pentyloxy)-2-chloropyridine (2.4 g, 78% yield) as a brown
solid.
[0681] 11-INMR (400 MHz, CDC13) 6 1.47-1.53 (2 H, m), 1.59-1.64 (2 H, m),
1.71-1.76 (2 H,
m), 3.42 (2 H, t, J= 6.4 Hz), 3.91 (2 H, t, J= 6.4 Hz), 4.44 (2 H, s), 7.07-
7.15 (2 H, m), 7.23-
7.28 (5 H, m), 7.96 (1 H, d, J = 3.2 Hz).
[0682] Step 2: Synthesis of 4-(5-(benzyloxy)pentyloxy)-2-hydrazinylpyridine
owoc I N2114.H20, Et0H owoLN- N H2
MW, 120 C, 8 h
83%
[0683] To a microwave glass vial was added 4-(5-(benzyloxy)pentyloxy)-2-
chloropyridine
(2.0 g, 6.5 mmol), hydrazine monohydrate (10 mL) and Et0H (10 mL), and the
mixture was
stirred under microwave conditions at 120 C for 8 h. When it was cooled to
room temperature,
water (20 mL) was added to the reaction. The resultant mixture was extracted
by ethyl acetate
(10 mL x 3) and the combined organic layers were washed by brine (15 mL x 3),
dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue
(1.6 g, 83% yield)
was directly used to the next step without further purification as brown oil.
[0684] Step 3: Synthesis of 7-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-
a]pyridin-3(2H)-
one
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0
ThsreA
0 N
.NH2 CD!, CH3CN
0
- OWON
80 C, 2 h
20%
[0685] To a solution of 5-ethoxy-2-hydrazinylpyridine (1.6 g, 5.4 mmol) in
acetonitrile (25
mL) was added CDI (1.3 g, 8.2 mmol), and the mixture was stirred at 80 C for
2 h. When it was
cooled to room temperature, water (20 mL) was added to the reaction. The
resultant mixture was
extracted by ethyl acetate (10 mL x 3) and the combined organic layers were
washed by brine
(15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo. The
residue was purified by column chromatography on silica (DCM/Me0H = 20/1) to
give 7-(5-
(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (360 mg, 20%
yield) as a white
solid.
[0686] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6
mm x 3.51.tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.)
Purity is
96.77%, Rt = 1.716 min. MS Calcd.: 327.16; MS Found: 328.2 [M+H]t
[0687] Step 4: Synthesis of 3-(7-(5-(benzyloxy)pentyloxy)-3-oxo-
[1,2,4]triazolo[4,3-
a]pyridin-2(3H)-yl)piperidine-2,6-dione
00
N-14NH Br 0
0
K2CO3, CH3CN
80 C, o/n
39%
[0688] The solution of 7-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-
a]pyridin-3(2H)-one
(300 mg, 0.9 mmol), 3-bromopiperidine-2,6-dione (438 mg, 2.3 mmol) and K2CO3
(253 mg, 1.8
mmol) in acetonitrale (10 mL) was stirred at 80 C overnight. When it was
cooled to room
temperature, water (10 mL) was added. The resultant mixture was extracted by
ethyl acetate (10
mL x 3) and the combined organic layers were washed by brine (10 mL x 3),
dried over
anhydrous sodium sulfate, filtered and concentrated. The residue was purified
by Prep-TLC
(DCM/Me0H = 20/1) to give 3-(7-(5-(benzyloxy)pentyloxy)-3-oxo-
[1,2,4]triazolo[4,3-
a]pyridin-2(3H)-yl)piperidine-2,6-dione (157 mg, 39% yield) as a white solid.
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[0689] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6
mm x 3.5 lm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.)
Purity is
99.45%, Rt = 1.836 min. MS Calcd.: 438.19; MS Found: 439.3 [M+H]t
[0690] Step 5: Synthesis of 3-(7-(5-iodopentyloxy)-3-oxo-
[1,2,4]triazolo[4,3-a]pyridin-
2(3H)-yl)piperidine-2,6-dione
00
00
_tNH 0
_tNH
TMSI, CHCI3, rt,
79%
[0691] To a solution of 3-(7-(5-(benzyloxy)pentyloxy)-3-oxo-
[1,2,4]triazolo[4,3-a]pyridin-
2(3H)-yl)piperidine-2,6-dione (157 mg, 0.4 mmol) in CHC13 (5 mL) was added
TMSI (143 mg,
0.7 mmol), and the mixture was stirred at room temperature overnight. Then the
mixture was
washed by sat. NaHS03 (5 mL x 2), washed by brine (5 mL x 2), dried over
anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by Prep-TLC
(DCM/Me0H = 15/1)
to give 3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-
yl)piperidine-2,6-dione
(130 mg, 79% yield) as a white solid.
[0692] LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6 mm
x 3.5 lm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.)
Purity is
100%, Rt = 1.754 min. MS Calcd.: 458.05; MS Found: 459.1 [M+H]
[0693] Step 6: Synthesis of N-((1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(4-(5-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridin-7-yloxy)pentyl)piperazin-1-yl)nicotinamide
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o H
(NH
N,)
N_ty0
c, 0.. 0
__________________ DIEA, CH3CN, 80 C, o/n
J
0 34% N
N¨N HO
0 NZ:: 0
WI Os
CI
[0694] A solution of 3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-
a]pyridin-2(3H)-
yl)piperidine-2,6-dione (85 mg, 0.2 mmol), N-((1r,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(piperazin-1-yl)nicotinamide (87 mg, 0.2 mmol), and
ethyldiisopropylamine (72 mg, 0.6 mmol) in acetonitrile (5 mL) was stirred at
80 C overnight.
When it was cooled to room temprature, water (5 mL) was added and the mixture
was extracted
by ethyl acetate (5 mL x 3) and the combined organic layers were washed by
brine (5 mL x 3),
dried over anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by
Prep-HPLC to give N-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(4-
(5-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-
a]pyridin-7-
yloxy)pentyl)piperazin-l-y1)nicotinamide (50 mg, 34% yield) as a white solid.
[0695] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6
mm x 3.51.tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 3.0 min, then under this condition for 1.0 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.)
Purity is
100%, Rt = 2.877 min; MS Calcd.: 797.34; MS Found: 798.3 [M+H]t
[0696] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm x 4.6
mm x 3.5
1.tm); Column Temperature: 40 C; Flow Rate: 1.0 mL/min; Mobile Phase: from
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in
10
min, then under this condition for 5 min, finally changed to 95% [water + 10
mM NH4HCO3]
and 5% [CH3CN] in 0.1 min and under this condition for 5 min.) Purity is
93.85%, Rt = 9.967
min.
[0697] 1-HNMR (400 MHz, DMSO-d6) 6 1.12 (6H, s), 1.21 (6H, s), 1.43-1.47
(2H, m), 1.49-
1.53 (2H, m), 1.73-1.78 (2H, m), 2.13-2.17 (1H, m), 2.32 (2H, t, J= 7.2 Hz),
2.43-2.47 (5H, m),
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2.61-2.62 (1H, m), 2.87-2.93 (1H, m), 3.59 (4H, s), 4.01-4.07 (3H, m), 4.30
(1H, s), 5.28 (1H, dd,
J= 12.4, 5.2 Hz), 6.35 (1H, dd, J= 8.0, 2.4 Hz), 6.52 (1H, d, J=1.6 Hz), 6.86
(1H, d, J= 8.8 Hz),
7.00 (1H, dd, J= 8.8, 2.4 Hz), 7.21 (1H, d, J= 2.4 Hz), 7.63 (1H, d, J= 9.2
Hz), 7.80 (1H, d, J=
8.0 Hz), 7.90 (1H, d, J= 8.8 Hz), 7.95 (1H, dd, J= 9.2, 2.4 Hz), 8.62 (1H, d,
J= 2.4 Hz), 11.09
(1H, s).
[0698] Chemical Formula: C41H48C1N906, Molecular Weight: 798.33.
[0699] Total H count from HNMR data: 48.
[0700] Exemplary Synthesis of Exemplary Compound 49
0
tNH
N
N 0
N H
CI 1.1 0
N-((1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-6-(4-(5-
((2-(2,6-
dioxopiperidin-3-y1)-3-oxo-2,3-dihydro-11,2,41triazolo[4,3-alpyridin-6-
y1)oxy)pentyl)piperazin-l-y1)nicotinamide
[0701] Synthetic Scheme
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61 ow Br
--n"-N'NH2
CI -41r-'
HOIN __________________ owo-CilCI
N2H4.H20
OWO
60% NaH, DMF MW, 170 C, 18 h
rt, 2 h
0 0
0
CD!, CH3CN
0 K2CO3, CH3CN 0
80 C, 2 h 80 C, o/n
(NH
H 0 N
N N
____________________________________ CI
TMSI, CH3CI = õ,õ
0
rt, oin DIEA, CH3CN, 80
C, o/n
0
.= 0
NJ
0
N.. H rr
CI =
;1:r 0
[0702] Step 1: Synthesis of 5-(5-(benzyloxy)pentyloxy)-2-chloropyridine
OW Br
CI
IT
CIIi
owo"
HON 60% NaH, DMF
rt, 2 h
68%
[0703] To a solution of 6-chloropyridin-3-ol (1.0 g, 7.7 mmol) in DMF (10
mL) was added
sodium hydride (60% dispersed in mineral oil, 371 mg, 9.3 mmol) at 0 C, and
the mixture was
stirred at room temperature for 30 min. Then ((5-bromopentyloxy)methyl)benzene
(2.0 g, 7.7
mmol) was added to the reaction and the resulted mixture was stirred at room
temperature for 2 h.
When the reaction was completed (monitored by TLC), water (30 mL) was added.
The resultant
mixture was extracted by ethyl acetate (10 mL x 3) and the combined organic
layers were
washed by brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and
concentrated.
The residue (1.6 g, 68% yield) was directly used to the next step without
further purification as a
brown solid.
[0704] Step 2: Synthesis of 5-(5-(benzyloxy)pentyloxy)-2-hydrazinylpyridine
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CI
'NH2
owo" N2H4.H20
MW, 170 C, 18 h
82%
[0705] To a microwave glass vial was added 5-(5-(benzyloxy)pentyloxy)-2-
chloropyridine
(1.6 g, 5.2 mmol) and hydrazine monohydrate (20 mL), and the mixture was
stirred under
microwave conditions at 170 C for 18 h. When it was cooled to room
temperature, water (20
mL) was added to the reaction. The resultant mixture was extracted by ethyl
acetate (10 mL x 3)
and the combined organic layers were washed by brine (15 mL x 3), dried over
anhydrous
sodium sulfate, filtered and concentrated in vacuo. The residue (1.3 g, 82%
yield) was directly
used to the next step without further purification as brown oil.
[0706] Step 3: Synthesis of 6-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-
a]pyridin-3(2H)-
one
-NH 2 NH
CD!, CH3CN
OWON ____________________________________________________________ 0
80 C, 2 h
19%
[0707] To a solution of 5-(5-(benzyloxy)pentyloxy)-2-hydrazinylpyridine
(1.3 g, 4.4 mmol)
in acetonitrile (30 mL) was added CDI (1.1 g, 6.7 mmol), and the mixture was
stirred at 80 C
for 2 h. When it was cooled to room temperature, water (20 mL) was added to
the reaction. The
resultant mixture was extracted by ethyl acetate (10 mL x 3) and the combined
organic layers
were washed by brine (15 mL x 3), dried over anhydrous sodium sulfate,
filtered and
concentrated in vacuo. The residue was purified by column chromatography on
silica
(DCM/Me0H = 20/1) to give 6-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-
a]pyridin-3(2H)-
one (280 mg, 19% yield) as a white solid.
[0708] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6
mm x 3.51.tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.)
Purity is
98.98%, Rt = 1.728 min. MS Calcd.: 327.16; MS Found: 328.1 [M+H]t
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[0709] Step 4: Synthesis of 3-(6-(5-(benzyloxy)pentyloxy)-3-oxo-
[1,2,4]triazolo[4,3-
a]pyridin-2(3H)-yl)piperidine-2,6-dione
_LNH 0
0 0 ...1(NH Br
- owo-.-Nc
o K2c03,cH3cN __
80 C, o/n
41%
[0710] The solution of 6-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-
a]pyridin-3(2H)-one
(280 mg, 0.9 mmol), 3-bromopiperidine-2,6-dione (438 mg, 2.3 mmol) and K2CO3
(253 mg, 1.8
mmol) in acetonitrile (10 mL) was stirred at 80 C overnight. When it was
cooled to room
temperature, water (10 mL) was added. The resultant mixture was extracted by
ethyl acetate (10
mL x 3) and the combined organic layers were washed by brine (10 mL x 3),
dried over
anhydrous sodium sulfate, filtered and concentrated. The residue was purified
by Prep-TLC
(DCM/Me0H = 20/1) to give 3-(6-(5-(benzyloxy)pentyloxy)-3-oxo-
[1,2,4]triazolo[4,3-
a]pyridin-2(3H)-yl)piperidine-2,6-dione (155 mg, 41% yield) as a white solid.
[0711] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6
mm x 3.5 lm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.)
Purity is
85.76%, Rt = 1.675 min. MS Calcd.: 438.19; MS Found: 439.2 [M+H]t
[0712] Step 5: Synthesis of 3-(6-(5-iodopentyloxy)-3-oxo-
[1,2,4]triazolo[4,3-a]pyridin-
2(3H)-yl)piperidine-2,6-dione
-\rNNII 0 TMSI, CHCI3 3.. e\rs-AN_tNII 0
rt, I 0-0N o/n, 79%
0
[0713] To a solution of 3-(6-(5-(benzyloxy)pentyloxy)-3-oxo-
[1,2,4]triazolo[4,3-a]pyridin-
2(3H)-yl)piperidine-2,6-dione (155 mg, 0.4 mmol) in CHC13 (5 mL) was added
TMSI (143 mg,
0.7 mmol), and the mixture was stirred at room temperature overnight. Then the
mixture was
washed by sat. NaHS03 (5 mL x 2), washed by brine (5 mL x 2), dried over
anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by Prep-TLC
(DCM/Me0H = 15/1)
to give 3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-
yl)piperidine-2,6-dione
(130 mg, 79% yield) as a white solid.
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CA 03095912 2020-10-01
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[0714] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6
mm x 3.5 lm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.)
Purity is
95.44%, Rt = 1.706 min. MS Calcd.: 458.05; MS Found: 459.1 [M+H]t
[0715] Step 6: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(4-(5-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide
0
r"-*NH 0
0
ci op 0 N ,)
I
DIEA, CH3CN, 80 C, o/n ci 111W oLA 0
39%
[0716] A solution of 3-(6-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-
a]pyridin-2(3H)-
yl)piperidine-2,6-dione (85 mg, 0.2 mmol), N-((1r,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(piperazin-1-yl)nicotinamide (87 mg, 0.2 mmol), and
ethyldiisopropylamine (72 mg, 0.6 mmol) in acetonitrile (5 mL) was stirred at
80 C overnight.
When it was cooled to room temprature, water (5 mL) was added and the mixture
was extracted
by ethyl acetate (5 mL x 3) and the combined organic layers were washed by
brine (5 mL x 3),
dried over anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by
Prep-HPLC to give N-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-6-(4-
(5-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-
a]pyridin-6-
yloxy)pentyl)piperazin-l-yl)nicotinamide (58 mg, 39% yield) as a white solid.
[0717] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x
4.6
mm x 3.5 lm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 3.0 min, then under this condition for 1.0 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min.)
Purity is
100%, Rt = 2.890 min; MS Calcd.: 797.34; MS Found: 798.3 [M+H]t
[0718] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm x 4.6
mm x 3.5
lm); Column Temperature: 40 C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95%
[water + 10
mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in
10
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CA 03095912 2020-10-01
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min, then under this condition for 5 min, finally changed to 95% [water + 10
mM NH4HCO3]
and 5% [CH3CN] in 0.1 min and under this condition for 5 min.) Purity is
93.46%, Rt = 10.027
min.
[0719] 1-El NMR (400 MHz, DMSO-d6) 6 1.12 (6H, s), 1.21 (6H, s), 1.44-1.48
(2H, m), 1.52-
1.58 (2H, m), 1.74-1.79 (2H, m), 2.15-2.19 (1H, m), 2.30 (2H, t, J= 7.2 Hz),
2.43-2.50 (4H, m),
2.51-2.67 (2H, m), 2.86-2.95 (1H, m), 3.60 (4H, s), 3.97 (2H, t, J= 6.4 Hz),
4.05 (1H, d, J= 9.2
Hz), 4.30 (1H, s), 5.38 (1H, dd, J= 5.2, 12.8 Hz), 6.86 (1H, d, J= 9.2 Hz),
7.00 (1H, dd, J= 8.4,
2.4 Hz), 7.10 (1H, dd, J= 10.0, 2.0 Hz), 7.21 (1H, d, J= 2.4 Hz), 7.25 (1H, d,
J= 10.0 Hz), 7.36
(1H, s), 7.62 (1H, d, J= 9.2 Hz), 7.90 (1H, d, J= 8.8 Hz), 7.95 (1H, dd, J=
9.2, 2.4 Hz), 8.62
(1H, d, J= 2.4 Hz), 11.10 (1H, s).
[0720] Chemical Formula: C41F148C1N906, Molecular Weight: 798.33.
[0721] Total H count from HNMR data: 48.
[0722] Exemplary Synthesis of Exemplary Compound 50
0
N H=CI NH
0'
N-((1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-4-(4-((4-
(2-(2,6-
dioxopiperidin-3-y1)-3-oxo-2,3-dihydro-11,2,41triaz010[4,3-a1pyridin-7-
y1)piperazin-1-
y1)methyl)piperidin-1-y1)benzamide
[0723] Synthetic Scheme
280
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
/--\ CI NHNH2 4)
Br CI Boe-N NH
NH3NF12.H20 CM, CF13CNa1 NH Bri-C)
________________ ' Bac Nr-\N-dN ___________________________ . Bac
Nr-\N-N
Na0-tBu, Pd2(dba)3 - \__/ -
120 C, 48 h reflux, 16 h BoeN",----1 Na-OtBu, CH3CN
Xantphos,toluene
h
22% yield for two steps
reflux, 48
100 C, 3 h 23%
46%
o / Nic-cri # raj 0=14
1_40N e,r,1_40N *.
0
0
------N,..\7 TFA/DCM, rt, 2 h NaBH3CN, N
0
HNõ.õ......./ NH o IP NO,C) 0
BocAsi,..---' 0 98% Me0H/DCE/HOAc
rt, ()in
36%
0)k'NH3
0 N-..:.' 0 0
CI
TFA, DCE __ HO ip 4::N
rt., 2 h
Na...... r'N '-----N -c-1111 EDCI, HOBt, DIPEA - CI
Nia,õ õ----,, --- .---61 -c1-61
DMF, rt, o/n
83% N.,,,..) 0 N,...9
0
52%
[0724] Step 1: Synthesis of tert-butyl 4-(2-chloropyridin-4-yl)piperazine-1-
carboxylate
/--\ CI
BrCI Boc¨N NH
\/
I ____________________________ 0- Boc¨N N N
N Na0-tBu, Pd2(dba)3
Xantphos, toluene
100 C, 3 h
46%
[0725] To a solution of 4-bromo-2-chloropyridine (5.8 g, 30.2 mmol) in dry
toluene (150
mL) was added sodium tert-butoxide (4.3 g, 45.0 mmol), Pd2(dba)3 (0.55 g, 0.60
mmol),
Xantphos (1.0 g, 1.80 mmol) and tert-butyl piperazine-l-carboxylate (5.6 g,
30.2 mmol). The
reaction mixture was stirred at 100 C for 3 h under nitrogen and then cooled
to rt. The organic
layer was washed with water and brine and then dried over anhydrous sodium
sulfate, filtered,
and concentrated. The residue was purified by silica gel chromatography column
(PE/EA = 8:1)
to give tert-butyl 4-(2-chloropyridin-4-yl)piperazine-1-carboxylate (3.6 g,
46%) as a yellow
solid.
[0726] 1H NMR (400 MHz, DMSO-d6) 6 1.42 (9H, s), 3.38-3.41 (8H, m), 6.83-
6.86(2H, m),
7.96 (1H, d, J = 6.0 Hz).
[0727] Chemical Formula: C14H20C1N302, Molecular Weight: 297.78.
[0728] Total H count from HNMR data: 20.
[0729] Step 2: Synthesis of tert-butyl 4-(2-hydrazinylpyridin-4-
yl)piperazine-1-carboxylate
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CA 03095912 2020-10-01
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CI NHNH2
NH2NH2.1-120 /
(N Boc¨N N¨( µN
120 C, 48 h
¨/ ¨/
[0730] To a solution of tert-butyl 4-(2-chloropyridin-4-yl)piperazine-1-
carboxylate (5.0 g,
16.8 mmol) in hydrazine monohydrate (98%, 40 mL), was stirred at 120 C for 48
h under
nitrogen. Water (100 mL) was added to the mixture. The resultant mixture was
extracted by ethyl
acetate (50 mL x 3), washed by brine (100 mL), dried over anhydrous sodium
sulfate, filtered,
and concentrated in vacuo . The residue (4.8 g, 30% purity) was directly used
to the next step
without further purification as a brown solid.
[0731] Step 3: Synthesis of tert-butyl 4-(3-oxo-2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridin-7-
yl)piperazine-1-carboxylate
0
NHNH2 OH
Boc¨N N N CDI, CH3CN
N
'N)
¨/ reflux, 16 h Boc
22% yield for two steps
[0732] To a solution of tert-butyl 4-(2-hydrazinylpyridin-4-yl)piperazine-1-
carboxylate (4.8
g, 30% purity, 4.9 mmol) in acetonitrile (100 mL) was added CDI (1.6 g, 9.8
mmol), and the
mixture stirred at 100 C for 16 h. When it was cooled to room temperature,
water (100 mL) was
added to the reaction. The resultant mixture was extracted by ethyl acetate
(100 mL x 3), washed
by brine (150 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The
residue was purified by coloumn chromatography on silica (DCM/Me0H = 20/1) to
give tert-
butyl 4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-
carboxylate (1.2 g,
22% yield for two steps) as a yellow solid.
[0733] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50
mm*4.6
mm*3.5 [tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 90%
[(total 10mM AcONH4) water/CH3CN=900/100 (v/v)] and 10% [(total 10mM AcONH4)
water/CH3CN=100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN=900/100
(v/v)]
and 90% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 1.6 min, then under
this
condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4)
water/CH3CN=900/100
(v/v)] and 10% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 0.1 min and
under this
condition for 0.7 min). Purity is 99.11%, Rt = 1.418 min; MS Calcd.: 319.7; MS
Found: 320.2
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[M+H]
[0734] 1E1 NMR (400 MHz, DMSO-d6) 6 1.42 (9H, s), 3.21-3.23 (4H, m), 3.42-
3.43 (4H, m),
6.13 (1H, d, J= 1.6 Hz), 6.60 (1H, dd, J= 8.0, 2.0 Hz), 7.65 (1H, d, J= 8.0
Hz), 11.90 (1H, s).
[0735] Chemical Formula: Ci5H2iN503, Molecular Weight: 319.36
[0736] Total H count from HNMR data: 21.
[0737] Step 4: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-
2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate
0
1-4
l(NH 13r-tiFi
N ' r-NNI
riN NH
Na-OtBu, CH3CN
Boc'N) 0
reflux, 48 h
23%
[0738] The solution of tert-butyl 4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-
a]pyridin-7-
yl)piperazine-1-carboxylate (320 mg, 1.0 mmol), 3-bromopiperidine-2,6-dione
(390 mg, 2.0
mmol) and sodium tert-butoxide (120 mg, 1.2 mmol) in acetonitrale (20 mL) was
stirred at
100 C overnight. When it was cooled to room temperature, water (20 mL) was
added. The
resultant mixture was extracted by ethyl acetate (20 mL x 3), washed by brine
(30 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The residue was
purified by Prep-TLC
(DCM/Me0H = 20/1) to give tert-butyl 4-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-
dihydro-
[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate (100 mg, 23%
yield) as a yellow
solid.
[0739] 1H NMR (400 MHz, DMSO-d6) 6 1.47 (9H, s), 2.16-2.20 (1H, m), 2.47-
2.50(1H, m),
2.66-2.70 (1H, m), 2.90-2.99 (1H, m), 3.31-3.33 (4H, m), 3.47-3.49 (4H, m),
5.27-5.31 (1H, m),
6.20 (1H, d, J= 1.2 Hz), 6.73 (1H, dd, J= 7.6, 2.0 Hz), 7.80 (1H, d, J= 8.0
Hz), 11.11 (1H, s).
[0740] Chemical Formula: C24126N605, Molecular Weight: 430.46.
[0741] Total H count from HNMR data: 26.
[0742] Step 5: Synthesis of 3-(3-oxo-7-(piperazin-1-y1)-[1,2,4]triazolo[4,3-
a]pyridin-2(3H)-
yl)piperidine-2,6-dione
0
0
;al-4
TFA/DCM, rt, 2 h
Boc
N
0 NH
98% 0
[0743] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-
dihydro-
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[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate (0.40 g, 0.93
mmol) in
dichloromethane (20 mL) was added TFA (8 mL), then stirred at room temperature
for 2 h and
concentrated in vacuo to give 3-(3-oxo-7-(piperazin-l-y1)41,2,4]triazolo[4,3-
a]pyridin-2(3H)-
y1)piperidine-2,6-dione (0.30 g, 98%) as a yellow solid, which was used to the
next step without
further purification.
[0744] Step 6: Synthesis of tert-butyl 4-(444-(2-(2,6-dioxopiperidin-3-y1)-
3-oxo-2,3-
dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-
yl)benzoate
0 Nay
,CN(1-4N W
0 0
-)st.0 NH
NaBH3CN, __________________________
NH
Me0H/DCE/HOAc
rt, o/n
36%
[0745] To a solution of 3-(3-oxo-7-(piperazin-1-y1)41,2,4]triazolo[4,3-
a]pyridin-2(3H)-
yl)piperidine-2,6-dione (0.30 g, 0.91 mmol) in dry methano1/1,2-
dichloroethane/HOAc (20 mL/4
mL/0.1 mL) was added tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (0.26 g,
0.91 mmol). The
mixture was left to stir for 30 min under N2 gas. Then sodium cyanoborohydride
(0.11 g, 1.82
mmol) was added and the reaction mixture was left to stir for 16 h at room
temperature. The
solvent was removed and the residue partitioned between dichloromethane and
water, washed
with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo to give
crude product. The residue was purified by prep-TLC to give compound tert-
butyl 4444(442-
(2,6-di oxopiperidin-3 -y1)-3 -oxo-2,3 -dihydro-[1,2,4]tri azol o [4,3 -a]pyri
din-7-yl)piperazin-1-
yl)methyl)piperidin-l-yl)benzoate (0.20 g, 36%) as a yellow solid.
[0746] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50
mm*4.6
mm*3.51.tm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 90%
[(total 10mM AcONH4) water/CH3CN=900/100 (v/v)] and 10% [(total 10mM AcONH4)
water/CH3CN=100/900 (v/v)] to 10% [(total 10mM AcONH4) water /CH3CN=900/100
(v/v)]
and 90% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 1.6 min, then under
this
condition for 2.4 min, finally changed to 90% [(total 10mM AcONH4)
water/CH3CN=900/100
(v/v)] and 10% [(total 10mM AcONH4) water/CH3CN=100/900 (v/v)] in 0.1 min and
under this
condition for 0.7 min). Purity is 87.07%, Rt = 2.195 min.; MS Calcd.: 603.3;
MS Found: 604.4
[M+H]t
[0747] Step 7: Synthesis of 4-(444-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-
dihydro-
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[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-
yl)benzoic acid
0 0
01= pr--cri
TFA, DCE HO
Chijc \
o
rt., 2 h N NH
83% 0
[0748] To a solution of tert-butyl 4-(4-((4-(2-(2,6-dioxopiperidin-3-y1)-3-
oxo-2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-
yl)benzoate (0.10 g, 0.16
mmol) in dichloromethane (10 mL) was added TFA (5 mL), then stirred at room
temperature for
2 h, then concentrated in vacuo to give 4-(4-((4-(2-(2,6-dioxopiperidin-3-y1)-
3-oxo-2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-
yl)benzoic acid (0.075 g,
83%) as a yellow solid, which was used to the next step without further
purification.
[0749] Step 8: Synthesis of N4(1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-4-(4-((4-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridin-7-y1)piperazin-1-y1)methyl)piperidin-1-
y1)benzamide
110
(:)4/
,c1r1H
0 0 N
HO
ci
N I 0
N EDCI, HOBt, DIPEA
0 DMF, rt, o/n
52%
0 NajN
[0750] A solution of 4-(4-((4-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-
dihydro-
[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-
yl)benzoic acid (75 mg, 0.14
mmol), 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI) (39
mg, 0.21
mmol), 1-hydroxybenzotriazole hydrate (HOBt) (28 mg, 0.21 mmol) and
ethyldiisopropylamine
(88 mg, 0.69 mmol) in DMF (5 mL) was stirred for 30 min, and then 4-((lr,3r)-3-
amino-2,2,4,4-
tetramethylcyclobutoxy)-2-chlorobenzonitrile (38 mg, 0.14 mmol) was added. The
mixture was
stirred at room temperature overnight and water (10 mL) was added. The aqueous
layer was
extracted by dichloromethane (20 mL x 2). The combined organic layer was
washed by brine (10
mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo. The residue
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was purified by prep-HPLC to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobuty1)-4-(44(4-(2-(2,6-dioxopiperidin-3-y1)-3-oxo-2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-
yl)benzamide (57 mg, 52%)
as a white solid.
[0751] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50
mm*4.6
mm*3.5 pm); Column Temperature: 40 C; Flow Rate: 2.0 mL/min; Mobile Phase:
from 95%
[water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%
[CH3CN] in 3.0 min, then under this condition for 1.0 min, finally changed to
95% [water + 10
mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min).
Purity is
98.22%, Rt = 3.022 min; MS Calcd.: 807.4; MS Found: 808.3 [M+H]t
[0752] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm*4.6
mm*3.5
pm); Column Temperature: 40 C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95%
[water + 10
mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in
10
min, then under this condition for 5 min, finally changed to 95% [water + 10
mM NH4HCO3]
and 5% [CH3CN] in 0.1 min and under this condition for 5 min). Purity is
99.00%, Rt = 10.305
min.
[0753] 1H NMR (400 MHz, DMSO-d6) 6 1.13 (6H, s), 1.22 (6H, s), 1.79-1.81
(3H, m), 2.09-
2.15 (1H, m), 2.19-2.21 (2H, m), 2.49-2.50 (7H, m), 2.60-2.67 (1H, m), 2.76-
2.92 (3H, m), 3.22-
3.26 (4H, m), 3.86 (2H, d, J= 12.8 Hz), 4.05 (1H, d, J= 9.2 Hz), 4.32 (1H, s),
5.23 (1H, dd, J=
12.4, 5.2 Hz), 6.12 (1H, s), 6.70 (1H, dd, J= 8.0, 1.6 Hz), 6.95 (2H, d, J=
9.2 Hz), 7.00 (1H, dd,
J= 8.8, 2.4 Hz), 7.21 (1H, d, J= 2.4 Hz), 7.48 (1H, d, J= 8.8 Hz), 7.72 (3H,
t, J= 8.4 Hz), 7.91
(1H, d, J= 8.8 Hz), 11.04 (1H, s).
[0754] Chemical Formula: C43H50C1N905, Molecular Weight: 808.37.
[0755] Total H count from HNMR data: 50.
[0756] General Synthetic Scheme C-3
[0757] Synthesis of building block N-((1r,30-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobuty1)-4-(4-formylpiperidin-1-y1)benzamide
CI 0 01
N
N
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[0758] Synthetic Scheme:
rOH
F
0
K2CO3, DMSO hla\ OH 1.37% NaOH HO =
ND
2. HCI
N)__\
OH
0
N:
'NH2
N HCI CI Es 0
N 00
HATU, DIEA, DMF, 30 C, 70 min
OH
CI 0
Dess-Martin
N
DCM, 30 C, 2h
Lo
[0759] Step 1: Synthesis of Ethyl 4-(4-(hydroxymethyl)piperidin-1-
yl)benzoate
OH
Na-NOH
K2CO3, DMSO
0 0
[0760] To a solution of ethyl 4-fluorobenzoate (27 g, 0.16 mol) in DMSO
(500 mL) was
added K2CO3 (44 g, 0.32 mol) and piperidin-4-ylmethanol (32 g, 0.19 mol) at 25
C. The
resulting solution was stirred at 100 C for 12 h. The reaction was diluted
with H20 (600 mL).
The resulting mixture was extracted with Et0Ac (200 mL x 3). The combined
organic layers
were dried over anhydrous sodium sulfate and concentration. The crude product
was slurry in
PE/MTBE=1:1 to afford ethyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (30 g,
71% yield) as
a white solid, which was used into next step without further purification.
[0761] Chemical Formula: C15H21NO3; Molecular Weight: 263.34.
[0762] 111 NMR (400 MHz, DMSO-d6): 6 7.91 (d, J = 8.8 Hz, 2H), 6.87 (d, J=
8.8 Hz, 2H),
4.30-4.35 (m, 2H), 3.90 (d, J = 12.8 Hz, 2H), 3.54 (d, J= 6.4 Hz, 2H), 2.82-
2.89 (m, 2H), 1.85 (d,
J= 12.8 Hz, 2H), 1.71-1.77 (m, 1H), 1.35-1.54 (m, 6H).
[0763] Total H count from 111 NMR data: 21
[0764] Step 2: Synthesis of 4-(4-(Hydroxymethyl)piperidin-1-yl)benzoic acid
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0 0
oco
NaOH
OH
1.1 THF, Me0H, H20, 30 O, 12h
HO HO
[0765] To a solution of ethyl 4[4-(hydroxymethyl)-1-piperidylThenzoate (52
g, 197.47 mmol,
1 eq) in tetrahydrofuran (250 mL), methanol (250 mL) and water (250 mL) was
added sodium
hydroxide (31.6 g, 0.79 mmol, 4 eq). The mixture was stirred at 30 C for 12
hours. Thin layer
chromatography (petroleum ether: ethyl acetate=1:1) showed the reaction was
completed. The
mixture was adjusted to pH 3-4 with hydrochloric acid (2 M) and filtered. The
filter cake was
dried in vacuum. The residue was triturated with ethyl acetate (500 mL) to
give 444-
(hydroxymethyl)-1-piperidylThenzoic acid (35 g, 148.76 mmol, 75% yield) as a
white solid.
