Note: Descriptions are shown in the official language in which they were submitted.
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POLYCYCLIC COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY
ACCELERATED
FIBROSARCOMA POLYPEPTIDES
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present disclosure claims the benefit and priority to U.S.
Provisional Application
No. 62/728,581, filed 7 September 2018, and is a continuation-in-part of U.S.
Patent Application
No. 15/853,166, filed 22 December 2017, published as U.S. Patent Application
Publication No.
2018/0179183A1 on 28 June 2018, which claims priority to U.S. Provisional
Application No.
62/438,803, filed 23 December 2016 and U.S. Provisional Application No.
62/582,698, filed 7
November 2017, 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; 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. 62/406,888, filed on
October 11, 2016; 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,
are incorporated herein by reference in their entirety. Furthermore, all
references cited herein are
incorporated by reference herein in their entirety.
STATEMENT REGARDING FEDERALLY FUNDED RESEARCH
[0003] This invention was made with government support under grant number
NIH
R35CA197589, as issued by the National Institutes of Health. The government
has certain rights
in the invention.
FIELD OF THE INVENTION
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[0004] The description provides bifunctional compounds comprising a target
protein binding
moiety and an E3 ubiquitin ligase binding moiety, and associated methods of
use. The
bifunctional compounds are useful as modulators of targeted ubiquitination,
especially with
respect to Rapidly Accelerated Fibrosarcoma (RAF) proteins, which are degraded
and/or
otherwise inhibited by bifunctional compounds according to the present
disclosure.
BACKGROUND
[0005] 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. For example, since the discovery of Nutlins, the first
small molecule
E3 ligase mouse double minute 2 homolog (MDM2) inhibitors, additional
compounds have been
reported that target MDM2 (i.e., human double minute 2 or HDM2) E3 ligases (J.
Di, et al.
Current Cancer Drug Targets (2011), 11(8), 987-994).
[0006] Tumor suppressor gene p53 plays an important role in cell growth
arrest and
apoptosis in response to DNA damage or stress (A. Vazquez, et al. Nat. Rev.
Drug. Dis. (2008),
7, 979-982), and inactivation of p53 has been suggested as one of the major
pathway for tumor
cell survival (A. J. Levine, et al. Nature (2000), 408, 307-310). In cancer
patients, about 50%
were found with p53 mutation (M. Hollstein, et al. Science (1991), 233, 49-
53), while patients
with wild type p53 were often found p53 down regulation by MDM2 through the
protein-protein
interaction of p53 and MDM2 (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-
109). Under
normal cell condition without oncogenic stress signal, MDM2 keeps p53 at low
concentration. In
response to DNA damage or cellular stress, p53 level increases, and that also
causes increase in
MDM2 due to the feedback loop from p53/MDM2 auto regulatory system. In other
words, p53
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regulates MDM2 at the transcription level, and MDM2 regulates p53 at its
activity level (A. J.
Levine, et al. Genes Dev. (1993) 7, 1126-1132).
[0007] Several mechanisms can explain p53 down regulation by MDM2. First,
MDM2 binds
to N-terminal domain of p53 and blocks expression of p53-responsive genes (J.
Momand, et al.
Cell (1992), 69, 1237-1245). Second, MDM2 shuttles p53 from nucleus to
cytoplasm to facilitate
proteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564). Lastly,
MDM2 carries
intrinsic E3 ligase activity of conjugating ubiquitin to p53 for degradation
through ubiquitin-
dependent 26s proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-
299). As
such, because MDM2 functions as E3 ligase, recruiting MDM2 to a disease
causing protein and
effectuating its ubiquitination and degradation is an approach of high
interest for drug discovery.
[0008] One E3 ligase with exciting therapeutic potential is the von Hippel-
Lindau (VHL)
tumor suppressor, the substrate recognition subunit of the E3 ligase complex
VCB, which also
consists of elongins B and C, Cul2 and Rbx 1 . 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. The first small molecule ligands of Von Hippel
Lindau (VHL) to
the substrate recognition subunit of the E3 ligase were generated, and crystal
structures were
obtained confirming that the compound mimics the binding mode of the
transcription factor HIF-
1 a, the major substrate of VHL.
[0009] 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),
Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). 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.
[0010] Inhibitors of Apotosis Proteins (IAPs) are a protein family involved
in suppressing
apoptosis, i.e. cell death. The human TAP family includes 8 members, and
numerous other
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organisms contain TAP homologs. IAPs contain an E3 ligase specific domain and
baculoviral
TAP repeat (BIR) domains that recognize substrates, and promote their
ubiquitination. IAPs
promote ubiquitination and can directly bind and inhibit caspases. Caspases
are proteases (e.g.
caspase-3, caspase-7 and caspace-9) that implement apoptosis. As such, through
the binding of
caspases, IAPs inhibit cell death. However, pro-apoptotic stimuli can result
in the release of
mitochondrial proteins DIABLO (also known as second mitrochondria-derived
activator of
caspases or SMAC) and HTRA2 (also known as Omi). Binding of DIABLO and HTRA2
appears to block TAP activity.
[0011] SMAC interacts with essentially all known IAPs including XIAP, c-
IAP1. c-IAP2.
NIL-IAP, Bruce, and survivin. The first four amino acids (AVPI) of mature SMAC
bind to a
portion of IAPs, which is believed to be essential for blocking the anti-
apoptotic effects of I.APs.
[0012] Bifunctional compounds such as those that are described in U.S.
Patent Application
Publications 2015-0291562 and 2014-0356322 (incorporated herein by reference),
function to
recruit endogenous proteins to an E3 ubiquiuin ligase for degradation. In
particular, the
publications describe bifunctional or proteolysis targeting chimeric (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.
[0013] An ongoing need exists in the art for effective treatments for
disease associated with
overexpression or aggregation of Rapidly Accelerated Fibrosarcoma (RAF), or
the
overactivation of RAF (such as constitutively active RAF). For example,
current BRaf inhibitors
(such as, vemurafenib and dabrafenib) may target V600 mutant BRaf. Thus, a
need exists for
diseases or disorders (such as, melanoma, lung cancer, pancreatic cancer,
and/or colorectal
cancers) that have different BRaf mutations that are insensitive to currently
marketed agents.
Furthermore, resistance mutations can emerge in response to BRaf/MEK inhibitor
therapy. For
example, the p61 splice variant can emerge in melanoma patients treated with
BRaf/MEK
inhibitor therapy, which leaves these patients with no clinical options.
Currently marketed
agents also bind to and cause paradoxical activation of wild-type BRaf, which
results in clinical
complications. In addition, the family of hypoactive Class III BRaf mutants
that signal through
heterodimerization with CRaf, constitute 40% of BRaf mutations in non-small
cell lung cancer
(NSCLC), and also appear sporadically across other cancers, cannot be targeted
with any
currently approved or clinical-stage BRaf inhibitors. Class I BRAF mutants
(V600E, V600K,
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V600D) have high kinase activity, are Ras and dimerization independent, and
are sensitive to
vemuragenib. Class II BRAF mutants has high to intermediate kinase activity,
are Ras-
independent and dimerization dependent, and are insensitive to vemurafenib.
Class III BRAF
mutatns have lot to no kinase activity, are Ras and dimerization dependent,
and are insensitive to
vemurafenib.
[0014] Thus, non-specific effects and the inability to target and modulate
RAF, remain an
obstacle to the development of effective treatments. As such, small-molecule
therapeutic agents
that effectively targets RAF (e.g., effectively inhibiting and/or degrading
mutant forms of BRaf,
while sparing wild-type BRaf) and that leverage or potentiate VHL's,
cereblon's, MDM2's, and
IAPs' substrate specificity would be very useful.
SUMMARY
[0015] 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
(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.,
renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer,
ovarian cancer, thyroid
cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular
carcinoma, and
melanoma), cardiofaciocutaneous syndrome, neurofibromatosis type 1, Costello
syndrome,
Noonan Syndrome, LEOPARD (Lentigo, Electrocardiographic abnormalities, Ocular
hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth,
Deafness) syndrome.
[0016] As such, in one aspect the disclosure provides bifunctional or
PROTAC compounds,
which comprise an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3
ubquitin 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
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ubiquitin ligase to effect degradation (and inhibition) of that protein. In a
preferred embodiment,
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 miniute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM), or
an TAP E3
ubiquitin ligase binding moiety (i.e., a "ILM"). For example, the structure of
the bifunctional
compound can be depicted as:
PTM _________________________ ULM
[0017] The respective positions of the PTM and ULM moieties (e.g., VLM,
CLM, MLM or
ILM) 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.
[0018] 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 ULM
where PTM is a protein/polypeptide targeting moiety, L is a linker, e.g., a
bond or a chemical
group coupling PTM to ULM, and ULM is a TAP E3 ubiquitin ligase binding
moiety, or a 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).
[0019] For example, the structure of the bifunctional compound can be
depicted as:
PTM L VLM or CLM or MLM or ILM
wherein: PTM is a protein/polypeptide targeting moiety; "L" is a linker (e.g.
a bond or a
chemical linker group) coupling the PTM and at least one of VLM, CLM, MLM,
ILM, or a
combination thereof; VLM is Von Hippel-Lindau E3 ubiquitin ligase binding
moiety that binds
to VHL E3 ligase; CLM is cereblon E3 ubiquitin ligase binding moiety that
binds to cereblon;
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MLM is an MDM2 E3 ubiquitin ligase binding moiety; and ILM is a TAP binding
moiety which
binds to TAP.
[0020] In certain preferred embodiments, the ILM is an AVPI tetrapeptide
fragment. As
such, in certain additional embodiments, the ILM of the bifunctional compound
comprises the
amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or their
unnatural mimetics,
respectively. In additional embodiments, the amino acids of the AVPI
tetrapeptide fragment are
connected to each other thorugh amide bonds (i.e., ¨C(0)NH¨ or ¨NHC(0)¨).
[0021] In certain embodiments, the compounds as described herein comprise
multiple
independently selected ULMs, multiple PTMs, multiple chemical linkers or a
combination
thereof.
[0022] In certain embodiments, ILM comprises chemical moieties such as
those described
herein.
[0023] In additional embodiments, VLM can be hydroxyproline or a derivative
thereof.
Furthermore, other contemplated VLMs are included in U.S. Patent Application
Publication No.
2014/03022523, which as discussed above, is incorporated herein in its
entirety.
[0024] In an embodiment, the CLM comprises a chemical group derived from an
imide, a
thioimide, an amide, or a thioamide. In a particular embodiment, the chemical
group is a
phthalimido group, or an analog or derivative thereof. In a certain
embodiment, the CLM is
thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof,
or derivatives
thereof. Other contemplated CLMs are described in U.S. Patent Application
Publication No.
2015/0291562, which is incorporated herein in its entirety.
[0025] In certain embodiments, MLM can be nutlin or a derivative thereof.
Furthermore,
other contemplated MLMs are included in U.S. Patent Application 15/206,497
filed 11 July 2016,
which as discussed above, is incorporated herein in its entirety. In certain
additional
embodiments, the MLM of the bifunctional compound comprises chemical moieties
such as
substituted imidazolines, substituted spiro-indolinones , substituted
pyrrolidines , substituted
piperidinones , substituted morpholinones , substituted pyrrolopyrimidines,
substituted
imidazolopyridines, substituted thiazoloimidazoline, substituted
pyrrolopyrrolidinones, and
substituted isoquinolinones.
[0026] In additional embodiments, the MLM comprises the core structures
mentioned above
with adjacent bis-aryl substitutions positioned as cis- or trans-
configurations.
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[0027] In certain embodiments, "L" is a bond. In additional embodiments,
the linker "L" is a
connector with a linear non-hydrogen atom number in the range of 1 to 20. The
connector "L"
can contain, but not limited to the functional groups such as ether, amide,
alkane, alkene, alkyne,
ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The
linker can contain
aromatic, heteroaromatic, cyclic, bicyclic and tricyclic moieties.
Substitution with halogen, such
as Cl, F, Br and I can be included in the linker. In the case of fluorine
substitution, single or
multiple fluorines can be included.
[0028] In certain embodiments, VLM is a derivative of trans-3-
hydroxyproline, where both
nitrogen and carboxylic acid in trans-3-hydroxyproline are functionalized as
amides.
[0029] In certain embodiments, CLM is a derivative of piperidine-2,6-dione,
where
piperidine-2,6-dione can be substituted at the 3-position, and the 3-
substitution can be bicyclic
hetero-aromatics with the linkage as C-N bond or C-C bond. Examples of CLM can
be, but not
limited to, pomalidomide, lenalidomide and thalidomide and their derivatives.
[0030] 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 ILM and a PTM, a PTM
and a VLM,
or a PTM and a CLM, or a PTM and a MLM, preferably linked through a linker
moiety, as
otherwise described herein, wherein the VLM/ILM/CLM/MLM is coupled to the PTM
through a
linker to target protein that binds to PTM for degradation. Similarly, the PTM
can be coupled to
VLM or CLM or MLM or ILM through a linker to target a protein or polypeptide
for
degradation. Degradation of the target protein will occur when the target
protein is placed in
proximity to the E3 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
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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.
[0031] In still another aspect, the description provides methods for
treating or ameliorating 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.
[0032] 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.
[0033] 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 disclosure
may be utilized in numerous combinations, all of which are expressly
contemplated by the
present description. These additional aspects 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 disclosure, and in particular cases, to provide
additional details respecting
the practice, are incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] 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 disclosure. The drawings
are only for the
purpose of illustrating an embodiment of the disclosure and are not to be
construed as limiting
the disclosure. Further objects, features and advantages of the disclosure
will become apparent
from the following detailed description taken in conjunction with the
accompanying figures
showing illustrative embodiments of the disclosure, in which:
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[0035] Figures 1A and 1B. Illustration of general principle for
bifunctional compounes of
the present disclosure. (A) Exemplary bifunctional compound comprises 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 bifunctional compounds 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
degradation by the proteosomal machinery of the cell.
[0036] Figure 2A. Table 1A. Examplary protein targeting moieties and
compounds of the
present disclosure.
[0037] Figure 2B. Table 1B. Exemplary protein targeting moieties and
compounds of the
present disclosure.
[0038] Figure 2C. Table 1C. Examplary protein targeting moieties and
compounds of the
present disclosure.
[0039] Figure 2D. Table 1D. Examplary protein targeting moieties and
compounds of the
present disclosure.
[0040] Figure 3A. Table 2A. Data of exemplary protein targeting moieties
and compounds
of the present disclosure.
[0041] Figure 3B. Table 2B. Data of exemplary protein targeting moieties
and compounds
of the present disclosure.
[0042] Figure 3C. Table 2C. Data of exemplary protein targeting moieties
and compounds
of the present disclosure.
[0043] Figure 3D. Table 2D. Data of exemplary protein targeting moieties
and compounds
of the present disclosure.
[0044] Figure 4. Illustration of general principle of bifunctional
compounds of the present
disclosure.
[0045] Figure 5. Exemplary bifunctional compound of the present disclosure
induces mutant
selective degradation of BRAF.
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[0046] Figure 6A, 6B, and 6C. Exemplary bifunctional compound of the
present disclosure
induces mutant BRAF degradation, inhibit cell proliferation, and suppresses
MAPK signaling,
while sparing wild-type BRAF.
[0047] Figure 7. Exemplary bifunctional compound of the present disclosure
induces
degradation of vemurafenib resistant mutant p61.
[0048] Figure 8A and 8B. Exemplary bifunctional compound of the present
disclosure
induces degradation of mutant BRAF in vivo (a) and decreases tumor volume (B).
[0049] Figure 9A and 9B. What mechanism underlies the selectivity of the
exemplary
bifunctional compound.
[0050] Figure 10. Wild-type BRAF is unable to recruit Cullin 2 (active E3
ligase).
DETAILED DESCRIPTION
[0051] 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.
[0052] Presently described are compositions and methods that relate to the
surprising and
unexpected discovery that an E3 ubiquitin ligase protein (e.g., inhibitors of
apoptosis proteins
(TAP), a Von Hippel-Lindau E3 ubiquitin ligase (VHL), a cereblon E3 ubiquitin
ligase, or a
mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase) 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 result in
the ubiquitination
of a chosen target protein, which leads to degradation of the target protein
by the proteasome
(see Figure 1). The present disclosure also provides a library of compositions
and the use thereof.
[0053] 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
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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.
[0054] 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 disclosure
belongs. The terminology used in the description is for describing particular
embodiments only
and is not intended to be limiting of the disclosure.
[0055] 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 disclosure. The
upper and lower limits of these smaller ranges may independently be included
in the smaller
ranges is also encompassed within the disclosure, 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 disclosure.
[0056] The following terms are used to describe the present disclosure. 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 disclosure.
[0057] The articles "a" and "an" as used herein and in the appended claims
are used herein to
refer to one or to more than one (i.e., to at least one) of the grammatical
object of the article
unless the context clearly indicates otherwise. By way of example, "an
element" means one
element or more than one element.
[0058] 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
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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.
[0059] 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."
[0060] 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.
[0061] As used herein in the specification and in the claims, the phrase
"at least one," in
reference to a list of one or more elements, should be understood to mean at
least one element
selected from anyone or more of the elements in the list of elements, but not
necessarily
including at least one of each and every element specifically listed within
the list of elements and
not excluding any combinations of elements in the list of elements. This
definition also allows
that elements may optionally be present other than the elements specifically
identified within the
list of elements to which the phrase "at least one" refers, whether related or
unrelated to those
elements specifically identified. Thus, as a nonlimiting example, "at least
one of A and B" (or,
equivalently, "at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in
one embodiment, to at least one, optionally including more than one, A, with
no B present (and
optionally including elements other than B); in another embodiment, to at
least one, optionally
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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.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] 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
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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.
[0066] 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, TAP 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.
[0067] 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
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.
[0068] 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.
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The term effective subsumes all other effective amount or effective
concentration terms, which
are otherwise described or used in the present application.
[0069] Compounds and Compositions
[0070] In one aspect, the description provides compounds comprising an E3
ubiquitin ligase
binding moiety ("ULM") that is an TAP E3 ubiquitin ligase binding moiety (an
"ILM"), a
cereblon E3 ubiquitin ligase binding moiety (a "CLM"), a Von Hippel-Lindae E3
ubiquitin
ligase (VHL) binding moiety (VLM), and/or a mouse double minute 2 homologue
(MDM2) E3
ubiquitin ligase binding moiety (MLM). In an exemplary embodiment, the ULM is
coupled to a
target protein binding moiety (PTM) via a chemical linker (L) according to the
structure:
(A) PTM-L-ULM
wherein L is a bond or a chemical linker group, ULM is a E3 ubiquitin ligase
binding moiety,
and PTM is a target protein 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 described herein can be
synthesized with any
desired number and/or relative position of the respective functional moieties.
[0071] The terms ULM, ILM, VLM, MLM, 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 TAP (i.e., ILMs), MDM2 (i.e., MLM), cereblon (i.e., CLM), and
VHL (i.e., VLM).
Further, the term ILM is inclusive of all possible TAP E3 ubiquitin ligase
binding moieties, the
term MLM is inclusive of all possible MDM2 E3 ubiquitin ligase binding
moieties, the term
VLM is inclusive of all possible VHL binding moieties, and the term CLM is
inclusive of all
cereblon binding moieties.
[0072] In another aspect, the present disclosure provides bifunctional or
multifunctional
compounds (e.g., PROTACs) useful for regulating protein activity by inducing
the degradation
of a target protein. In certain embodiments, the compound comprises an ILM or
a VLM or a
CLM or a MLM coupled, e.g., linked covalently, directly or indirectly, to a
moiety that binds a
target protein (i.e., a protein targeting moiety or a "PTM"). In certain
embodiments, the
ILM/VLM/CLM/MLM and PTM are joined or coupled via a chemical linker (L). The
ILM
binds the TAP E3 ubiquitin ligase, the VLM binds VHL, CLM binds the cereblon
E3 ubiquitin
ligase, and MLM binds the MDM2 E3 ubiquitin ligase, and the PTM recognizes a
target protein
and the interaction of the respective moieties with their targets facilitates
the degradation of the
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target protein by placing the target protein in proximity to the ubiquitin
ligase protein. An
exemplary bifunctional compound can be depicted as:
(B) PTM¨ILM
(C) PTM¨CLM
(D) PTM¨VLM
(E) PTM¨MLM
[0073] In certain embodiments, the bifunctional compound further comprises
a chemical
linker ("L"). For example, the bifunctional compound can be depicted as:
(F) PTM¨L¨ILM
(G) PTM¨L¨CLM
(H) PTM¨L¨VLM
(I) PTM¨L¨MLM
wherein the PTM is a protein/polypeptide targeting moiety, the L is a chemical
linker, the ILM is
a TAP E3 ubiquitin ligase binding moiety, the CLM is a cereblon E3 ubiquitin
ligase binding
moiety, the VLM is a VHL binding moiety, and the MLM is a MDM2 E3 ubiquitin
ligase
binding moiety.
[0074] In certain embodiments, the ULM (e.g., a ILM, a CLM, a VLM, or a
MLM) shows
activity or binds to the E3 ubiquitin ligase (e.g., TAP E3 ubiquitin ligase,
cereblon E3 ubiquitin
ligase, VHL, or MDM2 E3 ubiquitin ligase) with an IC50 of less than about 200
i.i.M. The IC50
can be determined according to any method known in the art, e.g., a
fluorescent polarization
assay.
[0075] In certain additional embodiments, the bifunctional compounds
described herein
demonstrate an activity with an IC50 of less than about 100, 50, 10, 1, 0.5,
0.1, 0.05, 0.01, 0.005,
0.001 mM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005,
0.001 iiM, or less than
about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less than
about 100, 50, 10, 1, 0.5,
0.1, 0.05, 0.01, 0.005, 0.001 pM.
[0076] In certain embodiments, the compounds as described herein comprise
multiple PTMs
(targeting the same or different protein targets), multiple ULMs, one or more
ULMs (i.e.,
moieties that bind specifically to multiple/different E3 ubiquitin ligase,
e.g., VHL, TAP, cereblon,
and/or MDM2) or a combination thereof. In any of the aspects or embodiments
described herein,
the PTMs and ULMs (e.g., ILM, VLM, CLM, and/or MLM) can be coupled directly or
via one
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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.
[0077] In certain embodiments, where the compound comprises multiple ULMs,
the ULMs
are identical. In additional embodiments, the compound comprising a plurality
of ULMs (e.g.,
ULM, ULM', etc.), at least one PTM coupled to a ULM directly or via a chemical
linker (L) or
both. In certain additional embodiments, the compound comprising a plurality
of ULMs 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.
[0078] In certain embodiments, the compound may comprise a plurality of
ULMs and/or a
plurality of ULM' s. In further embodiments, the compound comprising at least
two different
ULMs, a plurality of ULMs, and/or a plurality of ULM' s further comprises at
least one PTM
coupled to a ULM or a ULM' directly or via a chemical linker or both. In any
of the
embodiments described herein, a compound comprising at least two different
ILMs 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 ULM'), such as an ILM, a VLM, a CLM,
a MLM, an
ILM', a VLM', a CLM', and/or a MLM'.
[0079] 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.
[0080] The term "independently" is used herein to indicate that the variable,
which is
independently applied, varies independently from application to application.
[0081] 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,
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isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl,
cyclopentyl, cyclopen-
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.
[0082] The term "Alkenyl" refers to linear, branch-chained or cyclic C2-C10
(preferably C2-C6)
hydrocarbon radicals containing at least one C=C bond.
[0083] The term "Alkynyl" refers to linear, branch-chained or cyclic C2-C10
(preferably C2-C6)
hydrocarbon radicals containing at least one CC bond.
[0084] 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-(C1-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.
[0085] The term "unsubstituted" shall mean substituted only with hydrogen
atoms. A range of
carbon atoms which includes Co means that carbon is absent and is replaced
with H. Thus, a
range of carbon atoms which is Co-C6 includes carbons atoms of 1, 2, 3, 4, 5
and 6 and for Co, H
stands in place of carbon.
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[0086] The term "substituted" or "optionally substituted" shall mean
independently (i.e., where
more than substituent occurs, each substituent is independent of another
substituent) one or more
substituents (independently up to five substitutents, preferably up to three
substituents, often 1 or
2 substituents on a moiety in a compound according to the present 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 (C1\1), 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 ¨SiRiR2R3
groups where each of Ri and R2 is as otherwise described herein and R3 is H or
a Ci-C6 alkyl
group, preferably R1, R2, R3 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)õ,- or alternatively an
optionally substituted -(OCH2).,-, -(OCH2CH2).,- or -(CH2CH20).,- group, which
may be
substituted with any one or more of the above-described substituents. Alkylene
groups -(CH2),,,-
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
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C1-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 sideshain of an amino acid as otherwise described herein and
optionally substituted
amide (preferably carboxamide substituted as described above) or urethane
groups (often with
one or two Co-C6 alkyl substitutents, which group(s) may be further
substituted). In certain
embodiments, the alkylene group (often a single methylene group) is
substituted with one or two
optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl group, most
often methyl or 0-
methyl groups or a sidechain of an amino acid as otherwise described herein.
In the present
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.
[0087] The term "substituted" (each substituent being independent of any other
substituent) shall
also mean within its context of use Ci-C6 alkyl, Ci-C6 alkoxy, halogen, amido,
carboxamido,
sulfone, including sulfonamide, keto, carboxy, Ci-C6ester (oxyester or
carbonylester), Ci-C6keto,
urethane -0-C(0)-NR1R2 or ¨N(R1)-C(0)-0-R1, nitro, cyano and amine (especially
including a
Ci-C6 alkylene-NR1122, a mono- or di- Ci-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)6,-
(here, m and n are in
context, 1, 2, 3, 4, 5 or 6), -S-, -S(0)-, SO2- or ¨NH-C(0)-NH-, -(CH2)60H, -
(CH2)SH, -
(CH2)C00H, Ci-C6 alkyl, -(CH2)60-(Ci-C6 alkyl), -(CH2)nC(0)-(Ci-C6 alkyl), -
(CH2)60C(0)-
(Ci-C6 alkyl), -(CH2)6C(0)0-(Ci-C6 alkyl), -(CH2),INHC(0)-R1, -(CH2)C(0)-
NR1R2, -
(0CH2)60H, -(CH20),C00H, Ci-C6 alkyl, -(0CH2)60-(Ci-C6 alkyl), -(CH20)C(0)-(Ci-
C6
alkyl), -(0CH2)NHC(0)-Ri, -(CH20),C(0)-NR,R2, -S(0)2-Rs, -S(0)-Rs (Rs is Ci-C6
alkyl or a
¨(CH2).-NR,R2 group), NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl),
depending on the
context of the use of the substituent. R, and R2 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 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
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optionally substituted C1-C6 alkyl groups (methyl, ethyl or hydroxymethyl or
hydroxyethyl is
preferred, thus providing a chiral center), a sidechain of an amino acid group
as otherwise
described herein, an amido group as described hereinabove, or a urethane group
0-C(0)-N121122
group where Ri and R2 are as otherwise described herein, although numerous
other groups may
also be used as substituents. Various optionally substituted moieties may be
substituted with 3 or
more substituents, preferably no more than 3 substituents and preferably with
1 or 2 substituents.
It is noted that in instances where, in a compound at a particular position of
the molecule
substitution is required (principally, because of valency), but no
substitution is indicated, then
that substituent is construed or understood to be H, unless the context of the
substitution suggests
otherwise.
[0088] 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 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,
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isothiazole, 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.
[0089] The term "substituted aryl" refers to an aromatic carbocyclic group
comprised of at least
one aromatic ring or of multiple condensed rings at least one of which being
aromatic, wherein
the ring(s) are substituted with one or more substituents. For example, an
aryl group can
comprise a substituent(s) selected from: -(CH2),OH, -(CH2),-0-(Ci-C6)alkyl, -
(CH2)n-0-(CH2)n-
(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, Cl) 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
indole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), an optionally
substituted quinoline,
and combinations thereof.
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[0090] "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.
[0091] The term "heteroaryror "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).,-0-
Ci-C6 alkyl group or
an optionally substituted -(CH2).,-C(0)-0-C1-C6 alkyl group), an optionally
substituted pyridine
(2-, 3, or 4-pyridine) or a group according to the chemical structure:
r 0
______________________________________________________________ RHET
i_RHET 0
LURE
RuRE
0
0
RHET N:32.1
RHET RHET
Jµir
0
RHET -rjN1(321
yC
wherein:
SC is CHRss, NRuRE; or 0;
RHET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6
alkyl
(preferably substituted with one or two hydroxyl groups or up to three halo
groups
24
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(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 C1-C3
alkyl);
Rss is H, CN, NO2, halo (preferably F or CO, optionally substituted C1-C6
alkyl
(preferably substituted with one or two hydroxyl groups or up to three halo
groups),
optionally substituted 0-(Ci-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);
RuRE is ri¨,
a Ci-C6 alkyl (preferably H or Ci-C3 alkyl) or a ¨C(0)(Ci-C6 alkyl), each of
which groups is optionally substituted with one or two hydroxyl groups or up
to three
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 C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up
to three halo groups (e.g. CF3), optionally substituted 0(C1-C6 alkyl)
(preferably
substituted with one or two hydroxyl groups or up to three halo groups) or an
optionally substituted acetylenic group ¨CC-Ra where Ra is H or a C1-C6 alkyl
group
(preferably C1-C3 alkyl).
[0092] The terms "aralkyl" and "heteroarylalkyl" refer to groups that comprise
both aryl or,
respectively, heteroaryl as well as alkyl and/or heteroalkyl and/or
carbocyclic and/or
heterocycloalkyl ring systems according to the above definitions.
[0093] The term -arylalkyl" as used herein refers to an aryl group as defined
above appended to
an alkyl group defined above. The arylalkyl group is attached to the parent
moiety through an
alkyl group wherein the alkyl group is one to six carbon atoms. The aryl group
in the arylalkyl
group may be substituted as defined above.
[0094] 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
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are subsumed under the definition of heterocycle, depending on the context of
its use. Exemplary
heteroaryl groups are described hereinabove.
[0095] Exemplary heterocyclics include: azetidinyl, benzimidazolyl, 1,4-
benzodioxanyl, 1,3-
benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl,
dihydropyranyl,
dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-
dioxane, 1,4-dioxane,
furyl, homopiperidinyl, i idaz olyi, imidazolinyl, imidazolidinyl, indolinyl,
indoiyl,
isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,
naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine,
piperazinylõ N-
methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl,
pyrazolinyl, pyridyl,
pyrimidinyl, pyrroli di ny I , pyn-o I i n yl, pyrrol y I , qu i no lin yl,
tetrah ydrofuranyi tetrahydropyran yl ,
tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene,
oxane, oxetanyl,
oxathiolanyl, thiane among others.
[0096] 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, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, ¨SO-alkyl, ¨SO-substituted alkyl, ¨S Oaryl,
¨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).
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[0097] The term "cycloalkyl" can mean but is in no way limited to univalent
groups derived
from monocyclic or polycyclic alkyl groups or cycloalkanes, as defnied herein,
e.g., saturated
monocyclic hydrocarbon groups having from three to twenty carbon atoms in the
ring, including,
but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl and the like.
The term "substituted cycloalkyl" can mean but is in no way limited to a
monocyclic or
polycyclic alkyl group and being substituted by one or more substituents, for
example, amino,
halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro,
mercapto or sulfo,
whereas these generic substituent groups have meanings which are identical
with definitions of
the corresponding groups as defined in this legend.
[0098] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in
which at least one
ring carbon atom of its cyclic structure being replaced with a heteroatom
selected from the group
consisting of N, 0, S or P. "Substituted heterocycloalkyl" refers to a
monocyclic or polycyclic
alkyl group in which at least one ring carbon atom of its cyclic structure
being replaced with a
heteroatom selected from the group consisting of N, 0, S or P and the group is
containing one or
more substituents selected from the group consisting of halogen, alkyl,
substituted alkyl,
carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these
generic substituent
group have meanings which are identical with definitions of the corresponding
groups as defined
in this legend.
[0099] 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.
[0100] The term "independently" is used herein to indicate that the variable,
which is
independently applied, varies independently from application to application.
[0101] The term "lower alkyl" refers to methyl, ethyl or propyl
[0102] The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.
[0103] In any of the embodiments described herein, the W, X, Y, Z, G, G', R,
R', R", Q1-Q4,
and A, can independently be covalently coupled to a linker and/or a linker to
which is attached
one or more PTM, ULM, ILM or ILM' groups.
[0104] Exemplary CLMs
[0105] Neo-imide Compounds
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[0106] 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
õoõ..0Q4,...,.zz..,........_.< avvi._ N/ /
N QC)4........,..k
Q3
11 / __________ Z 11
/ \ )Z
IQ 2/,'..----'' W 7K) Q2 ./. ..,..;;%\..... w
____________________________________________________________ N
1 Q1
Rn
Rn \G'
Rn R'
(al) (b)
G
1
G N Z
\ _________________________ N
X X/ X x
Q4....,.......,,k
Q3
II / N ) __ Z Qe4N jjj.
I I Rn
Q2k ..sM/ ________________ N
Rn Qi A/ A \G' 02 /6õ..7\.,1 y .....,....,..õ
Z
X Rn
(c) (dl)
G
1
N Z X X
X
Qr.4
Q
,......,....A
Qe4 N jsr.r 0/
.......... wl / )- Z
II
M Rn
Q2/QN A 01
Rn
Rn Rn
(e) (f),
G
1
X z
X X G N
X
/
Q4
Q( WA _____________________ N
Qe4N sj.sr
11 N 11 Rn
y A ,..w, 1)
Z
Q1
Rn
, Rn Rn ,
(a2) (d2)
28
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X G X X
\
Z
71() Z
vv 1-0
Rn Rn , or Rn Rn
(a3) (a4)
wherein:
W of Formulas (a) through (e) [e.g., (al), (b), (c), (dl), (e), (f), (a2),
(d2), (a3), and (a4)] is
independently selected from the group CH2, 0, CHR, C=0, S02, NH, optionally
substituted cycloalkyl (e.g., optionally substituted 3-6 member cycloalkyl,
optionally
substituted cyclopropyl group or optionally substituted cyclobutyl group),
optionally
substituted heterocycloalkyl, and N-alkyl;
W3 is selected from C or N;
X of Formulas (a) through (e) is independently selected from the group absent,
0, S and CH2,
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;
Z of Formulas (a) through (e) is independently selected from the group absent,
0, S or CH2
except that both X and Z cannot be absent or CH2,
G and G'of Formulas (a) through (e) are independently selected from the group
H, optionally
substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", -(CH2),,-0-
P(=0)(0-C1_6a1ky1)(OH), -(CH2),,-0-P(=0)(0-C1_6alky1)2,-(CH2),, -0-P(=0)(OH)2,
-
CH2OCOO(CH2CH20),,,CH3, CH2-heterocycly1 optionally substituted with R', and
benzyl optionally substituted with R';
n" is an integer from 8 to 35 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. 18.
19. 20. 21. 22. 23
24. 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35);
Q1 - Q4 of Formulas (a) through (e) each independently represent a carbon C
substituted
with a group independently selected from H, R, N or N-oxide;
A of Formulas (a) through (e) is independently selected from the group H,
optionally
substituted linear or branched alkyl, cycloalkyl, Cl and F;
R of Formulas (a) through (e) comprises, but is not limited to: H, -CONR'R", -
OR', -NR'R",
-SR', -502R', -S 02NR' R", -CR' R"-, -CR' NR' R"-, (-CR' 0),,R", halogen,
optionally
substituted-aryl (e.g., an optionally substituted C5-C7 aryl), optionally
substituted alkyl-
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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-
heteroaryl (e.g., an optionally substituted C5-C7 heteroaryl), unsubstituted
or 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 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 Y
(e.g., optionally
substituted with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl
(e.g., a C3-
C6 c yclo alkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted
,
' 0
, 0
)1):
Y
(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)), optionally substituted-cycloalkyl (e.g., optionally substituted C3-C7
cycloalkyl),
optionally substituted-heterocyclyl (e.g., optionally substituted C3-C7
heterocyclyl), -
P(0)(OR')R", -P(0)R'R", -0P(0)(OR')R", -0P(0)R'R", -Cl, -F, -Br, -I, -CF3, -
CN, -
NR' S 02NR' 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;
each of x, y, and z are independently 0, 1,2, 3,4, 5, or 6;
R' and R" of Formulas (a) through (e) are independently selected from a H,
optionally
substituted linear or branched alkyl, optionally substituted cycloalkyl,
optionally
substituted aryl, optionally substituted heteroaryl, optionally substituted
heterocyclic, -
C(=0)R, optionally substituted heterocyclyl;
n and n' of Formulas (a) through (e) are each individually an integer from 1-
10 (e.g., 1-4, 1, 2,
3, 4, 5, 6, 7, 8, 9, or 10);
:zz"---":------- represents a single bond or a double bond; and
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. of Formulas (a) through (e) represents a bond that may be stereospecific
((R) or (S)) or
non-stereo specific.
[0107] Exemplary CLMs
[0108] In any of the compounds described herein, the CLM comprises a
chemical structure
selected from the group:
X X G X X G
Q .,n) __ N/
N/
c)Q4........õ,,,K
cl.,.... 4......1(
111"........_vvr NI) Z 11 N ________ Z
/ \ __________________________________________________________ )
Q2/. ,...õ."=\ vv
N
1 Qi
Rn
Rn \G'
Rn/ R'
(al) (b)
G
1
X X N Z
471i X x
_________________________ N /G
Q(.....Q4,.......
Q4
II N 02
/ ) Z Q N j'Pr
I I Rn VV/ A N
Q1/ \ Q 2/ cr.7%.,..1 y .......===== ..õ,
Rn Z
x G' Rn
(c) (dl)
G
1
N Z X X
X x
C)4 uµrt, __
or
Qe4N jµrd
I I Rn I I ,N )- Z
Qy. Q ====".(..0" '''========... \ Alf /
Q2/ar.......N''....'--A Rn
R Rn
R,
(e) (f),
G
1
X xNz
X X G
03'WA2:)4
srvZ N/
Q()4N sjj.
II N 11 Rn
/ ) ____ Z
Rn
Rn Rn
(a2) (d2)
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X G X X
Qi C ______
R/'' Or Rn/ A
plavvi _______________________ Z Q2 VV/ -1\40
Qi
Rn Rn
,
(a3) (a4)
wherein:
W of Formulas (a) through (e) [e.g., (al), (b), (c), (dl), (e), (f), (a2),
(d2), (a3), and (a4)] is
independently selected from the group CH2, 0, CHR, C=0, SO2, NH, optionally
substituted cycloalkyl (e.g., optionally substituted 3-6 member cycloalkyl,
optionally
substituted cyclopropyl group or optionally substituted cyclobutyl group),
optionally
substituted heterocycloalkyl (e.g., an optionally substituted 3-6 member
heterocyloalkyl),
and N-alkyl;
W3 is selected from C or N;
X of Formulas (a) through (e) is independently selected from the group absent,
0, S and CH2;
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;
Z of Formulas (a) through (e) is independently selected from the group absent,
0, S, andCH2
except that both X and Z cannot be absent or CH2;
G and G' of Formulas (a) through (e) are independently selected from the group
H,
optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", -
(CH2),,-
0-P(=0)(0-C1_6a11y1)(OH), -(CH2),,-0-P(=0)(0-C 1_6a1ky1)2, -(CH2),,-0-
P(=0)(OH)2, -
CH2OCOO(CH2CH20),,,CH3, CH2-heterocycly1 optionally substituted with R', and
benzyl optionally substituted with R'; -
n" is an integer from 8 to 35 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. 18.
19. 20. 21. 22. 23
24. 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35);
Q1 - Q4 of Formulas (a) through (e) each independently represent a carbon C
substituted
with a group independently selected from H, R, N or N-oxide;
A of Formulas (a) through (e) is independently selected from the group H,
optionally
substituted linear or branched alkyl, cycloalkyl, Cl and F;
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R of Formulas (a) through (e) comprises, but is not limited to: H, -CONR'R", -
OR', -NR'R",
-SR', -S 02R' , -S 02NR' R", -CR' R"-, -CR' NR' R"-, (-CR' 0),,R", halogen,
optionally
substituted heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl),
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-
heteroaryl (e.g., an optionally substituted C5-C7 heteroaryl), 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 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)),
,
,
,.......
, 0
optionally substituted Y
(e.g., optionally substituted
with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-
C6
c yclo alkyl), or aryl (e.g., C5-C7 aryl)),
optionally substituted
,
' 0
)H:
/
, 0
Y
(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)), optionally substitutedcycloalkyl (e.g., optionally substituted C3-C7
cycloalkyl),
optionally substituted-cycloalkyl (e.g., optionally substituted C3-C7
cycloalkyl),
optionally substituted-heterocyclyl (e.g., optionally substituted C3-C7
heterocyclyl), -
P(0)(OR')R", -P(0)R'R", -0P(0)(OR')R", -0P(0)R'R", -Cl, -F, -Br, -I, -CF3, -
CN, -
NR' S 02NR' 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, wherein
at least one R (e.g., at least one of 0, OH, N, NH, NH2, C1-C6 alkyl, C1-C6
alkoxy,
optionally substituted-cycloalkyl (e.g., optionally substituted C3-C7
cycloalkyl),
optionally substituted-heterocyclyl (e.g., optionally substituted C3-C7
heterocyclyl), -
33
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alkyl-aryl (e.g., an ¨alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7
aryl, or a
combination thereof), aryl (e.g., C5-C7 aryl), heteroaryl aryl (e.g., C5-C7
heteroaryl),
amine, amide, or carboxy) is modified to be covalently joined to a PTM, a
chemical
linker group (L), a ULM, a CLM' (e.g., CLM' is an additional CLM that has the
same or
different structure as a first CLM), or a combination thereof
each of x, y, and z are independently 0, 1,2, 3,4, 5, or 6;
R' and R" of Formulas (a) through (e) are independently selected from a bond,
H, optionally
substituted linear or branched alkyl, optionally substituted cycloalkyl,
optionally
substituted aryl, optionally substituted heteroaryl, optionally substituted
heterocyclic, -
C(=0)R, optionally substituted heterocyclyl;
n and n' of Formulas (a) through (e) are each individually an integer from 1-
10 (e.g., 1-4, 1, 2,
3, 4, 5, 6, 7, 8, 9, or 10);
. of Formulas (a) through (e) represents a bond that may be stereospecific
((R) or (S)) or
non-stereospecific
[0109] In certain embodiments described herein, the CLM or ULM comprises a
chemical
structure selected from the group:
0
N H
jK1 0
Rn
Formula (g)
wherein:
W of Formula (g) is independently selected from the group CH2, C=0, NH, and N-
alkyl;
A of Formula (g) is independently selected from a H, methyl, alkyl (e.g., a or
C1-C6 alkyl
(linear, branched, optionally substituted));
R of Formula (g) is independently selected from a Hõ OHõ NH2, halogen, methyl,
optionally
substituted linear or branched alkyl (e.g., optionally substituted linear or
branched C1-C6
alkyl), optionally substituted C1-C6 alkoxy, optionally substituted-cycloalkyl
(e.g.,
optionally substituted C3-C7 cycloalkyl), optionally substituted-heterocyclyl
(e.g.,
34
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optionally substituted C3-C7 heterocycly1),optionally substituted-alkyl-aryl
(e.g., an ¨
alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a
combination thereof),
optionally substituted aryl (e.g., C5-C7 aryl), amine, amide, or carboxy);
n of Formulas (g) represent an integer from 1 to 4 (e.g., 1, 2, 3, or 4),
wherein at least one R
(e.g., at least one of OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-
aryl (e.g., an ¨
alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a
combination thereof),
aryl (e.g., C5-C7 aryl), amine, amide, or carboxy) is modified to be
covalently joined to a
PTM, a chemical linker group (L), a ULM, CLM (or CLM') or combination thereof;
and
. of Formula (g) represents a bond that may be stereospecific ((R) or (S)) or
non-
stereo specific.
[0110] In any of the embodiments described herein, the W, X, Y, Z, G, G',
R, R', R", Ql-
Q4, and Aof Formulas (a) through (g) [e.g., (al), (b), (c), (dl), (e), (f),
(a2), (d2), (a3), (a4), and
(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.
[0111] In any of the aspects or embodiments described herein, the CLM
comprises from 1 to
4 R groups on Qi, Q2, Q3, Q4, or a combination, wherein each R is an
independently selected
functional groups or atoms, for example, OH, halogen, C1-C6 alkyl, C1-C6
alkoxy, optionally
substituted-cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl),
optionally substituted-
heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl), -alkyl-aryl
(e.g., an ¨alkyl-aryl
comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof),
aryl (e.g., C5-C7
aryl), amine, amide, cyano, or carboxy, and optionally, one of which is
modified to be covalently
joined to a PTM, a chemical linker group (L), a ULM, CLM (or CLM') or
combination thereof.
[0112] In some embodiments, the CLM is represented by the following
structures with the
dashed lines indicating linker attachment points:
CA 03109981 2021-02-17
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0 0 0
0 0 0 0 0
0
1.1 N-20
1.1 40)
NH
NH
0 0 :5
0
[0113] 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.
36
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o 0\ o 0\ 0 0
,......./..,,,_....,<. ...._Z NH
......./.... ....JK. NH NH
1...õ, 0 1/ Nil" 1/ 0
.-=\\(
Rn/ 0 Rn 0 Rn 0
0 S
0 0 0 0\
\ ________________________________________________________________
,õ..."-:õ.,___,=<. __ ....... NH __ \ NH NH
N H N111..... __ 0 1../....," ______ 0
All Alk
Rn 0 Rn 0 Rn 0
O 0 0 0 0 0
,õ....."..,_. ..,/K. NH __________ =,......."...../< ______ NH
NH
1 N ______ 0 N yl ............\.(N
S
/."---...../
1\/
Rn Rn 0
Rn S
0 0
r,.., ..õ.. N __ NH N ...õ. ____ NH ,,...,N. ________ NH
o
N _____________________________________________________________________ 0
Rn 0 7 N 0 A.(
Rn 0
O Rn 0
O 0 0 C. 0 0
\ N
.,,...,N....1( NH NH ,..õN.., _______ NH
1/ N _____________ 11 N
N _____________________________________________________________________ 0
N,./...,
Rn Rn Rn
0 0 0
0 0 0
0 \ /
,...........,...,,K ( __ NH ...õ---",.... ....iK.
NH
0 A(N
Rn 0 Rn 0 Rn 0
____________________ 0 N
0 0 H
0 0 0 0
\\ 41 \\ /0
iN ( ) r/N ( NE _____________________________ 0 ly N ) __ 0
7--g2
Rn 0 Rn Rn
37
8
O uH 0
µ HN \
______________________________________________________________ N
HN ____
HN ____
HN _______________________________________________
).---*----/I /
O (
N HN __ \
\ '''.....4 \
O 0 0 0 0 0
O uH S uH
uH
HN µ HN __ \
).-----/i HN
0 _____________________________________________________ ( N/1
I ( N
HN
1 ______________________________ \
)r--1
HO 0 0 0 0
0 0
O uH 0
uH 0
uH
HN ________________________ HN _______________________ HN
)./ Y'=-./N
0 __ ( 1 0 ___ ( N ) ( N /
)rN
HN 0 __
\ HN __ \ N HN __ \
O 0 0 0 0 0
0 uH 0 uH
O uH
HN _________________________________________________________
N _______________________________
0 N ______ NVY ) N)/IN 0 ( )
1
)f, HN __ \ HN ___________ N
HN ____ \ N \ 11
0 0 0 0
O 0
O uH S LJH
uH
HN ____________________________________________________ HN __
HN __________________________________ ).-----/i
).---*----/ N 0 __ ( N/1
)r_,1
HN ____ \ HN \ HN __ \
O 0 0 0 0 0
tHOS0/6IOZSI1LIDcl
t9SISO/OZOZ OM
LT-ZO-TZOZ T8660T0 YD
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o o\
O : 0 0
________________________________________________________________________ NH
___________________________________________ NH
__________________ NH ....,..--/K .,õ----<
rNONN.\
) __ 0 NW...
) _______________________________________________ 0 1
7"------õ,<N _____________________________________________________
) __ 0
/*----.A.,(
.--=-=...A( ______________________ NH
__________________ NH ____________________ NH
/
Rn 0 S
Rn 0 0 Rn 0 0
O 0 0 0 =0 S \
\NH
__________________ NH ____________________ NH ,,...--1
..õ..--=<
N ___________________ 0
5.
) ) /I .,......,\.(N
) __ 0
-f _______________________________________________________________ NH
AI NH NH
1./...,..,..NlIAillik... /\
Rn 0 0 Rn 0 0 Rn 0 0
O 0 0 0\ 0 0\
__________________ NH .õ--1(
---/K
1 N ) __ 0 1/ N ) __ 0 NH NH
____________________________________________________ 1/ N ) __
S
...... ,...,.
________________________________________________________________________ NH
__________________ NH _____________________ NH
Rn
Rn Rn 0 0
0 S 0
0 0 0 0 0 0\
\
___________________________________________ NH
__________________ NH N
N,.........._....,,<
________________________________________________________________________ NH
./.....,N.,,.,..z....,...., j.K =-----j(
,.../1 ...,..,õ ) ______________________ NH
0 1/...,....7. ) _______________ 0 (....;1,..N
__ ) 0
__________________ NH
________________________________________________________________________ NH
Rn 0 0
Rn 0 0 Rn 0 0
O 0 0 0 0 0
N
NH ?
) ___________________________________________ NH
) ly
N....... ,...JKN
NH
0
1/ ....--1(,.... N
) ____________________ 0 11 N
Nt....,..,.."- )
=.N.4---A( __________________________________ NH _______________________ NH
NH
Rn Rn Rn
0 0 0 0 0 0
O 0\ 0 0 0 0 OH
NH
/
? _______________________________________________________________________ N/
.,...--IK
1 N ) __ 0 N
) 0 1/..... (N _____ ) __
0
.-----....
t/-*\\(
NH NH
)NH
Rn Rn 0 0
Rn/ 0< 0 0
O 0 0 0 0
NH
N 4.,...
________________________________________________________________________ NH
/ 1
..,...-1(
/.",./....A( / ) 0 _____ 1 N 0
y 02 NH )
_________________________________________ NH
NH 0 0
Rn Rn 0
Rn 0 0
39
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H
0
0 NH 0 NH N S
N / NNNN'ss' r/ NNNN'sss.
1 /
0 0
0
Rn7 Rn'
H Rn'
H
S N, ,0
0 0 0
N N. N NNN'sss.
O
Alk
YO
Al k 1 /
H H
RnY Rn 0,,N,...,,0 Rn 0 0N,,..,.S
0
0 NHC)
N N
N.
,
Rn
7.s
Rn Rn
0 NH
I N NN (N,,
Rn H
0 ONO Rn/ H Rn H
N 0...õ N
0 0
NN (NN
1/No
YKI0 N..../0
Rn
Rn Rn'
o ONHO 0 ONH 0 ONHO
N NN NiN=
YNO yo 1 /
7N0
H
Rn
1 Rn Rn 01 H
0 ON 0 N
0
Yo S0 VO
RI Rn Rn
I 17
0 0
HI\ HI\
N
0 0 'NI
UH UH
0 0
0 0 0 uu u
H __
uH
N
Z. ==.,..;,.,.,N.,....s.,.,;...,. ,,
0 __ ( N O - 1
.,.,.,..,...,,.,õ..N,,,,,,...................,,
0 0 0
0,...,..! .....,,N^..,0 0
H
UN
0
0
0 N 0
H
UN UN UN
Ow/ Ow/ Ow/
1 1 1
............-=,..,..._õ/õ,N.,....,...õ
,............s.,...,N,......,,,,,,,, .,,,,,,,,.,õ,..._..N...,,,......
0
NO ONO 0 ON
H H
0
tHOS0/6IOZSI1LIDcl t9SISO/OZOZ OM
LT-ZO-TZOZ 1866010 YD
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O 0\ 0 0\ 0 0
......Z _________ N
___________________________________________ NH NH
H
N _________________________________ 0 Nliiii... 0
0
Rn Rn Rn
O 0 0 0 0 S
\ > >
\ __ NH
________________ NH ______________________ NH
NE7-4
0
Nu ____________________________________________ 0 N ______ 0
A: ________________________________ lAil:A"
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
JK:NI )
\ _______________ NH
I
\ __________________________________________ NH
1 N.......
...........KN
_______________________________________________________________________ NH
N _________________________________________________________________________ 0
Rn R Rnn 0
O 0\ OH
/ 0 0 0 0\
N
r.....,,
____________________________________________ NH
_______________________________________________________________________ NH
N ___________________ 0
11
N/ N 0
.....,,.. N
Rn 0 Rn Rn
O 0\ 0 0 0\
/NH
( __________________________________________ N, 0
N _________________________________ 0 _______________________ N __ N
Rn Rn Rn
O 0
______________________ 4. 0 0
N
\ ________________________________________________ /N ____ NH
________________________________________________________________ 0
N __________________ 0
S
02
Rn Rn
42
Pr
uH
uH 0
HN ______________________________________________________________ S
HN __
\ ________________________ N 0 __ ( N/
S HN HN __ \
\ 0 0
0
uH
uH HN
HN
.0 __ K N
S _______________ ( \ N
HN
0 0
0 0
uH uH uH
HN ________________________ HN ______________________ HN ____________ N
N74 0 _________________________________________________ K ) ___ N
1
__________ N
I K .....,.., ) )........---
0 HN _____________
HN ____________________________________________________________________ N
\ o N HN __ \ ).------.......sN \
0 0 0 0
uH uH
uH
HN ___________________________________________________ HN __
HN
HN
y.....= ...........,,N 0 __ ( Nc.:-
.......:....., ...lj
.,....... 1
).i.,---- HN __ \ HN __ \ N
\ N
\ 0 0 0 0
0 0
uH
uH uH
(RN _______________________________________________________
HN _____________________________
HN ___
\ __ N N 0 _______ N
N _________________________________________________________
HN __
S HN\
/ o \ HO 0
0 S
0 0
tHOS0/6IOZSI1LIDcl
t9SISO/OZOZ OM
LT-ZO-TZOZ T8660T0 VD
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o o
o ......o o o
___________________________________________ NH
__________________ NH ________________________________________________ NH
N ) __ 0 NIVII... ) 0 .. N
) _________________________________________________________________________ 0
__________________ NH ____________________ NH _______________________ NH
Rn S
Rn 0 Rn 0
0 0\ 0 0 0 S
__________________ NH \ __ NH NH
)
Nilm=-= _____________ 0 Wno. ) i 0 _________ N
0
) )
-..
Alk ______________ NH Alk / _______________________ NH
NH
Rn 0 Rn 0 Rn 0
0 0 S 0 0 0\
__________________ NH _____________________ NH
N _______________ ) __ 0 N ) __ 0 N ______ )
S NH
_______________________________________________________________________ NH
__________________ NH _____________________ NH
Rn Rn 0
Rn 0 0/
0 0
0 0 0 0\
,................õ....K
___________________________________________ NH
N ________________ NH N
N.,....................K
_______________________________________________________________________ NH
.---...--(
) ______________________________________________ ...õ,.......
....IN ) 0
1 N ____ ) __ 0 N
_______________________________________________________________________ NH
__________________ NH ____________________ NH N
Rn 0
Rn 0 Rn 0
0 0 0 0 0 0
_________________ NH r.......õN
/õ....... .....JK NH
NN............,( NH
N ) __ 0 ilit.......... ....f 0
I
) __ 0
N
S _______________ NH N? /........../N
_______________________________________________________________________ NH
02
Rn 0 Rn 0
R
0 n
0 0\ 0 0\ 0 0 OH
__________________ NH
___________________________________________ N/ _______________________ NI/
N ________________ ) __ 0 N ) __ 0 N ) __
0
__________________ NH ____________________ NH _______________________ NH
Rn Rn 0 Rn 0
0 0 0 0
____________________________________________________ =
NH N
) ____________________ 0 N ) __ 0
NH __________________ NH
Rn
Rn 0 0
44
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o H o 0 N 0 0
0
0 0 S
Rn Rn Rn
0 H 0 ow N.,,..,,
PaJ
0 0
O o 0 0Alk
s
N 0 N =
Alk
OH
Rn Rn Rn
0 0
1 o
O s
0 0 0
0 N
N N
N
Rn H Rn
H H
O Rn N 0 0 N 0 o 0
0
ri N N N NN
N/47õ/,......1 ,...........,
H
H
(D 0
Rn 0 N 0
0 Rn Rn
N 0
0 0 c)
N N
N NN
,.,........:.,..,...., ......,...
1 ir
NN .A..,.......",
Rn
Rn Rn
1 0 0
0 0 H
N 0
0 0
0 N
NN NN
N
Rn Rn
Rn
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101
H H
N
N 0 c) 0 ON
0
N= NJ N
Rn Rn Rn
H
0 N 0
0
Rn
6 ________________________________________ ) < 0 0
\ ___________________ NH ________________________________ NH
0
Rn "...--\-N HN __________ 0
Rn (-N HN 0
N) < 0 0
____________________ NH NH
XRn -N HN ________________ 0 Re......'\ _________________ -N HN 0
/
___________ 0 0 ) </
\ ___________________ NH
Rn NN HN _________ 0
[0114] In any of the compounds described herein, the CLM comprises a
chemical structure
selected from the group:
46
CA 03109981 2021-02-17
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00 0 0 0
v Q4.õ,...-1 NH (1Q4
NH P4=Q5 -NH
13 N 0 V -----/ __ N Q-3 N tO
OR2. %-- \--- Q2. )/% 6 Q \---
Qi W Qi W 0 2 1
R1 R1 R1
(h) (i) (i)
0
C)4. Ql.
Q3 -Q5 0 0 Q2=Q3 -NH
612 A A /
Qi\ / N tO
Di y NL/NH Q3
L
R1' 0 11.
R1
0
R1
(k) (I) (m)
00 0 0 00
1 Nt1\15 0 Cezi---Ic_t_l_LIF-1 ce4rAN Ntlx _R2
" (52. %-- i \ 62: /---v\i \ /7
W N Qi W 0 Qi -
\R1 R1
(n) (o) (10)
H R3
0 N 0 \
0 NH 0
R'\ 0 ,-NH
N
I
=
HN
X-1 R1
(r)
(a)
47
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R3
\
NH o 00
o N
= HN_r¨N,i1-1 0 NH
, _________________________________________________ 00
W ______________________________________________
oi
(s) (t)
R1 0
00
x=( ______________________________________________ NH
NH
N
X 2-0
0
(u) (v)
0 0
2
_c() _,\¨NH Q Qi, A _c4r0R4
R3 \ N __ ¨o ? 1
A I N
sx3;
Q4 "
R-, 0 0
(w) (x)
Q1-Q5 0 0 0
Qc(:)4_ , _______________________________________________ NH
b3(:).4 ,N 0 &
N t
R4 ¨/¨NH NQW \_ O
0 HN) R1
(y) (z)
00
1C)1=,( '¨NH
QIC 1 N¨ 0
Q3
0
(aa)
48
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0 (R5) n (R2)1
\ 0 0
QC)1_kl /
X = X
________________________________________________________ NH
\Al
112 ___________________________ R6 Q-jK
1
0
Q3 ______________________ ) .
L_ 7
Q4
R' ,C)2
(ab) (R3) 11
(ac)
0 R2 R2
\ / 0 \
________________________________________________________ N H
_...-N
---/ \
I I N ___ (1, N __
Q2
Q --X
1 (R)1 \ R' _______________________ 0
R1 R2 (ae)
(ad)
R4 0
0 0 0
kR4
NH
HN-.........<
N ______________________________ 0
0
N 0
R'/
(ag)
(af) H 0
0.,IN.ft
0 0\
Q(:)4...............,../K
) __ NH N Z
113 N¨(CH2)--N _________ 0
Q2 \i" n \ HO
0
Qi
R1
(ah) HO
0 0 (al)
____________________________________ N H
C)'
: N _________ 0
Q2
(qi)
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H
0 N 0 0
R' Q2=Qi \ ________ NH 0 0
\)'LN R31 1\1 2 ___ 1 1
0 QcQ4---"AN4\---NH
Xi (R ')n
I : R5 0 01
0
(R2)n (ak)
(al) (am)
Q2-Q3
// .