[0766] NMR: (400MHz, DMSO-d6) 6: 12.19 (s, 1H), 7.74 (d, J=8.8 Hz, 2H),
6.93 (d,
J=8.8 Hz, 2H), 4.48 (br t, J=5.2 Hz, 1H), 3.90 (d, J=12.8 Hz, 2H), 3.27 (br t,
J=5.2 Hz, 2H), 2.86
-2.72 (m, 2H), 1.72 (d, J=12.8 Hz, 2H), 1.66 - 1.51 (m, 1H), 1.17 (dq, J=4.0,
12.0 Hz, 2H)
[0767] Chemical Formula: C13H17NO3, Molecular Weight: 235.28.
[0768] Total H count from HNMR data: 17.
[0769] Step 3: Synthesis of N-13-(3-chloro-4-cyano-phenoxy)-2,2,4,4-
tetramethyl-
cyclobuty11-4-14-(hydroxymethyl)-1-piperidyllbenzamide
CI 00 N1-12
op OH ___________________________________ N
N 01 ao 0
H 40 HATU, DIEA, DMF,
30 C, 70 min N
HO 0H
[0770] To a solution of 4[4-(hydroxymethyl)-1-piperidylThenzoic acid (38 g,
161.51 mmol,
1 eq) and 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-chloro-benzonitrile
(50.9 g, 161.51
mmol, 1 eq, hydrochloride) in dimethylformamide (800 mL) was added
diisopropylethylamine
(83.5 g, 646.04 mmol, 112 mL, 4 eq). The mixture was stirred at 30 C for
10min, and then o-(7-
azabenzotriazol-1-y1)-n,n,n',n'-tetramethyluronium hexafluorophosphate (64.48
g, 169.59 mmol,
1.05 eq) was added. The mixture was stirred at 30 C for 1 hour. LCMS showed
the reaction was
completed and desired MS can be detected. The mixture was poured into water (4
L) and filtered.
The filter cake was concentrated and triturated with methanol (500 mL x 2) to
give N-[3-(3-
chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobuty1]-4- [4-(hydroxymethyl) -
1-
piperidyl]benzamide (72 g, 137.89 mmol, 85% yield, 95% purity) as a white
solid.
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[0771] LCMS: MS (ESI) m/z: 496.1 [M+1] +
[0772] 111 NMR: (400MHz, DMSO-d6) 6: 7.90 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8
Hz, 2H),
7.48 (d, J=9.2 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.00 (dd, J=2.4, 8.8 Hz, 1H),
6.95 (d, J=8.8 Hz,
2H), 4.48 (t, J=5.2 Hz, 1H), 4.31 (s, 1H), 4.05 (d, J=9.2 Hz, 1H), 3.86 (d,
J=12.8 Hz, 2H), 3.27 (t,
J=5.6 Hz, 2H), 2.80 - 2.70 (m, 2H), 1.73 (d, J=11.2 Hz, 2H), 1.63- 1.52(m,
1H), 1.27- 1.15(m,
8H), 1.12 (s, 6H).
[0773] Chemical Formula: C28H34C1N303, Molecular Weight: 496.04.
[0774] Total H count from HNMR data: 34.
[0775] Step 4: Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-
tetramethyl-
cyclobuty11-4-(4-formy1-1-piperidyl)benzamide
0 0
Dess-Martin
..'NH
N N oT
DCM, 30 C, 2h
NOH
LO
[0776] To a solution of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-
cyclobuty1]- 4-
[4-(hydroxymethyl)-1-piperidyl]benzamide (65 g, 131.04 mmol, 1 eq) in
dichloromethane (700
mL) was added Dess-Martin reagent (76.70 g, 180.83 mmol, 1.38 eq). The mixture
was stirred at
30 C for 2 hours. Thin layer chromatography (dichloromethane: methano1=1:1)
showed the
reaction was completed. The reaction was adjusted to pH 8-9 with saturated
sodium bicarbonate.
The mixture was diluted with water (3 L) and extracted with dichloromethane
(1.5 L x 3). The
combined organic phase was washed with saturated brine (1.5 L x 2), dried with
anhydrous
sodium sulfate, filtered and concentrated in vacuum. The residue was purified
by silica gel
chromatography (dichloromethane: methano1=100:0 to 50:1) to give N-[3-(3-
chloro-4-cyano-
phenoxy)-2,2,4,4-tetramethyl-cyclobuty1]-4-(4-formyl- 1-piperidyl)benzamide
(34.6 g, 67.94
mmol, 51% yield, 97% purity) as a white solid.
[0777] 111 NMR: (400MHz, DMSO-d6) 6: 9.63 (s, 1H), 7.90 (d, J=8.8 Hz, 1H),
7.74 (d,
J=8.8 Hz, 2H), 7.49 (d, J=9.2 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.03 - 6.94 (m,
3H), 4.32 (s, 1H),
4.05 (d, J=9.2 Hz, 1H), 3.76 (td, J=3.6, 12.8 Hz, 2H), 3.01 - 2.92 (m, 2H),
2.62 - 2.55 (m, 1H),
2.62 -2.55 (m, 1H), 1.92 (dd, J=3.6, 12.8 Hz, 2H), 1.62 - 1.48 (m, 2H), 1.21
(s, 6H), 1.12 (s, 6H).
[0778] Chemical Formula: C28H32C1N303, Molecular Weight: 494.02.
[0779] Total H count from HNMR data: 32.
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[0780] General Synthetic Scheme C-4
[0781] Synthesis of building block N4(1r,30-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobuty1)-4-(4-(2-oxoethyl)piperidin-1-y1)benzamide
0
I*
N 40 H
.....' 4N
N
CI 0 0
[0782] Synthetic Scheme:
0 0
HO
. 0 OBn 0 OH
0
OBn 0H... ...õ,õõC131 H2,Pd/C . ....õ,,_,Cy
DIEA, DMF, 100 C Me0H
F HO HO
N
OH
M r0
a j=rH2 N
N H 0 N Dess-artin N ,
=wDCM, rt, overnight 0
. . c, 0 0
HATU, DIEA, DMF
[0783] Step 1: Synthesis of benzyl 4-14-(2-hydroxyethyl)piperidin-1-
y11benzoate
0
0 HO 40) OBn
40 OBn _________________________ NH N
D.-
DIEA, DMF, 100 C
F HO
[0784] Into a 100-mL round-bottom flask, was placed benzyl 4-fluorobenzoate
(2.3 g, 10.0
mmol, 1.0 equiv), N,N-dimethylformamide (30.0 mL), 2-(piperidin-4-yl)ethan-1-
ol (1.3 g, 10.0
mmol, 1.0 equiv), N,N-Diisopropylethylamine (3.87 g, 29.9 mmol, 4.0 equiv).
The resulting
solution was stirred for 12 h at 90 C. The resulting mixture was concentrated
under vacuum. The
residue was applied onto a silica gel column with ethyl acetate/petroleum
ether (1/1). This
resulted in 2.1 g (62%) of benzyl 444-(2-hydroxyethyl)piperidin-1-yl]benzoate
as a yellow solid.
[0785] LC-MS (ES): 340.25m/z [ME1], tR = 1.20min, (1.90 minute run).
[0786] Step 2: Synthesis of 4-14-(2-hydroxyethyl)piperidin-1-yll benzoic
acid
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0
OBn OH
H2,Pd/C /*N
HO) Me0H HO
[0787] To a solution of benzyl 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoate
(500 mg, 1.47
mmol, 1.00 equiv) in 20.0 mL methyl alcohol (30.0 mL)was added Pd/C (10%, 300
mg) under
nitrogen atmosphere in a 100.0 mL round bottom flask. The flask was then
vacuumed and
flushed with hydrogen. The reaction mixture was hydrogenated at room
temperature for 12 hours
under hydrogen atmosphere using a hydrogen balloon, then filtered through a
Celite pad and
concentrated under reduced pressure. This resulted in 300.0m g (82.0%) of 444-
(2-
hydroxyethyl)piperidin-1-ylThenzoic acid as a yellow solid.
[0788] LC-MS (ES): 250.00m/z [ME1], tR = 0.74min, (2.00 minute run).
[0789] Step 3: Synthesis of 4-14-(2-hydroxyethyl)piperidin-1-y11-N-1(1r,30-
3-(3-chloro-
4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyllbenzamide
0 N
OH
j3.:NH2
4111 N
CI S 0
CI WI 0 0
HO HATU, DIEA, DMF
[0790] Into a 100-mL round-bottom flask, was placed 444-(2-
hydroxyethyl)piperidin-1-
yl]benzoic acid (300.0 mg, 1.2 mmol, 2.0 equiv), N,N-dimethylformamide (10.0
g, 136.8 mmol,
227.0 equiv), N,N,N',N'-Tetramethy1-0-(7-azabenzotriazol-1-y1)uronium
hexafluorophospate
(686 mg, 1.8 mmol, 3.0 equiv), 2-chloro-4-[(1r,30-3-amino-2,2,4,4-
tetramethylcyclobutoxy]benzonitrile hydrochloride (190.0 mg, 0.6 mmol, 1.0
equiv), N,N-
Diisopropylethylamine (466.0 mg, 3.6 mmol, 6.0 equiv). The resulting solution
was stirred for 1
h at room temperature. The reaction was then quenched by the addition of 60 mL
of water. The
resulting solution was extracted with 3x30 mL of ethyl acetate and the organic
layers combined
and dried over anhydrous sodium sulfate and concentrated under vacuum. The
residue was
applied onto a silica gel column with ethyl acetate/petroleum ether (1:1).
This resulted in 250.0
mg (81%) of 4-[4-(2-hydroxyethyl)piperidin-1-A-N-R1r,3r)-3-(3-chloro-4-
cyanophenoxy)-
2,2,4,4-tetramethylcyclobutyl]benzamide as a yellow solid.
[0791] LC-MS (ES): 510.25m/z [ME1], tR = 1.35min, (1.90 minute run).
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[0792] Step 4: Synthesis of 4-14-(2-oxoethyl)piperidin-1-y11-N-1(1r,30-3-(3-
chloro-4-
cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl1benzamide
OH =
WI 0
Dess-Martin N
j:RENI so j:REN1= DCM, rt, overnight WI
N
CI 0 CI 0
[0793] Into a 100-mL round-bottom flask, was placed 444-(2-
hydroxyethyl)piperidin-1-y1]-
N-R1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide
(200.0 mg,
0.4 mmol, 1.0 equiv), dichloromethane (20.0 mL), Dess-Martin (249.0 mg, 0.60
mmol, 1.5
equiv). The resulting solution was stirred for 4 h at room temperature. The
resulting solution was
extracted with of ethyl acetate and the organic layers combined and
concentrated under vacuum.
The residue was applied onto a silica gel column with ethyl acetate/petroleum
ether (1:1). This
resulted in 80.0 mg (40%) of 444-(2-oxoethyl)piperidin-1-y1]-N-R1r,30-3-(3-
chloro-4-
cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide as a yellow solid.
[0794] LC-MS (ES): 508.20m/z [ME1], tR = 1.19min, (2.00 minute run).
[0795] Exemplary Synthesis of Exemplary Compound 51
00
N-< ,)=O
L ,N
0
NON)
N. #1-Ni
0
0,
CI
rac-N-((1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-4-(4-
(2-(4-(2-
(2,6-dioxopiperidin-3-y1)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c1pyridin-6-
yl)piperazin-1-
yl)ethyl)piperidin-1-yl)benzamide
[0796] Synthetic scheme:
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O o /---\ o
g0H TMSCHN2
N ' 0 Boc-N NH
\__/ .---,........A. ..--
NI' 0 LiOH
.- ___________________________ ..- o
0
CI OH __ Me0H CI
DIEA, DMF
N
Me0H/H20
0 0 Boc--N."--) 0
0
0 0
0
0
H 40 N NH N.;:=-===.._.-4 _ti:zt
H2N¨t _________________________ HN 0 N 0
0 .-,- 40
i....õ ,.... OH '
CI 0' = 0
HOAc
Boc'N'-')
NaBH(OAc)3, DCM
0 0
N' NH
r-N
N,...) 0
H N24* N
0
0'
CI
[0797] Step 1: Synthesis of 3,4-dimethyl 6-chloropyridine-3,4-dicarboxylate
0 0
/
N ).(1 OH TMSCHN2 N 0
CI )..i0H _________________________ )... .rio
Me0H CI
0 0
[0798] Into a 100-mL round-bottom flask, was placed 6-chloropyridine-3,4-
dicarboxylic acid
(200.0 mg, 1.0 mmol, 1.0 equiv), methanol (5.0 mL), acetonitrile (5.0 mL),
TMSCHN2 (2.0 mL),
N,N-Diisopropylethylamine (516.0 mg, 4.0mmo1, 4.0 equiv). The resulting
solution was stirred
for 2 h at room temperature. The reaction was then quenched by the addition of
water (30mL).
The resulting solution was extracted with ethyl acetate (20.0 mL x 3)and the
organic layers
combined and concentrated under vacuum. The residue was applied onto a silica
gel column with
ethyl acetate/petroleum ether (1:1). The resulting mixture was concentrated
under vacuum. This
resulted in 220 mg (96%) of 3,4-dimethyl 6-chloropyridine-3,4-dicarboxylate as
a yellow solid.
[0799] LC-MS (ES): 230.10m/z [ME1], tR = 1.01min, (1.90 minute run).
[0800] Step 2: Synthesis of 3,4-dimethyl 6-14-1(tert-
butoxy)carbonyllpiperazin-1-
yllpyridine-3,4-dicarboxylate
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0 0
\.Ao/ Boc¨N NH
N
N
DIEA, DMF
0 B0?1 0
[0801] Into a 100-mL round-bottom flask, was placed 3,4-dimethyl 6-
chloropyridine-3,4-
dicarboxylate (200.0 mg, 0.9 mmol, 1.0 equiv), N,N-dimethylformamide (5.0 mL),
tert-butyl
piperazine-l-carboxylate (325.0 mg, 1.7 mmol, 2.0 equiv), N,N-
Diisopropylethylamine (450.0
mg, 3.5 mmol, 4.0 equiv). The resulting solution was stirred for 2 h at 100 C.
The reaction was
then quenched by the addition of water(80mL). The resulting solution was
extracted with ethyl
acetate (30.0 mL x3) and the organic layers combined and concentrated under
vacuum. The
residue was applied onto a silica gel column with ethyl acetate/petroleum
ether (1:3). This
resulted in 320.0 mg (97%) of 3,4-dimethyl 644-[(tert-
butoxy)carbonyl]piperazin-1-yl]pyridine-
3,4-dicarboxylate as a yellow solid.
[0802] LC-MS (ES): 380.10m/z [ME1], tR = 1.19min, (2.0 minute run).
[0803] Step 3: Synthesis of 6-14-1(tert-butoxy)carbonyll piperazin-1-yll
pyridine-3,4-
dicarboxylic acid
0 0
N 0 LiOH N OH
I _I
Me0H/H20OH
Boc,N) 0
Boc'N) 0
[0804] Into a 100-mL round-bottom flask, was placed 3,4-dimethyl 644-[(tert-
butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylate (320.0 mg, 0.8 mmol,
1.0 equiv),
methanol (10.0 mL), water(5 mL), lithium hydroxide (96 mg, 4 mmol, 5 equiv).
The resulting
solution was stirred for 5 h at room temperature. The resulting mixture was
concentrated under
vacuum. This resulted in 300.0 mg (101%) of 644-[(tert-
butoxy)carbonyl]piperazin-1-
yl]pyridine-3,4-dicarboxylic acid as a white solid.
[0805] LC-MS (ES): 296.20m/z [ME1], tR = 0.52min, (1.90 minute run).
[0806] Step 4: Synthesis of 3-11,3-dioxo-6-(piperazin-1-y1)-1H,211,311-
pyrrolo 13,4-
clpyridin-2-yll piperidine-2,6-dione
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00
0
0
NH
N).(OH N
N HINk.) 0
HOAc
0
Boc'N')
[0807] Into a 100-mL round-bottom flask, was placed 644-[(tert-
butoxy)carbonyl]piperazin-
1-yl]pyridine-3,4-dicarboxylic acid (300.0 mg, 0.8 mmol, 1.0 equiv), acetic
acid (20.0 mL), 3-
aminopiperidine-2,6-dione (218 mg, 1.7 mmol, 2.0 equiv). The resulting
solution was stirred for
2 h at 130 C. The reaction was then quenched by the addition of water (30 mL).
The resulting
solution was extracted with ethyl acetate (30 mL x3)and the organic layers
combined and dried
in an oven under reduced pressure. and concentrated under vacuum. The residue
was applied
onto a silica gel column with dichloromethane/methanol (3:1). This resulted in
60.0 mg (20%) of
341,3-dioxo-6-(piperazin-1-y1)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-
2,6-dione as a
yellow solid.
[0808] LC-MS (ES): 344.20m/z [ME1], tR = 0.66min, (1.90 minute run).
[0809] Step 5: Synthesis of 4-14-(2-14-12-(2,6-dioxopiperidin-3-y1)-1,3-
dioxo-111,211,311-
pyrrolo13,4-c]pyridin-6-y11piperazin-1-y11ethyl)piperidin-1-y11-N-1(1r,30-3-(3-
chloro-4-
cyanophenoxy)-2,2,4,4-tetramethylcyclobutyllbenzamide
c
HNTh H
0 õ-N 0
N `jyNN
N
0 1$
NI \
0
N 0
0 010 0"---1- 0
NH CI
NaBH(OAc)3, DCM
HN
111P
0
N 411
CI
[0810] Into a 100-mL round-bottom flask, was placed 341,3-dioxo-6-
(piperazin-1-y1)-
1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2,6-dione hydrochloride (60.0
mg, 0.2mmo1,
1.0 equiv), dichloromethane (10 mL), 4-[4-(2-oxoethyl)piperidin-1-A-N-R1r,3r)-
3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (80.0 mg, 0.1 mmol, 1.0
equiv),
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Sodium triacetoxyborohydride (110.0 mg, 3.0 equiv). The resulting solution was
stirred for 4 h at
room temperature. The reaction was then quenched by the addition of 40 mL of
water. The
resulting solution was extracted with dichloromethane (20 mL x 3)and the
organic layers
combined and concentrated under vacuum. The crude product (4.0 mL) was
purified by Prep-
HPLC with the following conditions: Column, Sunfire Prep C18 OBD Columnõ
10um,19*250mm; mobile phase, Water(0.1% formic acid) and acetonitrile (30.0%
acetonitrile
up to 52.0% in 8 min); Detector, UV 254nm. 5.0 mL product was obtained. This
resulted in 50.5
mg (38.2%) of 444-(24442-(2,6-dioxopiperidin-3-y1)-1,3-dioxo-1H,2H,3H-
pyrrolo[3,4-
c]pyridin-6-yl]piperazin-1-yl]ethyl)piperidin-1-y1]-N-R1r,30-3-(3-chloro-4-
cyanophenoxy)-
2,2,4,4-tetramethylcyclobutyl]benzamide as a yellow solid.
[0811] 1H NMR (300 MHz, DMSO-d6) 6 11.07 (s, 1H), 8.57 (s, 1H), 7.87 (d, J
= 8.7 Hz,
1H), 7.70 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 9.1 Hz, 1H), 7.29 (s, 1H), 7.17
(d, J = 2.2 Hz, 1H),
7.02-6.87 (m, 3H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.29 (s, 1H), 4.02 (d, J =
9.1 Hz, 1H), 3.28 (s,
5H), 2.59-2.41 (m, 9H), 2.00 (t, J = 11.3 Hz, 1H), 1.73 (d, J = 12.8 Hz, 2H),
1.45 (s, 3H), 1.14 (d,
J = 27.2 Hz, 14H).
[0812] LC-MS (ES): 835.25m/z [ME1], tR = 2.56min, (4.80minute run).
[0813] Exemplary Synthesis of Exemplary Compound 52
00
N _______________________________________________________
rNNTh=
0
N
N
CI
(rac)-N4(1r,30-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty1)-4-(4-
(2-(4-(6-
(2,6-dioxopiperidin-3-y1)-5,7-dioxo-6,7-dihydro-511-pyrrolo[3,4-d]pyrimidin-2-
y1)piperazin-
1-y1)ethyl)piperidin-1-y1)benzamide
[0814] Synthetic scheme:
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NH
ii 0.5eq H2SO4
NH S)'LNH2 NH
(-
NoNANH2
Boc' N DIEA, iPrOH, 100 C, 24 h 0
Boe
Et0Na, Et0H, reflux, 2h Ne.
I LiOH
0 _______________________________________________ r-N N 0
o 0 0 0
Bec'N 0
Et0H/H20, rt, 8 h
DMFDMA, rt, 2 h .-^-0 (:)./
0
N I
0
0 I
0
HCI _tNH
0 00
H2N 0 0 0
NH
N),I.LOH Nj'\.,..-A N¨ ,)=o
Ac20
114N¨.\¨ o TFA
I OH I N
r-N N-).( Pyridine, reflux r-N N DCM (--N N-----\
BoeN,) 0 Boc'N) 0
HN 0
00
00 r,j'\_A _tNH
I N 0
N -., ill 1.1 N
(NON N----'
0
CI *0 0
s H
N-... N
_________________________ ..-
NaBH(0Ac)3, DCM, -..0 Os'----tr.
0
CI
[0815] Step 1: Synthesis of tert-butyl 4-carbamimidoylpiperazine-1-
carboxylate
NH
),L 0.5eq H2SO4
NH
NH ___________________________________
S NH2
Boc,N) rNANH 2
DIEA, iPrOH, 100 C, 24 h N)
Boc'
[0816] Into a 250-mL round-bottom flask, was placed tert-butyl piperazine-l-
carboxylate (10
g, 53.69 mmol, 1.00 equiv), i-propanol (150 mL),
(methylsulfanyl)methanimidamide (7.4 g,
82.09 mmol, 1.00 equiv), DIEA (25 mL, 3.00 equiv). The resulting solution was
stirred for 24 h
at 100 C in an oil bath. The resulting mixture was concentrated under vacuum.
The resulting
solution was diluted with acetonitrile (150 mL), then stirred for 30 min. The
solids were
collected by filtration. This resulted in 11.5 g (94%) of tert-butyl 4-
carbamimidoylpiperazine-1-
carboxylate as a white solid.
[0817] Step 2: Synthesis of 1,4-diethyl (2Z)-2-1(dimethylamino)methylidene1-
3-
oxobutanedioate
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CA 03095912 2020-10-01
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0 0
0 0 DMFDMA, rt, 2 h
0
[0818] Into a 250-mL round-bottom flask, was placed 1,4-diethyl 2-
oxobutanedioate (10 g,
53.14 mmol, 1.00 equiv), DM}DMA (12.65 g, 106.30 mmol, 2.00 equiv) at 0 C.
The resulting
solution was stirred for 2 h at room temperature. The residue was applied onto
a silica gel
column with ethyl acetate/petroleum ether (7/3). This resulted in 2.79 g (22%)
of 1,4-diethyl
(2Z)-2-[(dimethylamino)methylidene]-3-oxobutanedioate as yellow oil.
[0819] LC-MS (ES): m/z 243.95 [MW], tR =0.64min, (1.90minute run).
[0820] Step 3: Synthesis of 4,5-diethyl 2-14-1(tert-
butoxy)carbonyllpiperazin-1-
yllpyrimidine-4,5-dicarboxylate
0
0 0
NH
N )L0
r
Boc Et0Na, Et0H, reflux, 2h
AN I I 0
N 0 rN N
' N IN1) 0
Boc'
[0821] Into a 250-mL round-bottom flask, was placed tert-butyl 4-
carbamimidoylpiperazine-
1-carboxylate (1.0 g, 4.38 mmol, 1.00 equiv), ethanol (20 mL), 1,4-diethyl
(2Z)-2-
[(dimethylamino)methylidene]-3-oxobutanedioate (1.065 g, 4.38 mmol, 1.00
equiv), Et0Na (596
mg, 8.76 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 75 C
in an oil bath. The
resulting mixture was concentrated under vacuum. The resulting solution was
extracted with
ethyl acetate (100 mL) and the organic layers combined. The resulting mixture
was washed with
brine (100 mL). The mixture was dried over anhydrous sodium sulfate. The
residue was applied
onto a silica gel column with ethyl acetate/petroleum ether (1/5). This
resulted in 873.0 mg
(49%) of 4,5-diethyl 2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-
dicarboxylate as
light yellow oil.
[0822] LC-MS (ES): m/z 409.20 [MW], tR = 1.19min, (1.90minute run).
[0823] Step 4: Synthesis of2-14-1(tert-butoxy)carbonyllpiperazin-1-
yllpyrimidine-4,5-
dicarboxylic acid
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0 0
N)L0 LiOH N)Li OH
I 0
I Et0H/H20, rt, 8 h
0
Boc'N OH
0
Boc'N)
[0824] Into a 100-mL round-bottom flask, was placed 4,5-diethyl 244-[(tert-
butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylate (873.0 mg, 2.14
mmol, 1.00 equiv),
ethanol/water(5/2) (14 mL), lithium hydroxide (256.7 mg, 10.72 mmol, 5.00
equiv). The
resulting solution was stirred for 8 h at room temperature. The resulting
mixture was
concentrated under vacuum. This resulted in 1.02 g (crude) of 244-[(tert-
butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylic acid as a white
solid.
[0825] LC-MS (ES): m/z 352.45 [MW], tR = 0.73min, (1.90minute run).
[0826] Step 5: Synthesis of tert-butyl 4-16-(2,6-dioxopiperidin-3-y1)-5,7-
dioxo-
511,611,711-pyrrolo[3,4-d]pyrimidin-2-yllpiperazine-1-carboxylate
0
HCI NH
0 0 0
N).Li OH Ac2O
N
NH4N¨t
I OH
Pyridine, reflux N
Boc 0 Boc'N) 0
'N)
[0827] Into a 100-mL round-bottom flask, was placed 244-[(tert-
butoxy)carbonyl]piperazin-
1-yl]pyrimidine-4,5-dicarboxylic acid (735.0 mg, 2.09 mmol, 1.00 equiv). This
was followed by
the addition of acetic anhydride (10 mL), after stirred 2h at 130 C,
concentrated under vacuum.
To this was added pyridine (10 mL), 3-aminopiperidine-2,6-dione hydrochloride
(445.0 mg, 2.70
mmol, 1.30 equiv). The resulting solution was stirred overnight at 120 C in an
oil bath. The
resulting mixture was concentrated under vacuum. The resulting solution was
diluted with
dichloromethane (100 mL). The solids were filtered out. The residue was
applied onto a silica
gel column with ethyl acetate/petroleum ether (7/3). This resulted in 243.0 mg
(26%) of tert-
butyl 446-(2,6-dioxopiperidin-3-y1)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-
2-
yl]piperazine-1-carboxylate as brown oil.
[0828] LC-MS (ES): m/z 467.10 [M tR = 1.10min, (2.00minute run).
[0829] Step 6: Synthesis of3-15,7-dioxo-2-(piperazin-1-y1)-511,611,711-
pyrrolo13,4-
dlpyrimidin-6-yllpiperidine-2,6-dione
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0 0 0 0
r4NH
N¨t TFA I N
N DCM
Boc 0
HN) 0
[0830] Into a 50-mL round-bottom flask, was placed tert-butyl 446-(2,6-
dioxopiperidin-3-
y1)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl]piperazine-1-carboxylate
(243.0 mg, 0.55
mmol, 1.00 equiv), dichloromethane (5.0 mL), trifluoroacetic acid (2.0 mL).
The resulting
solution was stirred for 2 h at room temperature. The resulting mixture was
concentrated under
vacuum. This resulted in 320.0 mg (crude) of 345,7-dioxo-2-(piperazin-1-y1)-
5H,6H,7H-
pyrrolo[3,4-d]pyrimidin-6-yl]piperidine-2,6-dione as brown oil.
[0831] LC-MS (ES): m/z 345.25 [MW], tR = 0.61min, (1.90minute run).
[0832] Step 7: Synthesis of 4-14-(2-14-16-(2,6-dioxopiperidin-3-y1)-5,7-
dioxo-511,611,711-
pyrrolo[3,4-dlpyrimidin-2-yllpiperazin-1-yllethyl)piperidin-1-yll-N-1(1r,30-3-
(3-chloro-4-
cyanophenoxy)-2,2,4,4-tetramethylcyclobutyllbenzamide
H
HNTh
0 TZ.IN 0
c/NyN
N
N\
0 gam 0
,
0 r_N\
c -
NaBH(OAc)3, DCM,
0
H
N= 410, cf. 0
CI
[0833] Into a 100-mL round-bottom flask, was placed 444-(2-
oxoethyl)piperidin-1-y1]-N-
R1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide
(90 mg, 0.18
mmol, 1.00 equiv), dichloromethane (10 mL), 3-[5,7-dioxo-2-(piperazin-l-y1)-
5H,6H,7H-
pyrrolo[3,4-d]pyrimidin-6-yl]piperidine-2,6-dione (61.24 mg, 0.18 mmol, 1.00
equiv). This was
followed by the addition of DIEA (0.5 mL), after stirred at 30 C for lh. To
this was added
NaBH(OAc)3 (122.89 mg, 0.58 mmol, 3.00 equiv). The resulting solution was
stirred for 5 h at
30 Cin an oil bath. The resulting solution was extracted with dichloromethane
(150 mL) and the
organic layers combined. The resulting mixture was washed with brine (50 mL).
The mixture
was dried over anhydrous sodium sulfate and concentrated under vacuum. The
crude product
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was purified by Prep-HPLC with the following conditions: Column, )(Bridge Prep
C18 OBD
Column, 5um, 19*150 mm; mobile phase, water (10mmol/L bicarbonate amine) and
acetonitrile
(30.0% acetonitrile up to 51.0% in 8 min); Detector, UV 254nm. This resulted
in 50 mg (34%) of
444-(24446-(2,6-dioxopiperidin-3-y1)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-
d]pyrimidin-2-
yl]piperazin-1-yl]ethyl)piperidin-1-A-N-R1r,3r)-3-(3-chloro-4-cyanophenoxy)-
2,2,4,4-
tetramethylcyclobutyl]benzamide as a yellow solid.
[0834] 1H NMR (400 MHz, d6-DMS0): M1.12 (s, 1H), 8.90 (s, 1H), 7.91-7.89
(d, J=8.4Hz,
1H), 7.74-7.72 (d, J=7.6Hz, 2H), 7.49-7.47 (d, J=8.8Hz, 1H), 7.20 (s, 1H),
6.99-6.94 (m, 3H),
5.16-5.13 (m, 1H), 4.32 (s, 1H), 4.06-3.83 (m, 7H), 2.88-2.57 (m, 5H), 2.39-
2.33 (m, 2H), 2.07-
2.01 (m, 1H), 1.78-1.75 (m, 2H), 1.54-1.35 (m, 3H), 1.21 (m, 8H), 1.12 (s,
6H); LC-MS (ES):
m/z 836.45/838.45 [MH-], tR = 2.17min, (2.95minute run).
[0835] Chemical formula: C44H50C1N906 [835.36/837.36].
[0836] Total H count from HNMR data: 50.
[0837] D. Exemplary Synthetic Schemes for Exemplary BRaf Targeting Moiety
Based
Compounds
[0838] General Synthetic Approach
[0839] The synthetic realization and optimization of the bifunctional
molecules as described
herein may be approached in a step-wise or modular fashion. For example,
identification of
compounds that bind to the target molecules can involve high or medium
throughput screening
campaigns if no suitable ligands are immediately available. It is not unusual
for initial ligands to
require iterative design and optimization cycles to improve suboptimal aspects
as identified by
data from suitable in vitro and pharmacological and/or ADMET assays. Part of
the
optimization/SAR campaign would be to probe positions of the ligand that are
tolerant of
substitution and that might be suitable places on which to attach the linker
chemistry previously
referred to herein. Where crystallographic or NMR structural data are
available, these can be
used to focus such a synthetic effort.
[0840] In a very analogous way one can identify and optimize ligands for an
E3 Ligase, i.e.
ULMs/ILMs/VLMs/CLMs/ILMs.
[0841] With PTMs and ULMs (e.g. ILMs, VLMs, CLMs, and/or ILMs) in hand, one
skilled
in the art can use known synthetic methods for their combination with or
without a linker moiety.
Linker moieties can be synthesized with a range of compositions, lengths and
flexibility and
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functionalized such that the PTM and ULM groups can be attached sequentially
to distal ends of
the linker. Thus a library of bifunctional molecules can be realized and
profiled in in vitro and in
vivo pharmacological and ADMET/PK studies. As with the PTM and ULM groups, the
final
bifunctional molecules can be subject to iterative design and optimization
cycles in order to
identify molecules with desirable properties.
[0842] In some instances, protecting group strategies and/or functional
group
interconversions (FGIs) may be required to facilitate the preparation of the
desired materials.
Such chemical processes are well known to the synthetic organic chemist and
many of these may
be found in texts such as "Greene's Protective Groups in Organic Synthesis"
Peter G. M. Wuts
and Theodora W. Greene (Wiley), and "Organic Synthesis: The Disconnection
Approach" Stuart
Warren and Paul Wyatt (Wiley).