Qi sQ4
0 ?-( 0
04:05 NH N4 _________
i ____________________
03 to , ______ / pl -CD
O2-Qi R4 NH
R1 0 ,
wherein:
W is independently selected from CH2, 0, CHR, C=0, S02, NH, optionally
substituted
cycloalkyl, optionally substituted heterocyclalkyl, and N-alkyl;
Ql, Q2, Q3, Q4, Q5 are each independently represent a carbon C or N
substituted with a group
independently selected from H, R', N or N-oxide;
R1 is selected from absent, H, OH, CN, C1-C3 alkyl, C=0;
R2 is selected from the group absent, H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO,
C(=0)NH2;
R3 is selected from H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl
(e.g., substituted
C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxyl), substituted
alkoxy (e.g.,
substituted C1-C6 or C1-C3 alkoxyl);
R4 is selected from H, alkyl, substituted alkyl;
R5 and R6 are each independently H, halogen, C(=0)R', CN, OH, CF3;
X is C, CH, C=0, or N;
Xi is C=0, N, CH, or CH2;
R' is selected from H, OH, halogen, amine, cyano, alkyl (e.g., C1-C3 alkyl),
substituted alkyl
(e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted
alkoxy (e.g.,
substituted C1-C3 alkoxyl), NR2R3, C(=0)0R2, optionally substituted phenyl;
n is 0-4;
/ is a single or double bond; and
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the CLM is covalently joined to a PTM, a chemical linker group (L), a ULM, CLM
(or CLM')
or combination thereof.
[0115] In any aspect or embodiment described herein, the CLM or CLM' is
covalently joined to
a PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination
thereof via an R
group (such as, R, R1, R2, R3, R4 or R'), W, X, or a Q group (such as, Qi, Q2,
Q3, Q4, or Q5) of
Formulas (h) through (ab).
[0116] In any of the embodiments described herein, the CLM or CLM' is
covalently joined to a
PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination
thereof via W, X,
R, R1, R2, R3, R4, R5, R', Qi, Q2, Q3, Q4, and Q5 of Formulas (h) through
(ab).
[0117] In any of the embodiments described herein, the W, X, R1, R2, R3, R4,
R', Qi, Q2, Q3, Q4,
and Q5 of Formulas (h) through (ab) can independently be covalently coupled to
a linker and/or a
linker to which is attached to one or more PTM, ULM, ULM', CLM or CLM' groups.
[0118] 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:
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0 0 0 0
NH -NH
D 1 N 0 N 0
Rn----7-
R' //S ---0
0 R1
(an)
(ao)
eN 0
0
Rn----1
_....---.,õ __________________________________________ N
N NH H
____________/-
Rn- / 0
0
R1 R1
(ap) (aq)
o 0 H
NH
0
Rn----c 1 71 ____________ \ -CN
W 1 N
1 ,
R1
R2 N'
(ar)
(as)
0
N_ NH
0
NJ\
Rn----kc / R1
(at)
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H
0 0 N ,0
N NH
N R3 N ________ 0
Rn------7-1 \ (
N \
0
(au) (av)
0\
N 0
N NH
R3-(\N 0 Rn- \
\ 7 1 \ ji _ 1 0
0 0 1
(aw) (ax)
FN, ?
Rn---c-
HN 0
NH
0
(ay)
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0 R5
0 0
aid( NH
N
/1 ...........w/N = R6
: ________________________________________________________ 0
i, /
R'VQ2
Rn (az) (ba)
0 R2 0
NH
,N ____ NH
1 N __ / _____ 0 -:.------ \
N 0
yvv/
R'
Rn
R1 (bc)
(bb)
R4 o
cy<R4
o 0
N
)1 N __
HN-......\(
N 0
0
,N 0 (be)
(bd)
H IN
0 0
O \
> __________________________________ NH
.....,...--K N 0 V
1 / N¨(CH2)--N ____ 0
------...w \
HO __________________________________________ 5:
Rn (bf) R1
O (bg)
H
,
wherein:
W is independently selected from the group CH2, CHR, C=0, S02, NH, and N-
alkyl;
R1 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;
R of the CLM is H;
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R' is H or an attachment point for a PTM, a PTM', a chemical linker group (L),
a ULM, a
CLM, a CLM',
Qi and Q2 are each independently C or N substituted with a group independently
selected
from H or Cl-C3 alkyl;
/ is a single or double bond;
n is an integer from 1 to 4 (e.g., 1, 2, 3, or 4); and
R comprises : H, -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -
CR'NR'R"-, (-CR'0).,R", halogen, optionally substituted heterocyclyl,
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
Cl-C6 alkyl,
an optionally substituted C5-C7 aryl, or combinations thereof), optionallys
ubstituted
heteroaryl (e.g., an optionally substituted C5-C7 aryl), -optionally
substituted linear or
branched alkyl (e.g., a Cl-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 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)),
,
,
,.......
ii 00)(
optionally substituted Y
(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)),
optionally substituted
, 0
)1):
Y
(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)),
optionally substituted cycloalkyl, optionally substituted heterocyclyl, -
P(0)(OR')R", -P(0)R'R", -0P(0)(OR')R", -0P(0)R'R", -Cl, -F, -Br, -I, -CF3, -
CN, -
NR' S 02NR' 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.
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[0119] In any aspect or embodiment described herein, at least one R of Ql, Q2,
Q3, Q4, Q5, or a
combination thereof (e.g., at least one of OH, NH2, C1-C6 alkyl, C1-C6 alkoxy,
-alkyl-aryl (e.g.,
an ¨alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a
combination thereof),
aryl (e.g., C5-C7 aryl), amine, amide, or carboxy) is modified to be
covalently joined to a PTM,
a chemical linker group (L), a ULM, a CLM' (e.g., CLM' is an additional CLM
that has the
same or different structure as a first CLM), or a combination thereof.
[0120] In any of the embodiments described herein, the W, R1, R2, Ql, Q2, Q3,
Q4, and R of
Formulas (ac) through (an) 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.
[0121] In any of the embodiments described herein, the R1, R2, Ql, Q2, Q3, Q4,
and R of
Formulas (ac) through (an) 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.
[0122] In any of the embodiments described herein, the Ql, Q2, Q3, Q4, and R
of Formulas (ac)
through (an) 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.
[0123] In any aspect or embodiment described herein, R of Formulas (ac)
through (an) 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.
[0124] In any aspect or embodiment described herein, the CLM is selected
from:
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N
0 0
Linker ________________ NH I
N 0 Linker N NH
W \ _
R1 0
R1
H
0 0 N ,0 H
0 N 0
0
(N Linker
I , LinkerN N
N%\
/ __________________________________________ N 0
N _____________________ NH Linker ___ , ___ ,/
HN __________________________________________________________ 0
Linker ______ N 0
/ _________________________________________________________ NH
Of
0
0 0\
N_ NH N NH
\
N _______________________ 0 Linker __
\/ \ _ N 0
ilk R1 0
Linker
0 0 0 0
\ ________________________________ NH LinkerA \ _________________ NH
N ) ___________________________________ 0 [ 1 N 0
rN R' 7//S/-----*-'0
1\1) 0 0
Linker 0 0
0 0 NH Linker¨A
NH
1 N ) __ 0
N ) __ 0
rN e IC)
Linker N
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0 0 0
NN4 _NIF-1 Linker 0 _t
N NH
Linker 0 yN--..N
--- 'NI 0 0
\K
0
\
0
Linker 0 N 0
. \
0 0
LinkerrN,N¨NH
N-NN,,,:tH
"1\14 lF1 7N-..\( 0
_1._, ,N 0 0
0 Linker'N
\N-.... 0 0
Linker 1\1 Linker
N-1\41
HN 0
F
0 NH
Of
LinkerN
0
¨(NI
'l
Linker \
0 / HN ¨C)
¨ NH NH
o 0 ,
wherein R' is a halogen and R1 is as described in any aspect or embodiment
described herein.
[0125]
In certain cases, the CLM can be imides that bind to cereblon E3 ligase. These
imides
and linker attachment point can be but not limited to the following
structures:
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0 0 0 0
NH
NH
N 0 N 0
HN 0 0 0
I I
Linker Linker
0 0
0 0
NH
NH
N 0
N 0
)
0
HN
I
I Linker
Linker
0 0 N
NH N
N ) __ 0
0 NH 0
I Linker 0 N 0
Linker H
R'
N N
1 , y N N , . ., . . . , ====,. , , , õ = . . ,
. . . . , . / \ . , Linker
Linker
0 0
0 N 0 0 N 0
H H
0 0
NH
N ) __ 0
rN
N Linker 0
0 0
NH
N ) __ 0
N
r
N
Linker , wherein
R' is a halogen.
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[0126] Exemplary VLMs
[0127] In certain embodiments of the compounds as described herein, the ULM
is a VLM
and comprises a chemical structure of ULM-a:
=
X1NY -------------------------
x20
ULM-
wherein:
a dashed line indicates the attachment of at least one PTM, another ULM or VLM
or MLM
or ILM or CLM (i.e., ULM' or VLM' or CLM' or ILM' or MLM'), or a chemical
linker
moiety coupling at least one PTM, a ULM' or a VLM' or a CLM' or a ILM' or a
MLM'
to the other end of the linker;
X1, X2 of Formula ULM-a are each independently selected from the group of a
bond, 0,
NRY3, CRY3RY4, C=0, C=S, SO, and S02;
12)(3, RY4 of Formula ULM-a are each independently selected from the group of
H, optionally
substituted linear or branched C 1_6 alkyl (e.g., optionally substituted by 1
or more halo),
optionally substituted C 1_6 alkoxyl (e.g., optionally substituted with 0-3 RP
groups);
RP of Formula ULM-a is 0, 1, 2, or 3 groups, each independently selected from
H, halo, -OH,
C1-3 alkyl, C=0;
W3 of Formula ULM-a is selected from the group of an optionally substituted T,
an
la 113
optionally substituted A optionally substituted ¨T-N(R., )
optionally
substituted ¨T-Aryl, an optionally substituted ¨T-Heteroaryl, an optionally
substituted T-
biheteroaryl, an optionally substituted ¨T-Heterocycle, an optionally
substituted ¨T-
biheterocycle, an optionally substituted -NR1-T-Aryl, an optionally
substituted -NR1-T-
Heteroaryl or an optionally substituted -NR1-T-Heterocycle;
X3 of Formula ULM-a is C=0, Ri, Ria; Rib;
Ri; ia;
tc Rib are each independently selected from the group consisting of H,
linear or
branched Ci-C6 alkyl group optionally substituted by 1 or more halo or -OH
groups,
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RY3C=0, RY3C=S, RY3S0, RY3S02, N(RY3RY4)C=0, N(RY3RY4)C=S, N(RY3RY4)S0, and
NRY3RY4)S 02;
T of Formula ULM-a is selected from the group of an optionally substituted
alkyl, ¨(CH2).-
group, wherein each one of the methylene groups is optionally substituted with
one or
two substituents selected from the group of halogen, methyl, optionally
substituted
alkoxy, -(CH2)m,C(=0)(CH2)m,C(=0)(OH),
(CH2)m'OCOCH2(CH2)m,OCH2(CH2)m,CO(CH2)m,OH,
(CH2)m'OCOCH2(CH2)m,CO(CH2)m,OH, a linear or branched C1-C6 alkyl group
optionally substituted by 1 or more halogen or OH, C(0) NR1Rla , or NR1Rla or
R1 and
,s la
I( are joined to form an optionally substituted heterocycle, or -OH
groups or an amino
acid side chain optionally substituted;
each m' is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
W4 of Formula ULM-a is an optionally substituted -NR1-T-Aryl, wherein the aryl
group may
be optionally substituted with an optionally substituted 5-6 membered
heteroaryl,
optionally substituted aryl, or optionally substituted alkoxy, an optionally
substituted -
NR1-T-Heteroaryl group or an optionally substituted -NR1-T-Heterocycle,
wherein -NR1
is covalently bonded to X2 and R1 is H or CH3, preferably H; and
n is 0 to 6, often 0, 1,2, or 3, preferably 0 or 1.
[0128] In any of the embodiments described herein, T is selected from the
group of an
optionally substituted alkyl, ¨(CH2).- group, wherein each one of the
methylene groups is
optionally substituted with one or two substituents selected from the group of
halogen, methyl,
optionally substituted alkoxy, -(CH2)m,C(=0)(CH2)m,C(=0)(OH),
(CH2)m'OCOCH2(CH2)m,OCH2(CH2)m,CO(CH2)m,OH, (CH2)m'OCOCH2(CH2)m,CO(CH2)m,OH,
a linear or branched C1-C6 alkyl group optionally substituted by 1 or more
halogen, C(0)
NR1,.I( la
, or NR1Rla or R1 and Rla are joined to form an optionally substituted
heterocycle, or -
OH groups or an amino acid side chain optionally substituted; each m' is
individually an integer
from 1 to 4 (e.g., 1, 2, 3, or 4), and n is 0 to 6, often 0, 1, 2, or 3,
preferably 0 or 1.
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[0129] In any aspect or embodiment described herein, W4 of Formula ULM-a is
R1 71
, 1 H
iR 4a ' R 4a N Ri4a
;
= ' uaN R .N R14a g;
R14b 1R14b
Rub ""Rub N
R14b
R15 R15 R15 , R15 R15 ,
H
R14a R1
=,, gi
R14b 1
N
,K
R15
,or R15 , wherein:
W5 is optionally substituted phenyl, an optionally substituted napthyl, or
optionally
substituted 5-10 membered heteroaryl (e.g., W5 is optionally substituted with
one or more
[such as 1, 2, 3, 4, or 5] halo, CN, optionally substituted linear or branched
C1-C12 alkyl
optionally having one or more (e.g., 1, 2, 3, 4 or more) carbon atoms replaced
with an
oxygen atom, optionally substituted haloalkyl, optionally substituted alkoxy,
hydroxy, or
optionally substituted haloalkoxy);
R14a, R14b, are each independently selected from the group of H, haloalkyl,
optionally
substituted alkoxy, optionally substituted hydroxyl alkyl, -
(CH2)m,C(=0)(CH2).X(=0)(OH), (CH2)m'OCOCH2(CH2)m,OCH2(CH2)m,CO(CH2)m,OH,
(CH2)m'OCOCH2(CH2)m,CO(CH2)m,OH, or optionally substituted linear or branched
alkyl optionally with one or more carbon atoms replaced with an oxygen;
each m' is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
R1 is H, linear or branched C1-C6 alkyl group optionally substituted by 1 or
more halo or -OH
groups;
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W6 is an optionally substituted 8-14 membered bicyclic heterocycle (e.g., 0
,
, . , .
, .
,
'
-
----IIIIIIII 111111 or
---'- 0 ); and
Ri5 is selected from the group of H, halogen, CN, OH, NO2, N R14aR14b, OR14a,
CONR14aR14b,
NR14aCOR14b, SO2NR14aR14b, NRi4a SO2R14b, optionally substituted alkyl,
optionally
substituted haloalkyl, optionally substituted alkoxy, optionally substituted
haloalkoxy
optionally substituted aryl, optionally substituted heteroaryl, optionally
substituted
cycloalkyl, or optionally substituted cycloheteroalkyl.
[0130] In
any aspect or embodiment described herein, W5 of Formula ULM-a is selected
from the group of an optionally substituted phenyl or an optionally
substituted 5-10 membered
heteroaryl (e.g., W5 is optionally substituted with one or more [such as 1, 2,
3, 4, or 5] halo, CN,
optionally substituted linear or branched C1-C12 alkyl optionally having one
or more (e.g., 1, 2,
3, 4 or more) carbon atoms replaced with an oxygen atom, optionally
substituted haloalkyl,
optionally substituted alkoxy, optionally substituted haloalkoxy, or hydroxy),
Ri5 of Formula ULM-a is selected from the group of H, halogen, CN, OH, NO2, N
R14aR14b, OR14a, CONR14aR14b, NR14aCOR14b, SO2NR14aRl4b, NR14a SO2R14b,
optionally
substituted alkyl, optionally substituted haloalkyl, optionally substituted
alkoxy, optionally
substituted haloalkoxy, optionally substituted aryl, optionally substituted
heteroaryl, optionally
substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
[0131] In aspect or embodiment described herein, W4 substituents for use in
the present
disclosure also include specifically (and without limitation to the specific
compound disclosed)
the W4 substituents which are found in the identified compounds disclosed
herein. Each of these
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W4 substituents may be used in conjunction with any number of W3 substituents
which are also
disclosed herein.
[0132] In aspect or embodiment described herein, ULM-a, is optionally
substituted by 0-3 RP
groups in the pyrrolidine moiety. Each RP is independently H, halo, -OH, C1-
3a1ky1, C=0.
[0133] In aspect or embodiment described herein, the W3, W4 of Formula ULM-
a can
independently be covalently coupled to a linker which is attached one or more
PTM groups.
and wherein the dashed line indicates the site of attachment of at least one
PTM, another
ULM (ULM') or a chemical linker moiety coupling at least one PTM or a ULM' or
both to ULM.
[0134] In certain embodiments, ULM is VHL and is represented by the
structure:
¨
HQ. HO Rci
-N).......1(El R14a
N
' ' 'Rub N .,d0R14b
&N"""11141µ
w3-o o, 0 41)
w 3 'LO
(R16)0 R15 (R16)0
R15
¨ ¨ or¨ ¨ ,
ULM-b
wherein:
W3 of Formula ULM-b is selected from the group of an optionally substituted
aryl, optionally
R9
1¨(¨R10
substituted heteroaryl, or R11 ;
R9 and Rio of Formula ULM-b are independently hydrogen, optionally substituted
alkyl,
optionally substituted cycloalkyl, optionally substituted hydroxyalkyl,
optionally
substituted heteroaryl, or haloalkyl, or R9, Rio, and the carbon atom to which
they are
attached form an optionally substituted cycloalkyl;
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Ril of Formula ULM-b is selected from the group of an optionally substituted
heterocyclic,
optionally substituted alkoxy, optionally substituted heteroaryl, optionally
substituted aryl,
0 0
s R12
1_N¨(1R18)r)
R13
or =
R12 of Formula ULM-b is selected from the group of H or optionally substituted
alkyl;
R13 of Formula ULM-b is selected from the group of H, optionally substituted
alkyl,
optionally substituted alkylcarbonyl, optionally substituted
(cycloalkyl)alkylcarbonyl,
optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl,
optionally
substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;
R14a, R14b of Formula ULM-b, are each independently selected from the group of
H, haloalkyl,
optionally substituted alkoxy, optionally substituted hydroxyl alkyl, -
(CH2)m,C(=0)(CH2).X(=0)(OH), (CH2)m'OCOCH2(CH2)m,OCH2(CH2)m,CO(CH2)m,OH,
(CH2)m'OCOCH2(CH2)m,CO(CH2)m,OH, or optionally substituted linear or branched
alkyl optionally with one or more carbons replaced with an oxygen;
R1 is H, linear or branched Cu-C6 alkyl group optionally substituted by 1 or
more halo or -OH
groups;
each m' is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
W5 of Formula ULM-b is selected from the group of an optionally substituted
phenyl or an
optionally substituted 5-10 membered heteroaryl,
R15 of Formula ULM-b is selected from the group of H, halogen, CN, OH, NO2, N
R14aR14b,
OR14a, CONR14aR14b, NR14aCOR14b, SO2NR14aRl4b, NR14a SO2R14b, optionally
substituted
alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy
optionally
substituted aryl, optionally substituted heteroaryl, optionally substituted
cycloalkyl, or
optionally substituted cycloheteroalkyl;
each R16 of Formula ULM-b is independently selected from the group of H, CN,
halo,
optionally substituted alkyl optionally having one or more carbon atoms
replaced with an
oxygen atom (e.g., optionally substituted with CN or OH), optionally
substituted
haloalkyl, hydroxy, or optionally substituted haloalkoxy;
o of Formula ULM-b is 0, 1, 2, 3, or 4;
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R18 of Formula ULM-b is independently selected from the group of H, halo,
optionally
substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy
or a linker;
and
p of Formula ULM-b is 0, 1, 2, 3, or 4, and wherein the dashed line indicates
the site of
attachment of at least one PTM, another ULM (ULM') or a chemical linker moiety
coupling at least one PTM or a ULM' or both to ULM.
Ri7
yN
--..../
[0135] In certain embodiments, R15 of Formula ULM-b is Xa
wherein R17 is H, halo,
optionally substituted C3_6cycloalkyl, optionally substituted C1_6alkyl,
optionally substituted Ci_
6a1keny1, and C1_6haloalkyl; and Xa is S or 0.
[0136] In certain embodiments, R17 of Formula ULM-b is selected from the
group methyl,
ethyl, isopropyl, and cyclopropyl.
[0137] In certain additional embodiments, Ri5 of Formula ULM-b is selected
from the group
consisting of:
F cs CI Br
csss-.%- (- CS--- N "s=-=------- /--"N
/ ,I1
N . S--,./ . S = S = S == S =
, , ,, ,
F3C
oi ___________________ )N 1 0' __
S
1 __ b 1 ____ l N-N N-N N-N 1 = S ; S ; H = / ; H
= -N
0 =
Nzõ.1
N Ni 1 h ________ Cs.:-- / __ N e--1\j 1 (1\i = / ;
N \WC'. ,(S.' 0 ; 0 ;
, ,
KI-----0 r, 0 rõs /
zt..... ; r!) / F ; r1) / F; s2)------N . ..,.....N
\-=------N OH 7 1 > ____
N 7
-rTrj
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1 ________________ -\N
and \ /I .
[0138] In certain embodiments, R11 of Formula ULM-b is selected from the
group consisting
of:
0 0 F 0 0
F Br
1¨N 1¨N 1¨N 1¨N
,
. . , .
,= ,
0
0 0 0
CN
F = = Br. ; Br ;
, ,
0 0
0 0 ON
1¨N 1¨N
1¨N 1¨N
F ; CN ; CN = =
, ,
0 0
0
1¨N OMe 1¨N
OMe 1 ¨N
. CI ;
, ,
0
0
1¨N 0
CI
)\---.....
1¨N 1¨N I
\..---
OMe = ;and N.
,
[0139] In certain embodiments, ULM has a chemical structure selected from
the group of:
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HO HO
)õ..,,N,....\.........(H R14a HO
N H
R14a
H 4 )
Ri Riaa N
N
1 illik N Ri
0 \x 0
Ri5
OyNH
R15 '
R15
R3
I s.,
ULM-c ULM-d ULM-e
wherein:
Ri of Formulas ULM-c, ULM-d, and ULM-e is H, ethyl, isopropyl, tert-butyl, sec-
butyl,
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted
alkyl,
optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or
haloalkyl;
Ri4a of Formulas ULM-c, ULM-d, and ULM-e is H, haloalkyl, optionally
substituted alkyl,
methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl,
(CH2)m'OCOCH2(CH2)m,OCH2(CH2)m,CO(CH2)m,OH,
(CH2)m'OCOCH2(CH2)m,CO(CH2)m,OH, or cyclopropyl;
each m' is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
R15 of Formulas ULM-c, ULM-d, and ULM-e is selected from the group consisting
of H,
halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally
substituted aryl;
optionally substituted alkyl, optionally substituted haloalkyl, optionally
substituted
haloalkoxy, cycloalkyl, or cycloheteroalkyl;
X of Formulas ULM-c, ULM-d, and ULM-e is C, CH2, or C=0
R3 of Formulas ULM-c, ULM-d, and ULM-e is absent or a bond or an optionally
substituted
or 6 membered heteroaryl; and
wherein the dashed line indicates the site of attachment of at least one PTM,
another ULM
(ULM') or a chemical linker moiety coupling at least one PTM or a ULM' or both
to
ULM.
[0140] In certain embodiments, ULM comprises a group according to the
chemical
structure:
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HO,
N R143
RF:90o 0,
R11
R15
¨ ¨ ,
ULM-f
wherein:
Ri4a of Formula ULM-f is H, haloalkyl, optionally substituted alkyl, methyl,
fluoromethyl,
hydroxymethyl, ethyl, isopropyl, (CH2),,,,OCOCH2(CH2).,OCH2(CH2).,CO(CH2).,OH,
(CH2).'000CH2(CH2).,CO(CH2).,OH, or cyclopropyl;
each m' is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
R9 of Formula ULM-f is H;
Rio of Formula ULM-f is H, ethyl, isopropyl, tert-butyl, sec-butyl,
cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl;
0
0
s R12 5 ).,
)L.
¨1\1 ¨N I j--(R18)p ¨N 1 ¨(Ris)p
. 1\
R \-------r
Rii of Formula ULM-f is 13 ,
r
(R18)p 0
/ --N D(R18)=.<1\1%
1 \N 1 \N ..4N p(R18)-C?
, , =
or optionally
substituted heteroaryl;
p of Formula ULM-f is 0, 1, 2, 3, or 4;
each Ri8 of Formula ULM-f is independently halo, optionally substituted
alkoxy, cyano,
optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;
Ri2 of Formula ULM-f is H, C=0;
Ri3 of Formula ULM-f is H, optionally substituted alkyl, optionally
substituted alkylcarbonyl,
optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted
aralkylcarbonyl,
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optionally substituted arylcarbonyl, optionally substituted
(heterocyclyl)carbonyl, or
optionally substituted aralkyl,
R15 of Formula ULM-f is selected from the group consisting of H, halogen, Cl,
CN, OH, NO2,
optionally substituted heteroaryl, optionally substituted aryl; optionally
substituted
cycloheteroalkyl;
:.... rõ-o r_s /
rio
N
/ ; / F ; II) / 1 = S
OH
7
-re
F cs CI Br F3C
( cs-(
N N __
s-,_ . S-, . S = S = S = S = S =
, , , , , , ,
1 1 Cill 1 _____ 01
----"N
N js
N-N N-N 1 N N
- - - - - -3
H = / ; O'N = / = S ; / =
NI' = V =
1 1 1 1 1 1
0 ;and
the dashed line of Formula ULM-f indicates the site of attachment of at least
one PTM,
another ULM (ULM') or a chemical linker moiety coupling at least one PTM or a
ULM'
or both to ULM.
[0141] In certain embodiments, the ULM is selected from the following
structures:
OH
OH OH 0
0 0
4-Yrji iNN N
H
H H 0 WA
0 NIA 0 1\11-1 0
0 0
-
- - N
N S z N ULM-a3 a----'
SN---' --.."
ULM-a2
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OH OH OH
0 Ni.rq 0 0
OH , NicrN F
H H
0 NH 00 H NH 0
0 0 0 NH
OH
N S N SN.," N
ULM-a4 ULM-a5 ULM-a6
OH OH
OH
0 0 0
44ril .1' N'..ir N1 '''KlIt'N'tfrN/
H
0 i CiN/
NH H 0 H 0
0 NH 0 0 NH
N4
N /\
N ULM-a9
0,
ULM-a7 ULM-a8 N
F OH OH
0 0 0
fr.N/LNIc.rNr. ' NY)rNF IE1
H H
0 NH 0 NH H 0 ..
0 0 0 W
ULM-a12 ¨
ULM-a10 N ULM-al all s z N
S--,,---"
OH OH 0
0
0 µ jrAN
=,' N N ','i,)A
H k ::)1 n N-).iN
H
0 NB NB 0 NB
0 0 0
ULM-a13 CI
ULM-a14 CN ULM-a15
N
s'
wherein n is 0 or 1.
[0142] In certain embodiments, the ULM is selected from the following
structures:
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3...,..... tl ,
0 ?.....N4.,-A- '..'"?1
'1
1.µ ,... 0-kv)--sfs
..
µ ,s,
, ..t.. ....; , .N.
N \-- )---,,AN
41
H K < H \
OH OH bH
ULM-b1 ULM-b2 ULM-b3
'')....,<
0 al
, õ...) ...,.. y --õ, K,:. 0- -)L--,--'
.., o 1 i ,, 1 40) 0
..,--,--- Le
,
tg,4 \
OH OH
ULM-b4 ULM-b5 ULM-b6
qN -z--- \
=,,,,, , '''',I1 ( .11 0
,y 0 akyj'17/" 1) ,,õ-,s1 n ====''''L,1"
,
A =1 0 -1" 1 , , ."¨=-
_________________________________________________________________ ti
\
\ OH bH
OH
ULM-b7 ULM-b8 ULM-b9
)N,..
-0?
c........) /4-7\
'
-- ''N
014 OH OH
ULM-b10 ULM-bll ULM-b12
72
ULM-b7 ULM-b8 ULM-b9
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HO, HO,.. H
HO)___)--1. . :IN ---\
JO)
----, .
--",),,,--k- v \\ -.CN-,,,,,=-L. c/
=''''' ''Nr
'...
sl. , 6 '
, - N s 1
, el------N $ , -'14
%-----N ',ps,
t , \\,-- N ,P--
ULM-el ULM-e2 ULM-e3
HO\_____ HOõ
HO HO
H
in---' = ri H ,
C
0 ,..µ......õ, N
k., ,,- -= cs ..---1,. -A k,
1 N
)-
1 b
..i. '
N
t=-, r.,
ULM-e4 ULM-e5 ULM-e6
HO\ Haõ HO.,
o 1 ,/ 1 O
õ. ,,L,
s,./.....1 ,..0-
µ p f,õ ,..,
ir---1 ro
S..1-1.
.y,..N ,_...
\.:--õN
',....-===
ULM-e7 ULM-e8 ULM-e9
HO ;='=:>=f--,A, H H
\).---k H ri --, 1.---\ .N
f 'µ,. .,N,-. l' 'IL .
t , ....õ.. 1 .\-14/ -1(--1,( .
= 'N. ,a. -),
.-..õJõ,..\''t 0 /...õ7 % ) ..:L:. 0 b
,.µ
........ , iµs,õ...1.,, ,,, --,..,,.. 0 ...
--- y 0 --,
r\o
,,--- v
s õ,....õ4
N 14 N i s\,,..
ts, S\t,- N .i.'-
ULM-c10 ULM-ell ULM-c12
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i
, I
--Ak µ
- CI
--- 1'0
.,.
.:, , '1-'94 , ,'-': =I \ ,1 )'=--N4
.....- , I. - :
1'
ULM-c13 ULM-c14 ULM-c15
HON 1-10\ _ HO
S KII
ULM-dl ULM-d2 ULM-d3
HO
H
6 1
i , \:=:;;N
ULM-d4 ULM-d5 ULM-d6
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HO,
)¨"\ )7Lõ /
N
0 "--\\
µ6,N ,t4
/"--1 ey
HO ULM-d7 ULM-d8 ULM-d9
HN
/
¨N
wherein, the phenyl ring in ULM-al through ULM -a15, ULM -111 through ULM-b12,
ULM-cl
through ULM-c15 and ULM-dl through ULM-d9 is optionally substituted with
fluorine, lower
alkyl and alkoxy groups, and wherein the dashed line indicates the site of
attachment of at least
one PTM, another ULM (ULM') or a chemical linker moiety coupling at least one
PTM or a
ULM' or both to ULM-a.
[0143] In one embodiment, the phenyl ring in ULM-al through ULM-a15, ULM-
bl
through ULM-b12, ULM-cl through ULM-c15 and ULM-dl through ULM-d9 can be
functionalized as the ester to make it a part of the prodrug.
[0144] In certain embodiments, the hydroxyl group on the pyrrolidine ring
of ULM-al
through ULM-a15, ULM-bl through ULM-b12, ULM-cl through ULM-c15 and ULM-dl
through ULM-d9, respectively, comprises an ester-linked prodrug moiety.
[0145] In any of the aspects or embodiments described herein, the ULM and
where
present, ULM', are each independently a group according to the chemical
structure:
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RI:
Rx/
4
x,,R2,,
ULM-g
wherein:
121' of ULM-g is an optionally substituted C1-C6 alkyl group, an optionally
substituted -
(CH2),OH, an optionally substituted -(CH2),SH, an optionally substituted
(CH2)n-0-(Ci-
C6)alkyl group, an optionally substituted (CH2)n-WCOCW-(Co-C6)a1ky1 group
containing
an epoxide moiety WCOCW where each W is independently H or a Ci-C3 alkyl
group, an
optionally substituted -(CH2)nCOOH, an optionally substituted -(CH2)nC(0)-(Ci-
C6 alkyl),
an optionally substituted -(CH2),NHC(0)-Ri, an optionally substituted -
(CH2),C(0)-
NR1R2, an optionally substituted -(CH2)n0C(0)-NR1122, -(CH20)ntl, an
optionally
substituted -(CH2),OC(0)-(Ci-C6 alkyl), an optionally substituted -(CH2)nC(0)-
0-(Ci-C6
alkyl), an optionally substituted -(CH20),COOH, an optionally substituted -
(OCH2),0-
(Ci-C6 alkyl), an optionally substituted -(CH20)nC(0)-(Ci-C6 alkyl), an
optionally
substituted -(OCH2),NHC(0)-Ri, an optionally substituted -(CH20),C(0)-NR1R2, -
(CH2CH20)ntl, an optionally substituted -(CH2CH20),COOH, an optionally
substituted -
(OCH2CH2)n0-(Ci-C6 alkyl), an optionally substituted -(CH2CH20)nC(0)-(Ci-C6
alkyl),
an optionally substituted -(OCH2CH2).NHC(0)-Ri, an optionally substituted -
(CH2CH20),C(0)-NR1R2,an optionally substituted -SO2Rs, an optionally
substituted
S(0)Rs, NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl);
Ri and R2 of ULM-g are each independently 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);
Rs of ULM-g is a Ci-C6 alkyl group, an optionally substituted aryl, heteroaryl
or heterocycle
group or a -(CH2),,NR1122 group,;
X and X' of ULM-g are each independently C=0, C=S, -S(0), S(0)2 , (preferably
X and X'
are both C=0);
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R2' of ULM-g is an optionally substituted ¨(CH2)-(C=0)u(NRi)v(S02)a1ky1 group,
an
optionally substituted ¨(CH2)-(C=0)u(NRi)v(S02)wNR1NR2N group, an optionally
substituted ¨(CH2)n-(C=0)u(NRi)v(S02)w-Ary1, an optionally substituted ¨(CH2)n-
(C=0)u(NROv(S02)w-Heteroary1, an optionally substituted ¨(CH2)-(C=0)vNRi(S02)w-
Heterocycle, an optionally substituted -NR1-(CH2),-C(0),i(NROv(S02)w-alky1, an
optionally substituted -NR1-(CH2)n-C(0)u(NRi)v(S02)w- NR1NR2N, an optionally
substituted -NR1-(CH2)n-C(0)u(NR1)v(S02)w-NR1C(0)R1N, an optionally
substituted -
NR1-(CH2)n-(C=0)u(NRi)v(S02)w-Aryl, an optionally substituted -NR1-(CH2)n-
(C=0)u(NR1)v(S02)w-Heteroaryl or an optionally substituted -NR1-(CH2)n-
(C=0)vNR1(S02)w-Heterocycle, an optionally substituted -X'2'-alkyl group; an
optionally
substituted -XR2'- Aryl group; an optionally substituted -XR2'- Heteroaryl
group; an
optionally substituted -XR2'- Heterocycle group; an optionally substituted;
R3' of ULM-g is an optionally substituted alkyl, an optionally substituted
¨(CH2).-
(0)u(NROv(S02)w-alkyl, an optionally substituted ¨(CH2)n-C(0)u(NRi)v(S02)w-
NR1NR2N,
an optionally substituted ¨(CH2)n-C(0)u(NRi)v(S02)w-NR1C(0)R1N, an optionally
substituted ¨(CH2)n-C(0)u(NRi)v(S02)w-C(0)NRiR2, an optionally substituted
¨(CH2)n-
C(0)u(NRi)v(S02)w-Aryl, an optionally substituted ¨(CH2)n-C(0)u(NRi)v(S02)w-
Heteroaryl, an optionally substituted ¨(CH2)n-C(0)u(NROv(S02)w-Heterocycle, an
optionally substituted -NR1-(CH2)n-C(0)u(NROv(S02)w-alkyl, an optionally
substituted -
NR1-(CH2)n-C(0)u(NRi)v(S02)w- NR1NR2N, an optionally substituted -NR1-(CH2)n-
C(0)u(NRi)v(S02)w-NR1C(0)R1N, an optionally substituted -NR1-(CH2)n-
C(0)u(NRi)v(S02)w-Aryl, an optionally substituted -NR1-(CH2)n-
C(0)u(NRi)v(S02)w-
Heteroaryl, an optionally substituted -NR1-(CH2).-C(0)u(NROv(S02)w-
Heterocycle, an
optionally substituted -0-(CH2)n-(C=0)u(NROv(S02)w-alkyl, an optionally
substituted -
0-(CH2)n-(C=0)u(NRi)v(S02)w-NR1NR2N, an optionally substituted -0-(CH2)n-
(C=0)u(NRi)v(S02)w-NR1C(0)R1N, an optionally substituted -0-(CH2)n-
(C=0)u(NROv(S02)w-Aryl, an optionally substituted -0-(CH2)n-(C=0)u(NRi)v(S02)w-
Heteroaryl or an optionally substituted -0-(CH2).-(C=0)u(NR1)v(S02)w-
Heterocycle; ¨
(CH2),-(V)'(CH2)n-(V),¨alkyl group, an optionally substituted ¨(CH2)-
(V)n¨(CH2)n-
(V).,-Aryl group, an optionally substituted ¨(CH2).-(V).,-(CH2).-(V).,-
Heteroaryl group,
an optionally substituted ¨(CH2).-(V).,-(CH2).-(V).,-Heterocycle'group, an
optionally
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substituted -(CH2)n-N(Rr)(C=0)m-(V),,-alkyl group, an optionally substituted -
(CH2)n-
N(Ri,)(C=0)m,-(V),,-Aryl group, an optionally substituted -(CH2)n-N(Rr)(C=0)m-
(V)n-
Heteroaryl group, an optionally substituted -(CH2).-N(Ri,)(C=0)m,-(V).,-
Heterocycle
group, an optionally substituted -XR3- alkyl group; an optionally substituted -
XR3- Aryl
group; an optionally substituted -XR3- Heteroaryl group; an optionally
substituted -X'3'-
Heterocycle group; an optionally substituted;
RiN and R2N of ULM-g are each independently H, Ci-C6 alkyl which is optionally
substituted
with one or two hydroxyl groups and up to three halogen groups or an
optionally
substituted -(CH2),-Aryl, -(CH2),-Heteroaryl or -(CH2),-Heterocycle group;
V of ULM-g is 0, S or NRi;
Ri of ULM-g is the same as above;
R1 and Ri, of ULM-g are each independently H or a Ci-C3 alkyl group;
XR2' and XR3' of ULM-g are each independently an optionally substituted -CH2),-
, -CH2),-
CH(Xv)=CH(Xv)- (cis or trans), -CH2),-CtICH- , -(CH2CH20),- or a C3-C6
cycloalkyl
group, where Xv is H, a halo or a Ci-C3 alkyl group which is optionally
substituted;
each m of ULM-g is independently 0, 1,2, 3,4, 5, 6;
each m' of ULM-g is independently 0 or 1;
each n of ULM-g is independently 0, 1,2, 3,4, 5, 6;
each n' of ULM-g is independently 0 or 1;
each u of ULM-g is independently 0 or 1;
each v of ULM-g is independently 0 or 1;
each w of ULM-g is independently 0 or 1; and
any one or more of R1', R2', R3', X and X' of ULM-g is optionally modified to
be covalently
bonded to the PTM group through a linker group when PTM is not ULM', or when
PTM
is ULM', any one or more of R1', R2', R3', X and X' of each of ULM and ULM'
are
optionally modified to be covalently bonded to each other directly or through
a linker
group, or a pharmaceutically acceptable salt, stereoisomer, solvate or
polymorph thereof.
[0146] In any of the aspects or embodiments described herein, the ULM and when
present,
ULM', are each independently a group according to the chemical structure:
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R1'
_
_
F
R3 xz (iii1\1 ' ____________________________________ RI
0 ,
ULM-h
wherein:
each of R1', R2' and R3' of ULM-h are the same as above and X is C=0, C=S, -
S(0) group
or a S(0)2 group, more preferably a C=0 group, and
any one or more of R1', R2'and R3' of ULM-h are optionally modified to bind a
linker group
to which is further covalently bonded to the PTM group when PTM is not ULM',
or
when PTM is ULM', any one or more of R1', R2', R3' of each of ULM and ULM' are
optionally modified to be covalently bonded to each other directly or through
a linker
group, or
a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or
polymorph thereof.
[0147] In any of the aspects or embodiments described herein, the ULM, and
when present,
ULM', are each independently according to the chemical structure:
R1'
=
_
R-3-'----A .. R2'
0 0 ,
ULM-i
wherein:
any one or more of R1', R2'and R3' of ULM-I are optionally modified to bind a
linker group
to which is further covalently bonded to the PTM group when PTM is not ULM',
or
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when PTM is ULM', any one or more of R1', R2', R3' of each of ULM and ULM' are
optionally modified to be covalently bonded to each other directly or through
a linker
group, or
a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or
polymorph thereof.
[0148] In further aspects of the disclosure, R1' of ULM-g through ULM-i is
preferably a
hydroxyl group or a group which may be metabolized to a hydroxyl or carboxylic
group, such
that the compound represents a prodrug form of an active compound. Exemplary
preferred R1'
groups include, for example, -(CH2),OH, (CH2),-0-(C1-C6)alkyl group, -
(CH2),COOH, -
(CH20).H, an optionally substituted -(CH2),OC(0)-(Ci-C6 alkyl), or an
optionally substituted -
(CH2),C(0)-0-(Ci-C6 alkyl), wherein n is 0 or 1. Where R1' is or contains a
carboxylic acid
group, a hydroxyl group or an amine group, the hydroxyl group, carboxylic acid
group or amine
(each of which may be optionally substituted), may be further chemically
modified to provide a
covalent link to a linker group to which the PTM group (including a ULM'
group) is bonded;
[0149] X and X', where present, of ULM-g and ULM-h are preferably a C=0, C=S, -
S(0)
group or a S(0)2 group, more preferably a C=0 group;
[0150] R2' of ULM-g through ULM-i is preferably an optionally substituted -NR1-
T-Aryl, an
optionally substituted -NR1-T-Heteroaryl group or an optionally substituted -
NR1-T-Heterocycle,
where R1 is H or CH3, preferably H and T is an optionally substituted ¨(CH2).-
group, wherein
each one of the methylene groups may be optionally substituted with one or two
substituents,
preferably selected from halogen, an amino acid sidechain as otherwise
described herein or a C1-
C3 alkyl group, preferably one or two methyl groups, which may be optionally
substituted; and n
is 0 to 6 (e.g., 0, 1, 2 or 3, such as 0 or 1). Alternatively, T may also be a
¨(CH20).- group, a ¨
(OCH2),- group, a ¨(CH2CH20),- group, a ¨(OCH2CH2),- group, all of which
groups are
optionally substituted.
[0151] Preferred Aryl groups for R2' of ULM-g through ULM-i include optionally
substituted
phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl or
naphthyl group is
optionally connected to a PTM group via a linker group to which is attached a
PTM group
(including a ULM' group), a halogen (preferably F or Cl), an amine, monoalkyl-
or dialkyl
amine (preferably, dimethylamine), F, Cl, 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
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group itself is optionally connected to a PTM via a linker 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 indole, indolizine or
azaindolizine (2, 3, or 4-
azaindolizine), an optionally substituted quinoline, an optionally substituted
group according to
the chemical structure:
HET so0
r
RHET
R
,- - = = = N
LURE
RuRE
0
RHET
0
RHET RHET
=isj.ss"
RPRO1
RPRO
Ir--kN -(CH2),
0
wherein:
SC of ULM-g through ULM-i is CHRss, NRuRE, or 0;
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RHET of ULM-g through ULM-i is H, CN, NO2, halo (preferably Cl or F),
optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups (e.g. CF3), optionally substituted 0(C i-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 C1-C3
alkyl);
Rss of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl),
optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups), optionally substituted 0-(C1-C6 alkyl) (preferably
substituted with one
or two hydroxyl groups or up to three halo groups) or an optionally
substituted -C(0)(C1-
C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to
three halo
groups);
RuRE of u= . --- Em g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3
alkyl) or a ¨
C(0)(C1-C6 alkyl) each of which groups is optionally substituted with one or
two
hydroxyl groups or up to three halogen, preferably fluorine groups, or an
optionally
substituted phenyl group, an optionally substituted heteroaryl, or an
optionally substituted
heterocycle, preferably for example piperidine, morpholine, pyrrolidine,
tetrahydrofuran);
RPR of ULM-g through ULM-i is H, optionally substituted C1-C6 alkyl or an
optionally
substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group
selected from the
group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole,
diazole,
oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran,
thiene,
dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,
quinoline,
(each preferably substituted with a C1-C3 alkyl group, preferably methyl or a
halo group,
preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RpRol and RPRO2 of ULM-g through ULM-i are each independently H, an optionally
subsituted C1-C3
alkyl group or together form a keto group; and
each n of ULM-g through ULM-i is independently 0, 1,2, 3,4, 5, or 6
(preferably 0 or 1), or
an optionally substituted heterocycle, preferably tetrahydrofuran,
tetrahydrothiene,
piperidine, piperazine or morpholine (each of which groups when substituted,
are
preferably substituted with a methyl or halo (F, Br, Cl), each of which groups
may be
optionally connected to a PTM group (including a ULM' group) via a linker
group.
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DPRO1
3(RPRO2
linN-(CH2R) Pn R
[0152] In certain preferred aspects, 0 of ULM-g through ULM-i is a
RpRo
0
RPRO
N-(CH2), II
/
N-(CH2),
0 or group,
where RPR and n of ULM-g through ULM-i are the same as above.
[0153] Preferred heteroaryl groups for R2' of ULM-g through ULM-i include an
optionally
substituted quinoline (which may be attached to the pharmacophore or
substituted on any carbon
atom within the quinoline ring), an optionally substituted indole, an
optionally substituted
indolizine, an optionally substituted azaindolizine, an optionally substituted
benzofuran,
including an optionally substituted benzofuran, an optionally substituted
isoxazole, an optionally
substituted thiazole, an optionally substituted isothiazole, an optionally
substituted thiophene, an
optionally substituted pyridine (2-, 3, or 4-pyridine), an optionally
substituted imidazole, an
optionally substituted pyrrole, an optionally substituted diazole, an
optionally substituted triazole,
a tetrazole, an optionally substituted oximidazole, or a group according to
the chemical structure:
HET
r
t.-4 0
_RHET
"ez N
RuRE
RuRE
0
0
RHET
RHET A I _ RHET
=Pr
0
RHET
yC
wherein:
SC of ULM-g through ULM-i is CHRss, NRuRE, or 0;
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RHET of ULM-g through ULM-i 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(C i-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 of ULM-g through ULM-i is H or a Ci-C6 alkyl
group (preferably Ci-C3 alkyl);
Rss of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or CO, 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)(C1-
C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to
three halo
groups);
RuRE of ULM-g through ULM-i is H, a Ci-C6 alkyl (preferably H or Ci-C3 alkyl)
or a ¨
C(0)(Ci-C6 alkyl), each of which groups is optionally substituted with one or
two
hydroxyl groups or up to three 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 of ULM-g through ULM-i 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(C i-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), each of which groups may be optionally
connected to a
PTM group (including a ULM' group) via a linker group.
[0154] Preferred heterocycle groups for R2' of ULM-g through ULM-i include
tetrahydrofuran,
tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrollidine,
morpholine, oxane or
thiane, each of which groups may be optionally substituted, or a group
according to the chemical
structure:
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RPRO1
RPRO2 RPRO1
RPRO \/ RPRO2 RPRO
/
¨11-3(N¨(CH2), RHET __ 1--:.-....\ /
L------
0 or 0
RPRO
----\ / 0
II
/PRO
N¨(CH2)n 5,ss
172r---- N¨(CH2)n
preferably, a 0 or group,
wherein:
RPRO of ULM-g through ULM-i is H, optionally substituted C1-C6 alkyl or an
optionally
substituted aryl, heteroaryl or heterocyclic group;
RPR01 and RPR 2 of ULM-g through ULM-i are each independently H, an optionally
subsituted Ci-C3 alkyl group or together form a keto group and
each n of ULM-g through ULM-i is independently 0, 1,2, 3,4, 5, or 6 (often 0
or 1), each of
which groups may be optionally connected to a PTM group (including a ULM'
group)
via a linker group.
[0155] Preferred R2' substituents of ULM-g through ULM-i also include
specifically (and
without limitation to the specific compound disclosed) the R2' substituents
which are found in the
identified compounds disclosed herein (which includes the specific compounds
which are
disclosed in the present specification, and the figures which are attached
hereto). Each of these
R2' substituents may be used in conjunction with any number of R3'
substituents which are also
disclosed herein.
[0156] R3' of ULM-g through ULM-i is preferably an optionally substituted
¨T-Aryl, an
optionally substituted¨T-Heteroaryl, an optionally substituted ¨T-Heterocycle,
an optionally
substituted-NR1-T-Aryl, an optionally substituted -NR1-T-Heteroaryl or an
optionally
substituted-NR1-T-Heterocycle. In a preferred embodiment R1 is H or a Ci-C3
alkyl group,
preferably H or CH3, T is an optionally substituted ¨(CH2).- group, wherein
each one of the
methylene groups may be optionally substituted with one or two substituents,
preferably selected
from halogen, a Ci-C6 alkyl group (linear, branched, optionally substituted)
or the sidechain of
an amino acid as otherwise described herein, preferably methyl, which may be
optionally
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substituted; and n is 0 to 6,e.g. 0, 1, 2, or 3 ( such as 0 or 1).
Alternatively, T may also be a ¨
(CH20),- group, a ¨(OCH2),- group, a ¨(CH2CH20),- group, a ¨(OCH2CH2),- group,
each of
which groups is optionally substituted.
[0157] Preferred aryl groups for R3' of ULM-g through ULM-i include
optionally substituted
phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl or
naphthyl group is
optionally connected to a PTM group (including a ULM' group) via a linker
group and/or a
halogen (preferably F or Cl), an amine, monoalkyl- or dialkyl amine
(preferably, dimethylamine),
an amido group (preferably a ¨(CH2)õ,-NR1C(0)R2 group where m, Ri and R2 are
the same as
above), a halo (often F or Cl), OH, CH3, CF3, OMe, OCF3, NO2õCN or a S(0)2Rs
group (Rs is
a a Ci-C6 alkyl group, an optionally substituted aryl, heteroaryl or
heterocycle group or a -
(CH2).NR1R2 group), each of which may be substituted in ortho-, meta- and/or
para- positions of
the phenyl ring, preferably para-), or an Aryl (preferably phenyl), Heteroaryl
or Heterocycle.
Preferably said substituent phenyl group is an optionally substituted phenyl
group (i.e., the
substituent phenyl group itself is preferably substituted with at least one of
F, Cl, OH, SH,
COOH, CH3, CF3, OMe, OCF3, NO2, CN or a linker group to which is attached a
PTM group
(including a ULM' group), wherein the substitution occurs in ortho-, meta-
and/or para- positions
of the phenyl ring, preferably para-), a naphthyl group, which may be
optionally substituted
including as described above, an optionally substituted heteroaryl (preferably
an optionally
substituted isoxazole including a methylsubstituted isoxazole, an optionally
substituted oxazole
including a methylsubstituted oxazole, an optionally substituted thiazole
including a methyl
substituted thiazole, an optionally substituted pyrrole including a
methylsubstituted pyrrole, an
optionally substituted imidazole including a methylimidazole, a
benzylimidazole or
methoxybenzylimidazole, an oximidazole or methyloximidazole, an optionally
substituted
diazole group, including a methyldiazole group, an optionally substituted
triazole group,
including a methylsubstituted triazole group, a pyridine group, including a
halo- (preferably, F)
or methylsubstitutedpyridine group or an oxapyridine group (where the pyridine
group is linked
to the phenyl group by an oxygen) or an optionally substituted heterocycle
(tetrahydrofuran,
tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine,
tetrahydroquinoline, oxane
or thiane. Each of the aryl, heteroaryl or heterocyclic groups may be
optionally connected to a
PTM group (including a ULM' group) via a linker group.
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[0158] Preferred Heteroaryl groups for R3' of ULM-g through ULM-i include
an optionally
substituted quinoline (which may be attached to the pharmacophore or
substituted on any carbon
atom within the quinoline ring), an optionally substituted indole (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)6,-0-
Ci-C6 alkyl group or
an optionally substituted -(CH2)6,-C(0)-0-C1-C6 alkyl group), an optionally
substituted pyridine
(2-, 3, or 4-pyridine) or a group according to the chemical structure:
r..------.õ- sc
ET
ro
0 ¨ ¨1 1 _IRHET
HET t, ..ji'
N \ N
LURE
RU RE
0
0
RHET ir...k..... )
RHET IIIIIIIjN4
RHET
N 1 N
0
N'32z'
or RHET 1 ,
K ')
yc
,
wherein:
SC of ULM-g through ULM-i is CHRss, NRuRE, or 0;
RHET of ULM-g through ULM-i is H, CN, NO2, halo (preferably Cl or F),
optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups (e.g. CF3), optionally substituted 0(C i-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 C1-C3
alkyl);
Rss of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or CO, optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
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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)(C 1-
C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to
three halo
groups);
RuRE of ULM-g through ULM-i is H, a Ci-C6 alkyl (preferably H or Ci-C3 alkyl)
or a ¨
C(0)(Ci-C6 alkyl), each of which groups is optionally substituted with one or
two
hydroxyl groups or up to three 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 of ULM-g through ULM-i is N or C-R, where RIrc 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(C i-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). Each of said heteroaryl groups may be
optionally
connected to a PTM group (including a ULM' group) via a linker group.
[0159] Preferred heterocycle groups for R3' of ULM-g through ULM-i include
tetrahydroquinoline, piperidine, piperazine, pyrrollidine, morpholine,
tetrahydrofuran,
tetrahydrothiophene, oxane and thiane, each of which groups may be optionally
substituted or a
group according to the chemical structure:
RpRoi RPRO1
RPRO2 RPRO2
RPRO RPRO RPRO
/ A / ._....-, /
_lr-----\<N-(CH2),-, RHET ..
ft.....,e -(c H2) N-
(CH2),
1."--- 177-r------
0 or 0 , preferably, a 0
0
/RpRo
.ssel
N-(CH2),,
or group,
wherein:
RPR of ULM-g through ULM-i is H, optionally substituted C1-C6 alkyl or an
optionally
substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group
selected from the
group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole,
diazole,
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oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran,
thiene,
dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,
quinoline,
(each preferably substituted with a Ci-C3 alkyl group, preferably methyl or a
halo group,
preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RPR01 and RPR 2 of ULM-g through ULM-i are each independently H, an optionally
subsituted Ci-C3 alkyl group or together form a keto group, and
each n of ULM-g through ULM-i is 0, 1,2, 3,4, 5, or 6 (preferably 0 or 1),
wherein each of
said Heteocycle groups may be optionally connected to a PTM group (including a
ULM'
group) via a linker group.
[0160] Preferred R3' substituents of ULM-g through ULM-i also include
specifically (and
without limitation to the specific compound disclosed) the R3' substituents
which are found in the
identified compounds disclosed herein (which includes the specific compounds
which are
disclosed in the present specification, and the figures which are attached
hereto). Each of these
R3' substituents may be used in conjunction with any number of R2'
substituents, which are also
disclosed herein.
[0161] In certain alternative preferred embodiments, R2' of ULM-g through
ULM-i is an
optionally substituted -NRi-X'2'-alkyl group, -NRi-X'2'-Aryl group; an
optionally substituted -
NRi- X'2'-HET, an optionally substituted -NRi-X'2'-Aryl-HET or an optionally
substituted -
NRi- XR2'-HET-Aryl,
wherein:
Ri of ULM-g through ULM-i is H or a C1-C3 alkyl group (preferably H);
XR2' of ULM-g through ULM-i is an optionally substituted ¨CH2)n- , ¨CH2)n-
CH(Xv)=CH(Xv)- (cis or trans), ¨(CH2)n-CtICH- , -(CH2CH20).- or a C3-C6
cycloalkyl
group; and
Xv of ULM-g through ULM-i is H, a halo or a C1-C3 alkyl group which is
optionally
substituted with one or two hydroxyl groups or up to three halogen groups;
Alkyl of ULM-g through ULM-i is an optionally substituted C 1-C io alkyl
(preferably a Cl-C6
alkyl) group (in certain preferred embodiments, the alkyl group is end-capped
with a halo
group, often a Cl or Br);
Aryl of ULM-g through ULM-i is an optionally substituted phenyl or naphthyl
group
(preferably, a phenyl group); and
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HET of ULM-g through ULM-i is an optionally substituted oxazole, isoxazole,
thiazole,
isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,
dihydrofuran,
tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine,
piperidine, piperazine,
morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when
substituted,
each preferably substituted with a Ci-C3 alkyl group, preferably methyl or a
halo group,
preferably F or CO or a group according to the chemical structure:
Sc
HET RHET
Ryjr ¨
42< ,===
LURE
RURE
0
0
RHETrn N':4227
RHET RHET
Jsr
0 RPRO1
,RPRO2 RPRO1
RPRO2
RPRO
ri<
RHET j iN¨(CH2), r RHET L NI¨
L' yd.
o
0 0 =
SC of ULM-g through ULM-i is CHRss, NRuRE, or 0;
RHET of ULM-g through ULM-i is H, CN, NO2, halo (preferably Cl or F),
optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups (e.g. CF3), optionally substituted 0(C1-C6 alkyl)
(preferably substituted
with one or two hydroxyl groups or up to three halo groups) or an optionally
substituted
acetylenic group ¨CC-Ra where Ra is H or a C1-C6 alkyl group (preferably C1-C3
alkyl);
Rss of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or CO, optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups), optionally substituted 0-(C1-C6 alkyl) (preferably
substituted with one
or two hydroxyl groups or up to three halo groups) or an optionally
substituted -C(0)(Ci-
C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to
three halo
groups);
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RuRE of u= . --- Em g through ULM-i is H, a Ci-C6 alkyl (preferably H or Ci-C3
alkyl) or a -
C(0)(Ci-C6 alkyl), each of which groups is optionally substituted with one or
two
hydroxyl groups or up to three halogen, preferably fluorine groups, or an
optionally
substituted heterocycle, for example piperidine, morpholine, pyrrolidine,
tetrahydrofuran,
tetrahydrothiophene, piperidine, piperazine, each of which is optionally
substituted;
Yc of ULM-g through ULM-i 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(C i-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);
RPR of ULM-g through ULM-i is H, optionally substituted Ci-C6 alkyl or an
optionally
substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group
selected from the
group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole,
diazole,
oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran,
thiene,
dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,
quinoline,
(each preferably substituted with a Ci-C3 alkyl group, preferably methyl or a
halo group,
preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RPR 1 and RPR 2 of ULM-g through ULM-i are each independently H, an optionally
subsituted Ci-C3 alkyl group or together form a keto group, and
each n of ULM-g through ULM-i is independently 0, 1,2, 3,4, 5, or 6
(preferably 0 or 1).
[0162] Each of said groups may be optionally connected to a PTM group
(including a ULM'
group) via a linker group.
[0163] In certain alternative embodiments of the present disclosure, R3' of
ULM-g through
ULM-i is an optionally substituted -(CH2).-(V).,-(CH2).-(V)a-Rs3'group, an
optionally
substituted-(CH2).-N(RF)(C=0)õ,,-(V)a-Rs3' group, an optionally substituted -
X'3' -alkyl group,
an optionally substituted -XR3'-Aryl group; an optionally substituted -XR3'-
HET group, an
optionally substituted -XR3'-Aryl-HET group or an optionally substituted -XR3'-
HET-Aryl group,
wherein:
Rs3' is an optionally substituted alkyl group (Ci-Cio, preferably Ci-C6
alkyl), an optionally
substituted Aryl group or a HET group;
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121' is H or a Ci-C3 alkyl group (preferably H);
V is 0, S or NR1';
XR3' is ¨(CH2).- , -(CH2CH20).-, ¨CH2).-CH(Xv)=CH(Xv)- (cis or trans), ¨CH2).-
CHCH- ,
or a C3-C6 cycloalkyl group, all optionally substituted;
Xv is H, a halo or a Ci-C3 alkyl group which is optionally substituted with
one or two
hydroxyl groups or up to three halogen groups;
Alkyl is an optionally substituted Ci-Cio alkyl (preferably a Ci-C6 alkyl)
group (in certain
preferred embodiments, the alkyl group is end-capped with a halo group, often
a Cl or
Br);
Aryl is an optionally substituted phenyl or napthyl group (preferably, a
phenyl group); and
HET is an optionally substituted oxazole, isoxazole, thiazole, isothiazole,
imidazole, diazole,
oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran,
thiene,
dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,
benzofuran,
indole, indolizine, azaindolizine, quinoline (when substituted, each
preferably substituted
with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or
Cl), or a
group according to the chemical structure:
,ro
RHET c? > >¨ --1 I I __ RHET
..------N \ N/\
% 1
RuRE
RuRE
0
0
RHET 11..................'n RHET ¨'N RHET ).LI
Ni:22.4-
......l_
N_......../
N
=J'''''
0 PRO1
\ ,RPRO2 RPRO1
R
RPRO2
PRO r.----`c / RHET ¨<
')
RHET 1 IL,__ /N¨(CH2), rx
1
yc or
0 0 =
,
SC of ULM-g through ULM-i is CHRss, NRuRE, or 0;
RHET of ULM-g through ULM-i is H, CN, NO2, halo (preferably Cl or F),
optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups (e.g. CF3), optionally substituted 0(C i-C6 alkyl)
(preferably substituted
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with one or two hydroxyl groups or up to three halo groups) or an optionally
substituted
acetylenic group ¨CC-Ra where Ra is H or a Ci-C6 alkyl group (preferably Ci-C3
alkyl);
Rss of ULM-g through ULM-i 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);
RuRE of u= . --- Em g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3
alkyl) or a ¨
C(0)(Co-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;
Yc of ULM-g through ULM-i is N or C-R, where RYc is H, OH, CN, NO2, halo
(preferably Cl or F), optionally substituted C1-C6 alkyl (preferably
substituted with one or
two hydroxyl groups or up to three halo groups (e.g. CF3), optionally
substituted 0(C1-C6
alkyl) (preferably substituted with one or two hydroxyl groups or up to three
halo groups)
or an optionally substituted acetylenic group ¨CC-Ra where Ra is H or a C1-C6
alkyl
group (preferably Ci-C3 alkyl);
RPR of ULM-g through ULM-i is H, optionally substituted Ci-C6 alkyl or an
optionally
substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group
selected from the
group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole,
diazole,
oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran,
thiene,
dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,
quinoline,
(each preferably substituted with a Ci-C3 alkyl group, preferably methyl or a
halo group,
preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RPR 1 and RPR 2 of ULM-g through ULM-i are each independently H, an optionally
subsituted Ci-C3 alkyl group or together form a keto group;
each n of ULM-g through ULM-i is independently 0, 1,2, 3,4, 5, or 6
(preferably 0 or 1);
each m' of ULM-g through ULM-i is 0 or 1; and
each n' of ULM-g through ULM-i is 0 or 1;
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wherein each of said compounds, preferably on the alkyl, Aryl or Het groups,
is optionally
connected to a PTM group (including a ULM' group) via a linker group.
[0164] In alternative embodiments, R3' of ULM-g through ULM-i is -(CH2)n-
Aryl, -
(CH2CH20).-Aryl, -(CH2)n-HET or -(CH2CH20).-HET,
wherein:
said Aryl of ULM-g through ULM-i is phenyl which is optionally substituted
with one or two
substitutents, wherein said substituent(s) is preferably selected from -
(CH2),OH, Ci-C6
alkyl which itself is further optionally substituted with CN, halo (up to
three halo groups),
OH, -(CH2)nO(C1-C6)alkyl, amine, mono- or di-(Ci-C6 alkyl) amine wherein the
alkyl
group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up
to three
halo (preferably F, Cl) groups, or
said Aryl group of ULM-g through ULM-i is substituted with -(CH2),OH, -(CH2)n-
0-(Ci-
C6)alkyl, -(CH2)n-0-(CH2)n-(Ci-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, Cl) groups, CN, NO2, an optionally substituted -
(CH2).-(V).-
CH2),-(V).-(Ci-C6)alkyl group, a -(V).,-(CH2CH20).-RPEG group where V is 0, S
or
NRF, Ri, is H or a C1-C3 alkyl group (preferably H) and RP' is H or a C1-C6
alkyl group
which is optionally substituted (including being optionally substituted with a
carboxyl
group), or
said Aryl group of ULM-g through ULM-i is optionally substituted with a
heterocycle,
including a heteroaryl, selected from the group consisting of oxazole,
isoxazole, thiazole,
isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,
dihydrofuran,
tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine,
piperidine, piperazine,
morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine, (when
substituted
each preferably substituted with a Cl-C3 alkyl group, preferably methyl or a
halo group,
preferably F or Cl), or a group according to the chemical structure:
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Sc
RHET >¨ I I __ RHET
N
RuRE
RuRE
0
0
RHET NI(k
RHET I to _ RHET
0 RPRoi
,RPRO2 RPRO1
RPRO
/RPRO2
/ HET r"\
RHET 7¨(CH2)n R
,\(yc or
0 0
SC of ULM-g through ULM-i is CHRss, NRuRE, or 0;
RHET of ULM-g through ULM-i is H, CN, NO2, halo (preferably Cl or F),
optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups (e.g. CF3), optionally substituted 0(C i-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 C1-C3
alkyl);
Rss of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or CO, optionally
substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups), optionally substituted 0-(C1-C6 alkyl) (preferably
substituted with one
or two hydroxyl groups or up to three halo groups) or an optionally
substituted -C(0)(Ci-
C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to
three halo
groups);
RuRE of ULM-g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3 alkyl)
or a ¨
C(0)(Co-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;
Yc of ULM-g through ULM-i is N or C-R, where RIrc is H, OH, CN, NO2, halo
(preferably Cl or F), optionally substituted C1-C6 alkyl (preferably
substituted with one or
two hydroxyl groups or up to three halo groups (e.g. CF3), optionally
substituted 0(C1-C6
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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);
RPR of ULM-g through ULM-i is H, optionally substituted Ci-C6 alkyl or an
optionally
substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group
selected from the
group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole,
diazole,
oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran,
thiene,
dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,
quinoline,
(each preferably substituted with a Ci-C3 alkyl group, preferably methyl or a
halo group,
preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RPR 1 and RPRO2 of ULM-g through ULM-i are each independently H, an optionally
subsituted Ci-C3 alkyl group or together form a keto group;
HET of ULM-g through ULM-i is preferably oxazole, isoxazole, thiazole,
isothiazole,
imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran,
tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine,
piperidine, piperazine,
morpholine, quinoline, (each preferably substituted with a Ci-C3 alkyl group,
preferably
methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine,
azaindolizine,
or a group according to the chemical structure:
0
HET 2¨ 0 Dj¨RHET
,===
LURE
RuRE
0
0
RHET N':4227
RHET RHET
Jsr
0 RPRO1
RPRO2 RPRO1
RPRO2
RPRO
rIA
RHET 7¨(CH2),
o
"=-yc r RHET
0 0
SC of ULM-g through ULM-i is CHRss, NRuRE, or 0;
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RHET of ULM-g through ULM-i 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(C i-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);
Rss of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or CO, optionally
substituted Ci-C6 alkyl (preferably substituted with one or two hydroxyl
groups or up to
three halo groups), optionally substituted 0-(C1-C6 alkyl) (preferably
substituted with one
or two hydroxyl groups or up to three halo groups) or an optionally
substituted -C(0)(C1-
C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to
three halo
groups);
RuRE of u= . --- Em g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3
alkyl) or a ¨
C(0)(Co-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;
Yc of ULM-g through ULM-i is N or C-R, where RYc is H, OH, CN, NO2, halo
(preferably Cl or F), optionally substituted C1-C6 alkyl (preferably
substituted with one or
two hydroxyl groups or up to three halo groups (e.g. CF3), optionally
substituted 0(C1-C6
alkyl) (preferably substituted with one or two hydroxyl groups or up to three
halo groups)
or an optionally substituted acetylenic group ¨CC-Ra where Ra is H or a C1-C6
alkyl
group (preferably Ci-C3 alkyl);
RPR of ULM-g through ULM-i is H, optionally substituted Ci-C6 alkyl or an
optionally
substituted aryl, heteroaryl or heterocyclic group;
RPR01 and RPR 2 of ULM-g through ULM-i are each independently H, an optionally
subsituted Ci-C3 alkyl group or together form a keto group;
each m' of ULM-g through ULM-i is independently 0 or 1; and
each n of ULM-g through ULM-i is independently 0, 1,2, 3,4, 5, or 6
(preferably 0 or 1),
wherein each of said compounds, preferably on said Aryl or HET groups, is
optionally
connected to a PTM group (including a ULM' group) via a linker group.
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[0165] In
still additional embodiments, preferred compounds include those according to
the
chemical structure:
R1'
=
:7
_______________________________________________ RI
0 0 ,
ULM-i
wherein:
R1' of ULM-i is OH or a group which is metabolized in a patient or subject to
OH;
R2' of ULM-i is a ¨NH-CH2-Aryl-HET (preferably, a phenyl linked directly to a
methyl
substituted thiazole);
R3' of ULM-i is a ¨CHRcR3'-NH-C(0)-R3'1 group or a ¨CHRcR3'-R3'2 group;
12cR3' of ULM-i is a Ci-C4 alkyl group, preferably methyl, isopropyl or tert-
butyl;
R3P1 of ULM-i is Ci-C3 alkyl (preferably methyl), an optionally substituted
oxetane group
(preferably methyl substituted, a ¨(CH2).00H3 group where n is 1 or 2
(preferably 2), or
CH3 CH20 ____________
1.1 ......\_.
____________________ ...--Irrs'
a \
group (the ethyl ether group is preferably meta-substituted on
the phenyl moiety), a morpholino grop (linked to the carbonyl at the 2- or 3-
position;
0
RHET ..----1N _ 1 _
''-=.----i
R3P2 of ULM-i is a group;
Aryl of ULM-i is phenyl;
HET of ULM-i is an optionally substituted thiazole or isothiazole; and
RHET of ULM-i is H or a halo group (preferably H);
or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph
thereof, wherein
each of said compounds is optionally connected to a PTM group (including a
ULM'
group) via a linker group.
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[0166] In certain aspects, bifunctional compounds comprising a ubiquitin E3
ligase binding
moiety (ULM), wherein ULM is a group according to the chemical structure:
,Z2....( R15
Ri5
R25
R25
G ' - -1C R25 4(R16)o SR7 kJ' _z,,,zi
Y R14R14
(R16)o
, E R25 Y G/ R1 :1R 14
M , E
M
,
ULM-j1 ULM-j2
wherein:
each RS and R6 of ULM-j is independently OH, SH, or optionally substituted
alkyl or RS, R6,
and the carbon atom to which they are attached form a carbonyl;
R7 of ULM-j is H or optionally substituted alkyl;
E of ULM-j is a bond, C=0, or C=S;
G of ULM-j is a bond, optionally substituted alkyl, -COOH or C=J;
J of ULM-j is 0 or N-R8;
R8 of ULM-j is H, CN, optionally substituted alkyl or optionally substituted
alkoxy;
M of ULM-j is optionally substituted aryl, optionally substituted heteroaryl,
optionally
R9
1¨R10
substituted heterocyclic or R11 ;
each R9 and Rio of ULM-j is independently H; optionally substituted alkyl,
optionally
substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally
substituted
thioalkyl, a disulphide linked ULM, optionally substituted heteroaryl, or
haloalkyl; or R9,
R10, and the carbon atom to which they are attached form an optionally
substituted
cycloalkyl;
Ri 1 of ULM-j is optionally substituted heterocyclic, optionally substituted
alkoxy, optionally
Ri2
1-14
substituted heteroaryl, optionally substituted aryl, or R13;
R12 of ULM-j is H or optionally substituted alkyl;
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R13 of ULM-j is H, optionally substituted alkyl, optionally substituted
alkylcarbonyl,
optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted
aralkylcarbonyl,
optionally substituted arylcarbonyl, optionally substituted
(heterocyclyl)carbonyl, or
optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate,
each R14 of ULM-j is independently H, haloalkyl, optionally substituted
cycloalkyl,
optionally substituted alkyl or optionally substituted heterocycloalkyl;
R15 of ULM-j is H, optionally substituted heteroaryl, haloalkyl, optionally
substituted aryl,
optionally substituted alkoxy, or optionally substituted heterocyclyl;
each R16 of ULM-j is independently halo, optionally substituted alkyl,
optionally substituted
haloalkyl, CN, or optionally substituted haloalkoxy;
each R25 of ULM-j is independently H or optionally substituted alkyl; or both
R25 groups can
be taken together to form an oxo or optionally substituted cycloalkyl group;
R23 of ULM-j is H or OH;
Zi, Z2, Z3, and Z4 of ULM-j are independently C or N; and
o of ULM-j is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt,
stereoisomer, solvate or
polymorph thereof.
[0167] In certain embodiments, wherein G of ULM-j is C=J, J is 0, R7 is H,
each R14 is H,
and o is 0.
[0168] In certain embodiments, wherein G of ULM-j is C=J, J is 0, R7 is H,
each R14 is H,
R15 is optionally substituted heteroaryl, and o is 0. In other instances, E is
C=0 and M is
R9
1¨R10
R11 .
[0169] In certain embodiments, wherein E of ULM-j is C=0, Rii is optionally
substituted
R12 R9
¨NI, 1¨Rio
heterocyclic or R13 , and M is R11 .
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R9
1¨eR10
[0170] In certain embodiments, wherein E of ULM-j is C=0, M is R11
, and Ril is
0 0
)\--.....
1¨N 1 p
¨(R ) 1-11)\---;r(Rit3)
\__ 18 p \-----\N-
or , each R18 is independently halo,
optionally
substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or
haloalkoxy; and p is 0, 1, 2,
3, or 4.
[0171] In certain embodiments, ULM and where present, ULM', are each
independently a group
according to the chemical structure:
R15
R6 R C
......./õf
Se:23 R14
R25
G'
R25 N R14R14
1
,E
M ,
ULM-k
wherein:
G of ULM-k is C=J, J is 0;
R7 of ULM-k is H;
each R14 of ULM-k is H;
o of ULM-k is 0;
R17
1 ......-N
jj
R15 of ULM-k is S ; and
R17 of ULM-k is H, halo, optionally substituted cycloalkyl, optionally
substituted alkyl,
optionally substituted alkenyl, and haloalkyl.
[0172] In other instances, R17 of ULM-k is alkyl (e.g., methyl) or cycloalkyl
(e.g., cyclopropyl).
[0173] In other embodiments, ULM and where present, ULM', are each
independently a group
according to the chemical structure:
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R6 R /.....R15
R541 __ 23 R14
Rn25
p
cc -, (R16)0
R25
NI - R1'4R14
E
nr
,
wherein:
G of ULM-k is C=J, J is 0;
R7 of ULM-k is H;
each Ri4 of ULM-k is H;
o of ULM-k is 0; and
R15 of ULM-k is selected from the group consisting of:
Br F3
/
, C
N; 1 1_1-3 1 1 1 __ ifii 1 __ c[ 1 __ hi
s ; s ; ________ s h , . __ s b . s- \ ; s- ii ; s ;
,,N ____________________________________________________ ......_N
1 1 __ CIN ____________________________________ H
N-- __
__ N-N N N-N / ________ 0 N
H =, / = H =, 0N , - = / = ,
/ = N =
, , ,
cN,... H ______________________________________________________ cl....\1H
1_ -1 _____ f---=.--y _____ h 1 __ 01 _rilH
\--0. 0 = =0 ? ......-----1. = 0 ; NC
, , , ,=
N-0 H
N S SU-N 1 __ S-N
\ II
N ; N-N ; N-N =
,
OR30
1 CIF1 /431 l_cO N 1 3
_\
N ; NJ' ; N ; and
wherein R30 of ULM-k is H or an optionally substituted alkyl.
[0174] In other embodiments, ULM and where present, ULM', are each
independently a group
according to the chemical structure:
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R15
R6 R23 R14
R
Z i
R5/1 5(23 1:114 R 6 R5inõ,. 23 I
7N ---- \ R7 H
R25 (-4' ', (R16)o R25 ,N \riic 1
ki `16/o
R25 Nil - R14R14 R25 N G
/ R14
,
ME
ME ,
ULM-kl ULM-k2
wherein:
E of ULM-k is C=0;
R9
1 ( R10
M of ULM-k is R11 ;and
Rii of ULM-k is selected from the group consisting of:
0 0 F 0 0
F Br
1¨N
0
0 0 0
CN s 1¨N
i¨N 1¨N ¨N
F = Br ; Br ;
, ,=
0 0
0 0 ON
1¨N 1¨N
1¨N 1¨N
F ; N; ON;
,=
0 0
0
¨N OMe 1¨N
1¨N
\ OMe CI ;
,= ,
0
i¨N 0
CI 0
)--
1¨N 1¨N 1
\-----N OMe = ;and .
,
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[0175] In still other embodiments, a compound of the chemical structure,
R15
R6 R _pR15
R6 D
Z
R5;. _________ c,,23 1:114 R5niõ,. 1 µ23 \
rx7 N ---- \ R7 H
R25
G' (R16)0 R25 ,N \pp 1
N G ..w/R ki `16/o
R25 Fil R14R14 R25 1 14
MEE R14
M ,
ULM-kl ULM-k2
wherein E of ULM-k is C=0;
0
, Nci
Rii of ULM-k is ¨NH R20 , and
R9
1¨R10
M of ULM-k is R11 ;
q of ULM-k is 1 or 2;
R20 of ULM-k is H, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally
R21
HN¨IK
substituted aryl, or R22.
R21 of ULM-k is H or optionally substituted alkyl; and
R22 of ULM-k is H, optionally substituted alkyl, optionally substituted
alkoxy, or haloalkyl.
[0176] In any embodiment described herein, Rii of ULM-j or ULM-k is selected
from the group
consisting of:
0\\
0\\ 0\\ 0 ( 0 Ok\
\ ,\
/
__________________ s )
(
¨NH . ¨NH . 1¨NH )
¨NH . . z¨NH ____ . ¨NH .
, , , , , ,
0 0
0 Ok
¨Ntb ¨NH
4* 1NH 0
\ __________________________________________ / '11
¨ .
\ ,¨NH
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NC ON 0
0 0 0
1¨NH . ON
1¨NH . . 1
, ,¨NH ,¨NH
11.
0 0 OMe 0 Me0
1¨NH OMe 1¨NH 1¨NH
,
1::_c) ) 0, \
N 0\ N=, -N 0
( \\ C)
\ / 1 \ / 5 7 _____ \
1-NH _______ 1¨NH ____ / . 1 NH ___________ NH ________ ¨NH NH2,
o 0, 0 0 /
, _________ \ 0 ( , __ ( 0 (
,¨NH HN¨µ 1¨NH HN¨µ li
¨N ,
¨NH NH2, -\ 1¨NH
0 ; 0 =
, =
. 0 0 F
1 ______________________________ OV 1¨N 1¨N
1¨NH = . 1¨NH = 0-N = = =
0 0 0 0
F Br , s CN
1¨N , 1¨N ¨N 1¨N
= = F = =
0 0 0
0 0
1¨N ¨N 1¨N
1¨N 1¨N
Br; Br ; F ; CN ; ON;
0
0 ON 0
_N; _N
OMe
¨N
\ OMe
= . .
, , ,
0 0
¨N 1¨N 0
CI 0 CI 0 OMe
1¨N i¨N 1¨N
CI ; OMe = = = =
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0 Br 0 0 0
)\---- 0
1¨N 1¨N 1¨N 1¨N I
\---N
1¨N)L-
= OMe; CI.
OMe= \---.
, ,
N,V
(17 141r 141r 1¨ II N N-N
N-N 1¨ 11 1¨ 1
S-N = S-N = 0-N = H = 0---\= SjN=
,
H
0 S S 0 N N-NH . - = N- = N- = N-
= N--- ;
,
N-..... N-..., N--7 N-...."
N
I 1¨ I 1¨ 1 1 ___________________________________ er\jr _____
ON; SN= C) ; S = %Co = ` S =
, , ,
N=N
N/ . =
..-NH . __________________________ CP N= N\
1 = 1 _______________________________ ?= 1 /) 1¨K\; N j
N=> ;
/,
0
).\
1¨N I
\----.
and N.
[0177] In certain embodiments, Ril of ULM-j or ULM-k is selected from the
group consisting of:
0 0 F 0 0
0 F ,
¨N , 1-N ¨N
;
= =
, F ;
0 0
0 0 ON
1¨N 1¨N
1¨N ¨N
F ; CN; CN = =
0
0 0 0
CN 1¨N Br
1¨N , ¨N 1¨N
= Br; Br = =
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0 0
1¨N 1¨N 0
CI 0
1¨N
\,-e.
OMe; CI = =
,
0
0 R\
1¨N OMe, OMe
7
1¨N ¨NH )
\ .
0
0 0 0
* li
¨NH ON;
0 0 0 OMe
¨NH 1¨NH OMe 1¨NH
. .
0 0 0
0 Me0
1¨NH lit; 0 (
1¨NH\----N 1¨NH HN¨µ
=OMe = 0 ;
, ,
0 /
( o(
1¨NH HN¨ 1 __ er7
0 ; 0-N
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¨c---N
:1
0--
z., 1 S / 1
1.1
,.....õ1,
c ; c,õ \\\....."- ---õ,.. ---4\\=\ ...õ,
..,õ,- , c; \\.,.......;,.. ,..... ,...õ---
1,4,e/
...V
U i
,
S
11 d mi 0.-
[0178] In certain embodiments, ULM (or when present ULM') is a group according
to the
chemical structure:
R17 N
\ )
X
HO,
N
Y
0
M 0
,
ULM-1
wherein:
X of ULM-1 is 0 or S;
Y of ULM-1 is H, methyl or ethyl;
R17 of ULM-1 is H, methyl, ethyl, hydoxymethyl or cyclopropyl;
R9
/-eRi0
M of ULM-1 is is optionally substituted aryl, optionally substituted
heteroaryl, or R11 ;
108
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R9 of ULM-1 is H;
Rio of ULM-1 is H, optionally substituted alkyl, optionally substituted
haloalkyl, optionally
substituted heteroaryl, optionally substituted aryl, optionally substituted
hydroxyalkyl,
optionally substituted thioalkyl or cycloalkyl;
R11 of ULM-1 is optionally substituted heteroaromatic, optionally substituted
heterocyclic,
R12
¨1\1
optionally substituted aryl or Ri3;
R12 of ULM-1 is H or optionally substituted alkyl; and
R13 of ULM-1 is H, optionally substituted alkyl, optionally substituted
alkylcarbonyl,
optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted
aralkylcarbonyl,
optionally substituted arylcarbonyl, optionally substituted
(heterocyclyl)carbonyl, or
optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate.
[0179] In some embodiments, ULM and where present, ULM', are each
independently a group
according to the chemical structure:
R17 N
\ )
S
HO,
,
___________________________________ H .
N
R 9>ro Y
R10
R11
,
ULM-m
wherein:
Y of ULM-m is H, methyol or ethyl
R9 of ULM-m is H;
Rio is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl;
Rii of ULM-m is optionally substituted amide, optionally substituted
isoindolinone,
optionally substituted isooxazole, optionally substituted heterocycles.
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[0180] In other embodiments of the disclosure, ULM and where present, ULM',
are each
independently a group according to the chemical structure:
R17 N
S
HO,
0
N.......1(FNII
R9.> 0
Rlo
R11 ,
ULM-n
Wherein:
Ri7 of ULM-n is methyl, ethyl, or cyclopropyl; and
R9, Rio, and Ri 1 of ULM-n are as defined above. In other instances, R9 is H;
and
Rio of ULM-n is H, alkyl, or or cycloalkyl (preferably, isopropyl, tert-butyl,
sec-butyl,
cyclopentyl, or cyclohexyl).
[0181] In any of the aspects or embodiments described herein, the ULM (or when
present, ULM')
as described herein may be a pharmaceutically acceptable salt, enantiomer,
diastereomer, solvate
or polymorph thereof. In addition, in any of the aspects or embodiments
described herein, the
ULM (or when present, ULM') as described herein may be coupled to a PTM
directly via a bond
or by a chemical linker.
[0182] In certain aspects of the disclosure, the ULM moiety is selected from
the group consisting
of:
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HO, HO, HO,
H
c N
N N N
O 0 0
7L(LO 7L(LO )"'.(LO
N N N
0 Br 0 0
S S S
. \--=--N
. \--=-N \;--N
HO, HO, F
i=
c N &)N HR
. H
O O0
N
7L(LO 7L(L 0
0
N 0 N 7L(LO
---. --- N
S S 0
4 1 \:----N
CI \-----N S --,...
\;---N
HOõ 1-10,
. ____ H 1 - H Br
N HO,
).....c(N
>LrLO 70
N
O,NH N 0
S ---.. (LO
\--=-*N \-----N c),NH
F
HOõ
C S ---.
. ____ H \----N
)....,c(N 1-10,
& ).....1cH 1-10,
N N
0 . H
7L(0 N & ......c(N
N I 0 N
O 0
--..
S N >LrLO
0 ---,
S\,_N c),NH
CZ S ---.
\--=-N
1-10,. __ H
)....,c(N F 1-10,
O N
7L(0 0
O N >Lr0
--... c),NH
S
S
Vh' \---N
1 1 1
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HQ, FIR HQ,
. H
N
N N N
0 0
>Lr0 7L(0 4104 7L(LO
N S\---
H N N
0 0 Br
--.. ---
S
(:)
\---=N
0
/ -'sU II
FIR HO, HQ,
. H , . __ H . H
__________ .....c(NI
N N N
O >LrLO 0
7L(0 . 7L(LO
N N
0 (:),INH 0 Br
---.. --..
S S
\----;N =
a \---=-N
FIR
F
H
HQ,
, __ \ ,H HO __
. H
1 1C/N
0
O N 7 0
70 0 N
0
N
--... 0 NH
S \--:--N
S
\----:- S ---..
NC 110 \---=N
FIR Br
FIR FIR H
__________ H H
ON
......c(N --1\-7,..Ic. N N
0
N
O 0 N
0 7L(LO
>Lr0 SvYC)
olr ,NH (:)NH --...
I S ---
\;.---N
S N Br S
\--:--N
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FIR HQ, FIR
i= ___ H , __ \ H /- H
c ......ccN
...... J.L1
O OyL ii 0 0
>Lr0 0
OH HN OH
S\ ---:N '1,17 S ..) S --,
FIR
i= ___ H FIR
>Lr
_____________________________________ H FIR
1(
,....I(N
N /- H
O N c NN
),.....0 0
7L,r0
(:) NH
0
)'`-- S ---
\--r-N 0 N
\
F S ''-
--:"---N 0 N
S
FIR -'-
4. \--=-N
i= ___ H FIR
c ),...7(N H HQ,
......µ(N
N H
O )...1vLN 0
>LrLO 0 Q--"ICN
0
0 NH OyL 0
---.. 0 N
S --, = N S\--=--N 0
---...
S\--=N
4.
HO,, CN
i= __ \ .H
N FIR HO,
, __
H
_____________________________________ ).....1cH .
,.....ccN
7L(Lo O 714..17% 0 .
N
N
0
----.
0
4.
S\----zN N 0 N
S
--:--- S____,
CN = CN \ N
FIR \ N
,
)yiLH\ .1-I
N
O
HN,S,,, ----,
S \____,N
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HO ________________________ ,, HO ________________ HO,
N N N
0 0
7L(LO 11104 >LrIC) HSO
0
N 0 NH 0 N
= I. ,
Si
4. S -,..
\:.-----N
HO,, _______________________________________________ HO __
. H . H
......IcN ......e
HO,,
N H _____________ N
AVLO
HO N
N 0 N
0 0
H0 -,..
HN S
4. 1\1-- 0 N
--...
S\....,__N . \--=-N
HO,,
4. HQ,
i= _______ H . H
c ..,7(N
HO,,
N H N
0 ,....\.(N _________ 0
7L(0 0170
N
N 0 N
0 0
-.... __...7L0 -....
S S
\---=
44, \--:--
N
Br N 0 N ---..
S
HR
= \---."-N
HQ,
. H H
__________ ,...N N
HO,,
N i= H HO
>LrLO o'''YLO
N
0 NH 0 O N
H
--,
S\N S
14111 0 N
S ---.. \:-----
-N
\---:"-N
ON NC
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HO,. HOõ. H ,OH HO, H
c \ 0 HN 0 0 NH
ClyL
0
N --,-/S 7 'Ts"),.,
Sv_.N
NH
0TO
0,NH
0)\
----. -----
S I S IH
V.--N
N
0
7L(LO
HO,. HR. N
&
H H 0
S
4
N 7L(Lo --T:-.
0 0 1 \N
7L(0
N 0 N
0 H0a.: H
S I S
411 \-.---N
. \--=-N N
0
LrLO
\\ 0 N
---,.
OMe S
\--:---N
Me0
HO,.
41
H
HR.
H
N .....I(N HR.
0 N
arLO n y 0
N
N \S2Y0 0
0 0
---. N
S\,....... 0 Me0 0
. N
II ,
s N \_-=- S -
\;.----N
HR.
H HR.
....e HO,, .....7(1-
1
H N
N ).....\.(N
N
N 0
OrLO0 0
0 0
N HeYLC)
0 ONH
S -,..
. \----N
)''= S --''
=.---- S
\ N
-\--=-N
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HO HQ, HOõ
H i= __ H i= __ H
N >L17LN 0 N
0 0 0
>LrLO >LrLO
N 0 NH OH
0
----. --... --..
S\----N S
L) S\--7=N
* NC 001 \...N .-=-
N
HO, HQ, I
cz.....\c= H
HOõ
i= H
0 Me0 0 71..., IrL1 0 c .....c(N
0 0 N
---. 0 N >LrLO0
S .... 0 NH
S\___,.N ----.
S
HO,v r_\ OMe
0
HO,,
H
........e
=
/-
N
Me0 0 0 OMe
7L(LN 0
0 HO,
---. H
N 0 N ),...e
N
S
HOõ. -...
0
&\ ,1-1 14`17L0
le-""c(N 0 NH
---..
)k"=-(LO CI S
\--=-N
HQ,
N
0 c ....,c(H
i=
--, N
N0
CI 0 Me0
HQ,
HOõ 0 N i= ___ H
. _______ H
........el S\ __r_ N
N
N O0 >LrLO0
7L(L
CI 0 NH
(:),NH ---.
1 ---..
S\ ,.....N N\5 S
V.--N
--.
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HON/ HO HQ,
OH
.N--I(N
1\17-.7(N
0 0 0
>Lr0 0 0
0 N 0 NH
S ' Me0 ---.
* Me0 \:.--N S\_N
FIR
FIR, FIR i= H
H . H
F N
7L..(N 0 o, N FF>yLo 0
0
>Lr0 NH2
--...
0 N 0 NH S\---=N
/\ ---.
S\,...._N
. N
N6
FIR
. H
( ).....el
HO,
. _____ H FIR F N
( )...1(N i= H F 0
c ,..1(N F>H7L0
714... JLI 0 o, N (N,NH
0
1 --...
0 S\
,___N
0 N OMe (:),NH
1 S --- FIR
__\,--z.-N c ,..1(H
i
N
FIR 714....(LN 0 0
HO,, i H
c ,..1(N
. H
& ).....1(N N N
N F 0
0 (C)
7L(LO (N.,NH
. 0
N ---.
0 1 S
---. \--N HO
Sx,_____N
II FIR
H
N
N N
7LrL ,
N
0 0
0 0 N
0,0 ¨N
\:.--N
117
SIT
0
=
r µN
N/
0
N
N)L-cN
H
0H
N%\s * .
N-%-\ *
-.. N=N, * N¨
NH , NH N 0
0
N
# 0 CYNIV
N(1)
0 o Y7
)L-c_ NI)
)\.....c_N31 N'
H H
''OH N'OH
H
'OH
N---%\
WO
S
N.%\s . -,...
NH S
NR
N--"\
0 0
---,.
0 0
N 4.....,N
0)LO.
N OV
0 H
".....O 'OH
H
''OH N
H
N-%\ * N.-%\ ()H
N"--\
N¨I S
===.. --,.. ---
0 0
N N N
0y7 OyNIV 0
0 0 0
".....O
N N"16'-cN NI'
H H H
'OH ''OH 'OH
N%---"\s * N--%\ * N"--\s
S *
-,.. .... --,..
J0 0 0 0
N N N
0y7 d 0y7
# 0 CYNIV 0 0
)1...._O
N N N
H ' H H
'OH ''OH ''OH
t1100/610ZSI1/13.1
t9SISO/OZOZ OM
LT-ZO-TZOZ T8660T0 YD
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HO,, HO, ____________________ FIR,
H i= H H
.,.,c(1\1
N N N
0 0
7L(LO . 7L(LO 7L(LO
N N
0 0 0 N
--.. --..
N .1__-_-Z S = al
N OMe \.-:----N
Ho
s---
HO, "4---)....INj N i HO,
H --... ,
H
& ________ .......e N & ,....e
N HN 714.....(LN 0 0 .
0 0
VrLO 0 N
0H 0 N
=\----zN
*
HO
HO.
'N .....\,(H
H N
),....e HO,
00
7 0 1 ic_..t H
>L(NIL 0 N
7 .
0.,N 0 N
I --,
S\.,...._N
4. 0 N
HO.
H HO, 4. 0
),.....e
c ....1(H i=
N N
HS,
0 S---
.N
N -.
7L(LO 0 ---
1411 0 141 --.. N HN
S 0
0
\_.----N 0
HO,.
4. N
H
_..,..e
7L...(NLO HO
N Ho
IP
Os .& .,,,(H
714.,(LN 0 0 . /--_\ Mec)
S'eN
N ----
0
-....
S
4.
0 N
a HN
0 N
4.
IIP
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HR
---HQ
S'N HR.
.,.... N 1 ,e11-1
--... N
NH
I ICN3'.)
0 HN
0 N 0 N
N
0
* Ill
4. S ---..
\--=-N
HR. HO,.
H H
N(N ( ,....\(N HO,,
1 ylcH
0 N N
0
>Lr0 7L(13
o NH 0
---- N OH 70
S 0
\s--N N
, 1 HI ' 0
0 ---.
2'0 0 S
HR
\---.:-'N
. 4.
___________ H HR.
_...(N1 1 ylcH
N HO,
- 0--"N
N
0
>LrLO 700
NH
). N 0 N
--... 0
\--=----N S
H2N '''' \--r-"N
F10. ft
=
(N711 HR.
H HO
>LrL
''. __ ,...iccH
N
(D.,NH 0 N
, 1 HN) S ----
VO
N
0 10N
---,
(D'O S
1 --...
HR. . \--%N S
\:------N
H R
,..e
..
HR. H c.....c(' H
N H N
>LrL0 & ____ .......µN
O N 0
0
NH
H2N
\.--r--N 7L(L-S
(:),,,NH
1 S =.. -N S -'-
\.:-.---N1
\.--r--N
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HQ.. o-N HO Ha
. )õ...c(H H
I ic-""le N N
HN 0 0
0 N
--,... ---.
S S
= -1\I
\--=-N -1\1
\---=-N
Ho, N HOt, ___ ),..."ccH HO PH
' H
b N
--...
I lc N N
0 0
HN 7L,r0 7L(0
0
0 N 0 N N
0 --,
S I s -....
. . \---::-'N
.
HO,, HQ, HO,,
. H H H
...."c(N1 ......e /-
N N N
0 c0
0 0
0NH
- S
\.----N 1\i \.:-.---N \:--N
HO.. OH HO
i= __ H 1, OH _
c----c(' H
H N
N
N
1"'= 0 0
/ 0
-IV
\--=-
VLIVLO
0 N 0
7Tc0 0
-1\1 S
"N --,.
\----;"-N
HO,, = \--=.1\1
HQ,
H
c ...".\(N .......e
HQ,
N i= __ H N
0 c ......(N N 0
0 0
0
S / 0 0 / 0
----. --..
-IV --ni s
\--=-*N / 0 \s-----N
--,.
S
V.--N
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HO,, HO,, HO,,
N N N
O 0 0
It
0 0 0
---, --....
¨N 0 ¨ S ¨N S
\--:--N Ni \:-.--; N \--=--N
HO,, HO, HR
......ccN ( .......c(N ......ccN
N N N
O 0
0 0 7TcL, 0
1104
---, --- ---,
¨IV 0\----N ¨Ni S ¨IV S\---
- \-..--N N
HO,, HR HO,
H ,
i _______________________ . ______________________________ H
N N N
0
0 filt 0 410 7TcLo 0
\ \ \
¨NI 0 ¨Ni S -Thi S
HR HR HR
. H . ____ H H
N N N
O 0 = 0
.
7TcL) 0 VT:L) 0 0
/ 0
--...
0
\--=-N \----=N \:---N
HO,, HR HO,,
. H H . H
).....(N
N N N
O 0 = 0
410
/ 0 / 0
--,
S ---N 0
\--:--N \:-.---1\1 \--=--N
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HO,õ HO,õ HO,õ
H H H
( N c(
N N
0
VILO 7Tc0 0 . 0
---. N'S --- NN
\ i --.
¨N 0 7--Ni S 0 S
\---=N \--=--N \---;N
HQ, HO,õ HR.
H H H
)......c(N ,...,c(1\1 ).....c(N
N HLN N
0 410 0 0
0
--.. Nc / 0
T
\ / ---,
¨N 0 /)¨NSx..____N S S\----N
\:---N
HR. HO,õ HR.
H H H
).......e ).....c(N _.,...e
N N N
0 = 0 0
O VLJCO HCLO
/ 0 HN N N NN N
--- ---.--,
¨Ni 0 )=INI S )\---g S
\::---N \--5--N \---r---N
HQ, HR. HQ,
H H H
.....1(1\1 N...1(N1
N N
0
O 7L)L0 VHCO
/ 0 0 N N N NN
--- --- ---.
----N 0 )=-- s )\--O s
\--=-N \:---N \:---N
HO,, HR. HO,õ
H H H
.......c(N1
N N N
0 0 0
O 70 0
Z S S N
N NN
---. --- \ , --.
-----N S S NH S
\--szN )=-- \--=--N \---;N
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HO,õ HO,õ HO,õ
H H H
( N c( N c(
N
O 0 0
HNN
7L/1(0 71
S 1(cLO 0
N ---. --- V N ---,
)---i
\---=N1 )\---0 S
\--=--N 1%
N S
\:.---N
HO, HO,õ HO,õ
H H H
,
.....sc(N
......ccN ,...,c(1\1
N N N
O 0 0
VL)0 0 0
V
0 N NI ---, 71**12(cL --.. I --,
S
)-----j S\ -_--N ;\--S S\,___N N
\:.---N
HO,õ
HO,õ HO,õ H
),....el ).....c(N1
N
N N 0 0
O 0
7L)L0 0
)kNI:1 ---.
S NN ---, HN S
)-----1 S
\:.--N )------N
\--5--N \----;1\1
HO,õ
HQ, HQ,. H
Q,....c(N
H H
,..,1(1\1 & .....1(N
N N 0
O 0 VHCO
VLJO 0
NO 0 ---. --- I\I S
2-1 S
\----;1\1 S
\--=--N \---=N
HO HQ,.
H H
N N
.......c(N1 ),...,c(N
O 0
VLO 0
/ N
le S ---. I S --...
)---j S
\--szN
\..---N
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SN HO,
HO,,.
LIO 0
jNI)fC) HN
HN
>rLC)
0
OyNH r
¨N1
FIR HR HO
c )......e & ),....c(N ,..7(N
N N HO N
0 . S
yL0 0 410 ,,,,.yL0 0 110
S7Y0
OF \N
N
S S S
\ * ..--N 0 0
\---=N \--.--zN
HO,, HO
õ.
HR.
H ,....1(N
HO N
N 0 0 /s \ 0 o,
0 * õ0=(:)
HeYLO
N C)NH ONH
0 S S
S \.-----N \_----N
* \--:=---N
)----- )-----
HR, HO,,
Z 0
H .....\,(H
-N-7....7(N N
\ (1\1(Fil N
HSvY0 0 4110 7L,r0 ilt
0
N c)NH N
0
S S S
* \--=-N
\:-----N
* \----N
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.spH HR. =
H H H0 ..7: H
e N N
N)7....4
N
. 0
OAy
7HN 0 (:)i-1 N
--- 0
N....VS S\---:--N S ---...
41 \--=-N
HO,,a1(
HR. HR.r_i H
OH
H
ci......e N N
0
1\1)41
0 tilt 0
0
Me0 * 0 Me0 0 0 0 N
S S
*
\---N \-----N
Ho,.
s--
1 c-31 :ICI N
R H. HR
F
H H
& N....1 )(N & c(N
F N
F 0 F 0
HN
F>0 . 0 *
F>YLO 0 N
NH2 0 NH
S
-... /'
s ---..
\---N \----N
HS.
S*---N Ho,
s
,
0:41:- 9 ---% Ho,
o , . s
,N ---%
HN
0 HN i ICN3-.44\
0 N HN
0 N 0
II 08
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HR Ho, HQ,
H S H
)......el --N
(1\--Xl. N
C3rNH
N
>Lt70 =
0 HN
7L(0 =
OrNH 0 N N
HN) s
\:.---N 0
S
?COrLO 411 \---N
HQ, HQ, HO,,
H H H
c/...IN QAN fy_IN
vLro 0 . vLro 0 * 7L(Lo 0 411,
0
N 0 N 0 N
S S S
lit \---;--N
41 \--.-=-N \--=-N
HR. HQ, HO,.
H H
N N H
& ),.7(N ),....el
N
0 ilt 0 Alp 0 0 .
0
/ 0 / 0 / 0
-N1 s --NI s ¨NI s
N
HR. H0i,L \ ,H HR.
H N H
)......e N(-.1( )......e
N 0 N
0 . 7L,r0 lot 0
0 N 0 .
0
/ 0 S /o
\-..--- N
-1\1 S -1\1
S
\---:--N 4. \--=--N
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OH
r_1µ H
Ho, HO,
7
1 H
)...."c(N )....".c(N
0 0 * N N
0 N 0
0 . ),,,. 0 0 .
S z o z o
* \:---N
-N s
\--1--*N -1\1 s
\:.----N
HO,õ .91-1 H
HO,,. HO,,.
1 ic)-.47(N H H
c....7(N
0 *
VT(30 0
0 N
S z o
* \---::-N
-1\1 s
\.--N -IV S
\---N
HO,õ HO,õ HR.
H H H
N ,...7(N
N 0 N
0 * 0 . 0 4110
0 7c3L, 0
/ 0 /0
---N 0 ---N 0 ---N 0
\_---=N \--=-N
HO,, HO HO,,
õ.
H H H
),....7(N
N N
0 1110 0
N 1110 0 *
0 oN T 7c3, 0 0
VT3L, / 0
-N ¨Ni s -.- s
\:.-- 11 \:---N
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HO,, HO,, HO,,
H H H
),..7N
N N N(
0 . 0 . 0 .
. 0o
.0
s s 7 _N, s
\_--:---N \_--:---N \_--:---N
HR HO,, HR
H H H
N N N
0 * 0 * 0 illp
O 0 7TcL1 0
¨IV S N
¨1\1 S ¨1\1 S
HO,, HO,, HO
H H H
N N N
0 . 0 = 0 410,
O 0 0
/ 0 /0 / 0
¨1\1 S ¨1\1 0 ¨1\1 0
FIR FIR HR
_________ H H H
O . ....,\,(1\1 .....\,(N
N N N
0 1110i 0 *
O 0 0
VTI VT/
0 ¨1\1 0
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HO,õ HO,õ NO,,.
H H H
N N N
0 * 0 = vHco 0 =
0 0
/ 0 / N z S
-NI 0 -N S )=--I S
V---:-- N \-----N \---N
HO,õ HO, HO,
H H H
).......c(N & ),..,c(N .......c(N
N N N
7L/LO o, 7L/LO
o, 7L0
o,
N z 0 õ HN N N 0 N N
ti\I S
\r----N -1\S
\--=-N
HO,, Ng,. HO,,
H HH
)......e & ),...7(N
N N N
0 * = *
VLb 0 00
S N N N N N N
\ / \ i
?1\1 S
\---=-N 0 S
\--.-;--N S S
\--.-=-N
HO,õ HO,õ HO,
H H H
N N N
0 = 7Ljo 0 . HcLo 0 .
0
N N N N N N N
)\----g s )\--O s \ , s
NH
\---N \;---N \--:--N
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HO,, HO,, HO,,
H H H
).......el & 0
),..i(N )....7(N
N N N
0 * 7Ljco 0 = 7Ljc() 0 =
VLX
HN N 0 N S N
)---1 S
\-----N )---1 S
\-----N
\---N
HR HR HO
H H H
N N
0 = c( N 7L,/cLo 0 410 0 .
le
VLJLO VN5cLO
NI/ 0 S
)----j S
\r----N )-----1 S
\--:=N )\--O S
\--=-N
HO,, HO,, HO
H H
)......e & ),...7(NI \ .H
0 0
0 lit N
= 0 00 .
HN
)\--S S S
\:::---N 7-- \:.--N S
---N1
FIR HO,, HO
H H H
N N N
,,o
0 tipt 00 = 0 410
0
I S It 1
N S N S
\:---N \----N \---=-N
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HO, HO,
,
H ,
-, _______________________ N......c( H HO,
<-,
)........\,(N c N .
N
NtN
7L7cL0 0 *
0
------4"*---------0
N ' N
....õ
It -.......
--,
OH
N S N S
'.1 r'''? s
\
N --'----- N
\:..---- N \------N \
Ho, HQ,
:.
... N
CLN-....., . N =%
e=-,k ,/:= ---.......
.>µ.....,
N 1 0
. L-=2=,,,,,.:. ,7 0 -.,õ, =,.., ,>=-.
/". .
0
/NH
I ,
$ ,..)
HO, HO
..; ....................................................
, ________
H ., ; H
>14......(LN 0 0 = .1 .. ,s H N : \ ),
,.
--.-"4.---.J.=.0 V isµ =,== .N :
....õ,. µ;, . / sss, ,, = ...
.. - ¨ .. .....
-......../ / -.....-...,-
'i
HN)''''' \:::---N ==,µ.. N %
0 0 : ',....v., N \:.........,=:7
HQ. HQ
. .
'--., H ................. ; H
=i \ N -..",
i 'N . : .L.,., N. =,, '1 t \ H 4,
\ ...7 s% i b
? = .N ,,,,,
' ,... 11
'..1 ..- r '0 µ ,'
i ,."......,,, .....) N' ',
N =,::
.
/ =
.s. N )., ,. 1 -.-4`,, -- '=' 1
ksl,
.... ft µ'. 'N .,. .-.
S i .)' .. = S. 1 \44 N 'f
/ \==::;==.-N = i ...,..... ¨
%
t
l'.% ................................................ 8
: \ .? 4:s= \ S 1
,,, .....,
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HQ
HC).
;.' ....... H
HQ,.
1 = N¨..,.,
-- --Y-s t) , ,s, As.s.,-.<? `b 6 i N- \' =
% =
1 $ = ,,--.:\ ..,-.A....õ,....--";:;. % ,
,N $ $= -= 3 0 % )
%
/ ' S,. ;
,,,,, ....-.:2=N s P s. /
.:''.----. S 1
N ---- ' r K .s.>"- 6
õ,;(/ t'N
OH HQ
I 1 ) ., \
. - '
i
._1( \, H
P...õ..." -,r. __ k
.__ Ki-
-- N..
N i 13
's-----,, i:' .
=-s.õ..) 0 ...:/ ¨NH
6.= , õ.. ,--=,; 00 i
/ ¨ /.."'s , .
ON
'N. ..Y
S---('--"'
and
wherein the VLM may be connected to a PTM via a linker, as described herein,
at any
appropriate location, including, e.g., an aryl, heteroary, phenyl, or phenyl
of an indole group,
optionally via any appropriate functional group, such as an amine, ester,
ether, alkyl, or alkoxy.
Exemplary ILMs
[0183] AVPI tetrapeptide fragments
[0184] In any of the compounds described herein, the ILM can comprise an
alanine-
valine-proline-isoleucine (AVPI) tetrapeptide fragment or an unnatural mimetic
thereof. In
certain embodiments, the ILM is selected from the group consisting of chemical
structures
represented by Formulas (I), (II), (III), (IV), and (V):
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0 R3 R5
0 R3 R5
iNN//N\/ R6
R6 R
R1 N YN
R2 0 R4
R2 0 R7
(I) (II)
0
..:N.
0 R3
H W- ['Lk
1.4 R tr
"
(m) (w)
H Q shµ
roN =.=-=AN"..-'\. = -14
z
0
---;&\
0' N.
(V)
wherein:
R1 for Formulas (I), (II), (III), (IV), and (V) is selected from H or alkyl;
R2 for Formulas (I), (II), (III), (IV), and (V) is selected from H or alkyl;
R3 for Formulas (I), (II), (III), (IV), and (V) is selected from H, alkyl,
cycloalkyl and
heterocycloalkyl;
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R5 and R6 for Formulas (I), (II), (III), (IV), and (V) are independently
selected from H, alkyl,
cycloalkyl, heterocycloalkyl, or more preferably, R5 and R6 taken together for
Formulas
(I), (II), (III), (IV), and (V) form a pyrrolidine or a piperidine ring
further optionally
fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, each of
which can then
be further fused to another cycloalkyl, heterocycloalkyl, aryl or heteroaryl
ring;
R3 and R5 for Formulas (I), (II), (III), (IV), and (V) taken together can form
a 5-8-membered
ring further optionally fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or
heteroaryl rings;
R7 for Formulas (I), (II), (III), (IV), and (V) is selected from cycloalkyl,
cycloalkylalkyl,
heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl-C(0)-R4, arylalkyl,
heteroaryl,
heteroaryl-C(0)-R4, heteroaryl-R4, heteroaryl-naphthalene, heteroarylalkyl, or
-C(0)NH¨
R4, each one further optionally substituted with 1-3 substituents selected
from halogen,
alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero)cycloalkyl, (hetero)aryl,
¨C(0)NH¨R4,
or -C(0)¨R4; and
R4 is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl,
heterocycloalkylalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, further optionally substituted
with 1-3
substituents as described above.
[0185] As shown above, P1, P2, P3, and P4 of Formular (II) correlate with
A, V, P, and I,
respectively, of the AVPI tetrapeptide fragment or an unnatural mimetic
thereof. Similarly, each
of Formulas (I) and (III) through (V) have portions correlating with A, V, P,
and I of the AVPI
tetrapeptide fragment or an unnatural mimetic thereof.
[0186] In any of the compounds described herein, the ILM can have the
structure of
Formula (VI), which is a derivative of IAP antagonists described in WO Pub.
No. 2008/014236,
or an unnatural mimetic thereof:
R 0 R4
R N
R.3
(VI),
wherein:
RI of Formula (VI) is, independently selected from H, C1-C4ralky, Ci-
C4-
alkynyl or C3-Cio- cycloalkyl which are unsubstituted or substituted;
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R2 of Formula (VI) is, independently selected from H, C1-C4-
alkynyI or C3-Cio- cycloalkyl which are unsubstituted or substituted;
R3 of Formula (VI) is, independently selected from H, -CF3, -C2H5,
- CH2-Z or any R2 and R3 together form a heterocyclic ring;
each Z of Formula (VI) is, independently selected from H, -OH, F, Cl, -CH3, -
CF3. -CH2C1, -
CH2F or -CH,OH;
R4 of Formula (VI) is, independently selected from Ci-C 16 straight or
branched alkyl, CI-
C16-alkenyl, CI-C16- alkynyl, C3-Cio-cycloalkyl, -(CH2)o-6-Zi, -(CH2)o-6-aryl,
and -(CH2)0_
6-het, wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted;
R5 of Formula (VI) is, independently selected from H, Ci-Jo-alkyl, aryl,
phenyl, C3-7-
cycloalkyl, -(CH2)1-6-C3_7- cycloalkyl, -
(CH2)0-6-C3_7-cycloa1kyl-(CH2)o-
6-phenyl, -(CH2)04-CHE(CH2)14- phenyl.12, indanyl, -C(0)-C1-10-alkyl, -C(0)-
(CH2)1.6-C3.
7-cycloalkyl, -C(0)-(CH2)11.6-phenyl, - (CH2)a.6-C(0)-phenyl, -(CH2)G.6-het, -
C(0)-
(CH2)1_6-het, or R5 is selected from a residue of an amino acid, wherein the
alkyl,
cycloalkyl, phenyl, and aryl substituents are unsubstituted or substituted;
Z1 of Formula (VI) is, independently selected from -N(R10)-C(0)-Ci-io-alkyl. -
N(Rio)-C(0)-
(CH2)o-6-C3-7-cycloalkyl, -N(R1o)-C(0)-(CH2)&.6-phenyl, -N(R10)-C(0)(CH2)1_6-
het, -
C(0)-N(Ri )(RI2), -C(0)-0-C1-10-alkyl, -C(0)-0-(CH2)1-6-C3-7-cycloalkyl, -C(0)-
0-
(CH2)0_6-phenyl, -C(0)-0- (CH2)1_6-het, -0-C(0)-C1-10-alkyl, -0-C(0)-(CH2)i-6-
C3-7-
cycloalkyl, -0-C(0)-(CH2)0.6-phenyl, - 0-C(0)-(CH2)1_6-het, wherein alkyl,
cycloalkyl,
and phenyl are unsubstituted or substituted;
het of Formula (VI) is, independently selected from a 5-7 member heterocyclic
ring
containing 1 -4 heteroatoms selected from N, 0, and S, or an 8-12 member fused
ring
system including at least one 5-7 member heterocyclic ring containing 1, 2, or
3
heteroatoms selected from N, 0, and S, which heterocyclic ring or fused ring
system is
unsubstituted or substituted on a carbon or nitrogen atom;
Rio of Formula (VI) is selected from H, -CH3, -CF3, -CH2OH, or -CH2C1;
Ri and R12 of Formula (VI) are independently seleted from H, C3_7-
cycloa1ky1, -
(CH2)1_6-C3_7- cycloakyl, (CH2)o-6-phenyl, wherein alkyl, cycloalkyl, and
phenyl are
unsubstituted or substituted; or Rii and RI, together with the nitrogen form
het, and
U of Formula (VI) is, independently, as shown in Formula (VII):
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Rs R.#
XIR,1 =====.µ
R6 \
X
Oth)õ""""Rd-
-,
(VII),
wherein:
each n of Formula (VII) is, independently selected from 0 to 5;
X of Formula (VII) is selected from the group -CH and N;
R. and RI). of Formula (VII) are independently selected from the group 0, S.
or N atom or Co-
8-alkyl wherein one or more of the carbon atoms in the alkyl chain are
optionally replaced
by a heteroatom selected from 0, S. or N, and where each alkyl is,
independently, either
unsubstituted or substituted;
Rd of Formula (VII) is selected from the group Re-Q-(Rf)p(Rg)q, and Ar1-D-Ar2;
of Formula (VII) is selected from the group H or any Rc and Rd together form a
cycloalkyl
or het; where if Rc and Rd form a cycloalkyl or het, R5 is attached to the
formed ring at a
C or N atom;
p and q of Formula (VII) are independently selected from 0 or 1;
Re of Formula (VII) is selected from the group Ci_s-alkyl and alkylidene, and
each Re is
either unsubstituted or substituted;
Q is selected from the group N, 0, S, S(0), and S(0)2;
An and Ar2 of Formula (VII) are independently selected from the group of
substituted or
unsubstituted aryl and het;
Rf and Rg of Formula (VII) are independently selected from H. -C1-10-alkyl,
Ci_io-alkylaryl,
-OH, - (CH2)0.5-C3-7-cycloalky, -0-(CH2)G-6-aryl, phenyl, aryl, phenyl ¨
phenyl, -(CH2)1-6-het, -0-(CH2)1_6-het, -0R13. -C(0)-R13, -C(0)-N(R13)(R14), -
N(R13)(R14),
-S-R13, -S(0)-R13, -S(0)2-R13, -S(0)2- NRI3R14, -NR13-S(0)2-R14, -S-CE-lo-
alkyl, aryl-C1-4-
alkyl, or het-Ci4-alkyl, wherein alkyl, cycloalkyl, het, and aryl are
unsubstituted or
substituted, -S02-CI-2-alkyl, -S02-C1-2-alkylphenyl, -0-C14-a1kyl, or any Rg
and Rf
together form a ring selected from het or aryl;
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D of Formula (VII) is selected from the group -CO-, -C(0)-CI4-alkylene or
arylene, -CF2-, -
0-, -S(0)r where r is 0-2, 1,3-dioxalane, or Ci4-alkyl-OH; where alkyl,
alkylene, or
arylene are unsubstituted or substituted with one or more halogens, OH, -0-
C1_6-a1kyl, -
S-C1-6-alkyl, or -CF3; or each D is, independently selected from N(Rh);
Rh is selected from the group H, unsubstituted or substituted CI 4-alkyl,
aryl, unsubstituted
or substituted -0-(C14-cycloalkyl), -C(0)-C1-10-alkyl, - C(0)-0040-alkyl-aryl,
-C-0-Col-
10-alkyl, -C-0-00_10-alkyl-aryl, -S02-C1_10-alkyI. or -S02-(C0-10- alkylary1);
R6, R7, R8, and R9 of Formula (VII) are, independently, selected from the
group H, -C1-10-
alkyl, -Ci_10-alkoxy, aryl-C1-10- alkoxy, -OH, -0-C140-alkyl, -(CH2)0-6-C3-7-
cycloalkyl, -
0-(CH2)0_6-aryl, phenyl, -(CH2)1-6-het, -0-(CH2)1.6-het, -OR 13, -C(0)-R 13, -
C(0)-
N(R13)(R14), -N(RI3)(R14), -S-R13, -S(0)-RI3, -S(0)2- RI3, -S(0)2-NR13R14, or -
NR13-
S(0)2-R14; wherein each alkyl, cycloalkyl, and aryl is unsubstituted or
substituted; and
any R6, R7, R8, and R9 optionally together form a ring system;
R13 and Ri4 of Formula (VII) are independently selected from the group H,
Ci_10-alkyl, -
(CH2)i).6-C34-cycloalkyl, -(CH2)0.5- (CH)04 -(aryl)i-2, -C(0)-C1-10-alkyl, -
C(0)-(CH2)1-6-
C34-cycloa1kyl, -C(0)-0-(CH2)a.6-aryl, - C(0)-(CH2)a-6-0-fluorenyl, -C(0)-NH-
(CH2)0-6-
aryl, -C(0)-(CH2)0.6-aryl, -C(0)-(CH2)o-6-het, - C(S)-C1-10-alkyl, -C(S)-
(CH2)1-6-C3--7-
cycloalkyl, -C(S)-0-(CH2)0.6-aryl, -C(S)-(CH2)-0-fluorenyl, -C(S)-NH-(CH2)0-6-
aryl, -
C(S)-(CH2)o-6-aryl, or -C(S)-(CH2)1-6-het, wherein each alkyl, cycloalkyl, and
aryl is
unsubstituted or substituted: or any RI3 and Ri4 together with a nitrogen atom
form het;
wherein alkyl substituents of RI3 and Ri4 of Formula (VII) are unsubstituted
or substituted
and when substituted, are substituted by one or more substituents selected
from Ci_io-
alkyl, halogen. OH,- 0-C1_6-alkyl. -S-C1-6-alkyl, and -CF3; and substituted
phenyl or aryl
of R13 and Ri4 are substituted by one or more substituents selected from
halogen,
hydroxyl. Ci_4-alkyl, Ci_4-alkoxy, nitro, -CN, -0-C(0)-C14-alkyl, and -C(0)-0-
C14-aryl;
or a pharmaceutically acceptable salt or hydrate thereof.