[0843] General Synthetic Scheme D-1
Br Br
,N,NH
+
N
XVI XVII
M-Ar Ar'
XVIII ,N-Ar-L-GH
,N-Ar-L-Gl-PG ___________________________________
N
XIX )0(
C)
0 0
0
0
Ar'
X
VII
,N-Ar-L-G1
N
XXI
[0844] A compound of formula XVI may be reacted with a reagent II'
(commercially
available or readily prepared using standard reaction techniques known to one
skilled in the art)
under Chan-Lam cross-coupling conditions, e.g. copper (II) acetate, pyridine
or diethylamine or
triethylamine, 100 C, to produce a compound of formula XVII. M' represents a
boronic acid or
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boronic ester; Ar represents an aromatic or heteroaromatic ring system; L
represents an optional
linker, represents a primary or secondary amine, optionally cyclized into a 4
to 8 membered
heterocyclic ring, wherein PG represents a suitable protecting group,
including but not limited to
t-butoxycarbonyl or benzyl. Compounds of formula XVII may be may be reacted
with a reagent
XVIII under palladium-catalyzed cross-coupling conditions, e.g. [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium, tri-tert-butylphosphine
tetrafluoroborate,
cesium fluoride, 1,4-dioxane, 90 C, to produce a compound of formula XIX. M
represents a
functional group capable of undergoing palladium-catalyzed transmetallation,
e.g. a boronic acid,
boronic ester, or trialkylstannane and Ar' represents an aromatic or
heteroaromatic ring system
with optional substituents. A compound of formula XIX may then be converted to
a compound
of formula XX by treatment with a reagent suitable for the removal of PG, e.g.
hydrogen
chloride in 1,4-dioxane or methanol when PG is t-butyl. A compound of formula
XX may also
be reacted with a compound of formula VII to provide compounds of formula XXI,
wherein X is
a suitable leaving group such as fluorine or chlorine, Y is C=0, the aromatic
ring of VII may
have further optional substituents, and reaction conditions are those for a
nucleophilic aromatic
substitution, e.g. triethylamine, DMSO, 80 C. In cases where the group Ar'
contains optional
substituents, e.g. a ketone, these may undergo further functionalization, e.g.
by treatment with
hydroxylamine hydrochloride and pyridine at room temperature, to provide
further compounds
of formula XXI.
[0845] General Synthetic Scheme D-2
Br Br
,N-Ar-L-31H
1
N
)(XII
XVII
0 0
XVIII
tNH
Br N
VII 1N-Ar-L' _
)(xi
N
)0(111
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[0846] .. Alternatively, a compound of formula XVII may be converted to a
compound of
formula XXII by using conditions analogous to those for the conversion of XIX
to XX in
Scheme 5. A compound of formula XXII may then be treated with a compound of
formula VII
as defined in Scheme 5 to produce a compound of formula XXIII. The compound of
formula
XXIII may then be treated with a reagent XVIII as defined in Scheme 5 to
produce a compound
of formula XXI. In cases where the group Ar' contains optional substituents,
e.g. a ketone, these
may undergo further functionalization, e.g. by treatment with hydroxylamine
hydrochloride and
pyridine at room temperature, to provide further compounds of formula XXI.
[0847] Exemplary Synthesis of Exemplary Compound 42:
[0848] (E)-2-(2,6-dioxopiperidin-3-y1)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-
dihydro-1H-inden-
5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-1-y1)-4-
methylisoindoline-1,3-dione
HO-N
= 0
0
N 0 0
[0849] Step A: 2-(2,6-dioxopiperidin-3-y1)-4-methy1-5-(4-(4-(4-(1-oxo-2,3-
dihydro-1H-
inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-
1,3-dione
0
0
N=
N N 0
N 0
0
[0850] To a solution of 4-chloro-2-(2,6-dioxopiperidin-3-y1)-5-(4-(4-(4-(1-
oxo-2,3-dihydro-
1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-1-
yl)isoindoline-1,3-dione
(100 mg, 0.14 mmol) in1,4-dioxane 10 mL and H20 1 mL were added methylboronic
acid (33.6
mg, 0.56 mmol), Pd(aMPhos)C12 (9.9 mg, 0.014 mmol), and CsF (85.12 mg, 0.56
mmol). The
resulting solution was irradiated at 90 C with MW for 2 h. After cooling to
rt, it was diluted
with EA (50 mL), and the mixture was washed with brine (3 x 20 mL). The
organic phase was
dried over Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified
by prep-TLC to afford 2-(2,6-dioxopiperidin-3-y1)-4-methy1-5-(4-(4-(4-(1-oxo-
2,3-dihydro-1H-
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inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-
1,3-dione (70
mg, 72.1% yield). LCMS (ES): m/z 706.3 [M+H]t
[0851] Step B: (E)-2-(2,6-dioxopiperidin-3-y1)-5-(4-(4-(4-(1-(hydroxyimino)-
2,3-dihydro-
1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-1-y1)-4-
methylisoindoline-
1,3-dione
HO-N
= 0
0
N,N
N 0 0
[0852] To a solution of 2-(2,6-dioxopiperidin-3-y1)-4-methy1-5-(4-(4-(4-(1-
oxo-2,3-dihydro-
1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-1-
yl)isoindoline-1,3-dione
(70 mg, 0.10 mmol) in acetonitrile 3 mL and pyridine 3 mL was added
hydroxylamine
hydrochloride (69.5 mg, 1.0 mmol). The mixture was stirred at 40 C for 20
min. Then it was
diluted with DCM (20 mL), and the mixture was washed with brine (10 mL). The
organic phase
was concentrated and purified by prep-TLC to afford (E)-2-(2,6-dioxopiperidin-
3-y1)-5-(4-(4-(4-
(1-(hydroxyimino)-2,3-dihydro- 1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenyl)piperazin-1-y1)-4-methylisoindoline-1,3-dione (19.6 mg, 27.8% yield)
as yellow solid.
1-EINMR (400 MHz, DMSO-d6): 6 11.09 (s, 1H), 10.89 (s, 1H), 8.72 (s, 1H), 8.58-
8.57 (m, 2H),
7.83 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H),
7.50-7.41 (m, 4H),
7.23-7.17 (m, 3H), 5.13-5.09 (m, 1H), 3.61-3.42 (m, 8H), 3.04-2.97 (m, 2H),
2.93-2.82 (m, 3H),
2.62-2.56 (m, 5H), 2.08-2.00 (m, 1H); LCMS (ES): m/z 721.3 [M+H]t
[0853] Exemplary Compound 41 may be prepared by a procedure analogous to
that
described for Examplary Compound 42.
[0854] E. Exemplary Synthetic Schemes for Exemplary BRD4 Binding Moiety
Based
Compounds
[0855] Exemplar Synthesis of Exemplary Compound 45: 2-((S)-4-(4-
chloropheny1)-
2,3,9-trimethy1-611-thieno13,24111,2,41triazolo14,3-al 11,41diazepin-6-y1)-N-
(4-(2-(2-(2-(2-((3-
(2,6-dioxopiperidin-3-y1)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-
yDoxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyDacetamide
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o NH2 HCI
0 0 0
OH HI (55% in water) OHCI 0 OH
______________________________________________ AO NH _________________
0 NH2 Red Phosphorus HO NH2
imidazole, MeCN Imidazole / (Ph0)3P, reflux
0 N 0 ayN
0
0
BocHN 41111.-1-11 BocHN
HO W
Na2CO3, DMF, 80 C
Is
(2)
N N
(1) HCI / dioxane
CI N 0
OH
TBTU, DIPEA, DMF
S
I N
y.
afah ,
N N 41111111P
WI 0
0
N,AniCI
0
[0856] Step 1: Preparation of 2-amino-4-hydroxybenzoic acid
[0857] A
mixture of 2-amino-4-methoxybenzoic acid (1.0 g, 5.98 mmol), red phosphorus
(556 mg, 17.94 mmol) and 55% hydroiodic acid (10 mL) was heated at 100 C for
14 h in a
sealed tube. The reaction mixture was poured into ice water. The pH of the
solution was adjusted
to 6-7 by sodium carbonate. The solution was extracted with ethyl acetate (20
mL x 3). The
combined organic phases were dried over anhydrous sodium sulfate, filtered and
concentrated in
vacuum to afford crude 2-amino-4-hydroxybenzoic acid (400 mg, 44% yield) which
was used in
the next step without further purification. 1HNMR (400MHz, DMS0- d6): (57.53-
7.55 (m, 1H),
6.12 (s, 1H), 5.99 -6.02 (m, 1H).
[0858] Step 2: Preparation of 2-acetamido-4-acetoxybenzoic acid
[0859] To a mixture of 2-amino-4-hydroxybenzoic acid (400 mg, 2.61 mmol)
and imidazole
(888 mg, 10.06 mmol) in acetonitrile (20 mL) was added acetyl chloride (789
mg, 10.06 mmol)
dropwise at 0 C. The solution was stirred at rt for 10 h and then quenched by
water (40 mL).
The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic
layers were
washed with brine, dried over anhydrous sodium sulfate and filtered. Volatiles
were evaporated
in vacuum and the residue was purified by column chromatography (ethyl
acetate/petroleum
ether = 2:1) to afford 2-acetamido-4-acetoxybenzoic acid (350 mg, 57%
yield).1HNMR
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(400MHz, DMS0- d6): 6 11.19 (s, 1H), 8.30 (s, 1H), 8.01-8.03 (m, 1H), 6.92-
6.95 (m, 1H), 2.30
(s, 3H), 2.15 (s, 3H).
[0860] Step 3: Preparation of 3-(7-hydroxy-2-methy1-4-oxoquinazolin-3(4H)-
yl)piperidine-
2,6-dione
[0861] To a mixture of 2-acetamido-4-acetoxybenzoic acid (400 mg, 1.69
mmol), 3-
aminopiperidine-2,6-dione hydrochloride (333 mg, 2.02 mmol), triphenyl
phosphite (2.0 mL) in
acetonitrile (10 mL) was added imidazole (383 mg, 5.63 mmol). The reaction
solution was
heated to reflux for 10 h. The solution was evaporated under reduced pressure
and the residue
was re-crystallized (20% ethyl acetate in hexane) to afford 3-(7-Hydroxy-2-
methy1-4-
oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (110 mg, 19% yield).1ENMR (400MHz,
DMSO-
d6): 6 10.94 (s, 1H), 10.51 (s, 1H), 7.84-7.86(m, 1H), 6.92-6.94 (m, 1H), 6.85
(s, 1H), 5.16-5.20
(m, 1H), 2.73-2.85 (m, 1H), 2.58-2.63 (m, 5H), 2.13-2.15 (m, 1H).
[0862] Step 4: Preparation of tert-butyl (4-(2-(2-(2-(2-((3-(2,6-
dioxopiperidin-3-y1)-2-
methy1-4-oxo-3,4- dihydroquinazolin-7-
yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)carbamate
[0863] To a mixture of 3-(7-hydroxy-2-methy1-4-oxoquinazolin-3(4H)-
yl)piperidine-2,6-
dione (161 mg, 0.348 mmol) and 2-(2-(2-(2-(4-((tert-
butoxycarbonyl)amino)phenoxy)ethoxy)ethoxy)ethoxy)ethyl methanesulfonate (100
mg, 0.348
mmol, prepared according to procedures of similar intermediate described in US
2015/0291562)
in DMF (5.0 mL) was added sodium carbonate (74 mg, 0.696 mmol). The mixture
was stirred at
80 C for 6 h. The resulting mixture was cooled to rt. Ethyl acetate (30 mL)
was added and the
organic layer was washed with water and brine. The organic layer was dried
over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The residue
was purification by
preparative TLC to afford tert-butyl (4-(2-(2-(2-(243-(2,6-dioxopiperidin-3-
y1)-2-methyl-4-oxo-
3,4- dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)carbamate
(55.4 mg, 24%
yield).1HNMIt (400MHz, DMSO-d6): 6 10.98 (s, 1H), 9.08 (s, 1H), 7.91-7.93 (m,
1H), 7.32-7.34
(m, 2H), 7.07-7.09 (m, 2H), 6.82-6.84 (m, 2H), 5.20-5.24 (m, 1H), 4.24 (s,
2H), 3.99 (m, 2H),
3.79 (m, 2H), 3.70-3.71 (m, 2H), 3.56-3.60 (m, 8H), 2.79-2.87 (m, 1H), 2.57-
2.70 (m, 5H), 2.17-
2.18 (m, 1H), 1.47 (s, 9H). LC-MS: (ES): m/z 655.3 [M+H]t
[0864] Step 5: Preparation of 24(S)-4-(4-chloropheny1)-2,3,9-trimethyl-6H-
thieno[3,2-
fl[1,2,4]triazolo[4,3-a][1,4]diazepin-6-y1)-N-(4-(2-(2-(2-(243-(2,6-
dioxopiperidin-3-y1)-2-
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methyl-4-oxo-3,4-dihydroquinazolin-7-
yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide
(Exemplary Compound 45)
[0865] To a pre-mixed solution containing (S)-2-(4-(4-chloropheny1)-2,3,9-
trimethyl-6H-
thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (6.11 mg,
0.01525 mmol) in
DMF (2.00 ml), TBTU (7.34 mg, 0.02287 mmol) and DIPEA (7.96 tL, 0.04575 mmol)
was
added 3-(7-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-4-
oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (8.46 mg, 0.01525 mmol, prepared
by treating the
product from step 4 with HC1 in dioxane) and the mixture was left to stir for
2 h. The mixture
was diluted with ethyl acetate and water. The organic layer was washed with
sodium bicarbonate,
water (3 x) and brine. The resulting solution was filtered through a thin pad
of silica gel and then
concentrated in vacuo to give a crude solid. This material was purified by
silica gel
chromatography on a Teledyne Combiflash ISCO eluting with Me0H/DCM (0:100 to
7:93) to
yield 24(S)-4-(4-chloropheny1)-2,3,9-trimethyl-6H-
thieno[3,24][1,2,4]triazolo[4,3-
a][1,4]diazepin-6-y1)-N-(4-(2-(2-(2-(243-(2,6-dioxopiperidin-3-y1)-2-methyl-4-
oxo-3,4-
dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide (10.1
mg, 0.01077
mmol, 71.1 % yield). 1-EINNIR (400 MHz, methanol-d4) E 8.55 (s, 1H), 7.96 -
8.00 (m, 1H), 7.36
- 7.50 (m, 6H), 7.03 - 7.09 (m, 2H), 6.87 (dd, J = 3.03, 9.10 Hz, 2H), 5.22
(td, J = 5.40, 10.91 Hz,
1H), 4.70 -4.74 (m, 1H), 4.22 (d, J = 3.33 Hz, 2H), 4.10 (d, J = 4.30 Hz, 2H),
3.85 -3.91 (m,
2H), 3.79 - 3.84 (m, 2H), 3.64 - 3.71 (m, 7H), 3.55 - 3.64 (m, 2H), 3.42 -
3.50 (m, 2H), 2.71 (s,
3H), 2.66 (d, J = 3.33 Hz, 2H), 2.44 (d, J = 3.33 Hz, 3H), 1.89 (s, 3H), 1.68
(d, J = 3.33 Hz, 2H),
1.29 (br. s., 3H). LC/MS (ES): m/z 937.19/939.19 [M+H]t
[0866] Exemplar Synthesis of Exemplary Compound 44: 24(S)-4-(4-
chloropheny1)-
2,3,9-trimethy1-611-thieno [3,2-f] 11,2,41triazolo [4,3-a] 11,41diazepin-6-y1)-
N-(4-(2-(2-(2-(24(3-
(2,6-dioxopiperidin-3-y1)-2-methy1-4-oxo-3,4-dihydroquinazolin-8-
yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide
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0 0 COOH NH2 HCI
)0
* OH HI (55% in water) OH AcCI 0 N 0
NH2 Red Phosphorus
NH2 imidazole, MeCN 00
0
OH imidazole / (Ph0)3P
reflux
H 0
O35
0 N = 0, n
c3.0Ms
BocHN = N
N 0
Na2CO3, DMF, 80 C
BocHN
[0867] This molecule was synthesized using the same method as described in
Example 1.
The key intermediate was prepared according the scheme listed above. 1-H NMR
(400 MHz,
methanol-d4) E 8.55 (s, 1H), 7.96 - 8.00 (m, 1H), 7.36 - 7.50 (m, 6H), 7.03 -
7.09 (m, 2H), 6.87
(dd, J = 3.03, 9.10 Hz, 2H), 5.22 (td, J = 5.40, 10.91 Hz, 1H), 4.70 -4.74 (m,
1H), 4.22 (d, J =
3.33 Hz, 2H), 4.10 (d, J = 4.30 Hz, 2H), 3.85 - 3.91 (m, 2H), 3.79 - 3.84 (m,
2H), 3.64 - 3.71 (m,
7H), 3.55 - 3.64 (m, 2H), 3.42 - 3.50 (m, 2H), 2.71 (s, 3H), 2.66 (d, J = 3.33
Hz, 2H), 2.44 (d, J =
3.33 Hz, 3H), 1.89 (s, 3H), 1.68 (d, J = 3.33 Hz, 2H), 1.29 (br. s., 3H). LCMS
(ES): m/z
937.19/939.19 [M+H]t
[0868] Exemplary Synthesis of Exemplar Compound 43: 2-((S)-4-(4-
chloropheny1)-
2,3,9-trimethyl-611-thieno13,24111,2,41triazolo14,3-al 11,41diazepin-6-y1)-N-
(4-(2-(2-(2-(2-0-
oxo-2-((S)-6-oxopiperidin-3-yl)isoindolin-4-
yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide
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0 0 0 e'
0 NH ci)L0 o NH MsCI, TEA ONH c NH
____________________ ' NaN3
or'r NaBH4 DCM, 5oC- o).r DMF, 65 C
0 OH THF, -15 oC 0 OH 0 OMs
0 N3
NH
Boc, c NH 0
Pd/C, H2, 40 Psi HCI(g) H2N"<¨ 0
HNI, =
CH3OH, 12 h dioxane, it HCI
Br NH2
NH e NO2
H H2, Pd/C CH3CN NH
H2N,,<¨ 0 + 02N r-N
HCI ________________________ 0 0 TEA, reflux 0 N,..\ ,o 40 N
,..(- 0
0 0
ill ====.----No..---...,.0_ Dess-Martin reagent io ON...õNo....õ..õ0
-....- "s0----N,OH ¨.- ====.----",.
0"---Nr-
02N 02N
CH2Cl2 H
I NH2
NaBH3CN NH
0 NIX¨
THF/Me0H/HOAc 0
0
o
H2N . \
Me0H / THF
H ,-,
0--\_0
\ ICI' H2, Pd/C
----\ 02N . o\---\
0-\ANs.
4. 0
0--\_4i -......)
= 0
[0869] The key intermediate for the preparation of this compound was
synthesized according
the scheme listed above. The final step of amide coupling was carried out
under the same
condition as described in Example 1. 1H NMR (400 MHz, CDC13) d 9.03 (s, 1H),
7.45 (dd, J =
8.71, 13.21 Hz, 4H), 7.31 -7.37 (m, 3H), 7.24 (d, J = 7.24 Hz, 1H), 6.84 (d, J
= 9.00 Hz, 2H),
6.78 (d, J = 8.02 Hz, 1H), 6.75 (br. s., 1H), 4.66 - 4.73 (m, 2H), 4.20 (d, J
= 2.74 Hz, 1H), 4.07 -
4.12 (m, 2H), 3.80 - 3.90 (m, 3H), 3.64 -3.77 (m, 10H), 3.52 - 3.58 (m, 1H),
3.35 -3.42 (m, 3H),
2.68 (br. s., 3H), 2.52 - 2.59 (m, 2H), 2.41 (s, 3H), 2.02 - 2.08 (m, 2H),
1.69 (s, 3H), 1.26 (s, 3H).
LC-MS (ES): m/z 895.22/897.22 [M+H]t
[0870] Protein Level Control
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[0871] This description also provides methods for the control of protein
levels with a cell.
This is based on the use of compounds as described herein, which are known to
interact with a
specific target protein such that degradation of a target protein in vivo will
result in the control of
the amount of protein in a biological system, prerferably to a particular
therapeutic benefit.
[0872] The following examples are used to assist in describing the present
invention, but
should not be seen as limiting the present invention in any way.
[0873] Exemplary Embodiments of the Present Disclosure
[0874] The present disclosure encompasses the following specific
embodiments. These
following embodiments may include all of the features recited in a proceeding
embodiment, as
specified. Where applicable, the following embodiments may also include the
features recited in
any proceeding embodiment inclusively or in the alternative.
[0875] An aspect of the present disclosure provides a cereblon E3 ubiquitin
ligase binding
compound having a chemical structure selected from:
x x X X
cro: µAZ (;1.4
Q3
I I
Q2
A
Rn \G' Rn Rn R'
(al) (b)
X
X X
_________________________ N/
Q3 Q(Q4N'Is$'1c
Z
x/ \
Qi
Rn G' Rn Rn
(c) (dl)
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X xN Q3 (14(X
Q(C)4N5j4")(
I I Rn I I NhAAA
Qi
Qi A
Rn
Rn Rn
(e)
X )(
X X
QC14N-54J-
Q3
I I
Qi Qi
Rn
_____________________________ Z Rn
Rn/ Rn
(a2) (d2)
Q3
Z
.11-1
Qi
Rn
RnQ2/
(a3)
wherein:
W is selected from the group consisting of CH2, CHR, C=0, SO2, NH, N,
optionally
substituted cyclopropyl group, optionally substituted cyclobutyl group, and N-
alkyl;
W3 is selected from C or N;
each X is absent or independently selected from the group consisting of 0 and
S,
Y is selected from the group consisting of CH2, -C=CR', NH, N-alkyl, N-aryl, N-
hetaryl, N-
cycloalkyl, N-heterocyclyl, 0, and S;
each Z is absent or independently selected from the group consisting of 0 and
S;
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G and G' are independently selected from the group consisting of H, alkyl
(linear, branched,
optionally substituted), OH, R' OCOOR, R' OCONRR", CH2-heterocyclyl optionally
substituted with R', and benzyl optionally substituted with R';
Qi, Qz, Q3, and Q4 represent a carbon C substituted with a group independently
selected from
R', N or N-oxide;
A is independently selected from the group H, alkyl (linear, branched,
optionally substituted),
cycloalkyl, Cl and F;
R comprises -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -
CR'NR'R"-,
(-CR' 0),,R", -aryl, -hetaryl, -alkyl (linear, branched, optionally
substituted), -cycloalkyl,
-heterocyclyl, -P(0)(OR')R", -P(0)R'R", -0P(0)(OR')R", -0P(0)R'R", -Cl, -F, -
Br, -I,
-CF 3, -CN, -NR' S 0 2NR' R", -NR' CONR'R", -CONR' C OR", -NR' C(=N-CN)NR'R", -
C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C-NO2)NR'R", - S 02NR' COR", -NO2, -
CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=0)(C=N-R')R", -SF5 and -0CF3;
R' and R" are independently selected from the group consisting of a bond, H,
alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=0)R, heterocyclyl, each of
which is
optionally substituted;
n' integer from 1-10;
represents a single bond or a double bond;
represents a bond that may be stereospecific ((R) or (S)) or non-
stereospecific; and
Rn comprises 1-4 independent functional groups, optionally substituted linear
or branched
alkyl (e.g., a C 1 -C6 linear or branched alkyl optionally substituted with
one or more
halogen, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally
substituted aryl (e.g., an optionally substituted C5 -C7 aryl), optionally
substituted alkyl-
aryl (e.g., an alkyl-aryl comprising at least one of an optionally substituted
C1-C6 alkyl,
an optionally substituted C5 -C7 aryl, or combinations thereof), optionally
substituted
alkoxyl group (e.g., a methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy;
wherein
the alkoxyl may be substituted with one or more halogen, alkyl, haloalky,
fluoroalkyl,
cycloalkyl (e.g., a C3 -C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted
)/Nc
, 0 0
(e.g., optionally substituted with one or more
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halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl),
or aryl (e.g.,
0
C5-C7 aryl)), optionally substituted
(e.g., optionally
substituted with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl
(e.g., a C3 -
C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms; and
each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6,
n is an integer from 1-10 (e.g., 1-4).
[0876]
Another aspect of the present disclosure provides a bifunctional compound
having
the chemical structure:
CLM¨L¨PTM,
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate,
polymorph or
prodrug thereof,
wherein:
the PTM is a small molecule comprising a protein targeting moiety;
the L is a bond or a chemical linking moiety covalently coupling the CLM and
the
PTM; and
the CLM is a small molecule cereblon E3 ubiquitin ligase binding moiety of
claim
1, wherein when n is 2, 3, or 4, then at least one of R. or W is modified to
be covalently joined to
the linker group (L) or a PTM.
[0877]
In any aspect or embodiment described herein, the CLM is linked to the PTM,
the
chemical linker group (L), or a combination thereof via W, X,
R2, R3, R4, R', Qi, Qz, Q3, Q4,
and Qs.
[0878]
In any aspect or embodiment described herein, the PTM is a moiety that binds
BRD4,
BRaf, Estrogen Receptor (ER), or Androgen Receptor (AR).
[0879]
In any aspect or embodiment described herein, the compound may further
comprise a
second E3 ubiquitin ligase binding moiety coupled through a linker group.
[0880]
In any aspect or embodiment described herein, the second E3 ubiquitin ligase
binding
moiety binds or targets an E3 ubiquitin ligase selected from the group
consisting of Von Hippel-
Lindau (VLM), cereblon (CLM), mouse double-minute homo1og2 (MLM), and
inhibitors of
apoptosis proteins (ILM).
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[0881] In any aspect or embodiment described herein, the CLM is represented
by a chemical
structure selected from the group consisting of:
o o
o
o o
______________________________________________________________ NH
_______________________________ NH
0 1/
Rn
0
0
Rny
0 0 0 0
_______________________________ NH __________________________ NH
_________/N 0 1/.___. / __ 0
Rn Rn
0 0 C)
0 0
F
F o 0 0\
0 0
_______________________________ NH
______________________________________________________________ NH
"----/K
/ 0 N ___________ 0
Rn Rn
0 0\
0 0 \
7 NH
NH
___________________________________________________________________ 0
1 N
/
Rn 0
0
Rn
0 0\ 0
0 N (
_______________________________ 0 , JKN NI, \)-NH
\ < 0
Rn/ 0
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0 0 0 0
_____________________________ NH
NH
/1
Rn 0 Rn 0
H
N 0
0 o
0 0
_____________________________ NH
_.,..JK N
71 .........\(N ___________________ 0 1
Rn
00 Rn
0\ 0 0\
_____________________________ NH
N __________________________________________________________ NH
N.-------/K .--
N __________________________ N ____________ 0
N--A(
Rn(/ 0 Rn 0
H
N
0 o o
X
( __ N,
N
N
Rn RnY
=
[0882] In any aspect or embodiment described herein, the linker (L)
comprises a chemical
structural unit represented by the formula:
-(AL)q-
wherein:
(AL)q is a group which is connected to at least one of the CLM, the PTM, or a
combination
thereof;
q is an integer greater than or equal to 1;
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each AL is independently selected from the group consisting of, a bond,
CRL1RL2, 0, S, SO,
SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3S02NRL4, CO,
CRL1=CRL2, CC, SiRL1RL2, P(0)RL1, P(0)ORL1, N1L3C(=NCN)NRL4, NR13C(=NCN),
NRL3C(=CNO2)NRL4, C3_iicycloalkyl optionally substituted with 0-6 RL1 and/or
RL2
groups, C3-iiheteocycly1 optionally substituted with 0-6 RL1 and/or RL2
groups, aryl
optionally substituted with 0-6 RL1 and/or RL2 groups, heteroaryl optionally
substituted
with 0-6 RL1 and/or RL2 groups, where Ril or RL2, each independently are
optionally
linked to other groups to form cycloalkyl and/or heterocyclyl moiety,
optionally
substituted with 0-4 RL5 groups; and
RL1, RL2, RL3, RL4 and RL5 are, each independently, H, halo, C1-8a1ky1, 0C1-
8a1ky1, SC1-8a1ky1,
NHC1-8alkyl, N(C1-8a1ky1)2, C3-11cycloalkyl, aryl, heteroaryl, C3-
11heterocyclyl, OCi_
8cyc10a1ky1, SC1-8cycloalkyl, NHC1-8cycloalkyl, N(C1-8cycloalky1)2, N(C1-
8cycloalkyl)(C1-8alkyl), OH, NH2, SH, SO2C1-8alkyl, P(0)(0C1-8alkyl)(C1-
8alkyl),
P(0)(0C1-8alky1)2, CC-C1-8alkyl, CCH, CH=CH(C1-8alkyl), C(C1-8alky1)=CH(C1-
8alkyl),
C(C1-8alky1)=C(C1-8alky1)2, Si(OH)3, Si(C1-8a1ky1)3, Si(OH)(C1.8alky1)2, COC1-
8alkyl,
CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8alkyl, 502N(C1-
8alky1)2,
SONHC1-8alkyl, SON(C1-8alky1)2, CONHC1-8alkyl, CON(C1-8alky1)2, N(C1-
8alkyl)CONH(C1-8alkyl), N(C1-8alkyl)CON(C1-8alky1)2, NHCONH(C1-8alkyl),
NHCON(C1-8alky1)2, NHCONH2, N(C1-8alkyl)S02NH(C1-8alkyl), N(C1-8alkyl) 502N(Ci-
8a1ky1)2, NH SO2NH(C1-8a1ky1), NH SO2N(C1-8alky1)2, NH 502NH2.
[0883] In any aspect or embodiment described herein, the AL is selected
from the group
consisting of:
-N(R)-(CH2).-0(CH2),-0(CH2)0-0(CH2)p-O(CH2)q-0(CH2),-OCH2-,
-0-(CH2).-0(CH2),-0(CH2)0-0(CH2)p-O(CH2)q-0(CH2),-OCH2-,
-0-(CH2).-0(CH2),-0(CH2)0-0(CH2)p-O(CH2)q-0(CH2),-0-;
-N(R)-(CH2).-0(CH2),-0(CH2)0-0(CH2)p-O(CH2)q-0(CH2),-0-;
-(CH2).-0(CH2),-0(CH2)0-0(CH2)p-O(CH2)q-0(CH2),-0-;
-(CH2).-0(CH2),-0(CH2)0-0(CH2)p-O(CH2)q-0(CH2),-OCH2-;
NTh-
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1-(CH2)m-N N-(CH2)n-NH
1-(CH2)m-N N-(CF12)n-0
--;--(CH260(CH2)n-N N-(CH2)0-NH
--HCH260(CH2)n-N N-(CH2)0-0
--HCH260(CH2)n-N/KN-(CH2)0-NHµ
--1,--(CH2)m0(CH2)n-N/V7-(CH2)0-0
,
(CH2)m-:- -1-N\ 0
-1:-NDCJ
0
(NCH2)m-h
(CFA)rr,i
\N-(CH2)m4H ; ,(CH2)m ;
(CH2) =
_____________________________________________________ r
0 0
0 __
.. N
3 1 8
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H )-0(CH2)m0(CH2)n0(CH2)p0(CH2)q0CH2
X =
-I-NH =
0(CH2),,O(0H2),,O(CH2)p0(CH2)q0CH2
-I-NH =
0(CH2),,O(0H2),,O(CH2)p0(0H2)q0CH2
-I-NH =
A o(cH2)õ0(cH2),,o(cH2)poccH2)gocH2
-I-NH =
0(CH2),,O(CH2),,OCH2
0(CH2)m0(CH2)IOCH2
\i<N-
X ;and
nr.H
; wherein
m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20;
when the number is zero, there is no N-0 or 0-0 bond
R of the linker is H, methyl and ethyl;
X of the linker is H and F
1-N
N---(CH2)m0CH2
where m of the linker can be 2, 3, 4, 5;
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----.,' C)),:
, N / '
N WC)) '=,,,N 0())
H
H H
%
q.---.,-0-.,..õ.--.,0,--,,,O.,õ.--.,(:),µ
H H
/N0()0()(),
H H
%/N .(300C)0µ(
H H
ri
><o
0
H
><0 NNX
õ
0
H
H
>C)N,,/
/
0 0
, H ,
\ A __ \
, 0 / _ ¨N N¨ ¨ ¨ ¨N N¨ ¨
0 \ __ '/
--0 __ / ___ N N
\ __________________________________ 0¨ -
320
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/
H H H H
1\1()0()e%<
H H
N 00 C 0\.0,
, N %'N 00/
H H H
'iNIC)C3C) \''( 'iNIN %000'
H H
9% (:) ,0
;''N S 134%! ;'/Ni
H H H
1/N1C)()µr ,./ õ."..,,,,O.,,,,-,--..,.>
/ N
H H H
1 / 0 \_ /-7
7-71-- %/, N o< -:-N-C)
-1=N 0 H
H
HN - \
..--0-0" \ ______________________ /0 ,<
_
A H
,
, ,
/-.....f"N\
, .,
r N
N L.,./N,...../.%-
f
H H , N
H
,
: c :N.,,=,,,_õ.0
H - H
H =
0
'
. NO'C' \ *
.00 n-N\
1 -," N . Nr \- I r- ,
-1-NH ' H \ ______________________ 0
1
N
H = )
,\
H - I
N /
,õ,.....õ..,--,õ0 el \ / /7 ' N
H, \
1
0
\ I :
AN 1-1
N-\_ r:- ________________________________________ ._
/ 0 >N01)o
--/ \ N 4n :
\ ________________________________________________________ /
321
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...r...õõØ..,.......^-,00.......,N:1-,
,
H
o
2-2E-
,
Oey'L'L
0 = 0 ;
,
OH
0
OeY41.1. ,Lz1, 0 0 j'ccss
0 ; ;
0 0
0
0
0 0
0 cr
. ;
\.
'LLL. 0
H 0
C) C)(µ\
cs' = 0 = 'N-
55' =
0 0 0
H 1 1
51 = l'- 51 = l'-
cc'
0 0
,.v....--,..õ,0.......õ....--,.0,---.1.rih.
0
''1=,5--(s . 0 = 0
,
0 0 0
322
EZ
0
-11-r N
Hss- 0 N
N e iN
0
. . o __
IsV 1 0
-/ N.,.._,z.,_õ_,,,,,,,,..____,),
0 N o
, ,
,...._ z0-1
-....., f
N¨N,
0
0
c c c c
=
0 ...--..,,....0
0 0 N //".ro...",.0 Isl
0 1
NO 0 1r
'
0 I / 0 N ,,
c c c
=.fre I = iy0(3 = 6r0
0 0 \N I 0 /
N I
N ,
c c c
= ,/.r0 0 0
= /Y0 0
= /YC)
ty
0 0 0
N I I
IN
\
c c c
0
r NX
0
Y
o
,
=o t ,
N,
0
c c c
= 0
= -65-6H0.1',- = ss-60-1.Lz-
OLS9Z0/6IOZSI1LIDcl 918661/610Z OM
TO-OT-OZOZ ZT6S600 VD
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HO
0 0 N 0
\ NZN j4 -csss Nj-Los,r
= 0
=
/¨
0 / __ \\ C----1)C -/-1
/¨ /-0 5
( \i-Nr-\N-/ N'o
\/ . 1-N N-f
\/ . 1-N N-f
\/
5 /--\
1-N N-CN-;µ I-Nr-\N-CN-i-
,
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I.
aõ.,õ-s s z -.,. .,..õ,...,,,,,,, 0 ,,rµi,..--..,õ,.0
H H H E I
0..õ..; - x/
µ
,;1%, Os'\ ,,:rq /\r0 1 ss; kr\l 1
N
H 1 H H
/X ../,..../.õ,,,-
x/ X = H, F
H ) , 0 lip
,411 lb ' '''N ()N
H
../
...,N \ / 0 1=11 1
H k 40 0 \
N
H
0
H
H
%'N'''() 0 , µ,.._ ::N,..-.0 0 , õ.....
' N
H
H 0 0
,
0 0 7'N ,1,--io 0 \ ,,,N µ,..õ
, , - \, ,--
H H _E Ni
0 0
H H H
N x/%
H E I
H H N _E Niõ,...õ..õ....
(:),--;=,
,
H -' 0
"N .µ , N
µ H
H
N ,
N
X X
0 r o\i_ 11\N \ / \ -1- / 0\ r \_:_
N 1 N i
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-1-NH *
N\ 7 , -1-NH * N) ,
' -1-NH
¨\ /1-
\-0 N \¨ Or:- * 11¨\N i:-
¨ r\_0
, 0
-1-NH * /¨ 0 -1-NH , -1-NH
,
N N¨ 0¨\ , / N¨\_ r:- N¨\ /-:-
\__/ / __\ ¨ o \-0
,
0 _:-
-c -1-7 K¨) _ p-\ p-...\ õ
-'-NH / 0 ¨\ - -:-N H
\ _ _
\ / I \ / __ ¨ _ _
, µµ.
II C 0 ¨\,-
- ¨ / - \ s H
\ _ _ nµ
,\Nõ--,.,.....õ----..0,--N
<NO'rsi
H
0,.;v
.õ.µ,N,,,---...s \ µ1110 s H (:)r.'x ' <N ,
0/ \ 0 ; \NI c,/\) ''NTh' 1
H H = 1
- N
N
. /
_______________________________________ /'
1-1Ni=-<>"0¨d FiN.--Ø. " 0 ¨( fIN...-0-..0-0
X N
X = H, F X
'
ar\l'===-0.."0¨µN i j¨\_ _ 0--.10¨µ j-0
/ 1 N 1
1 1 1
HNi===-0".10 = ,. 1411"0-.10 = - ,
1
,\'''N.....0,.iiiI0 --
/ \ ..i H
N¨
' N---k_
\¨/ N
\ L
P o
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r',
0
HN
... H!si0 ..0
p ,,,10
' i_iµ HN.
N
-A"
X
0 ....._,,,---;.,....õ, =K --/ N ....---
,,,.,,,0õ,_õ..%_;.,-
HN0, H E 1 -;--- 4 ./,
X X
ieØ,%0
/`/CNo
0' H 411, \ , H 410 \ /
X
-\--
0 ' 0 '
H H
H
,,,, .,N./.Ø,, \ , ,,,,,N....0
o -=/,o 0
\ / ,
,_ '
0 0 1
_.....,%0..a
HN....0-.0* orµc -HN-.01 4Ik ,== ..,L, -
N/ \ \-
-;--
_ I_ _ I _
* / HNN\,'.' H N\,,(
1-IN. I .0 = lo)
/
N%
r--N N N ' ,,
N
- 7\...--Nr---N -ii -N/
, - /
M-"
H
0
/--\-K \N
--N N /' --NXN-(
N-i --NN- -- \ ,i
\__/ / I
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.-
(
--NN --NN
-;-NXN-(
/ /
-:- XN-(
/
$:
0-\__
N - \ HO HQ
I/¨\ ,
-:-N N-\ / __ I /--\
I /-- N \ __________________________________________________________ \O-/N
-:-N N 0-' N -:-N \/ N \/ \/
_____________ 0-µ_. _ .
- --
1 /--\ /
o)ra
I /--\
HN ,
-:-N N- j \ -:-N N
\- NI N ,-- µ.
\-/ 0 -1-- 0-'
-:-N N-µ / 1-1N \---\ ,
-:-N N
\- N t. 0-:-
0
-;-N r-\N-{ __ \- 1\-INI--( \N-r - / HN \-
oNN
N
0
-i -
. i
/-:-
\,
-141-CN-µ __ j 11 N-CN-µ j-eo
N N N __ '
i
/--\ -/ 1 \ FIµNI-CIN
"10 0-1' HNI'Ll Ni I
-i-- 0--\ =
,,, N
õO
HN )(INI H
N,..N.......õ-----.)\----N,,Ox
-i- F F
where each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20.
[0884] In any aspect or embodiment described herein, the AL is selected
from the group
consisting of:
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-
- %
Nr"--N
µ....._/N -,'.. 10--N N-':- N---N N 1-
\¨/I
Nr----\ --- Nn N- N"
r\__(:D--Nr-\N0 ,
,,,0--7-- \...,....)q0.-7- \........../N - \____/
N / ' N / m
= \
ro
' N
--/I 'NN ,0N , /........y.-N\ i
N 94 N,,' N.,
, -/-0 WI-
1
0 N
0#
, ,0--7-NO.sµµNIN,,,,,
.,,
,-,
N , -
/
, :o......7--N___\__
---\ ,
0---/
N N-/-
01 n4-i N,,CI.V.'N _ rj1 s' s,\CoN N
,
...,
N;,
"m
, ,Or000l rl\f' --,LeNi NN
õ
, ,0--7--NON
-=-N NJ
N
`-,,'
---µ1=1 .',
ON /-----\
s 0_7-N j C 1 , %,,I3V'Na, rN ,,,Q,..../---NN-"No .
N
0
0
0 Isi
, 0,....0000,1.,,,õ
/
.....N 4N 0 i kip
H ; H = H ;
a0õ_,,,,,,,0,-/"......,..--y-\la
41,1 11111IP N 41 I Illij o .
H = H
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0
0,Ø0õkõ,
4N 0 4N WI
H = H =
; ,
F 0 0
F
/
isl
H = H =
; ;
,,,N V
11 410
0 ; 0 ;
0
N-----(3-...../\--- (1 -...../\..-../k, ....-11 0
H ;
411 0
0
0 ,ss
0 0j-,s sThC)0(),rcr
sv = H =
,
4N
0
-..,.,
0 ,
H ss N./\....õ.õ.0 0j.cr ., 4NWOOr
\,.
:.õ-...-.... 0 jj......, r' ",,,,...../"..,...õ,.
H
S = H 0 ;
0
0 crtr., ..--..õ.0
N
110 4N lei (2= ,,
4N '()'=0()J./ . H
H cc's = H =
,
0
0
N
H / 4N------õ---,.....---..../ . 4- N 0 0-"...--(3 /.\(3-
...A../ .
0
0
4N el lei eY\- 0
INI,"c)
I - I
= H = H ; ;
/-.N.........--..,..õØ.õ......N
H
Thr 11 OThr"Lµ
0 ; 0 = 0 ;
330
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o
/ o
H crwoThr /,,,N 0 . f. I0 0
0,..),..v.
; H
0 = H =
)
4 N ,====-=====.õ.0 N,.,
H
VI
U µ F 0 0 N,
U
eY 4
N OC)(3,,s' `(N al / H
0Thrµ
0 = H ; H 0 ;
/ 0 FN __.._0 N
H 1 0
N
N
12, )(µ 4 ef7 U / '2, -,..
N,.........õ.0 0
eY eY t /
H H
0 = 0 = 0 ; F =
, ,
0 r< N 0 0.)2,?_ 0
H/-..N.."...,.õ...".o...---.,,O..,..).õ
/ .
fsis,....,..a...,....--".........,0..".....;
/ ' =====.o,/
= H
0
0 0
/
0 1,1(3 0 / 4
N--..10 0 / cr\N 0\.0j
N OC)Js/ H H
1 F F = H i =
)
0
0 0 0
/
N 110 4 0
.4 \
/ '&N '=,.. N N 0 /
H 0 H
; . H H =
)
0 0 r" N
--.. ---=,.,.....0 0
110 / 4NIC) 0 /
H-.--i H i N
F F H 0
;
0
11 '_8 L:J
1 ; µ /
NI:3 . 110 ci
./ H H H
H 0 = 0 = F =
,
0
`',
0 4N,--\ N. 101 I 0 0
4 N Orssr . µ.---0--0-y 's'
0
H ' 0
H 0 = F =
0 0 0
/ 4 0,0)-00 "Jõ00, ,O.0 0
0
F = H = H ;
0 0
4 e0.õ0 0 ''2,
I=0
\ 0 i 0 6 ====.,
N--- / / -.re `...,
/
1 0 4N
= 0 ,r . H E
"4111IXF F =
111-1111 F 1 H .
;
0 0 0
4
isrro,,,, '., /
N .
F ; F , F .
,
\
\
0 0 Fs 0
4N N !(3' 0 0 0 H 1
H 1 H E
F =
,
331
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0
'N ,0,0 0 0,)
I cos, N 0 0 0 4N 0 0 4 ,cr0 0 0
H H E /
1-1
F ," = rPrr = H
, =
0
0 4-, 0 0,)i
" v<N,Cr 0 o(N,Cr 0
H H ,,o,õ0 0 41/4L.
''N
F ; F ; F = H ;
I
N N /
H = H and H , wherein each m and n
is
independently selected from 0, 1, 2, 3, 4, 5,6, 7, 8,9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20.
[0885] In any aspect or embodiment described herein, the AL is selected
from the group
consisting of:
,
7'4:)()NOrN-N-= ;03 0 N \
H H
:*
=.% 0 N`K ,%,00 H
H ; = =
. ,0,,
40 o,......,0,.. ,
N % Cc Oli ow.N:t:
. H = H ;
= :0 41 0 N H
H . .
,
isr,- ,--0 0 r
. .
,
,
,'N `,, 0 N1
N 0 N
i)
I,
i = ;
.,
(0.õ,...,..===.,N..."..1
c.N 0 IsL N 0 N
i) Lci ,
/ 0 =
;'= .
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= =
NJ 7sN1
N 0 N cN N
0, I
I's = ;'µ =
% 0 N .. N _.=
H, N N
. 1
H
/ N 0 ,
= H ,'%
I,...),............,N.,,
; ;
N
N
c..N (:)0N):
cN (:)0./=.0). .
H =
,
)N-1
/
c..N .=e=O.'N,`µ' 'O N" .
H . H .
/
/ ., N
/
./
s/
"00"µ
c.N N 0/Y% F F
U F F
00'µ`
F F = ; ;
./
µµ,ON
L,N NL c,N NL
U U
e.Y.N)% e.Y.N)%
F F H = F F H =
' N
' U
Oi\N-µ` N
FE H
s: c,N
= F F H =
F F =
; ; ;
Il._. NJ1 iN
cN %; N (:)/\/' N
F F ; FE H
;
333
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N
ON
F F = H .
s ,
ON"I`
H . H =
s,;() 0V\0()01s:
H
OH OH =
0
OH
OH H
OH
; 0
0 = H
0 ; 0
0
H ; =
0 0
s,00j.L
H . H ;
0
H ''', O'C)0() =
0
H ;
334
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' H
N ))s
r oC)) () \ /hko/\:,= 0
m
i n / n
/ õ...,tyØ,,,(.......0)::=,:s. ,,\.4..*,(,..../.... y....), J
sss,.Ns,,.(s,,,,,,,, r.... /,
m
n n n
0
0 '
/orõ,, õ...\_... s Nõ......(,.....õ.õ..0),..../
\
mõ
m
n
0
\ s..,. N 0.4õ))(= \ ,,.N.õ....,.........4"),.,/
\j.::õ.....,N.....8 /
= ,, =
lIe Ill'
= m n
0 0 0
/ \ Ni H
N I
H =
('='(0('-'r ,'C
,s, f( ) N N ( 0 \ N -....1
"ss m \
_______________________ n o
2\
/ \ H
N
\ 10\4 _________ N\ /N n1 ( \ /0 \ 0 .s µ ., s .
OH)s s \21 ( \(\/rs
\ \ n
o
P n \ 10
/ \ \ H ,
\<(0\4 __ N\ /N ( \/0 0 N¨ - = , ,
7 ______.s. =,,,,:
o n n
n
P
\
\
=%;.oN ,,,,,.,--.,...., N
.s.:s \oN ....,..,....,.,. \..:
N %
\
i n n
N N
m
m
=,,,,, ) i
. =-'
N ( 'KC) s' - 4'\N/ \ N \ \
, m \ __ / m
\
ts,
= ) o s( ss, V 1 -------\
s
N = \
I
- =
,
7=.%
0 =
\,.
Na 0 m
41 N / \N¨E
1 / \ . / \ / / \
/ ________________________ 0 ______________ NH
1 )( - N 11-/ \ r
1-N N ( m -
-1--N N- - _.
1 \ / i-N\
/N ( m -
1 \ /N ___________________________________ ( m 1 \ /
335
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¨1--( \ N¨ ¨ ¨,_< __ f / \
N l 41 ¨1¨( \ ( i(m ¨1--( \11 __ (C
/ __ \ / __ 0 / __ \ / ___ N
________ N N __ On N N __ On
___________ / \ __ / 0 /) \ /
m 0 ( )
im
,
0 0
V...._....../ n H
a H
4 \A m \ N\/ \ ,N
n
________________ / n
/ N ________ \ ) Nm \ / ( \./OL 1,µ \Ks
)in ON (,
\ -
--N/ \ / \ N ( \/0\, sNx \ , ) ( N (in
/
/ _______________ \ (/ .. 0
"
¨ ¨N N J --/ \ _________ ON (
o 1 s
\ __________ / \ __ / m
\'' ___ N N 1 / \ 0 N __ \se >,(,'' ) __________ \N ON (,?<,
r ' 1
n \
/ m
¨ ¨N N
_ / \
ss
/ \ (/ ___________ Of 4m ,0\A N\
\ __________ / o
336
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_CC c
_io __/\N¨
0
i
k / m
0-- 0--
/ \ / \
0 S
/K1 N\ /N - n (cµin N\ /N¨ -
,
0 ___________________________
/
e " `in-N
0- 0-
/'
0
N N._____ / m
__No---
e in N N'
N/ eõN.,
M
SE)' 5n N'2N e'S :n jA
N'5(
e " "n-N
'21
M rn M
N ;1/4 n
0
k¨ 1m \ m
337
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...õ..---.....,
N)sc
F F
...,
:),c,-0.,1,.....,..õ.õ,N,.....,...õ.....0,...,..,...K.,...
N.,....,...,...,
=>(,.Ø,11.....\cõN,....õ...õ,,,
n m
M m n
h 0 OH
n ) H
= 0 N N
m =;,(0.,........,e,N,..,..........
"in "II
/ N)'
)CF
v0H
/40X, =)23 N ......,,.........õ =;,,,,,,\
0.,...kx,".......LeõNõ..........õ...,
n
"m "n
N N
I 0
t.0 N....,.......õ..,
N/ \ m n
\ -
ON _____ /Hn \
0 /NA
/ \ =N .....,..s.....õ. ,,,N-\_ \ 4 0
( n \ __ / /L¨\ NJ'A
m
....õ,..õ.õ./1.....3,,
, 0
¨ M
i \
,r5
===,,,..õ,õN,..../: N-I'l< 5-',<N :IN
OH
N)' 0 N ,.....,....õ...,..
..,.....,......õ..ir.õ....õ_........-
%
' \ M
0 '1.NrTi r=A'5
N.õ...........õ,5-
m n ...õ,õõ..,...y.N...õ....
F
., ,
% N''. M
/N\=1
= 0 n /Th \_______/_."..._ \ m
NH
M
n o
N
ec N\ n
y/01 =,,,,,õ..õõN,..,/
N
H , N
\(\ 4
N F C -- -
:3<
m
N( o
= n n
N = \ A '). Y(D/r1.1
, \ "--....,at......y
M
N,I.,.....y.........õ,
m n
338
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.----D- _.... s
N N
k / 1
n
N / "---
,
...,,,,õ......õ,N,' _ ¨N
N.-----D___
,''
ei
N
\
m 0 '
N '''
\ N
H n
..
,
NH2
O / ________ N __________ N \s/
\
m
)d m N N _____ n 0 __ r
---
O 0-----/ss
2/ ) m NO0-0 0\ z
O )n
/ \ )nA
N N
0 ( /c \ / \o
`, / m
HO
% \ ,= r\N
NON
' = P 0-----
,
,' \H.--N1\ j n P '
()%c r ANj\ j
m n
m
0
HO
µ ,
' r-----\ N r------\N %_ ,
' t / I =
m n
X
N ii:' N =
\(o.,..i.....N,,,rN ./Lii..N.õ....,...õ.
m
1 n
.,'
/
' 0
339
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\ H
C) N :
A
z
z , Y
/ \N ./
' \ m /
H
I P
N[ , iN1 rNI\
NJ/
v...,../N,s_ \N ..- -..,..., ill ..
,NIA.N
"m
"141N )1t, "'z,N
m
csse
H n
N,>
,Nlge ,N1/
m
1\IRA.N,)
0 \N, ,N1f,
"m
h i'hN
m Nicd 0 m Nvs ;c1---/--NtN-,'.
,
NX.
µ,(0
.(,/ri ()NH
s m r 0
340
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0-(-) / __ \
0
N N- - _____ N (
0
\ _________ / \\....s.......//N,1 N
\ ____________________________________________ (
0-'
\N QC
) / '
i
N/ N rsi+/-7 \N __ n
N __ icµn \ N/
le
`=,/ 0 __________ 0
N
f'-
/ \N __________ / _
N Nni+jr"-- \ - - /0 i
m n _ _
==,/
/--,
N/ \ N N- fr) n = \
0 ( 0
ie ji \/ ( N Wn
)-0 -h
0 __ /K1 itl \
- 0
\
0 / ) __ Oil )
0
, n
,
01, N/Nrsi- H 0 __
V......../N
a H
4
/--,
341
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1
1 ''µON
rN1)-0-:- ( N1)10.---1-
I I
N
0 ___________________________________________________________________ /
=,..7-..õ....;====-,-
N,y NV"
m
1 Y
,
N,> ,
' 0 n
m
CN\ '
m
...= , ri\T-' ----:.---
n
/-----\ ,
n0.---N 1\1-µ
N 1 7.--=,..,,,N \J
-)-N N-:-
)6_0_0, in \__,
C7 (N\ ,N
N,> m
m
....õ- ,\-
sci----Nr--\N-s_11--(---N\
\____,
N._....../N----/)
f--N ______ \ , ) , r------\ r---\N,
'
,...
p--7 0---c_ - - so-A __/)---N\__J N-o, =
m /.
n
,.
1 NN 'N..2\- %."01`rN"-.-..-y----..N .- `
N
\ ) n
µ,0 ` 0
-s Nad=;\
\ 4}.... r-\ , oti-N'N ¨N.2,, n
N."; ';'s
N \._. j
CF3
N 1
, 1-00¨
N N-:-
\__/
NI --...N.,.: m L.N/
. ,
342
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. % Em n 0 P
% 0 0 0 ,/
H
% 0 0 '
.,\(,: ,,,4..............A,,I,,r............ , ,
H ,
m m n
H ,
N
m n o P
H ,
N /
\ /
i
m n o
. \
;,, 0 E)or \ 7(,), r N
\ 0 0 0 0
m n 0 P
H ,
N ,))(
m n o m o
H
\ 0 0,1),c 0
m n m n 0
H
N (,,r
m n 0 P q
H %
N % (1,,\
m n 0 P
1
%)0 N
m n 0 P
343
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N/s='õ
II Nait...,
n
, N
,./
o
V7 o m
m
,./
" o
m
_
nO p0 0
.,....i Ix
...,/
,
m N
m
n
ho -
,
m \Oo 11 N \ N C µ
\ ________________________________________ /
/,..
\ 1.1 o'''''' _ ¨ 41 NI \ N - ¨
/ N _______________ /
-'- \
_
_
n ,
n \
¨_
/
N
1,-
N
m m / =\
)
N i \ N i ¨ N ,.:- N- ¨ --
/ -...
,
1
- 11 o N¨ - _ . ,
/
..-ff
=..,
\ ..-
n
m
\s/
0 s
,
',.
\
\ n r
m m
0
ON
,
m
o.....1 ,l'
m
,
,
,
,
0 N \ 0 rH> N
=
/ m
344
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- / \
\ __ / ' m
N
m
\
/µ', i= \
________________________________________________________ /.=
ill ,..,õ,. N N .
1
_ ii / __ \ )
2,
. \
. 0). <= \
,,,,,....,,õNNN..,,,,,,,,,,02,::
'N '
_ N ______________________ ON- - _ . N/ \
\ __ /
N X\
m
0
. N
\
, 4i, / ______ \
N
\
0 s 0 s
\ m
,
i 41 N / ____ \ __
' N
\ ____________ / \ _______ N" \ \N- ! \ /
m
1 1
=,,,,,,,....,., N,/,
0
0
00), \
\
1110 / m
345
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----(k
m o
------------------------------------------------------------ 0
) m
sn
/ \ __ ON¨ci-i'l) ex ....\-- N...................+K_____NH¨ ¨
\ ___ / . n .." =s, m ,",
2/ ) m N N¨ ¨
¨ ¨Nk\¨ -
-0
m n
--/
A \ / ___ N N __ \
--, N¨ ¨ 0
0
\ N
/
2,) m N N __ n / __ N/ \ __ /
0
0 _______________________ 0
--,/ N
'
/ __________________ \ / N
/ \ ______________________________________________________________ /
/
N N / __ N\ /N
0 _____________ / \/ 0
1 A
/ \ / n
/ \
/ __ \ /1
0 0 /On \ /1¨ ¨
N ___________________________________________________________
--,/
/---
0
> ___________________ N, m
N¨:¨
)) N/ \N /
6) N ) (in
--,/
cs-
346
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. ____________________________________________________ 0
.__
/ __________________
A \ ) N /
\ \--
0
1
,
1
-......,......õ,õN.,.........,,,,,,,,,,,N.....õ....;..Ar 1 \
________________________________________ /
/'''
/ \ __ W o __ )( O
i\ f-- ,
N
NkN \.n
0 ___ c\ti / n
0 __ i(n N/ __ ) z
P-- /--- \ __
--,/
______________________________________________________ N __ )
o __
`s,/ s=,/
\ _______________ NH N/ NH
N/ N ___________ 1õ ,, N
c`.
Nr) QC
0 __ it
0 ______________________________________________ ien
1 / \ Ocm
s' 1 / \ ¨1¨ / N¨ I N OC;1µ'
¨i¨N\ /N \. n V........yN.,.......Z...----0 H __ 1 \ __ / \ \
/ /
347
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\
o.,,..,,,,=,..,..,.,,,,,õ0,>c
\ ,-0 ' 0
..µ
,\(:
m h)H \ 0õ,,,,,,,.=,,,.,...,,,,,.. =,s
n
0...'
\
,,..0
Nd=r
Otli i 0
0 NW0X
I 0
hrs''0
m m m
NW0<s =
n \ 0
N.,L)Ci
/ \
I 0 1 n m
2( 00 NU' '
N =
, 0 n
0...j
=
N =
0
0 oo
,./
0
s /CP
N0
N = : 0
,-=== 1 0
X
70 =
I ...%,1,..1/,-õ,.,,,A0
N...õ,..õ=,,,, n n
0
0...4
N = 1\
=,,
, N 0 I
07(17'ro
0(3C\N i n n
0
,
....
l'OLI:l 0 ;
\
n
m 0
I--0 ,.
0,),:,'
0,%(.....õ,n,0õ.y.,..,,N '7:''= 0 I N, i
-i,
m H
-i---0
348
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s/
\ A
CI:3r)N 0-õON..sil_
N
\ A \
1
ON
\ A
'So
'SS
i . '-'-=C Ili
0 00)<
n
1 (0¨ -
ONO)
0IN n
N
\\ rN
n
\ Th::\
, 1 000)(
n
IN 0---f-
n I n
\ A\i
, 1
, I 0
ON 0
)ç0
1
0".)
n
n 0,
\ 0,,,ca, .õ...,'
1 \
\
ON \ A Os
n
' N
1
ON n
0)% )ç
(\
n
ON
0
= 0
0 '
n
ON
k.0 \\10\
/ --%
\ A
m
2%.r
\[:*/
I
0
\ ,0
1
0
0
0
0
349
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,....:3..> n
\ / ..,--
<0,-""\(Ly=-0/
I / n
n
ON 0 \ N
.,,,....0
1
O N ....../ ../:,
/
0 0 \ N
m
n
..\..õ0 N ...,/ ..õ.....a.,
1
ON ...:.µ,...0
1, \iiii FsC
,...../ ../".
_..,....= n
0.....,....ro,/
0 = 0 \ N \
m
ss(s C' I
,
0
..i
..../
=
0
0 \ N
m
ON ../:-.= 0
_.../
F F
0 0
),
Y: 1
\ / N
M
\.....õ0,.... .=,/
.,
...../
,=.--
ON
n
0 \ N M
\ ......õ0õ...õ.a..... ,,,/
1 F,C
ON 0
\ 0 1 = /
I
= s '`...va..,,
.,
,....,,... IN \
0
0
n
\ 0 1 = /
o
I
.....,,,...=====,,,, õN
'
0()4
NC
\ Oc\
1
ON
350
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o sõ,
,,,
F F n
j2,:r 0
F a 0 '
F F
7:27-0
r
0 0/
= /
0-------
' 0
SS CF
I 0
7' N
ON
0
I FsC
0
u 0
7,=0w0 õ
sNi- w, 0-0
1
.555 , 0 0
0
= OZ000N1 i
0 s
I
i 0
/ 0 0
I
0 ' ,I0'(=))0)0
= \ 0 0 m M
n
=
,N
i
351
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CF3
0 \
,m m
n
n
,Th n
m m
n
% 0
% OH 00
m 0 /
/.
m
n
.;
m m
n
ss( 0
0
\ .=
N \
0
:-..,
, 0
0
, 0
0
/ õ,/,=,..õ0
0
,
352
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)27,,..0õ....
,....% ../
\ ,,,.......... õ,,.......,,,,,, N...,...
'I0 \,.......,..,.N
1
)2(o
)27,õ../.0,,........,.=
' o2 \, = ss(
..' C) =
v
' c / 0 ==,,.,.....õ,,N
I
0õ........ *....,,,,, N NC
i's. /Lir
ss
=\
= 0 \,,..õ........,,N
C) =
0===' = v
0 /
`s.=
/ \
......Li,,O,,....õ
x
1 v
õ
0 F3C
1 =, = = x
0 \
>( N
1
\
e%
N., F3C
1 )7:r 0
= 0 \ .,,..... N 0
n
fj,õ0.,........,...õ.
ssc, 0 ,
0 = 1."./
r====
,...,,,,\.,,.......7,,.,N
= 0 ..õ.......,,,,,N
NC
HO v
x
0 \
X/ 0 0. \...,...,,,...,N
0 \
..,/
r"..
= 0 \,,....,...,.N
CN
o
x\ .='
.,'=
0 \
0 \ v
v , \
\,........,,,, N õ.............õ, N...,...
1
0,õ..,........,,,,,,,... N.,,,,,,..,,,,='
)(
= 0 \,......,õõ N ,.......õ,,,,õ 0 õ,....õ,.,,,,, \ ,...Ø),;.:
1
N
353
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=. 0
0A,
,
0F3 \ 0
0 =
0
1 =
...õ,,,,,,,,0 == /
0?µ=
\ 0
,==
CF3
..õõzr,..õ,
= ,
. OA
7'0 N,...õ..,.........'' ' 0
I 0
,,, ,0)---A."==,0........."µõ,.......õ0õ,õ,.,..,, µ /
CF, \
\ ,
= 0 \
0
,,,õ...,,,N = 0
\
.,
/ V \
/ \
=,,,,,...,,.;õ,=,N / ', 0...,..7.-----'' %
0 -...s....
F F ---__
= ,
= OA.
= ,
V\
=,,,õ.õ,.õN
1
NCN
1
354
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,-A-
.,,,,ON" = N .
-7L-0
= 0
NW02(\ F3C,...,..,.N)cc
n
/-0
NWO2r\
- / ( __ N\/
\ , ¨N\
NWO )
n
.
N \ A Th10 \
\
,,=\ '',.\:II,õ
n
m
=I\N \ 0
..,
0 \
õ,..,..N.,,...,.,.. 0 =
0 ,.=\ '`,,C1,õ
n
0
--h0
0 /
--- \
,,,,(.7.N.,......
0
n
\,(00 N 0
x,
0 = 0
0
\ 0
)! NO
HO n
0 =,,,,..,,,,,N''''', ,, .....*==,,......,,,õ
0
\ 0
Nt=rNO ,
x
0 0 .
0 =
,.=
,,,,,,..,,,,,''''''''''N ,,=,'
0,,,.,..,,,,
355
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N N
r
N =,...,..,......N
' \ 0 =
n P
N N
r
\ 0
s N ,( N
((<0).1.....r.,.... \
\
n P
N N
r
N N
\
n
,
0 / -V., NO\ / i __ 0
o
NO
41% o
n \ : '=/,_
0 o
NH2
, ______ N Ni----)
0 a
\H 1 OWO
I
I ,
0=
i
N
N N
r
ss>,(0,1,,rsi,N -.,..,,..,,,,N 0),(,.< =<,,
m
n P
356
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H
NN,: NC2rN(
H
m
0
C N
, 0
H
NN\: N)rN
H
m
0 0
, 0
H
NNO NCr0(
m
,
0 0
, 0
H
NN Nr0
m
0
N o
, o
.,,o............,, ,,......,... ,,
N
,..........õ.N.,õ,.,..,,, ..,,,==.,,,,N:i
0
N N N)C
H
.................N ,...............,N.
0 s ,-
....,23,...,,.,.,......., ,õ,...........
N=N 2,,,
N
0
H ,
...........,,,.N........." .......-...,N'c.
0
>04...1 rN-w0x.
N)
/µ4eWO N 0 rN"
, 0.,,o......N,,.)
õ4.
r-N :zowowN,---\ 0w.0,-Ø/
%---0 .
.,
,,,owowo.s. u3 .;
N
/ '
357
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.õ
/ .
I
wherein each m, n, o, p, q, and r is independently 0, 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[0886]
In any aspect or embodiment described herein, the AL is selected from the
group
consisting of:
0- -
/¨\-0/--\0- - = / \-0/¨\0¨rS` = iii¨\-0/¨\0¨/-0
\__/
, , ;
//,¨\_ /¨\ /-0\ /0¨\ / /¨\ /¨\ /-0\ /0¨\ /¨\
O 0¨/ ___ o.' ____________________________ \-0 0¨/
\-0 0- - =
, ,
//--\ /-0µ / ___ \ ___________________________________________ i /0-- .
//¨\_di . //--\ / . //--\___; 1/--\(:) .
,
_________________________________________ ,
, , , ,
/1¨\_ /--\ r¨\_ /¨\ j¨N-I /¨\_ /¨\ _r0 HN
/ ---
O HN--- = ' 0 0 ' = ' 0 0 \__/
, , ;
,,,¨\_ /¨\ /-0\ /o¨\ / ,,¨\ /¨\ /¨o\ /o¨\
o o¨/ \¨NH = ' _______________________ \-0
0¨/ \-0 HN--- =
= ' =
,_ /¨\ ¨0\ /0 ¨\ /¨\ 1¨N-1_ _ -- -- = '
.
o o ¨// \¨ o o ¨/ = =
, , ,
- -, - - = - . \ . _ _ _(¨)_/¨\_ _ _ . _ _
, , , ,
-- = di. -- = 0/--- -Ai 0/-Thµ -- . 0/ \---
, ; ;
o o¨, o--
-- = 0/ \ / = \ = \. .
; , , ;
0 , ,
, ¨\__,/ II ,
__ \ / 0, --
__ _ _ = lik \__,/ .
0¨,
, ; , ;
- 0 0
0 -- - = 0/¨\0¨/¨ \
, ; =
,
o--
. 0/¨\ o 0¨/¨ \__/ .
= 0/--\o¨r \ /o¨\\¨
/¨ /--\ ,/
0 o-- -- 411 0 0¨,
; .
,
358
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,,0/¨`0-1-- -- = 01 \-(5" -- = 01 \-01-
; ; ;
0--
__ . 0/ \ _____ / = 01--\ ____ r-`0-_ --* 0-, ,,
\-0
; ; ;
. 0-\ /0--
= = 0 _/0-- \_ .. = 0-\ ,---
\-0
, ; ;
-- = 0/ \-0/¨`0-- -- # cno-/ \-ci -- * 0/--\o-/ \o--
o
= ________________________________________ 01 \-0/ \-cil -- * Cl \ 1-\-di --
/\N-/- \
, ; ;
--\N-/ \o-- -- \N-/ \-di --
/ ___ /
, ___ ; __________________________________ ,
__ / __ \N /-o\ /o- __ / _________________ \ /-o\ i-oµ
_____________________________ i \ < \N-1 N .. /
-\ __ / ; ___ / ; ____
-- = 0/--\N
0-
0- -
- - <\-d/ --< \N-ro\ r \-1
.. N
/ _____________________________ / . , =
, ,
,
-- = 0/-\N-\
( - / \_ /--\ /--\
__________________________________________________________ - 11 0 N N--- --
= N N---
\__/ = \__/ =
,
. N/-\N-/-0\ /0- - __ = d" .. \
\ __________________________________________ /0 =
. =
N/
1j /--\
__ . 0/ \ _____ 7 . 0/-\ r N\__/N ---
. .