[0187] In any of the compounds described herein, the 1LM can have the
structure of
Formula (VIII), which is based on the IAP ligrands described in Ndubaku, C.,
et al. Antagonism
of c-IAP and XIAP proteins is required for efficient induction of cell death
by small-molecule
IAP antagonists, ACS Chem. Biol., 557-566,4 (7) ( 2009), or an unnatural
mimetic thereof:
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1
0
H o1
õm, \
H
'NH
0' A2
(Al)
(VIII),
wherein each of Al and A2 of Formula (VIII) is independently selected from
optionally
substituted monocyclic, fused rings, aryls and hetoroaryls; and
R of Formula (VIII) is selected from H or Me.
[0188] In a particular embodiment, the linker group L is attached to Al of
Formula (VIII).
In another embodiment, the linker group L is attached to A2 of Formula (VIII).
[0189] In a particular embodiment, the ILM is selected from the group
consisting of
0
0
..11
N H
N :)=( r\r
0 N H = H N
0 0 N H
0
N
N
and
(A) (B)
[0190] In any of the compounds described herein, the ILM can have the
structure of
Formula (IX), which is derived from the chemotypes cross-referenced in
Mannhold, R., et al.
IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today,
15 (5-6), 210-9
( 2010), or an unnatural mimetic thereof:
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R2
0 R1
H
i H _
0 0 NH
-
(IX),
wherein R1 is selected from alkyl, cycloalkyl and heterocycloalkyl and, most
preferably,
from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl , and R2 of
Formula (IX) is selected
from ¨0Ph or H.
[0191] In any of the compounds described herein, the ILM can have the
structure of
Formula (X), which is derived from the chemotypes cross-referenced in
Mannhold, R., et al. IAP
antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15
(5-6), 210-9
( 2010), or an unnatural mimetic thereof:
w 0 x
=r R3
N R4 t
R2
- N
0 H
(X),
wherein:
R1 of Formula (X) is selected from H, ¨CH2OH, --CH2CH2OH, --CH2NH2, --
CH2CH2NH2;
X of Formula (X) is selected from S or CH2;
R2 of Formula (X) is selected from:
Oil
õ
N
.., I 0
iliv I*
R3 and R4 of Formula (X) are independently selected from H or Me
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[0192] In any of the compounds described herein, the ILM can have the
structure of
Formula (XI), which is derived from the chemotypes cross-referenced in
Mannhold, R., et al.
TAP antagonists: promising candidates for cancer therapy, Drug Discov. Today,
15 (5-6), 210-9
( 2010), or an unnatural mimetic thereof:
R2
0
0
4
i it 14111 0
R1rl-.'N 0
H
(XI),
wherein R1 of Formula (XI) is selected from H or Me, and R2 of Formula (XI) is
selected
from H or
S
N----
H
0.e...N -1S
i
[0193] In any of the compounds described herein, the ILM can have the
structure of
Formula (XII), which is derived from the chemotypes cross-referenced in
Mannhold, R., et al.
TAP antagonists: promising candidates for cancer therapy, Drug Discov. Today,
15 (5-6), 210-9
( 2010), or an unnatural mimetic thereof:
1
0,..NH
1
N R1
N NE: 0 0
iej N N
R2 H H
(XII),
wherein:
R1 of Formula (XII) is selected from:
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ff'sN%(,) N AthiõN\
0 41.1)
; and
R2 of Formula (XII) is selected from:
zg.õ.
0
[0194] In any of the compounds described herein, the IAP E3 ubiquitin
ligase binding
moiety is selected from the group consisting of:
Br
0 N
H2N
= H
[0195] In any of the compounds described herein, the ILM can have the
structure of
Formula (XIII), which is based on the IAP ligands summarized in Flygare, J.A.,
et al. Small-
molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20
(2), 251-67 ( 2010),
or an unnatural mimetic thereof:
0 n(
N N
H
NR1
Z
n Tr- 0, 2 or, preferably, 1
wherein:
Z of Formula (XIII) is absent or 0;
R1 of Formula (XIII) is selected from:
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/ \
...---
* OH 0
,
Rl
01 *
RR) of is selected from H, alkyl, or aryl;
X is selected from CH2 and 0; and
8
is a nitrogen-containing heteroaryl.
[0196] In any of the compounds described herein, the ILM can have the
structure of
Formula (XIV), which is based on the TAP ligands summarized in Flygare, J.A.,
et al. Small-
molecule pan-TAP antagonists: a patent review, Expert Opin. Ther. Pat., 20
(2), 251-67 ( 2010),
or an unnatural mimetic thereof:
0 0 ................................ 'NH
- S
R
: H
....,
R1
z-. N '
H
(XIV),
wherein:
Z of Formula (XIV) is absent or 0;
R3 and R4 of Formula (XIV) are independently selected from H or Me;
R1 of Formula (XIV) is selected from:
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/ \
,
Rl
* ON
Rlo of is selected from H,\,alkyl, or aryl;
..."..4,
X
,,
X of is selected from CH2 and 0; and
i \
.6-
. õ
of '\
or is a nitrogen-containing heteraryl.
[0197] In any of the compounds described herein, the ILM is selected from
the group
consisting of:
H
0
/PMN
i H
H . and
,
which are derivatives of ligands disclose in US Patent Pub. No. 2008/0269140
and US
Pat. No. 7,244,851.
[0198] In any of the compounds described herein, the ILM can have the
structure of
Formula (XV), which was a derivative of the TAP ligand described in WO Pub.
No. 2008/128171,
or an unnatural mimetic thereof:
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H 0 ( 1L7'1 j'i,
)..--
z---k
N -R1
H
(XV)
wherein:
Z of Formula (XV) is absent or 0;
R1 of Formula (XV) is selected from:
i \
R" X
*
*
*
,
Ritl
. 0
R1 of is selected from H, alkyl, or aryl;
",.õµ
X
* 1
..,õ,.., 1
X of is selected from CH2 and 0; and
Cs\,"
i
.1..11.4..õ
, / \
of or is a nitrogen-containing heteraryl; and
R2 of Formula (XV) selected from H, alkyl, or acyl;
[0199] In a particular embodiment, the ILM has the following structure:
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/
\__e<
N ,..
_\....0
N ¨
k I
,õ,-.....-.
[0200] In any of the compounds described herein, the ILM can have the
structure of
Formula (XVI), which is based on the IAP ligand described in WO Pub. No.
2006/069063, or an
unnatural mimetic thereof:
H 0 1;. r----\
,N ,L,N .,1 ..t4 /
.-- --?:-- ' '1r
H A
ka
VN )1
Ar
(XVI),
wherein:
R2 of Formula (XVI) is selected from alkyl, cycloalkyl and heterocycloalkyl;
more preferably,
from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably
from
cyclohexyl;
0
\
s'(::!.)
of Formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl; more
preferably, 5-membered nitrogen-containing heteroaryl, and most preferably
thiazole; and
Ar of Formula (XVI) is an aryl or a heteroaryl.
[0201] In any of the compounds described herein, the ILM can have the
structure of
Formula (XVII), which is based on the IAP ligands described in Cohen, F. et
al., Antogonists of
inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg.
Med. Chem. Lett.,
20(7), 2229-33 (2010), or an unnatural mimetic thereof:
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\
Jõ.
(
(XVII),
wherein:
R1 of Formula (XVII) is selected from te group halogen (e.g. fluorine), cyano,
/
.("/
/ /
o
X of Formula (XVII) is selected from the group 0 or CH2.
[0202] In any of the compounds described herein, the ILM can have the
structure of
Formula (XVIII), which is based on the IAP ligands described in Cohen, F. et
al., Antogonists of
inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg.
Med. Chem. Lett.,
20(7), 2229-33 (2010), or an unnatural mimetic thereof:
1 0
z 6
s
R
(XVIII),
wherein R of Formula (XVIII) is selected from alkyl, aryl, heteroaryl,
arylalkyl,
heteroarylalkyl or halogen (in variable substitution position).
[0203] In any of the compounds described herein, the ILM can have the
structure of
Formula (XIX), which is based on the IAP ligands described in Cohen, F. et
al., Antogonists of
inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg.
Med. Chem. Lett.,
20(7), 2229-33 (2010), or an unnatural mimetic thereof:
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N N
N
H
0 'N
\\N
(XIX),
N
wherein ----- is a 6-member nitrogen heteroaryl.
[0204] In a certain embodiment, the ILM of the composition is selected
from the group
consisting of:
0 ? r>
N r\r st4
= H H
0 t4
0 N CI
fro\
*
';rskµii
N and \44
[0205] In certain embodiments, the ILM of the composition is selected
from the group
consisting of:
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0
= H 0 Ni 1
z 0 "-= N H
S NLI\1=11 N
_= H
0 0N
H
0---
rej
ro 0
...-i
0 Nri...
N
H O N F S
H , and ,
0
Hi).L
N
N IQ
H
S IN
.
[0206] In any of the compounds described herein, the ILM can have the
structure of
Formula (XX), which is based on the TAP ligands described in WO Pub. No.
2007/101347, or an
unnatural mimetic thereof:
c_,.
0
H
N
N
N
N R1
H
0 0)N
H (XX),
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wherein X of Formula (XX) is selected from CH2, 0, NH, or S.
[0207]
In any of the compounds described herein, the ILM can have the structure of
Formula (XXI), which is based on the IAP ligands described in U.S. Pat. No.
7,345,081 and U.S.
Pat. No. 7,419,975, or an unnatural mimetic thereof:
0 R2
===N
0
R- (XXI),
wherein:
R2 of Formula (XXI) is selected from:
R6
HN _____________________________________________________ R6
R5 of Formula (XXI) is selected from: 0 and \ _______ ; and
W of Formula (XXI) is selected from CH or N; and
R6
HN ____________________________ R6
R6 of 0 and \ ___________________________________________________
are independently a mono- or bicyclic fused aryl or
heteroaryl.
[0208]
In certain embodiments, the ILM of the compound is selected from the group
consisting of:
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0 = r\v!..1\
= .
,-
0
N 14 H =
0 ==
,
,and
[0209] In any of the compounds described herein, the ILM can have the
structure of
Formula (XXII) or (XXIV), which are derived from the IAP ligands described in
WO Pub. No.
2015/006524 and Perez HL, Discovery of potent heterodimeric antagonists of
inhibitor of
apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem.
58(3), 1556-62
(2015), or an unnatural mimetic thereof, and the chemical linker to linker
group L as shown:
R6
"NH
wkirp.
HN, R2
N 1:%1
- 1 Linker
R4 NH
(XXII);
'NH
,
R1
\:,N¨..wa Linker
R3 NH
(XXIII); or
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NH
R6 0
HN R2
40-7µ..NH
Link er
N
(XXIV),
wherein:
R1 of Formula (XXII), (XXIII) or (XXIV) is selected from optionally
substituted alkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally
substituted heterocyclyl, optionally substituted arylalkyl or optionally
substituted aryl;
R2 of Formula (XXII), (XXIII) or (XXIV) is selected from optionally
substituted alkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally
substituted heterocyclyl, optionally substituted arylalkyl or optionally
substituted aryl;
or alternatively,
R1 and R2 of Formula (XXII), (XXIII) or (XXIV) are independently selected from
optionally
substituted thioalkyl wherein the substituents attached to the S atom of the
thioalkyl are
optionally substituted alkyl, optionally substituted branched alkyl,
optionally substituted
heterocyclyl, -(CH2)vCOR20, -CH2CHR21COR22 or -CH2R23,
wherein:
v is an integer from 1-3;
R2 and R22 of ¨(CH2)vCOR2 and -CH2R23 are independently selected from OH,
NR24R25
or OR26;
R21 of -CH2CHR21COR2 is selected from NR24R25;
R23 of -CH2R23 is selected from optionally substituted aryl or optionally
substituted
heterocyclyl, wherein the optional substituents include alkyl and halogen;
R24 of NR24R25 is selected from hydrogen or optionally substituted alkyl;
R25 of NR24R25 is selected from hydrogen, optionally substituted alkyl,
optionally
substituted branched alkyl, optionally substituted arylalkyl, optionally
substituted
heterocyclyl, -CH2(OCH2CH20)õ,CH3, or a polyamine chain, such as spermine or
spermidine;
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R26 of OR26 is selected from optionally substituted alkyl, wherein the
optional
substituents are OH, halogen or NH2; and
m is an integer from 1-8;
R3 and R4 of Formula (XXII), (XXIII) or (XXIV) are independently optionally
substituted alkyl, optionally substituted cycloalkyl, optionally substituted
aryl,
optionally substituted arylalkyl, optionally substituted arylalkoxy,
optionally
substituted heteroaryl, optionally substituted heterocyclyl, optionally
substituted
heteroarylalkyl or optionally substituted heterocycloalkyl, wherein the
substituents
are alkyl, halogen or OH;
R5, R6, R7 and R8 of Formula (XXII), (XXIII) or (XXIV) are independently
hydrogen,
optionally substituted alkyl or optionally substituted cycloalkyl; and/or a
pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
[0210] In a particular embodiment, the ILM according to Formulas (XXII)
through
(XXIV):
R7 and R8 are selected from the H or Me;
R5 and R6 are selected from the group comprising:
y
R3 and R4 are selected from the group comprising:
rTh 0
1
Ics,õ
[0211] In any of the compounds described herein, the ILM can have the
structure of
Formula (XXV), (XXVI), (XXVII), or (XXVIII), which are derived from the IAP
ligands
described in WO Pub. No. 2014/055461 and Kim, KS, Discovery of
tetrahydroisoquinoline-
based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21),
5022-9 (2014),
or an unnatural mimetic thereof, and the chemical linker to linker group L as
shown:
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R.8.
-HH
= c,.. .,0
R6s -T-
HN R2
'-r-A
)0
'---
010),,,,.
Lihker
(XXV);
R8.
-NH
HN
, .,...N, 4/.............,\
__________________________ Linker
', .. 4/
(XXVI);
R.Nil '")
________ 17 R2
S.....1
'NH
0 I)/
-
--=.,
N ______________________ Linker
/
R31
(xxvm; and
fe.NH P
1,,...4 H2
e 4,i%.
R6 HN ...... < ,¨ --(, ,).
, s.,
d >/
o----
.N _____________________ Linker
/
R31
(xxvim,
wherein:
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R2 of Formula (XXV) through (XXVIII) is selected from H, an optionally
substituted alkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally
substituted heterocyclyl, optionally substituted arylalkyl or optionally
substituted aryl;
or alternatively;
R1 and R2 of Formula (XXV) and (XXVIII) are independently selected from H, an
optionally
substituted thioalkyl ¨CR6oR61,-,a 70
tc wherein R6 and R61 are selected from H or methyl,
and R7 is an optionally substituted alkyl, optionally substituted branched
alkyl,
optionally substituted heterocyclyl, -(CH2)vCOR20, -CH2CHR21COR22 or -CH2R23;
wherein:
v is an integer from 1-3;
R2 and R22 of ¨(CH2)vCOR2 and -CH2CHR21COR22 are independently selected from
OH,
NR24R25 or OR26;
R21 of -CH2CHR21COR22 is selected from NR24R25;
R23 of -CH2R23 is selected from an optionally substituted aryl or optionally
substituted
heterocyclyl, where the optional substituents include alkyl and halogen;
R24 of NR24R25 is selected from hydrogen or optionally substituted alkyl;
R25 of NR24R25 is selected from hydrogen, optionally substituted alkyl,
optionally substituted
branched alkyl, optionally substituted arylalkyl, optionally substituted
heterocyclyl, -
CH2CH2(OCH2CH2)mCH3, or a polyamine chain
[CH2CH2(CH2)81\TH]vCH2CH2(CH2)(75,NH2 , such as spermine or spermidine,
wherein .3 = 0-2, Iv = 1-3, (75 = 0-2;
R26 of OR26 is an optionally substituted alkyl, wherein the optional
substituents are OH,
halogen or NH2,
m is an integer from 1-8;
R6 and R8 of Formula (XXV) through (XXVIII) are independently selected from
hydrogen,
optionally substituted alkyl or optionally substituted cycloalkyl; and
R31 of Formulas (XXV) through (XXVIII) is selected from alkyl, aryl,
arylalkyl, heteroaryl
or heteroarylalkyl optionally further substituted, preferably selected form
the group
consisting of:
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, A
0
101 011
E
, and
[0212] In any of the compounds described herein, the ILM can have the
structure of
Formula (XXIX) or (XXX), which are derived from the IAP ligands described in
WO Pub. No.
2013/071039, or an unnatural mimetic thereof:
0
Y R44
HN
0
N
H H
(XXIX),
e 0 , 0 u
: n
X y -
H 1
0
I R 0
0
Fe. 1 x )
N
H H
0 0 R14 (XXX),
wherein:
R43 and R44 of Formulas (XXIX) and (XXX) are independently selected from
hydrogen, alkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl
further optionally
substituted, and
R6 and R8 of Formula (XXIX) and (XXX) are independently selected from
hydrogen,
optionally substituted alkyl or optionally substituted cycloalkyl.
each X of Formulas (XXIX) and (XXX) is independently selected from:
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0
0 H
0 0 N v N
H H 1N : 2
v
N -
1 -: 2 1µ = 2
-\ 0
401 HN 1 \)H N
).L 0
if3 N
H 3 3
0
H 0 0
N (s)
1 s 2 V A/ 1 H
N H 0
N /
1 = 2
/ 1v/ = 2
H 0
1 Nv&
7: 2
OTh H H 0
NI/\)%3 N 0µ%3 1 µ 2
II3 , If3
3 , 0 0 ,
0 0 0
HR) H
1 1 2 1 N 2 11¨N
0 7 ,
0
\)-N
(31if3 Oie3 2 3 ,
0
H 0
N &dt H
1 s 2 v N
1 1 2
3 0 o3
,an d =
,
47.si
,- Nµ
I N
each Z of Formulas (XXIX) and (XXX) is selected from C , wherein each
represents a point of attachment to the compound; and
each Y is selected from:
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4
H H
1V N N A
1 s
1V H
N A
A N
* -.....- 1
0 *
dfzt H
H
N A
V Y
1 H H
V y H
N A VNA
y
1 1V Y 1 i
0 X
i ISI =
4 , 14 4 1$1
0 0.de4
H H
H N A VNA
N A V
V y 1 1
1 z
0
1.1 0
0 0A44N(N H
, ,
H
H VN A Y
N A 1
H V
H A VN A
v N
1
0 r
1 / (:)
Nk N el HN0 Aµ 01
4 H 4,c) 4 , 4
,
H Me
N A H
Ni A
V N A
_
HI),%4 0
N
* 1N :
z
I. 0
04/
= 4
0 ifzi
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H H
N,NA VN A
1 µ z 4 1
S
1 1
lx
NH
H
N A
iv 'r
H
ON_____\_ j--I4 41 ¨CH 1 ======,-=
V :
1
N=N , 2¨NH¨Il , /L1. , and 4
,
wherein:
¨ I 1 represents a point of attachment to a ¨C=0 portion of the compound;
¨ I 2 represents a point of attachment to an amino portion of the compound;
- I 3 represents a first point of attachment to Z;
¨ I 4 represents a second point of attachment to Z; and
A is selected from -C(0)R3 or
H H 0 0
0 N N-N\ 0
HN-N, V \ N- \ NI'
sN \1/4,11.... 0 vii.... /0 II 0 y.... S vO-OH
N1/4/L-z-IV N N NC-0 N
H H
OH
F el F
, or a tautomeric form of any of the foregoing, wherein:
R3 of -C(0)R3 is selected from OH, NHCN, NHSO2R10, NHOR11 or N(R12)(R13);
R1 and R11 of NHSO2R1 and NHOR11 are independently selected from -C1-C4
alkyl,
cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, any of which are optionally
substituted,
and hydrogen;
each of R12 and R13 of N(R12)(R13) are independently selected from hydrogen, -
Ci-C4 alkyl, -
(Ci-C4 alkylene)-NH-(Ci-C4 alkyl), benzyl, -(Ci-C4 alkylene)-C(0)0H,
-(Ci-C4 alkylene)-C(0)CH3, -CH(benzy1)-COOH, -Ci-C4 alkoxy, and
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-(Ci-C4 alkylene)-0-(C1-C4 hydroxyalkyl); or R12 and R13 of N(R12)(R13) are
taken together
with the nitrogen atom to which they are commonly bound to form a saturated
heterocyclyl optionally comprising one additional heteroatom selected from N,
0 and S,
and wherein the saturated heterocycle is optionally substituted with methyl.
[0213] In any of the compounds described herein, the ILM can have the
structure of
Formula (XXXI), which are derived from the IAP ligands described in WO Pub.
No.
2013/071039, or an unnatural mimetic thereof:
RI
i 1442
.rn \
R4 6
(XXXI),
wherein:
W1 of Formula (XXXI) is selected from 0, S, N-R', or C(R8a)(R8b);
W2 of Formula (XXXI) is selected from 0, S, N-R', or C(R8c)(R86
); provided that W1 and
W2 are not both 0, or both S;
R1 of Formula (XXXI) is selected from H, C1-C6alkyl, C3-C6cycloalkyl, -C1-
C6alkyl-
(substituted or unsubstituted C3-C6cycloalkyl), substituted or unsubstituted
aryl,
substituted or unsubstituted heteroaryl, -C1-C6alkyl-(substituted or
unsubstituted aryl), or
¨C1-C6alkyl-(substituted or unsubstituted heteroaryl);
when X1 is selected from 0, N-R', S, S(0), or S(0)2, then X2 is C(R2aR2b);
or:
X1 of Formula (XXXI) is selected from CR2cR2d and )(2 is cR2a,sI(2b,
and R2' and R2a together
form a bond;
or:
X1 and X2 of Formula (XXXI) are independently selected from C and N, and are
members of
a fused substituted or unsubstituted saturated or partially saturated 3-10
membered
cycloalkyl ring, a fused substituted or unsubstituted saturated or partially
saturated 3-10
membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10
membered aryl
ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
or:
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X1 of Formula (XXXI) is selected from CH2 and X2 is C=0, C=C(Rc)2, or C=NRc;
where
each RC is independently selected from H, -CN, -OH, alkoxy, substituted or
unsubstituted
C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or
unsubstituted C2-
05heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
heteroaryl, -Ci-C6a1kyl-(substituted or unsubstituted C3-C6cycloalkyl), -C 1-
C6alkyl-
(substituted or unsubstituted C2-05heterocycloalkyl), -C1-C6alkyl-
(substituted or
unsubstituted aryl), or -C1-C6alkyl-(substituted or unsubstituted heteroaryl);
RA of N-R' is selected from H, C1-C6alkyl, -C(=0)C1-C2alkyl, substituted or
unsubstituted
aryl, or substituted or unsubstituted heteroaryl;
R2a, R2b, R2c, R2d of cR2c-rsI(2d
and CR2a's2b
I( are independently selected from H, substituted or
unsubstituted C 1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl,
substituted or
unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-
05heterocycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -
C1-C6alkyl-
(substituted or unsubstituted C3- C6cycloalkyl), -C1-C6alkyl-(substituted or
unsubstituted
C2-05heteroc yclo alkyl), -C1-C6alkyl- (substituted or unsubstituted aryl), -C
i-C6alkyl-
(substituted or unsubstituted heteroaryl) and - C(=0)RB;
RB of - C(=0)RB is selected from substituted or unsubstituted C1-C6alkyl,
substituted or
unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-
05heterocycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -
C1-C6alkyl-
(substituted or unsubstituted C3- C6cycloalkyl), -C1-C6alkyl-(substituted or
unsubstituted
C2-05heteroc yclo alkyl), -C1-C6alkyl- (substituted or unsubstituted aryl), -C
i-C6alkyl-
(substituted or unsubstituted heteroaryl), or - NRDRE;
RD and RE of NRDRE are independently selected from H, substituted or
unsubstituted C 1-
C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or
unsubstituted C2-
05heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
heteroaryl, -Ci-C6alkyl- (substituted or unsubstituted C3-C6cycloalkyl), -C 1-
C6alkyl-
( sub stituted or unsubstituted C2- C5heterocyclo alkyl), -Ci-C6alkyl-
(substituted or
unsubstituted aryl), or -C1-C6alkyl- (substituted or unsubstituted
heteroaryl);
m of Formula (XXXI) is selected from 0, 1 or 2;
-U- of Formula (XXXI) is selected from -NHC(=0)-, -C(=0)NH-, -NHS(=0)2-, -
S(=0)2NH-,
-NHC(=0)NH-, -NH(C=0)0-, -0(C=0)NH-, or -NHS(=0)2NH-;
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R3 of Formula (XXXI) is selected from C1-C3alkyl, or C1-C3fluoroalkyl;
R4 of Formula (XXXI) is selected from -NHR5, -N(R5)2, -N-F(R5)3 or -0R5;
each R5 of -NHR5, -N(R5)2, -N-F(R5)3 and -0R5 is independently selected from
H, Ci-C3alkyl,
C1-C3haloalkyl, C1-C3heteroalkyl and -Ci-C3alkyl-(C3-05cycloalkyl);
or:
R3 and R5 of Formula (XXXI) together with the atoms to which they are attached
form a
substituted or unsubstituted 5-7 membered ring;
or:
R3 of Formula (XXXI) is bonded to a nitrogen atom of U to form a substituted
or
unsubstituted 5-7 membered ring;
R6 of Formula (XXXI) is selected from -NHC(=0)R7, -C(=0)NHR7, -NHS(=0)2R7, -
S(=0)2NHR7; -NHC(=0)NHR7, -NHS(=0)2NHR7, -(Ci-C3alkyl)-NHC(=0)R7, -(Ci-
C3alkyl)-C(=0)NHR7, -(Ci-C3alkyl)-NHS(=0)2R7, -(Ci-C3alkyl)-S(=0)2NHR7; -(Ci-
C3alkyl)-NHC(=0)NHR7, -(Ci-C3alkyl)-NHS(=0)2NHR7, substituted or unsubstituted
C2-Cioheterocycloalkyl, or substituted or unsubstituted heteroaryl;
each R7 of -NHC(=0)R7, -C(=0)NHR7, -NHS(=0)2R7, -S(=0)2NHR7; -NHC(=0)NHR7, -
NHS(=0)2NHR7, -(Ci-C3alkyl)-NHC(=0)R7, -(Ci-C3alkyl)-C(=0)NHR7, -(Ci-C3alkyl)-
NHS(=0)2R7, -(Ci-C3alkyl)-S(=0)2NHR7; -(Ci-C3alkyl)-NHC(=0)NHR7, -(Ci-C3alkyl)-
NHS(=0)2NHR7 is independently selected from Ci-C6alkyl, Ci-C6haloalkyl, Ci-
C6heteroalkyl, a substituted or unsubstituted C3-ClOcycloalkyl, a substituted
or
unsubstituted C2- Cioheterocycloalkyl, a substituted or unsubstituted aryl, a
substituted or
unsubstituted heteroaryl, -Ci-C6alkyl-(substituted or unsubstituted C3-
Ciocycloalkyl), -
Ci-C6alkyl- (substituted or unsubstituted C2-C 10heterocyclo alkyl, -C 1-
C6alkyl-
(substituted or unsubstituted aryl), -Ci-C6alkyl-(substituted or unsubstituted
heteroaryl), -
(CH2)p-CH(substituted or unsubstituted ary1)2, -(CH2)p-CH(substituted or
unsubstituted
heteroary1)2, -(CH2)p-CH(substituted or unsubstituted ary1)(substituted or
unsubstituted
heteroaryl), -(substituted or unsubstituted aryl)-(substituted or
unsubstituted aryl), -
(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl),
-(substituted
or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -
(substituted or
unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
p of R7 is selected from 0, 1 or 2;
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R8a, R8b, K ,s8c, and R8d of c(R8a)(R8bµ
) and C(R8c)(R8(
) are independently selected from H, Ci-
C6a1kyl, C1-C6fluoroalkyl, Ci-C6 alkoxy, Cl-C6heteroalkyl, and substituted or
unsubstituted aryl;
or:
R8a and R8d are as defined above, and R8b and R8' together form a bond;
or:
R8a and R8d are as defined above, and R8b and R8' together with the atoms to
which they are
attached form a substituted or unsubstituted fused 5-7 membered saturated, or
partially
saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms
selected from
S, 0 and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a
substituted
or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3
heteroatoms
selected from S, 0 and N;
or:
R8' and R8d are as defined above, and R8a and R8b together with the atoms to
which they are
attached form a substituted or unsubstituted saturated, or partially saturated
3 -7
membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected
from S, 0
and N;
or:
R8a and R8b are as defined above, and R8' and R8d together with the atoms to
which they are
attached form a substituted or unsubstituted saturated, or partially saturated
3 -7
membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected
from S, 0
and N;
where each substituted alkyl, heteroalkyl, fused ring, spirocycle,
heterospirocycle, cycloalkyl,
heterocycloalkyl, aryl or heteroaryl is substituted with 1 -3 R9; and
each R9 of R8a, R8b,
R8c and R8d is independently selected from halogen, -OH, -SH, (C=0),
CN, Ci-C4alkyl, C1-C4fluoroalkyl, Ci-C4 alkoxy, Ci-C4 fluoroalkoxy, -NH2, -
NH(Ci-
C4alkyl), -NH(Ci-C4alkyl)2, - C(=0)0H, -C(=0)NH2, -C(=0)Ci-C3alkyl, -
S(=0)2CH3, -
NH(Cl-C4alkyl)-0H, -NH(Ci-C4alkyl)-0-(C-C4alkyl), -0(Cl-C4alkyl)-NH2; -0(C1-
C4alkyl)-NH-(C)-C4alkyl), and -0(Ci-C4alkyl)-N-(C)-C4alkyl)2, or two R9
together with
the atoms to which they are attached form a methylene dioxy or ethylene dioxy
ring
substituted or unsubstituted with halogen, -OH, or Ci-C3alkyl.
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[0214]
In any of the compounds described herein, the ILM can have the structure of
Formula (XXXII), which are derived from the IAP ligands described in WO Pub.
No.
2013/071039, or an unnatural mimetic thereof:
..,X2 xl R 1
X'-' w2
W.õ ,U 1
y-
Fe 0 IR'5 (XXXII),
wherein:
W1 of Formula (XXXII) is 0, S, N-R', or C(R8a)(R8b);
W2 of Formula (XXXII) is 0, S, N-R', or C(R8c)(¨t( 86
); provided that W1 and W2 are not both
0, or both S;
R1 of Formula (XXXII) is selected from H, C1-C6alkyl, C3-C6cycloalkyl, -C1-
C6alkyl-
(substituted or unsubstituted C3-C6cycloalkyl), substituted or unsubstituted
aryl,
substituted or unsubstituted heteroaryl, -C1-C6alkyl-(substituted or
unsubstituted aryl), or
¨C1-C6alkyl-(substituted or unsubstituted heteroaryl);
when X1 of Formula (XXXII) is N-R', then X2 is C=0, or CR2c¨ 2d,
_I( and X3 is CR2aR2b;
or:
when X1 of Formula (XXXII) is selected from S, S(0), or S(0)2, then X2 is
cR2o_I(-s 2d,
and X3
is cR2aR2b;
or:
when X1 of Formula (XXXII) is 0, then X2 is CR2' 2d
_I( and N-R' and X3 is CR2aR2b;
or:
when X1 of Formula (XXXII) is CH3, then X2 is selected from 0, N-R', S, S(0),
or S(0)2,
and X3 is CR2aR2b;
when X1 of Formula (XXXII) is CR2e¨tc 2f and X2 is CR2' 2d,
tc
and R2e and R2c together form a
bond, and X3 of Formula (XXXII) is CR2aR2b;
or:
X1 and X3 of Formula (XXXII) are both CH2 and X2 of Formula (XXXII) is C=0,
C=C(Rc)2,
or C=NRc; where each Rc is independently selected from H, -CN, -OH, alkoxy,
substituted or unsubstituted C 1-C6alkyl, substituted or unsubstituted C3-
C6cycloalkyl,
substituted or unsubstituted C2-05heterocycloalkyl, substituted or
unsubstituted aryl,
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substituted or unsubstituted heteroaryl, -C1-C6alkyl-(substituted or
unsubstituted C3-
C6cyclo alkyl), -C1-C6a1kyl-(substituted or unsubstituted C2- C5heteroc yclo
alkyl), -C -
C6alkyl-(substituted or unsubstituted aryl), or ¨C1-C6alkyl- (substituted or
unsubstituted
heteroaryl);
or:
X1 and X2 of Formula (XXXII) are independently selected from C and N, and are
members
of a fused substituted or unsubstituted saturated or partially saturated 3-10
membered
cycloalkyl ring, a fused substituted or unsubstituted saturated or partially
saturated 3-10
membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10
membered aryl
ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring,
and X3 is
CR2aR2b;
or:
X2 and X3 of Formula (XXXII) are independently selected from C and N, and are
members
of a fused substituted or unsubstituted saturated or partially saturated 3-10
membered
cycloalkyl ring, a fused substituted or unsubstituted saturated or partially
saturated 3-10
membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10
membered aryl
ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring,
and XI of
Formula (XXXII) is CR2'R2f;
RA of N-RA is selected from H, Ci-C6alkyl, -C(=0)Ci-C2alkyl, substituted or
unsubstituted
aryl, or substituted or unsubstituted heteroaryl;
R2a, R2b, R2c, R2d, R2e, and R2f of CR2'R2d, 2b
tc and CR2eR2f are independently selected
from H, substituted or unsubstituted C1-C6a1kyl, substituted or unsubstituted
Ci-
C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or
unsubstituted
C2-05heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
heteroaryl, -Ci-C6alkyl-(substituted or unsubstituted C3- C6cyclo alkyl), -Ci-
C6alkyl-
(sub stituted or unsubstituted C2-05heterocyc lo alkyl), -Ci-C6alkyl-
(substituted or
unsubstituted aryl), -Ci-C6a1kyl-(substituted or unsubstituted heteroaryl) and
- C(=0)RB;
RB of -C(=0)RB is selected from substituted or unsubstituted Ci-C6alkyl,
substituted or
unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-
05heterocycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -
Ci-C6alkyl-
(sub stituted or unsubstituted C3- C6cyclo alkyl), -Ci-C6alkyl-(substituted or
unsubstituted
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C2-05heteroc yclo alkyl) , -C1-C6alkyl- (substituted or unsubstituted aryl), -
C i-C 6alkyl-
(substituted or unsubstituted heteroaryl), or - NRDRE;
RD and RE of NRDRE are independently selected from H, substituted or
unsubstituted Ci-
C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or
unsubstituted C2-
05heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
heteroaryl, -Ci-C6a1kyl- (substituted or unsubstituted C3-C6cyclo alkyl) , -C
1-C6alkyl-
( sub stituted or unsubstituted C2- C5heterocyclo alkyl) , -Ci-C6alkyl-
(substituted or
unsubstituted aryl), or -C1-C6alkyl- (substituted or unsubstituted
heteroaryl);
m of Formula (XXXII) is selected from 0, 1 or 2;
-U- of Formula (XXXII) is selected from -NHC(=0)-, -C(=0)NH-, -NHS(=0)2-, -
S(=0)2NH-, -NHC(=0)NH-, -NH(C=0)0-, -0(C=0)NH-, or -NHS(=0)2NH-;
R3 of Formula (XXXII) is selected from Ci-C3alkyl, or C1-C3fluoroalkyl;
R4 of Formula (XXXII) is selected from -NHR5, -N(R5)2, -N-F(R5)3 or -0R5;
each R5 of -NHR5, -N(R5)2, -N-F(R5)3 and -0R5 is independently selected from
H, C1-C3alkyl,
C 1-C3halo alkyl, C 1-C3hetero alkyl and -C i-C3alkyl-(C3-05cyclo alkyl);
or:
R3 and R5 of Formula (XXXII) together with the atoms to which they are
attached form a
substituted or unsubstituted 5-7 membered ring;
or:
R3 of Formula (XXXII) is bonded to a nitrogen atom of U to form a substituted
or
unsubstituted 5-7 membered ring;
R6 of Formula (XXXII) is selected from -NHC(=0)R7, -C(=0)NHR7, -NHS(=0)2R7, -
S(=0)2NHR7; -NHC(=0)NHR7, -NHS(=0)2NHR7, -(Ci-C3alkyl)-NHC(=0)R7, 4Ci-
C3alkyl)-C(=0)NHR7, -(C 1 -C3alkyl)-NHS (=0)2R7, -(C 1 -C3alkyl)-S (=0)2NHR7; -
(C 1 -
C3alkyl)-NHC(=0)NHR7, -(Ci-C3alkyl)-NHS (=0)2NHR7, substituted or
unsubstituted
C2-Cioheterocycloalkyl, or substituted or unsubstituted heteroaryl;
each R7 of -NHC(=0)R7, -C(=0)NHR7, -NHS(=0)2R7, -S(=0)2NHR7; -NHC(=0)NHR7, -
NHS (=0)2NHR7, -(Ci-C3alkyl)-NHC(=0)R7, -(Ci-C3alkyl)-C(=0)NHR7, -(C i-
C3alkyl)-
NHS (=0)2R7, -(C 1 -C3alkyl)-S (=0)2NHR7; -(C 1 -C3alkyl)-NHC(=0)NHR7, -(C 1 -
C3alkyl)-
NHS (=0)2NHR7 is independently selected from Ci-C6alkyl, Ci-C6haloalkyl, Ci-
C6heteroalkyl, a substituted or unsubstituted C3-Cl0cycloalkyl, a substituted
or
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unsubstituted C2- Cioheterocycloalkyl, a substituted or unsubstituted aryl, a
substituted or
unsubstituted heteroaryl, -C1-C6alkyl-(substituted or unsubstituted C3-Ciocyc
lo alkyl), -
C1-C6alkyl- (substituted or unsubstituted C 2-C 10heteroc yclo alkyl, -C1-
C6alkyl-
(substituted or unsubstituted aryl), -C1-C6alkyl-(substituted or unsubstituted
heteroaryl), -
(CH2)p-CH(substituted or unsubstituted ary1)2, -(CH2)p-CH(substituted or
unsubstituted
heteroary1)2, -(CH2)p-CH(substituted or unsubstituted ary1)(substituted or
unsubstituted
heteroaryl), -(substituted or unsubstituted aryl)-(substituted or
unsubstituted aryl), -
(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl),
-(substituted
or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -
(substituted or
unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
p of R7 is selected from 0, 1 or 2;
R8a, R8b, R8c, and R8d of c(R8a)(R8bµ
) and C(R8c)(R8(
) are independently selected from H, C 1-
C6alkyl, C1-C6fluoroalkyl, Ci-C6 alkoxy, C1-C6heteroalkyl, and substituted or
unsubstituted aryl;
or:
R8a and R8d are as defined above, and R8b and R8' together form a bond;
or:
R8a and R8d are as defined above, and R8b and R8' together with the atoms to
which they are
attached form a substituted or unsubstituted fused 5-7 membered saturated, or
partially
saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms
selected from
S, 0 and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a
substituted
or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3
heteroatoms
selected from S, 0 and N;
or:
R8' and R8d are as defined above, and R8a and R8b together with the atoms to
which they are
attached form a substituted or unsubstituted saturated, or partially saturated
3 -7
membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected
from S, 0
and N;
or:
R8a and R8b are as defined above, and R8' and R8d together with the atoms to
which they are
attached form a substituted or unsubstituted saturated, or partially saturated
3 -7
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membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected
from S, 0
and N;
where each substituted alkyl, heteroalkyl, fused ring, spirocycle,
heterospirocycle, cycloalkyl,
heterocycloalkyl, aryl or heteroaryl is substituted with 1 -3 R9; and
each R9 of R8a, K 8b,
R8c and R8d is independently selected from halogen, -OH, -SH, (C=0),
CN, C1-C4a1kyl, C1-C4fluoroalkyl, Ci-C4 alkoxy, Ci-C4 fluoroalkoxy, -NH2, -
NH(Ci-
C4alkyl), -NH(C1-C4alky1)2, - C(=0)0H, -C(=0)NH2, -C(=0)C1-C3alkyl, -
S(=0)2CH3, -
NH(C1-C4alkyl)-0H, -NH(C1-C4alkyl)-0-(C-C4alkyl), -0(C1-C4alkyl)-NH2; -0(C1-
C4alkyl)-NH-(C1-C4alkyl), and -0(C1-C4alkyl)-N-(C1-C4alky1)2, or two R9
together with
the atoms to which they are attached form a methylene dioxy or ethylene dioxy
ring
substituted or unsubstituted with halogen, -OH, or C1-C3alkyl.
[0215] In any of the compounds described herein, the ILM can have the
structure of
Formula (XXXIII), which is derived from the IAP ligands described in WO Pub.
No.
2013/071039, or an unnatural mimetic thereof:
(,x3 XI
, - W2
-T. 'rim P-41 '
" \ =
R4 6
n
r`=
(XXXIII),
wherein:
W1 of Formula (XXXIII) is selected from 0, S, N-R', or C(R8a)(R8b);
W2 of Formula (XXXIII) is selected from 0, S, N-R', or C(R8c)(''K 8(
); provided that W1 and
W2 are not both 0, or both S;
R1 of Formula (XXXIII) is selected from H, C1-C6alkyl, C3-C6cycloalkyl, -C1-
C6alkyl-
(substituted or unsubstituted C3-C6cycloalkyl), substituted or unsubstituted
aryl,
substituted or unsubstituted heteroaryl, -C1-C6alkyl-(substituted or
unsubstituted aryl), or
-C1-C6alkyl-(substituted or unsubstituted heteroaryl);
when X1 of Formula (XXXIII) is selected from N-R', S, S(0), or S(0)2, then X2
of Formula
(XXXIII) is CR2cR2d, and X3 of Formula (XXXIII) is CR2aR2b;
or:
when X1 of Formula (XXXIII) is 0, then X2 of Formula (XXXIII) is selected from
0, N-R'
,
S, S(0), or S(0)2, and X3 of Formula (XXXIII) is CR2aR2b;
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or:
when X1 of Formula (XXXIII) is CR2eR2f and X2 of Formula (XXXIII) is CR2cR2d,
and R2e
and R2' together form a bond, and X3 of Formula (XXXIII) is CR2aR2b;
or:
X1 and X2 of Formula (XXXIII) are independently selected from C and N, and are
members
of a fused substituted or unsubstituted saturated or partially saturated 3-10
membered
cycloalkyl ring, a fused substituted or unsubstituted saturated or partially
saturated 3-10
membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10
membered aryl
ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring,
and X3 of
Formula (XXXIII) is CR2aR2b;
or:
X2 and X3 of Formula (XXXIII) are independently selected from C and N, and are
members
of a fused substituted or unsubstituted saturated or partially saturated 3-10
membered
cycloalkyl ring, a fused substituted or unsubstituted saturated or partially
saturated 3-10
membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10
membered aryl
ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring,
and X1 of
Formula (V11,1 I) is CR 2eR2f;
RA of N-RA is H, Ci-C6a1kyl, -C(=0)Ci-C2alkyl, substituted or unsubstituted
aryl, or
substituted or unsubstituted heteroaryl;
R2a, R2b, R2c, R2d, R2e, and R2f of CR2cR2d, CR2aR2b
and CR2eR2f are independently selected
from H, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted
Ci-
C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or
unsubstituted
C2-05heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
heteroaryl, -Ci-C6alkyl-(substituted or unsubstituted C3- C6cyclo alkyl), -C i-
C6alkyl-
(sub stituted or unsubstituted C2-05heterocyclo alkyl), -Ci-C6alkyl-
(substituted or
unsubstituted aryl), -Ci-C6a1kyl-(substituted or unsubstituted heteroaryl) and
- C(=0)RB;
RB of -C(=0)RB is substituted or unsubstituted Ci-C6alkyl, substituted or
unsubstituted
C6cycloalkyl, substituted or unsubstituted C2-05heterocycloalkyl, substituted
or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C6alkyl-
(substituted or
unsubstituted C3- C6cycloalkyl), -C -C6alkyl-(substituted or unsubstituted
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Csheterocycloalkyl), -Ci-C6a1kyl- (substituted or unsubstituted aryl), -C1-
C6alkyl-
(substituted or unsubstituted heteroaryl), or - NRDRE;
RD and RE of NRDRE are independently selected from H, substituted or
unsubstituted Ci-
C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or
unsubstituted C2-
05heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
heteroaryl, -Ci-C6a1kyl- (substituted or unsubstituted C3-C6cyclo alkyl), -C1-
C6alkyl-
(sub stituted or unsubstituted C2- Csheterocyclo alkyl), -Ci-C6alkyl-
(substituted or
unsubstituted aryl), or -C1-C6alkyl- (substituted or unsubstituted
heteroaryl);
m of Formula (XXXIII) is 0, 1 or 2;
-U- of Formula (XXXIII) is -NHC(=0)-, -C(=0)NH-, -NHS(=0)2-, -S(=0)2NH-, -
NHC(=0)NH-, -NH(C=0)0-, -0(C=0)NH-, or -NHS(=0)2NH-;
R3 of Formula (XXXIII) is Ci-C3alkyl, or C1-C3fluoroalkyl;
R4 of Formula (XXXIII) is -NHR5, -N(R5)2, -N-F(R5)3 or -0R5;
each R5 of -NHR5, -N(R5)2, -N-F(R5)3 and -0R5 is independently selected from
H, C1-C3alkyl,
C1-C3halo alkyl, C1-C3hetero alkyl and -Ci-C3alkyl-(C3-05cyclo alkyl);
or:
R3 and R5 of Formula (XXXIII) together with the atoms to which they are
attached form a
substituted or unsubstituted 5-7 membered ring;
or:
R3 of Formula (XXXIII) is bonded to a nitrogen atom of U to form a substituted
or
unsubstituted 5-7 membered ring;
R6 of Formula (XXXIII) is selected from -NHC(=0)R7, -C(=0)NHR7, -NHS(=0)2R7, -
S(=0)2NHR7; -NHC(=0)NHR7, -NHS(=0)2NHR7, -(Ci-C3alkyl)-NHC(=0)R7, -(Ci-
C3alkyl)-C(=0)NHR7, -(C 1 -C3alkyl)-NHS(=0)2R7, -(C 1 -C3alkyl)-S(=0)2NHR7; -
(C 1 -
C3alkyl)-NHC(=0)NHR7, -(Ci-C3alkyl)-NHS(=0)2NHR7, substituted or unsubstituted
C2-Cioheterocycloalkyl, or substituted or unsubstituted heteroaryl;
each R7 of -NHC(=0)R7, -C(=0)NHR7, -NHS(=0)2R7, -S(=0)2NHR7; -NHC(=0)NHR7, -
NHS (=0)2NHR7, -(Ci-C3alkyl)-NHC(=0)R7, -(Ci-C3alkyl)-C(=0)NHR7, -(Ci-C3alkyl)-
NHS (=0)2R7, -(C 1 -C3alkyl)-S(=0)2NHR7; -(C 1 -C3alkyl)-NHC(=0)NHR7, -(C 1 -
C3alkyl)-
NHS (=0)2NHR7 is independently selected from Ci-C6alkyl, Ci-C6haloalkyl, Ci-
C6heteroalkyl, a substituted or unsubstituted C3-Cl0cycloalkyl, a substituted
or
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unsubstituted C2- Cioheterocycloalkyl, a substituted or unsubstituted aryl, a
substituted or
unsubstituted heteroaryl, -C1-C6alkyl-(substituted or unsubstituted C3-
Ciocyclo alkyl), -
C1-C6alkyl- (substituted or unsubstituted C 2-C 10heteroc yclo alkyl, -C1-
C6alkyl-
(substituted or unsubstituted aryl), -C1-C6alkyl-(substituted or unsubstituted
heteroaryl), -
(CH2)p-CH(substituted or unsubstituted ary1)2, -(CH2)p-CH(substituted or
unsubstituted
heteroary1)2, -(CH2)p-CH(substituted or unsubstituted ary1)(substituted or
unsubstituted
heteroaryl), -(substituted or unsubstituted aryl)-(substituted or
unsubstituted aryl), -
(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl),
-(substituted
or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -
(substituted or
unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
p of R7 is 0, 1 or 2;
R8a, R8b, R8c, and R8d of c(R8a)(R8bµ
) and C(R8c)(R8(
) are independently selected from H, C 1-
C6alkyl, C1-C6fluoroalkyl, Ci-C6 alkoxy, C1-C6heteroalkyl, and substituted or
unsubstituted aryl;
or:
R8a and R8d are as defined above, and R8b and R8' together form a bond;
or:
R8a and R8d are as defined above, and R8b and R8' together with the atoms to
which they are
attached form a substituted or unsubstituted fused 5-7 membered saturated, or
partially
saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms
selected from
S, 0 and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a
substituted
or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3
heteroatoms
selected from S, 0 and N;
or:
R8' and R8d are as defined above, and R8a and R8b together with the atoms to
which they are
attached form a substituted or unsubstituted saturated, or partially saturated
3-7
membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected
from S, 0
and N;
or:
R8a and R8b are as defined above, and R8' and R8d together with the atoms to
which they are
attached form a substituted or unsubstituted saturated, or partially saturated
3 -7
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membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected
from S, 0
and N;
where each substituted alkyl, heteroalkyl, fused ring, spirocycle,
heterospirocycle, cycloalkyl,
heterocycloalkyl, aryl or heteroaryl is substituted with 1 -3 R9; and
each R9 of R8a, K=-= 813,
R8c and R8d is independently selected from halogen, -OH, -SH, (C=0),
CN, C1-C4a1kyl, C1-C4fluoroalkyl, Ci-C4 alkoxy, Ci-C4 fluoroalkoxy, -NH2, -
NH(Ci-
C4a1kyl), -NH(C1-C4a1ky1)2, - C(=0)0H, -C(=0)NH2, -C(=0)C1-C3alkyl, -
S(=0)2CH3, -
NH(C1-C4alkyl)-0H, -NH(C1-C4alkyl)-0-(C-C4alkyl), -0(C1-C4alkyl)-NH2; -0(C1-
C4alkyl)-NH-(C1-C4alkyl), and -0(C1-C4alkyl)-N-(C1-C4alky1)2, or two R9
together with
the atoms to which they are attached form a methylene dioxy or ethylene dioxy
ring
substituted or unsubstituted with halogen, -OH, or C1-C3alkyl.
[0216] In any of the compounds described herein, the ILM can have the
structure of
Formula (XXXIV), which is derived from the IAP ligands described in WO Pub.
No.
2013/071039, or an unnatural mimetic thereof:
4)(2 xl
\ W3
R3 Li w2
T.,
R4
(XXXIV),
wherein:
W1 of Formula (XXXIV) is selected from 0, S, N-R', or C(R8a)(R8b);
W2 of Formula (XXXIV) is selected from 0, S, N-R', or C(R8c8c ); provided that
W1 and
h
W2 are not both 0, or both S;
W3 of Formula (XXXIV) is selected from 0, S, N-R', or C(R8e)(R8f), providing
that the ring
comprising W1, W2, and W3 does not comprise two adjacent oxygen atoms or
sulfer
atoms;
R1 of Formula (XXXIV) is selected from H, C1-C6alkyl, C3-C6cycloalkyl, -C1-
C6alkyl-
(substituted or unsubstituted C3-C6cycloalkyl), substituted or unsubstituted
aryl,
substituted or unsubstituted heteroaryl, -C1-C6alkyl-(substituted or
unsubstituted aryl), or
¨C1-C6alkyl-(substituted or unsubstituted heteroaryl);
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when X1 of Formula (XXXIV) is 0, then X2 of Formula (XXXIV) is selected from
CR2cR2d
and N-RA, and X3 of Formula (XXXIV) is CR2aR2b;
or:
when X1 of Formula (XXXIV) is CH2, then X2 of Formula (XXIV) is selected from
0, N-RA,
S, S(0), or S(0)2, and X3 of Formula (XXXIV) is CR2aR2b;
or:
when X1 of Formula (XXXIV) is CR2e¨I( 2f and X2 of Formula (XXXIV) is CR2' 2d,
tc and R2'
and R2' together form a bond, and X3 of Formula (XXXIV) is CR2aR2b;
or:
X1 and X3 of Formula (XXXIV) are both CH2 and X2 of Formula (XXXIV) is C=0,
C=C(Rc)2, or C=NRc; where each Rc is independently selected from H, -CN, -OH,
alkoxy, substituted or unsubstituted C1-C6a1kyl, substituted or unsubstituted
C3-
C6cycloalkyl, substituted or unsubstituted C2-05heterocycloalkyl, substituted
or
unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl-
(substituted or
unsubstituted C3-C6c yclo alkyl), -C1-C6alkyl-(substituted or unsubstituted C2-
05heterocycloalkyl), -Ci-C6a1kyl-(substituted or unsubstituted aryl), or ¨C1-
C6alkyl-
(substituted or unsubstituted heteroaryl);
or:
X1 and X2 of Formula (XXXIV) are independently selected from C and N, and are
members
of a fused substituted or unsubstituted saturated or partially saturated 3-10
membered
cycloalkyl ring, a fused substituted or unsubstituted saturated or partially
saturated 3-10
membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10
membered aryl
ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring,
and X3 of
Formula (XXXIV) is CR2aR2b;
or:
X2 and X3 of Formula (XXXIV) are independently selected from C and N, and are
members
of a fused substituted or unsubstituted saturated or partially saturated 340
membered
cycloalkyl ring, a fused substituted or unsubstituted saturated or partially
saturated 3-10
membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10
membered aryl
ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring,
and X1 of
Formula (VLIV) is CR2122f;
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RA of N-RA is selected from H, Ci-C6alkyl, -C(=0)Ci-C2alkyl, substituted or
unsubstituted
aryl, or substituted or unsubstituted heteroaryl;
R2a, R2b, R2c, R2d, tc -=-= 2e,
and R2f of CR2'R2d, cR2aR2b and cRK.2erN2f
are independently selected
from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted
Ci-
C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or
unsubstituted
C2-05heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
heteroaryl, -Ci-C6a1kyl-(substituted or unsubstituted C3- C6cycloalkyl), -C1-
C6alkyl-
(substituted or unsubstituted C2-05heterocycloalkyl), -Ci-C6alkyl-(substituted
or
unsubstituted aryl), -Ci-C6alkyl-(substituted or unsubstituted heteroaryl) and
- C(=0)RB;
RB of -C(=0)RB is selected from substituted or unsubstituted Ci-C6alkyl,
substituted or
unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-
05heterocycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -
Ci-C6alkyl-
(substituted or unsubstituted C3- C6cycloalkyl), -C1-C6alkyl-(substituted or
unsubstituted
C2-05heterocycloalkyl), -C1-C6alkyl- (substituted or unsubstituted aryl), -Ci-
C6alkyl-
(substituted or unsubstituted heteroaryl), or - NRDRE;
RD and RE of NRDRE are independently selected from H, substituted or
unsubstituted Ci-
C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or
unsubstituted C2-
05heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
heteroaryl, -Ci-C6a1kyl- (substituted or unsubstituted C3-C6cycloalkyl), -C1-
C6alkyl-
(substituted or unsubstituted C2- C5heterocycloalkyl), -Ci-C6alkyl-
(substituted or
unsubstituted aryl), or -C1-C6alkyl- (substituted or unsubstituted
heteroaryl);
m of Formula (XXXIV) is selected from 0, 1 or 2;
-U- of Formula (XXXIV) is selected from -NHC(=0)-, -C(=0)NH-, -NHS(=0)2-, -
S(=0)2NH-, -NHC(=0)NH-, -NH(C=0)0-, -0(C=0)NH-, or -NHS(=0)2NH-;
R3 of Formula (XXXIV) is selected from Ci-C3alkyl, or C1-C3fluoroalkyl;
R4 of Formula (XXXIV) is selected from -NHR5, -N(R5)2, -N-F(R5)3 or -0R5;
each R5 of -NHR5, -N(R5)2, -N-F(R5)3 and -0R5 is independently selected from
H, Cl-C3alkyl,
C1-C3haloalkyl, C1-C3heteroalkyl and -Ci-C3alkyl-(C3-05cycloalkyl);
or:
R3 and R5 of Formula (XXXIV) together with the atoms to which they are
attached form a
substituted or unsubstituted 5-7 membered ring;
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or:
R3 of Formula (XXXIV) is bonded to a nitrogen atom of U to form a substituted
or
unsubstituted 5-7 membered ring;
R6 of Formula (XXXIV) is selected from -NHC(=0)R7, -C(=0)NHR7, -NHS(=0)2R7, -
S(=0)2NHR7; -NHC(=0)NHR7, -NHS(=0)2NHR7, -(Ci-C3alkyl)-NHC(=0)R7, -(Ci-
C3alkyl)-C(=0)NHR7, -(C 1 -C3alkyl)-NHS(=0)2R7, -(C 1 -C3alkyl)-S(=0)2NHR7; -
(C 1-
C3alkyl)-NHC(=0)NHR7, -(Ci-C3alkyl)-NHS(=0)2NHR7, substituted or unsubstituted
C2-Cioheterocycloalkyl, or substituted or unsubstituted heteroaryl;
each R7 of -NHC(=0)R7, -C(=0)NHR7, -NHS(=0)2R7, -S(=0)2NHR7; -NHC(=0)NHR7, -
NHS (=0)2NHR7, -(Ci-C3alkyl)-NHC(=0)R7, -(Ci-C3alkyl)-C(=0)NHR7, -(Ci-C3alkyl)-
NHS (=0)2R7, -(C 1 -C3alkyl)-S(=0)2NHR7; -(C 1 -C3alkyl)-NHC(=0)NHR7, -(C 1 -
C3alkyl)-
NHS (=0)2NHR7 is independently selected from Ci-C6alkyl, Ci-C6haloalkyl, Ci-
C6heteroalkyl, a substituted or unsubstituted C3-ClOcycloalkyl, a substituted
or
unsubstituted C2- Cioheterocycloalkyl, a substituted or unsubstituted aryl, a
substituted or
unsubstituted heteroaryl, -Ci-C6alkyl-(substituted or unsubstituted C3-Ciocyc
lo alkyl), -
Ci-C6alkyl- (substituted or unsubstituted C 2-C 10heteroc yclo alkyl, -C1-
C6alkyl-
(substituted or unsubstituted aryl), -Ci-C6alkyl-(substituted or unsubstituted
heteroaryl), -
(CH2)p-CH(substituted or unsubstituted ary1)2, -(CH2)p-CH(substituted or
unsubstituted
heteroary1)2, -(CH2)p-CH(substituted or unsubstituted ary1)(substituted or
unsubstituted
heteroaryl), -(substituted or unsubstituted aryl)-(substituted or
unsubstituted aryl), -
(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl),
-(substituted
or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -
(substituted or
unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
p of R7 is selected from 0, 1 or 2;
R8a, R8b, R8c, R8d, R8e, and R" of C(R8a)(R8b), C(R8c)(R8d) and C(R8e)(R8f)
are independently
selected from H, Ci-C6alkyl, Ci-C6fluoroalkyl, Ci-C6 alkoxy, Ci-C6heteroalkyl,
and
substituted or unsubstituted aryl;
or:
R8a, R8d, R8e, and R" of C(R8a)(R8b), C(R8c)(R8() and C(R8e)(R8f) are as
defined above, and
R8b and R8c together form a bond;
or:
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R8a, R8b, R8d, and R8f of C(R8a)(R8b), c(R8c)(R8db
) and C(R8e)(R8f) are as defined above, and
R8c and R8e together form a bond;
or:
R8a, R8d, R8e, and R8f of C(R8a)(R8b), c(R8c)(R8(b
) and C(R8e)(R8f) are as defined above, and
R8b and R8c together with the atoms to which they are attached form a
substituted or
unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic
ring or
heterocyclic ring comprising 1 -3 heteroatoms selected from S, 0 and N, a
substituted or
unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted
fused 5-10
membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, 0 and N;
or:
R8a, R8b, R8d, and R8f of C(R8a)(R8b), c(R8c)(R8(b
) and C(R8e)(R8f) are as defined above, and
R8c and R8e together with the atoms to which they are attached form a
substituted or
unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic
ring or
heterocyclic ring comprising 1 -3 heteroatoms selected from S, 0 and N, a
substituted or
unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted
fused 5-10
membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, 0 and N;
or:
R8c, R8d, R8e, and R8f of C(R8c)(R8() and C(R8e)(R8f)are as defined above, and
R8a and R8b
together with the atoms to which they are attached form a substituted or
unsubstituted
saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle
comprising
1 -3 heteroatoms selected from S, 0 and N;
or:
R8a, R8b, R8e, and R8f of C(R8a)(R8b) and C(R8e)(R8f) are as defined above,
and R8c and R8d
together with the atoms to which they are attached form a substituted or
unsubstituted
saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle
comprising
1-3 heteroatoms selected from S, 0 and N;
or:
R8a, R8b, R8c, and R8d of C(R8a)(R8b) and C(R8c)(R8() are as defined above,
and R8e and R8f
together with the atoms to which they are attached form a substituted or
unsubstituted
saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle
comprising
1-3 heteroatoms selected from S, 0 and N;
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or:
where each substituted alkyl, heteroalkyl, fused ring, spirocycle,
heterospirocycle, cycloalkyl,
heterocycloalkyl, aryl or heteroaryl is substituted with 1 -3 R9; and
each R9 Of R8a, R8b, R8c, R8d R8e, and R8 tc8f
a
is independently selected from halogen, -OH, -SH,
(C=0), CN, C1-C4a1kyl, C1-C4fluoroalkyl, Ci-C4 alkoxy, Ci-C4 fluoroalkoxy, -
NH2, -
NH(Ci- C4a1kyl), -NH(C1-C4alky1)2, - C(=0)0H, -C(=0)NH2, -C(=0)C1-C3alkyl, -
S(=0)2CH3, -NH(Ci-C4alkyl)-0H, -NH(Ci-C4alkyl)-0-(C-C4alkyl), -0(Ci-C4alkyl)-
NH2;
-0(Ci-C4alkyl)-NH-(C1-C4alkyl), and -0(Ci-C4alkyl)-N-(C1-C4alky1)2, or two R9
together
with the atoms to which they are attached form a methylene dioxy or ethylene
dioxy ring
substituted or unsubstituted with halogen, -OH, or C1-C3alkyl.