/--\ /
_ _ . 0/0-/-N N ---
__ ,,0/-\0-/-N\ .. > - -
359
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rNi'
-- = Nr-\N-/ 0--
; \/ ;
07Th -, 0
0--.7---\
-,_ (3C) 0 C)10(3'
0 0- 0
--
0
-, /--\ /
N N\ >
0 lei
-K \N-rN
/
\/
00 - /
; ; ;
N''
__< \N_/ ( _______________ /\N- - - < \N ) 0
-- \N-( \N--- r-\_ /-\ j ______________________________________________ NH
/ / _____________ / __ / = ' 0 0 \
=
; ; , ,
//-\_ /-\ /-0, HN--- /-\_ /-\ /-0 0
0 0-/ \ µ ' ___________________ 0 0-/ \/ -/ NH
0 = 0 =
, ,
/33
/,-\_0/-\0_/-0\ /0-\ / _______ \
\-0 HN--- =
,
0,\
0\
/-\ j-NH
,-\-0/-\0_/-0\ /0-\_ /-\ ) NH __ =
0 0 .
0 0
. 0/-\0 j-Ck H/N--- = 0/-\0_/-0 0 \ / - \ /
NH
0 = 0. =
,0
/-0 0-\ /
. / 0 0-/ \-/ \-0 -cN---
;
0\
______________________________________ W . 0/-\0_/-0\ /0-\ /-\ ) N,I-1 /
__
0 =
360
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- - 0 HN---
lik 0- \
\ - - = 41-1 - - = 0/ N'H
0 = 0 0
, , ;
0 0
= 0 ,
0
)/ ____________ N'H
II
; HN--- --
;
0/ \-0/ HN---
;
0 0
__ = 0/-\0-/ ./ _________ = 0-\ / ./
\-0 HN---
; =
,
_______________ 0
. 0/ \ ______________ / -)/ ________________ N/1-1/ - - * 0/ \ -o' NI-1/
O 0 =
__ . 0/0 -/ N'H -- * o¨\ /o¨j¨ /
NH
O ; 0 =
,
0
4. 0 0 0-\ / \
\ -/ -/ N/11 = __ \¨d )i N/ I-1 _ _ =
O 0 /
0 HN---
=
; , ,
0
, FIN-
. /-\ )\-NH
; 0 0
-- \ / N,H -- \ /
-- 0
= =
, ,
0 0 0
0->\-N1-1 NH
0/--\ /iN---
, , ;
/9 , o
'c
---0¨/¨\¨o/ HN--- -- * -\ / I-N- . =
\ __ / 0\ /
HN---
, , ;
HN0 0
= 0-/ i< _
--- --
; \ ________________ ;
0 0
NH
-- = 0/--\0j \0 j-I\I-1% * 0/ \-0/--\0j- \
; .
y
0 0
-- . j\
-NI-,1 . /-\ / _______________________________________ \_ /
1 0 0 0-/ l<
0 HN---
; .
,
361
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23) o
/ __ 'c \ o¨\ __
/ i<
4. 01 _____ \ 0/ __ \ ¨or¨\¨ 0 H N -- - - - =
/ \-0 H N - - -
___________________________________ 0
NH <
\N_/ ____________________________________________________ \_ / __ 'C
- - < -- -( \N -/ \Oi-
' - - ______ 0 HN---
____ /
0 = __ /
, ; ,
- ____________________ - < ________ NH/ --UN __ r 0\ 1-`)/ NH'
/ 0 /
0 =
)
--1 \NJ- \
0 _____________ r 0. H N - --
____ / \ - - -( _______ \N-/- \ ___ / \ NH
O - \
0 = / =
0
___/ _______________ \N_F \__/ \_ / ___ _ _ / \N _/- 0\ r
NH
0\ ______ /0 - \/ ,
0 ________________________ H N - - -
\ __ / 0 =
0, Or\ = OrN
HN"
- - N,
µ----0 = 0 =
0
0\\ r\l/f
= _________ 0/ __ \ 11-\N 7-N, NI:I - - .
/.._.I._/0 H - -
0 N
; .
,
/ __ \ /__\
- __________________ - = 0/-\ r N \ 7 - ,,
N H 0 . /-\ 0_/ - \
__/ )/N N
,
NH
0 0
/-- \
N N
= ______________________ 0/-\0-/-11\ __ ) ____________ -N/1-1/ - - < \N-r
\-/ )/ N/1-1
0 /
0 =
D 0
- ___ - < _________ \N-rN
NH' ___ -- < \N-/ N
/ 0 HN
; , / 0 . N - . =
,
- ___ - -K __ \N-K _____________ \N 0
NH ,/--\ _____________________________________ r \ HN- ,, ____ \ Q-\
' \ __ / )'
/ ______________________________________________________________________ NH
/ / NH --
0
; , 0 =
, 0 ;
362
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0 0 , 0
/1¨\_(:)/ H'N___ . //¨\ i F.N___. ,:--\ ,-Nql ,,,¨\ i-N-1
, , ` ; 0 .
;
õ Si
NILL-õi __ * 0
fa, O N---0 ,,. N-0
0
, , ,
,.. N_o''Si Ni -C) \- - --if
Q--- -,
O 0()
O 0 N-0
z __. __ * 0 N-0
/ N...----x
0---N.,-----
-- =, ;
õ 01$0 N-0 N NONA___
; ,
-. Si
N- N-
-- --
O0- 0.---..,..õ..0Q-
.
; ,
ifk 0 * 0
,...,----N N-0 N0()I--0.
-- 0"--N,---).
.NA__. ifb 0()NI__,
-- * ON N-0
_
0
õ
Ot 0 N-0
N-0
0'\0___ Si
-- ; .
,
õ Si
N-C) Si
N --
o0--
O0Q-
-. Si N- Si N-43
Q--- ,,Q---
OWO /\/\/\.%d
0
õ Si
W. Si r \
-- 0,---
0/\.(:)./\./Q-
/(:)\.
0
õ Si
N- -- -- * N/¨\N-Or\I-
O C)
\ ____________________________________________ / ---- ,
.=
, ,
363
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,0
-- . N/-.....\ ...) -14 -- lie N\---i ----\-----.
\......,/N .--
;
._ 40 N -0
r--=
(Th L?-- - =- 0,
j...y-0
N
. Nr\N ---\--0N--o 140i N/
- -
0
\---i
=
/..,..01.. / _O ..._ -, .
N-0
.N
--
NrTh
NT
N-0 N-0
O N j / = N \..... j
_....õ N-0 O N-0
lik N \____ j 0 ---\____, s , __=
_-
/--\ /¨ /-0, /¨\ /-0, /0- - /¨\
/¨ 0, /0 ¨\ ,,
--0 0- - = --o 0¨/ ' = --o 0¨/ \ i __ = --o
0¨/ \ i \-0 =
, , , ,
/¨\ /-0\ /0¨\ /¨\ /¨\ /-0\
/0¨\ /¨\ /-0, I
--o 0¨/ _____ \-0 0-- = --o 0¨/ \-
0 0¨/ ' = ¨0 =
, , ,
/ \_ / N` _/- / __ \ 0- - /--\ / \
- -0 0 = 0
/ / _____ / = -- \ 1 = -0 0-1 0 = -0
/ /
/ \¨ / \_ / /¨\ _/ \_ // /¨\ /-0\ /¨S,
--0 0 0 = --a 0 0 = ¨0 0 =
/ / /
/ __ \ /--\ 0 / 0 0 ________________ 0
-- \ _/ \ _/¨ % / \ / \ __ /¨ ¨ %
-0-0 /¨ '' = 0 0 0 .. ' = 0
\ .
/ / /
/--\ ___ /--\ _rg /-- \ /¨ 0\ / ___ \ /¨ \ / __ \ / \
- -0 0 ' = 0 0-1 / 0- - = --0 0-1
0-1 0- - =
/ /
/
/¨\ _/ \_ /¨\ / __ \ ___________ ,c=¨\_ /¨ 0 ___
/ ________________________________________________________ \ __ , ¨\ /--\
--0 __________ 0 0 0-- = --0 0
0 = 0 0-- =
, ,
,
/--\
--01¨\ r-`0¨/ \O-- . --0/-\-/-\-0/-\0-- . - -NI N---
.
, , ,
364
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0 0- -
/¨\ ________ r \ /¨\ \ /--\ __ / \¨ 'I /--\ ____________ rO\/
- -N N ` - -N N¨ 0- - - -N N 0 - -N N
\__/ = \__/ ; \__/ = \__/
/ / ;
/__\
/--\ _/¨N\ 7¨ p¨\ /--\ /¨Os ,o¨\ / _________________ \ /--\
--N N , \N N/ `' \-0 \N N---
\_/ ; \/ / \__/ =
/
/-0\ /-0µ\-1
N N--- --N N-1 / ` - -N N¨/ \
\__/ = \__/ = \__/
/ / ;
- -N/--\N_/ \N
\/ - - / __ \ /--\ /-0\ -_N N /--\
N 0 \ _____________________ N N ____ / 0 0--
\
_________________ \/ = \/ ¨\ r \/ = \ =
/ / /
--/--N n - /--\
- -
N/¨\ \ /N ¨\ /0 ¨\ 1 /0- - .N N 0/ \ /¨ . - -N, /N¨\_/¨\_/0- - .
/ / \ _________________ /
/--\ /--\ /--\
- -N\ /N¨\ /¨N\ ,N--- . --0
, µ /¨N\ /N¨\ /0- - . \ ,
.....j , .
__________________ / \ ____________ = ,
o /¨\ /-0\ F---- /¨\ /-0\
__0µ /¨\ j ___ NH --0 0-1 --0 0-1 ¨NH
, = ¨0 0 0 = 0
/ / / ;
0 0
/¨\ /-0\ /0¨\ / /¨\ /-0\
/0¨\ /¨\ i¨N-µ1
--0 0-1 \-0 HN--- = --0 0 / \-0
0 =
/ /
0 / \ HN-
,p¨\ i>
/¨\ /-0\ /0¨\ /¨\ NH --0
µ c _____ ' / NH
\-0 0-1 ____________________ \-0 0¨>\¨ µ` = 0 = 0 =
/ / /
p /50 0 i ________ /, 0¨\ /
\ -\ o \ ¨NH
--0/ \-0/ HN--- = --0/¨\0¨/ HN--- --0/¨\ / H\N---
= 0 =
/ ; / /
b0
--0/ \-0/ ¨1\l/H --0/¨\0¨/ / NH --0 __
//¨\¨/¨>/¨NH/ / 4(
0 0
; / 0 = - -0 HN--- =
/ /
/
/¨\ \¨N-1 \O-7 \¨/ ¨1µ11-1/ µb¨/ \o¨/ ¨Ni-i
-- i
o o o
, , ;
o
µb¨/ \-0/ _/ ¨N111-1 µb¨/--\
0 0 =¨/ ¨/ _________________ NH )\¨NH
\
; ¨0 0
0
/ ;
365
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O 0 0
/ __ \ /¨\ )\¨N-I /¨\ /-0\ ¨1=1\1-1 /¨\ /¨\ j¨N-µ1
--O \-0 0 ` ; -0 0¨f % ; -0 \ ' 0
=
,
O 0 0
/¨\ /-0\ )\¨Np / ___________ \ /O NH / ____ \ /¨\ )¨N!-,1
; , = -0 \-0 \
=
,
O b0 b0
/¨\ _/¨\_)¨N,H / __ \ / __ (< / \¨ / \_ /
--0 0 ` = - -0 0¨/ \-0
HN--- = --O 0 0 HN--- =
, ,
,
0 0
/ \ /0 ¨\ / \\ / \__/ ¨\ / ./
-0 \-0 HN--- = 0¨/ \-0 HN--- =
, ,
//0 0
//
µ0¨/ \-0/ \-0/ 1-1---= µb-/ \0¨/ \-0/ H\N---.
, ,
o o
/
µµ /-0\ / __ \ / µ < _________ \ /¨o\ / \ /
o i \-0 HN--- = 0¨/ / 0¨/ HN--- =
, ,
/0 0
\ /-0\ /-0\ / ______ < \ /-0\ /0¨\ /-4
o ______________ i ____________________________ i HN- = 0¨/ HN--- =
, ,
/9 /9
µb_/ \__/ ¨\ ___ /--'C \ _/ \_
HN- = 0 0 _______ HN--- =
, ,
0 0 /¨\
\ _/ \ _/¨\__/-4 \ _r() N N N
0 0 \
\\
0 HN--- = H--- = \¨ 0 =
, ,
,
O 0
/--\ / ____ \ j--N-i /--\ / __ \ / --NN¨/ \¨/C)-¨ / NH
--N N¨f 0 ` --N N ___ / \-0 HN---
\__/ = \__/ = 0
, ,
;
/¨\ /-0\ /O¨\ / /¨\ /-0 ____ rO\
\ HN---
--N N¨f ¨NH --N N¨f
0 . \__/ 0 =
, ,
0 0
0 / _________ \ j¨N-i / ________ \ / ./
- -N N¨f / 0 ______ ` - -N ______ N¨f \-0 HN---
\_/ = \__/
, ;
366
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0
HN,' HN/
/¨\ /-0\__/0¨\_0/ __ Eti_ p_...../....._N/Th _._./. , \¨Np¨\ / )
0
--N N¨ __
,
\_..__/N
0
\ =
, ,
0
Isi
0 f /--\
\ ,--\ -, NH 7. \ HN-_ /¨\ /¨N NH
N ,
N N ¨/
- ______ -0,
\__/ 0
, , ;
/--\
/¨N\ /N¨>/_ / /--\ j¨NI
/\ )
- -0 0¨' NH - -0 0 ¨1=11-1/
0 ; 0 =
,
/--\
/¨N\ / /N¨)i_ /--\ /¨
/\ )
- -N N NH - -N N ¨NH
0
, ;
/--\ _/ _________ ( \iN / 0 - -N/¨\N¨( \N
--N ____________________________________ N ¨)i¨N/H 'INI N
\¨/ / -¨ / NH
\/ 0 . N HN
-, = 0 =
, , ,
N-0 N-0
,o- - _ ,,_ --
= .
() ,
N
\
N-C)
I / -- -- ,,0
''03 - = ,'(:) 0 =
, ; ,
N '1-/ _ .)11
,.001-(..,, ¨ ' 0/.\.(:) = ''00
; , ;
n j:/).. __
1)> ", _
1,t.,)-- --
,0,....-....õ......... . , ,%.,...........õ,--...0 . , - 0 0
.
, , ,
,
ii tt.,.)_N-C) _ )---
,,0,,..õ-==\õ,,,--.%.
0" ,
' . ,C)0
, ;
I /
_,.0o0 --
= ''0 --
, ,
N-C) N-
- -= Q---
0
.
, ,
367
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N-0 N- \O
09- --
¨ . ' (1/.\/\/"\ .
, ,
N-0 N- \O
i-N - - 0 ff- - - . ' .f,o/\ .
, ,
N-0 /\ N-0 N ,.
--- - -N N __ ( j
'-o()0 \/ -- N
; , =
,
r\ N-0 -
N 1 i _c ' _ _ _ _ NON ;),i-o
; ; ,
1----\N_-\0 N-0 --NI- N-0 -=
. I
N 0- . N
, 0 -
, ,
'N WO NN N-0
/
;
rNi 0 N-0 rN1\,N N-0
, -N NN,=--- , -NIN ON---.
N/ \ N-0
\ ____ /N N- \ ; and --NN.
[0887] In any aspect or embodiment described herein, the AL is selected
from:
0 ; 0 ;
OH
0
'111_
OeY'.. ..õ...-=-..õ,Ø,õ,,,-
,..o,..--........õØ...,
0 = 1,- / =
0 0
/ .
,
0
, N.....,.---........õ.. 0 ,....,.......--...,...õ.,,...0 ,...Th(47-1.
o
368
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417..
0 0
cv =
\.
\z..
0 0
0 H
0j-is' ,,
= µ 0 =
0 0 0
H 1 1
'LL( N 0).= N o0)'. N 0)==
..,
1 = µ11( 1 = '7,- e =
e =
0 4,,..
't.1...ri= 0'r
, e = 0 ; 0 ;
0 0 0
0 0 ,..,,0.(\.
, Of; ....õ...-
....õ,,Ø...õ,........õ,.0j.t.,/ . -,-
0
=
,
. -
4.,,, ,\i=õ---.,..õOyt,cyõ=-=.,,,--
L.N....õ....--..õ.0,....õ--,0õ.....õ,..., .
;
: . .
. ,---' , .=.--,,trt
\s<,õõ,';i= . \ .;.õ,4' : \ ::;;;.. $ ' '4 ,:? %._ ._.:,,
.'"'k...,
=
>,..1.:.:
:0 =
,,,==
e. \
'..Y.
µ-i-(.. N %: ..,..___,,,c
...,......z v.......4: !:.õõ 4-.--(;\ :',..---s,
\ .;.
..,--.:,, =:, ; P: = - :r
, ,
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'/' N C)0C)-0 \'µ '1-N
H H
H H
'/IN'woNly'o-µ. '/ N NI Ire
H H
0 0 ,
'/IN 00C):'-' '/IN
H H
0 0
, ,
''''N ON )-'n :'- %-N N)()'''
, -
H H H H ,
'i'N 0()C)µ-µ` %N ()C)\
H H
H H
'il'N ON lr -
µ,
0 \ -i, N : N 0 ,
.-
0 \
H H
0 0 ,
-,4.N,,--,,õ,0=,...,,-",..0õ,"\,.0;,. -i. .---,..,...õ-
-----.,,,,O....õõ,--...õõ0,,,
H H
0 0
'il'N N 0,i-
H H H H
,
i N 0 'il'N
'r'(3"\
H H
H
'il
r\l.r'iµ;
H c H
0 ,
I
',11-N ONIµ
H H H H
'ilisN1 N µ-µ 'iiN C)N
H H H H ,
H
',LN N \'µ 'ill'NJONi,
H H H
F F F F F\ IF H
H F F H H
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HN = 0 X Y 1 HN . 0-X-Yt
F
J_ _ _ 7
II 0 X Y 1 ¨ 1
H;NIC-N=)/-0-X-Y-:-
F
H- \N.- . 1
0-X-y-i- --µc -
1 HN-0-0-X-YH-
N
1 Y. '
- \ = / N '
HN ,
N --N ,
F
ss,
--I"N 1p ys'= ,
-1-N H F0 6X-s:,?
H H
= ' \
- =,r.. N - . ,x-.-?' N
_,' I*
H ,-
H 0'
,
..õ._,1 ip,
-;
-1
¨1=1 Y-% -1-N N N¨\ '7',
0
'a.
/¨
-;-N . N N¨/-c_,,/ / N---- _.¨ y ,
-;-NH
o o
, 2 2
NH-X-Y 0--X-Y
wherein:
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'X" in above structures can be linear chain with atoms ranging from 2 to 14,
and the
mentioned chain can contain heteroatoms such as oxygen; and
"Y" in above structures can be 0, N, S(0),, (n=0, 1, 2).
[0888] In any aspect or embodiment described herein, the linker (L)
comprises a structure
selected from:
(yLl
)0-2
111
011:1µ/0-2 1110
or
wherein:
WL1 and WL2 are each independently absent, a 4-8 membered ring with 0-4
heteroatoms,
optionally substituted with RQ, each RQ is independently a H, halo, OH, CN,
CF3, Ci-C6
alkyl (linear, branched, optionally substituted), Ci-C6 alkoxy (linear,
branched, optionally
substituted), or 2 RQ groups taken together with the atom they are attached
to, form a 4-8
membered ring system containing 0-4 heteroatoms;
YL1 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-C6 alkoxy (linear,
branched,
optionally substituted);
n is 0-10; and
a dashed line indicates the attachment point to the PTM or CLM moieties.
[0889] In any aspect or embodiment described herein, the linker comprises a
structure
selected from:
(RQ)0-6
(yLl )0_2 ofL 1 )= 0_2
QL 4110
n
(QRLQ)o-6 411110
or
wherein:
WL1 and WL2 are each independently absent, aryl, heteroaryl, cyclic,
heterocyclic, C1-6 alkyl
and optionally one or more C atoms are replaced with 0, C1-6 alkene and
optionally one
or more C atoms are replaced with 0, C1-6 alkyne and optionally one or more C
atoms are
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replaced with 0, bicyclic, biaryl, biheteroaryl,or biheterocyclic, each
optionally
substituted with RQ, each RQ is independently a H, halo, OH, CN, CF3,
hydroxyl, nitro, C
CH, C2-6 alkenyl, C2-6 alkynyl, Ci-C6 alkyl (linear, branched, optionally
substituted),
Ci-C6 alkoxy (linear, branched, optionally substituted), 0C1-3a1ky1
(optionally substituted
by 1 or more ¨F), OH, NH2, NRY1RY2, 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;
YL1 is each independently a bond, NRyLi, 0, 5, NRYL2, cRYL1RYL2,
C=S, SO, SO2, Cl-
C6 alkyl (linear, branched, optionally substituted) and optionally one or more
C atoms are
replaced with 0; Cl-C6 alkoxy (linear, branched, optionally substituted);
QL is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms,
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);
RyLi, R' are each independently H, OH, C1-6 alkyl (linear, branched,
optionally substituted
by 1 or more halo, C1.6 alkoxyl), or R1, R2 together with the atom they are
attached to,
form a 3-8 membered ring system containing 0-2 heteroatoms);
n is 0-10; and
a dashed line indicates the attachment point to the PTM or CLM moieties.
[0890] In any aspect or embodiment described herein, the linker (L) is a
polyethylenoxy
group optionally substituted with aryl or phenyl comprising from 1 to 10
ethylene glycol units.
[0891] In any aspect or embodiment described herein, the PTM is an estrogen
receptor (ER)
binding moiety represented by the chemical structure:
XPTM1"-Th XPTM1Th e
RPTM3
XPTM2
RPTM4 Xpi-m
Xpi-m \
\ \
RPTM2¨ / I RPTM2
RPTM 1
;---RPTM1
PTM-I or PTM-II
wherein:
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XpTm S 0 or C=0;
each of XpTmi and XPTM2 is independently selected from N or CH;
RpTmi is independently selected from OH, 0(CO)RpTm, 0-lower alkyl, wherein
RpTm is an
alkyl or aryl group in the ester;
RpTm2 and RPTM4 are independently selected from H, OH, halogen, CN, CF3, S02-
alkyl, 0-
lower alkyl;
RpTm3 and RPTM5 are independently selected from H, halogen;
PTM-I has at least one RPTM2 and at least one RPTM3 on each respective rings;
and
the
indicates the site of attachment of at least one of the linker, the CLM, a
CLM', or a
combination thereof.
[0892] In
any aspect or embodiment described herein, the PTM is an estrogen receptor
(ER)
binding moiety represented by the chemical structure:
RPTM4 TXp jziA,
XPTM
RPTM1---
RPTM3
XPTM
or
Formula (IPTM)
(222:
RPTM1- LPTM
-- I I
RPTM3
XPTM
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Formula (IIpTm)
wherein:
each XpTM is independently CH, N;
6722. indicates the site of attachment of at least one of the linker (L), the
CLM, a CLM', ULM, an ILM,
a VLM, MLM, a ULM', a ILM', a VLM', a MLM', or a combination thereof;
each RPTM1 is independently OH, halogen, alkoxy, methoxy, ethoxy, 0(CO)RpTm,
wherein the
substitution can be a mono-, di- or tri-substitution and the RpTm is alkyl or
cycloalkyl group with 1
to 6 carbons or aryl groups;
each RPTM2 is independently H, halogen, CN, CF3, liner or branched alkyl,
alkoxy, methoxy, ethoxy,
wherein the substitution can be mono- or di-substitution;
each RpTM3 is independently H, halogen, wherein the substitution can be mono-
or di-substitution; and
RPTM4 is a H, alkyl, methyl, ethyl.
[0893] In any aspect or embodiment described herein, the PTM is an androgen
receptor (AR)
binding moiety (ABM) represented by a structure selected from the group
consisting of:
y2 I
R2 (RQ)0-6
Y5
/
CI
0 NI)rN y4 IIY3
yl 0
ABM-a ABM-b
yl 3
(.0k4i 11"Thl,
N L,
Rb Q
ABM-c ABM-0
; and
wherein:
is aryl, heteroaryl, bicyclic, or biheterocyclic, each independently
substituted by 1 or
more H, halo, hydroxyl, nitro, CN, CCH, C1-6 alkyl (linear, branched,
optionally
substituted; for example, optionally substituted by 1 or more halo, C1-6
alkoxyl), C1-6
alkoxyl (linear, branched, optionally substituted; for example, optionally
substituted by 1
or more halo), C2-6 alkenyl, C2-6 alkynyl, or CF3;
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Y1, Y2 are each independently Nit', 0, S, S02, heteroaryl, or aryl;
Y3, Y4, Y5 are each independently a bond, 0, NRY2, CRY1RY2, C=0, C=S, SO, SO2,
heteroaryl, or aryl;
Q is a 3-6 membered ring with 0-4 heteroatoms, optionally substituted with 0-6
RQ, each
RQ,is independently H, C1-6 alkyl (linear, branched, optionally substituted,
for example,
optionally substituted by 1 or more halo, C1-6 alkoxyl), halogen, Ci-6 alkoxy,
or 2 RQ
groups taken together with the atom they are attached to, form a 3-8 membered
ring
system containing 0-2 heteroatoms);
Ri, R2, Ra, Rb, Ryi, ¨Y2
are each independently H, C1-6 alkyl (linear, branched, optionally
substituted; for example, optionally substituted by 1 or more halo, Ci-6
alkoxyl), halogen,
C1-6 alkoxy, cyclic, heterocyclic or le, 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, C1-6 heteroalkyl, 0, aryl, heteroaryl, alicyclic,
heterocyclic,
biheterocyclic, biaryl, or biheteroaryl,each optionally substituted by 1-10
Rw2;
each Rw2 is independently H, halo, C1.6 alkyl (linear or branched optionally
substituted; for
example, optionally substituted by 1 or more F), -0Rw2A , C3-6 cycloalkyl, C4-
6
cycloheteroalkyl, C1-6 alkyl (optionally substituted)õ heterocyclic
(optionally substituted),
aryl (optionally substituted), or heteroaryl (optionally substituted),
bicyclic hereoaryl or
aryl, OC1_3alkyl (optionally substituted; for example, optionally substituted
by 1 or more
¨F) , OH, NH2, NRY1RY2, CN;
Rw2A is H, C1-6 alkyl (linear, branched), or C1-6 heteroalkyl (linear,
branched), each optionally
substituted by a cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, heteroaryl,
halo, or OC
3a1ky1; and
the dashed line indicates the site of attachment of at least one of the
linker, the CLM, a CLM', or a
combination thereof.
[0894] In any aspect or embodiment described herein, the PTM is a BET/BRD4
targeting
moiety comprising a group according to the chemical structure PTM-a:
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Zi
/(); õ,
Y\1 I/1
NN XY30
õ-\
PTM-a
wherein:
Yi, Y2 and Y3 are independently selected from the group of carbon, nitrogen or
oxygen and
together with the atoms to form an aromatic fused ring.
A and B are independently selected from the group of a 5-membered aromatic
ring, a 6-
membered aromatic ring, a heteroaromatic ring, a carbocyclic, a thiophene a
pyrrole ring,
a pyridine, a pyrimidine, a pyrazine, a pyrazole ring each optionally
substituted with alkyl,
alkoxy, halogen, an aromatic and a heteroaromatic ring; wherein ring A is
fused to the
central azepine (Y1=C) or diazepine (Y1 = N) moiety; and
Z1 is selected from the group of methyl or analkyl group, and
wherein the dashed line indicates the site of attachment of at least one of
the linker, the CLM,
a CLM', or a combination thereof.
[0895] In any aspect or embodiment described herein, the PTM is a BRaf
targeting moiety
that is represented by at least one of chemical structures PTM-Ia, PTM-Ib, PTM-
IIa, PTM-IIb,
PTM-IIIa, PTM-IIIb, PTM-IVa, PTM-IVb:
RPTM1
z=p-rm
WPTM: v \µµ%
RPTM2 II
,:,:YPTM¨RPTM3
/1
Zp-r
HO ,
a
RPTM4
1111
PTM-Ia
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IRPTM1
y
'pm/i
WPTM" µµµ=
RPTM2 ii
:1:YPTM¨RPTM3
1;1
VIDTM II_ t7
ZpTm
XPTM35 RPTM4
0
\
RRPTM5 / \
11
\ ..............
0 N
PTM36
X XPTM38
XPTM37
,
P TM-lb
RPTM5a RPTM6a
RPTM8
\ 0 RPTM7\ , 1
x, PTTN, RPTM9
RPTM6 APTM2 APTM4
y 1 ll
"PTM1 XPTM5
1 1 PTM6b / XPTM6 RPTM10
R
N N RPTM11
H,
P TM-IIa
RPTM6a
RPTM5a RPTM8
\ 0 RPTM7
RPTM9
RPTM6 N
1
XPTM1 N
RPTM10 1
RPTM6b /
N N RPTM11
H
,
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P TM-IIb
XPTM1 6
XPTM15 RPTM13
1 RPTM14 I
\ XI:)-1A&1
0 RPTM12
H
N i= XPTM17 0 RPTM17 XPTM1 ( XPTM9
RPTM1 8 \ II
y \
1
¨PTM20 XPTR
X
XPTM8
X --)..........., N XPTM12 "PTM7
RPTM1 6
'sPTM19
RPTM19 11 I
/ ¨PTM13 .,..7%. RPTM15
--- XPTM18
x
\ N N
H
RPTM21 0
RPTM20
,
P TM-III
RPTM22 0
,- ------ NH
RPTM25a RPTM26 N
0 N. ......õ. N
PTM25 XPTM29
R )
/ \ v \
I
XPTM21 ^PTM23
N
X \ N / X TM27
PTM28 N
¨PTM22 ------
XP
1 RPTM28
------
r`PTM27
RPTM29
RPTM25b XPTM26 RPTM30 /
0
XPTM24
I
% XpTM347:------XPTM 33
XPTM25 4
PTM24
N XPTM32-----.... R
/ x\ II
RPTM23
----- XPTM31
¨PTM30
\
/ RPTM32
RPTM31
,
PTM-IVa
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RPTM22 0
A- ----NH
RpTM25a
Of RPTM26 N N
RpTM25
v v
zpTM21 ^PTM23 N X
=======- PTM27
PTM28 o
- -pTM22
INDTM28
rvpTM27
RpTM29
RpmT25b XpTM26 RPTM30
XpTM24% pT
II xj34,XpTm33
XpTM25 PTM24
R
XpTm31
R
= -PTM23 XPTM30
RpTM32
mpTM31
PTM-IVb
wherein:
double dotted bonds are aromaric bonds;
VpTM, WpTM, XpTM, YpTM, ZpTM is one of the following combinations: C, CH, N,
N, C; C, N,
N, CH, C; C, 0, C, CH, C; C, S, C, CH, C; C, CH, C, 0, C; C, CH, C, S, C; C,
CH, N,
CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, C; C,
CH, C,
N, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N, N, C;
RpThu is covalently joined to a ULM, a chemical linker group (L), a CLM, an
ILM, a VLM,
MLM, a ULM', a CLM', a ILM', a VLM', a MLM', or combination thereof;
RpTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-M2,
wherein MI is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
RPTM3 is absent, hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl,
OCH3, NHCH3 or
M1-CH2-CH2-M2, wherein MI is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic
alkyl, aryl or heterocycle;
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RpTm4 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-M2,
wherein M1 is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
each of RPTM5 and RPTM22 is independently selected from the group consisting
of
F...............\ F
....-------\
N ------------- N --
...-----\ Fo. F
N-----"\
/N
\N
F -0.-
0 --- Flow-ON -------- F m=-Ø- ------ F __ ON
/ HO F................\ F
,
....------\
,
\N ______________________ ----....)
;
, ' N ----------- N --
/ HO -------------------------- He
HOZ---..j
HO)/
HO ___________________________________________________________________ .
,
XpTml, XPTM2, XPTM3, XPTM4, XPTM5, XPTM6, XPTM7, XPTM8, XPTM9, XPTM10, XPTM11,
XPTM12,
XPTM13, XPTM14, XPTM15, XPTM16, XPTM17, XPTM18, XPTM19, XPTM20, XPTM21,
XPTM22, XPTM23,
XPTM24, XPTM25, XPTM26, XPTM27, XPTM28, XPTM29, XPTM30, XPTM31, XPTM32,
XPTM33, XPTM34,
XpTm35, XPTM36, XPTM37, XPTM38 are independently selected from CH or N;
RpTm5a is selected from the group consisting of: H, optionally substituted
amide (e.g.,
optionally substituted with an alkyl, methyl, ethyl, propyl, or butyl group),
optionally
RPTM5 0
\s,
,- ----NH
substituted amine, ---.0 , -NHC(0)RpTm5;
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RpTM6a and RPTM6b are each independently selected from hydrogen, halogen, or
Ci-C6 alkyl
(linear, branched, optionally substituted);
RPTM6 is either of the following groups: absent, hydrogen, halogen, aryl,
methyl, ethyl, OCH3,
NHCH3 or M1-CH2-CH2-M2, wherein M1 is CH2, 0 and NH, and M2 is hydrogen,
alkyl,
cyclic alkyl, aryl or heterocycle.
RPTM7 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-
CH2-M2,
wherein M1 is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle.
RpTM8, RPTM9 or RPTM10 are independently selected from the group consisting of
absent,
hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl,
ethyl, OCH3,
NHCH3 or M1-CH2-CH2-M2, wherein M1 is CH2, 0 and NH, and M2 is hydrogen,
alkyl,
cyclic alkyl, aryl or heterocycle;
RPTM11 is absent, hydrogen, halogen, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-
M2 in
which Ml, wherein CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl
or
heterocycle;
RpTM12, RPTM13, RPTM14, RPTM15, RPTM16, RPTM17, RPTM18, RPTM19 are
independently selected
from the group consisting of absent, hydrogen, halogen, aryl, heteroaryl,
cycloalkyl,
heterocycle, methyl, ethyl, other alkyl, OCH3, NHCH3 or M1-CH2-CH2-M2, wherein
M1
is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
RpTm2o is a small group containing less than four non-hydrogen atoms;
RpTm2i is selected from the group consisting of trifluoromethyl, chloro,
bromo, fluoro, methyl,
ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, OCH3, NHCH3, dimethylamino or M1-CH2-CH2-M2, wherein M1 is CH2, 0
or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;
RpT1v125a and RPTM25b are each independently selected from hydrogen, halogen,
or Ci-C6 alkyl
(linear, branched, optionally substituted);
RpTM23, RPTM24, RPTM28, RPTM29, RPTM30, RPTM31, RPTM32 are independently
selected from the
group consisting of absent, bond, hydrogen, halogen, aryl (optionally
substituted),
heteroaryl (optionally substituted), cycloalkyl (optionally substituted),
heterocycle
(optionally substituted), methyl, ethyl (optionally substituted), other alkyl
(linear,
branched, optionally substituted), OCH3, NHCH3 or M1-CH2-CH2-M2, wherein M1 is
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CH2, 0 and NH, and M2 is hydrogen, alkyl (linear, branched, optionally
substituted),
cyclic alkyl (optionally substituted), aryl (optionally substituted)or
heterocycle
(optionally substituted);
RpTm25 is selected from absent, hydrogen, halogen, Ci-C6 alkyl (linear,
branched, optionally
substituted), OCH3, NHCH3 or SCH3;
RPTM26 is selected from absent, hydrogen, halogen, Ci-C6 alkyl (linear,
branched, optionally
substituted), OCH3, NHCH3 or SCH3;
RPTM27 is selected from the group consisting of absent, hydrogen, halogen, C i-
C6 alkyl (linear,
branched, optionally substituted), OCH3, NHCH3 or SCH3; and
at least one of RPTM8, RPTM9 or RPTM10, RPTM12, RPT1v13, RPT1v16, RPTM24,
RPTM29, and RPTM32 is
modified to be covalently joined to a ULM, a chemical linker group (L), a CLM,
an ILM,
a VLM, MLM, a ULM', a CLM', a ILM', a VLM', a MLM', or combination thereof
[0896] In any aspect or embodiment described herein, when RPTM9 is the
covalently joined
position, RpTm7 and RPTM8 are connected together via a covalent bond in a way
to form a bicyclic
group with the ring to which RpTm7 and RPTM8 are attached.
[0897] In any aspect or embodiment described herein, when RPTM8 is the
covalently joined
position, RpTm9 and RPTM10 are connected together via a covalent bond in a way
to form a
bicyclic group with the ring to which RpTm9 and RPTM10 are attached.
[0898] In any aspect or embodiment described herein, when RPTM10 is the
covalently
joined position, RPTM8 and RPTM9 are connected together via a covalent bond in
a way to
form a bicyclic group with the ring to which RPTM8 and RPTM9 are attached.
[0899] In any aspect or embodiment described herein, when RPTM12 is the
covalently joined
position, RPTM13 and RPTM14 are connected together via a covalent bond in a
way to form a
bicyclic group with the ring to which RPTM13 and RpTmi4 are attached, and/or
RpTm15 and RPTIVI16
are connected together via a covalent bond in a way to form a bicyclic group
with the ring to
which RPTM15 and RPTM16 are attached.
[0900] In any aspect or embodiment described herein, when RPTM13 is the
covalently joined
position, RPTM12 and RPTM16 are connected together via a covalent bond in a
way to form a
bicyclic group with the ring to which RPTM12 and RpTmi6 are attached, and/or
RpTm15 and RPTIV116
are connected together via a covalent bond in a way to form a bicyclic group
with the ring to
which RPTM15 and RPTM16 are attached.
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[0901] In any aspect or embodiment described herein, when RPTM16 is the
covalently joined
position, RPTM12 and RPTM13 are connected together via a covalent bond in a
way to form a
bicyclic group with the ring to which RpTm12 and RpTmn are attached, and/or
RpTmn and RpT1\414
are connected together via a covalent bond in a way to form a bicyclic group
with the ring to
which RpTmn and RPTM14 are attached.
[0902] In any aspect or embodiment described herein, when RPTM24 is the
covalently joined
position, RPTM31 and RPTM32 are connected together via a covalent bond in a
way to form a
bicyclic group with the ring to which RpTm31 and RpTm32 are attached, or
RpTm29 and RpTm30 are
connected together via a covalent bond in a way to form a bicyclic group with
the ring to which
RpTm29 and RPTM30 are attached.
[0903] In any aspect or embodiment described herein, when RPTM29 is the
covalently joined
position, RPTM24 and RPTM32 are connected together via a covalent bond in a
way to form a
bicyclic group with the ring to which RpTm24 and RpTm32 are attached, and/or
RpTA431 and RpT1\432
are connected together via a covalent bond in a way to form a bicyclic group
with the ring to
which RPTM31 and RPTM32 are attached.
[0904] In any aspect or embodiment described herein, when RPTM32 is the
covalently joined
position, RpTm24 and RPTM29 are connected together via a covalent bond in a
way to form a
bicyclic group with the ring to which RpTm24 and RpTm29 are attached, and/or
RpTm29 and RpT1\430
are connected together via a covalent bond in a way to form a bicyclic group
with the ring to
which RPTM29 and RPTM30 are attached.
[0905] In any aspect or embodiment described herein, the PTM has a
structure selected from
the group consisting of:
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R S X = CI, Br, F, H,
/ S bond, or a chemical
\ / NNN 0 moiety coupling the
z N 1;i R CLM to the PTM
NY N... o
R
0 N -,,,4
1111
CI 0 , X
,
R
----N
/ S S
N , N
R /N
X = CI, Br, F, H
II
0 Nk. , O-R
-,4
R 0 x ,
N
¨N µ0
CONH2
..,i/
---.. ¨N
Linker X = CI, Br, F, H Linker¨N X = CI,
Br, F, H
µN----
X , X
,
¨N
S
x
, )LNI/
"" ¨ H
---.. N ¨N
Linker¨N X = CI, Br, F, H H
µ11---
Linker
x
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S =--N
\ 0
N , N X / 0
lei /
0 N I\I
NI/
H )-----N j
. 0 N ____/ HN
N
Linker
CI 0
X = H, F
R
----=N1 X = CI, Br, F, H, R
R . NN 0 bond, or a chemical
moiety coupling the R .
/.,,,A.NH CLM to the PTM N 1;1
---N ----N
'IR
lik0 N N iHN¨R
x , R 0 ,
R
HO HO
--N ,-
0 0
\_
IR
, ,
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R Linker iSNN? 0 N/ \
R 0
'""jN4 w".
N-i N
0 NH 0 N 0 NH
/
N/ I N
N/ N\1 I N / , N
N
0
Linker NH2
0 \
N.-----< i
0 N
N ,
1 ¨Linker
/
N
/
N\ I
=
0 , ,
Linkefirx_N=R
0
NH2 N
0 \
t F .
b Linker
/ F / \
N
H ON---
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/
,--N
I/
N ---....¨ Linker
F = \ /
---------N
N 1
N
1111 , ________ (IN
F
RN. N---
N N Linker
H 0
0
-z.---N /
N ,, ri /.,.-N, (N0
1 HN (:)
1 ND:N% ( r
Linker 0 0 N_
V /
N N"¨j
1 \linker
Linker NH
0, 0 0
9 9 9
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I
N N
1
H N ' N
CF3 0/
0
ON 6
0
y S-4
N¨Linker
0 N,Linker /
N
H 0
,Linker
F 9 ND--IF / N\I
HO
HN ,N
N N
NN' N' 0
/ H ----
---- 0 F N 1
N
Linker F
F N
Linker F
N ii0
H
/
0 I
F N
H 0
ON N \ NH
\S/\
F N I
/----/ \O
HN I
0
Linker
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NN Linker
) = 0
i/
S-NH
ii
V N 0 F
F N / \¨N
\ 0 rN.Linker
9,1-I N 114 N
F
H
N:_-_-\
,Linker
0 / , 9 H \ N\I 0, 9 H F
/ \ / N
\S-N / N
\_--/ .-- \_...-I 4. N
----- / N N -
Linker
x 1 I
F N\)
N
I
F, F,
Qz\N 9R\ Q)N 9sµ
p-NH rs-NH
0/ F 0F
0 N õLinker 0 ,N õLinker
1 `C C - C
I I NI
/
F /
N N N N
H H ,
wherein:
R is H, a lower alkyl, a bond, or a chemical moiety coupling the CLM to the
PTM; and
Linker is a bond or a chemical linker moiety coupling the CLM to the PTM,
including
pharmaceutically acceptable salt forms thereof
[0906] In any aspect or embodiment described herein, the compound is
selected from the
group consisting of compounds 1-52.
[0907] A further aspect of the present disclosure provides a composition
comprising an
effective amount of a bifunctional compound of the present disclosure, and a
pharmaceutically
acceptable carrier.
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[0908] In any aspect or embodiment described herein, the composition
further comprises at
least one of additional bioactive agent or another bifunctional compound of
the present
disclosure.
[0909] In any aspect or embodiment described herein, the additional
bioactive agent is anti-
cancer agent, an anti-neurodegenerative agent, an antimicrobial agent, an
antiviral agent, an anti-
HIV agent, or an antifungal agent.
[0910] An additiona aspect of the present disclosure provides a composition
comprising an
effective amount of at least one compound of the present disclosure and a
pharmaceutically
acceptable carrier, additive, and/or excipient for treating a disease or
disorder in a subject, the
method comprising administering the composition to a subject in need thereof,
wherein the
compound is effective in treating or ameliorating at least one symptom of the
disease or disorder.
[0911] In any aspect or embodiment described herein, the disease or
disorder is associated
with the accumulation and/or aggregation of the target protein.
[0912] In any aspect or embodiment described herein, the disease or
disorder is selected
from the group consisting of asthma, autoimmune diseases such as multiple
sclerosis, various
cancers, 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.
[0913] In any aspect or embodiment described herein, the disease or
disorder is selected
from the group consisting of Alzheimer's disease, Amyotrophic lateral
sclerosis (Lou Gehrig's
disease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention
deficit hyperactivity
disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic
obstructive pulmonary
disease, Crohn's disease, Coronary heart disease, Dementia, Depression,
Diabetes mellitus type 1,
Diabetes mellitus type 2, Epilepsy, Guillain¨Barre syndrome, Irritable bowel
syndrome, Lupus,
Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity,
Obsessive¨compulsive
disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid
arthritis, Sarcoidosis,
Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome,
Vasculitis.
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[0914]
In any aspect or embodiment described herein, the disease or disorder is
selected
from the group consisting of aceruloplasminemia, Achondrogenesis type II,
achondroplasia,
Acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan
disease,
Adenomatous Polyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyase
deficiency,
Adrenogenital syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase
deficiency, Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha 1-
antitrypsin
deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral
sclerosis Alstrom
syndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratase
deficiency,
Anderson-Fabry disease, androgen insensitivity syndrome, Anemia Angiokeratoma
Corporis
Diffusum, Angiomatosis retinae (von Hippel¨Lindau disease) Apert syndrome,
Arachnodactyly
(Marfan syndrome), Stickler syndrome, Arthrochalasis multiplex congenital
(Ehlers¨Danlos
syndrome#arthrochalasia type) ataxia telangiectasia, Rett syndrome, primary
pulmonary
hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson
cutis gyrata
syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia,
Bilateral
Acoustic Neurofibromatosis (neurofibromatosis type II), factor V Leiden
thrombophilia, Bloch-
Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked
sideroblastic anemia,
Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous
sclerosis), prion
disease, Birt¨Hogg¨Dube syndrome, Brittle bone disease (osteogenesis
imperfecta), Broad
Thumb-Hallux syndrome (Rubinstein-Taybi syndrome), Bronze Diabetes/Bronzed
Cirrhosis
(hemochromatosis), Bulbospinal muscular atrophy (Kennedy's disease), Burger-
Grutz syndrome
(lipoprotein lipase deficiency), CGD Chronic granulomatous disorder,
Campomelic dysplasia,
biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cri du chat, CAVD
(congenital
absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP
(congenital
erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism,
Chondrodystrophy
syndrome (achondroplasia), otospondylomegaepiphyseal dysplasia, Lesch-Nyhan
syndrome,
galactosemia, Ehlers¨Danlos syndrome, Thanatophoric dysplasia, Coffin-Lowry
syndrome,
Cockayne syndrome, (familial adenomatous polyposis), Congenital erythropoietic
porphyria,
Congenital heart disease,
Methemoglobinemia/Congenital m ethaem ogl ob inaemi a,
achondroplasia, X-linked sideroblastic anemia, Connective tissue disease,
Conotruncal anomaly
face syndrome, Cooley's Anemia (beta-thalassemia), Copper storage disease
(Wilson's disease),
Copper transport disease (Menkes disease), hereditary coproporphyria, Cowden
syndrome,
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Craniofacial dysarthrosis (Crouzon syndrome), Creutzfeldt-Jakob disease (prion
disease),
Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome
(myotonic
dystrophy), Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,
spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,
Duchenne and Becker
types (DBMD), Usher syndrome, Degenerative nerve diseases including de Grouchy
syndrome
and Dejerine-Sottas syndrome, developmental disabilities, distal spinal
muscular atrophy, type V,
androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbe
disease), Di George's
syndrome, Dihydrotestosterone receptor deficiency, androgen insensitivity
syndrome, Down
syndrome, Dwarfism, erythropoietic protoporphyria Erythroid 5-aminolevulinate
synthetase
deficiency, Erythropoietic porphyria, erythropoietic protoporphyria,
erythropoietic uroporphyria,
Friedreich's ataxiaõ familial paroxysmal polyserositis, porphyria cutanea
tarda, familial pressure
sensitive neuropathy, primary pulmonary hypertension (PPH), Fibrocystic
disease of the
pancreas, fragile X syndrome, galactosemia, genetic brain disorders, Giant
cell hepatitis
(Neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthoma
elasticum),
Gunther disease (congenital erythropoietic porphyria), haemochromatosis,
Hallgren syndrome,
sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-
Lindau disease
(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria
syndrome
(progeria), Hyperandrogenism, Hypochondroplasia, Hypochromic anemia, Immune
system
disorders, including X-linked severe combined immunodeficiency, Insley-Astley
syndrome,
Kennedy's syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan
syndrome,
Jackson-Weiss syndrome, Kidney diseases, including hyperoxaluria,
Klinefelter's syndrome,
Kniest dysplasia, Lacunar dementia,Langer-Saldino achondrogenesis, ataxia
telangiectasia,
Lynch syndrome, Lysyl-hydroxylase deficiency, Machado-Joseph disease,
Metabolic disorders,
including Kniest dysplasia, Marfan syndrome, Movement disorders, Mowat-Wilson
syndrome,
cystic fibrosis, Muenke syndrome, Multiple neurofibromatosis, Nance-Insley
syndrome, Nance-
Sweeney chondrodysplasia, Niemann¨Pick disease, Noack syndrome (Pfeiffer
syndrome),
Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystic kidney disease,
polyostotic
fibrous dysplasia (McCune¨Albright syndrome), Peutz-Jeghers syndrome, Prader-
Labhart-Willi
syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan
syndrome),
primary pulmonary hypertension, primary senile degenerative dementia, prion
disease, progeria
(Hutchinson Gilford Progeria Syndrome), progressive chorea, chronic hereditary
(Huntington)
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(Huntington's disease), progressive muscular atrophy, spinal muscular atrophy,
propionic
acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial
hypertension, PXE
(pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen disease
(neurofibromatosis
type I), Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rett
syndrome, RFALS type
3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe
achondroplasia with
developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome,
sarcoma,
breast, leukemia, and adrenal gland (SBLA) syndrome, sclerosis tuberose
(tuberous sclerosis),
SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SED Strudwick
(spondyloepimetaphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal
dysplasia
congenita) SEMD, Strudwick type (spondyloepimetaphyseal dysplasia, Strudwick
type),
Shprintzen syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome,
South-
African genetic porphyria (variegate porphyria), infantile-onset ascending
hereditary spastic
paralysis, Speech and communication disorders, sphingolipidosis, Tay-Sachs
disease,
spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity
syndrome,
tetrahydrobiopterin deficiency, beta-thalassemia, Thyroid disease, Tomaculous
neuropathy
(hereditary neuropathy with liability to pressure palsies), Treacher Collins
syndrome, Triplo X
syndrome ( triple X syndrome), Trisomy 21 (Down syndrome), Trisomy X, VHL
syndrome (von
Hippel-Lindau disease), Vision impairment and blindness (Alstrom syndrome),
Vrolik disease,
Waardenburg syndrome, Warburg Sjo Fledelius Syndrome, Weissenbacher-Zweymuller
syndrome, Wolf¨Hirschhorn syndrome, Wolff Periodic disease, Weissenbacher-
Zweymuller
syndrome and Xeroderma pigmentosum.
[0915] In any aspect or embodiment described herein, the composition
further comprises an
additional bioactive agent.
[0916] In any aspect or embodiment described herein, the additional
bioactive agent is at
least one of an anti-cancer agent, an anti-neurodegenerative agent, an
antimicrobial agent, an
antiviral agent, an anti-HIV agent, an antifungal agent, or a combination
thereof.
[0917] In any aspect or embodiment described herein, the anticancer agent
is selected from
the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-
101,
pazopanib, G5K690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107,
TKI-
258, G5K461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054,
PHA-
739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK
inhibitor, an
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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, an mTORC1/2
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, IL13-PE38QQR, INO 1001 , IPdRi KRX-0402, lucanthone,
LY 317615,
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, N -[4-[2-(2-amino-4,7-
dihydro-4-oxo-1
H - pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl]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 45-(methyl sulfonylpiperadinemethyl)- indolylj -quinol one,
vatalanib, AG-013736,
AVE-0005, the acetate salt of [D- Ser(Bu t) 6 ,Azgly i0] (pyro-Glu-His-Trp-Ser-
Tyr-D-Ser(Bu
t )-Leu-Arg-Pro- Azgly-NH 2 acetate [C59H84N180i4 -(C2H402)x where x = 1 to
2.4], 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, gleevac,
gemcitabine, hydroxyurea,
idarubicin, ifosfamide, imatinib, leuprolide, levami sole, lomustine,
mechlorethamine, melphalan,
6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone,
nilutamide,
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octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,
procarbazine, raltitrexed,
rituximab, 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, droloxifene, 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, HAIR- 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 tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene,
tositumomab,
arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal
daunorubicin, Edwina-
asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor
antagonists, 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.
[0918] An additional aspect of the present disclosure provides a method for
inducing
degradation of a target protein in a cell comprising administering an
effective amount of a
compound of the present disclosure to the cell, wherein the compound
effectuates degradation of
the target protein.
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[0919] Another aspect of the present disclosure provides a composition
comprising an
effective amount of a compound of the present disclosure for use in a method
for treating cancer,
said method comprising administering the composition to a patient in need
thereof, wherein the
composition is effectuates for the treatment or alleviation of at least one
symptom of cancer in
the patient.
[0920] In any aspect or embodiment described herein, the 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; multiple myeloma, sarcomas, including
Ewing's
sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas,
peripheral
neuroepithelioma, synovi al 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 teratocarcinomas, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage
lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell
Leukemia, Pre-B
ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL,
Philadelphia chromosome positive ALL and Philadelphia chromosome positive
CIVIL.
[0921] While preferred embodiments of the invention have been shown and
described herein,
it will be understood that such embodiments are provided by way of example
only. Numerous
variations, changes and substitutions will occur to those skilled in the art
without departing from
the spirit of the invention. Accordingly, it is intended that the appended
claims cover all such
variations as fall within the spirit and scope of the invention.
[0922] EXAMPLES
[0923] A. Protein Degradation Bioassays:
397
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
[0924] The following bioassays evaluate the level of protein degradation
observed in various
cell types using representative compounds disclosed herein.
[0925] In each bioassay, cells were treated with varying amounts of
compounds
encompassed by the present disclosure. The degradation of the following
proteins may be
evaluated: estrogen receptor a (ERa), bromodomain-containing protein 4 (BRD4),
androgen
receptor (AR), and BRaf protein .
[0926] 1. ERE Luciferase Assay for compounds in Table 5.
[0927] T47D-KBluc cells (ATCC #CR12865, T47D human breast cancer cells
stably
transfected with estrogen responsive elementlpromoterlluciferase reporter
gene) were seeded into
96-well white opaque plates in RPMI growth medium supplemented with 1.0% fetal
bovine
serum (FBS) and allowed to adhere overnight in a 37 C humidified incubator.
The following day,
cells were treated with PROTACs in a 12-point concentration curve (top final
concentration of
300 iNt. with subsequent concentrations being 3-fold less with 2 Oil being the
lowest
concentration in the assay). Each PROTAC was tested independently in two
experiments on 96-
well plates. After 24 hours, media was removed and lvsis buffer was added to
the wells.
Following lysis, Bright.-GloTM L.uciferase Assay Substrate (Promega, Madison
WI) was added
and the luciferase activity was measured using a Cytati on 3 plate reader
(Bioiek'TM, Winooski,
VT). Each compound was assayed in duplicate and the activity was calculated as
IC50 using
GraphPad Prism software (San Diego, CA).
[0928] 2. Estrogen Receptor-alpha (ERa) degradation assay in MCF-7 cells
using
western blot method for Table 5.
[0929] The exemplary novel ERa degraders were assessed for their activity
in degrading
ERa in MCF-7 cells via western blot. The assay was carried out in the presence
of 10% FBS or
high percentage of human or mouse serum. Protocols of the western blot assay
are described
below.
[0930] MCF7 cells were grown in DMEM1F12 with 10% FBS and seeded at 24,000
cells per
well in -1.00 isti into 96-well dear tissue culture plates. The following day,
the cells were treated
with PROTACs in a 7-point concentration curve with 100 n.M being the top
concentration and
serial dilutions to make the other concentrations (30 niM, 10 riM, 3 nkl, 1
nIk4, and 0.3 nIk4). At
all concentrations, 0.01% DMISO is the final concentration in the well. The
following day, the
plates are aspirated, washed with 50 1_11 of cold PBS. The cells are lvsed
with 50 isti/well 4 C Cell
398
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
Lysis Buffer (Catalog# 9803; Cell Signaling Technology, Danvers, MA)
(2011'11\4: Tris-HCL (pH
7.5), 150 InIVI NaCl, ltn.M Na2EDTA, 1 mkt. EGTA, 1% Triton, 2.5 TriM sodium
pyrophosphate,
1 triM B-,..,lycerophosphate, 1 paM sodium vanadate, ug/ml leupeptin). Lysates
were clarified
at 16,000 x g for 10 minutes, and 2 lag of protein was subjected to SDS-PAGE
analysis and
followed by immunoblotting according to standard protocols. The antibodies
used were ERa
(Cell Signaling Technologies Catalog #8644), and Tubulin (Sigma Catalog
#T9026; St. Louis,
MO). Detection reagents were Clarity Western ECL substrate (Bio-Rad Catalog
4170-5060;
Hercules, CA).
[0931] Alternatively, MCF7 cells were grown in DMEM/F12 with 10% FBS and
seeded at
24,000 cells per well in 500 ul in 24-well clear tissue culture plates. The
following day, the cells
were treated with PROTACs in a 5-point concentration curve (100 111\4:, 33 nM,
11 11M, 3.7 nM,
and 1.2 nM) in the presence of 0.01% DMSO, After 72 hours, the wells are
aspirated and
washed with 500 .1 of PBS. The cells are lysed with 100 [tl/well 4 C Cell
Lysis Buffer
(Catalog# 9803; Cell Signaling Technology, Danvers, MA) (20.mM Tris-HCL (pH
7.5), 150 triM
.NaCI, 1 mM: Na2EDTA, 1 11'1M EGTA, 1% Triton, 2.5 rnM sodium pyrophosphate, 1
mM: B-
glycerophosphate, 1 mM sodium vanadate, 1
leupeptin). Lysates were clarified at 16,000
x g for 10 minutes, and 2 lag of protein was subjected to SDS-PAGE analysis
and followed by
immunoblotting according to standard protocols. The antibodies used were ERa,
(Cell Signaling
Technologies Catalog #8644), and Tubulin (Sigma Catalog #T9026; St. Louis,
MO). Detection
reagents were Clarity Western :ECL substrate (Bio-Rad Catalog 4170-5060;
Hercules, CA).
[0932] 3. Estrogen receptor-alpha (ERa) degradation assay using In-Cell
Westernim
Assay for Table 5.
[0933] Degradation of ERa by claimed compounds were determined in MCF7
cells using an
In-Cell WesternTM assay. Briefly, MCF7 cells were plated in 96-well plates
(2000 cells per well
in 100 ul media) and incubated at 37 C under an atmosphere of 5% CO2 in a
humidified
incubator overnight. One-hundred (100) ul of media containing test compound
(at 2x
concentration) was added to the appropriate wells to provide 11 serially
decreasing
concentrations (top final concentration, 1 [t1\4 then 3-fold less for the next
10 concentrations); a
vehicle control (DMSO) was also added for each compound. For each experiment,
all
compounds were assayed in duplicate plates. Cells were then incubated for 3 or
5 days in the
above-mentioned environment. The assay was terminated by removal of media, a
single wash
399
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
with ice-cold PBS and the addition of 5011.1 paraformaldehyde (PFA: 4% in
PBS). After 15
minutes in PFA at room temperature, the cells were permeabilized in Tris-
phosphate-buffered
saline with Tween (0.1%) (TBST) supplemented with Triton X-100 (0.5%) for 15
minutes. Cells
were then blocked in BSA (TBST with BSA, 3%) for one hour. Primary antibodies
for the
detection of ERa (rabbit monoclonal, 1:1000, Cell Signaling Technology Catalog
#8644) and
tubulin (mouse monoclonal, 1:5000, Sigma Catalog #T6074) in TBST with BSA (3%)
were
added. The cells were incubated overnight at 4 C. The cells were then washed
thrice with TBST
at room temperature and then incubated with anti-rabbit and anti-mouse
fluorescently-labelled
secondary antibodies (IRDye , LI-COR; Lincoln, NE) in LI-COR blocking buffer
(Catalog
#927-50000) for one hour at room temperature. Following 3 washes with TBST,
the buffer was
removed and the plates were read on an Odyssey infrared imaging system (LI-
COR , Lincoln,
NE) at 700 nm and 800 nm. Using commercial software (ImageStudioTM; LI-COR,
Lincoln, NE),
the staining intensity for ERa and tubulin in each well was quantified and
exported for analysis.
For each data point, ERa intensity was normalized to tubulin intensity and for
each compound all
normalized intensity values were normalized to the vehicle control. DC50 and
Dmax values were
determined following a 4-parameter IC50 curve fit using ACAS dose response
module (McNeil
& Co Inc.).
[0934] 4. AR ELISA Assay Protocol for Table 6
[0935] Compounds were evaluated in this assay in LNCaP and/or VCaP cells
utilizing
similar protocols. The protocols used with VCaP cells are described below. The
androgen
receptor ELISA assay was performed using PathScan AR Sandwich ELISA (Cell
Signaling
Catalog#12850) according to the following assay steps:
[0936] VCaP cells were seeded at 40,000 cells/well at a volume of 100
pt/well in VCaP
assay medium [Phenol red free RPMI (Gibco Cat#11835-030); 5% Charcoal Stripped
(Dextran
treated) FBS (Omega Scientific, Cat#FB-04); 1% penstrep (Life
Technologies,Gibco Cat#:
10378-016)] in Corning 3904 plates. The cells were incubated for a minimum of
3 days. Cells
were dosed with PROTACs diluted in 0.01% DMSO and the drug treatment was
allowed for 5
hours.
[0937] AR ELISA (Cell Signaling) was performed as follows. lx Cell
Signaling Cell lysis
buffer was made (Catalogue #9803; comes with the kit). Media from the treated
wells is
aspirated, and 100 [IL lx cell lysis buffer/well is added. The cells were
placed on a shaker for 10
400
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
minutes at 4 C. Twenty microliters of lysate was transferred to 100111 of
Diluent in ELISA plate
(0.15m/m1 ¨ 0.075 1.tg/m1). The lysate-diluent mixture was shaken for 30
minutes at 37 C.
Allow mouse AR antibody, anti-mouse antibody, TMB, and STOP solution to come
to room
temperature. The lx ELISA buffer included in kit was made and loaded in the
reservoir.. Media
from the plates was discarded, the ELISA plate tapped hard on paper towel, and
washed 4x 200
tl ELISA wash buffer using a plate washer.
[0938] One-hundred (100) IlL/well of mouse AR detection Ab was added; the
plates were
covered and shaken at 37 C for 1 hour; media was discarded from the plates,
the plates were
tapped on a paper towel, washed 4x with 200 [IL ELISA wash buffer with a plate
washer.
[0939] One-hundred (100) IlL/well of anti-mouse ¨ HRP conjugated Ab (comes
with the kit)
was added; the plates were covered and shaken at 37 C for 30 minutes; the TMB
reagent was
allowed to come to room temperature; the media was discard from the plate, the
plates were
tapped on paper towl, washed 4x with 200 [IL of ELISA wash buffer; the plates
were tapped the
plates on paper towl. One-hundred (100) [IL of TMB was added and the plates
shaken for 2
minutes ¨ while watching for color development. One-hundred (100) [IL Stop
solution was
added when light blue color developed. Plates were shaken and read at 450 nM.
[0940] Progression of prostate cancer in patients treated with anti-
androgen therapy usually
involves one of several mechanisms of enhanced Androgen Receptor (AR)
signaling, including
increased intratumoral androgen synthesis, increased AR expression and AR
mutations.
PROTACs (PROteolysis TArgeting Chimera), which use bi-functional molecules
that
simultaneously bind a target of choice and an E3 ligase, cause ubiquitination
via induced
proximity and degradation of the targeted, pathological protein. As opposed to
traditional target
inhibition, which is a competitive process, degradation is a progressive
process. As such, it is
less susceptible to increases in endogenous ligand, target expression, or
mutations in the target.
Thus, this technology appears to be ideal for addressing the mechanisms of AR
resistance in
patients with prostate cancer. Data was analyzed and plotted using GraphPad
Prism software.
[0941] 5. BRaf Protein In Vitro Degradation Assay (A375 cells) of Table 7
[0942] A375 cells were cultured in ATCC DMEM+10%FBS in 12 well plates, and
treated
with indicated compound from Tables 1-41 or 0.1% DMSO vehicle control for 16
hours. Cells
were harvested in Cell Signaling lysis buffer (Cat# 9803) with the addition of
Roche protease
inhibitor tablets (Cat# 11873580001), and lysates clarified by
microcentrifugation. Proteins were
401
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
separated by SDS-PAGE, and transferred onto nitrocellulose membranes using an
Invitrogen
iBlot system. Immunoblotting was performed for BRaf (Santa Cruz Cat# 9002),
CRAF (BD
Cat#610151), and pErk (Cell Signaling Cat#9106). GAPDH (Cell Signaling
Cat#2118) was used
as a loading control. Quantification was carried out using the BioRad Image
Lab 5 software.
[0943] 6. BRaf In-Cell Western Cellular Degradation Assay (A375 cells) of
Table 7
[0944] A375 cells were cultured in ATCC DMEM+10% FBS in 96-well plates, and
treated
with indicated compounds from Tables-43 or 0.1% DMSO vehicle control for 72
hours. Cells
were washed with PBS lx, and affixed to plate using 4% PFA in phosphate
buffered saline for
15 minutes; washed lx and permeabilized using 0.1% Triton-X-100 in PBS for 5
minutes;
washed 1X and blocked with LICOR blocker (Cat.# 927-50000) for 1 hour. Cells
were then
incubated with B-Raf antibody (Santa Cruz Cat# 9002, Santa Cruz Cat#528) and
tubulin
antibody (Sigma #T6074) in LICOR blocker for 18 hours. Cells were washed 3x
prior to adding
secondary antibodies (LICOR cat #926-32210 and 926-68071) and incubated for 1
hour. Cells
were washed 3x and imaged using LICOR Odyssey Software.
[0945] 7. BRD4 Western Protocol for Table 8
[0946] 22Rv-1 or VCaP cells were purchased from ATCC and cultured in
Dulbecco's
Modified Eagle's Medium (ATCC), supplemented with 10% FBS (ATCC) and
Penicillin/Streptomycin (Life Technologies). DMSO control and compound
treatments
(0.004M, 0.01[tM, 0.03 M and 0.1[tM) were performed in 12-well plates for 16
hours. Cells
were harvested, and lysed in RIPA buffer (50mM Tris pH8, 150mM NaCl, 1% Tx-
100, 0.1%
SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase
inhibitors.
Lysates were clarified at 16,000g for 10 minutes, and protein concentration
was determined.
Equal amount of protein (20[tg) was subjected to SDS-PAGE analysis and
followed by
immunoblotting according to standard protocols. The antibodies used were BRD4
(Cell
Signaling #13440), and Actin (Sigma #5441). Detection reagents were Clarity
Western ECL
substrate (Bio-rad #170-5060).
402
AVS0001PCT3
[0947] Table 1. Exemplary Estrogen
Receptor PROTACs
0
t..)
Ex. Chemical Structure
Name General o
,-,
#
Synthetic ,o
,-,
Method
,o
,o
cio
1 3-{544-
(5-{4-[(1S,2R)-6- A-2, A-8
0 0
NH hydroxy-
2-phenyl-1,2,3,4-
N ) 0
tetrahydronaphthalen-l-
N
yl]phenoxy}pentyppiperazin-
r
1-y1]-7-methoxy-l-oxo-2,3 -
HO 0 ON dihydro-
1H-i soindo1-2-
yl I piperidine-2,6-dione
P
0
.
.
N)
2 HO \
0 3-(5-(4-
(5-(4-((1R, 2S)-6- A-2, A-8 ."
."
0 0 hydroxy-
2-phenyl-1,2,3,4- Exp. ' ,
.