[0217]
In any of the compounds described herein, the ILM can have the structure of
Formula (XXXV), (XXXVI) or (XXXVII), which is derived from the IAP ligands
described in
Vamos, M., et al., Expedient synthesis of highly potent antagonists of
inhibitor of apoptosis
proteins (IAPs) with unique selectivity for ML-IAP, ACS Chem. Biol., 8(4), 725-
32 (2013), or an
unnatural mimetic thereof:
0 R2 X 11
R3
N N R4
0
0 N
n r. 0,
(xxxv),
0
11 ,
N- N ,
H =
0 :
H
(XXXVI),
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R2 nk + X H
IA 9 I \,-
.1- 1\ \
N L....-
r-v---- '
C::----- ' N
H
n fa 0, 1
(XXXVII),
wherein:
R2 of Formulas (XXXV) and (XXXVII) are independently selected from H or ME;
R3 and R4 of Formula (XXXV) are independently selected from H or ME;
X of Formulas (XXXV) and (XXXVII) is independently selected from 0 or S; and
R1 of Formulas (XXXV) and (XXXVII) is selected from:
(1101 OP 0 Sp 0
* * *
tio *
[0218] In a particular embodiment, the ILM has a structure according to
Formula
(XXXVIII):
Ei 0 R3 X¨X.
I X
i\jN)IN(
= Ho.
.., H
(XXXVIII),
wherein R3 and R4 of Formula (XXXVIII) are independently selected from H or
ME;
X ¨X.
I X
N
*'
* =
is a 5-member heteocycle selected from:
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S s
R \
NR ,µ,õN>
* .
' X
* ,NR
*
[0219] In a particular embodiment, the of Formula (XXXVIII) is *
[0220] In a particular embodiment, the ILM has a structure and attached to
a linker group
L as shown below:
, 0
r---?.
H 11 r\?ir
N 00
...
- H
_ 0 NH
0
411W
[0221] In any of the compounds described herein, the ILM can have the
structure of
Formula (XXXIX) or (XL), which is based on the IAP ligands described in
Hennessy, EJ, et al.,
Discovery of aminopiperidine-based Smac mimetics as IAP antagonists, Bioorg.
Med. Chem.
Lett., 22(4), 1960-4 (2012), or an unnatural mimetic thereof:
0 RI R'''
N A= 1 1,k,
: H i n
_
R'I
2 (XXXIX),
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0 R1 R2
, H
: H
u,
R' 3
(XL),
wherein:
R1 of Formulas (XXXIX) and (XL) is selected from:
1-------;
,_.,....õ.õ.
4: 1
R2 of Formulas (XXXIX) and (XL) is selected from H or Me;
R3 of Formulas (XXXIX) and (XL) is selected from:
$,¨,
\ 0 ,
n izt 0,1, 2
0
/
in\
0, I 40" e==N n . 0 I 2
---------------------------- ...' \
nO1
0 0 /
.. .4 ,.,.../ z Ott n = 0, 1 v ,
=
,
X of is selected from H, halogen, methyl, methoxy, hydroxy, nitro or
trifluoromethyl.
[0222] In any of the compounds described herein, the ILM can have the
structure of and
be chemically linked to the linker as shown in Formula (XLI) or (XLII), or an
unnatural mimetic
thereof:
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N
RIõrõ,,L0 Linker
FIN
(XLI),
N
FN
R1õ,r-L H
0 Linker
NHo
HN
(XLII).
[0223] In any of the compounds described herein, the ILM can have the
structure of
Formula (XLIII), which is based on the IAP ligands described in Cohen, F, et
al., Orally
bioavailable antagonists of inhibitor of apoptosis proteins based on an
azabicyclooctane scaffold,
J. Med. Chem., 52(6), 1723-30 (2009), or an unnatural mimetic thereof:
0 tr
N N
N
H 0 H
HN
0 (XLIII)
wherein:
R1 of Formulas (XLIII) is selected from:
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1
...... ...,-;-,-L,
,
6,-------,, --õ,
x - ,
,....--- ....õ--
X of is selected from H, fluoro, methyl or methoxy.
[0224] In a particular embodiment, the ILM is represented by the following
structure:
0 M
NH 11 tii,, N
z H Ff
- 0 ...
,
H N
/
0 'WI.
[0225] In a particular embodiment, the ILM is selected from the group
consisting of, and
which the chemical link between the ILM and linker group L is shown:
H
i \
- -,
N ill Ht,41
...-- 0
0 I
HN) ','
1
; and
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....ii., - N
¨ 0 ..=
HN
)----- I
0
[0226] In any of the compounds described herein, the ILM is selected from
the group
consisting of the structures below, which are based on the TAP ligands
described in Asano, M, et
al., Design, sterioselective synthesis, and biological evaluation of novel tri-
cyclic compounds as
inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18):
5725-37 (2013),
or an unnatural mimetic thereof:
(0.
(47
0 Yirs N 0 N
H ii H
' N 0
: H H
¨ 0 , 0 N 0
t 0 N ----
H 1-1
or .
[0227] In a particular embodiment, the ILM is selected from the group
consisting of, and
which the chemical link between the ILM and linker group L is shown:
. i,¨;õ L
¨NH 0 ( )
- RN ----- ,,01.--c ' ......L.;:._ ilr
NH
\ '' = ¨L----- I. N
N N --
, . co
OF i----1 1::140,,IAzo, 0
0
HN,-<, 0 OTNH
HN ' "
; and 1
[0228] In any of the compounds described herein, the ILM can have the
structure of
Formula (XLIV), which is based on the TAP ligands described in Asano, M, et
al., Design,
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sterioselective synthesis, and biological evaluation of novel tri-cyclic
compounds as inhibitor of
apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37
(2013), or an
unnatural mimetic thereof:
X
0
.N N
XJ
N 0
H
0
0 N
(XLIV),
wherein X of Formula (XLIV) is one or two sub stituents independently selected
from H, halogen
or cyano.
[0229] In any of the compounds described herein, the ILM can have the
structure of and
be chemically linked to the linker group L as shown in Formula (XLV) or
(XLVI), or an
unnatural mimetic thereof:
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X L
\ /
H 0 N
........., 0 ,
0 NO 41111
H
(XLV) or
X
,e(/-5 0
----
(r,
ra...r2Cy NF1
0
0
0, NH
HN '1
i 1
(XLVI),
wherein X of Formula (XLV) and (XLVI) is one or two substituents independently
selected from
H, halogen or cyano, and ; and L of Formulas (XLV) and (XLVI) is a linker
group as described
herein.
[0230] In any of the compounds described herein, the ILM can have the
structure of
Formula (XLVII), which is based on the IAP ligands described in Ardecky, RJ,
et al., Design,
sysnthesis and evaluation of inhibitor of apoptosis (IAP) antagonists that are
highly selective for
the BIR2 domain of XIAP, Bioorg. Med. Chem., 23(14): 4253-7 (2013), or an
unnatural mimetic
thereof:
0 0
H 41 H
(XL VII),
wherein:
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0
H
N
,,, =õ.....-11-,õ
R1 of Formula (XLVII) is a natural or unnatural amino acid; and
*
41 kiliVe
: õII Al IP
R2 of Formula (XLVII) is selected from: .
[0231] In any of the compounds described herein, the ILM can have the
structure of and
be chemically linked to the linker group L as shown in Formula (XLVIII) or
(XLIX), or an
unnatural mimetic thereof:
,...- -,.... -,;...õ
1 --21-----2---- L
NH
--(
2, HN' 'IR'._, 0,. NH
I
HN -"' '''?
(XLVIII), or
0 0
Hu HHH
Xr z
- 0 R ......"
(XLIX),
0
H
,N õI,
R1 of Formulas (XLVIII) and (XLIX) is a natural or unnatural amino acid;
and
L of Formula (XLVIII) and (XLIX) is a linker group as described herein.
[0232] In any of the compounds described herein, the ILM can have the
structure
selected from the group consisting of, which is based on the IAP ligands
described in Wang, J, et
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al., Discovery of novel second mitochondrial-derived activator of caspase
mimetics as selective
inhibitor or apoptosis protein inhibitors, J. Pharmacol. Exp. Ther., 349(2):
319-29 (2014), or an
unnatural mimetic thereof:
OH
NH
1
0
, and
[0233] In any of the compounds described herein, the ILM has a structure
according to
Formula (L), which is based on the TAP ligands described in Hird, AW, et al.,
Structure-based
design and synthesis of tricyclic TAP (Inhibitors of Apoptosis Proteins)
inhibitors, Bioorg. Med.
Chem. Lett., 24(7): 1820-4 (2014), or an unnatural mimetic thereof:
"
9
N
N N H
0
(L),
wherein R of Formula (L) is selected from the group consisting of:
0 rc-hi
111
I 0 n 0
,
e- z
HET
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r .µ....õ, ,
: x
...õ.õ .,.....,
. ....,õ ...,,,
R,
R1 of is selected from H or Me;
s -
R2 of is selected from alkyl or cycloalkyl;
0 n Ci 0 ...X.- . ,
%---7¨ X
_______________________________________________________ X
X of *
is 1-2 substitutents
independently selected from halogen, hydroxy, methoxy, nitro and
trifluoromethyl
0
'N'Il.,
Z of is 0 or NH;
HET
HET of ' is mono- or fused bicyclic heteroaryl; and
--- of Formula (L) is an optional double bond.
[0234] In a particular embodiment, the ILM of the compound has a chemical
structure
selected from the group consisting of:
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H j?
1\11\1.(N3.
H 0 H 0 0 NH 1.
NJI\IrN11-.
E H F S
)--:=N
N----A
0 /00
(o
N
H V
N'Cil )7--N
H W Iri0
N/N 0
0
E H
o o)---NH 0 NH
,
1\1::N
F F
0
H
N N
FN1 o '?C--- )
N
N,', 1\1) .
0
E H
- 0
0 N's 0
t
H i
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\NH
\NH
0 ..." H- __ 0
HN N
...."110
0
0.--"4440 N
S
S õi-0
N
,-
\>
0 / 0
,
\NH \NH
11.0 0
HN HN
=õõ,,,,
S N 1 S>....a
....N
N N
,---- .---'
, .
Exemplary MLMs
[0235] In certain additional embodiments, the MLM of the bifunctional
compound
comprises chemical moieties such as substituted imidazolines, substituted
spiro-indolinones,
substituted pyrrolidines, substituted piperidinones, substituted
morpholinones, substituted
pyrrolopyrimidines, substituted imidazolopyridines, substituted
thiazoloimidazoline, substituted
pyrrolopyrrolidinones, and substituted isoquinolinones.
[0236] In additional embodiments, the MLM comprises the core structures
mentioned
above with adjacent bis-aryl substitutions positioned as cis- or trans-
configurations.
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[0237] In still additional embodiments, the MLM comprises part of
structural features as
in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272, MK-8242, and NVP-CGM-
097, and analogs or derivatives thereof.
[0238] In certain preferred embodiments, MLM is a derivative of
substituted imidazoline
represented as Formula (A-1), or thiazoloimidazoline represented as Formula (A-
2), or spiro
indolinone represented as Formula (A-3), or pyrollidine represented as Formula
(A-4), or
piperidinone / morphlinone represented as Formula (A-5), or isoquinolinone
represented as
Formula (A-6), or pyrollopyrimidine / imidazolopyridine represented as Formula
(A-7), or
pyrrolopyrrolidinone / imidazolopyrrolidinone represented as Formula (A-8).
R7
R2 ,R4 ,R6
R2 4 )R
R1CN8
N
R
N
R3 R3
Formula (A-1) Formula (A-2)
.1311
-10
R12
A "Ri3
R2'Q.""Rizt
R1A" N R15
Formula (A-3) Formula (A-4)
191
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0
0
R16 .,J3
R18 R20
Ri 7 N
R-11 )X
R3- R4 R19 R21
R2
Formula (A-5) Formula (A-6)
R22 z .....-y 0 Y R27
II
¨R25
/
Nr-,N ,N N
R28 . R
, R3 26
R23 R24
R2
Formula (A-7) Formula (A-8)
wherein above Formula (A-1) through Formula (A-8):
X of Formula (A-1) through Formula (A-8) is selected from the group consisting
of carbon,
oxygen, sulfur, sulfoxide, sulfone, and N-Ra;
Ra is independently H or an alkyl group with carbon number 1 to 6;
Y and Z of Formula (A-1) through Formula (A-8) are independently carbon or
nitrogen;
A, A' and A" of Formula (A-1) through Formula (A-8) are independently selected
from C, N,
0 or S, can also be one or two atoms forming a fused bicyclic ring, or a 6,5-
and 5,5-fused
aromatic bicyclic group;
R1, R2 of Formula (A-1) through Formula (A-8) are independently selected from
the group
consisting of an aryl or heteroaryl group, a heteroaryl group having one or
two heteroatoms
independently selected from sulfur or nitrogen, wherein the aryl or heteroaryl
group can be
mono-cyclic or bi-cyclic, or unsubstituted or substituted with one to three
substituents
independently selected from the group consisting of:
halogen, -CN, Cl to C6 alkyl group, C3 to C6 cycloalkyl, -OH, alkoxy with 1 to
6
carbons, fluorine substituted alkoxy with 1 to 6 carbons, sulfoxide with 1 to
6 carbons,
sulfone with 1 to 6 carbons, ketone with 2 to 6 carbons, amides with 2 to 6
carbons,
and dialkyl amine with 2 to 6 carbons;
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R3, R4 of Formula (A-1) through Formula (A-8) are independently selected from
the group
consisting of H, methyl and Cl to C6 alkyl;
Rs of Formula (A-1) through Formula (A-8) is selected from the group
consisting of an aryl or
heteroaryl group, a heteroaryl group having one or two heteroatoms
independently selected
from sulfur or nitrogen, wherein the aryl or heteroaryl group can be mono-
cyclic or bi-
cyclic, or unsubstituted or substituted with one to three substituents
independently selected
from the group consisting of:
halogen, -CN, Cl to C6 alkyl group, C3 to C6 cycloalkyl, -OH, alkoxy with 1 to
6
carbons, fluorine substituted alkoxy with 1 to 6 carbons, sulfoxide with 1 to
6 carbons,
sulfone with 1 to 6 carbons, ketone with 2 to 6 carbons, amides with 2 to 6
carbons,
dialkyl amine with 2 to 6 carbons, alkyl ether (C2 to C6), alkyl ketone (C3 to
C6),
morpholinyl, alkyl ester (C3 to C6), alkyl cyanide (C3 to C6);
R6 of Formula (A-1) through Formula (A-8) is H or ¨C(=0)Rb, wherein
Rb of Formula (A-1) through Formula (A-8) is selected from the group
consisting of alkyl,
cycloalkyl, mono-, di- or tri-substituted aryl or heteroaryl, 4-morpholinyl, 1-
(3-
oxopiperazunyl), 1-piperidinyl, 4-N-Re-morpholinyl, 4-Re-l-piperidinyl, and 3-
Re-1-
piperidinyl, wherein
Re of Formula (A-1) through Formula (A-8) is selected from the group
consisting of alkyl,
fluorine substituted alkyl, cyano alkyl, hydroxyl-substituted alkyl,
cycloalkyl,
alkoxyalkyl, amide alkyl, alkyl sulfone, alkyl sulfoxide, alkyl amide, aryl,
heteroaryl,
mono-, bis- and tri-substituted aryl or heteroaryl, CH2CH2Rd, and CH2CH2CH2Rd,
wherein
Rd of Formula (A-1) through Formula (A-8) is selected from the group
consisting of
alkoxy, alkyl sulfone, alkyl sulfoxide, N-substituted carboxamide, -NHC(0)-
alkyl, -
NH-S02-alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R7 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of H, Cl to
C6 alkyl, cyclic alkyl, fluorine substituted alkyl, cyano substituted alkyl, 5-
or 6-membered
hetero aryl or aryl, substituted 5- or 6-membered hetero aryl or aryl;
R8 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of ¨Re-C(0)-
W, -Re-alkoxy, -Re-aryl, -Re-heteroaryl, and -Re-C(0)-W-C(0)-Rg, wherein:
Re of Formula (A-1) through Formula (A-8) is an alkylene with 1 to 6 carbons,
or a bond;
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Rf of Formula (A-1) through Formula (A-8) is a substituted 4- to 7-membered
heterocycle;
Rg of Formula (A-1) through Formula (A-8) is selected from the group
consisting of aryl,
hetero aryl, substituted aryl or heteroaryl, and 4- to 7-membered heterocycle;
R9 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of a mono-,
bis- or tri-substituent on the fused bicyclic aromatic ring in Formula (A-3),
wherein the
substitutents are independently selected from the group consistin of halogen,
alkene, alkyne,
alkyl, unsubstituted or substituted with Cl or F;
Rio of Formula (A-1) through Formula (A-8) is selected from the group
consistin of an aryl or
heteroaryl group, wherein the heteroaryl group can contain one or two
heteroatoms as
sulfur or nitrogen, aryl or heteroaryl group can be mono-cyclic or bi-cyclic,
the aryl or
heteroaryl group can be unsubstituted or substituted with one to three
substituents,
including a halogen, F, Cl, -CN, alkene, alkyne, Cl to C6 alkyl group, Cl to
C6 cycloalkyl,
-OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1 to 6
carbons, sulfoxide
with 1 to 6 carbons, sulfone with 1 to 6 carbons, ketone with 2 to 6 carbons;
Rii of Formula (A-1) through Formula (A-8) is -C(0)-N(Rh)(121), wherein Rh and
12' are
selected from groups consisting of the following:
H; optionally substituted linear or branched Cl to C6 alkyl; alkoxy
substituted alkyl;
mono- and di-hydroxy substituted alkyl (e.g., a C3 to C6), sulfone substituted
alkyl;
optionally substituted aryl; optionally substituted heteraryl; mono-, bis- or
tri-
substituted aryl or heteroaryl; phenyl-4-carboxylic acid; substituted phenyl-4-
carboxylic acid, alkyl carboxylic acid; optionally substituted heteroaryl
carboxylic
acid; alkyl carboxylic acid; fluorine substituted alkyl carboxylic acid;
optionally
substituted cycloalky, 3-hydroxycyclobutane, 4-hydroxycyclohehexane, aryl
substituted cycloalkyl; heteroaryl substituted cycloalkyl; or Rh and Ri taken
together
form a ring;
R12 and R13 of Formula (A-1) through Formula (A-8) are independently selected
from H, lower
alkyl (C1 to C6), lower alkenyl (C2 to C6), lower alkynyl (C2 to C6),
cycloalkyl (4, 5 and
6-membered ring), substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, 5- and 6-
membered aryl and heteroaryl, R12 and R13 can be connected to form a 5- and 6-
membered ring with or without substitution on the ring;
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R14 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl,
heteroaryl, substituted
heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted
cycloalkyl,
cycloalkenyl and substituted cycloalkenyl;
R15 of Formula (A-1) through Formula (A-8) is CN;
R16 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of C1-6
alkyl, C1-6 cycloalkyl, C2-6 alkenyl, C1-6 alkyl or C3-6 cycloalkyl with one
or multiple
hydrogens replaced by fluorine, alkyl or cycloalkyl with one CH2 replaced by
S(=0), -S, or
-S(=0)2, alkyl or cycloalkyl with terminal CH3 replaced by
S(=0)2N(alkyl)(alkyl), -
C(=0)N(alkyl)(alkyl), -N(alkyl)S(=0)2(alkyl), -C(=0)2(allkyl), -0(alkyl), C1-6
alkyl or
alkyl-cycloalkyl with hydron replaced by hydroxyl group, a 3 to 7 membered
cycloalkyl or
heterocycloalkyl, optionally containing a -(C=0)- group, or a 5 to 6 membered
aryl or
heteroaryl group, which heterocycloalkyl or heteroaryl group can contain from
one to three
heteroatoms independently selected from 0, N or S, and the cycloalkyl,
heterocycloalkyl,
aryl or heteroaryl group can be unsubstituted or substituted with from one to
three
substituents independently selected from halogen, C1-6 alkyl groups,
hydroxylated C1-6
alkyl, C1-6 alkyl containing thioether, ether, sulfone, sulfoxide, fluorine
substituted ether
or cyano group;
R17 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of
(CH2)nC(0)NRkR1, wherein Rk and RI are independently selected from H, C1-6
alkyl,
hydrxylated C1-6 alkyl, C1-6 alkoxy alkyl, C1-6 alkyl with one or multiple
hydrogens
replaced by fluorine, C1-6 alkyl with one carbon replaced by S(0), S(0)(0), C1-
6
alkoxyalkyl with one or multiple hydrogens replaced by fluorine, C1-6 alkyl
with hydrogen
replaced by a cyano group, 5 and 6 membered aryl or heteroaryl, aklyl aryl
with alkyl
group containing 1-6 carbons, and alkyl heteroaryl with alkyl group containing
1-6 carbons,
wherein the aryl or heteroaryl group can be further substituted;
R18 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of
substituted aryl, heteroaryl, alkyl, cycloalkyl, the substitution is
preferably -N(C1-4
alkyl)(cycloalkyl), -N(C1-4 alkyl)alkyl-cycloalkyl, and -N(C1-4 alkyl)
[(alkyl)-
(heterocycle-substituted)-cycloalkyl];
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R19 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of aryl,
heteroaryl, bicyclic heteroaryl, and these aryl or hetroaryl groups can be
substituted with
halogen, C1-6 alkyl, C1-6 cycloalkyl, CF3, F, CN, alkyne, alkyl sulfone, the
halogen
substitution can be mon- bis- or tri-substituted;
R20 and R21 of Formula (A-1) through Formula (A-8) are independently selected
from C1-6
alkyl, C1-6 cycloalkyl, C1-6 alkoxy, hydoxylated C1-6 alkoxy, and fluorine
substituted Cl-
6 alkoxy, wherein R20 and R21 can further be connected to form a 5, 6 and 7-
membered
cyclic or heterocyclic ring, which can further be substituted;
R22 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of H, C1-6
alkyl, C1-6 cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse
amide,
sulfonamide, reverse sulfonamide, N-acyl urea, nitrogen-containing 5-membered
heterocycle, the 5-membered heterocycles can be further substituted with C1-6
alkyl,
alkoxy, fluorine-substituted alkyl, CN, and alkylsulfone;
R23 of Formula (A-1) through Formula (A-8) is selected from aryl, heteroaryl, -
0-aryl, -0-
heteroaryl, -0-alkyl, -0-alkyl-cycloalkyl, -NH-alkyl, -NH-alkyl-cycloalkyl, -
N(H)-aryl, -
N(H)-heteroaryl, -N(alkyl)-aryl, -N(alkyl)-heteroaryl, the aryl or heteroaryl
groups can be
substituted with halogen, C1-6 alkyl, hydoxylated C1-6 alkyl, cycloalkyl,
fluorine-
substituted C1-6 alkyl, CN, alkoxy, alkyl sulfone, amide and sulfonamide;
R24 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of ¨CH2-
(C1-6 alkyl), -CH2-cycloalkyl, -CH2-aryl, CH2-heteroaryl, where alkyl,
cycloalkyl, aryl
and heteroaryl can be substituted with halogen, alkoxy, hydoxylated alkyl,
cyano-
substituted alkyl, cycloalyl and substituted cycloalkyl;
R25 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of C1-6
alkyl, C1-6 alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl,
aryl, heteroaryl,
substituted aryl or heteroaryl, 5,6,and 7-membered nitrogen-containing
saturated
heterocycles, 5,6-fused and 6,6-fused nitrogen-containing saturated
heterocycles and these
saturated heterocycles can be substituted with C1-6 alkyl, fluorine-
substituted C1-6 alkyl,
alkoxy, aryl and heteroaryl group;
R26 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of C1-6
alkyl, C3-6 cycloalkyl, the alkyl or cycloalkyl can be substituted with ¨OH,
alkoxy,
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fluorine-substituted alkoxy, fluorine-substituted alkyl, -NH2, -NH-alkyl, NH-
C(0)alkyl, -
NH-S(0)2-alkyl, and -S(0)2-alkyl;
R27 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of aryl,
heteroaryl, bicyclic heteroaryl, wherein the aryl or heteroaryl groups can be
substituted
with C1-6 alkyl, alkoxy, NH2, NH-alkyl, halogen, or -CN, and the substitution
can be
independently mono-, bis- and tri-substitution;
R28 of Formula (A-1) through Formula (A-8) is selected from the group
consisting of aryl, 5
and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl, saturated
heterocycle such as
piperidine, piperidinone, tetrahydropyran, N-acyl-piperidine, wherein the
cycloalkyl,
saturated heterocycle, aryl or heteroaryl can be further substituted with ¨OH,
alkoxy,
mono-, bis- or tri-substitution including halogen, -CN, alkyl sulfone, and
fluorine
substituted alkyl groups; and
Ri- of Formula (A-1) through Formula (A-8) is selected from the group
consisting of H, alkyl,
aryl substitituted alkyl, alkoxy substituted alkyl, cycloalkyl, aryl-
substituted cycloalkyl,
and alkoxy substituted cycloalkyl.
[0239] In certain embodiments, the heterocycles in Rf and Rg of Formula
(A-1) through
Formula (A-8) are substituted pyrrolidine, substituted piperidine, substituted
piperizine.
[0240] More specifically, non-limiting examples of MLMs 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.
[0241] Using MLM in Formula A-1 through A-8, the following PROTACs can be
prepared to target a particular protein for degradation, where 'L" is a
connector (i.e. a linker
group), and "PTM" is a ligand binding to a target protein.
[0242] In certain embodiments, the description provides a bifunctional
molecule
comprising a structure selected from the group consisting of:
R7
f 8
R2 ,R4 ,R6 R2 F4 /R
-
--' N
PTM-L R1N-k---N R5 PTM-Lf R1N-k ----S I
-:3 N '143 N
,
,
Formula (A-9) Formula (A-10)
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Rii
= Ri" _ .. Iii ,R1
D
PTM¨L "
õ,...C..1" N
¨io
PTM¨L¨ R2...Q."R14
¨E A'),
I1 R15
Formula (A-11) Formula (A-12)
0
0
'N
Ri7 k 1 t R18N R20 i 1
PTM-4 i Ri'k<X i R4
PTM¨L
Rig R21
R2
Formula (A-13) Formula (A-14)
PTM¨L¨
R22 Z.,.--1(\ Y R--
_
PTM_Lf R 'N ----NsR
N,rN
28 k
_ -- 26
R23 24 R3
,and ,
Formula (A-15) Formula (A-16)
wherein X, Ra, Y, Z, A, A', A", Ri, R2, R3, R4, R5, R6, Rb, 12', Rd, R7, Re,
Rf, Rg, R9, Rio, R11, R12,
Ri3, Ri4, Ri5, R16, R17, Rk, RI, R18, R19, R20, R21, R22, R23,R24, R25, R26,
R27, R28, and Ri- are as
defined herein with regard to Formulas (A-1) through (A-8).
[0243] In certain embodiments, the description provides bifunctional or
chimeric
molecules with the structure: PTM-L-MLM, wherein PTM is a protein target
binding moiety
coupled to an MLM by L, wherein L is a bond (i.e., absent) or a chemical
linker. In certain
embodiments, the MLM has a structure selected from the group consisting of A-1-
1, A-1-2, A-1-
3, and A-1-4:
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R1' R1'
(I) N R3'
N R4 H N \ = '
PTM-L- - R5,
c....,,
\ I / PTM-L- R5
(I) N R3'
I
( / 10
R4' -
(:) R6\7'
R6' - '
Ri R2' _
A-1-1 A-1-2
(N ____________________________ \ r\li R4 _ N) \ -R,t -
'
N
PTM-L
I ( / o PTM-L-
/ o
\ I- -
R2' R2'
A-1-3 A-1-4
wherein:
R1' and R2' of Formulas A-1-1 throught A-1-4 (i.e., A-1-1, A-1-2, A-1-3, and A-
1-4) are
independently selected from the group consisting of F, Cl, Br, I, acetylene,
CN, CF3 and
NO2;
R3' is selected from the group consisting of -OCH3, -OCH2CH3, -OCH2CH2F, -
OCH2CH2OCH3, and -OCH(CH3)2;
R4' of Formulas A-1-1 throught A-1-4 is selected from the group consisting of
H, halogen, -
CH3, -CF3, -OCH3, -C(CH3)3, -CH(CH3)2, -cyclopropyl, -CN, -C(CH3)20H, -
C(CH3)20CH2CH3, -C(CH3)2CH2OH, -
C(CH3)2CH2OCH2CH3,
C(CH3)2CH2OCH2CH2OH, -C(CH3)2CH2OCH2CH3, -C(CH3)2CN, -C(CH3)2C(0)CH3, -
C(CH3)2C(0)NHCH3, -C(CH3)2C(0)N(CH3)2, -SCH3, -SCH2CH3, -S(0)2CH3, -
S(02)CH2CH3, -NHC(CH3)3, -N(CH3)2, pyrrolidinyl, and 4-morpholinyl;
R5' of Formulas A-1-1 throught A-1-4 is selected from the group consisting of
halogen, -
cyclopropyl, -S(0)2CH3, -S(0)2CH2CH3, 1-pyrrolidinyl, -NH2, -N(CH3)2, and -
NHC(CH3)3; and
R6' of Formulas A-1-1 throught A-1-4 is selected from the structures presented
below where
the linker connection point is indicated as
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Beside R6' as the point for linker attachment, R4' can also serve as the
linker attachment
position. In the case that R4' is the linker connection site, linker will be
connected to the terminal
atom of R4' groups shown above.
[0244] In certain embodiments, the linker connection position of Formulas
A-1-1
throught A-1-4 is at least one of R4' or R6' or both.
[0245] In certain embodiments, R6' of Formulas A-1-1 throught A-1-4 is
independently
selected from the group consisting of H,
1
F
\./ OH F
õ *
C<F ro-
.......* , *
, , , , ,
, ,
K
1 1 1 , _ T -
N N N N
F
Y y`OH yF y(F y-0
0,* 0,* 0,*
, , , , ,
N
, ,
N
-T-
II
N
C 1O ( ) (N ) ( )
N N N
* * 1::* 0- I
--S
1/ 0 N
0 1
C, ,
1 --- .
__
N N rN EN
\-----(
N N N N
x
0-*
0 0
, , , , ,
1
I - 1 i
T -
N Al
i N
N
\
Y
*
o* " CY
F F 0-*
0
, ,
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1 i 1 _ I
N N
C
r N (N L ) ) ====,N,---
N aN
.=%".....LN
y 0 y ON
*
* 1
, , , , and wherein "*" indicates the
point of
attachment of the linker.
[0246] In certain embodiments, the linker of Formula A-4-1 through A-4-6
is attached to
at least one of R1', R2', R3', R4', R5', R6', or a combination thereof.
[0247] In certain embodiments, the description provides bifunctional or
chimeric
molecules with the structure: PTM-L-MLM, wherein PTM is a protein target
binding moiety
coupled to an MLM by L, wherein L is a bond (i.e., absent) or a chemical
linker. In certain
embodiments, the MLM has a structure selected from the group consisting of A-4-
1, A-4-2, A-4-
3, A-4-4, A-4-5, and A-4-6:
z-)12' Z x,-,/ Ri 2'
% _________________________________________________________ 1\1
R10\
N -R11' NH NH
0=
R7' ,õ R1" 0 ='.. R " C R
R7' -õ 1
- R7' -õ1"
\ N
\ - N
- /
-
z
PTM-L- .4,...--;,õ... N
PTM-L- .....c.,,,, N 1
PTM-L- .,...4,7< N
====;:õ.õ,, \=-= _ ''--....,,
- - -
R8' R8 R8'
A-4-1 A-4-2 A-4-3
z i=i\j,Rii IR,,,z 12'
/ z /=µ/R12'
NI\ N N
/( /(N1
NH NH
O=n-/ NH
R7' -õR1" R7' - --;õ R1"
R7' \0=('-... N,R1"
PTM-L- 4..x.,--..,, N 1PTM-L- .4.:-....S.,: N z
..z....
I 1 PTM-L- .iõ.7.,õ N
1
-====...,,,, y .......õ( _
- - R8 .....õ.õ...,),,,-
- ' -
R8'
A-4-4 A-4-5
A-4-6
wherein:
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R7' of Formula A-4-1 through A-4-6 (i.e., A-4-1, A-4-2, A-4-3, A-4-4, A-4-5,
and A-4-6) is
one or more (e.g., 1, 2, 3, or 4) halogens;
R8' of Formula A-4-1 through A-4-6 is one or more groups (e.g., 1, 2, 3, or 4
groups)
selected from the group consisting of H, -F, -Cl, -Br, -I, -CN, -NO2,
ethylnyl, cyclopropyl,
methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -OH, other C1-6
alkyl,
other C1-6 alkenyl, and C1-6 alkynyl, mono-, di- or tri-substituted;
R9' of Formula A-4-1 through A-4-6 is selected from the group consisting of
alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
aryl,
substituted aryl, hetero aryl, substituted heteroaryl, cycloalkyl, substituted
cycloalkyl,
alkenyl, and substituted cycloalkenyl;
Z of Formula A-4-1 through A-4-6 is selected from the group consistin of H, -
OCH3, -
OCH2CH3, and halogen;
R10' and R11' of Formula A-4-1 through A-4-6 are each independently selected
from the
group consisting of H, (CH2)n-R', (CH2)n-NR'R", (CH2)n-NR'COR", (CH2)n-
NR'SO2R",
(CH2)n-COOH, (CH2)n-COOR', (CH)n-CONR'R", (CH2)n-OR', (CH2)n-SR', (CH2)n-SOW,
(CH2)n-CH(OH)-W, (CH2)n-COR', (CH2)n-S 02R', (CH2)n-SONR'R", (CH2)n-SO2NR'R",
(CH2CH20)m-(CH2)n-R', (CH2CH20)m-(CH2)n-OH,
(CH2CH20)m-(CH2)n-OR',
(CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m(CH2)n-
NR'S 02R", (CH2CH20)m(CH2)n-COOH, (CH2CH20)m(CH2)n-COOR', (CH2CH20)m-
(CH2)n-CONR'R", (CH2CH20)m-(CH2)n-S 02R',
(CH2CH20)m-(CH2)n-COR',
(CH2CH20)m-(CH2)n-SONR'R", (CH2CH20)m-(CH2)n-SO2NR'R", (CH2)p-(CH2CH20)m-
(CH2),W, (CH2)p-(CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR', (CH2)p-
(CH2CH20)m-(CH2).-NR'R", (CH2)p-(CH2CH20)m-(CH2)n-NR'COR",
(CH2)p-
(CH2CH20)m-(CH2)n-NR'S 02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH,
(CH2)p-
(CH2CH20)m-(CH2)n-COOR', (CH2)p-(CH2CH20)m-(CH2)n-CONR'R",
(CH2)p-
(CH2CH20),,-(CH2),-SO2R', (CH2)p-(CH2CH20),,-(CH2),-COR', (CH2)p-(CH2CH20)m-
(CH2),-SONR'R", (CH2)p-(CH2CH20),,-(CH2),-SO2NR'R", Aryl-(CH2)n-COOH, and
heteroaryl-alkyl-CO-alkyl-NR'R"m, wherein the alkyl may be substituted with
OR', and
heteroary1-(CH2).-heterocycle wherein the heterocycle may optionally be
substituted with
alkyl, hydroxyl, COOR' and COW; wherein R' and R" are selected from H, alkyl,
alkyl
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substituted with halogen, hydroxyl, NH2, NH(alkyl), N(alkyl)2, oxo, carboxy,
cicloalkyl
and heteroaryl;
m, n, and p are independently 0 to 6;
R12' of Formula A-4-1 through A-4-6 is selected from the group consisting of -
0-(alkyl), -
0-(alkyl)-akoxy, -C(0)-(alkyl), -C(OH)-alkyl-alkoxy, -C(0)-NH-(alkyl), -C(0)-N-
(alkyl)2, -S(0)-(alkyl), S(0)2-(alkyl), -C(0)-(cyclic amine), and -O-aryl-
(alkyl), -0-aryl-
(alkoxy);
Rl" of Formula A-4-1 through A-4-6 is selected from the group consisting of H,
alkyl, aryl
substitituted alkyl, aloxy substituted alkyl, cycloalkyl, ary- substituted
cycloalkyl, and
alkoxy substituted cycloalkyl.
[0248] In any of the aspects or embodiments described herein, the alkyl,
alkoxy or the
like can be a lower alkyl or lower alkoxy.
[0249] In certain embodiments, the linker connection position of Formula
A-4-1 through
A-4-6 is at least one of Z, R8', R9', R10', R11", R12", or R1".
[0250] The method used to design chimeric molecules as presented in A-1-1
through A-
1-4, A-4-1 through A-4-6 can be applied to MLM with formula A-2, A-3, A-5, A-
6, A-7 and A-8,
wherein the solvent exposed area in the MLM can be connected to linker "L"
which will be
attached to target protein ligand "PTM", to construct PROTACs.
[0251] Exemplary MDM2 binding moieties include, but not limited, the
following:
[0252] 1. The HDM2/MDM2 inhibitors identified in Vassilev, et al., In
vivo activation
of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303,
pag:844-848
(2004), and Schneekloth, et al., Targeted intracellular protein degradation
induced by a small
molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008)
5904-5908,
including (or additionally) the compounds nutlin-3, nutlin-2, and nutlin-1
(derivatized) as
described below, as well as all derivatives and analogs thereof:
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CI
0 .
0
---k ---
HN3N N"'1140 CI
-, 0 0 N
0
)------
(derivatized where a linker group L or a ¨(L-MLM)group is attached, for
example, at the
methoxy group or as a hydroxyl group);
Br
0 O
r----XN AN
H 0"-N--- N -I . N Br
0 07
...,
0
(derivatized where a linker group L or a ¨(L-MLM) group is attached, for
example, at the
methoxy group or hydroxyl group);
CI
0 4410
A --
(NN ----..,,, =
CI
N
N
0
...,. 0 0
0
)-------
(derivatized where a linker group L or a ¨(L-MLM) group is attached, for
example, via the
methoxy group or as a hydroxyl group); and
[0253] 2. Trans-4-Iodo-4'-Boranyl-Chalcone
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0
I 1
I 13,0H
1
OH
(derivatized where a linker group L or a a linker group L or a-(L-MLM) group
is attached, for
example, via a hydroxy group).
Exemplary Linkers
[0254] In certain embodiments, the compounds as described herein include
one or more
PTMs chemically linked or coupled to one or more ULMs (e.g., at least one of
CLM, VLM,
MLM, ILM, or a combination thereof) 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 (AL)q is
a group coupled to
ULM.
[0255] In any aspect or embodiment described herein, the linker (L) to
ULM (e.g., VLM,
ILM, CLM, or MLM) connection or coupling is a stable L-ULM connection. For
example, in
any aspect or embodiment described herein, when a linker (L) and a ULM is
connected via a
heteroatom, any subsequent heteroatom, if present, is separated by at least
one single carbon
atom (e.g., -CH2-), such as with an acetal or aminal group. By way of further
example, in any
aspect or embodiment described herein, when a linker (L) and a ULM is
connected via a
heteroatom, the heteroatom is not part of a ester.
[0256] 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 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47,
48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,
67, 68, 69, 70, 71, 72, 73,
74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,
93, 94, 95, 96, 97, 98, 99,
or 100), and wherein L is covalently bound to the PTM and the ULM, and
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.
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[0257]
In any aspect or embodiment described herein, the linker group L is-(AL)q,
wherein:
(AL)q is a group which is connected to at least one of a ULM moiety, a PTM
moiety (e.g., a
CLM or a VLM), or a combination thereof;
q of the linker is an integer greater than or equal to 1 (e.g., 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
32, 33, 34, 35, 36,
37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,
56, 57, 58, 59, 60,
61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,
80, 81, 82, 83, 84,
85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100);
each AL is independently selected from the group consisting of, a bond, CRL1RI-
2, 0, S, SO,
SO2, NR13, SO2NR13, SONR13, CONR13, NRUCONRIA, NRI3S02NRIA, CO,
cRLl_cRL2, CC, siRL1RL2, p(0µ r,)KL1,
P(0)OR', NRI3C(=NCN)NRIA, NRI3C(=NCN),
NRI-3C(=CNO2)NRL4, C34icycloalkyl optionally substituted with 0-6 RL1 and/or
RI-2
groups, C5-13 spirocycloalkyl optionally substituted with 0-9 121-1 and/or RI-
2 groups, C3-
llheterocyclyl optionally substituted with 0-6 121-1 and/or RI-2 groups, C5_13
spiroheterocycloalkyl optionally substituted with 0-8 121-1 and/or RI-2
groups, aryl
optionally substituted with 0-6 121-1 and/or RI-2 groups, heteroaryl
optionally substituted
with 0-6 121-1 and/or RI-2 groups, where 121-1 or RI-2, each independently are
optionally
linked to other groups to form cycloalkyl and/or heterocyclyl moiety,
optionally
substituted with 0-4 RI-5 groups; and
Ru, RL2, r's L3,
RL4 and RI-5 are, each independently, H, halo, C1_8alkyl, OC1_8alkyl,
SC1_8alkyl,
NHC1_8alkyl, N(C1-8alky1)2, C311cycloalkyl, aryl, heteroaryl, C3-
11heterocyclyl, 0C3-
8cyc10a1ky1, SC3_8cycloalkyl, NHC3_8cycloalkyl,
N(C3_8cycloalky1)2, N(C3_
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(Ci_8alky1)=CH(Ci_8alkyl),
C(C 1_8a11y1)=C(C 1_8a11y1)2, Si(OH)3, Si(C 1_8a1ky1)3, Si(OH)(C 1_8a1ky1)2,
COC 1_8a1ky1,
CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHCi_8alkyl,
SO2N(Ci_8alky1)2,
SONHC i_8a11y1, SON(Cl_8alky1)2, CONHC 1_8a1ky1,
CON(Ci_8alky1)2, N(C1-
8alkyl)CONH(Ci_8alkyl), N(C 1_8a1ky1)CON(Cl_8a1ky1)2,
NHCONH(Ci_8alkyl),
NHCON(C 1_8a1ky1)2, NHCONH2, N(C 1_8a1ky1)S 02NH(C 1_8a1ky1), N(C 1_8a1ky1)
SO2N(C1-
8alky1)2, NH SO2NH(Ci_8alkyl), NH SO2N(Ci_8alky1)2, NH SO2NH2.
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[0258]
In any aspect or embodiment described herein, 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.
[0259]
In any aspect or embodiment described herein, e.g., where q of the linker is
greater than 2, (AL)q is a group which is ALi and (AL)q, wherein the units AL
are couple a PTM to
a ULM.
[0260]
In any aspect or embodiment described herein, e.g., where q of the linker is
2,
(AL)q is a group which is connected to ALI and to a ULM.
[0261]
In any aspect or embodiment described herein, e.g., where q of the linker is
1, the
structure of the linker group L is ¨ALI¨, and ALI is a group which is
connected to a ULM moiety
and a PTM moiety.
[0262]
In any aspect or embodiment described herein, the linker (L) comprises a group
represented by a general structure selected from the group consisting of:
-NR(CH2),-(lower alkyl)-, -NR(CH2),-(lower alkoxyl)-, -NR(CH2),-(lower
alkoxyl)-OCH2-,
-NR(CH2),-(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2),-(cycloalkyl)-(lower
alkyl)-
OCH2-, -NR(CH2),-(hetero cycloalkyl)-, -NR(CH2CH20),-(lower alkyl)-0-CH2-, -
NR(CH2CH20),-(hetero c yclo alkyl)-0 -CH2- , -
NR(CH2CH20)n-Aryl-0 -CH2- , -
NR(CH2CH20),-(hetero aryl)-0-CH2-, -NR(CH2CH20),-(cyclo alkyl)-0-(hetero ary1)-
0-
CH2-, -NR(CH2CH20),-(cyclo alkyl)-0-Aryl-0-CH2-, -NR(CH2CH20),-(lower alkyl)-
NH-Ary1-0-CH2-, -NR(CH2CH20),-(lower alkyl)-0-Aryl-CH2, -NR(CH2CH20)n-
cycloalky1-0-Aryl-, -NR(CH2CH20),-cyclo alkyl-0 -(hetero aryl)l- , -
NR(CH2CH2)n-
(cycloalkyl)-0-(heterocycle)-CH2, -NR(CH2CH2),-(heterocycle)-(heterocycle)-
CH2, -
N(R1R2)-(heterocycle)-CH2; wherein:
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.
[0263]
In any aspect or embodiment described herein, the linker (L) comprises a group
represented by a general structure selected from the group consisting of:
-N(R)-(CH2).-0(CH2),-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-OCH2-,
-0-(CH2).-0(CH2),-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-OCH2-,
-0-(CH2).-0(CH2),-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-0-;
-N(R)-(CH2).-0(CH2),-0(CH2),-0(CH2)p-O(CH2)q-0(CH2),-0-;
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-(CH2)m-0(CH2),-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),-0-;
-(CH2)m-0(CH2),-0(CH2)0-0(CH2)p-0(CH2)q-0(CH2),OCH2-;
-(CH2),0 N N (0H2)00 (CH2)p-
\ __
-
1-(CH2)m-N N¨(CH2)n-NH
-r(CH2)m-N N---(C1-12)n-0
µA,
--:---(CH2)m0(CF12)n¨N N¨(CF12)0-NH
=
µ/.
--i--(CH2)m0(C1-12)n¨N N¨(C1-12)0-0
=
t(CH2)m0(CF12)n¨NNN¨(CF12)0-4µ.
--i--(CH2)m0(C1-12)n¨N/KN¨(C1-12)o-0µCµ
,
(CH2)m -i-N 0
_______ 0 =
(bH2),,H-
(CFA)n:1
,(CH26
-:-( \N-(C1-12)m4H ; ;
i'10)µ =
C( H26 =
,
r -
or's
_______________________________________________________ 0
N _________________________________________________
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______________________________ Ts- /¨
N N
/
/I- \
N N -(CH2),,C.) (CH2),,O(CH2)ACH2),-
\ ______________________________________ =
41¨( )-0(CH2)m0(CH2)nO(CH2)p0(CH2)q0CH2
X =
-I-NH =
0(CH2),,O(CH2),,O(CH2)p0(CH2)q0CH2
-I-NH =
0(CH2),,O(CH2),,O(CH2)p0(CH2)q0CH2
-I-NH =
A o(cH2)m0(cH2)no(cH2)po(cH2)qocH2
-I-NH
0(CH2)m0(CH2)nOCH2
0(CH2)m0(CH2)nOCH2
X ;and
N---(CH260CH2
=
wherein
each m, n, o, p, q, and r of the linker is 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;
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X of the linker is H and F
N
(rsi-4
N¨k-21mn.,,,"rsi-4
2
Th
where m of the linker can be 2, 3, 4, 5
N y w
N 0
%/N
N \
0 0
s=sON /
ss= /\""
0 0
H ,
N
= 0
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/
N =e%,
H H H H
/0; '/N1C)0='()e%<
H H
/ ,
%/N 010%C iNIs NWOO'
H H H
NJ =()==()\( ''NJ
H H
0
0õ0
NSO C):%!
H H H
%/NI N
,(:),,,, /'N \/) (:) ,<
/
H H H
/ 1
/---/- -:-N-()/
--/LN 0 H
H
., = \ 10 0-\ ,
A 'Fi'N' N
....0--N 0 0 -\ , __/ µ,\ 00,
/
H
/
--/' N L...,/N...,/--/"- ..,' .,,... N
H H / N
H
N;(,
H
1\v__Iy -;/, N ...0 401 ,:. .;/.;
H - H
H . /
`
0
0 '
. NO / 1 ,s,N ,..,c)N 0.
1 -/-N 110 N /). µx \-1.--
-1-NH ' H \ _____ t
,
H . )
/.
/ H A
- /7
/ 1-NH 0 , \
1
0
1
/ 0 HN
-1--N N 4 __ :
, \ ______________________________________________________ ,
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"1/,_OeY'Itt
'ILL>00.r\
0 = 0 =
OH
0
µ111.
0 = =
0 0
,111.01HL00
rrrr ,tzL000j-
,csr
= .
0
,,,,,00j-Lcsss
0 = =
'ILL
0 0
0 rs
cs'
. .
\
\ 0 0
H
is' = 0 = \
N
00j=,,
is' =
0 0 0
H 1 I
,iic N O/;
N 00 61j'.
= ''IL
N ,C)j
is'
,
0 0
0 0
L,,,.../"--...- =-=,../-y'L'i-
"tz,eY'Ll'`
nii,,,," . 0 = 0
0 0 0
rr
0 0
,Itz, 0 )==,s . 1,2, 0 0 j- a
rr' = 0
'111.
-'1.. 4_ 0 0 \
; .
,
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0
X
\
N
I
/ I
0 0 N /
0
OC)Ji . 0()A/ .
0 0)-/ .
; ; ;
, \
I I I
0 /
0 N 0
. ...-.,õ0
0 'A/ . OC)')/
, , ;
N
I 0 / N
I 0 / ,
I 0
\ o..-^,,,.0j1..../ \ 0j-/ .
0
OC)j-/ .
; ; ,
0
0
N , 0,=,.õ.0,...),õ/ la 6 0 k et r/
;
0
N2.
0 µii N
0 i.si
N
. NO
0 .
rN
01 N N 0
0
4=,rN0j.-.,
0 0
scs5511
Nj4
0 ; ;
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HO
N 0
_roA-
Csss 1\1)-css=,r C) _N/¨\N_/ ______ AD\
N
1¨N N
0 ; 11/, \=N \__/
=
\
/¨ 5 /--\
1¨N N 1¨N N¨CN¨)i. -1¨N/¨\N¨CN-1-
\_/ .
, , ,
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µ. '
No 0 0 \ >I\10 1
H H H i 1
0õ)( -
µ X
H 1 H 1/ H
./,.. .
X x' X = H, F
H H
'NI. 0 ' ) :-
H
. /
H .,
,µO 0õ , / -/, >N 40 \ \(
H
- ' N 0
H
, H
N;;, ,/- H ';c1\10 0 ,
1
0 0
/ 'hi Th=-"o 0 , \,, %-No 0
H "\_
:
= H 1
0 - N
0
le y='µ`-,
H H ' HTh I
N
X/,%
XY,%
,
"N
H
H H E 1
XYN % N (), - N 0,'
/ H
' N µ..N.,,,..õ..--,õ,õ0õ,,,.T...
H \ H
N &
N N,
0 ,
X X
...
-H\-N-Ii=-(=1)-0 -1-
-H\N
ro\_:_ \ / \ / 0\ r0\_:_
N
1 i
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1 1
--NH * NI/--\71\r:¨ , --NH * 3
N \ri:_ 1
/ ¨:¨N H
\ ¨ * N/¨ \N\ri
_______________ \-0 N¨ 0¨:¨
\-0
1 1 0 1
--NH .
N N-1(_ j0¨µ
1
1
1
1
¨:¨N H / 0 --NH ¨1¨ = _ O¨ \ /0 ¨),(
\ ____________________________________ I ¨ __ / __
¨ ¨
I
¨:¨N H . _ _ 0 ¨µ,,
rs
H N N ' N 0
H
(Dy
H E 1
H ¨ N
N.
TII\l' "=*.m 0¨d '
fIN".-0..10¨d "F11\1' ""--0¨== 0 ¨0
/
I
xI N
X X = H, F
\ .
N
'-9¨U ¨µ¨)--\_ ANI.-0..'10-0¨\_ T¨TN."--0¨..0¨µ j-0
1 1 ,
Inv
.
1
\ '
,XNmiii10
1..0 1--
N/----\
1 HNI"'.-CIN
H ss=
N \ / ' 0 ---- \
, ____________________________________ x:_ \----,____
\¨/ N NNJ
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HN"0
?\ HN'Or HN.-0"cb____ ?';--
-,'-- / \
0
N -/--
....0,,,10,,, i0.0
HN / \ HN / \ HN = ,,,_
X
HN0-d it ,,_
I-11 H E I '--- v, v,
X X
%0 veCaµ
, N0
/.
N
H lik \ , H 441k \ i
--V 0 '
X 0 '
H H
0 \ /.... ,,N....,0, 0 \ ,_ , \
0 0 ' 0 0 ' µ. 0 0 '
.....,µO.a
'
HN0-d ilk 0
r": -HIIN-__CiN . //\
"i--
i I
HN
\
1-11\1 0
N.,/./ I-1-N
' ' '-
''0 0
r-----N
-/-1\1/ 1\1
\...,.../N
H .
0
---.
/--\-( \ --N N N1 /' --N \XN-(
N- --NN- ______ \ ,/
\__/ / / _____________________ /
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.-
-/
--NN --NN -;-NXN-( N-' --NDCN-(
/ / I/
0-µ
N - \-- I HO HQ
/--\
-:-N N- __________________________________ /--\ j __________________ \ ); -
I /--\
-:-N N 0- ` :-N N N
0-µ _
________________________________________ - \ 11 - -- 0
I /--\ / \
1 /--\
HN Or\i \
-:-N N- j -:-N N
N
-:-N N- ,
-:-N N
N t. 0-:-
0 0
-;-N/-\N-( \-'7'' IIT\I--( \N-/- - \-
HN
\/ / N
0
-7-
.i
\,
11N-CN-(1 11N-CN-µ )-Ori -(IN-CN-µ )H-
N N N
-I-NH 0 -.1.--
\__\
/--\ ,/
ON-0"10 0-''' HNI"(-7 I\1 )rµ
-i.-- 0---\ =
/. N
00
H
I-IN --4 NI, µ.-N....,..------2\---=\,,.0;<
-7- F F
wherein each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, 6.
[0264] many aspect or embodiment described herein, the linker (L) is
selected from the
group consisting of:
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-
= %
0---C
N
/----\ ' =f=-=,/"'N____N/-\N ,' _
7"--\ _y--N NI
r---\ , I-D___Nr--\N
N-- = s, = ,0 \N--< =,,, ,
(\-)-0 =
\-----/ \
N / 1\1 / m
= `
ro
' N
N õ0 N , /.........y' NO0 i
Nz-1\1 NI/ N ,
, -1-0
1
0 N
.µ 0--7-NµsµNON,,,,, 1 /+)rNON -;
-,I-0 ,
=', ,=
N = -
õO ---/-- NO-- Nr-- , f--N-----\ NTh
, ,P----/---N____ /\ ,
c,- N = = N N-i =
-
\-/I
, -
N -N %,,N ' =
, m N/
1
'=
"m
'0 rN1' MI-eNN N
N3-"IN
-,-
O---7--
\--i\I N,õ
õO ---7- NJ I `,,ONa7 rN NN
N = 4 N --
NON.;
0
\ o
ga 000,õ
/
WI WI N .
H ' H ' H
5 5 5
0....Ø--õ,..-ب.,r, 0 0
4.N 111F
H ; H =
0
Ai 0001.t'L
rt
N WI 8 ric,N VI
H ' H '
5 5
219
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F o o
0 oaõ...-..õ_õ.o,
H ; H '
4N '
H 0 4N
0".--.00.Thr.A H 00"---.--'"--0"---)-(A
0 ; 0 ;
=
0 tsc
/
(:) N /.\C)./\.()ji
H / =
5 5
/
N 0
H
0 ,ss
/ = H =
, ,
=
/
N
H
0 =-=õ,.
/ 0 0 0j.
j.,s N / . H
c5' = H 0
, ,
0
0 r,s5NO H 0 0
, N O--/= rI / . r,"
= H =
, , , ,
0
0
4N.--.......õ...0 0
0
H
N,
0
0
r< 0 0 N 0 0.---Y\
N
0 4 0
N
H ; H ' H
5 '
5
/.., õ..."., õ,,,,.. õ0............."..
N ---- --- 1
t 1\1 ......õ,,,
H
-1ly\- Fswe
",õ.õ-----.--Thr'
FN1
0 ; 0 ; 0 ;
0 0
,-, -),"
.... - /
0 . H
H 0
; H
0 ' H
5 5
0
N
F 4(N''''''.---(31 "z1
H
OYµ 4N 101 c,,C),/,0,) c 0 /
' 0 ' H " ; H 0 ;
5 5 5
220
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N 0
H 1 , ...
0-r
\ H I
N isss,.. 0
0-rµ FNil
rss'
H
0 ; 0 1 ' 0 ; F .
1
0 SS\ N õ,....o\ 0
H
s 4C.../\------",=-==== ,...----\.õ-- ====)c,
0- '
; H , =
1 1
0
0 0 0 4N------"---. 0 0/
/,,N.,-,...........".0,..".õ,.Ø..õ),...õ , H
sr . H
N i /
I F F = H z =
1 1 1 1
0
0 0 0
N,
4 N ......'"'"" =====.. N / N
0
H A H r ; H 0
1
0 0
4[10 `===,
H i '-..
i 4 N H \
F F ; H
1 1
0
0 N
0 0 / -... ,
4Ni0e
N /
/ . H -----
H H
H 0 ' 0 ' F .