14 4. 0
tetrahydronaphthalen-1- Procedure ,
o
,
NNH
yl)phenoxy)pentyl)piperazin- included
1-y1)-7-methoxy-1-
0
O
oxoisoindolin-2-
yl)piperidine-2,6-dione
3 0 o 3-[5-[4-
[5-[4-[(1R,2S)-6- A-4, A-8
hydroxy-2-phenyl- tetralin-1-
Exp. 1-d
n
N 10
HO
0 yl]
Procedure 1-i N/NN phenoxy]pentyl]piperazin-1- included
cp
t..)
111111 ON y1]-4-
methoxy-1-oxo-
isoindolin-2-yl]piperidine -
o
,-,
t..)
I.
2,6-dione
u,
-.1
o
403
AVS0001PCT3
4 0 0 3-[5-[4-
[5-[4-[(1R,2S)-6- A-4, A-5, A-8
HO hydroxy-2-
phenyl- tetralin-1-
ifh . 0 (NN N
yl]phenoxy]pentyl]piperazin- o
w
NN.NN 1-y1]-4-[2-(2- o
111111 10
methoxyethoxy)ethoxy]-1-
oxo-isoindolin-2-
,-,
40 r)O
yl]piperidine-2,6-dione cio
,-,
,0
r.-N 3-(5-{4-[(1-{4-[(1S,2R)-6- A-4, A-5, A-
N
hydroxy-2-phenyl-1,2,3,4-
12
HO 0 N
tetrahydronaphthalen-1-
yl]phenylIpiperidin-4-
0 0
? N 0
yl)methyl]piperazin-1-y1} -4-
[2-(2-
p
2
0
I.
,õ-
r 0 H methoxyethoxy)ethoxy]-1- .
'-'
oxo-2,3-dihydro-1H-
"
isoindo1-2-yl)piperidine-2,6-
N)0"0
0) 0
dione
0
,
I
0
,
6 r.N 3-(5-{4-
[(1-{4-[(1R,2S)-6- A-4, A-5, A-
N 0 0 N N
hydroxy-2-phenyl-1,2,3,4- 12
tetrahydronaphthalen-1-
O 0 0
0
yl]phenylIpiperidin-4-
N
yl)methyl]piperazin-1-y1 1 -4-
[2-(2-
?
1-d
1101 r0 (NH
methoxyethoxy)ethoxy]-1- n
,-i
oxo-2,3-dihydro-1H-
isoindo1-2-yl)piperidine-2,6-
cp
t..)
0) 0
I
dione ,-,
O-
t..)
u,
-4
o
404
AVS0001PCT3
7 Nn
(3S)-3-(5-{2-[4-(4-{4- A-5, A-9
/¨ N
[(1 S,2R)-6-hydroxy-2-
phenyl-1,2,3,4-
o
0 /
tetrahydronaphthal en-1- t..)
o
,-,
yl]phenoxy}buty1)-1,4- ,.tD
,-,
. -..,o,--.õ,....õ0...õ...---....0 0
di azepan-l-yl] ethy1I-4-[2-(2- ,.tD
oo
i NI, 0
methoxyethoxy)ethoxy]-1-
HO
..ii*
NH
oxo-2,3 -dihydro-1H-
i soindo1-2-yl)piperidine-2,6-
di one
0
8 Nn
(3S)-3-[5-[2-[4-[4-[4- A-5, A-9
/ N
[(1R,2S)-6-hydroxy-2-
phenyl-tetralin-1-
0¨/
yl]phenoxy]butyl] -1,4- P
di azepan-l-yl] ethyl] -4- [2-(2-
ow
,,,' oC)/=-=,c) 0
methoxyethoxy)ethoxy]-1-
"
NI, 0 oxo-
isoindolin-2- "
11. 4.
NH
yl]piperidine-2,6-dione 2
o HO
,
,
.
,I,
,
0
9 \ HO 345- {
44241- { 4-[(1S,2R)-6- A-2, A-13
0
hydroxy-2-pheny1-1,2,3,4-
0
* NO---\__Nr--\N 0
tetrahydronaphthal en-1-
yl]phenylIpiperidin-4-
õ ,1 \---/ N.....tti
yl)ethyl]piperazin-1-y1I-7-
1-d
n
0 methoxy-l-
oxo-2,3 -dihydro-
'-,
.
1H-i soindo1-2-yl)piperidine-
2,6-di one
cp
t..)
o
,-,
O-
t..)
u,
-4
o
405
AVS0001PCT3
\ HO 3-[5-[4-[2-[1-[4-[(1R,2S)-6- A-
2, A-13
0
0
hydroxy-2-phenyl-tetralin-1-
yl]pheny1]-4-
*piperidyflethyl]piperazin-1-
0
t..)
o
\---/ N-tti y1]-7-
methoxy-1-oxo-
,o
,-,
0
isoindolin-2-yl]piperidine- ,o
,o
cio
.
2,6-dione
o,
11 rN
3-[5-[4-[[1-[4 -[(1R,2S)-6- A-4, A-12
HO N
hydroxy-2-phenyl-tetralin-1-
yl]phenyl]-4-
O 0 0
N 0
piperidyl]methyl]piperazin-1-
y1]-4-(2-methoxyethoxy)-1-
oxo-isoindolin-2-
P
0 0
NH
yl]piperidine-2,6-dione N)
0
0"
,,
.
12 No 3-[5-[4-
[4,4-difluoro-5-[4- A-2, A-10
o
,
HO 0 0
[(1R,2S)-6-hydroxy-2- o
,
F F
phenyl-tetralin-1-
eqk 40, cN___j NN
N____t_NH yl]phenoxy]pentyl]piperazin-
Nxõ 0 1-y1]-7-
methoxy-1-oxo-
isoindolin-2-yl]piperidine-
411k
2,6-dione
1-d
n
1-i
cp
t..)
o
,-,
o
O-
t..)
o
u,
-4
o
406
AVS0001PCT3
13 No
(3R)-3-[5-[4-[5-[4-[(1R,2S)- A-2, A-8
HO
0 0
6-hydroxy-2-phenyl-tetralin-
1-
0
N NH
= . 0
(NN 0 yl]phenoxy]pentyl]piperazin- t..)
o
,-,
ill N
1-y1]-7-methoxy-l-oxo- isoindolin-2-yl]piperidine-
2,6-dione
o
o
cio
,-,
o
Ilk
14 No
(3S)-3-[5-[4-[5-[4-[(1R,2S)- A-2, A-8
0 0
6-hydroxy-2-phenyl-tetralin-
1-
HO NH
= i, 0 (NN
0
yl]phenoxy]pentyl]piperazin-
s 1-y1]-7-
methoxy-1-oxo- p
ill
isoindolin-2-yl]piperidine-
2,6-dione
.
.
4110
,,
,,0
.
,
,
.
,
15 r-N 3-[5-[4-
[[1-[4-[(1R,2S)-6- A-2, A-12 .
,
HO 0 0 N N 0
hydroxy-2-phenyl -tetralin-1-
yl]pheny1]-4-
O 0
N p
piperidyl]methyl]piperazin-1-
y1]-7-methoxy-1-oxo-
0 NH
isoindolin-2-yl]piperidine-
2,6-dione
1-d
n
,-i
o cp
,-,
=
,.,
-a
,-,
u,
-4
=
407
AVS0001PCT3
16 \o 3-[5-[4-
[5-[4-[(1R,2S)-2-(4- A-2, A-11
fluoropheny1)-6- hydroxy-
tetralin-l-yl]phenoxy]-
o
0
= ____/
1,2,3,3 a,4,5,6,6a-
N
octahydropental en-2-
t..)
o
,-,
,-,
HO =III1
yl]piperazin-1-y1]-7- ,.tD
cio
= . F 0 N 0
H methoxy-l-
oxo-isoindolin-2-
yl]piperidine-2,6-dione
17 0 0 0 3-[5-[4-
[[6-[[4-[(1R,2S)-6- A-16
N¨
hydroxy-2-phenyl-tetralin-1 -
NH
yl]phenoxy]methy1]-2-
?-0
N pyri
dyl]methyl]piperazin-1-
y1]-7-methoxy-1-oxo-
HO 0 0 ONI Nj isoindolin-2-
yl]piperidine- P
2,6-di one
O .
N)
,,
401
,,0
.
,
,
.
,
18 F rN 345- {4-
[(1-{2,6-difluoro-4- A-1, A-2 ,
HO 0 N N 0 [(1 S,2R)-6-hydroxy-2-
phenyl-1,2,3,4-
F
tetrahydronaphthal en-1 -
0
yl]phenylIpiperidin-4-
'4
N 0 yl)methyl]piperazin-1-y1} -7-
methoxy-l-oxo-2,3 -dihydro-
1-d
NH 1H-
isoindo1-2-yl)piperidine- n
2,6-di one
cp
0
t..)
o
,-,
O-
t..)
u,
-4
o
408
AVS0001PCT3
19 F r-N 3 -(5-(4-
((1-(2,6-difluoro-4- A-1, A-2, A-8
HO 0 0 N N 0
q1R,2S)-6-hydroxy-2-
phenyl-1,2,3,4-
o
O F 0
N p
tetrahydronaphthal en-1-
yl)phenyl)piperidin-4-
yl)methyl)piperazin-l-y1)-7-
t..)
o
,-,
,o
,-,
,o
,o
0 NH methoxy-l-
oxoisoindolin-2- cio
,-,
o,
yl)piperidine-2,6-dione
0
20 F 3 - [7-
(difluoromethoxy)-5- [4- A-3, A-8
HO F----c0 [5-[4-
[(1R,2S)-6- hydroxy-2-
phenyl-tetralin-1-
0
yl]phenoxy]pentyl] piperazin-
tip . 0 \\____\___
1-y1]-1-oxo-isoindolin-2-
2
P
N yl]piperidine-2,6-dione
0
N\.... j
0
410 _ N
,,
H
2
0
,
21 F 3-[5-[4-
[4,4-difluoro-5-[4- A-6, A-10
0
F"0
[(1R,2S)-6-hydroxy-2-
,
phenyl-tetralin-1-
0 0
yl]phenoxy]pentyl] piperazin-
HO _Nli 1-y1]-7-
(difluoromethoxy)-1-
F F N
40
is ONNON 0 oxo-i soindolin-2-
01
yl]piperidine-2,6-dione
1-d
n
1-i
cp
t..)
o
,-,
o
O-
t..)
o
u,
-4
o
409
AVS0001PCT3
22 F 3-[7-
(difluoromethoxy)-5-[4- A-2, A-13
F-4 [2-[1-
[4-[(1R,2S) -6-
HO 0 hydroxy-2-
phenyl-tetralin-1- o
0
yl]pheny1]-4- t..)
o
r---NN 0
piperidyflethyl]piperazin-1-
,o
it 4/ NO----\___N ,-
,
\--/ N-....oLIH y1]-1-
oxo-isoindolin-2- ,o
,o
cio
yl]piperidine-2,6-dione
,-,
o,
0
fli
23 F 3-[7-
(difluoromethoxy)-5-[4- A-3, A-14
F---( [2-[3-[4-
[(1R,2S)-6-hydroxy-
O---O¨_\_ 0 2-phenyl-tetralin-1-
= 7----\
N N
yl]phenoxy]cyclobutyl]ethyl]
piperazin-1-y1]-1-oxo-
P
.
HO II N
isoindolin-2-yl]piperidine-
.
= .
2,6-dione
,,
,,
Orr\II 0
,,0
.
.
o
24 H 3-[5-[4-
[2-[1-[2-fluoro-4- A-2, A-12 ,
,
011 HO
phenyl-tetralin-l-yl]phenyl]-
4. [(1R,2S)-
6-hydroxy-2-
F N 4-
piperidyflethyl]piperazin-
1-y1]-7-methoxy-l-oxo-
= ii No-\N 'µ /---\,..
0 isoindolin-2-yl]piperidine-
2,6-dione
0
1-d
=
/ n
1-i
cp
t..)
o
,-,
o
O-
t..)
o
u,
-4
o
410
AVS0001PCT3
25 HO 3-{744-
(5-{4-[(1R,2S)-6- A-7, A-8
¨ \NN/\N¨ --... hydroxy-
2-phenyl-1,2,3,4-
= /
\ N
rs1"- tetrahydronaphthal en-1- 0
t..)
0
0 N 0 yl]phenoxy
} pentyppiperazin-
. = /
1-y1]-3 -oxo-2H,3H-
o
,-,
,o
,-,
H
[1,2,4]triazolo[4,3-a]pyridin- ,o
,o
cio
. 2-y1}
piperidine-2,6-dione
o,
26
o _0_7(7_ \
3-[5-[4-[2-[3-[4-[(1R,2S)-6- A-17
0 hydroxy-2-
phenyl-tetrali n-1-
= 7-----\
N N
\-1 0
yl]phenoxy] cyclobutyl] -2-
oxo-ethyl]piperazin-1-y1]-7-
HO *N methoxy-l-
oxo-i soindolin-2-
= lik
yl]piperidine-2,6-d P
.
0-XrsoI:ii
.
Hu,'
27 F 3 -[7-
(difluoromethoxy)-5-[4- A-3, A-15
OH F-----( [2-[1-
hydroxy-3-[4-[(1R,2S)- ,,
,,0
.
,
0 6-hydroxy-
2-phenyl-tetralin- ,
.
,
41 1----N
N N
yl]phenoxy] cyclobutyl] ethyl]
.
,
HO 44110, N
piperazin-l-y1]-1-oxo-
= lit
isoindolin-2-yl]piperidine-
2,6-di one
0 N 0
H
28 OH \ 3-[5-[4-
[2-[1-hydroxy-3-[4- A-2, A-15 1-d
0-0L__ 0
[(1R,2S)-6-hydroxy-2- n
1-i
it /-----,
N N
\-1 0
phenyl-tetralin-1-
yl]phenoxy] cyclobutyl] ethyl]
cp
t..)
,-,
Ho it, N piperazin-
l-y1]-7-methoxy-1- ,o
O-
= 111
oxo-isoindolin-2-
yl]piperidine-2,6-dione
t..)
o,
u,
-4
o
0s,'- 0
H
411
AVS0001PCT3
N71 3-(6'-{4-
[(1-14-[(1R,2S)-6- A-6, A-12
Nc---------
1....,,,N hydroxy-2-
phenyl-1,2,3,4-
29
tetrahydronaphthal en-1-
0
HO = 010 0
yl]phenylIpiperidin-4- t..)
o
,-,
11111 N
yl)methyl]piperazin-1-y1 1-3'-
oxo-2',3'-
,o
,-,
,o
,o
cio
,-,
1110 IH
dihydrospiro[cycl oprop ane-
1,1'4 soindole]-2'-
o,
0
yl)piperidine-2,6-dione
30 3-[6'-[4-
[[1-[2-fluoro-4- A-6, A-12
NrID [(1R,2
S)-6-hydroxy-2-
N
4IL 40/ N phenyl-
tetralin-l-yl]pheny1]-
HO
W F
4-piperidyl]methyl]piperazin-
0
1-y1]-3'-oxo-spiro
P
0 N 0
[cyclopropane-1,1'-
isoindoline]-2'-yl]piperidine-
0
.
2,6-di one
',7;
NH
,,
,,0
0
,
0
'8
,
31 rN
A-1, A-2 0
,
HO 0 N N 0
0
N ,
0
NH
1-d
n
1-i
0 cp
t..)
o
,-,
o
O-
t..)
o
u,
-4
o
412
AVS0001PCT3
[0948] Table 2. Exemplary Androgen Receptor PROTACs
Ex.
General
Chemical Structure
Name o
#
scheme t..)
o
rac-N-((lr,4r)-4-(3-chloro-4-
,o
cyanophenoxy)cyclohexyl)-
N 0 0 6-(4-
((4-(2-(2,6- ,o
,o
cee
,-,
,isa N _,\¨NH 0
dioxopiperidin-3-y1)-7- Exp. o,
32 N H 1 I
0, NN-,N N
methoxy-1,3- Procedure
CI IS s = o 0 o
dioxoisoindolin-5- provided
yl)piperazin-1-
yl)methyl)piperidin-l-
yl)pyridazine-3-carboxamide
rac-N-((lr,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
p
.
rN 0 0
tetramethylcyclobuty1)-2-(4-
o
((4-(2-(2,6-dioxopiperidin-3-
NN N
,,
N
41-1,11(Grisi N-¨NEI 0 y1)-7-methoxy-1,3-
,,
2'
33
B-1, B-2
dioxoisoindolin-5-
.
,
Ci I. 0 0 0 0
yl)piperazin-1- '8
,
yl)methyl)piperidin-1-
,
yl)pyrimidine-5-
carboxamide
rac-N-((lr,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
ci 0
N
0 0
tetramethylcyclobuty1)-4-(4-
./NH Si
_tNH ((4-(2'-(2,6-dioxopiperidin- Synthesis 1-d
n
34 N 3-
y1)-3'- described in
rN
oxospiro[cyclopropane-1,1'-
detail cp
N,)
isoindolin]-6'-yl)piperazin-1- t..)
=
,-,
,o
yl)methyl)piperidin-1-
O-
t..)
yl)benzamide
o,
u,
-.1
o
413
AVS0001PCT3
rac-N-((lr,4r)-4-(3-chloro-4-
cyanophenoxy)cyclohexyl)-
N 0 0 5-(4-((((lr,3r)-3-((2'-(2,6- Synthesized o
N)---i Na-NN'I'i
---"c
dioxopiperidin-3-y1)-3'- following the t..)
o
,-,
o
35 c, ifk ro.,µNH N
oxospiro[cyclopropane-1,1'- route
0 0
isoindolin]-5'- described for o
o
cio
yl)oxy)cyclobutyl)(isopropyl Ex. Comp. 34
o
)amino)methyl)piperidin-l-
yl)pyrazine-2-carboxamide
rac-N-((lr,4r)-4-(3-chloro-4-
cyanophenoxy)cyclohexyl)-
N
\\ ....ص10 5-(4-
((((lr,3r)-3-((2'-(2,6- Synthesized
0)__CN/ INION 0
36 CI
dioxopiperidin-3-y1)-3'- following the
\ _it
----c O ....0
.,µNH N N NH
oxospiro[cyclopropane-1,1'- route
0 0
isoindolin]-6'- described for P
.
0
yl)oxy)cyclobutyl)(isopropyl Ex. Comp. 34
.
)amino)methyl)piperidin-1-
r;
yl)pyrazine-2-carboxamide
."
"
.
rac-N-((lr,3r)-3-(3-chloro-4-
.
,
cyanophenoxy)-2,2,4,4-
o
,
tetramethylcyclobuty1)-5-(4-
Synthesized
N ((((1r,30-3-((2'-(2,6-
%XyN Na-\____Nci"."/
N--....ot
dioxopiperidin-3-y1)-3'-
following the
37 / sN
route
CI 40 .0NH 0
oxospiro[cyclopropane-1,1'-
described for
0
isoindolin]-5'-
yl)oxy)cyclobutyl)(isopropyl
Ex. Comp. 34
1-d
)amino)methyl)piperidin-1-
n
1-i
yl)pyrazine-2-carboxamide
cp
t..)
o
,-,
o
O--,
t..)
o
u,
-.1
o
414
AVS0001PCT3
rac-N-((lr,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
N,
\\ N
Synthesized tetramethylcyclobuty1)-5-(4- o
0
((((lr,3r)-3-((2'-(2,6- t..)
o
38 cl fi
.,µNH N-j ---c N.....11-1
dioxopiperidin-3-y1)-3'- following the
route
,.tD
,
0
isoindolin]-6'
-1,1'- ,.tD
0 0
described for cio
-
Ex. Comp. 34
yl)oxy)cyclobutyl)(isopropyl
)amino)methyl)piperidin-l-
yl)pyrazine-2-carboxamide
N
\\
rac-N-((lr,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
ci 40
tetramethylcyclobuty1)-6-(4- C-1 and Exp.
46 01.= N1_H 1_ /¨
(5-((2-(2,6-dioxopiperidin-3- procedure P
\ / N N¨\ y1)-1-oxo-
1,2,3,4- provided as
.
0"¨N \¨
well
\--\ 00
tetrahydroisoquinolin-6-
yl)oxy)pentyl)piperazin-1-
"
"
0 N\¨NH
0".,
o
yl)nicotinamide ,
.
,
.
H
,
0 ONO
rac-N-((lr,3r)-3-(3-chloro-4-
cyanophenoxy)-2,2,4,4-
N
tetramethylcyclobuty1)-6-(4- C-1 and Exp.
47
rNO (5-((2-(2,6-dioxopiperidin-3- procedure
0
y1)-1,3-dioxo-1,2,3,4-
provided as
N H1rC.N)
tetrahydroisoquinolin-6- well
0
yl)oxy)pentyl)piperazin-1- 1-d
n
1-i
ci Vs. N 0 N
yl)nicotinamide
cp
t..)
o
,-,
.c.-::=--,
t..)
u,
-.1
o
415
AVS0001PCT3
0 0 rac-N-
((lr,3r)-3-(3-chloro-4-
N-A _tNH
cyanophenoxy)-2,2,4,4-
N
N 0
r
tetramethylcyclobuty1)-6-(4- . .\/'\./..)14.-
'""'N'
48 N)
(5-((2-(2,6-dioxopiperidin-3- Exp procedure
t..)
o
,-,
/
N..... H
y1)-3-oxo-2,3-dihydro- provided ,.tD
I
1-,
vD
Si oj:rN 1-rI ` N [1,2,4]triazolo[4,3-a]pyridin-
,.tD
cio
ci 0 7-
yl)oxy)pentyl)piperazin-1-
yl)nicotinamide
0 rac-N-
((lr,3r)-3-(3-chloro-4-
_tNH
cyanophenoxy)-2,2,4,4-
N
N 0 tetramethylcyclobuty1)-6-(4-
r N 0 -lc
49 N 0 (5-((2-
(2,6-dioxopiperidin-3- Exp procedure
N H
y1)-3-oxo-2,3-dihydro- provided
I I
0 (3):rNIN [1,2,4]triazolo[4,3-a]pyridin-
P
ci 0 6-
yl)oxy)pentyl)piperazin-1- o
yl)nicotinamide
rac-N-((lr,3r)-3-(3-chloro-4-
,)
cyanophenoxy)-2,2,4,4- ,,0
.
0 0,, 0
'
0 tetramethylcyclobuty1)-4-(4- ,
.
,
.
50 N 11 0 NjN \ ((4-(2-(2,6-
dioxopiperidin-3- ,
0 Exp procedure
y1)-3-oxo-2 3-dihydro-
a N r NLL'sN' /
NH = ' . . provided
[1,2,4]tnazolo[4,3-a]pyndin-
N 0
7-yl)piperazin-1-
yl)methyl)piperidin-1-
yl)benzamide
1-d
n
1-i
cp
t..)
o
,-,
o
O-
t..)
o
u,
-4
o
416
AVS0001PCT3
Co 0
N-((lr,3r)-3-(3-chloro-4-
N ' NH
cyanophenoxy)-2,2,4,4-
I N 0
rN
tetramethylcyclobuty1)-4-(4- o
r.,,,,...õ---.õ...,õN 0 (2-(4-(2-
(2,6-dioxopiperidin- C-3, C-4 and t..)
o
,-,
51 3-y1)-1,3-
dioxo-2,3-dihydro- Exp procedure ,o
,-,
(00 1H-
pyrrolo[3,4-c]pyridin-6- provided ,o
vD
N .,. ----tirEN1 yl)piperazin-1-
cio
,-,
-, = s.
0
ypethyl)piperidin-1- o,
0'
ci yl)benzamide
00 N \'-NH
N-((lr,3r)-3-(3-chloro-4-
_.
,....._/1 N
0 cyanophenoxy)-2,2,4,4-
tetramethylcyclobuty1)-4-(4-
N
N N" ANo
(2-(4-(6-(2,6-dioxopiperidin-
C-3, c-4 and
52
r 3-y1)-5,7-
dioxo-6,7-dihydro- exp procedure P
40 N.,.......õ.. 5H-
pyrrolo[3,4-d]pyrimidin- provided .
Is1-.
¨1:41H 2-
yl)piperazin-1-
--, 0
,.. 0
yl)ethyl)piperidin-1- .
,,
0
yl)benzamide ,,0
Ci
.
,
,
.
,
.
,
1-d
n
1-i
cp
t..)
o
,-,
o
O-
t..)
o
u,
-4
o
417
AVS0001PCT3
[0949] Table 3. Exemplary BRaf PROTACs
Ex.
Synthetic
Chemical Structure
Name 0
#
Scheme t..)
o
HO-N
1-
yD
I 39 (E)-2-(2,6-
dioxopiperidin-3-y1)-6-(4-
,o
,o
cio
(4-(4-(1-(hydroxyimino)-2,3-dihydro-
,-,
o,
/----\ 0 1H-inden-5-
y1)-3-(pyridin-4-y1)-1H- D-1
N
-- N 411 N / N 0
NH pyrazol-1-
yl)phenyl)piperazin-l-y1)-
----.. NA
I 4-
phenylisoindoline-1,3-dione
N , 0 0
N0 0
N) HO-N rNN (E)-2-(2,6-
dioxopiperidin-3-y1)-5-(4-
\ -.....t. tH
p
. N / 0 (4-(4-(1-(hydroxyimino)-2,3-dihydro-
2
40 V N 0 pyrazol-1-
yl)phenyl)piperazin-l-y1)-
1H-inden-5-y1)-3-(pyridin-4-y1)-1H-
D-1
¨14
.
N)
¨ 6-
methylisoindoline-1,3-dione 0"
IV
\ /
0
I
F'
N
0
,
0
,
00
N --NH
0
rN (E)-2-(2,6-
dioxopiperidin-3-y1)-5-(4-
0 N) 0 (4-(4-(1-(hydroxyimino)-2,3-dihydro- Custom
41 1H-inden-5-y1)-3-(pyridin-4-y1)-1H- synthesis
HO'N
\ / N pyrazol-1-
yl)phenyl)piperazin-l-y1)- provided 1-d
a
n
¨N 4-phenylisoindoline-1,3-dione
cp
o
\ N/
,o
w
o,
vi
--4
o
418
AVS0001PCT3
00
N\--NH
0 r 0 N
(E)-2-(2,6-di oxopiperi din-3 -y1)-5-(4-
t..)
o
HO- 0 N) 0 (4-(4-(1-
(hydroxyimino)-2,3-dihydro- Custom ,-,
,o
,-,
42 1H-inden-5-
y1)-3-(pyridin-4-y1)-1H- synthesis ,o
,o
N
cio
\ / N pyrazol-1-
yl)phenyl)piperazin-l-y1)- provided
o,
i
-N 4-methylisoindoline-1,3-dione
\N i
P
.
.
N)
,,
,,0
.
,
,
.
,
.
,
Iv
n
1-i
cp
t..)
o
,-,
o
t..)
o
u,
-4
o
419
AVS0001PCT3
[0950] Table 4. Exemplary BRD4 PROTACs
Ex. # Chemical Structure
Name
0
0
24(R)-4-(4-chloropheny1)-2,3,9- t..)
o
,-,
N-N\>_ N '-----4 46'
2-
trimethy1-6H-thieno[3,
_K \---\
1-,
H H ,
f][1,2,4]triazolo[4,3- vD
(N vD
cee
a][1,4]diazepin-6-y1)-N-(4-(2-(2-
,-,
(2-(2-((l-oxo-2-((R)-6-
-- N,, (s)
oxopiperidin-3-yl)isoindolin-4-
CI
yl)amino)ethoxy)ethoxy)ethoxy)eth
0 oxy)phenyl)acetamide
H
24(R)-4-(4-chloropheny1)-2,3,9-
0N1 0
S .--------N
trimethy1-6H-thieno[3,2-
f][1,2,4]triazolo[4,3-
1 N AINI N- N
p
/..1 0co 0
a][1,4]diazepin-6-y1)-N-(4-(2-(2- 0
44 411 0
(2-(2-((3-(2,6-dioxopiperidin-3-y1)-
.H
0
N "' N
2-methyl-4-oxo-3,4- r;
dihydroquinazolin-8-
2'
0
CI
yl)oxy)ethoxy)ethoxy)ethoxy)ethox
0
,
y)phenyl)acetamide
0
,
o
24(R)-4-(4
-chloropheny1)-2,3
,9-
S :-,----N
trimethy1-6H-thieno[3,2-
/
1 , N Aisi
f][1,2,4]triazolo[4,3-
0 0 C)c),O.No'0
H Si 0
NNarsLai
a][1,4]diazepin-6-y1)-N-(4-(2-(2-
NXN
(2-(243-(2,6-dioxopiperidin-3-y1)-
11110,
2-methyl-4-oxo-3,4-
1-d
CI
i
dihydroquinazolin-7-
yl)oxy)ethoxy)ethoxy)ethoxy)ethox
n
1-i
cp
0
y)phenyl)acetamide t..)
o
,-,
O-
t..)
u,
-.1
o
420
AVS0001PCT3
[0951] Table 5. Characterization of Exemplary Estrogen Receptor PROTACs
Target
Ex. Observed ER ER
o
Engagement NMR
# [M+H]/Z DC5o* Dmax *
w
o
IC50 (nM)
1 743.58 58.2 C B
6 10.93 (s, 1H), 10.56-10.43 (m, 1H), 9.18-9.13 (m, 1H), 7.16-7.13 (m,
cee
,-,
3H), 6.84-6.83 (d, J = 6.4Hz, 2H), 6.69 (s, 1H), 6.62-6.61 (m, 2H), 6.55-
o,
6.52 (m, 3H), 6.28-6.26 (d, J = 8.4Hz, 2H), 4.99-4.97 (m, 1H), 4.29-4.25
2 743.58 0.79 B A
(m, 1H), 4.23-4.18 (m, 1H), 4.17-4.15 (m, 1H), 4.06-
4.00 (m, 2H), 3.85-
3.83 (m, 5H), 3.56-3.53 (m, 1H), 3.34-3.33 (m, 4H), 3.10-3.02 (m, 4H),
3.00-2.85 (m, 2H), 2.60-2.58 (m, 3H), 2.16-2.08 (m, 1H), 1.91-1.88 (m,
1H), 1.76-1.69 (m, 5H), 1.43-1.41 (m, 2H). (DMSO-d6, 400 MHz)
6: 10.96 (s, 1H), 9.12 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.25 -6.98 (m, 4H),
6.83 (d, J=6.8 Hz, 2H), 6.72 - 6.43 (m, 5H), 6.26 (d, J=8.6 Hz, 2H), 5.06 .. P
3 743.57 1.35 A A
(dd, J=5.0, 13.2 Hz, 1H), 4.56 - 4.11 (m, 3H), 3.94 -
3.70 (m, 5H), 3.30 - .
3.25 (m, 1H), 3.21 - 2.77 (m, 8H), 2.64-2.55 (m, 5H), 2.46 - 2.26 (m, 2H),
rõ
2.16- 1.94 (m, 2H), 1.80 - 1.22 (m, 7H). (DMSO-d6, 400 MHz)
rõ
6 10.98 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H), 7.40 (d, J= 8.8 Hz, 1H), 7.17 -
2
o
,
7.07 (m, 4H), 6.83 - 6.82 (m, 2H), 6.65 - 6.60 (m, 2H), 6.54 - 6.47 (m,
3H), 6.27 - 6.29 (m, 2H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.44 - 4.40 (m,
,
4 831.65 1.42 A A 1H), 4.29- 4.17(m, 4H), 3.81 (t,
J= 6.4 Hz, 2H), 3.62 - 3.60 (m, 3H), 3.53
-3.51 (m, 3H), 3.43 -3.41 (m, 4H), 3.24 - 3.17 (m, 6H), 2.97 - 2.88 (m,
4H), 2.78 -2.74 (m, 3H), 2.61 -2.56 (m, 2H), 2.44 - 2.37 (m, 2H), 2.10 -
1.97 (m, 2H), 1.71 - 1.53 (m, 5H), 1.41 - 1.38 (m, 2H). (DMSO-d6, 400
MHz)
842.66 >300 C
1-d
n
6 842.67 2.18 C
7 859.68 102 D B
cp
t..)
6 10.99 (s, 1H), 9.12 (s, 1H), 8.16 (s, 1H), 7.36 (s, 2H), 7.17 - 7.10 (m,
o
,-,
,o
3H), 6.83 (d, J=6.8 Hz, 2H), 6.66 - 6.59 (m, 2H), 6.52 (d, J=8.8 Hz, 2H), O-
t..)
8 859.68 0.34 B B 6.50 - 6.46 (m, 1H), 6.26 (d,
J=8.4 Hz, 2H), 5.10 (dd, J=5.2, 13.2 Hz, 1H), o,
u,
-.1
4.59 (d, J=17.2 Hz, 1H), 4.41 (d, J=17.2 Hz, 1H), 4.22 - 4.16 (m, 3H), 3.82
(t, J=6.0 Hz, 2H), 3.73 - 3.67 (m, 2H), 3.60 - 3.55 (m, 2H), 3.48 - 3.42 (m,
421
AVS0001PCT3
2H), 3.37 - 3.35 (m, 2H), 3.22 (s, 3H), 3.03 - 2.82 (m, 6H), 2.82 - 2.69 (m,
10H), 2.63 -2.61 (m, 1H), 2.42 - 2.36 (m, 1H), 2.15 -2.04 (m, 1H), 2.03 -
1.95 (m, 1H), 1.81 - 1.69 (m, 3H), 1.66- 1.60 (m, 2H), 1.58- 1.50 (m, o
2H). (DMSO-d6, 400 MHz)
t..)
o
1-
9 768.61 >300 D B
o
1-
6 10.90 (s, 1H), 8.28 (s, 1H), 7.19 - 7.07 (m, 3H), 6.83 (d, J=6.4 Hz, 2H), ..
o
o
co
6.64 (d, J=8.4 Hz, 1H), 6.59 (s, 2H), 6.52 (d, J=8.8 Hz, 2H), 6.49 - 6.44
1¨
(m, 2H), 6.19 (d, J=8.8 Hz, 2H), 5.02 - 4.91 (m, 1H), 4.96 (dd, J=5.2, 13.2
768.61 0.86 B A
Hz, 1H), 4.26 - 4.19 (m, 1H), 4.14 -4.06 (m, 2H), 3.82 (s,
3H), 3.55 -3.45
(m, 2H), 3.30 - 3.10 (m, 12H), 2.98 -2.85 (m, 3H), 2.59 - 2.53 (m, 1H),
2.44 -2.41 (m, 1H), 2.38 -2.35 (m, 2H), 2.13 -2.03 (m, 1H), 1.95 - 1.87
(m, 1H), 1.75 - 1.65 (m, 3H), 1.48- 1.33 (m, 3H), 1.26- 1.12 (m, 2H).