1 1 1 1
0
0
0 .0' s 0
0
=- = A'N
\ ----'00Thrµ 0 H 4N
H 0 ; F ' H
1 1
0 0 0
Ario 0 '---. / 4 .0j:7A 1 .....y...Dõ, 'N .,..D.,....,11,,,,,, o
N N .., N ..., N
F . H ' H ' H / ;
1 1 1
0 0
/
4N 0 IO I'0 \ 1:)
.
/ =
FNI /
H 4N
' H 0 rprr H E
F F
1 1 1 1
0 0 0
,z.....^.,,..0
FI H
/ro 1.. ---'¨'''''= 121 I ,is 4 N
_ r
N .
F F F .
1 1 1 1
0
0
1.1 µ
4 N y \ Thq !C) 0 0 0 H
H H E \ ,4( =Cr \
,rps . 0 ,,,,, = Fls 0 oss. ;
F .
1 1 1
0
...cy.0 0 0.). , j ,s
411 H
/ H E
; H r.r.'" =
1 1 1
/
N:C) 0 0
E 0 'N.
1\1 0,X
H
4NI 0 / iCr 0 S rsis .õ0 I.
. H H VI:3
F F ; F ' H '
1 1 1
221
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l'N1L3
; H and H , wherein each m and n
is
independently selected from 0, 1, 2, 3, 4, 5,or 6.
[0265] In
any aspect or embodiment described herein, the linker (L) is selected from the
group consisting of:
N)2 N)2Z
c3,cN ,3zc N
c3za,,N
\sss!
N,sss! N1 c3zzN
N,sss!
N,sg cyze,, N N
N
N N,sss!
N/\
cz, )iN,sss!
N)\
\1\I
222
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N
N
x ss- N,ss ck, N õ,=N
C)a0
xN xN
H
N
ss
xN c3zz N N,sss!
C)
/
H
N N
(32zNI N vz,N N,sss!
e
/
1/\ ss(N/N/\
(3N N 0 N,sss!
N N ss'sN ''''µµµµµN
s'ss
\/0 \N`sss!
ss(NN
ssssN ''''µµµµNN
0 N,ss
0 N
AN N
0 N hc)¨ N/ \NA-
\ /
223
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in"'"N( /NI- ..----0--.NN/\ \zN
\NA
N \/ ) _______ N \/ z\ N 1 ____ 5 K N \/ ) N \/ /\ N
/) ) \
/ / / 5
N N N _______________ /¨N, N NI-
\ \ sry \ __
irs
/) ) / ( 5 / / ( 5
N N N _______________ /¨N, N\ N
\ \ \
c sAIAP c
( 5
N\Z ) ________ NI( z(N ________ ,/r7NZ\ ) N\Z /N
/ \ 5 \ 5
-rN\ ) /) N N /¨N\ N NI-
/ 'AI -µr /
5 /) /) \ \
-rNI\ N N /¨N ___ I \ N N-
) / jv 'vs ) /
HO HO HO
______________________________________________________________ ( \
N\/ /N ______ ( z\ / (\ / N H N\ /N zN H N N
\ z /NA-
224
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HO HO
\
%, s /
-hN/ N ______ ( \N¨Y N \ N ______________ (
\ _______ / / \ __ / /
HO
/ 5 ( 5
_____ V --N N NI- N N/ NI-
/ /
-hd N __ ( \ N ______ / l' \ \ c
\ ________________
/ \ 5
--N _____ N/ ) ____ H N N NI- N/ \NI-
\ \ / \ /
N N \____ j -----\__N4 .µ..- NONO----\-- \/
1\1\
N 1/4N
N µ3'2", Lk, O__.\ N1/2
N
V---1, ,
'", N
/ \ 5 / \ 5 / \
1-N\ /N¨C., 1-N No.---CN 1-N\ /Nw..0,
N/ \ /
AN
Ne..
i-N3CN4
Ny
AN
No
225
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N
AN AN
/ ____________________________________________________ \
= N
\ ____________________________________________________ /
NI/ \-0 Nk/ \,N4
\ ___________________ / \
.s4\s ________ NI/ \N¨h_,NN
1¨NN
cr0,
0 0
N,s5s! c3zz,,N
N11:117
,32(N t32c,N
226
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jizrO)s! im.,õ\\01,s
N N
c3zz,, N (322,, N
N N N 4
N
N
XN NA ' N ,sss
, N
sss!
N
N
,sss! V \
N% N
'3zz, N
N\\ N\\
N N ...S
c3zz N cz,, N
N
.N\(
,3zcN
,32c N N ,s5s:s
N ,ss5!
227
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s / /\/N
\./N N.--1","
N¨F
c3zcN
L'a<N
N
N,sss!
.ziN Ny \N
AN ?s.N sssN
s'<.N
L3z2,N
ANNI-n0 NA NA
;rrrN%
?ssN N4 (z''N N--4 Ny
Ny Ny µ?3µ1\I
Ny
/11\1'32; N,
(zr µos
Ar nX ArN ====0>.'
= Nt......¨ .0 228
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Ao (:)-.0s
a
.N IN
<5
N?$-
/\)i, NN NN
,(N ).i\N/ p,(N
NN N NN
OH OH OH
OH N.., OH N)',
AN N ja cs
ss
N 1/4N -10
0 ss
N,, N
N N',
N/ V:)N
XC)N XC)N
229
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N)C,
,css
?ssN
OH
N
,NN
NC)"C NC)OX
0
;s5so
N c)e
s's50
NC) OC)
?0
N() OC))(
OO
NC)0C)C)
?0
230
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)0 0
0 0
sss-5
.ss(
0
N0c)0c)0\
.55s
0
-
ssso,
- ss
o
0
,
0 0
340/\,zi,
= o
.=, o o
231
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%, )e0///.N
0 .' =, 0
= , % ......... 0 ........_....... 0
..............."=%%%,..............õ. 0 ............õsõ.......N=N(
N,...,....../ 0 ===.,.........................%%.......
.........===="................... 0,.......;
\ 0 \
[0266] In any aspect or embodiment described herein, the linker (L) is
selected from the
group consisting of:
o'' ' N(" N
HN-N.% , :v%1:) HI(
,
...õ0,,õ,..za.,..v;
..õ0.7.7,.1\1%..-% % ,00
H
H
,
....0,
.0,
.vo 1100 o-1'
õ
N N 0
. H = H ;
,
H . .
'0
-µ',
. .
i
\O N
NON.
/ 01
'N I ; .
,
>,..0 N.,...) ,"N
N 0 N. N 0 N
/ 0 =
-,
,
i
7'N .11'N
N ON N 0
. ;
'0 N
;,
Nis =
_.=. -...=-= -s..
H
N
N ,
S.
/ N =
,
. 7` ,= .
,
232
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,CDN
N
(:)0
c N
N (:)()()), .
H ;
,
s'N-M.
cN ,=0-.0,N;µ'
H
H = ;i'0 0;%
;
,
,
./i N
#
,
,'N 1
%, õ...-...._
U (D/Y()%-%
c,N F F
i j F F
V
FE . .
,
,(ON
N I\1 c,N N1
UV ON-%% V 0/(N-%%
F F
H , FE H;
.
, N
it' ,\, 0 N ,=-=-)
H
H F F =
, ,
N /1%N
N c,N (:)- x
(:)A/c?;
N `
F F . FE H.
, ,
"N
N c,N I\1
U .
c,N (:)=y= x ON1.`
N `
.
FE H , .
H,
,
, , N
I . .
N;-
0
V`
H . ' ' -, µC) H ;
`
,
H
,
233
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OC)10sx
OH OH =
0
OH
OH H
OH
;1001
= ; 0
0 H ;
Yo0C)ON:/
0 ; = =
0
0
H ;
0 0
N'' 01.4 =,- . H
' ¨
0
H = ''',ICOC)0C)'/ =
0
H ; ' =
= H ,
H
[0267] In any aspect or embodiment described herein, the linker (L) is
selected from the
group consisting of:
234
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/ , \
sk\A _________ N\ 7 ( \/0)\ / ) N ____________ N-F)
m \ ________________ / m \ /
n
/ \
%
ss ) N ss, (N \./0).4e,
.
n o õ j/ )na ON (K
/ \ \ _
\
- -N ______ N ( \/0)e0 s - / \, ,X, A ( /N (lin
m M 0 s 0
/sss
--/
0)Css . s
\ (/ --N __ N _____ N __ (1
/ \ \
N i O/
\/ ci \ _____ / m
\ ,
/
/ ) N/ _______ \ ___ ON (1/ '
sss< /'' ) \ ______ ON
n ______________________________________________ / (f"
- -N/
_
0/C s>,,(0\/) m \ _____ / N/ \ i \
n
N (
\./0r
s.
\ N (/ ____ j o ss o
\ __________ /
235
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N ' ; '
)% ,-
N,...... 0(//,,........,, )>:
''0.,....,.(......../õ...........,0)..., ......./...,, c...
s= =ci /H\ /sss:s
m I 0 0 =
in n
y,...ty,.0,......(./....õ, rs \
0 = = 0 ,,,/ ,'yN\K \r(k/'
= M
III i
n /
n n
0
% H
;µN(:)),,,
0
,
m m,
in
0
% H
/ H
(
\,õ.N.,......,...õ..........õ......õõ0 s=.-
\.õ.N.,.........õ......,µ ,, \ii \ =
..,µ / / =:' \ ,..\ /112,õ
ilIA¨' n
0 0 0
---t
N \ N 0 1
i
M 0 n
0
n N
/ N c
, = "V
'l
................,,,* / N
m C\N = \
M 0 == \ m 0
_________________ N o
1 i
A)>0
/ \
____ N
o..../.;(...õ crosc
c-r\
n
' n
\ m N
1
I A,
o
N
=,/
. o' .
=:*, N .....,,,õõ.õ.. __ ,..õõ..........N*,,,:s ' \\(k ) N N (
m ____ n m __ n
_____ H 1 _
-1--N __ N-- 1 / __ \ _______ 1( __ 1 / \
t \ __ / -!-N \ /N ( m --- !,N
1 \ /N ( /( i, N / \
¨1¨N
1 \ /N ( _______________________________________________ rm
236
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, \
-1--( N-- _
/ l_i \ (C t_< IL
\ i __ NH t_ \ ( r -
i \ / / __ (, < / m
r¨ r¨
/ ___________________ \ / __ o / __ \ 1/ ____ N
_____________________________________ N N ( n
/ __ Nµ
/N ( 1 n / \ ______ /
0 ( )m '-, / m
I-,
,--,
o , o ,
n n H
\I\
/-',
0¨
0--
¨
S''ON
/¨\ / \ n
_(
ie iill N\ /N
0 0 M
=,/ `õ/
e', N
0-- 0¨ ¨
0 0
=,,,,..,,,,..õ.1.,,,),õN,.......,...
___________________________________________ ov, 5:µ N
N'.5(
n
,.................õ,,N/ `)(õN,........./....õ....
i N,....../.>
111
,5 F'
e in S' fl:N
'4
.....,......,.õ,.-..,),,N,õ,,.,,,.
0
Xr1 N
S: Nµl<
n
e ,B N N\ r
,,..........,...õ,N ....,,,z,
i
n m ;---
, ril
.õ0
\ 'Hil N1
N.L At NH,,
M n
237
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Ni3zc,
N \
d, in N F F
)( N 0(,,'r -'= / N...õ,..õ,..,,, = 0
,s
n m
M m n
N Xs
-- N
\(\ ) 0 OH
n H
= 0 N N
N
:)(,0N.,õõ,...õ
)m \ _0_ -
m
/ is( C F3
õ....N.,` \
OH N .
\ 0 = 0
.` N,.....,...õ ,\.=,õ
,,t...r.Thc..)r.õN,,,,..õ,,,..-
n
m n
m n
NN )s(
--- \
= 0 N
'L07 \,- N
''-'0 ___ ON __ )nN\ / Z----.--.\ ( \
\
-- N / =N\,.õ,/' N
\¨ N
( n \ / ... ' N .-.../
, 0 n
................./(..õ)õ,,N..õ.....
..N
- M
N = µ
..., N\µ4'N
NµZ)Zt
=,,...õõõ,,,N: 53..\,,
S n OH
N
..õ,.,.,=,..õi.,),,N.,,õ,,,=õ,,
/ N
m n F ...õ..,...., (..õ...)
N,.....s.=.õ,,,.,.-
,
,1\ N/ , \,M\ .
= 0 , , m N
n \.....õ/N--.1_, s
111
''1-1'1--1 (' c'r,---'****
N
N ..-''''..****\. N'2'122, - ¨N n
n
0
N i
N N
H ' N
µ21 N\ ' m o
n
F
õ/ N)s(= ,10 =,,.,.......,, N ,,,/
m
i -
M
m n
238
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N ---D- ......_ 1
i
N i,' _ ¨N
i m
,
N---a_1 ,
m
N
\ N
H n
NH2
0 _____ / N N \ ___________ ____2/
0
m 0
2/ ) m N N ___ n 0 __ r
---
---\
)4 m N00.-0 1 / A
0 0\,
in
sys,
/\ )n
___________ N N
\ ___ / o
m
239
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KN[ , srN1'
NI7
\I" .11,,K
\ im
(111 NaTN
,N1,!5 ,Nlge /Y.5
H 3 TL'r, r'N\
N,>
is N\ C, r1:4N1
,N1Q.N) ,N1,e \N, N1,1,
\ im 0
4:N
,Ncse 0 ,NI/e NN ,I
' m N =H r/;c) N H ,,
240
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I
:- '''\0'
rN 1 rN)1 1 i
% I n
\-0 /
1
1
= , = 7-
), N
0 ¨ : ¨
,
.)-----/
/ ; - \--N = -I-O'n
sCrV',N rN\
CN\ '
m
l'\1
. , (N.-0-'-
n
1 , NC)---Nr--N
7-0
.-,
\ ,. kl-N N-:- \A,..`' . N\53sCY, .Q 1\11a<
--0-0-0 n \__/
,N.H)
N,> m
m
N----z\ ,
1 µ"-
bN N
\ H "
0- N
\N_,_ \_____\_.
,/ N---9
" 1--\N
0---7-N \O---0-:- -b--0--N\_____/ ----\N-0,,,
N N m , .
/-\
Nci ¨Ns...2,r , -01-yr Cri jµI'µ`
1
/---\
\ 4 NON2,_ , p.i_jr-N N ----N,:,:-
}.._
Na(I %
CF3
_
rN ' 1-f)O-N N-;
\/
N-...N l'. .,
,-- mL. Ni/s
241
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;
00t1000,)),(%
/ m n o P
q
,cw00t.i.00H),(%
r m n o P
,
,
00t1.0f.( , H
0 N }c
. ,
r m n o r m n
i H
0 0 ON oeµ` )frr
i H
/ m s
n o P q
,
, H
OH0t1Ø1.N m)(,,
/ m n o P
%)(t00000'
s ,
m n o p
,
m n o
H ,
m n m
H
,
m m n
H
% =)4Am-.00i-.
s
m n o P
N
\00t10
,
m n o
242
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\ % 0 Ot101.01.0(,ec
s
m n o P q
00t1.00.1,c%
m n o p
H
N
% 0
m 11 o
m n
H
0.,)0tIN HX%
in n na n o
H .
%).(r000N
s
m n o P q
H
(%0(,K=OtI0(,N
m n o p
1
%)ON
m n o P
, \
N
,
.
m n % 0 n 0 = n % m
=
243
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N .
8 Nai.r
n
, \ , = N,,,,.õ,õ,,,e
0 ..../ .
0
m
m
n 0 i''.41n
n 0 p 0 ,
"0
m
_
o
n 0 p 0 \
, N,,,,o),\
,./
,
m
m
o
,
====,/ N\(,) / 11 N \ N 0 ,
m \ __ /
0
_
/ N¨ . NI \ N- ¨
/
-
N _
,
n
n \
""--'c
¨2 _______________________________________________________
N
/
N
m m
=
N i \ ¨
N, i
).\ A /.... ,
_/\
0,1,...y.
1--
-
.
N ,/, s =
=
=
8
1 A
=
s
m
N
,
N j
s s
M m
= i',
N
= 'm
m
,
,
,
,
/ m m
244
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¨N N - 4 \ 1 / \-
( 0..=
N..õ,,,,..õ.....õ0 ,..........,
\ _____________________________________ / i m
N
m
N.
=
/.=
0 0,,,,....õ...,,,õN
) ___________________________________________________
)`., ¨ / \ . N N
\/
0 0,,,,,....õ.., N.......õ.
0
. 0(.= \
_ . \ . / \, .
=
`,..,
; \
0 0,.,,,,,,,,,,,..õ...õ.õ0 iii
.=
. : \ ________ /,,
,. .
i
i / ________ \i.
\ , ___________
N ..,,,,.,,,,,Ø,õ,/,,,,,,ox< 0 0)C=
m
i = / \
: \ /N __ \ / \ i
m
C'0
= 01
0
/ m '
245
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__ H
_
m 0 1
N no( ---------------------------------------------------- 0,(-Fd--,,,
N---4E9 )rn ON¨es)
o ,n
/ \ ..,.:ONõ.................õ 0-
......1
i
/ N __ ON ¨C'N' )' x-0 .0'%s NH¨ ¨ ' 7(`/K
\ ___ / )sss m
;
,
%
===,-, .......1-111 0/ n \
\ \µ..,I 4.y........... ,...,y \
il ) M __________________________ N
--A
\ 0
=
0
m n
a \ N¨ ¨ --/ -5.--> \ N¨ ¨ ¨ _0 ________ /
/
N N
\ __ 0¨ ¨
--,/
/ \ / 0
N N __
)) m ____ N N __ n / \ ______ /
0
0 ________________________ 0 ¨
N
/ \ _____________ / __ N _________________________________________________ /
'
_______ N N / \ __ /
/ \ ___________________________________________________________ /
N
is--
/ \ ___ i n
/ ______ \ /1\1 \ s/ss / \
0 0
)()n \ /
/--, --,/
N
O\ A
N¨:¨
/ \ N c) N/ )
A \ /
c n \ m
0 __
--,/
/-'-
246
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,
. _____________________________________________________ 0
i 0
)
/ \
a N( ______________________________________________________________ /N¨ -
- ¨0/ 0 __
,....,0,........../.... ,,
/'' N 0
\/N/\N
/\/ 0 01''
V.
nI\
0 __ vIN
i ____________ /N __ n
0 _____________________________ ill
\s.)N N k:)(ii /N.
0¨ekn /
__________________________________________________________ N ___ NiFI's''
N 11, N __ Win JO I .)
0 ____________ /-µ111 \ - ,../ Nn __pi-----C(N ' / ) __ 7 - -
_ p r - - - - = -0 /\ __ N n N
/ \ C)( NH
i
/N n n N
H c '.
icrl 0 _____________________________________________________ n
/'- /'=
247
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= ) /'--
0 ( km / ___ \- 0 ( kin
\ ______ N N-\ ______ N 0
\ __________ / \-- N, \I N
0¨.-
,
) / :
/ \ / i_
Q(
N N __
n
0
=-,/ --,/
,
/ \ __ I _ ,
0 -'
NrN --pri - - - --0
/ jn N \ /N
0
n ijr- =
¨ / i
0 ___________________ c., m
/
i'=
Y.'
/ ) __ Off ) n - ___________________________________ r 0
\O ( km \ - ¨ 0 N/ (N __ W
0 _______________________________________________ )(111 \ __ (
\ ______________________________ N N
0
f'
/ _____________________________________________________________ )
0 , ,
N ' ____________ 0
0 H 0
.=,/ \___._.../N H A, /, ',,/
/',, n 1-=
/ ________________________________________________________________________
1C1's
1 / \ 0)(ni 'ICN \ / .. 1 / \
V 0
________ N TN\ /N n''',Ir \ \
-k/ \
rN1'
1\1/ ,N16,4
N1-. \N,
\ /m
m 1
Ngt: m
,Nige m csss:
H
m
248
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ss
--, ,....õ..Ø.,...
0 0 =
==='
C) =
)'.....s.l.") IC' \
N.(n
,...,ZN \ =
0 n ::**0
S' 0 ).3C/N WoX
i
--, =...õ.....a.,
Ns\,
1 0
0 m '..(...****)rs 0
m m cpNWO.
n \ 0
;s
0 /
/ \
\s,õO 0 N''''' N
1
0 I
n in
..
in/
n in
0-..L
=¨=
\,....-
' .... 0
N--.....7.------/
x
,......õ,....................,0
=
0
0
,.1
/
Lici = 0
' 0 ,='==''.
vON =
.=' \
'
1 "c¨bN,.o.õ,ic,,rõ.o
n ,.../...cr,O.,..........x.õ......õ,õ, N ,-..11
0 --4N = 7'-=N
s.:
I ,
, 0
0
n n
o ...'''O/
µµ,
= N -- 0
0 i
,....Ly `,/.... \,.
..".\
0 0 =
0 \ N
(j/ m
n
0
I ---0
..7:". 1
'....''ON, =
,......zr,,O,,E,,,......õ,.....,(.1:0),.......N
= 0 -'='.
H
m
249
---\.
0
;I
.
.)---j .
.
o
)
,s
c.
.
\ / \
)--\
..
.,
z¨
%
. - -
.
. 0 .
d
i---
6o
1
0
cil
l=-) R
8, ..
c,
1--
- )-- ?--- .-
,A___
co-
, _____________________ ..4,µ,._.
, .,.,,:
-k"
. --\-- --\ - -
- \ 0`, . ' - \ . , .
I
0,
,
\ 0)._.\ 0
. ,-
0 . . . 0 .
0)--i
__________________________ I.) )__ _____
\
_______________________________________________________________________________
____________ ) \ 0) \
z¨\ \ \ = zµ ____ / 0z __ 1 )
_________ / Iii \¨ \
i
% .
,¨i
i
, X
c) 0 --1- . 0 0 0 . 0
ls.)
,-- , \ 0
0 0 8 0 =
.
.
c. z¨ z
..
'--1. --1---
z
-4--
..
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n ---0---, %,0
0 1 ,
.-- _._i NC
ON 0 \ N
0-..4..
s\ 0 N
0 0 \ N \
n
\ 0 N
F,C
ON.......''
0
im
,
0c)4
--- --
F F
N., 0 - n
n
/ N \
/ ..---
ON - n
11,(..,0 .....,./.
1 F3C
ON 0
s 0 1
0
n
\ ...õ0,...õ,.0,..,, ....,./'
s
1
ON
0
NC
I
ON
251
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F F
NX0C)><
...,
..,,
F 0
F F
0
\\....:
0
_\......-4:74:1- 0
n ON____Ø----------------:-.----
C)
rr\O-7----
%
1 N
0 N CF,
W
ekit.n.0µ \
NN n
F3C
0
m
.),
......ZN .
s N
I
,''COON
,...............,N,O.,...õ,o
0
NI,....:
0 S...-
0
1
, 0 0
n
F F F F
Li.,0,................Y.0,...,.......õ....õ0
.........zio,.............õ...õ,.........v0,......Y......õ.....õ,0
o
252
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CF,
0 \ (
\ /
in
n
n
µ 0 0
0
n
in in
.*st\N =
n
% OH
m
,14,1=õ,"..,...,..)=õ
ii.
m
n
0,,(,.1õ,,.....i3O 0 =
m
n
0
/ =
A
-- ' VC11171\
/
r....
, 0
,
0
/
, No
253
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x
1
..,........"N
s ..=
j% Ci =
v
1
C) ,,..., N NC
,/
/ 0 ...,,,,,..,...õ,N %s= 0
\
0 = v
0 /
,...,crõ0..,..,,,
s<
N C)
=
1 ../
/ 0 ..,,,,......,õõN
/ 00. =sf
e..... \
F3C
0
=(
1 =./ Ci =
of 00 '====,....õ...,
...)::(0,.................
1
0 Ns\
F3CN
,,i
r''c) s,......,.......,,N
.(
0
,
1
i===,o
õ....,,,,,.....74,,N
,,,...../...,õ N
NC
HO
N =,,, OX\
\ -ff
/ 0 N
oo'f \
,./
i',o
,,,...../...,õ N
...)::(0,................... =
`=
/ = Ci
=
..o ,
' 0
=/0 s,......,.....,õ N õ,,,...........õ N.....,
1
)&o 0
)::::r
==,......./...,Nõ,,,...,..,,,,..,,,....,,,,.....õ0õ...,.......0),.,:
1
N
254
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,.
./
õN
i/) = ,
I
0
= 0
CF 3 == N
o1
=
02 \
I 0
CF3 \
)::1 = ,
.,.
i'
)iii3 = ,
;.c
I %=-1
=,õ,..,,,.õ,==N /"µ
F F
)::::y = ,
02\
0
.,
= ,
02\
I
NCN
)( =
.....õ...,,,N,..........õ,,,N,,,
I
255
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AN %
.,,,,ON =
' n /
,
f 0
N Wo%c F3C,,...,,,,,,.
N .
N
" \
n
NW=,.
0 =
/
) ____________________________________________________
11
,.. \
N ........:,..0 .
..,=\
N \ M
NW,.,\,= 0
0 \ 0
s==' ',,,cii
,=\
0
n
0
1 7C:r N)c
/
0
0
,=\ '''\\ray
11.1.1'N
õi f\ro
n
0
,=\
.),.,
0 = 0
0
HO n
= ' 0 ,...,,,e ,=\ '''Iiii,,
n
))(
0 0
=
oN
0 '
N'
/'..0
0,
256
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NiVrNi
r
,
n(,2)N .,,.,....N
0 '
n P
N N
r
,
N N,(.= 0)./1) (i
N s
n P
N N
r
s n(,<N -,.......,,....õN,,,,/
,
n
/ 0
/ _______________________ NO\
o __ /
/ ____________________________________________________ NO
,
c) o
i.
NH2 0
/ ___ N Nn W I,
0 a
I
I /
0-
i
0 ( _______ NQ
) :
n ,
257
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H
NN NCIN)s(%
H
m
,
O
' 0 o
ir\ "/
H
N NN(
N H '
m
1 0 'Clo
,1\ N
, 0
%
H %
N N s
N
m
N
. 0
H
N N rr0(
N
m
1 0 113o
,I\ N
, 0
.Ø..--. ,,..--. 0
N N ,
oN
N X
N \
H
N
0
oN
0 coN
N
H ,
µ 0 r N 0):µ
N
258
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rN=,
N
N;4
=! w W
, 0 0 N\.3
OWOWO
r-X
.... .
i
0., %/isC)0()
Cr ll'
/.0W0W0."
s õ
:\N
wherein m, n, o, p, q, r, s are independently 0, 1,2, 3,4, 5, 6,7, 8, 9, 10,
11, 12, 13, 14, 15, 16,
17, 18, 19, or 20.
[0268] In any aspect or embodiment described herein, the linker (L) is
selected from the
group consisting of:
a--
/¨\-0/¨\0- -= / \-0/0¨/¨Ck; /
, \ 0 ¨0¨/¨ o
,
,,,¨\_ /¨\ //o¨\ / /¨\ /¨\ /-0\ /0¨\ /¨\
0 0¨/`-0 = ' `-0 0¨/ __________ `-0 0-- =
, ,
,, __ \ P __________________ \_ i . ,,/ \ / . 1,/-- \ . /1- \ _ -
- .
% ; ' \ __ / 5 U 5 5 \- - - 5 U 5
/1-- \- /- \ , \_ /- \ _/-
N1,1-I /¨\_ /¨ j¨O HN---
\__/ .
0 HN--- = ' 0 0 ` = ' 0 0
, , ,
,/ __ \ /¨\ /-0\ /O¨\ / / _________ \ /¨\ /¨\
\-0 0¨/ \ __ NH = ' \-0 0¨/ ____ \-0 HN--- =
,/ ______________________________________________________________ \ /¨\ ¨/ /¨
0\ /0 ¨\ /¨\ r¨ N.-1 _ _ = _ _ _ _ = /
\-0 0 _________________ \-0 0¨/ ,
-- = = -- = %
-- * di . -- = or -- -- * 0/--\ -- * 0/ \- --
;
= ______________ 0/ \ '
-
' - . 0µ, __ =
0¨,,, = 0--
, ; , ,
_ /--\ /--\_ ,, = \__,,, =
- -% /1¨f µ¨c) - 0¨
- o
__ * 0-1
, , ,
259
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0 0-- -- . 0 0 '
, ,
II 0/0¨/¨ 0 \/0- - --
5..0/¨\0_/-0\__/0¨\_d/
. .
__ . 0"-- \O ¨/¨ 0\ /0 ¨ \ ¨ \--\ ./
\-0/ 0- - -- i . 0 0¨'
-- = 0/0 ¨/- - - - - * 0/ \¨di -- . a/ \¨o1
; --
; .
,
= _____________ 0/ \ ________________ /o- - = 01--\ r-`0-- -- * 0- \, /
-0
; ; .
,
0 0\ __ /0 - - 5,0 - \ r
__ = ¨\ _______ P-- __ * \-0
. 0/ _______ \-01-`0-- -- = o/--\o¨/ \¨di -- * o/--\o¨/ \o--
, ;
o
= __________ o" ____ \-0/ ________________ \¨d/ -- 5,0/ \ / ¨\-01 - - <
\NJ¨ µ'
_________________________________________________________ / .
- - < \ N / \O- - - - < N¨/ \
\ \_ 1/ < _/ \__/ - -
0 - - N
/ / _______________ /
, , ,
/ ___ \N _/¨ 0\ __/0 - \ N
/ ' / \N¨/¨ \ _______________________________________________ / \
0--
- __ / < __ / \/ .
, , ,
/--\
-- = 0 N-
---(\¨di
0 ________________________________________ ro 0 - -
LI,
/ _____________________________ / .
N--- - - = N N---
\__/ ; \ __/ ;
,
. N/¨\N¨ro\ /0-- = / ____________________ \
o ___________________________________________ \ i
o =
,
260
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NJ
ii /--\
= __________ 0/ \ ___ 7 ____________ = 0,-\ __ /-N\ 7-
; .
,
/--\
N N--- N/ > - -
- - = 0/-\0-/- \__/
j- ________________________________________________
= --
0 0 \
, ,
rN--
c)ON) -- = N/--\N ____________________________ / \O- -
; \/ .
,
CD/ -,
0---/Th
0
0-_ WI (:)(:) 0 C)00-,
0 .
-- ,0 ,
/--__/---0
0 .
'. 0 /--\ /
l "N_rN
< \N-rN
\ >
N _ _
00 el - , . - - \ \__/ - -
/ .
, / .
./
rN
-- \N-/ ______________________
-- \N-) -- \N-( \ 0
/ / . / ,N--- . /1-\_0/-\0
'
, , __________ / , ,
/-\ j-0 HN---
'-\_0/-\ 0\0/ /o¨_,,
o o \NH
0 = 0 =
0
_ /-\ /-0\ /0-\ / _____________ ./
0 0-/ _______ \-0 HN--- =
,
0
j-
/-\ j-O\ /0-\j-N,H __ . N1-1
0
\-0 0 N = =
HN--- 0 0
= 0/-\ 0
0-/- ______________
\
\\ = 0"0 -" \__/ N/H
0 = 0 =
, ,
261
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0
-- =/
= 0/¨\0¨/¨Ck¨/ ¨\
\-0/ HN---
,
0
\ /O¨\ /¨\ j¨N,1-1, = 0/
= r -- _________ 0 /¨\ 0¨ \-0 0
0 ;,
= 0 HN---
\ ,
\\ / \ /
. (:)¨*/ ______________ N/1-1 = 0 /1 NH
0 ; o' o =
o o
= o ,
>/ ____________ N/I-1 __ = HN--- -- 0 4. / _0
\ / =/
HN---
0 =
, ; ,
O 0
__ = 0/¨\0¨/ =/ _______ * 0¨\ / ./
\-0 HN--- __ . 0/ \
; =
, 0
-- . 0/ \-01 -1,1 -- 41 01-`0-/
= 0 0 =
, , ,
0 0¨), /
-- * o¨\ _____________ /o¨)/ N11-1 = \__/
o/ NH
0 =
, ,
0
\ ________________
. 0¨ /
\-0 )/ __ NH/ _ _ . 0/ H\N___ - - \ __ / I-1
N/
0 0 =
0 0
HN---
,
-- \ / __ -- . '\ \¨NH \ . õ
* j¨N1-1
0 N
0 = ; 5 5
0
-- \ /
NH
µ` -- * 0/¨\ __________________________ / 1-1 0 HN--
-
, ; ,
O 0
0
= _____________ 0¨\ /-11\1 = 0 /
\ HN--- -- = 0¨/ ./
HN---
,
O 0
-- = 0/¨\0¨/ \0j¨NH
.
262
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0 0
_ _ . 01 ___ \ _ 0/ ¨ \c) i¨ N,H, _ _ . 0/ ¨ \ /¨\0 j¨ NH
,
o o
. / ________ \ / \ /
--./ / \_ / \_ /
00¨¨o HN--- -- * 0 0 0 H N---
=
0 0
= __________ 0/ __________ \ /o¨\_0/ __ II _ _ 1 \N j¨ 0\ AIN
\ N __________________________________________________________ / \ j\¨N,1-1
-\ __________________________________ / 0 ,
, 0 ; /
0
- - < \ N ¨ / \¨ / ./
0 H N--- - - < .
\N ¨ / \
¨/ NH
' __ / = ___ / 0 =
, , ,
< __ \N j¨ 0\ /0¨\ __< __ \ ro\
N H N¨f ro\ __ T
/ /
0 \O =
0 0
_________________ \j ___ 1\1,1-1 /
./
- - < / 0 ` -- < \N¨/¨ \¨/ \-0 H N---
____ / / =
r\N
0 _____________ ,-0 N H 0 , 0, 0 1m
H N - -
-- -N¨/¨\/ ¨/ -
\--- N
/ 0 0 ;
,
nr\ N
N H
N N
- - - - * 01 \-/-\jHC`
0 ; \/ =
,
0
7--/ H N NI/f /--\
0/¨\ /¨N 7 ¨)r /
--- . /-...\) \ - .._ _ _ 4.
0 N --._ N H
0 =
/--\
* 0/0 ¨/¨N\¨/N N/1-1/ - - * 0/¨\0¨/¨N/\ __ ) ¨1\11-1/
0 =0 =
, ,
N/¨\N N/\ ) 1 4,
H
- - < \N¨/¨ \ ¨/ ¨/-1\1/1-1/ - - < \NJ¨
/ 0 / 0 =
263
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/\
-- <N-<
\N-/ ___________ -i- '
N
NH' .N.r \N
/ / /
0 = \N) HN NH
., .
0
, , .
0 ,
- _________ * _______________ NH /,'\ r0\ HN--- ,
/ / \
0
, %= 0 ,. :
, 0 HN--- =
,
0,
iii--\ __ /-4(HN---;,/--\ _____________ >\-NH'/--\ j NH __ =0 N-0
, ; ' 0
, . =
., 0 ,
i_(,)-N--() __ _ * 0 ,,
N-0 N 0
O \ ---- \ ._.-., , , VI
.. 0-
/ - -
. , 0 00N. 5
-R/- -- - * N-0
. -
/ / --
, .
,
* 0 N-0
\----"No.,...NA). * ON.,....0N...õ__
/ -- . N---
, .
0 ,
.,
. j)__ 0 N-C)
OC) ---
0(), =
., 0 ,
N---()
N-0
OC)1(")-- -- IS (:)\----NO----\..,--___.
,
* 0 ,
X0x11--C),
-- *
CDNA--
, ;
* 0
X0X, . 0
-- * \-----\, N-0
,
., 0 ;
N-C) '
OC) I / -- el N-C)
, 0 'c)Q- -
- .
. , 0 ,
0
- -
e.\/* Q---
, 0 .
., 0 ,
N '
O(DQ--- el
C).'""..... .*:4 - -
, .
N-C)
0 0
- --
, .
,
264
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i------\
N
. 1\1/-\N-0, -- 0 /Th j\--1N - =N \___11-\---N- ,
V......_/N . -- .
;
.._ .
-- 44Ik
N .
. =
.._ --fik N \___ j
i------\N
--\--0 0
-0 -, Is
0
I /
N/ N/Th
=
\N r\1\10
N-0 N-0
' .
O
0
---\_,, __ . N \....... r"\ jN ----\---\,_.0
=
i--\ /- \0,
/- \ /- 0\ p - - /- \ /- 0\ /0¨\ /
--o o--= --o 0¨' ,= --o 0¨' _________ ' = --
o 0¨' \-0 ,=
, , ,
/--\ /¨o\ /0¨\ /¨\ /--\ /¨o\ /0¨\ /¨\ /¨ ON /--
-
--o o-1 \-o o--= - -0 _______ o-1 \-o o-
i , = --o =
,
--01 \-0/;\o-1 ;--0/ \ ________________________________________ /0-, 0/--\o¨/
\o-, 0/¨\ /--\
0--;
/ ___ \_ / __ \_ / /--\ j _____ \_ / /¨\
--o o o = --o o o = --o o¨f . ,.
, , ,
r. 2¨\0_/ ___________________________ \o ,
. __ o/
, u , ,
/¨\ /¨o\ / _______________________________ \
/--\ _/ \ _____________________________________________________ / \
--o o¨I ,= o o-1 1 o--= --o o o o--=
, , ,
/--\ j ____ \_ /--\ / __ \ /o¨\ /--\
/ ______________________________________________________ \ __ /o __
¨\ /--\
--o o o o--= --o \
\¨o o- oo--;
, ,
/--\ /¨\ /¨o\
- 0
3\1- . - -N N __ '
- /- ___ /- -/ \O - -; - - Or- 0/0 - -; - -NI \ 0
265
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/¨\/ \/¨\ __________________________ / \¨ ii /¨\ /-0\ /0--
--N N¨ O-- --N N 0 --N N /
; \/ ; \__/ ;
;
/--\
/¨\ /¨N\ /N--- p¨\ /¨\ /¨o, ,o¨\ / __________________ \
--N N¨f , \¨N N¨/ ' ' \-0 \¨N N---
\__/ \/
; ;
/P /--\
/¨ /¨ \
¨\¨/¨\¨N N--- --N \N _____________________ r 0\ r 0,
' --N N
\/ ; ; \__/ =
;
--N/--\N / \
\/
/ ______________________ \ /--\ /,/\
N --0 \¨N N¨/ ' --N N
,
\/ . , / ¨\ /-0\ /
; ; ' ___________ /0- - .
. =
;
/--\ /--\
p__ --N\ 7¨\_0/ _________________________ \ /o-- __,\(--\
--N\ /N¨\ /0¨\ N¨¨P--; / ; ;
/--\ /--\ /--\
--N\ /N¨\ /¨N\ / ,N---. - -0, /¨N\ / /1\1¨\ o-
-
= , .
, , ____________________________________________
o /¨\ /¨o\ HN--- /¨\ _/-0 0¨\
--0 /¨\ j-1\1-1 --0 0¨/ 0 0 \¨
NH/
. = - -0 0 . . 0 = 0 =
; ; ;
0 0
/¨\ /-0\ /0¨\ / /¨\ /¨o\ /o¨\ /¨\ i¨NH
--0 0¨/ _________________ \-0 HN ___ = --0 0¨/ \-0 0
; ;
0 / __ \ HN-
0/)/ ,p¨\ /¨\ /-0\ /0¨\ /¨\ N,I-1 0 \
µ NH
\-0 0 ; ; 0 =
;
o p _______ , JD _________ /
,
¨\ ,
/ _______ \_ / /--\ / ___ "'c o \ /0
\ ¨NH
¨0 0 HN---= ¨0 0¨' HN---
= --0/¨\ / I-N---= 0 =
; ; ; ;
/ \_ / \ / / 0
- -0 0 //NH0/¨\0¨ / ¨N1/1/-1 0/¨\¨¨NH/
/ ./
= - -0 HN---= = 0 0
0
; ; ; ;
0 /-0, /
,-4-I µb¨/ \¨/ ¨N1/1-1 NO¨/ \o¨/ ¨1\1/F1
/--\
¨0 0 0 =
o
b¨I
\¨o/ ¨NH µb¨/ \¨P¨)/ N'H /--\ i \ j¨NH
0 0 = - -0 0¨/ b \ .
, , ,
O 0 0
/ __________________________________________________________________ \ /¨\
i¨N,1-1 /¨\ /-0\ ¨4-1 /¨\ /¨\ j¨NH
--0 \-0 0 ' = - -0 0¨/ ' 0
; ;
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O 0 0
rO\ )\-1\11 / __ \ /0¨\ \-1\iµFi /)\¨NH
0 \ ` 0 \-0. \ ______
, , ,
O 9 0
/¨\ _/¨\_)¨N\I-1 /¨\ / ___ \ / ___ 4( / \_ / \_ /
--0 0 - -0 0 0 HN--- ` = - -0
0¨/ \-0 HN--- = =
, , ,
9 4)
/ _____
0¨\ / 'K µ / /
--0 \ / \-0 HN--- = b¨f \¨/ ¨\¨o HN--- =
, ,
//0
'c
b¨/ \-0/ \-0/ HN--- = 0¨/ \O¨/ \-0/ IL--- =
9 p
________________ / __ /< µ, \ ____ / __ \ /¨ /
HN--- U¨' " O¨ HN---
/0 0
rO\ / .µ rO\ /0¨\
0¨/ / HN 0¨/ HN---
p p
\o¨/ \¨/0¨\ _____ /¨i\dN µ0¨/ \¨ /--\ ______ /--\ 0 HN---
0 0 /¨\ _/-0 HN---
\ _/ \ \ _r()\__/¨\ _____ /-4 -N N \ __ /
\\
0 0 HN--- 0 HN--- \¨ 0 =
,
% o
./(
--N/--\N / \O¨i¨N\H` --N/--\N¨/ \-0/ 141--- - -1\1/--\N¨/ \¨/0¨)rN/1-1/
\__/ 0 =
, , ,
/¨\ /-0\ rO\ HN---
/
--N N \¨ NH N N /
0 0 =
, ,
0 0
\_
--N/--\N_/-0\ / \c) j-1\1-µ1 --N/--\N J-0\ / /
.
0 HN---
; \__/ .
,
/
0 HN
/¨\ /-0\ /0¨\ / __________ ./ HN
__________________ \-0 HN--- ,o HN
_______ 0 /0¨\¨N/ --N N /
\/ \____/N
\ _____________________________________________________________ / =
, , ,
0
O I\17f /--\
/ ___ \ /¨\ i¨Np /......1f-- \ HN-- __0/--\ __ rN\__7¨)r r
--0 \¨N N \N---/ NH
0 =
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/--\
N/ __
/--\ /-N N-)r ,
0 0-/ \- NH - -0 /--\ -/- \ __ )
- _r\i'Fil
0
0 0 =
; ;
/--\
/--\ /-N N / ->/_
--N N" \- NH --N N/\ )' -1\111-11
\/ . 0 \__/ 0 =
; ;
/-\ / ______ ( \N-\ il N N
/ `.rl--\N-K \N C) --N
--N ____ N ' i N \/ /
\/ 0 . N HN'
NH
; - ' 0 =
N-0 N-0
`.0'. -.- , .0-- -
; 0 =
;
N-C)
0--
. , ,0 I / --. ,.0 --
; 0 =
---
, 0 ; '00 =
;
N
v N-C) N-
-. õ0 -
0 . ,,00.,)--
; ; ;
N, --0\ N
\
0
!--
. ,¨
, ;
N-0
-0, )
- 1.õ,r- ¨
0 =
N-0 N-0
-- , --
.
, ,
N-0 N-0
-- - , --
.owo . -0c)-
, ,
N-0 N-0
-- , --
'00c)-
=
; ,
/--\ N-0 `.N N-
õ
--N N-U
;=
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NON--\_....0 N-0 N N-C) 'N N-o
- -
\_____c_...._. I
NC:,...,..,,,,-.11.)---
1.,.....,,N.,.......o,....-.õ._,õ.-X.)--
; ,
-0 ...... .......Nr3N,0N-0 .....
,,N \.....)
-- / \
N ____ N \ ON -\ = and --NIN
, .
[0269] In any aspect or embodiment described herein, 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.
CO
(yL1)
(yL1) 0_2
II 0_2 0 0
or ,
wherein:
Wu and WI-2 are each independently absent, a 4-8 membered ring with 0-4
heteroatoms,
optionally substituted with RQ, each 12Q is independently a H, halo, OH, CN,
CF3, Cl-C6
optionally substituted linear or branched alkyl, optionally substituted linear
or branched
C i-C6 alkoxy, or 2 12Q groups taken together with the atom they are attached
to, form a 4-
8 membered ring system containing 0-4 heteroatoms;
Yu is each independently a bond, optionally substituted linear or branched C1-
C6 alkyl, and
optionally one or more C atoms are replaced with 0; or optionally substituted
linear or
branched C1-C6 alkoxy;
n is 0-10; and
indicates the attachment point to the PTM or ULM moieties.
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[0270] In any aspect or embodiment described herein, 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.
(Re)0-6
(yLl )0_2 0
4111 QL 41110
n i
,
(R Q)0-6
(yLl )0_2
aln
,
(RQ)0-6
of Li )0_2
0
QL (YU )0-2
n
or
(RQ)0-6
(yLi)0_2
, AO QL (YL1)0-2
n
wherein:
Wu and WI-2 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 12Q is independently a H, halo, OH, CN, CF3,
hydroxyl, nitro, C
CH, C2-6 alkenyl, C2-6 alkynyl, optionally substituted linear or branched C1-
C6 alkyl,
optionally substituted linear or branched C1-C6 alkoxy, optionally substituted
OC1_3alkyl
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(e.g., 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, NRYL1, 0, S, NRYL2, CRYURYL2, C=0,
SO, SO2,
optionally substituted linear or branched C1-C6 alkyl and optionally one or
more C atoms
are replaced with 0; optionally substituted linear or branched C1-C6 alkoxy;
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, optionally
substituted
linear or branched C1_6 alkyl (e.g., optionally substituted by 1 or more halo
or 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;
Ryu, -YL2
tc are each independently H, OH, optionally substituted linear or
branched C1_6 alkyl
(e.g., optionally substituted by 1 or more halo or 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
indicates the attachment point to the PTM or ULM moieties.
[0271] In additional embodiments, the linker group is optionally
substituted
(poly)ethyleneglycol having between 1 and about 100 ethylene glycol units
(e.g., 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, etc.,
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.
[0272] 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
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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.
[0273]
In any aspect or embodiment described herein, the linker (L) includes an
optionally substituted Ci-Cioo alkyl (e.g., e.g., Ci, C2, C3, C4, C5, C6, C7,
C8, C9, C10, C11, C12, C13,
C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28,
C29, C30, C31, C32, C33, C34,
C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49,
C50, C51, C52, C53, C54, C55,
C56, C57, C58, C59, C60, C61, C62, C63, CM, C65, C66, C67, C68, C69, C70, C71,
C72, C73, C74, C75, C76,
C77, C78, C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91,
C92, C93, C94, C95, C96, C97,
C98, C99, or Cioo alkyl), wherein each carbon is optionally substituted with
(1) a heteroatom
selected from N, S, P, or Si atoms that has an appropriate number of
hydrogens, substitutions, or
both to complete valency, (2) an optionally substituted cycloalkyl or bicyclic
cycloalkly, (3) an
optionally substituted heterocyloalkyl or bicyclic heterocyloalkyl, (4) an
optionally substituted
aryl or bicyclic aryl, or (5) optionally substituted heteroaryl or bicyclic
heteroaryl. In any aspect
or embodiment described herein, the linker (L) does not have heteroatom-
heteroatom bonding
(e.g., no heteroatoms are covalently linker or adjacently located).
[0274]
In any aspect or embodiment describe herein, the linker (L) includes an
optionally
substituted Ci-Cioo alkyl (e.g., Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11,
C12, C13, C14, C15, C16,
C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31,
C32, C33, C34, C35, C36, C37,
C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, C52,
C53, C54, C55, C56, C57, C58,
C59, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73,
C74, C75, C76, C77, C78, C79,
C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93, C94,
C95, C96, C97, C98, C99, or
Cioo alkyl), wherein:
each carbon is optionally substituted with CRLlRL2, 0, 5, SO, S02, NRI-3,
S02NRI-3, SONRI-3,
CONRI-3, NR1-3C0NRI-'4, NRI-3S02NRI-'4, CO, cRLi=cRL2,
siRuRL2, P(0)R',
P(0)OR', NRL
3C(=NCN)NRI-'4, NRI-3C(=NCN), NR1-3C(=CN02)NRIjI, C3-11cycloalkyl
optionally substituted with 0-6 121-1 and/or RI-2 groups, C5-13
spirocycloalkyl optionally
substituted with 0-9 121-1 and/or RI-2 groups, C3-11 heteocyclyl optionally
substituted with
0-6 121-1 and/or RI-2 groups, C5-13 spiroheterocyclyl optionally substituted
with 0-8 121-1
and/or RI-2 groups, aryl optionally substituted with 0-6 121-1 and/or RI-2
groups, heteroaryl
optionally substituted with 0-6 121-1 and/or RL2 groups, where 121-1 or RI-2,
each
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independently are optionally linked to other groups to form cycloalkyl and/or
heterocyclyl moiety, optionally substituted with 0-4 RI-5 groups; and
Ru, RI-2, RI-3, RI-'4 and RI-5 are, each independently, H, halo, C1_8alkyl,
OC1_8alkyl, SC1_8alkyl,
NHC1_8alkyl, N(C1-8alky1)2, C3-licycloalkyl, aryl, heteroaryl, C3-
liheterocyclyl, 0C3-
8cyc10a1ky1, SC3_8cycloalkyl, NHC3_8cycloalkyl,
N(C3_8cycloalky1)2, N(C3_
8cycloalkyl)(Ci_8alkyl), OH, NH2, SH, SO2C1_8alkyl,
P(0)(0C1_8alkyl)(C1_8alkyl),
P(0)(0C1_8alky1)2, CC-C 1_8 alkyl, CCH, CH=CH(C 1_8 alkyl), C(C 1_8
alky1)=CH(C 1_8 alkyl),
C(C 1_8 alky1)=C(C 1_8 alky1)2, Si(OH)3, Si(C 1_8 alky1)3, Si(OH)(C 1_8
alky1)2, COC 1_8 alkyl,
CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHCi_8alkyl, SO2N(C1_8alky02,
SONHC 1_8 alkyl, SON(C1_8alky1)2, CONHC 1_8a1ky1,
CON(Ci_8alky1)2, N(C 1-
8a1ky1)CONH(C 1_8 alkyl), N(C1_8alkyl)CON(C1_8alky02,
NHCONH(C 1_8 alkyl),
NHCON(C 1_8 alky1)2, NHCONH2, N(C 1_8a1ky1)S 02NH(C 1_8a1ky1), N(C 1_8 alkyl)
S 02N(C 1-
8a1ky1)2, NH SO2NH(C1_8alkyl), NH SO2N(C1_8alky1)2, NH SO2NH2.
[0275]
In any aspect or embodiment described herein, the linker (L) does not have
heteroatom-heteroatom bonding (e.g., no heteroatoms are covalently linker or
adjacently located).
[0276]
In any aspect or embodiment described herein, the linker (L) includes about 1
to
about 50 (e.g., 1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24, 25,
26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 49, or 50)
alkylene glycol units that are optionally substituted, wherein carbon or
oxygen may be
substituted with a heteroatom selected from N, S, P, or Si atoms with an
appropriate number of
hydrogens to complete valency. For example, in any aspect or embodiment
described herein, the
linker (L) has a chemical structure selected from:
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;
00t1000,)),(%
/ m n o P
q
,cw00t.i.00H),(%
r m n o P
,
,
00t1.0f.( , H
0 N }c
. ,
r m n o r m n
i H
0 0 ON oeµ` )frr
i H
/ m s
n o P q
,
, H
OH0t1Ø1.N m)(,,
/ m n o P
%)(t00000'
s ,
m n o p
,
m n o
H ,
m n m
H
,
m m n
H
% =)4Am-.00i-.
s
m n o P
N
\00t10
,
m n o
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\
00 N
0 N
wherein carbon or oxygen may be substituted with a heteroatom selected from N,
S, P, or Si
atoms with an appropriate number of hydrogens to complete valency, and m, n,
o, p, q, r, and s
are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19,
and 20.
[0277]
In any aspect or embodiment described herein, the present disclosure is
directed
to a compound which comprises a PTM group as described above, which binds to a
target
protein or polypeptide (e.g., RAF), which is ubiquitinated by an ubiquitin
ligase and is
chemically linked directly to the ULM group or through a linker moiety L, or
PTM is
alternatively a ULM' group which is also a ubiquitin ligase binding moiety,
which may be the
same or different than the ULM group as 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.
[0278]
In any aspect or embodiment described herein, the linker group L is a group
comprising one or more covalently connected structural units independently
selected from the
group consisting of:
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/*
* I * *
X
K' * * *
* *
0 R1 R1
** / _ /* N)(* * * (:) 1
N 1
4,1\14,
- _______________________ _ - 4< )1
The X is selected from the group consisting of 0, N, S, S(0) and S02; n is
integer from 1-5, 5;
0 *
12I-1 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.
[0279] 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
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.
Exemplary PTMs
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[0280] In preferred aspects of the 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
disclosore. Any
protein in a eukaryotic system or a microbial system, including a virus,
bacteria or fungus, as
otherwise described herein, are targets for ubiquitination mediated by the
compounds according
to the present disclosure. Preferably, the target protein is a eukaryotic
protein.
[0281] PTM groups according to the present disclosure include, for example,
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: RAF inhibitors,
Hsp90 inhibitors,
kinase 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 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.
[0282] 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.
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 catrabolism), 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
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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 eurkaryotes (e.g., c-RAF, A-RAF, and/or B-RAF) 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 (e.g.,
v-RAF and/or v-Mil), among numerous others.
[0283] 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.
[0284] 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,
cardiofaciocutaneous syndrome, neurofibromatosis type 1, Costello syndrome,
Noonan
Syndrome, LEOPARD syndrome. In certain additional embodiments, the disease is
renal cell
carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer,
thyroid cancer,
pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular
carcinoma, and melanoma.
[0285] 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
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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,
cardiofaciocutaneous syndrome, neurofibromatosis type 1, Costello syndrome,
Noonan
Syndrome, LEOPARD syndrome, 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 (e.g., murine
retrovirus or avian
retrovirus, such as avian retrovirus MH2), bacteria, fungus, protozoa or other
microbe or may be
a disease state, which is caused by overexpression of a protein and/or the
presence of a protein
that is constitutively activated, which leads to a disease state and/or
condition.
[0286] 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.
[0287] 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,
as well as other small molecules that may target a protein of interest. These
binding moieties are
linked to at least one ULM group (e.g. VLM, CLM, ILM, and/or MLM) through at
least one
linker group L.
[0288] 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. 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, Bc1IBax and other partners in the apotosis pathway, C5a
receptor,
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HMG-CoA reductase, 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, Ras/Raf/MEK-ERK 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, adenosine receptors, adenosine kinase and AMP
deaminase,
purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), fames yltransferases,
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.
[0289] 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.
[0290] 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
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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 RAF 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),
among numerous others. The compositions described below exemplify some of the
members of
the small molecule target proteins.
[0291] Exemplary protein target moieties according to the present
disclosure include, RAF
inhibitors, 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).
[0292] 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 herein below are incorporated by reference herein
in their entirety.
[0293] In any aspect or embodiment described herein, the PTM is a small
molecule
comprising a B-RAF protein targeting moiety.
[0294] In any aspect or embodiment described herein, the PTM targets and/or
binds RAF.
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:
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IRPTM1
v
"pi-m/
WPTM-3 %\oµ
RPTM2 ii
II Y ¨R
II ,/ PTM PTM3
V pi- 1 Z ,7
ZpTm
RPT M4
/ \
N
/ i ----__
HO N
PTM-Ia
IRPTM1
v /
"pi-m
WPTM' 0
RPTM2 I I 0%
II \ Y
II ,,, PTM¨R PTM3
Vp-i-NIAI Z /7
Zpi-m
XPTM35 RPTM4
0
\
RRPTM5 \ // H
.......--N Z / \
S
\ ¨_____
0
XPTM36 ....... XPTM38 N
XPTM37
PTM-Ib
IRPTM1
v
"pi-m/
\NPTM-; µµ0%
IIII
Y ¨R
II , , PTM PTM3
Vpi-a Z /7
RPTM2a ZpTm
RPTM4
/ \RPTM2b
-----_____.
N
PTM-Ic ,
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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;
Xplm35, XPTM36, XPTM37, and XPTM38 are independently selected from CH and N;
RpTM1 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 Ml is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
RpTm2a and RPTM2b is hydrogen, OH, halogen;
RPTM3 is absent, hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl,
OCH3, NHCH3 or
M1-CH2-CH2-M2, wherein Ml 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 Ml is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle; and
RPTM5 is selected from the group consisting of
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F FN
N -------------------------- N --
N..-----\
/N
\N \
/ -----) > -------------- ( /N -------------------- F ¨0-
0 ---------------- F Ime¨ON ------- F ww--0- ------ F ________ ON
, F F
, N------\
\N 7 HO----)
N N
/ HO HO\
HOV---j
HO----....) /
HO
[0295] 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-Ilb:
RPTM5a RPTM6a
RPTM8
\ 0 RPTM7 1
\ XPTM3 RPTM9
RPTM6 XPTM2 XPTM4
1 1 1
f`PTM1% XPTM5
vRpTimi 0
RPTM6b /
1 XPTM6
1
N N RPTM1 1
/
RPTM6c
PTM-IIa or
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RPTM6a
RPTM5a RPTM8
\ 0 RPTM7
RPTM9
RPTM6 N
1
XPTM1 N
RPTM6b /
1 RPTM10
N RPTM11
N
/
RPTM6c
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
RPTM5 0 \ , /RPTM5b
,
\, S N/
- --, NH
,
_ -
propyl, or butyl group), H, ---"µ. - , ---.i. , -NHC(0)RpTm5;
RPTM5 is selected from the group consisting of
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F..............\ FN
N N --
...------\ Fo_ F
N...-----\
/N
\N \
F -0-
0 ------------- F Ime-ON ------- F ww-0.- ------- F _______ ON
..............\
,
\, N------\ 7 HO'.....) , ,
F F
1 N N
Z/
/N HO HO HO
\
HO'.....) /
HO
,
RpTM5b is hydrogen or a linear or branched C1-C4 alkyl (e.g., methyl or
ethyl);
Rm-m6a and RPTM6b are each independently selected from hydrogen, halogen, or
optionally
substituted linear or branched C1-C6 alkyl;
RpTM6 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-
CH2-M2,
wherein Ml is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
RpTM6c is hydrogen or a linear or branched C1-C4 alkyl (e.g., methyl or
ethyl);
RpTM7 is absent, hydrogen, halogen, aryl, methyl, ethyl, 0CH3, NHCH3 or M1-CH2-
CH2-M2,
wherein Ml 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, 0CH3,
NHCH3 or M1-CH2-CH2-M2, wherein Ml is CH2, 0 and NH, and M2 is hydrogen,
alkyl,
cyclic alkyl, aryl or heterocycle;
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RpTmii is absent, hydrogen, halogen, methyl, ethyl, OCH3, NH CH3 or M 1-CH2-
CH2-M2,
wherein Ml is CH2, 0 or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
and
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, or two of RPTM8, RPTM9, and RPTM10 are
modified to form a polycyclic (e.g., bicyclic) fused ring with a chemical
linker group.
[0296] In certain embodiments, the PTM may comprise a chemical group
selected from the
group of chemical structures consisting of:
RPTM5 0
\
" s,
" ----NH
0 RPTM6a
RPTM8
I
0 RPTM7
XPTM3 PR TM9
RPTM6 "PTM2 "PTM4
v 1 11
"PTM1 ........................,... _.,..õ. XPTM....5R Frmi 0
RPTM6b /
1 XPTM6
I
N
RPTM11
H
or
RPTM5 0
\s,
, 'NH
0 RPTM6a
RPTM8
0 RPTM7
\.........../.=........ ,..,./. R PTM9
RPTM6 N
1
XPTM1....................õ,, N.,,................./"........
RPTM6b /
1 RPTM10
N
RPTM11
H
,
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wherein RPIM5, RPIM6a, RPIM6b, RpTM6, RpT1\47, Rpl-M8, RpTM9, Rp1M10, RpTmll
are as described
herein.
[0297] In some embodiments, when RpTm9 is the covalently joined position,
RpTm7 and RpTms
can be connected together via a covalent bond in a way to form a bicyclic
group with the ring to
which RPTM7 and RPTM8 are attached.
[0298] 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.
[0299] 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.
[0300] 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:
0 XPTM6
XPTM15
RPTM13
1 RPTM14 I
\ .........,XPTM10 RPTM12
H oõ. XPTM17 0 RPTM17 XPTM1 .r XPTM9
i
RPTM18 \ 1 1
y \
- -PTM20j XP-
IN/..1.=,.............õ........ .../..XPTM....8
y 8 N XPTM 12
XPTM7 RPTM16
z,PTM19
x 11 I
/ PTM13 RPTM19 -------XPTM18
RPTM15
\ N N
H 0
RPTM20
RPTM21
PTM-III
wherein:
XpTm7, XpTm8, XpTm9, XpT1\410, XPT1V111, XPTM12, XPTM13, XPTM14, XPT1VI15,
XPT1VI16, XPTM17,
XpTM18, XPTM19, XPTM20 are independently CH or N;
RpTm12, RPT1VI13, RPT1VI14, RPTM15, RPTM16, RPTM17, RPT1VI18, RPT1VI19 are
independently selected
from the group consisting of absent, hydrogen, halogen, aryl, heteroaryl,
cycloalkyl,
heterocycle, methyl, ethyl, other alkyl, OCH3, NHCH3 or M 1-CH2-CH2-M2,
wherein Ml
is CH2, 0 and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or
heterocycle;
RpTm20 is a small group containing less than four non-hydrogen atoms;
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RpTA421 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 M 1-CH2-CH2-M2, wherein Ml 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.
[0301] 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 Rplmi4 are attached; and/or Rplmi5 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.
[0302] 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 Rplmi6 are attached; and/or Rplmi5 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.
[0303] 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 Rplmi3 are attached; and/or Rplmi3 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.
[0304] 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:
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RPTM22 0
\s,
,-- ------ NH
RPTM25a RPTM26 N
0 ..õ..- '
I /
RPTM25 ,,PTM29 ) \ ,, \
XPTM21 APTM23
x \ N N .,..../ XPTM27
XPTM28 roo.
¨PTM22 .4"-4"--
------
RPTM27
RPTM29
RPTM25b XPTM26 RPTM30 /
XPTM24 4
_ 1
% APTM34 --------X733
XPTM25 \
APTM32
/N \ II
XPTM30-----XPTM31
RPTM23 \
RPTM31/ RPTM32
PTM-IVa or
RPTM22 0
\s,
,-- ----- NH
RPTM25a RPTM26 N
0
XPTM2 y .õ=0' .
I /
RPTM25 APTM23
x \ N .....,..,XPTM27
XPTM28 Nizo
¨PT NM
22 "s"'"'
/ "PTM28
----
RPTM27
RPTM29
RPMT25b XPTM26 RPTM30 /
XPTM24
õ I
%.-----K APTM34---XPTM33
XPTM25 RPTM24
XPTM32------
N
/ /
----XPTM31
RPTM23 XPTM30
/ \
RPTM31
RPTM32
PTM-IVb ,
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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
F....._____\ F
N.------\
N ------------------------ N --
..-----N Fµc> F
--------------------------------------------------------------- /N
\N \
F -0-
0 ---------------- Fiona-ON ------ Fmn.-0- -------- F _______ ON
/ HO F....._____\ F
,
, N.-------\
\ '.......) /
N N
/ HO HO" HOZ/
HO'.......) /
HO
RPTM25a 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 Ml 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
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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;
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.
[0305] .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 RpTm31 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.
[0306] 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 RpTm3i and RpTm32 can be
connected
together via a covalent bond in a way to form a bicyclic group with the ring
to which RpTm31 and
RpTM32 are attached.
[0307] 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.
[0308] In any aspect or embodiment described herein, the PTM may comprise a
chemical
group selected from the group of chemical structures consisting of PTM-Va or
PTM-Vb:
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RPTM35
RPTM34
1 RPTM36
\ XPTM36 /
XPTM35 X
(D PTM37 1'PTM37
1 1
H....,===******. "TM38 1 RPTM38
N XPTM39
µ,,,,,
RPTM33
RPTM39
or
PTM-Va
RPTM35
RPTM34
v 1 ,RPTM36
\ "PTM36 /
0
/
XPTM35 XPTM37 1'PTM37
1 v 1
0 H
N
^PTM38 v RPTM38
"PTM39
.,
RPTM33 N
,-,
µ..,
,
PTM-Vb
wherein:
XpTm35, XPTM36, XPTM37, XPTM38, and XPTM39 are independently CH or N;
RPTM33 is a halogen or a linear or branched C1-C4 haloalkyl;
RPTM34, Rpm, RPTM36, RPTM37, and RPTM38 are each independently selected from
hydrogen,
halogen, or linear or branched C1-C4 alkyl (e.g., methyl, ethyl, propyl, or
butyl);
RpTm39 is an optionally substituted C4-C7 heterocycloalkyl (e.g., an
optionally substituted C5
or C6 heterocycloalkyl); and
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N is the point of attachment with 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.
[0309] 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,
PTM-8, PTM-9, PTM-10, PTM-11, PTM-12, and PTM-13:
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F,
0
0/ F
,N N
HO N 0 ,-
õ--
IN N
H
PTM-1
PTM-2
P p
s
õ - NH õ
F N__--..,('6W 0
0
0 --
. NH 1 "
0
F H
N N F F
H
PTM-3 PTM-4
P
0\, H F
NH
SP" F 0 F
N õ 0
rN--
N
1
N N
H
PTM-5 PTM-6
Nz-_¨\
/ 1 0\pH F
\S"
efit N
õ-- I
N 1 N F N\)
1
PTM-7 PTM-8
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F F
\N-$"-.1\1H
O F d F
I I
F /
N N N N
H H
PTM-9 PTM-10
,
,
,
HO I N
I /N
/ \ H
CI O
CI
¨N
PTM-11 PTM-12
0 N
1 /
H 1 N
N
F F F (o)
PTM-13
[0310] .. In any aspect or embodiment described herein, the ULM is selected
from the group
consisting of:
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-_ 0 __ _ _
- _
0
0
N 0 0 0 N 0
N N
,...14H 0 tIZH
0 .r1\1H
0 0
0
- - * = OH
N 0 0 N
- NR)r0 )r0 ---"\-\ 0 0 N `-'
.rNH NH
OH
0 0
N /S
1
0 0 4 \I STh S
\--NH ---kd \ N
HN
OH
ii
0 .
bH
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I
S \ N
lk D R14a
"14a
OH
0 Nv......0 ¨ = ONL.,.._ NH
H S ---\
0 R14a
OH
OH
OH
N ,
N \ N
R14a
- - 4110
OH
/ S
N-:-.--J
,
wherein the R14a is a H, methyl or hydroxymethyl.
[0311] In any aspect or embodiment described herein, at least one of: (i)
the PTM is selected
from the PTMs of compounds 1-873 or 307-873 of the present disclosure; (ii)
the chemical
linker group (L) is selected from the linkers of compounds 1-873 or 307-873 of
the present
disclosure; (iii) the ULM is selected from the ULMs of compounds 1-873 or 307-
873 of the
present disclosure; (iv) the compound further comprises a prodrug chemical
moiety selected
from the PTMs of compounds 796-873, or (v) a combination thereof.
[0312] In any aspect or embodiment described herein, the ULM is selected
from the group
consisting of:
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\o
\ 00
00 'NH
NH N 0
N 0 R
R 0
..----\ F---No 00
0 0 0
N H
'NH
N )o N
0
R R
0 0
\,--\
0 0 )-----NO 0 0
NH 'NH
N 0 N 0
R R
0 0
0 0\ 1() 0 0
NH
'NH
N 0 N 0
R R
0 0
. 0 00' 00
NH CI 'NH
N 0 N 0
R R
0 0
00 00
F NH F NH
N ) 0 _________ N __
? 0
R
0 R
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F 00 00 /
NH N
N 0 N
0
R R
0 0
00 00
NH NH
N 0 N 0
R
R 0
R 00 00
NH R \ __ NH
N 0 N 0
00
\ __________________________________________________________________ NH
00
N 0
H
N
N 0
R R
00 00
NH _______________________________________ NH
Ni^-- ) __ 0 Niiii,.. \ ) __ 0
R R
HO\ OH
13/
o 0 /-0
0
R N
N 0 NH
0 0
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i
o1
0
H
NNH
N H
0 0
o
pH p H
0
H
0 -/0 0
0
HN HN
F
0
1110 0
H
NNH S S
\ \
0 0 N
pH gH QH
0 0 0
1\11-- .--I \I\I-;
, N
---- -N N - ------N
H H H
0 0 0 0 0
HN HN HN
0
110 111110
S S S
\ \ N \
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PH PH
0 0
-- N
H 0 0 H 0 0
HN HN
OH
110 1.
S S
N \ N \
pH pH pH
0 0 0
-----INN -'---IN -
H H H
0HN/LO 0 0 0 1\fl
HN HN ,/LO
OH
110 0 0
S S \ S
N \ N \ \ 0
N
pH pH
0 0
-'"--N ------N
H H
0 0 0 0
HN HN
/
0 0
S S
N \ N \
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pH pH
0 p
0
-- N
H H
0 0 0 0
HN HN
0--__
7----../
O0
110 o
s s
pH pH p H
0 0
- -----ININ *
H H H
0 0 0 0 0 0
110 0 111
S S S
N \ \ N \
N
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pH pH
0 0
-----icli\ri-
------jN
H H
0 0 0 0
HN HN
0 0 0
S s
N \ \
\OH õ, pH
- \
I
N \
N.i
N-0 N-0
0 0
0 0
NH NH
S fh
\\ s .
\\ /
N/ N
CI CI
õ OH , õ,
sOH
õ " \
\
Ni N Ni
\
N-0 -0
0 0
HN HN
0 0
S 4#
( / S *
( /
N N
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H \OH \ \
N-0 N N-0 Ni
0 0
HN HN
0 0
S * S 4#
N N
õ
N
N
=
P H \O
\
Ni
0 0
HN HN H
0 0
S * S 4#
N N
10H
\
N-0 N N-0
0 0 XHN HN
0 0
S * S *
N N
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\----
\OH õµ
/ /NN
/
/N; N---N
--- N
0 0
0 0
NH NH
/S * /S *
/ /
N N
9H
\/ HO,,
----,N
v C)
tNi 0 0
0 HN
HN
ro
-N 410
S
\ S
\----=---N
HO,
C)
HN
0
r0 .
-N
S
\---=----N
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OH
,
0
.--i INC
OH N".
--
H
0
N 10HN
-- N
0
H
----N N
pH pH pH
,
0
-- N
H H H
0 0 0 0 0 0
HN HN HN
OH
. \ .
N
N/ \
\ o
pH o
õIL
0
--- 1\---1-
H
0 0 0
HN
00H
110 0
S
N \
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pH OH
H H
0 0 0 0
HN HN
0.....s.,..--...... ..,--. --...õ,,OH
0
0,...,
0 0 0
S S
\ \
N N
OH pH
0 - 0 .õ
N.
H H
0 0 0 0
HN / HN
0
S S 1
\ I
N and N .
Prodrug Bifunctional Compounds
[0313]
In any aspect or embodiment described herein, the bifunctional compound of the
present disclosure or the prodrug thereof further includes a plurality of
ethylene glycol units. In
any aspect or embodiment described herein, the bifunctional compounds of the
present
disclosure or the prodrug thereof further includes at least one (e.g., 1, 2,
3, 4, 5, 6, 7, 8, or more)
polyethylene glycol (PEG) chain. In any aspect or embodiment described herein,
the
bifunctional compound of the present disclosure or the prodrug thereof further
includes a
plurality (e.g., 2, 3, 4, 5, 6, 7, 8, or more) polyethylene glycol chains that
have uniform chain
length or a mixture of chain lengths. In any aspect or embodiment described
herein, the
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bifunctional compound or the prodrug thereof further includes a prodrug
portion selected from
exemplary compounds 796-873.
[0314] In any aspect or embodiment described herein, the bifunctional
compound of the
present disclosure or the prodrug thereof further includes at least one (e.g.,
1, 2, 3, 4, 5, 6, 7, 8,
or more) polyethyelene glycol chain as described herein, wherein each
polyethylene glycol chain
is covalently linked to the bifunctional compound at the same point as the PEG
chain attachment
in a compound selected from exemplary compounds 796-873. In any aspect or
embodiment
described herein, each PEG chain is attached directly or indirectly via a
variable (e.g., via a
methyl group or an 0) or in place of a variable of the VLM described herein
(e.g., RP, R14a, R14b,
W4, W5, RF, R2', R3'), the CLM described herein (e.g., G or G'), or a PTM as
described herein
(e.g., Rp1m6c). For example, in any aspect or embodiment described herein with
a VLM, the RP,
Ri4A, Ri4b, or a combination thereof is modified to be covalently linked
(e.g., the hydroxyl group
a
of RP or RR1', the methyl group of R14, R14b, or W5 is modified to be
covalently linked) directly
or indirectly to a moiety that includes a PEG chain or is replaced with a
moiety that includes a
PEG chain. Additionally, in any aspect or embodiment described herein with a
CLM, the G, G',
or a combination thereof is modified to be covalently linked (e.g., they
methyl of G or G' is
modified to be covalently linked) directly or indirectly to a moiety that
includes a PEG chain or
is replaced with a moiety that includes a PEG chain.
[0315] In any aspect or embodiment described herein, the bifunctional
compound of the
present disclosure or the prodrug thereof includes at least one (e.g., 1, 2,
3, 4, 5, 6, 7, 8, or more)
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O 0 0
' '0A0C)OH ' -0)-LO -"I 0
L (jskOH - -
13L0(3)`
k
I r r r
O 0 0
r r 0 r
0 0 0
., 0 00H
0 Or --1/y3sor
0 r 0 r 0 ' r
O 0 0 0
0 0) --1L40)' = ).
r r r r
0 0
0 0
= , )=,0,0).
-,())0.(,
Or
I r \
I r
O 0 0 0
H H 1 1
N N =&./or - ,c)),r Nor ,,I.r N Vor
'(.0) - "j-r k
0 r 0 r 0 r 0 r
O 0 0 0 0 0
,-1-0j-LN-03,
0 '0
H r H r r
O 0 0 0 0 0
= ,(3,0j-N,C31) , lo J.N,t'(39 ,,k0j-LoO)
I r I r r
0 0
- ssN
N
r r
,
wherein r is an integer from 8 to 35 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35). For example, in any
aspect or embodiment
described herein with a VLM, the RP, R14A, R14b, or a combination thereof is
modified to be
a
covalently linked (e.g., the hydroxyl group of RP, the methyl group of R14,
R14b, or W5 is
modified to be covalently linked) directly or indirectly to one of the above
recited structures or is
replaced with one of the above recited structures. Additionally, in any aspect
or embodiment
described herein with a CLM, the G, G', or a combination thereof is modified
to be covalently
linked (e.g., they methyl of G or G' is modified to be covalently linked)
directly or indirectly to
one of the above recited structures or is replaced with one of the above
recited structures. For
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example, in any aspect or embodiment described herein, each PEG chain can be
attached to the
VLM, CLM, or PTM via a chemical group selected from:
I 0 0 0 0 0
'0 0'
0 0 0
0 0
0 0 0 0
,,LO,
0 0 0 0
0 0 -
0 0 0 0
0 0 0 0 0 0
0 0 0 0 0
0 0
N
=
[0316] In any aspect or embodiment described herein, the polyethylene
glycol chain of the
bifunctional compound or prodrug thereof includes or is about 8 ethylene
glycol units to about 35 (e.g., 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 31, 32, 33, 34,
or 35), about 10 ethylene glycol units to about 35 ethylene glycol units
(e.g., about 10 to about 35
ethylene glycol units, about 10 to about 30 ethylene glycol units, about 10 to
about 25 ethylene glycol
units, about 10 to about 20 ethylene glycol units, about 10 to about 15
ethylene glycol units, about 15 to
about 35 ethylene glycol units, about 15 to about 30 ethylene glycol units,
about 15 to about 25 ethylene
glycol units, about 15 to about 20 ethylene glycol units, about 20 to about 35
ethylene glycol units, about
20 to about 30 ethylene glycol units, about 20 to about 25 ethylene glycol
units, about 25 to about 35
ethylene glycol units, about 25 to about 30 ethylene glycol units, or about 30
to about 35 ethylene glycol
units).
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[0317] In any aspect or embodiment described herein, methoxy polyethylene
glycol, or
polyethylene-glycol capped with a methyl group on one end, having an average
molecular weight of 1000
(such as mPEG-1000) may be used to prepare a prodrug bifunctional compounds of
the present disclosure.
For example, in any aspect or embodiment, methoxy polyethylene glycol, or
polyethylene-glycol capped
with a methyl group on one end, having an average chain length of 22 units
(such as mPEG-1000) may
be used to prepare a prodrug bifunctional compounds of the present disclosure.
The methods described
herein can be used to make longer or shorter PEG chains, of uniform or diverse
chain lengths.
[0318] In any aspect or embodiment described herein, the prodrug
bifunctional compound of the
present disclosure has a percent release of at least about 10%. For example,
in any aspect or embodiment
described herein, the prodrug bifunctional compound of the present disclosure
has a percent release of at
least about 10%, at least about 15%, at least about 20%, at least about 25%,
at least about 30%, at least
about 35%, at least about 40%, at least about 45%, at least about 50%, at
least about 55%, at least about
60%, at least about 65%, at least about 70%, at least about 75%, at least
about 80%, at least about 85%, at
least about 90%, about 10% to about 90%, about 10% to about 80%, about 10% to
about 70%, about 10%
to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to
about 30%, about
20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to
about 60%, about
20% to about 50%, about 20% to about 40%, about 30% to about 90%, about 30% to
about 80%, about
30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 40% to
about 90%, about
40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 50% to
about 90%, about
50% to about 80%, about 50% to about 70%, about 60% to about 90%, or about 60%
to about 80%, about
70% to about 90%, at about 30 minues, about 60 minues, about 1.5 hours, about
2 hours, about 2.5 hours,
about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours,
about 4.5 hours, about 6
hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about
8.5 hours, about 9 hours,
about 9.5 hours, or about 10 hours.
[0319] In any aspect or embodiment described herein, the prodrug
bifunctional compound of
the present disclosure has a half life of at least about 60 minutes. For
example, in any aspect of
embodiment described herein, the prodrug bifunctional compound of the present
disclosure has a
half life serum or plasma (e.g., human, cyano monkey, rat, mouse, pig, dog,
cat, etc., serum or
plasma) of less than or equal to about 1 minute, less than or equal to about 5
minutes, less than
or equal to 10 minutes, less than or equal to about 15 minutes, less than or
equal to about 30
minutes, less than or equal to about 45 minutes, less than or equal to about 1
hour, less than or
equal to 1.5 hours, less than or equal to about 2 hours, less than or equal to
about 2.5 hours, less
than or equal to about 3 hours, less than or equal to about 3.5 hours, less
than or equal to about 4
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hours, less than or equal to 4.5 hours, less than or equal to about 5 hours,
less than or equal to
about 5.5 hours, less than or equal to about 6 hours, less than or equal to
about 6.5 hours, less
than or equal to about 7 hours, less than or equal to about 7.5 hours, less
than or equal to about 8
hours, less than or equal to 8.5 hours, less than or equal to about 9 hours,
less than or equal to
9.5 hours, less than or equal to about 10 hours, less than or equal to about
11 hours, less than or
equal to about 12 hours, less than or equal to about 14 hours, less than or
equal to about 16 hours,
less than or equal to about 18 hours, less than or equal to about 20 hours,
less than or equal to
about 22 hours, less than or equal to about 24 hours, less than or equal to
about 26 hours, less
than or equal to about 28 hours, less than or equal to about 30 hours, less
than or equal to about
32 hours, less than or equal to about 34 hours, less than or equal to about 36
hours, less than or
equal to about 38 hours, less than or equal to about 40 hours, less than or
equal to about 42 hours,
less than or equal to about 44 hours, less than or equal to about 46 hours,
less than or equal to
about 48 hours, less than or equal to about 50 hours, about 15 seconds to
about 50 hours, about
15 seconds to about 45 hours, about 15 seconds to about 40 hours, about 15
seconds to about 35
hours, about 15 seconds to about 30 hours, about 15 seconds to about 25 hours,
about 15 seconds
to about 20 hours, about 15 seconds to about 15 hours, about 15 seconds to
about 10 hours,
about 15 seconds to about 5 hours, about 30 seconds to about 50 hours, about
30 seconds to
about 45 hours, about 30 seconds to about 40 hours, about 30 seconds to about
35 hours, about
30 seconds to about 30 hours, about 30 seconds to about 25 hours, about 30
seconds to about 20
hours, about 30 seconds to about 15 hours, about 30 seconds to about 10 hours,
about 30 seconds
to about 5 hours, about 1 minute to about 50 hours, about 1 minute to about 45
hours, about 1
minute to about 40 hours, about 1 minute to about 35 hours, about 1 minute to
about 30 hours,
about 1 minute to about 25 hours, about 1 minute to about 20 hours, about 1
minute to about 15
hours, about 1 minute to about 10 hours, about 1 minute to about 5 hours,
about 1 to about 50
hours, about 1 to about 45 hours, about 1 to about 40 hours, about 1 to about
35 hours, about 1 to
about 30 hours, about 1 to about 25 hours, about 1 to about 20 hours, about 1
to about 15 hours,
about 1 to about 10 hours, about 1 to about 5 hours, about 5 to about 50
hours, about 5 to about
45 hours, about 5 to about 40 hours, about 5 to about 35 hours, about 5 to
about 30 hours, about
to about 25 hours, about 5 to about 20 hours, about 5 to about 15 hours, about
5 to about 10
hours, about 10 to about 50 hours, about 10 to about 45 hours, about 10 to
about 40 hours, about
to about 35 hours, about 10 to about 30 hours, about 10 to about 25 hours,
about 10 to about
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20 hours, about 15 to about 50 hours, about 15 to about 45 hours, about 15 to
about 40 hours,
about 15 to about 35 hours, about 15 to about 30 hours, about 15 to about 25
hours, about 20 to
about 50 hours, about 20 to about 45 hours, about 20 to about 40 hours, about
20 to about 35
hours, about 20 to about 30 hours, about 25 to about 50 hours, about 25 to
about 45 hours, about
25 to about 40 hours, about 25 to about 35 hours, about 30 to about 50 hours,
about 30 to about
45 hours, about 30 to about 40 hours, about 35 to about 50 hours, about 35 to
about 45 hours,
about 40 to about 50 hours, in serum (e.g., human sera, monkey sera, dog sera,
cat sera, pig sera,
horse sera, etc.).
Therapeutic Compositions
[0320] 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.
[0321] 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
anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,
sulfate, bisulfate,
phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate,
bitartrate, succinate,
maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,
ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-
hydroxy-3
naphthoate)[salts, among numerous others.
[0322] 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.,
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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.
[0323] 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
disclosure may be administered in immediate release, intermediate release or
sustained or
controlled release forms. Sustained or controlled release forms are preferably
administered
orally, but also in suppository and transdermal or other topical forms.
Intramuscular injections
in liposomal form may also be used to control or sustain the release of
compound at an injection
site.
[0324] 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,
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magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol,
sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-
polyoxypropylene-block
polymers, polyethylene glycol and wool fat.
[0325] 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.
[0326] Sterile injectable forms of the compositions as described herein may
be aqueous or
oleaginous suspension. These suspensions may be formulated according to
techniques known in
the art using suitable dispersing or wetting agents and suspending agents. The
sterile injectable
preparation may also be a sterile injectable solution or suspension in a non-
toxic parenterally-
acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
Among the acceptable
vehicles and solvents that may be employed are water, Ringer's solution and
isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or
suspending medium. For this purpose, any bland fixed oil may be employed
including synthetic
mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride
derivatives are useful in
the preparation of injectables, as are natural pharmaceutically-acceptable
oils, such as olive oil
or castor oil, especially in their polyoxyethylated versions. These oil
solutions or suspensions
may also contain a long-chain alcohol diluent or dispersant, such as Ph. Hely
or similar alcohol.
[0327] 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.
[0328] Alternatively, the pharmaceutical compositions as described herein
may be
administered in the form of suppositories for rectal administration. These can
be prepared by
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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.
[0329] 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.
[0330] 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
disclosure 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 disclosure, 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.
[0331] Alternatively, the pharmaceutical compositions can be formulated in
a suitable lotion
or cream containing the active components suspended or dissolved in one or
more
pharmaceutically acceptable carriers. Suitable carriers include, but are not
limited to, mineral oil,
sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-
octyldodecanol,
benzyl alcohol and water.
[0332] 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.
[0333] 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.
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[0334] 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.
[0335] 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.
[0336] 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.
[0337] 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.
[0338] 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.
[0339] 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
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mg of active ingredient per unit dosage form. An oral dosage of about 25-250
mg is often
convenient.
[0340] 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.
[0341] 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.
[0342] 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.
[0343] 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
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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.
[0344] 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.
[0345] 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
disclosure, 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.
[0346] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical
application can include the following components: a sterile diluent such as
water for injection,
saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol
or other synthetic
solvents; antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as
ascorbic acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid;
buffers such as acetates, citrates or phosphates and agents for the adjustment
of tonicity such as
sodium chloride or dextrose. The parental preparation can be enclosed in
ampoules, disposable
syringes or multiple dose vials made of glass or plastic.
[0347] If administered intravenously, preferred carriers are physiological
saline or phosphate
buffered saline (PBS).
[0348] 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.
[0349] 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
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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.
Therapeutic Methods
[0350]
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.
[0351]
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,
cardiofaciocutaneous syndrome, neurofibromatosis type 1, Costello syndrome,
Noonan
Syndrome, LEOPARD (Lentigo, Electrocardiographic abnormalities, Ocular
hypertelorism, or
Pulmonary stenosis, Abnormal genitalia, Retarded growth, Deafness) syndrome,
which may be
treated using compounds according to the present disclosure are set forth
hereinabove.
[0352]
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, cardiofaciocutaneous syndrome, neurofibromatosis type 1,
Costello syndrome,
Noonan syndrome, or LEOPARD (Lentigo, Electrocardiographic abnormalities,
Ocular
hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth,
Deafness) syndrome.
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
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herein comprising, e.g., a ULM and a PTM, preferably linked through a linker
moiety, as
otherwise described herein, wherein the ULM is coupled to the PTM and wherein
the ULM
recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, such as an
E3 ubiquitin ligase
including cereblon, VHL, TAP, and/or MDM2) 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.
[0353] In additional embodiments, the description provides methods for
treating or
ameliorating 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.
[0354] 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.
[0355] 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 the patient,
the method
comprising administering to a patient in need an effective amount of a
compound according to
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 and/or overactivation (e.g., a constitutively active) of a
protein, which leads to a
disease state and/or condition
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[0356] 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.
[0357] Disease states or 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.
[0358] 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
melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma,
hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral
neuroepithelioma,
synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas,
gliobastomas,
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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 CML.
[0359] 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, anti-retrovirus and
anti-HCV agents,
antimicrobial agents, antifungal agents, etc.
[0360] 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
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,
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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-[442-(2-amino-4,7-dihydro-4-oxo-1H-
pyrrolo[2,3-
d[pyrimidin-5-yl)ethyl[benzoyll-, disodium salt, heptahydrate, camptothecin,
PEG-labeled
irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,
DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,
bevacizumab, IMC-1C11,
CHlR-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, levamisole, 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,
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-
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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.
[0361] The term "anti-HIV agent", "anti-retroviral", 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.
[0362] Other anti-HIV/anti-retrovirual 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-
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chloro-3 -(3 -methyl-2-butenyloxy)phenyl] -2methy13-furancarbothiamide),
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' -dichloro-4' ,4"-dimethoxy-5',5"-bis(methoxycarbony1)-6,6-
diphenylhexenoate), Methyl 3-
Bromo-5-(1-5-bromo-4-methoxy-3 -(methoxyc arb onyl)phenyl)hept-l-eny1)-2-
methoxybenzoate
(Alkenyldiarylmethane 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] -
4- [3 -(is oprop ylamino)-2-p yridinyl] piperazine, 1-
[5-[[N-(methyl)methylsulfonylamino]-2-
indolylcarbony1-4- [3 -(is oprop ylamino)-2-p yridinyl] piperazine, 1- [3 -
(Ethylamino)-2- [pyridinyl] -
4- [(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-
[(6-Formy1-2-indolyl)carbonyl]-443-
(isopropylamino)-2-pyridinyl]piperazine, 1- [[5-(Methylsulfonyloxy)-2-
indoyly)carbony1]-4- [3-
(isopropylamino)-2-pyridinyl]piperazine, U8 8204E, Bis(2-nitrophenyl)sulfone
(NSC 633001),
Calanolide A (NSC675451), Calanolide B, 6-B enzy1-5-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)methy1]-6-(phenylthio)thymine),
HEPT-M (1- [(2-
Hydroxyethoxy)methyl] -6-(3-methylphenyl)thio)thymine), HEPT-S
(1-[(2-
Hydroxyethoxy)methy1]-6-(phenylthio)-2-thiothymine), Inophyllum
P, L-737,126,
Michellamine A (NSC650898), Michellamine B (NSC649324), Michellamine F, 6-(3,5-
Dimethylbenz y1)- 1- [(2-hydroxyethoxy)methyl] -5-isopropyluracil, 6-
(3,5-Dimethylbenzy1)-1-
(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), Oltipraz (4-
Methy1-5-
(pyraziny1)-3H-1,2-dithiole-3-thione), N-
12-(2-Chloro-6-fluorophenethyl] -N' -(2-
thiazolyl)thiourea (PETT Cl, F derivative), N-12-(2,6-Difluorophenethyl] -N' -
[245-
bromop yridyl)] thiourea 1PETT
derivative), N-12-(2,6-Difluorophenethyl] -N' - [245-
methylpyridyNthiourea 1PETT Pyridyl derivative), N-[2-(3-Fluorofuranyl)ethyl]-
N' - [245-
chlorop yridyl)] thiourea, N- [2-(2-Fluoro-6-ethoxyphenethyl)] -N' - [2-(5-
bromopyridy1)] thiourea,
N-(2-Phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697,639, L-697,593, L-
697,661, 342-
(4,7-Difluorobenzoxazol-2-yl)ethyl } -5-ethyl-6-methyl(pypridin-2(1H)-thione
(2-Pyridinone
Derivative), 3- [[(2-Methoxy-5,6-dimethy1-3-pyridyl)methyl] amine] -5-ethy1-6-
methyl(pypridin-
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-
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Dimethylpheny1-2,3-dihydrothiazolo [2,3-a] isoindo1-5(9bH)-one, Tivirapine
(R86183), UC -38
and UC-84, among others.
[0363] 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.
[0364] 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.
General Synthetic Approach
[0365] 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.
[0366] In a very analogous way one can identify and optimize ligands for an
E3 Ligase, i.e.
ULMs/ILMs/VLMs/CLMs/ILMs.
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[0367] 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
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.
[0368] 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).
[0369] List of Abbreviations
[0370] AcOH, acetic acid
[0371] aq., aqueous
[0372] BINAP, 2,2 '-bis(diphenylphosphino)-1,1 '-binaphthalene
[0373] Boc, tert-butoxycarbonyl
[0374] Boc20, di-tert-butyl dicarbonate
[0375] BOP, (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hex
afluoropho sphate
[0376] CDC13, deuteriochloroform
[0377] CD30D, deuteriomethanol
[0378] CH3CN, acetonitrile
[0379] CH3OH, methanol
[0380] CsF, cesium fluoride
[0381] Cs2CO3, cesium carbonate
[0382] Cu(OAc)2, copper (II) acetate
[0383] Cy2NMe, dicyclohexylmethylamine
[0384] DCM, dichloromethane
[0385] DIAD, diisopropyl azodicarboxylate
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[0386] DIEA or DIPEA, diisopropylethylamine
[0387] DMAP, N,N-dimethylaminopyridine
[0388] DMF, N,N-dimethylformamide
[0389] DMSO, dimethylsulfoxide
[0390] DMSO-d6, hexadeuterodimethyl sulfoxide
[0391] Et2NH, diethylamine
[0392] Et0Ac or EA, ethyl acetate
[0393] HC1, hydrochloric acid
[0394] H20, water
[0395] HPLC, high performance liquid chromatography
[0396] IBX, 2-iodoxybenzoic acid
[0397] KOAc, potassium acetate
[0398] LCMS, liquid chromatography / mass spectrometry
[0399] Li0H, lithium hydroxide
[0400] Me0H, methanol
[0401] MsCl, methanesulfonyl chloride
[0402] N2, nitrogen
[0403] NaH, sodium hydride
[0404] NaBH3CN, sodium cyanoborohydride
[0405] NaBH(OAc)3, sodium triacetoxyborohydride
[0406] NaCl, sodium chloride
[0407] NaHCO3, sodium bicarbonate
[0408] NaI, sodium iodide
[0409] Na2SO4, sodium sulfate
[0410] n-BuLi, n-butyllithium
[0411] NH3, ammonia
[0412] NH4C1, ammonium chloride
[0413] NH2OH HC1, hydroxylamine hydrochloride
[0414] NMP, N-methylpyrrolidone
[0415] NMR, nuclear magnetic resonance
[0416] 02, oxygen
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[0417] Pd(aMPhos)C12, bis(di-tert-buty1(4-
dimethylaminophenyl)phosphine)dichloropalladium(II)
[0418] Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0)
[0419] Pd(dppf)C12, [1,11-
bis(diphenylphosphino)ferrocene[dichloropalladium(II)
[0420] Pd(OH)2, palladium hydroxide
[0421] Pd(PPh3)4, tetrakis(triphenylphosphine)palladium(0)
[0422] PE, petroleum ether
[0423] Ph3P, triphenylphosphine
[0424] Py, pyridine
[0425] PyB OP, (benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate
[0426] rt, room temperature
[0427] TBAF, tetra-n-butylammonium fluoride
[0428] TBDPSC1, tert-butyldiphenylsilyl chloride
[0429] TB S, tert-butyldimethylsilyl
[0430] tBuOK, potassium tert-butoxide
[0431] [tBu3PH[BF4, tri-tert-butyl phosphonium tetrafluoroborate
[0432] TEA, triethylamine
[0433] THF, tetrahydrofuran
[0434] TLC, thin layer chromatography
[0435] TMS OTf, trimethylsilyl trifluoromethanesulfonate
[0436] TsCl, p-toluenesufonyl chloride
[0437] Ts0H, p-toluenesulfonic acid
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[0438] Scheme 1A.
F., F
c2N- 2 0
s,
ii N
0 H F , i m' + __ M-Ar-L ________________ G-PG .. _
/ \
HN
I N II
F
F
---- F
---
HN
Ar-L-GH
III IV N-
F
0 0
op N_ a 0 ,0 F
;S/,
Y
X-L' V 0/ N
H 0 0 0
HN / \ Ar-L-Gre-L'ia Y'
VI n
N-
[0430] A compound of formula I may be reacted with a reagent II
(commercially available or
readily prepared using standard reaction techniques known to one skilled in
the art) under
palladium-catalyzed cross-coupling conditions, e.g. with a suitable palladium
catalyst such as
bis(di-tert-buty1(4-dimethylaminophenyl)phosphine)dichloropalladium(II),
suitable base such as
cesium fluoride, suitable solvent such as mixtures of 1,4-dioxane and water,
at a suitable
temperature such as 100 C, with or without microwave irradiation to produce a
compound of
formula III. One of M or M' represents a functional group capable of
undergoing palladium-
catalyzed transmetallation, e.g. a boronic acid, boronic ester, or
trialkylstannane; the other of M
or M' represents a functional group capable of undergoing palladium-catalyzed
oxidative
addition, e.g. an iodide, bromide, chloride, or trifluoromethanesulfonate; Ar
represents an
aromatic or heteroaromatic ring system; L represents an optional linker or
portion of a linker,
GI¨PG 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 III may be converted to a
compound of
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formula IV by treatment with a reagent suitable for the removal of PG, e.g.
hydrogen chloride in
1,4-dioxane when PG is t-butoxycarbonyl. Compound IV may then be reacted with
compound V
to produce compound VI, wherein L' represents an optional linker or portion of
a linker, Y is
CH2 or C=0, and X is either a suitable leaving group (e.g. OMs, OTs, Cl, etc.)
or an aldehyde
(CHO). When X is a leaving group, n is 0, and suitable reaction conditions are
those for an
alkylation reaction, e.g. diisopropylethylamine, potassium iodide, DMSO or
acetonitrile, 80 C.
When X is an aldehyde, n is 1, and suitable reaction conditions are those for
a reductive
amination reaction, e.g. sodium cyanoborohydride, methanol, dichloromethane,
acetic acid, room
temperature.
[0440] Scheme 1B.
0
s,
o N
+ M-Ar-L¨G-PG _____________________________________________________
/
I
Z'' N
F
F
ZI F _______________________________ ) I
Z
..--- F
----
,N / \ Ar-L¨GH
N-
III IV N-
O F
R
r(
N-W
X -L' ,S/, F
V 0/ N
i 0 R 0
________________ . Z F
--- N-W
VI /
N / \ Ar-L¨G-H-L' /.-Y
Z' n
N-
[0441] A compound of formula I may be reacted with a reagent II
(commercially available or
readily prepared using standard reaction techniques known to one skilled in
the art) under
palladium-catalyzed cross-coupling conditions, e.g. with a suitable palladium
catalyst such as
bis(di-tert-buty1(4-dimethylaminophenyl)phosphine)dichloropalladium(II),
suitable base such as
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cesium fluoride, suitable solvent such as mixtures of 1,4-dioxane and water,
at a suitable
temperature such as 100 C, with or without microwave irradiation to produce a
compound of
formula III. One of M or M' represents a functional group capable of
undergoing palladium-
catalyzed transmetallation, e.g. a boronic acid, boronic ester, or
trialkylstannane; the other of M
or M' represents a functional group capable of undergoing palladium-catalyzed
oxidative
addition, e.g. an iodide, bromide, chloride, or trifluoromethanesulfonate; Z
and Z' are each
independently H or a suitable protecting group such as t-butoxycarbonyl; Ar
represents an
aromatic or heteroaromatic ring system; L represents an optional linker or
portion of a linker,
GI¨PG represents a primary or secondary amine, optionally cyclized into a 4 to
8 membered
heterocyclic ring and/or fused to Ar, wherein PG represents a suitable
protecting group,
including but not limited to t-butoxycarbonyl or benzyl. Compounds of formula
III may be
converted to a compound of formula IV by treatment with a reagent suitable for
the removal of
PG, e.g. hydrogen chloride in 1,4-dioxane when PG is t-butoxycarbonyl.
Compound IV may
then be reacted with compound V to produce compound VI, wherein L' represents
an optional
linker or portion of a linker, Y is CH2 or C=0, X is either a suitable leaving
group (e.g. OMs,
OTs, Cl, etc.) or an aldehyde (CHO), and R is an optional substituent (e.g. F
or OCH3), and W is:
CD,N H2
H
0 N 0
-- or 0 .
[0442] When
X is a leaving group, n is 0, and suitable reaction conditions are those for
an
alkylation reaction, e.g. diisopropylethylamine, potassium iodide, DMSO or
acetonitrile, 80 C.
When X is an aldehyde, n is 1, and suitable reaction conditions are those for
a reductive
amination reaction, e.g. sodium cyanoborohydride, methanol, dichloromethane,
acetic acid, room
temperature. As needed, mixtures of enantiomers or diastereomers of any
compounds IV, V, or
VI may be resolved into their constituent enantiomers or diastereomers using
techniques known
to one skilled in the art, including but not limited to preparative high
performance liquid
chromatography or preparative supercritical fluid chromatography.
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NH2
[0443] In cases where W is 0 , the compound VI may be treated with
conditions suitable for imide cyclization, e.g. benzenesulfonic acid in
acetonitrile or N-
methylpyrrolidone at 100 C to afford a different compound of formula VI where
W is
H
0T N 0
j
-- .
[0444] In cases where one or both of Z or Z' are a protecting group, such
protecting group
may be removed from a compound VI, e.g. by treatment with trifluoroacetic acid
when Z and/or
Z' are t-butoxycarbonyl, to afford a different compound of formula VI wherein
Z and Z' are H.
[0445] It will further be apparent to one skilled in the art that the
positions of GI-PG in II
and X in V may be reversed throughout the synthetic sequence, such that the
positions of G
and - \ 1- are reversed in compound VI. In such cases, X may also be CH2OH or
an aldehyde
protected e.g. as its acetal, and may be converted to a compound where X is
CHO by oxidation
of the alcohol, e.g. with Dess-Martin periodinane, or deprotection of the
acetal, e.g. with
Amberlyst 15 in acetone and water at reflux, prior to reaction with V.
[0446] Scheme 2.
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00 W
as /0
N 0 /
X
VII
HN Ar-L-G1H
IV N-
N 0 0 0
W
CL,N 0
HN Ar-L-G1/ Y
VIII
N-
[0447] A
compound of formula IV may also be reacted with a compound of formula VII to
provide compounds of formula VIII, wherein X is a suitable leaving group such
as fluorine or
chlorine, Y is C=0, R represents one or more optional substituents, W is H or
CH3, and reaction
conditions are those for a nucleophilic aromatic substitution, e.g.
triethylamine, DMSO, 70 C.
[0448] Scheme 3A.
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F_, F
+ M-Ar-L-r
S,
0 H F
HN
I N IX
F F
H H
________________________________________ -
F 0 PG F 0
---- \ j---0 --- j-OH
HN / Ar-L HN / \ Ar-L
X N- XI Z
N-
0 F
N
H
HO"' N(:) c?--- ,N
SI/ -INI /0
;Si, F OH
-
Oi N 0
>cNH2 XII H
F
----
HN / \ Ar-L 0 Z
N-
4.
XIII
S \
N
[0449] A compound of formula I may be reacted with a reagent IX
(commercially available
or readily prepared using standard reaction techniques known to one skilled in
the art) under
palladium-catalyzed cross-coupling conditions, e.g. as shown in Scheme 1A or
1B, to produce a
compound of formula X. One of M or M' represents a functional group capable of
undergoing
palladium-catalyzed transmetallation, e.g. a boronic acid, boronic ester, or
trialkylstannane; the
other of M or M' represents a functional group capable of undergoing palladium-
catalyzed
oxidative addition, e.g. an iodide, bromide, chloride, or
trifluoromethanesulfonate; Ar represents
an aromatic or heteroaromatic ring system; L represents an optional linker or
portion of a linker,
and PG represents a suitable ester protecting group, e.g. methyl, ethyl, or t-
butyl. Compounds of
formula X may be converted to a compound of formula XI by treatment with a
reagent suitable
for the removal of PG, e.g. hydrogen chloride in 1,4-dioxane when PG is t-
butyl. Compound XI
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may then be reacted with compound XII, wherein Z is an optional substituent,
e.g. H, methyl, or
hydroxymethyl, to produce compounds of formula XIII under amide formation
conditions, e.g.
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate,
diisopropylethylamine,
DMF, room temperature.
[0450] Scheme 3B.
F., F
c:N, 2 0
S, + M-Ar-L-)_
N ,
W
F F
I H
W F 0 PG ___________ ).
F 0
..--. d ..--. j-OH
WN / \ Ar-L---"-- HN / \ Ar-L
N-
O R F
H / Y
HO-e: 0 a, ,;0 F OH
,S
)cXNH2 XII H F 0 0
.--
,-NH 0 HN
Ar-L sZ
N-
41tR
XIII
Y
[0451] A compound of formula I' may be reacted with a reagent IX
(commercially available
or readily prepared using standard reaction techniques known to one skilled in
the art) under
palladium-catalyzed cross-coupling conditions, e.g. as shown in Scheme 1A or
1B, to produce a
compound of formula X. One of M or M' represents a functional group capable of
undergoing
palladium-catalyzed transmetallation, e.g. a boronic acid, boronic ester, or
trialkylstannane; the
other of M or M' represents a functional group capable of undergoing palladium-
catalyzed
oxidative addition, e.g. an iodide, bromide, chloride, or
trifluoromethanesulfonate; Ar represents
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an aromatic or heteroaromatic ring system; L represents an optional linker or
portion of a linker;
PG represents a suitable ester protecting group, e.g. methyl, ethyl, or t-
butyl; and W represents
an optional protecting group, e.g. 2-(trimethylsilyl)ethoxymethyl. Where
necessary, e.g. when L
contains a primary or secondary amine or an alcohol, such functional groups
may be optionally
protected with a suitable protecting group, e.g. t-butoxycarbonyl when the
functional group is an
amine or t-butyldimethylsilyl when the functional group is an alcohol.
Compounds of formula X
may be converted to a compound of formula XI by treatment with a reagent
suitable for the
removal of the optional W, e.g. hydrogen chloride in 1,4-dioxane and methanol
or
ethylenediamine and tetra-n-butylammonium fluoride when W is 2-
(trimethylsilyl)ethoxymethyl;
followed by treatment with a reagent suitable for the removal of PG, e.g.
hydrogen chloride in
1,4-dioxane when PG is t-butyl. Compound XI may then be reacted with compound
XII,
wherein Z is an optionally substituted carbon, e.g. CH2, CD2, CH(Me),
CH(CH2OH), C(CH3)2, R
is an optional substituent, e.g. F or CH2OH, and Y is an optional substituent,
e.g. halogen, CN, or
optionally substituted aryl or heterocyclyl, to produce compounds of formula
XIII under amide
formation conditions, e.g. (benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate, diisopropylethylamine, DMF, room temperature. It will be
apparent to one
skilled in the art that when L contains a protected amine or alcohol, such
protecting group may
be removed as needed at the stage of compound X, XI, or XIII, e.g. by
treatment with
trifluoroacetic acid when said protecting group is t-butoxycarbonyl or
hydrochloric acid in
methanol when said protecting group is t-butyldimethylsilyl.
[0452] Scheme 4A.
OH
_
M-Ar-L->1_ M-Ar-L
R -)r
_,.... OH + XII -,- M-Ar-
L Z
0 PG 0
IX XIV XV .
S \
L,
N
I
__________ . XIII
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[0453] Alternatively, a compound of formula IX may be converted to a
compound of
formula XIV by using conditions analogous to those for the conversion of X to
XI in Scheme 3A
or 3B. A compound of formula XIV may be converted to a compound of formula XV
by using
conditions analogous to those for the conversion of XI to XIII in Scheme 3A or
3B. A
compound of formula XV may then be converted to a compound of formula XIII by
reaction
with a compound of formula I using conditions analogous to those for the
conversion of I and IX
to X in Scheme 3A or 3B.
[0454] Scheme 4B.
OH
0 0
j-NEI 0 HN
0 OH + X I I M-Ar-L
0 'PG 0
IX XIV XV
XIII
[0455] Alternatively, a compound of formula IX may be converted to a
compound of
formula XIV by using conditions analogous to those for the conversion of X to
XI in Scheme 3A
or 3B. A compound of formula XIV may be converted to a compound of formula XV
by using
conditions analogous to those for the conversion of XI to XIII in Scheme 3A or
3B. A
compound of formula XV may then be converted to a compound of formula XIII by
reaction
with a compound of formula I' using conditions analogous to those for the
conversion of I' and
IX to X, followed by optional deprotection of W, in Scheme 3B.
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[0456] Scheme 5.
Br Br
N
,NH + M'Ar -L-G-PG _________________________ ,
r-----\-
r----\
---.. N-Ar-L-GI-PG ..- -
..
N
1 1
N N
XVI II' XVII
M-Ar' Arr____\
Ar'
XVIII e
N-Ar-L-GH
N 1
XIX XX
00
NH 0 0
1101 X ,N-- 0 NH
Y Ar 1101 , N-t 0
-- Y
VII
-... ,N-Ar-L-G
I N
_________________ ..-
N/
XXI
[0457] 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
boronic ester; Ar represents an aromatic or heteroaromatic ring system; L
represents an optional
linker, 5-PG 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
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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.
[0458] Scheme 6.
Br Br
-PG _______
,N-Ar-L-G1 ,N-Ar-L-G1
1 1
N N
XXII
XVII
0 0
XVIII
,N1_,\-NH
Br XXI
VII
N
1
XXIII
[0459] 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.
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[0460] Scheme 7.
0 0
NH 0 0
0 y,N-tiO NH
0Br HC-L' (110 ,N_.\- 0
Y
, ,N-Ar-L-CHO X BrXV i-ND-L'
N ___________________________________ .
N-Ar-L
\ ---N=
N / I
N / XXVI
XXIV
0 0
_ti:11-1
401 ,N 0
Ar'
XVIII
_________________ ).- , ,N-Ar-L
N
I
N / XXVII
[0461] A compound of formula XXIV (prepared in an analogous manner to the
preparation
of XVII from XVI and II' in Scheme 5, with additional functional group
transformations as
necessary, which are well known to one skilled in the art) may be reacted with
a compound of
formula XXV to prepare a compound of formula XXVI under reductive amination
conditions,
e.g. sodium cyanoborohydride, acetic acid, methanol, room temperature. Herein
Ar represents
an aromatic or heteroaromatic ring system; L and L' represent an optional
linker or portion of a
linker, HO represents a primary or secondary amine, optionally cyclized into a
4 to 8
membered heterocyclic ring, and Y is CH2 or C=0. A compound of formula XXVI
may then be
treated with a reagent XVIII as defined in Scheme 5 to produce a compound of
formula XXVII.
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 XVII.
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[0462] Scheme 8.
0 0
NH 0 0
/\
$10 y,N- 01 tiO _tNH
N ,N 0
Br OHC-L'
Br Y
-- XXVIII
N-Ar-L-GH ___________________________________________ /0 L'
,.. , ..-
1 \ N
/ 1
N /
XXII XXVI'
00
t_ NH
1110 ,N 0
/\ Y
Ar XVIII At /GI L'
__________________ .-
- , N-Ar-L
,
N
I
N / XXVII'
[0463] Alternatively, a compound of formula XXII may be treated with a
compound of
formula XXVIII under reductive amination conditions, e.g. as in Scheme 7, to
provide a
compound of formula XXVI'. Herein Ar, L, L', GH, and Y are defined as in
Scheme 7. A
compound of formula XXVI' may then be treated with a reagent XVIII as defined
in Scheme 5
to produce a compound of formula XXVII'. 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 XVII'.
[0464] Scheme 9.
I 1
N N 7 0 iii0 H
F 7
*
CINH F
VII /--\
No 10 Y,t0
N
/----\ N
/ \ N
XXX
XIX
[0465] A compound of formula XIX may be reacted with a compound of formula
VII to
provide compounds of formula XXX, 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 sub
stituents, and reaction
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conditions are those for a nucleophilic aromatic substitution, e.g.
diisopropylethylamine, NMP,
130 C, with or without microwave irradiation.
[0466] Scheme 10.
00 H
I N
N H F
N XXVIII vAl---j
,S-N F 7---\
0"P H F / \ N ,S-N
01) H F
N---j
XIX
XXXI
[0467] Alternatively, a compound of formula XIX may be treated with a
compound of
formula XXVIII to provide a compound of formula XXXI under reductive amination
conditions,
e.g. sodium triacetoxyborohydride, ethanol, dichloromethane, room temperature.
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[0468] Scheme 11.
I
N
F V
I
0 OH
ii , N 'Lr
¨ 0
0"6 H F
N=:::-/
)0(XI I HO,
c)f
I Z
HN
NoF V 0
AI
XII I ,1_7(1\1H , N
7-----\ N
¨ 0 0114
,S-.-N
0"P H F \
/ N
N-:---/ S
\----::N
XXXII!
or
I
N
F H
N ON-1_7((:)
7-----\ 14I , N3........\ 0
Ss--N
0/bH F i \N
N-_-.1----/
)0(XI I
HO
N.-''e
I
No
F V -----LO -Z R
XII 1
_________________ I. 41, , N 'LVIN HN
H
7--\ N
¨ 0 1
IS--N
0"6 H F \
/ N Y
NIs--/
xxxiii
[0469] Alternatively, a compound of formula XXXII, prepared from a compound
of formula
XIX through simple transformations well-known by one skilled in the art, e.g.
alkylation or
reductive amination, may be reacted with a compound of formula XII to provide
a compound of
formula XXXIII under amide formation conditions, e.g. (benzotriazol-1-
yloxy)tripyrrolidinophosphonium hexafluorophosphate, diisopropylethylamine,
DMF, room
temperature
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[0470] Scheme 12A.
0 0 0 0
0 Ni
,_-\¨NH NH
0 + M-Ar-L-X . ,N-¨ 0
____________________________________________ ..-
Y Y
HO M-Ar-L-0
XXXIV XXXV
XXXVI
F
,
I Oi N 0 0 0
_____________ ...- H
F NH
401 0
Y
HN --- / \ Ar¨L-0
,N_,\¨
)(XXVII N¨
[0471] A compound of formula XXXIV may be reacted with a reagent XXXV
(commercially available or readily prepared using standard reaction techniques
known to one
skilled in the art) under nucleophilic substitution conditions, e.g. potassium
carbonate, potassium
iodide, DMSO, 60 C, to produce a compound of formula XXXVI. Alternatively,
the reaction
conditions may be those for a Mitsunobu reaction, e.g. triphenylphosphine,
diethylazodicarboxylate, THF. Herein Y is CH2 or C=0; one of M or M'
represents a functional
group capable of undergoing palladium-catalyzed transmetallation, e.g. a
boronic acid, boronic
ester, or trialkylstannane; the other of M or M' represents a functional group
capable of
undergoing palladium-catalyzed oxidative addition, e.g. an iodide, bromide,
chloride, or
trifluoromethanesulfonate; Ar represents an aromatic or heteroaromatic ring
system; and L
represents a linker. When the reaction is a nucleophilic substitution
reaction, X represents a
suitable leaving group, e.g. p-toluenesulfonate, methanesulfonate, iodide,
bromide, or chloride;
when the reaction is a Mitsunobu reaction, X is OH. A compound of formula
XXXVI may then
be further transformed by reaction with compound I under palladium-catalyzed
cross-coupling
conditions, e.g. with a suitable palladium catalyst such as bis(di-tert-
buty1(4-
dimethylaminophenyl)phosphine)dichloropalladium(II), suitable base such as
cesium fluoride,
suitable solvent such as mixtures of 1,4-dioxane and water, at a suitable
temperature such as 100
C, with or without microwave irradiation to produce a compound of formula XXX
VII.
[0472] Scheme 12B.
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R
M-Ar-L-X R R.
R" M-Ar-L-Z' R"
XXXIV XXXV
XXXVI
a, ,0
NH
,N
xxxvii Z'
N-
A compound of formula XXXIV may be reacted with a reagent XXXV (commercially
available
or readily prepared using standard reaction techniques known to one skilled in
the art) to prepare
a compound of formula XXXVI. In all cases, M represents a functional group
capable of
undergoing palladium-catalyzed transmetallation, e.g. a boronic acid, boronic
ester, or
trialkylstannane; or alternatively M represents a functional group capable of
undergoing
palladium-catalyzed oxidative addition, e.g. an iodide, bromide, chloride, or
trifluoromethanesulfonate; Ar represents an aromatic or heteroaromatic ring
system; L represents
a linker; R represents one or more optional substituents; and R' and R" are
either both
carboxylic esters, e.g. CO2CH2CH3, R is a carboxylic ester e.g. CO2CH3 and R'
is CN, or
together R and R' form either:
00
0 or -' Y , wherein Y is either CH2 or C=0.
In some cases, X is a primary or secondary amine, optionally cyclized into a 4
to 8 membered
heterocyclic ring, Y is a suitable leaving group such as fluorine or chlorine,
and reaction
conditions are those for a nucleophilic aromatic substitution, e.g.
triethylamine, DMSO, 70 C.
In these cases, Z becomes the corresponding secondary or tertiary amine
derived from X.
In other cases, X is a suitable leaving group, e.g. p-toluenesulfonate,
methanesulfonate, iodide,
bromide, or chloride, Y is OH, and reaction conditions are those for a
nucleophilic substitution,
e.g. potassium carbonate, potassium iodide, DMSO, 60 C. In these cases, Z is
0.
In other cases, X is OH, Y is OH, and reaction conditions may be those for a
Mitsunobu reaction,
e.g. triphenylphosphine, diethylazodicarboxylate, THF. In these cases, Z is 0.
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A compound of formula XXXVI may be further transformed into a different
compound of
formula XXXVI. When R' is a carboxylic ester and R" is CN, reduction of R" to
CHO may be
accomplished, e.g. by treatment with sodium hypophosphite and Raney nickel in
a mixture of
,,,.....\
0
pyridine, acetic acid, and water. When R' and R" together form 0 ,
solvolysis e.g. with
sodium hydroxide in an alcoholic solvent and tetrahydrofuran may afford a
compound where R'
is a carboxylic ester and R" is CH2OH. This compound may be further oxidized,
e.g. with
manganese dioxide, to afford an equivalent compound XXXVI where R' is a
carboxylic ester
and R" is CHO. Such compounds where R' is a carboxylic ester and R" is CHO may
then be
reacted with 3-aminoglutarimide in the presence of e.g. sodium
triacetoxyborohydride,
diisopropylethylamine, and acetic acid in methanol and dichloromethane to
afford a new
0 0
,N1 0
compound of formula XXXVI wherein R' and R" together are -- Y , wherein Y
is CH2.
A compound of formula XXXVI may then be further transformed by reaction with a
compound I
under palladium-catalyzed cross-coupling conditions, e.g. with a suitable
palladium catalyst such
as bis(di-tert-buty1(4-dimethylaminophenyl)phosphine)dichloropalladium(II),
suitable base such
as cesium fluoride, suitable solvent such as mixtures of 1,4-dioxane and
water, at a suitable
temperature such as 100 C, with or without microwave irradiation to produce a
compound of
formula XXXVII. Herein M', Z, and Z' are as defined in Scheme 1B.
In cases where one or both of Z or Z' are a protecting group, such protecting
group may be
removed from a compound XXXVII, e.g. by treatment with trifluoroacetic acid
when Z and/or Z'
are t-butoxycarbonyl, to afford a different compound of formula XXXVII wherein
Z and Z' are
H.
[0473] In cases where in R' and R" are both carboxylic esters in a compound
XXXVII,
hydrolysis e.g. with sodium hydroxide in methanol and water may afford a
different compound
XXXVII where R' and R" are CO2H. Such a compound may subsequently be reacted
with e.g.
3-aminoglutarimide, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate, and diisopropylamine in N,N-dimethylformamide to afford a
new
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0 0
µ=1,-1( _tNH
3\1 0
compound of formula XXXVII wherein R' and R" together are -' Y
, wherein Y
is C=0.
[0474] Scheme 13A.
F F
M-Ar-L
I
0,PG ___________________________ bN P 0
\ o N
N-0 0
i N-0 0
HN ....-
XXXVIII N
)00(IX
F F
s, OH
o N
______________ _
Ni N-0 0
H ,
N
XL
Z
0 F
N pH
H V N
P
HO"' NH Sj/ F 0 bi--11N
1 Ar-L N 0
H -
XLI N-0
N i\ f"
......