(DMSO-d6, 400 MHz)
6 10.95 (s, 1H), 9.09 (s, 1H), 7.38 (d, J= 8.03 Hz, 1H), 7.14 (m, 4H), 6.83
P
(d, J= 6.53 Hz, 2H), 6.64 -6.59 (m, 2H), 6.56 -6.45 (m, 3H), 6.19 (d, J= .
8.66 Hz, 2H), 5.06 (dd, J= 12.99,5.08 Hz, 1H), 4.36 ¨ 4.27 (m, 1H), 4.19 -
.
11 798.63 2 B B
4.18 (m, 4H), 3.55 ¨3.53 (m, 4H), 3.26 (s, 3H), 3.11 (s,
4H), 2.96 (d, J=
5.9 Hz, 2H), 2.69 ¨ 2.57 (m, 1H), 2.32 ¨ 2.31 (m, 1H), 2.19 (d, J= 6.65 Hz,
2
4H), 2.14 - 2.04 (m, 3H), 1.98 ¨ 1.89 (m, 2H), 11.56 (m, 6H), 1.29- 1.01
,
(m, 3H). (DMSO-d6, 400 MHz)
,
10.91 (br s, 1H), 8.20 (s, 1H), 7.19 - 7.09 (m, 3H), 6.84 (br d, J=6.9 Hz,
2H), 6.67 - 6.58 (m, 5H), 6.54 - 6.43 (m, 2H), 6.30 (d, J=8.5 Hz, 2H), 4.97
12 779.56 1 A A
(dd, J=5.1, 13.2 Hz, 1H), 4.27 -4.07 (m, 5H), 3.83 (s,
3H), 3.39 -3.28 (m,
5H), 3.04 - 2.85 (m, 4H), 2.59 (br s, 3H), 2.43 - 2.22 (m, 4H), 2.15 - 1.88
(m, 4H), 1.82 - 1.56 (m, 4H). (DMSO-d6, 400 MHz)
6 10.91 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H), 7.18 -7.07 (m, 3H), 6.82 (d, 1-
d
J=6.8 Hz, 2H), 6.69 - 6.58 (m, 3H), 6.55 - 6.47 (m, 4H), 6.26 (d, J=8.8 Hz,
n
1-i
13 743.58 0.37 A A
2H), 4.96 (dd, J=5.2, 13.2 Hz, 1H), 4.29 - 4.06 (m, 3H), 3.85 - 3.78 (m,
cp
5H), 3.30 - 3.28 (m, 4H), 3.04 - 2.80 (m, 3H), 2.60 - 2.52 (m, 6H), 2.45 -
t..)
o
1-
2.34(m, 3H), 2.17- 1.99 (m, 1H), 1.97 - 1.82 (m, 1H), 1.76- 1.58 (m, 3H),
o
O'
1.56 - 1.45 (m, 2H), 1.43 - 1.29 (m, 2H). (DMSO-d6, 400 MHz)
t..)
vi
6 14 743.58 0.49 A A
10.91 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H), 7.18 -7.08 (m,
3H), 6.82 (d,
J=6.8 Hz, 2H), 6.66 - 6.58 (m, 3H), 6.55 - 6.47 (m, 4H), 6.26 (d, J=8.8 Hz,
422
AVS0001PCT3
2H), 4.96 (dd, J=5.2, 13.2 Hz, 1H), 4.28 - 4.10 (m, 3H), 3.85 - 3.78 (m,
5H), 3.30 - 3.28 (m, 4H), 3.05 - 2.80 (m, 3H), 2.58 - 2.51 (m, 6H), 2.38 -
2.33 (m, 2H), 2.32 - 2.24 (m, 1H), 2.18 - 2.00 (m, 1H), 1.97 - 1.86 (m,
o
1H), 1.74- 1.58 (m, 3H), 1.55- 1.44 (m, 2H), 1.43 - 1.34 (m, 2H).
t..)
o
1¨
(DMSO-d6, 400 MHz)
o
1-
6 10.91 (s, 1H), 8.23 (s, 2H), 7.17 - 7.09 (m, 3H), 6.83 (d, J=6.8 Hz, 2H),
o
o
co
6.64 (d, J=8.4 Hz, 1H), 6.59 (s, 2H), 6.53 (d, J=8.8 Hz, 2H), 6.49 - 6.45
1¨
(m, 2H), 6.20 (d, J=8.8 Hz, 2H), 4.96 (dd, J=5.0, 13.2 Hz, 1H), 4.25 -4.19
15 754.60 1.7 A A (m, 1H), 4.14 -4.06 (m, 1H),
4.15 -4.06 (m, 1H), 3.84 -3.80 (m, 3H),
3.51 (d, J=9.2 Hz, 7H), 3.28 (s, 4H), 2.98 - 2.83 (m, 1H), 3.03 - 2.82 (m,
2H), 2.58 (s, 1H), 2.32 - 2.26 (m, 1H), 2.22 - 2.04 (m, 4H), 1.94 - 1.87 (m,
1H), 1.80- 1.55 (m, 5H), 1.21 - 1.11 (m, 2H). (DMSO-d6, 400 MHz)
6 10.90 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H), 7.01 -6.92 (m, 2H), 6.87 -6.79
(m, 2H), 6.65 (d, J=8.4 Hz, 1H), 6.60 (s, 2H), 6.55 (d, J=8.8 Hz, 2H), 6.51
P
16 799.6 0.82 A B
- 6.44 (m, 2H), 6.26 (d, J=8.4 Hz, 2H), 4.96 (dd, J=5.4, 13.4 Hz, 1H), 4.75
0
(t, J=4.8 Hz, 1H), 4.27 - 4.06 (m, 3H), 3.85 - 3.80 (m, 3H), 3.29 - 3.25 (m,
2
u,
6H), 2.99 - 2.84 (m, 3H), 2.54 (d, J=4.4 Hz, 8H), 2.19 - 1.86 (m, 4H), 1.85
- 1.58 (m, 5H), 1.24 - 1.07 (m, 2H). (DMSO-d6, 400 MHz)
2
0
6 10.91 (s, 1H), 9.14 (s, 1H), 7.85 (br s, 1H), 7.48 -7.34 (m, 2H), 7.18 -
0
,
7.10 (m, 3H), 6.83 (br d, J=6.7 Hz, 2H), 6.69 - 6.60 (m, 5H), 6.54 - 6.47
,
(m, 2H), 6.30 (d, J=8.5 Hz, 2H), 5.08 -4.94 (m, 3H), 4.28 -4.17 (m, 2H),
17 778.57 1.5 B B 4.16 - 4.08 (m, 1H), 3.84 (s,
4H), 3.66 (br s, 1H), 3.04 -2.83 (m, 4H), 2.82
- 2.71 (m, 1H), 2.68 (br s, 1H), 2.63 - 2.54 (m, 2H), 2.48 - 2.26 (m, 2H),
2.15 -2.03 (m, 1H), 1.97 - 1.88 (m, 1H), 1.71 (br d, J=7.5 Hz, 1H).
(DMSO-d6, 400 MHz)
18 790.59 17.5 B B
1-d
6 10.89 (s, 1H), 8.19 (s, 1H), 7.22 - 7.16 (m, 3H), 6.90 (br d, J = 6.8 Hz,
n
1-i
2H), 6.68 (d, J = 8.4 Hz, 1H), 6.61 (br d, J = 9.2 Hz, 2H), 6.54 - 6.50 (m,
cp
19 790.58 4.5 B A
1H), 6.47 (s, 1H), 5.87 (d, J = 11.2 Hz, 2H), 4.95 (dd, J = 5.2, 13.2 Hz,
t..)
1H), 4.25 - 4.20 (m, 2H), 4.13 - 4.07 (m, 1H), 3.82 (s, 3H), 3.27 - 3.25 (m,
1¨
o
O'
6H), 3.03 -2.83 (m, 9H), 2.19 (br d, J = 7.2 Hz, 3H), 2.07 - 1.89 (m, 3H),
t..)
1.76- 1.58 (m, 5H), 1.16 (br d, J = 9.2 Hz, 2H). (DMSO-d6, 400 MHz)
vi
-.1
o
423
AVS0001PCT3
6 10.96 (s, 1H), 8.20 (s, 1H), 7.62 -7.20 (m, 1H), 7.18 -7.05 (m, 3H), 6.94
(s, 1H), 6.82 (d, J=6.4 Hz, 2H), 6.71 (s, 1H), 6.67 - 6.58 (m, 2H), 6.56 -
6.43 (m, 3H), 6.26 (d, J=8.8 Hz, 2H), 5.00 (dd, J=5.2, 13.2 Hz, 1H), 4.37 -
o
20 779.6 1.2 B B 4.29(m, 1H), 4.26 - 4.14 (m,
2H), 3.81 (t, J=6.4 Hz, 2H), 3.31 - 3.27 (m, t..)
o
1-
5H), 3.04 - 2.82 (m, 3H), 2.64 - 2.52 (m, 2H), 2.48 -2.42 (m, 3H), 2.41 -
o
1-
2.25 (m, 3H), 2.17 - 2.02 (m, 1H), 2.00 - 1.90 (m, 1H), 1.75 - 1.59 (m,
o
o
co
3H), 1.53 - 1.43 (m, 2H), 1.42 - 1.32 (m, 2H). (DMSO-d6, 400 MHz)
1-
6 10.98 (s, 1H), 8.15 (s, 1H), 7.68 - 7.34 (m, 1H), 7.21 - 7.05 (m, 3H), 6.95
(s, 1H), 6.84 (d, J=7.2 Hz, 2H), 6.73 (s, 1H), 6.68 - 6.58 (m, 4H), 6.50 (d,
21 815.6 2.5 B B J=8.2 Hz, 1H), 6.31 (d, J=8.4
Hz, 2H), 5.02 (dd, J=4.8, 13.2 Hz, 1H), 4.42
-4.27 (m, 1H), 4.27 -4.04 (m, 4H), 3.31 (s, 4H), 3.03 -2.78 (m, 3H), 2.68
- 2.55 (m, 1H), 2.48 (s, 6H), 2.41 - 2.32 (m, 3H), 2.16 - 1.90 (m, 4H),
1.72
(m,1H), 1.63 (m, 2H). (DMSO-d6, 400 MHz)
6 10.97 (s, 1H), 8.19 (s, 1H), 7.68 -7.20 (m, 1H), 7.18 -7.07 (m, 3H), 6.94
P
(s, 1H), 6.83 (d, J=6.4 Hz, 2H), 6.71 (s, 1H), 6.66 - 6.57 (m, 2H), 6.55 -
0
6.43 (m, 3H), 6.19 (d, J=8.4 Hz, 2H), 5.00 (dd, J=5.0, 13.2 Hz, 1H), 4.38 -
2
u,
22 804.6 4.4 B A 4.28 (m, 1H), 4.26 -4.17 (m,
1H), 4.12 (d, J=4.6 Hz, 1H), 3.30 (s, 9H),
3.01 - 2.78 (m, 4H), 2.71 - 2.55 (m, 2H), 2.44 - 2.26 (m, 5H), 2.16 - 2.03
2
0
(m, 1H), 2.02- 1.89 (m, 1H), 1.79- 1.62 (m, 3H), 1.40 (m, 3H), 1.27 -
0
1.06 (m, 2H). (DMSO-d6, 400 MHz)
,
0
,
6 10.96 (s, 1H), 9.12 (s, 1H), 8.16 (s, 1H), 7.63 -7.20 (m, 1H), 7.18 -7.06
(m, 3H), 6.94 (s, 1H), 6.81 (d, J=6.4 Hz, 2H), 6.71 (s, 1H), 6.67 - 6.58 (m,
2H), 6.51 - 6.37 (m, 3H), 6.24 (d, J=8.4 Hz, 2H), 5.00 (dd, J=5.2, 13.2 Hz,
23 791.6 1.8 B B 1H), 4.71 -4.60 (m, 1H), 4.40 -
4.29 (m, 1H), 4.26 - 4.13 (m, 2H), 3.32 -
3.27 (m, 9H), 3.04 - 2.80 (m, 3H), 2.63 -2.54 (m, 2H), 2.42 - 2.31 (m,
1H), 2.30 - 2.19 (m, 3H), 2.13 -2.03 (m, 4H), 2.02 - 1.91(m, 1H), 1.74 -
1-d
1.51 (m, 3H). (DMSO-d6, 400 MHz)
n
1-i
6 10.89 (s, 1H), 9.17 (s, 1H), 8.32 (s, 1H), 7.21 -7.10 (m, 3H), 6.86 (d,
J=6.4 Hz, 2H), 6.68 - 6.58 (m, 4H), 6.52 - 6.44 (m, 2H), 6.08 (d, J=8.0 Hz,
cp
t..)
o
24 786.6 0.7 B A
1H), 5.97 (d, J=14.2 Hz, 1H), 4.95 (dd, J=5.2, 13.2 Hz, 1H), 4.28 -4.16
1¨
o
O'
(m, 2H), 4.14 - 4.05 (m, 1H), 3.83 (s, 3H), 3.18 (s, 2H), 2.99 -2.85 (m,
t..)
3H), 2.54 -2.52 (m, 13H), 2.12- 1.86 (m, 3H), 1.71 (d, J=10.8 Hz, 3H),
vi
-.1
o
1.48 - 1.19 (m, 6H). (DMSO-d6, 400 MHz)
424
AVS0001PCT3
25 715.6 0.5 C
6 10.90 (s, 1H), 9.16 (s, 1H), 7.19 - 7.09 (m, 3H), 6.82 (br d, J = 6.6 Hz,
2H), 6.68 - 6.57 (m, 3H), 6.53 - 6.40 (m, 4H), 6.29 - 6.23 (m, 2H), 4.96
o
(dd, J = 5.1, 13.3 Hz, 1H), 4.53 (quin, J = 7.3 Hz, 1H), 4.31 -4.01 (m, 3H),
t..)
o
1-
26 769.6 0.7 A A 3.83 (s, 3H), 3.63 (br s, 1H),
3.33 -3.23 (m, 11H), 3.10 (td, J=8.8, 17.4
Hz, 1H), 1H), 3.03 - 2.79 (m, 3H), 2.55 (br s, 2H), 2.46 - 2.25 (m, 2H), 2.16 -
co
2.00 (m, 3H), 1.99 - 1.87 (m, 1H), 1.70 (br d, J=6.0 Hz, 1H). (DMSO-d6,
1-
400 MHz)
6 10.96 (s, 1H), 9.13 (br s, 1H), 8.20 - 7.39 (m, 1H), 7.22 - 7.08 (m, 3H),
6.97 - 6.93 (m, 1H), 6.81 (br d, J=7.7 Hz, 2H), 6.73 - 6.69 (m, 1H), 6.67 -
6.62 (m, 1H), 6.60 (d, J=2.3 Hz, 1H), 6.50 - 6.38 (m, 3H), 6.27 - 6.21 (m,
27 807.6 0.5 A B 2H), 5.00 (br dd, J=5.1, 13.2
Hz, 1H), 4.65 (br t, J=5.8 Hz, 1H), 4.37 -
4.30 (m, 1H), 4.25 -4.18 (m, 1H), 4.16 (br d, J=4.9 Hz, 1H), 3.28 -3.25
(m, 6H), 3.02 - 2.81 (m, 3H),2.61 -2.53 (m, 4H), 2.45 - 2.37 (m, 4H),
P
2.12- 1.90 (m, 5H), 1.76 - 1.64 (m, 3H). (DMSO-d6, 400 MHz)
.
6 10.91 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H), 7.18 -7.08 (m, 3H), 6.81 (br d,
.
J=7.7 Hz, 2H), 6.66- 6.59(m, 3H), 6.51- 6.39(m, 4H), 6.27 - 6.22 (m,
2H), 4.96 (br dd, J=5.1, 12.9 Hz, 1H), 4.65 (br t, J=6.3 Hz, 1H), 4.26 -
2
28 771.6 0.3 A A 4.19 (m, 1H), 4.16 (br d, J=4.6
Hz, 1H), 4.13 - 4.07 (m, 1H), 3.84 - 3.80
,
(m, 3H), 3.29 - 3.23 (m, 5H), 3.00 - 2.84 (m, 3H), 2.62 - 2.52 (m, 8H),
,
2.35 (br s, 2H), 2.09 - 1.88 (m, 4H), 1.78 - 1.66 (m, 3H). (DMSO-d6, 400
MHz)
29 750.6 2.4 C
6 10.87 (s, 1H), 9.20 (s, 1H), 8.26 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.24 -
7.07 (m, 3H), 6.99 (d, J=8.8 Hz, 1H), 6.86 (d, J=6.8 Hz, 2H), 6.75 - 6.56
(m, 4H), 6.50 (d, J=8.0 Hz, 1H), 6.09 (d, J=8.0 Hz, 1H), 5.97 (d, J=14.4
1-d
30 768.6 2.1 B B
Hz, 1H), 4.18 (d, J=4.4 Hz, 1H), 3.89 (s, 1H), 3.35 -3.23 (m, 8H), 3.19 (d,
n
1-i
J=6.8 Hz, 3H), 3.05 - 2.84 (m, 2H), 2.76 - 2.60 (m, 2H), 2.54 (s, 3H), 2.20
cp
(d, J=6.8 Hz, 2H), 2.06 (dd, J=6.0, 12.0 Hz, 1H), 1.83 (s, 1H), 1.75 (d,
t..)
o
J=12.0 Hz, 3H), 1.62 (s, 1H), 1.54 - 1.44 (m, 2H), 1.44 - 1.29 (m, 2H),
1¨
O'
31 C
1.21 (d, J=10.0 Hz, 2H). (DMSO-d6, 400 MHz)
t..)
vi
-.1
o
[0952] *ER DC50 (nM) A<1; 1<=B<10; 10<=C<100; D>=100
425
AVS0001PCT3
[0953] **ER Dmax(%) A>=75; 50<=B<75; C<50
[0954] Table 6. Characterization of Exemplary Androgen Receptor PROTACs
0
AR AR
Ex. # miz observed NMR
DC5o* Dmax**
32 824.54 A
cio
33 852.58 A
1H NMR (400 MHz, d6-DMS0): 6 10.88 (s, 1H), 8.22 (s, 1H), 7.91 (d, J=8.8
Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.53 - 7.45 (m, 2H), 7.21 (d, J=2.4 Hz, 1H),
34 832.61 6.99 (dd, J=9.2, 17.6 Hz, 4H), 6.73
(s, 1H), 4.33 (s, 1H), 4.06 (d, J=9.2 Hz, 1H),
3.86 (d, J=12.4 Hz, 3H), 3.32 - 3.29 (m, 9H), 2.80 (t, J=12.0 Hz, 3H), 2.59 -
2.54 (m, 4H), 2.22 (d, J=6.8 Hz, 2H), 1.81 (d, J=10.3 Hz, 4H), 1.55 - 1.47 (m,
2H), 1.45 - 1.31 (m, 2H), 1.25 - 1.17 (s, 8H), 1.13 (s, 6H)
35 849.6
0
36 849.61
37 877.64
38 877.64
1H NMR (400 MHz, DMSO-d6) 6 1.12 (6H, s), 1.21 (6H, s), 1.43-1.54 (4H, m),
810 . 3 1.74-1.78 (2H, m), 1.88-1.91 (1H, m), 2.30-2.44
(8H, m), 2.90-2.97 (3H, m),
46 A A 3.42-3.59 (7H, m), 4.03-4.07 (3H,
m), 4.30 (1H, s), 6.86-6.91 (3H, m), 6.99-
7.02 (1H, m), 7.22 (1H, d, J= 2.4 Hz), 7.64 (1H, d, J= 8.8 Hz), 7.79 (1H, d,
J=
8.8 Hz), 7.90-7.97 (2H, m), 8.62 (1H, d, J= 2.0 Hz), 10.90 (1H, s).
1-d
1H NMR (400 MHz, DMSO-d6) 6 1.12 (6H, s), 1.21 (6H, s), 1.37-1.58 (4H, m),
1.73-1.81 (2H, m), 1.86-1.91 (1H, m), 2.30-2.37 (2H, m), 2.40-2.46 (2H, m),
824.3 2.82-2.91(1H, m), 3.30-3.35 (4H, m), 3.55-3.65
(4H, m), 4.03-4.30 (6H, m),
47
5.54-5.63 (1H, m), 6.87 (1H, d, J= 9.6 Hz), 6.96-7.07 (3H, m), 7.21 (1H, d, J=
2.4 Hz), 7.63 (1H, d, J= 9.6 Hz), 7.90-8.04 (3H, m), 8.62 (1H, d, J= 2.4 Hz),
10.93 (1H, s).
48 798.6 A B 1H NMR (400 MHz, DMSO-d6) 6 1.12 (6H,
s), 1.21 (6H, s), 1.43-1.47 (2H, m),
426
AVS0001PCT3
1.49-1.53 (2H, m), 1.73-1.78 (2H, m), 2.13-2.17 (1H, m), 2.32 (2H, t, J= 7.2
Hz), 2.43-2.47 (5H, m), 2.61-2.62 (1H, m), 2.87-2.93 (1H, m), 3.59 (4H, s),
4.01-4.07 (3H, m), 4.30 (1H, s), 5.28 (1H, dd, J= 12.4, 5.2 Hz), 6.35 (1H, dd,
J
= 8.0, 2.4 Hz), 6.52 (1H, d, J=1.6 Hz), 6.86 (1H, d, J= 8.8 Hz), 7.00 (1H, dd,
J
= 8.8, 2.4 Hz), 7.21 (1H, d, J= 2.4 Hz), 7.63 (1H, d, J= 9.2 Hz), 7.80 (1H, d,
J
= 8.0 Hz), 7.90 (1H, d, J= 8.8 Hz), 7.95 (1H, dd, J= 9.2, 2.4 Hz), 8.62 (1H,
d, J
cio
= 2.4 Hz), 11.09 (1H, s).
1H NIVIR (400 MHz, DMSO-d6) 6 1.12 (6H, s), 1.21 (6H, s), 1.44-1.48 (2H, m),
1.52-1.58 (2H, m), 1.74-1.79 (2H, m), 2.15-2.19 (1H, m), 2.30 (2H, t, J= 7.2
Hz), 2.43-2.50 (4H, m), 2.51-2.67 (2H, m), 2.86-2.95 (1H, m), 3.60 (4H, s),
3.97
49
798.6 A A (2H, t, J= 6.4 Hz), 4.05 (1H, d, J= 9.2 Hz), 4.30
(1H, s), 5.38 (1H, dd, J= 5.2,
12.8 Hz), 6.86 (1H, d, J= 9.2 Hz), 7.00 (1H, dd, J= 8.4, 2.4 Hz), 7.10 (1H,
dd,
J= 10.0, 2.0 Hz), 7.21 (1H, d, J= 2.4 Hz), 7.25 (1H, d, J= 10.0 Hz), 7.36 (1H,
s), 7.62 (1H, d, J= 9.2 Hz), 7.90 (1H, d, J= 8.8 Hz), 7.95 (1H, dd, J= 9.2,
2.4
Hz), 8.62(1H, d, J= 2.4 Hz), 11.10(1H, s).
1H NIVIR (400 MHz, DMSO-d6) 6 1.13 (6H, s), 1.22 (6H, s), 1.79-1.81 (3H, m),
2.09-2.15 (1H, m), 2.19-2.21 (2H, m), 2.49-2.50 (7H, m), 2.60-2.67 (1H, m),
2.76-2.92 (3H, m), 3.22-3.26 (4H, m), 3.86 (2H, d, J= 12.8 Hz), 4.05 (1H, d, J
808.6
c,^9
50 A A = 9.2 Hz), 4.32 (1H, s), 5.23 (1H,
dd, J= 12.4, 5.2 Hz), 6.12 (1H, s), 6.70 (1H,
dd, J= 8.0, 1.6 Hz), 6.95 (2H, d, J= 9.2 Hz), 7.00 (1H, dd, J= 8.8, 2.4 Hz),
7.21 (1H, d, J= 2.4 Hz), 7.48 (1H, d, J= 8.8 Hz), 7.72 (3H, t, J= 8.4 Hz),
7.91
(1H, d, J= 8.8 Hz), 11.04 (1H, s).
1H NMR (300 MHz, DMSO-d6) 6 11.07 (s, 1H), 8.57 (s, 1H), 7.87 (d, J = 8.7
Hz, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 9.1 Hz, 1H), 7.29 (s, 1H),
7.17 (d,
51
835.59 A A J = 2.2 Hz, 1H), 7.02-6.87 (m, 3H), 5.07 (dd, J =
12.8, 5.3 Hz, 1H), 4.29 (s, 1H),
4.02 (d, J = 9.1 Hz, 1H), 3.88-3.70 (m, 5H), 3.29 (br s, 5H), 2.95-2.65 (m,
3H),
1-d
2.59-2.41 (m, 6H), 2.00 (m, 1H), 1.73 (d, J = 12.8 Hz, 2H), 1.45 (br, 3H),
1.17
(s, 6H), 1.09 (s, 6H)
1-EINMR (400 MHz, d6-DMS0): 6 11.12(s, 1H), 8.90(s, 1H), 7.91-7.89 (d,
836 . 59 J=8.4Hz, 1H), 7.74-7.72 (d, J=7.6Hz, 2H), 7.49-7.47
(d, J=8.8Hz, 1H), 7.20 (s,
52 A B 1H), 6.99-6.94 (m, 3H), 5.16-5.13
(m, 1H), 4.32 (s, 1H), 4.06-3.83 (m, 7H),
2.88-2.57 (m, 5H), 2.39-2.33 (m, 2H), 2.07-2.01 (m, 1H), 1.78-1.75 (m, 2H),
1.54-1.35 (m, 3H), 1.21 (m, 8H), 1.12 (s, 6H)
427
AVS0001PCT3
*AR DC50 (nM) A<1; 1<=B<10; 10<=C<100; D>=100
**AR Dmax(%) A>=75; 50<=B<75; C<50
0
[0955] Table 7. Characterization of Exemplary BRaf PROTACs
cio
BRaf BRaf
Ex. # MH+ NMR Transcript
DC5o* Dmax**
1H NMR (400 MHz, DMSO-d6): 6 11.03 (s, 1H), 10.87 (s, 1H), 8.72 (s, 1H), 8.57
(m, 2H),
39 C B 783.51 7.83 (d, J = 8.4 Hz, 2H), 7.62-7.60 (m, 2H),
7.56 (d, J = 8.4 Hz, 2H), 7.50-7.41 (m, 6H), 7.22
(d, J = 8.0 Hz, 2H), 7.17-7.15(m, 3H), 5.07-5.03 (m, 1H), 3.73 (m, 8H), 3.01
(s, 2H), 2.83-2.81
(m, 3H), 2.67 (s, 2H), 2.03-2.00 (m, 1H)
1H NMR (400 MHz, DMSO-d6): 6 11.15 (bs, 1H), 8.72 (s, 1H), 8.72 (s, 1H), 8.57
(d, J =
40 C A 721.48
5.6Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.77 (s, 1H), 7.49-7.57 (m, 4H), 7.41
(s, 1H), 7.17-7.30
p
(m, 3H), 5.09-5.13 (m, 1H), 3.20-3.35 (m, 8H), 2.80-3.12 (m, 6H), 2.52-2.75
(m, 3H), 1.90-
2.12 (m, 2H)
1H NMR (400 MHz, DMSO-d6): 6 11.04 (s, 1H), 10.88 (s, 1H), 8.69 (s, 1H), 8.57
(d, J = 4.8
41 C A 783.51 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.76 (d, J =
8.8 Hz, 2H), 7.40-7.56 (m, 10H), 7.22 (d, J = 4.8
Hz, 1H), 7.03 (d, J = 9.2 Hz, 2H), 5.00-5.05 (m, 1H), 3.02 (m, 9H), 2.83 (t, J
= 6.8 Hz, 2H),
1.99-2.01 (m, 3H)
1H NMR (400 MHz, DMSO-d6): 6 11.09 (s, 1H), 10.89 (s, 1H), 8.72 (s, 1H), 8.58-
8.57 (m,
42 C B 721.48 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 7.6
Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.50-7.41 (m,
4H), 7.23-7.17 (m, 3H), 5.13-5.09 (m, 1H), 3.61-3.42 (m, 8H), 3.04-2.97 (m,
2H), 2.93-2.82
(m, 3H), 2.62-2.56 (m, 5H), 2.08-2.00 (m, 1H)
*BRaf DC50 (nM) A<1; 1<=B<10; 10<=C<100; D>=100
1-d
**BRaf D(%) A>=75; 50<=B<75; C<50
[0956] Table 8. Characterization of Exemplary BRD4 PROTACs
Ex. BRD4 BRD4 Observed
# DC5o* Dmax** 11V1+111+ NMR
428
AVS0001PCT3
1-E1 NMR (400 MHz, CHLOROFORM-d) d 9.03 (s, 1H), 7.45 (dd, J = 8.71, 13.21 Hz,
4H),
7.31 -7.37 (m, 3H), 7.24 (d, J = 7.24 Hz, 1H), 6.84 (d, J = 9.00 Hz, 2H), 6.78
(d, J = 8.02
43 D B 895.22 Hz, 1H), 6.75 (br. s., 1H), 4.66 - 4.73 (m,
2H), 4.20 (d, J = 2.74 Hz, 1H), 4.07 - 4.12 (m,
2H), 3.80 -3.90 (m, 3H), 3.64 - 3.77 (m, 10H), 3.52 -3.58 (m, 1H), 3.35 -3.42
(m, 3H),
2.68 (br. s., 3H), 2.52 - 2.59 (m, 2H), 2.41 (s, 3H), 2.02 - 2.08 (m, 2H),
1.69 (s, 3H), 1.26
co
(s, 3H).
1H NMR (400 MHz, METHANOL-d4) d 7.60 - 7.65 (m, 1H), 7.30 -7.47 (m, 8H), 6.82 -
6.87 (m, 2H), 5.24 (dd, J = 5.67, 10.76 Hz, 1H), 4.69 (ddd, J = 2.84, 5.62,
8.56 Hz, 1H),
44 D C 937.19 4.26 - 4.31 (m, 2H), 4.02 -4.07 (m, 2H),
3.91 -3.96 (m, 2H), 3.77 - 3.81 (m, 2H), 3.70 -
3.74 (m, 2H), 3.63 - 3.69 (m, 6H), 3.53 - 3.61 (m, 1H), 3.43 - 3.49 (m, 2H),
2.81 (dt, J =
4.60, 14.33 Hz, 2H), 2.70 (s, 6H), 2.43 (s, 3H), 2.13 -2.20 (m, 1H), 1.68 (s,
2H), 1.26 -
1.29 (m, 2H).
1-EINMR (400 MHz, METHANOL-d4) d 8.55 (s, 1H), 7.96 - 8.00 (m, 1H), 7.36 -
7.50 (m,
6H), 7.03 -7.09 (m, 2H), 6.87 (dd, J = 3.03, 9.10 Hz, 2H), 5.22 (td, J = 5.40,
10.91 Hz, 1H),
45 C A 937.19 4.70 - 4.74 (m, 1H), 4.22 (d, J = 3.33 Hz,
2H), 4.10 (d, J = 4.30 Hz, 2H), 3.85 -3.91 (m,
2H), 3.79 - 3.84 (m, 2H), 3.64 - 3.71 (m, 7H), 3.55 - 3.64 (m, 2H), 3.42 -
3.50 (m, 2H), 2.71
(s, 3H), 2.66 (d, J = 3.33 Hz, 2H), 2.44 (d, J = 3.33 Hz, 3H), 1.89 (s, 3H),
1.68 (d, J = 3.33
Hz, 2H), 1.29 (br. s., 3H).
*BRD4 DC50 (nM) A<1; 1<=B<10; 10<=C<100; D>=100
**BRD4 Dmax(%) A>=75; 50<=B<75; C<50
1-d
429
CA 03095912 2020-10-01
WO 2019/199816 PCT/US2019/026570
[0957] 5. Industrial applicability
[0958] A novel bifunctional molecule, which contains a BRD4 or an androgen
receptor
recruiting moiety and an E3 Ligase Cereblon recruiting moiety, through PROTAC
technology is
described. The bifunctional molecules of the present disclosure actively
degrades BRD4,
leading to significant and persistent downstream MYC suppression and robust
cellular
proliferation suppression and apoptosis induction. PROTAC mediated protein
degradation
provides a promising strategy in targeting the "undruggable" pathological
proteins by traditional
approaches.
[0959] The contents of all references, patents, pending patent applications
and published
patents, cited throughout this application are hereby expressly incorporated
by reference.
[0960] Those skilled in the art will recognize, or be able to ascertain
using no more than
routine experimentation, many equivalents to the specific embodiments of the
invention
described herein. Such equivalents are intended to be encompassed by the
following claims. It is
understood that the detailed examples and embodiments described herein are
given by way of
example for illustrative purposes only, and are in no way considered to be
limiting to the
invention. Various modifications or changes in light thereof will be suggested
to persons skilled
in the art and are included within the spirit and purview of this application
and are considered
within the scope of the appended claims. For example, the relative quantities
of the ingredients
may be varied to optimize the desired effects, additional ingredients may be
added, and/or
similar ingredients may be substituted for one or more of the ingredients
described. Additional
advantageous features and functionalities associated with the systems,
methods, and processes of
the present disclosure will be apparent from the appended claims. Moreover,
those skilled in the
art will recognize, or be able to ascertain using no more than routine
experimentation, many
equivalents to the specific embodiments of the invention described herein.
Such equivalents are
intended to be encompassed by the following claims.
430