HN 0
__________________________ ...-
XLII Z
µs 1
N
[0475] A compound of formula I may be reacted with a reagent XXX VIII
(readily prepared
using standard reaction techniques known to one skilled in the art) under
palladium-catalyzed
cross-coupling conditions, e.g. [1,11-
bis(diphenylphosphino)ferrocene[dichloropalladium(II),
sodium carbonate, in a suitable solvent such as 1,4-dioxane / water mixture,
at a suitable
temperature such as 100 C, with or without microwave heating, to produce a
compound of
formula XXXIX. One of M or M' represents a functional group capable of
undergoing
palladium-catalyzed transmetallation, e.g. a boronic acid, boronic ester, or
trialkylstannane; the
other of M or M' represents a functional group capable of undergoing palladium-
catalyzed
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oxidative addition, e.g. an iodide, bromide, chloride, or
trifluoromethanesulfonate; Ar represents
an aromatic or heteroaromatic ring system; L represents an optional linker or
portion of a linker,
and PG represents a suitable ester protecting group, e.g. methyl, ethyl, or t-
butyl. Compounds of
formula XXXIX may be converted to a compound of formula XL by treatment with a
reagent
suitable for the removal of PG, e.g. sodium hydroxide in methanol and water at
40 C when PG
is methyl or ethyl. Compound XL may then be reacted with compound XLI, wherein
Z is an
optional substituent, e.g. H, methyl, or hydroxymethyl, to produce compounds
of formula XLII
under amide formation conditions, e.g. N-Rdimethylamino)-1H-1,2,3-triazolo-
[4,5-b]pyridin-l-
ylmethylenel-N-methylmethanaminium hexafluorophosphate N-oxide,
diisopropylethylamine,
DMF, room temperature.
[0476] Scheme 13B.
F F
r
o,PG ____________________________ bl, P 0
M-Ar-L \ o N
N-0 0
N ,
XXXVIII W
' N
XXXIX
F F
bN, P 0
S, OH
o N
HN ,-
N
XL
Z
0 F
F
\N
N 0 OH
HO"' NH Sji
N
XLI N-0
N kr 0
H HN 0
__________________________ )-
Z
XLII S
1
N
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[0477] A compound of formula I' may be reacted with a reagent XXX VIII
(readily prepared
using standard reaction techniques known to one skilled in the art) under
palladium-catalyzed
cross-coupling conditions, e.g. [1,11-
bis(diphenylphosphino)ferrocene[dichloropalladium(II),
sodium carbonate, in a suitable solvent such as 1,4-dioxane / water mixture,
at a suitable
temperature such as 100 C, with or without microwave heating, to produce a
compound of
formula XXXIX. One of M or M' represents a functional group capable of
undergoing
palladium-catalyzed transmetallation, e.g. a boronic acid, boronic ester, or
trialkylstannane; the
other of M or M' represents a functional group capable of undergoing palladium-
catalyzed
oxidative addition, e.g. an iodide, bromide, chloride, or
trifluoromethanesulfonate; Ar represents
an aromatic or heteroaromatic ring system; L represents an optional linker or
portion of a linker;
PG represents a suitable ester protecting group, e.g. methyl, ethyl, or t-
butyl; W represents an
optional protecting group, e.g. 2-(trimethylsilyl)ethoxymethyl; and the
isoxazole of compound
XXX VIII and following structures may have an optional substituent. Compounds
of formula
XXXIX may be converted to a compound of formula XL by treatment with a reagent
suitable for
the removal of the optional W, e.g. hydrogen chloride in 1,4-dioxane and
methanol or
ethylenediamine and tetra-n-butylammonium fluoride when W is 2-
(trimethylsilyl)ethoxymethyl;
followed by treatment with a reagent suitable for the removal of PG, e.g.
sodium hydroxide in
methanol and water at 40 C when PG is methyl or ethyl. Compound XL may then
be reacted
with compound XLI, wherein Z is an optional substituent, e.g. H, methyl, or
hydroxymethyl, to
produce compounds of formula XLII under amide formation conditions, e.g. N-
Rdimethylamino)-1H-1,2,3-triazolo-[4,5-b[pyridin-l-ylmethylene[-N-
methylmethanaminium
hexafluorophosphate N-oxide, diisopropylethylamine, DMF, room temperature.
Optionally, as
will be apparent to one skilled in the art, the order of the amide coupling
and palladium-
catalyzed cross-coupling steps may be reversed in the reaction sequence via
suitable
manipulations of M, M', and PG.
[0478] Scheme 14.
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N Br
N N
,N-Ar-oH N-Ar-0/ -)r0,
1 0 PG
N
XLV
XLIII XLIV
Br
N-Ar-O OH XII
N 0
N
XLVI
HO
HO
Br µ1(113 At'
N-Ar-O HN
XVIII
N 0
N 0
N N
XLVII S XLVIII S
[0479] A compound of formula XLIII may be reacted with a reagent XLIV
(commercially
available or readily prepared using standard reaction techniques known to one
skilled in the art)
under nucleophilic substitution conditions, e.g. cesium carbonate, DMF, 75 C,
to produce a
compound of formula XLV. Ar represents an aromatic or heteroaromatic ring
system; X
represents a suitable leaving group, e.g. p-toluenesulfonate,
methanesulfonate, iodide, bromide,
or chloride; L represents an optional linker; and PG represents a suitable
ester protecting group,
e.g. methyl, ethyl, or t-butyl. Compounds of formula XLV may be converted to a
compound of
formula XLVI by treatment with a reagent suitable for the removal of PG, e.g.
3 N hydrochloric
acid in 1,4-dioxane at room temperature when PG is t-butyl. Compound XLVI may
then be
reacted with compounds XII as defined in Scheme 3A or 3B to produce compounds
of formula
XLVII under amide formation conditions, e.g. (benzotriazol-1-
yloxy)tripyrrolidinophosphonium
hexafluorophosphate, diisopropylethylamine, DMF, room temperature. The
compound of
formula XLVII may then be treated with a reagent XVIII as defined in Scheme 5
to produce a
compound of formula XLVIII. In cases where the group Ar' contains optional
substituents, e.g.
a ketone, these may undergo further functionalization, e.g. by treatment with
hydroxylamine
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hydrochloride and pyridine at room temperature, to provide further compounds
of formula
XL VIII.
[0480] Intermediate 1: (3R)-N-[3-([5-bromo-1H-pyrrolo[2,3-b[pyridin-3-
ylicarbony1)-2,4-
difluorophenyll-3-fluoropyrrolidine-1-sulfonamide
0õ0
X F
....01 N
F H 0
F
---
HN / \ Br
N-
[0481] Step A: 2,6-difluoro-3-nitrobenzoyl chloride.
0 F
CI 40
F
NO2
[0483] Into a 150-mL round-bottom flask, was placed 2,6-difluoro-3-
nitrobenzoic acid (15.0
g, 73.8 mmol, 1.0 equiv), toluene (80 mL), thionyl chloride (80 mL). The
resulting mixture was
stirred at 80 C overnight and concentrated under reduced pressure. This
resulted in 14.1 g (86%)
of 2,6-difluoro-3-nitrobenzoyl chloride as a brown oil.
[0484] Step B: 5-bromo-3-[(2,6-difluoro-3-nitrophenyl)carbony11-1H-
pyrrolo[2,3-
b[pyridine.
F
0
Br
NO2
I
N N
H
[0485] 5-bromo-1H-pyrrolo[2,3-b]pyridine (11.0 g, 55.8 mmol, 1.1 equiv) was
mixed with
200 mL of chloromethane and aluminum trichloride (42.0 g, 318.2 mmol, 6.4
equiv) was added
portionwise. The reaction was stirred at room temperature for 1 hour and 2,6-
difluoro-3-
nitrobenzoyl chloride (11.0 g, 49.6 mmol, 1.0 equiv) was added. The reaction
was heated at 50
C overnight, then reaction mixture was cooled to room temperature and poured
to ice-water
(500 mL), extracted with ethyl acetate (500 mL x 3). The combined organic
layer was washed
with brine (500 mL x 2), dried over anhydrous sodium sulfate. The solvent was
concentrated to
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give (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-y1)(2,6-difluoro-3-nitrophenyl)
methanone (12.2 g) as
a yellow solid, which was directly used to the next step without further
purification. LCMS
(ES): m/z 381.30 [M+H] +.
[0486] Step C: 3-([5-bromo-1H-pyrrolo[2,3-b[pyridin-3-ylicarbony1)-2,4-
difluoroaniline.
F
0
Br 1 \ F NH2
N "
H
[0487] A mixture of (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-y1)(2,6-difluoro-3-
nitrophenyl)methanone (7.8 g, 20.4 mmol, 1.0 equiv), iron (5.6 g, 100.2 mmol,
4.9 equiv),
ammonium chloride (3.6 g , 68 mmol), hydrochloric acid (25.0 mL) in ethanol
(40 mL) and
tetrahydrofuran (40 mL) was refluxed overnight. After cooling to room
temperature, the mixture
was filtered via a pad of Celite. The filtrate was concentrated in vacuo and
the residue was
purified by column chromatography on silica gel (petroleum ether /ethyl
acetate = 1/2) to give
(3-amino-2,6-difluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone
(4.3 g, 60%
yield) as a yellow solid. LCMS (ES): m/z 351.80 [M+H] +.
[0488] Step D: (R)-3-fluoropyrrolidine-1-sulfonyl chloride.
CI
k.
.--N
FI')
[0489] An oven dried flask was charged with (R)-3-fluoropyrrolidine
hydrochloride (3.0 g,
24 mmol). tRiethylamine (7.2 g, 72 mmol) and dichloromethane (150 mL). The
mixture was
stirred for 15 minutes at room temperature and then cooled to about -30 C in a
dryice/acetonitrile bath for 10 minutes. Sulfuryl chloride (6.0 g, 48 mmol)
was added dropwise
over 10 minutes. The reaction mixture was stirred at about -30 C for an hour,
then stirred at
room temperature for 5 hours. The reaction mixture was diluted with aqueous
HC1 (1 N, 70 mL).
The layers were separated and the aqueous layers were extracted with
dichloromethane (50 mL x
3). The combined organic layer was washed with aqueous HC1 (1 N, 50 mL) and
brine (50 mL),
dried over anhydrous sodium sulfate. The solvent was concentrated to give (R)-
3-
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fluoropyrrolidine-l-sulfonyl chloride (4.5 g) as a white solid, which was
directly used to the next
step without further purification.
[0490] Step E: (3R)-N-1-3-([5-bromo-1H-pyrrolo[2,3-blpyridin-3-ylicarbony1)-
2,4-
difluoropheny11-3-fluoropyrrolidine-1-sulfonamide.
0\ 0
....01 N
F H 0
F
.----
HN / \ Br
N¨
[0491] To a solution of (3-amino-2,6-difluorophenyl)(5-bromo-1H-pyrrolo[2,3-
b]pyridin-3-
yl)methanone (8.0 g, 22.79 mmol, 1.0 eq) in pyridine (25.0 g) was added (R)-3-
fluoropyrrolidine-1-sulfonyl chloride (4.6 g, 24.60 mmol, 1.08 eq) and 4-
dimethylaminopyridine
(560.0 mg, 4.59 mmol, 0.2 eq). The reaction mixture was stirred for 12 hours
at 40 C. The
solvent was removed and water (20 mL) was added, adjusted pH=7-8 with aqueous
sodium
bicarbonate, extracted with ethyl acetate (100 mL x 2). The combined organic
layer was washed
with brine (50 mL x 2), dried over anhydrous sodium sulfate. The solvent was
removed in vacuo
and the residue was purified by column chromatography on silica gel with ethyl
acetate/petroleum ether (3:1) to give (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-
b]pyridine-3-carbony1)-
2,4-difluoropheny1)-3-fluoropyrrolidine-1-sulfonamide (6.4 g) as a yellow
solid LCMS (ES):
m/z 505.05 [M+H]t
[0492] Intermediate 2: (R)-N-(2,4-difluoro-3-(5-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
y1)-1H-pyrrolo [2,3-blpyridine-3-carbonyl)pheny1)-3-fluoropyrrolidine-1-
sulfonamide
0\ 0
....01 N
F H 0
F
...--
N¨ 0
[0493] Step A: (R)-N-(2,4-difluoro-3-(5-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-y1)-1H-
pyrrolo[2,3-blpyridine-3-carbonyl)pheny1)-3-fluoropyrrolidine-1-sulfonamide
[0494] To a solution of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-
carbony1)-2,4-
difluoropheny1)-3-fluoropyrrolidine-1-sulfonamide (1.0 g, 2.0 mmol) in 1,4-
dioxane were added
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KOAc (392.0 mg, 4.0 mmol), Pd(dppf)C12 (163.0 mg, 0.2 mmol), and
4,4,4',4',5,5,5',5'-
octamethy1-2,2'-bi(1,3,2-dioxaborolane) (1.02 g, 4.0 mmol) subsequently. The
resulting solution
was heated to 90 C overnight under N2. After cooling to room temperature, the
solvent was
removed under reduced pressure. The residue was purified by column
chromatography on silica
gel eluting with ethyl acetate/petroleum ether (1:1). This resulted in 551.0
mg (50%) (R)-N-(2,4-
difluoro-3-(5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrrolo[2,3-
b]pyridine-3-
carbonyl)pheny1)-3-fluoropyrrolidine -1-sulfonamide as a light brown solid.
LCMS (ES): m/z
551.15 [M+H] .
[0495] Intermediate 3: N-(3-[5-bromo-1H-pyrrolo[2,3-blpyridine-3-carbony11-
2,4-
difluoropheny1)-2-(dimethylamino)ethane-1-sulfonamide
0 0
\\Sõ/
N
0
HN Br
N¨
[0496] Step A: N-(3-1-5-bromo-1H-pyrrolo[2,3-blpyridine-3-carbony11-2,4-
difluorophenyflethene-1-sulfonamide
0 \ 0
\Sõ/
0
HN ¨
Br
N
[0497] Into a 100 mL round-bottom flask, was placed 345-bromo-1H-
pyrrolo[2,3-
b]pyridine-3-carbony1]-2,4-difluoroaniline (500 mg, 1.42 mmol, 1 equiv),
pyridine (20 mL,
248.47 mmol, 174.99 equiv), DMAP (35 mg, 0.29 mmol, 0.20 equiv),
ethenesulfonyl chloride
(360 mg, 2.84 mmol, 2.00 equiv), dichloromethane (20 mL). The resulting
solution was stirred
for 0.5 hour at room temperature. The reaction mixture was concentrated under
reduced pressure.
The residue was applied onto a silica gel column eluting with ethyl
acetate/petroleum ether (1:1).
This resulted in 300 mg (48%) of N-(345-bromo-1H-pyrrolo[2,3-b]pyridine-3-
carbony1]-2,4-
difluorophenyl)ethene-1-sulfonamide as a white solid. LCMS (ES): m/z
443.80[M+H] .
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[0498] Step B: N-(3- [5-bromo-1H-pyrrolo[2,3-blpyridine-3-carbony11-2,4-
difluoropheny1)-
2-(dimethylamino)ethane-1-sulfonamide
0 0
N
0
HN Br
N¨
[0499] Into a 100 mL round-bottom flask, was placed N-(345-bromo-1H-
pyrrolo[2,3-
b]pyridine-3-carbony1]-2,4-difluorophenyl)ethene-1-sulfonamide (300 mg, 0.68
mmol, 1 equiv),
dichloromethane (20 mL), dimethylamine (2.0 mL). The resulting solution was
stirred for 2
hours at room temperature. The reaction mixture was concentrated under reduced
pressure. This
resulted in 360 mg (crude) of N-(345-bromo-1H-pyrrolo[2,3-b]pyridine-3-
carbony1]-2,4-
difluoropheny1)-2-(dimethylamino)ethane-1-sulfonamide as a white solid. LCMS
(ES): m/z
488.85 [M+H] .
[0500] Intermediate 4: N-(3-[5-bromo-1H-pyrrolo[2,3-blpyridine-3-carbony11-
2,4-
difluoropheny1)-2,3-dihydroxypropane-1-sulfonamide
0
"S'N Br
Hoc--ro H F /
OH
N N
[0501] Step A: N-(3-1-5-bromo-1H-pyrrolo[2,3-blpyridine-3-carbony11-2,4-
difluorophenyl)prop-2-ene-1-sulfonamide
0
rB
N
[0502] Into a 25 mL round-bottom flask, was placed 345-bromo-1H-pyrrolo[2,3-
b]pyridine-
3-carbony1]-2,4-difluoroaniline (500 mg, 1.42 mmol, 1 equiv), pyridine (2 mL,
15 equiv), prop-
2-ene- 1-sulfonyl chloride (399.2 mg, 2.84 mmol, 2 equiv), DMAP (52.0 mg, 0.43
mmol, 0.3
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equiv). The resulting solution was stirred overnight at 45 C in an oil bath.
The resulting mixture
was concentrated. The residue was applied onto a silica gel column eluting
with ethyl
acetate/petroleum ether (1/1). This resulted in 480 mg (74%) of N-(345-bromo-
1H-pyrrolo[2,3-
b]pyridine-3-carbony1]-2,4-difluorophenyl)prop-2-ene-1-sulfonamide as a yellow
solid.
[0503] Step B: N-(3-1-5-bromo-1H-pyrrolo1-2,3-blpyridine-3-carbony11-2,4-
difluoropheny1)-
2,3-dihydroxypropane-1-sulfonamide
F
0
0
ii
S-1,1 HO/-{-011 H- F Br / 1
OH
N N
H
[0504] Into a 50 mL round-bottom flask, was placed N-(345-bromo-1H-
pyrrolo[2,3-
b]pyridine-3-carbony1]-2,4-difluorophenyl)prop-2-ene-1-sulfonamide (430 mg,
0.94 mmol, 1
equiv), acetone (20 mL), N-methylmorpholine N-oxide (226 mg), water (5 mL),
tetraoxoosmium
(4 mL). The resulting solution was stirred overnight at room temperature. The
reaction was then
quenched by the addition of water (20 mL). The resulting solution was
extracted with ethyl
acetate (30 mL x 3). The resulting mixture was washed with brine (20 mL x 1),
dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue
was applied
onto a silica gel column eluting with ethyl acetate/petroleum ether (1/1).
This resulted in 377 mg
(82%) of N-(345-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbony1]-2,4-
difluoropheny1)-2,3-
dihydroxypropane-1-sulfonamide as a white solid.
[0505] Intermediate 5: (R)-N-(3-(5-bromo-1H-pyrrolo1-2,3-blpyridine-3-
carbony1)-2,4-
difluoropheny1)-3-fluoropyrrolidine-1-carboxamide
0 F
FNNH 0
/
F
/
NH / \ Br
N-
[0506] To the solution of (3-amino-2,6-difluorophenyl)(5-bromo-1H-
pyrrolo[2,3-b]pyridin-
3-yl)methanone(2.0 g, 5.70 mmol, 1.00 equiv), triethylamine (8.6 g, 85.5 mmol,
15.00 equiv) in
dichloromethane (80 mL) was slowly added a solution of bis(trichloromethyl)
carbonate (2.5 g,
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8.55 mmol, 1.50 equiv) in dichloromethane (40 mL), followed by dropwise
addition of a solution
of (R)-3-fluoropyrrolidine (761.0 mg, 8.55 mmol, 1.50 equiv) in
dichloromethane (40 mL) at 0
C. The resulting solution was stirred for 30 minutes at 0 C in a water/ice
bath. The resulting
solution was quenched by the aqueous solution of ammonium chloride (40 mL),
extracted with
dichloromethane (40 mL x2). Then the organic layers were combined and
concentrated. The
residue was applied onto a silica gel column with chloroform/methanol (10:1).
This resulted in
541.0 mg (20%) of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbony1)-2,4-
difluoropheny1)-3-fluoropyrrolidine-l-carboxamide as a tawny solid. LCMS (ES):
m/z 467.10
[M+H] .
[0507] Scheme 15.
0 N'.1 0 N
I
I F3C
F3 401 N I N 0
N I T,..,N 1 XLIV H
H
- -'..,
CY Nu H 0
N N
XL IX C ) L C )
0
0
0 N
F3C 0 izi '
I 0
0- Nu OH
N
LI C )
0
0 N OH
F3C 0 N N
0
XII rL 1
LI I H 11--
(3,1_',N6LAN
_,..
H 0 0
N HN
( ) Z
0 /IR 0
\
Y
[0508] A compound of formula XLIX (readily prepared using standard reaction
techniques
known to one skilled in the art) may be reacted with a compound of formula.
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[0509] A compound of formula XLIX may be reacted with a reagent XLIV under
nucleophilic substitution conditions, e.g. diisopropylethylamine, potassium
iodide, acetonitrile,
100 C, to produce a compound of formula L. L' represents an optional linker
or portion of a
linker; Nu-H represents a suitable nucleophile such as an alcohol or secondary
amine; X
represents a suitable leaving group, e.g. p-toluenesulfonate,
methanesulfonate, iodide, bromide,
or chloride; L represents an optional linker; and PG represents a suitable
ester protecting group,
e.g. methyl, ethyl, or t-butyl. Compounds of formula L may be converted to a
compound of
formula LI by treatment with a reagent suitable for the removal of PG, e.g.
trifluoroacetic acid,
dichloromethane, 30 C when PG is t-butyl. Compound LI may then be reacted
with compounds
XII as defined in Scheme 3A or 3B to produce compounds of formula LII under
amide formation
conditions, e.g. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-
hydroxybenzotriazole,
triethylamine, DMF, 30 C.
[0510] Scheme 16.
0
0 N
I R
r,\---k
F3 isN 0 N-W
N-W
XLIX + c r _,...
X¨LAY' N
V ( ) LIII
0
[0511] A compound of formula XLIX as defined in Scheme 15 may be reacted
with
compound V to produce compound LIII, wherein L represents an optional linker
or portion of a
linker, Y is CH2 or C=0, X is either a suitable leaving group (e.g. OMs, OTs,
Cl, etc.) or an
aldehyde (CHO); R is an optional substituent (e.g. F or OCH3); and W is:
H
OIN:0
-' when Y is C=0; or
0,N H2
0 when Y is CH2.
[0512] When X is a leaving group, n is 0, Nu-H is a primary or secondary
amine or alcohol,
and suitable reaction conditions are those for an alkylation reaction, e.g.
potassium carbonate,
DMF, 70 C. When X is an aldehyde, n is 1, Nu-H is a primary or secondary
amine, and suitable
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reaction conditions are those for a reductive amination reaction, e.g. sodium
cyanoborohydride,
methanol, dichloromethane, acetic acid, room temperature. It will be apparent
to one skilled in
the art that the positions of Nu-H in XLIX and X in V' may also be reversed,
such that the
positions of Nu and (CH2)n are reversed in compound LIII. A compound of
formula LIII where
W is in an open chain form may be further transformed to another compound of
formula LIII
where W is a glutarimide by cyclization under appropriate conditions, e.g.
benzenesulfonic acid,
acetonitrile, 100 C.
[0513] Scheme 17.
F OH
H F 0 HN,
HI\D--L' Z
--- X HN / \ Ar-L- + µ
N- 0 IIR
LIV LV Y
OH
F
F 0 0 0
X
N N
H
liR
LVI Y
[0514] A compound of formula LIV (prepared using standard conditions known to
one skilled in
the art, analogous to the synthesis of compounds III in Scheme lA or 1B) may
be reacted with a
compound of formula LV (prepared using standard conditions known to one
skilled in the art,
analogous to the synthesis of compounds XV in Scheme 2) under reductive
amination
conditions, e.g. sodium triacetoxyborohydride, triethylamine, dichloroethane,
30 C, to produce a
compound of formula LVI. Herein, Ar is an aromatic or heteroaromatic ring
system; L and L'
are an optional linker or portion of a linker; X is H or an optional
substituent, which may be
optionally cyclized into L to form a ring; G-H
represents a primary or secondary amine,
optionally cyclized into a 4 to 8 membered heterocyclic ring; and R, Z, and Y
are as defined for
compound XII in Scheme 3B. It will be apparent to one skilled in the art that
the positions of
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C(0)X in LIV and G-H =
in LV may be reversed, with X optionally cyclized into L' to form a
ring, such that the positions of CHX and G are reversed in compound LVI.
[0515] Scheme 18.
F
OH
HND--L' \ X I\II al ,0
N-0 LIV 01/ N 0
0 H
HN 0 õ,. FH Ar-L N L /N
i
Z ---
, \
I N
\z9-' \ X OH
X HN 0
i
LVII LVIII
I A,
Y R
[0516] A compound of formula LIV (prepared using standard conditions known
to one
skilled in the art, analogous to the synthesis of compounds III in Scheme lA
or 1B) may be
reacted with a compound of formula LVII (prepared using standard conditions
known to one
skilled in the art) under reductive amination conditions, e.g. sodium
triacetoxyborohydride,
acetic acid, dichloromethane, methanol, 30 C, to produce a compound of
formula LVIII.
Herein, Ar is an aromatic or heteroaromatic ring system; L and L' are an
optional linker or
portion of a linker; X is H or an optional substituent, which may be
optionally cyclized into L to
form a ring;
= G-H
represents a primary or secondary amine, optionally cyclized into a 4 to 8
membered heterocyclic ring; R, Z, and Y are as defined for compound XII in
Scheme 3B; and
the isoxazole of compound LVII and following structures may have an optional
substituent. It
will be apparent to one skilled in the art that the positions of C(0)X in LIV
and G-H in LVII
may be reversed, with X optionally cyclized into L' to form a ring, such that
the positions of
CHX and G are reversed in compound LVIII.
[0517] Example synthesis of Compound 86
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0
0
F
f
rN NH
F
0 N) 0 0
bN..../s/....N
I
N N
H
[0518] Step A: (R)-tert-butyl 4-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-
1-
sulfonamido)benzoy1)-1H-pyrrolo[2,3-blpyridin-5-yl)phenyl)piperazine-1-
carboxylate.
F F rN,Boc
0 N
N N
H
[0519] A solution of (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-
carbony1)-2,4-
difluoropheny1)-3-fluoropyrrolidine-1-sulfonamide (0.50 g, 1.0 mmol) in 1,4-
dioxane/H20 (20
mL/2 mL), was added tert-butyl 4-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenyl)piperazine-1-carboxylate (0.43 g, 1.2 mmol), cesium fluoride (0.23
g, 1.5 mmol) and
Pd(aMPhos)C12 (0.11 g, 0.15 mmol) under an argon atmosphere. The mixture was
stirred at 100
C for 3 hours. After being cooled to room temperature, water was added. The
aqueous phase
was extracted with ethyl acetate (20 mL x 3), and the combined organic phases
were dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude
product was purified by
silica gel (dichloromethane/methanol = 12:1) to give compound (R)-tert-butyl 4-
(4-(3-(2,6-
difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoy1)-1H-pyrrolo[2,3-
b]pyridin-5-
yl)phenyl)piperazine-1-carboxylate (0.39 g, 57%) as a yellow solid. LCMS: m/z
685.2 [M+H];
1H NMR (400 MHz, DMSO-d6) 6 1.43 (9H, s), 2.06-2.12 (1H, m), 3.18-3.20 (4H,
m), 3.26-3.30
(1H, m), 3.37-3.53 (8H, m), 5.30 (1H, d, J = 52.0 Hz), 7.10 (2H, d, J = 8.8
Hz), 7.28 (1H, t, J =
8.4 Hz), 7.60-7.64 (3H, m), 8.09 (1H, d, J =2.8 Hz), 8.55 (1H, brs.), 8.66
(1H, d, J = 2.4 Hz),
9.87 (1H, s), 12.93 (1H, s).
[0520] Step B: (R)-N-(2,4-difluoro-3-(5-(4-(piperazin-1-yl)pheny1)-1H-
pyrrolo[2,3-
blpyridine-3-carbonyl)pheny1)-3-fluoropyrrolidine-1-sulfonamide.
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F r NH
F
0 N
t\ P
N-
i/ N
'
N N
H
[0521] To a solution of (R)-tert-butyl 4-(4-(3-(2,6-difluoro-3-(3-
fluoropyrrolidine-1-
sulfonamido)benzoy1)-1H-pyrrolo[2,3-b[pyridin-5-yl)phenyl)piperazine-1-
carboxylate (0.39 g,
0.57 mmol) in hydrochloric acid/1,4-dioxane (5 mL, 4.0 N) was stirred at room
temperature for 3
hours. Then the solvent was directly removed, then water (10 mL) was added and
the pH of the
mixture was adjusted to 8-9 by saturated sodium bicarbonate. The aqueous phase
was extracted
with ethyl acetate (10 mL x 3), and the combined organic phases were dried
over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to give (R)-N-(2,4-
difluoro-3-(5-(4-
(piperazin-1-yl)pheny1)-1H-pyrrolo[2,3-b[pyridine-3-carbonyl)pheny1)-3-
fluoropyrrolidine-1-
sulfonamide (0.30 g, 91%) as a yellow solid.
[0522] Step C: 2-(2-chloroethoxy)ethyl 4-methylbenzenesulfonate.
,-, 0
CI
cr 0
[0523] The mixture of 2-(2-chloroethoxy)ethanol (0.5 g, 4.0 mmol), tosyl
chloride (0.8 g, 4.0
mmol) and triethylamine (810 mg, 8.1 mmol) in dichloromethane (10 mL) was
stirred at room
temperature overnight. The mixture was poured into saturated sodium
bicarbonate solution (20
mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase
was
concentrated in vacuo and the residue was purified by column chromatography on
silica gel
(petroleum ether/ethyl acetate = 10/1) to give 2-(2-chloroethoxy)ethyl 4-
methylbenzenesulfonate
(0.9 g, 80% yield) as colorless oil. LCMS: m/z 279.1 [M+H]t
[0524] Step D: 5-(2-(2-chloroethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-
yl)isoindoline-1,3-
dione.
0
0 0
[0525] The mixture of 2-(2-chloroethoxy)ethyl 4-methylbenzenesulfonate (100
mg, 0.36
mmol), 2-(2,6-dioxopiperidin-3-y1)-5-hydroxyisoindoline-1,3-dione (98 mg, 0.36
mmol),
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ethyldiisopropylamine (93 mg, 0.72 mmol) and potassium iodide (59 mg, 0.36
mmol) in
dimethyl sulfoxide (5 mL) was heated at 45 C for 2 hours and then cooled to
room temperature.
The reaction mixture was poured into water (10 mL) and extracted with
dichloromethane (15 mL
x 3). The combined organic phase was concentrated in vacuo and the residue was
purified by
column chromatography on silica gel (dichloromethane/methanol = 20/1) to give
5-(2-(2-
chloroethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (48 mg,
35% yield) as a
white solid. LCMS: m/z 381.2 [M+H]t
[0526] Step E: (3R) N (3 (5 (4 (4 (2 (2 (2 (2,6 dioxopiperidin-3-y1)-1,3-
dioxoisoindolin-5-
yloxy)ethoxy)ethyl)piperazin-l-yl)pheny1)-1H-pyrrolo[2,3-b[pyridine-3-
carbonyl)-2,4-
difluoropheny1)-3-fluoropyrrolidine-l-sulfonamide.
0
0
I 10
0 NH
0 N) 0 /
0 H F
k, I
IN N
[0527] The mixture of 5-(2-(2-chloroethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-
yl)isoindoline-
1,3-dione (40 mg, 0.11 mmol), (R)-N-(2,4-difluoro-3-(5-(4-(piperazin-1-
yl)pheny1)-1H-
pyrrolo[2,3-b]pyridine-3-carbonyl)pheny1)-3-fluoropyrrolidine-1-sulfonamide
(61 mg, 0.11
mmol), ethyldiisopropylamine (28 mg, 0.22 mmol) and potassium iodide (18 mg,
0.11 mmol) in
dimethyl sulfoxide (5 mL) was heated at 80 C overnight. The mixture was
poured into water (10
mL) and extracted with dichloromethane (10 mL x 3). The organic phase was
concentrated in
vacuo and the residue was purified by pre-HPLC to give (3R)-N-(3-(5-(4-(4-(2-
(2-(2-(2,6-
dioxopiperidin-3-y1)-1,3-dioxoisoindolin-5-yloxy)ethoxy)ethyl)piperazin-1-
yl)pheny1)-1H-
pyrrolo[2,3-b]pyridine-3-carbony1)-2,4-difluoropheny1)-3-fluoropyrrolidine-1-
sulfonamide (31
mg, 30% yield) as a yellow solid. LCMS: m/z 929.3 [M+H]; 1H NMR (400 MHz, DMSO-
d6) 6
1.95-2.10 (3H, m), 2.53-2.59 (8H, m), 3.18-3.23 (4H, m), 3.24-3.31 (2H, m),
3.36-3.39 (2H, m),
3.47 (1H, s), 3.64 (2H, t, J = 6.0 Hz), 3.80 (2H, t, J =4.0 Hz), 4.35 (2H, t,
J = 4.0 Hz), 5.12
(1H, dd, J = 5.6, 9.6 Hz), 5.29 (1H, d, J = 12.8 Hz), 7.05 (2H, d, J = 8.8
Hz), 7.26 (1H, d, J = 8.8
Hz), 7.39 (1H, dd, J = 2.0, 8.4 Hz), 7.48 (1H, d, J = 2.4 Hz), 7.58-7.65 (3H,
m), 7.85 (1H, d, J =
8.4 Hz), 8.07 (1H, s), 8.53 (1H, d, J = 2.4 Hz), 8.65 (1H, d, J = 2.4 Hz),
9.85 (1H, brs), 11.1 (1H,
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s), 12.9 (1H, s).
[0528] Compounds 87-90 may be prepared in an analogous manner.
[0529] Example synthesis of compound 91
0
N 0
F rN NH
0 0c3.N 0 0
F)---/ N N
H
[0530] Step A: 2-(2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)ethoxy)ethanol.
0 (:)01:DH
)0B
0
[0531] To a solution of 2-(2-chloroethoxy)ethanol (2.0 g, 16.1 mmol) in N,N-
dimethylformamide (15.0 mL) was added 4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-yl)phenol
(3.54 g, 16.1 mmol), cesium carbonate (10.5 g, 32.2 mmol) and potassium iodide
(267 mg, 1.61
mmol). The reaction mixture was stirred at 60 C overnight. Then water (50 mL)
was added and
extracted with ethyl acetate (50 mL x 3), washed with brine (5 mL x 4). The
combined organic
phases were dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo. The
residue was purified by silica gel (petroleum ether/ethyl acetate = 2:1) to
give 2-(2-(4-(4,4,5,5-
tetramethy1-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethanol (2.1 g, 42%) as
yellow oil. 1H
NMR (400 MHz, DMSO-d6) 6 1.28 (12H, s), 3.49-3.52 (4H, m), 3.74 (2H, t, J =
4.8 Hz), 4.10-
4.12 (2H, m), 4.62-4.64 (1H, m), 6.93 (2H, d, J = 9.2 Hz), 7.60 (2H, d, J =
8.4 Hz).
[0532] Step B: 2-(2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)ethoxy)ethyl
methanesulfonate.
Is (:)().0Ms
0
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[0533] To a solution of 2-(2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)ethoxy)ethanol (350 mg, 1.14 mmol) in dichloromethane (15.0 mL) was
added
triethylamine (231 mg, 2.28 mmol) and methanesulfonyl chloride (157 mg, 1.37
mmol) under
nitrogen. The resulting reaction mixture was stirred at room temperature for 1
hour. Then aq.
sodium bicarbonate (20.0 mL) was added and extracted with dichloromethane (20
mL x 3),
washed by brine, dried and concentrated in vacuo to give crude 2-(2-(4-
(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethyl methanesulfonate as yellow oil,
which was used
for the next step without further purification. LCMS: m/z 404.2 [M+18] .
[0534] Step C: tert-butyl 4-(2-(2-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)phenoxy)ethoxy)ethyl)piperazine-1-carboxylate.
r ,Boc
N
opi 0c)N
O
[0535] To a solution of 2-(2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)ethoxy)ethyl methanesulfonate (1.14 mmol) in acetonitrile (20 mL)
was added
potassium carbonate (315 mg, 2.28 mmol) and tert-butyl piperazine-l-
carboxylate (234 mg, 1.25
mmol). The resulting reaction mixture was stirred at 80 C overnight. The
solvent was
concentrated in vacuo. The residue was extracted with ethyl acetate (20 mL x
3) and water (20
mL). The organic phase was dried and concentrated in vacuo. The residue was
purified by
preparative TLC (petroleum ether/ethyl acetate = 1:2) to give tert-butyl 4-(2-
(2-(4-(4,4,5,5-
tetramethy1-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethyl)piperazine-1-
carboxylate (280 mg,
52% for two steps) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) 6 1.27
(12H, s), 1.38
(9H, s), 2.35 (4H, t, J = 5.2 Hz), 2.47-2.50 (2H, m), 3.25-3.26 (4H, m), 3.57
(2H, t, J = 6.0 Hz),
3.70-3.73 (2H, m), 4.10-4.12 (2H, m), 6.92 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J
= 8.4 Hz).
[0536] Step D: (R)-tert-butyl 4-(2-(2-(4-(3-(2,6-difluoro-3-(3-
fluoropyrrolidine-1-
sulfonamido)benzoy1)-1H-pyrrolo[2,3-blpyridin-5-
yl)phenoxy)ethoxy)ethyl)piperazine-1-
carboxylate.
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F F rN,Boc
0 0c)N
Oz.-IN
)----/ N N"--
H
[0537] To a solution of tert-butyl 4-(2-(2-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)phenoxy)ethoxy)ethyl)piperazine- 1-carboxylate (114 mg, 0.238 mmol) in 1, 4-
dioxane/water
(10 mL/1 mL) was added (R)-N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbony1)-
2,4-
difluoropheny1)-3-fluoropyrrolidine-1-sulfonamide (120 mg, 0.238 mmol), cesium
fluoride (72.4
mg, 0.476 mmol) and Pd(aMPhos)C12 (16.9 mg, 0.0238 mmol). The resulting
reaction mixture
was stirred at 95 C for 16 hours. After cooling, water (20 mL) was added and
extracted with
ethyl acetate (15 mL x 3). The organic phase was dried and concentrated in
vacuo. The residue
was purified by preparative TLC (dichloromethane/methano1=20:1) to give (R)-
tert-butyl 4-(2-
(2-(4-(3-(2,6-difluoro-3-(3-fluoropyrrolidine-1-sulfonamido)benzoy1)-1H-
pyrrolo[2,3-b]pyridin-
5-yl)phenoxy)ethoxy)ethyl)piperazine- 1-carboxylate (60 mg, 33%) as a pale
yellow solid.
LCMS: m/z 773.3 [M+H]t
[0538] Step E: (R)-N-(2,4-difluoro-3 (5 (4 (2 (2 (piperazin- 1-
yl)ethoxy)ethoxy)pheny1)-1H-
pyrrolo[2,3-blpyridine-3-carbonyl)pheny1)-3-fluoropyrrolidine-l-sulfonamide
hydrochloride
F F rNHHCI
0 OoN
r Nj 11 F / 1
H
[0539] A solution of (R)-tert-butyl 4-(2-(2-(4-(3-(2,6-difluoro-3-(3-
fluoropyrrolidine-1-
sulfonamido)benzoy1)-1H-pyrrolo[2,3-b]pyridin-5-
yl)phenoxy)ethoxy)ethyl)piperazine-1-
carboxylate (60 mg, 0.0517 mmol) in hydrochloric acid/1,4-dioxane (5 mL, 4 M)
was stirred at
room temperature for 1 hour. The solvent was concentrated in vacuo to give
compound (R)-N-
(2,4-difluoro-3-(5-(4-(2-(2-(piperazin-1-yl)ethoxy)ethoxy)pheny1)-1H-
pyrrolo[2,3-b]pyridine-3-
carbonyl)pheny1)-3-fluoropyrrolidine- 1-sulfonamide hydrochloride as a pale
yellow solid, which
was used to next step without further purification. LCMS: m/z 673.2 [M+H]t
[0540] Step F: (3R) N (3 (5 (4 (2 (2 (4 (2 (2,6 dioxopiperidin-3-y1)-1,3-
dioxoisoindolin-5-
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yl)piperazin-l-yl)ethoxy)ethoxy)pheny1)-1H-pyrrolo[2,3-b[pyridine-3-carbony1)-
2,4-
difluoropheny1)-3-fluoropyrrolidine-l-sulfonamide
0
N-
0 0c3.N 0 0
F)----/ N N
H
[0541] To a solution of (R)-N-(2,4-difluoro-3-(5-(4-(2-(2-(piperazin-1-
yl)ethoxy)ethoxy)pheny1)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)pheny1)-3-
fluoropyrrolidine-1-
sulfonamide hydrochloride (0.0517 mmol) in dimethyl sulfoxide (3 mL) was added
2-(2,6-
dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (14.3 mg, 0.0517 mmol) and
triethylamine
(10.5 mg, 0.104 mmol). The reaction mixture was stirred at 70 C for 24 hours.
After cooling to
room temperature, water (10 mL) was added and extracted with ethyl acetate
(10.0 mL x 3). The
combined organic phase was washed with brine (2.0 mL x 4), dried over
anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The residue was purified by
preparative TLC
(dichloromethane/methano1=20:1) twice to give (3R)-N-(3-(5-(4-(2-(2-(4-(2-(2,6-
dioxopiperidin-
3-y1)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)ethoxy)pheny1)-1H-
pyrrolo[2,3-b]pyridine-
3-carbony1)-2,4-difluoropheny1)-3-fluoropyrrolidine-1-sulfonamide (6.7 mg,
14%) as a yellow
solid. LCMS: m/z 929.3 [M+H]t 1H NMR (400 MHz, DMSO-d6) 6 1.96-2.13 (3H, m),
2.58
(7H, s), 2.83-2.92 (1H, m), 3.26-3.30 (2H, m), 3.40-3.43 (6H, m), 3.48 (1H,
s), 3.63-3.67 (2H,
m), 3.76-3.80 (2H, m), 4.17-4.19 (2H, m), 5.05-5.09 (1H, m), 5.23-5.36 (1H,
m), 7.11 (2H, d, J =
8.4 Hz), 7.24-7.29 (2H, m), 7.34 (1H, s), 7.60-7.69 (4H, m), 8.10 (1H, s),
8.57 (1H, brs), 8.66
(1H, d, J = 2.4 Hz), 9.88 (1H, s), 11.09 (1H, s), 12.95 (1H, s).
[0542] Compounds 92-97 may be prepared in an analogous manner.
[0543] Example synthesis of compound 99
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gH
F 0
rNrC))LIµTcf i\o
0 HN
N -s_N
N N S
H µN \
[0544] Step A: tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate
Br . N/¨\NBoc
[0545] To a solution of 1,4-dibromobenzene (5.0 g, 21.2 mmol) in toluene
(100 mL) were
added tert-butyl piperazine-l-carboxylate (3.04 g, 16.3 mmol), Pd2(dba)3 (485
mg, 0.53 mmol),
t-BuOK (5.95 g, 53 mmol) and BINAP (485 mg, 0.53 mmol). The resulting solution
was stirred
at 90 C for 3 hours under N2 atmosphere. After cooling to room temperature,
the reaction was
quenched with H20 (50 mL), and the mixture was extracted with EA. The combined
organic
layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The
residue was
purified by silica gel to afford the desired product (1.2 g, 17% yield) as a
white solid. 1H NMR
(400 MHz, CDC13): 6 7.35 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 9.2 Hz, 2H), 3.57
(t, J = 4.8 Hz, 4H),
3.09 (t, J = 4.8 Hz, 4H), 1.48 (s, 9H).
[0546] Step B: tert-butyl 4-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenyl)piperazine-1-carboxylate
.4.7µ13 = Nr¨\NBoc
6
[0547] To a solution of tert-butyl 4-(4-bromophenyl)piperazine-1-
carboxylate (1.2 g, 3.53
mmol) in 1,4-dioxane (24 mL) were added 4,4,4',4',5,5,5',5'-octamethy1-2,2'-
bi(1,3,2-
dioxaborolane) (1.8 g, 7.06 mmol), Pd(dppf)C12 (258 mg, 0.35 mmol) and KOAc
(1.04 g, 10.59
mmol). The resulting solution was stirred at 90 C overnight under N2
atmosphere. TLC showed
the reaction was completed. After cooled to room temperature, the reaction was
diluted with 50
mL of EA, and the mixture was washed with water and brine. The organic phase
was dried over
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anhydrous sodium sulfate. The residue was purified by chromatography column to
afford the
desired product (1.0 g, 73% yield). LCMS (ES): m/z 482Ø
[0548] Step C: tert-butyl 2-(2-(4-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)phenyl)piperazin-1-yl)ethoxy)acetate
(
0 NB 11 N/¨\N¨r
[0549] To a solution of tert-butyl 4-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)phenyl)piperazine-1-carboxylate (550 mg, 1.42 mmol) in DCM (5 mL) was added
TFA (1.5
mL, 20.2 mmol). The resulting solution was stirred at 5 C for 2 hours. The
solvent was removed
under vacuum to afford a residue (547 mg, calculated), which was used directly
in next step. To
a solution of the residue (547 mg, 1.42 mmol) in dry DMF (5 mL) were added
K2CO3 (977 mg,
7.08 mmol), KI (470 mg, 2.83 mmol) and tert-butyl 2-(2-chloroethoxy)acetate
(550 mg, 2.83
mmol). The resulting solution was stirred at 90 C for 3 hours. After cooling
to room
temperature, the reaction was quenched with 20 mL of saturated NaCl solution,
and the mixture
was extracted with EA twice. The combined organic layer was concentration in
vacuo, and the
residue was purified by silica gel to afford the desired product (300 mg, 47%
yield in two steps)
as oil. 1H NMR (400 MHz, CDC13): 6 7.70 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8
Hz, 2H), 4.01 (m,
3H), 3.69 (m, 4H), 3.30 (m, 4H), 2.68 (m, 6H), 1.48 (s, 9H), 1.32 (s, 12H).
[0550] Step D: (R)-tert-butyl 2-(2-(4-(4-(3-(2,6-difluoro-3-(3-
fluoropyrrolidine-1-
sulfonamido)benzoy1)-1H-pyrrolo[2,3-b[pyridin-5-yl)phenyl)piperazin-1-
yl)ethoxy)acetate
0 ?I J
F\C
0 N
N
H F I
N N
[0551] To a solution of tert-butyl 2-(2-(4-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)phenyl)piperazin-1-yl)ethoxy)acetate (100 mg, 0.20 mmol) in 1,4-dioxane/
H20 (10 ml/ 1 mL)
were added (3R)-N-[3-([5-bromo-1H-pyrrolo[2,3-b[pyridin-3-yl] carbony1)-2,4-
difluorophenyll-
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3-fluoropyrrolidine-1-sulfonamide (134 mg, 0.36 mmol), Pd(aMphos)C12 (15 mg,
0.02 mmol)
and CsF (121 mg, 0.80 mmol). The resulting solution was stirred at 95 C for 3
hours under N2
atmosphere. TLC showed the reaction was completed. After cooling to room
temperature, the
reaction was diluted with 50 mL of EA, and the mixture was washed with water
and brine. The
organic phase was dried over anhydrous sodium sulfate and concentrated in
vacuo. The residue
was purified by chromatography column to afford the desired product (100 mg,
66% yield).
LCMS (ES): m/z 743.2 [M+H-16] .
[0552] Step E: (25,4R)-1-((S)-2 (2 (2 (4 (4 (3 (2,6-difluoro-3-((R)-3-
fluoropyrrolidine-1-
sulfonamido)benzoy1)-1H-pyrrolo[2,3-b[pyridin-5-yl)phenyl)piperazin-l-
yl)ethoxy)acetamido)-
3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-
2-carboxamide
OH
F 0
rN7vC))L1\7\rcN
F 0 N H 0 0
HN
0 H
N N S
H \
[0553] To a solution of (R)-tert-butyl 2-(2-(4-(4-(3-(2,6-difluoro-3-(3-
fluoropyrrolidine-1-
sulfonamido)benzoy1)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-
yl)ethoxy)acetate
compound with methanol (100 mg, 0.13 mmol) in 1,4-dioxane (2 mL) was added HC1
(g), 1,4-
dioxane (1 mL, 8 M). The resulting solution was stirred at 50 C for 3 hours.
TLC showed the
reaction was completed. After cooled to room temperature, the reaction mixture
was
concentrated to afford a crude product (93 mg, 100% yield, calculated), which
was used into next
reaction. To a solution of crude product (93 mg, 0.13 mmol) in dry NMP (5 mL)
were added
(2S,4R)-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-amino-3,3-
dimethylbutanoy1)-4-
hydroxypyrrolidine-2-carboxamide hydrochloride (91 mg, 0.19 mmol), DIEA (167
mg, 1.30
mmol) and PyBOP (203 mg, 0.39 mmol) subsequently. The resulting solution was
stirred at 10
C for 1 hour. After the reaction was quenched with brine (20 mL), the mixture
was extracted
with EA twice. The organic layers was concentrated, and the residue was
purified by silica gel
and preparative HPLC to afford the desired product (39 mg, 27% yield in two
steps) as a yellow
solid. 1H NMR (400 MHz, CD30D): 6 8.80 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H),
7.89 (s, 1H), 7.73
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(m, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 8.0
Hz, 2H), 7.07-7.14
(m, 3H), 5.13 - 5.30 (m, 1H), 4.71 (s, 1H), 4.50 - 4.65 (m, 4H), 4.34 (d, J =
15.6 Hz, 1H), 4.12
(m, 2H), 3.78-3.95 (m, 4H), 3.40-3.65 (m, 9H), 3.10 (m, 6H), 2.42 (s, 3H),
2.00-2.30 (m, 4H),
1.04 (s, 9H); LCMS (ES): m/z 550.3 [M/2+H]t
[0554] Compounds 98, 100-101, 102, 103-106, and 223-252 may be prepared in
an
analogous manner.
[0555] Example synthesis of compound 114
OH
0\P F
\,SI,
F F j\-NH 0 HN
/ r----Ni
...-CN
HN N
/ \ N\___J
-
41,
S \
1.----z-N
[0556] Step A: 1-(azetidin-3-y1)-4-(4-bromophenyl)piperazine hydrochloride
r -N
Br 410 NNõ)
HCI
[0557] To a solution of1-(4-bromophenyl)piperazine hydrochloride (2.0 g,
7.21 mmol) in
CH3OH/DCM (v/v =1/1, 30 mL) was added KOAc (1.4 g, 14.4 mmol) and cat. AcOH
(0.1 mL)
at room temperature. After stirring for 30 minutes, NaBH(OAc)3 (7.6 g, 36.1
mmol). The
mixture was stirred at 30 C overnight. After the reaction was quenched with
aqu.NaHCO3 (50
mL), the mixture was extracted with DCM (100 mL x 2). The combined organic
layer was
washed with brine (50 mL), dried over anhydrous sodium sulfate and
concentrated under vacuum
to afford crude the desired product (2.5 g) as a light brown solid, which was
used to next step
without further purification. To a solution of the above intermediates in
methanol (20 mL) was
added HC1(g)/CH3OH (10 mL). The resulting solution was stirred for 2 hours at
room
temperature. The solvent was removed under vacuum. The residue was triturated
with DCM and
filtered to afford the desired product 1-(azetidin-3-y1)-4-(4-
bromophenyl)piperazine
hydrochloride (2.0 g) as a brown solid.
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[0558] Step B: ethyl 2-(3-(4-(4-bromophenyl)piperazin-1-yl)azetidin-1-
y1)acetate
(NNN= orC)
NN
Br
[0559] To a solution of 1-(azetidin-3-y1)-4-(4-bromophenyl)piperazine
hydrochloride (2.0 g,
6.01 mmol) in CH3OH/DCM (v/v =1/1, 10 mL) was added KOAc (1.2 g, 12.1 mmol)
and cat.
AcOH (0.1 mL) at room temperature. After stirring for 30 minutes, NaBH(OAc)3
(6.3 g, 30.1
mmol). The mixture was stirred at 30 C overnight. After the reaction was
quenched with aq.
NaHCO3(30 mL), the mixture was extracted with DCM (50 mL x 3). The combined
organic
layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and
concentrated
under vacuum to afford the desired product ethyl 2-(3-(4-(4-
bromophenyl)piperazin-1-
yl)azetidin- 1-yl)acetate (1.0 g, crude) as a light brown solid, which was
used to next step without
further purification. LCMS (ES): m/z 384.1; 382.1 [M+H] +.
[0560] Step C: methyl 2-(3-(4-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenyl)piperazin -1-yl)azetidin-1-y1)acetate
4b,
0
[0561] To a solution of ethyl 2-(3-(4-(4-bromophenyl)piperazin-1-
yl)azetidin-1-y1) acetate
(1.0 g, crude) in methanol (20 mL) was added HC1 (g)/CH3OH (10 mL). The
resulting solution
was stirred at 60 C for 2 hours. The solvent was removed under vacuum. The
residue was taken
up with DCM (100 mL), and the mixture was washed with NaHCO3 (30 mL x 3). The
organic
phase was concentrated under vacuum. The residue (500 mg) was used into next
reaction without
further purification. To a solution of the above intermediates (500 mg, 1.4
mmol) in 1,4-dioxane
(20 mL) was added KOAc (267 mg, 2.8 mmol), Pd(dppf)C12 (190 mg, 0.14 mmol),
4,4,5,5-
tetramethy1-2-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1, 3,2-
dioxaborolane (700 mg, 2.8
mmol). The resulting solution was purged with N2 at room temperature for 10
minutes to remove
the excess 02. The mixture was stirred at 100 C overnight. After cooling to
room temperature,
the reaction was taken up with Et0Ac. The organic phase was concentrated under
vacuum. The
residue was purified by silica gel with PE/EA (10-1/1) to afford the desired
product methyl 2-(3-
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(4-(4-(4,4,5,5-tetramethy1-1,3,2- dioxaborolan-2-yl)phenyl)piperazin-1-
yl)azetidin-1-y1)acetate
(300 mg) as a brown solid. LCMS (ES): m/z 416.3 [M+H] +.
[0562] Step D: (2S,4R)-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3,3-
dimethyl-2-(2-(3-(4-
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)phenyl)piperazin-1-y1)azetidin-
1-
y1)acetamido)butanoy1)-4-hydroxypyrrolidine-2-carboxamide
OH
0
o ¨1\0(iHN
0 AIL Nr-\N-N-)\--
1\11-
\I3 Mr \____-/
ci
=
s \
N
[0563] To a solution of methyl 2-(3-(4-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)phenyl)piperazin-1-yl)azetidin-1-y1)acetate (300 mg, 0.72mmo1) in H20/THF
(v/v=1/5, 5 mL)
was added LiOH (34 mg, 1.5 mmol).The resulting solution was stirred at room
temperature for 1
hour. Then the solvent was removed under vacuum. The residue was used into
next reaction
without further purification. To a solution of the above intermediates in DMF
(5.0 mL) were
added DIEA (300 mg, 2.2 mmol), (2S,4R)-N-(4-(4-methylthiazol-5-yl)benzyl)-1-
((S)-2-amino-
3,3-dimethylbutanoy1)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (338
mg, 0.72 mmol)
and PyBOP (564 mg, 1.1 mmol) at room temperature. The resulting solution was
stirred at 20 C
for 2 hours. The reaction was quenched with H20 (10 mL), and the mixture was
extracted with
Et0Ac (20 mL x 3). The combined organic layer was concentrated under vacuum.
The residue
was purified by preparative TLC with DCM/CH3OH (20/1) to afford the desired
product
(2S,4R)-1-((S)-3,3-dimethy1-2-(2-(3-(4-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
y1)phenyl)piperazin-1-y1)azetidin-1-y1)acetamido) butanoy1)-4-hydroxy-N-(4-(4-
methylthiazol-
5-yl)benzyl)pyrrolidine-2-carboxamide (80 mg) as a light brown solid. LCMS
(ES): m/z 814.4
[M+H] +.
[0564] Step E: (25,4R)-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2 (2 (3 (4
(4 (3 (2,6-
difluoro-3-((R)-3-fluoropyrrolidine-1-sulfonamido)benzoy1)-1H-pyrrolo12,3-
blpyridin-5-
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yl)phenyl)piperazin-l-yl)azetidin-1-y1)acetamido)-3,3-dimethylbutanoy1)-4-
hydroxypyrrolidine-
2-carboxamide
OH
0,P F
F F j\-NH 0 HN
i-----\
/
N N----N
N-
S \
N
[0565] To a solution of (2S,4R)-1-((S)-3,3-dimethy1-2-(2-(3-(4-(4-(4,4,5,5-
tetramethy1-1,3,2-
dioxaborolan-2-y1)phenyl)piperazin-1-y1)azetidin-1-y1)acetamido)butanoy1)-4-
hydroxy-N-(4-(4-
methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (80 mg, 0.098 mmol) in
H20/1,4-dioxane
(v/v=1/5, 5.0 mL) were added CsF (45 mg, 0.29mmo1), Pd(amphos)C12 (8 mg,
0.01mmol), (R)-
N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbony1)-2,4-difluoropheny1)-3-
fluoropyrrolidine-
1-sulfonamide (70 mg, 0.14 mmol) at room temperature. The solution was purged
with N2 at
room temperature for 10 minutes to remove the excess 02. The resulting
solution was stirred at
80 C overnight. After cooling to room temperature, the reaction was taken up
with Et0Ac. The
combined organic layer was concentrated under vacuum. The residue was purified
by preparative
TLC with DCM/CH3OH (20/1) to afford the desired product (2S,4R)-1-((S)-2-(2-(3-
(4-(4-(3-
(2,6-difluoro-3-(((R)-3-fluoro -pyrrolidine)-1-sulfonamido)benzoy1)-1H-
pyrrolo[2,3-b]pyridin-5-
yl)phenyl)piperazin-l-yl)azetidin-l-y1)acetamido)-3,3-dimethylbutanoy1)-4-
hydroxy-N-(4-(4-
methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (35 mg) as a light yellow
solid. 1H NMR
(400 MHz, DMSO-d6): 6 9.02 (s, 1H), 8.71-8.75 (m, 2H), 8.68 (br, 1H), 8.12 (s,
1H), 7.61-7.66
(m, 4H), 7.42-7.46 (m, 5H), 7.19-7.21 (m, 2H), 7.06 (d, J = 8.0 Hz, 2H), 5.33-
5.35 (m, 0.5H),
5.22-5.23 (m, 0.5 H), 5.16 (d, J = 7.2 Hz, 1H), 4.53 (d, J = 9.6 Hz, 1H), 4.34-
4.47 (m, 5H), 4.24-
4.29 (m, 1H), 4.04 (s, 1H), 3.65-3.66 (m, 3H), 3.51-.3.61 (m, 5H), 3.22-3.34
(m, 6H), 3.08 (br,
3H), 2.41-2.47 (m, 3H), 1.93-2.07 (m, 5H), 0.94 (s, 9H); LCMS (ES): m/z 1111.3
[M+H],
1108.3 [M-H]t
[0566] Compounds 107-113, 115, 116, and 253-269 may be prepared in an
analogous
manner.
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[0567] Example synthesis of compound 117
HO-N
\
---
N 41 Ni---\N 0
0
---- ---N' \----/ N)=(NH
I
N Z 0 o
[0568] Step A: tert-butyl 4-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenyl)piperazine-1-carboxylate
Br
,
N \ / \N A 0 1
N
N
>0
[0569] The mixture of 4-(4-bromo-1H-pyrazol-3-yl)pyridine (5.0 g, 22.3
mmol) (previously
described in Bioorg. Med. Chem. Lett. 2008, 18, 4692-4695), tert-butyl 4-(4-
(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl)piperazine-l-carboxylate (8.7 g, 22.3 mmol) and
cupric acetate
(4.0 g, 22.3 mmol) in pyridine (30 mL) was stirred at 100 C overnight. The
mixture was
concentrated in vacuo and the residue was purified by column chromatography on
silica gel
(petroleum ether/ethyl acetate = 5/1) to give tert-butyl 4-(4-(4-bromo-3-
(pyridin-4-y1)-1H-
pyrazol-1-yl)phenyl)piperazine-l-carboxylate (10.8 g, 70% yield) as a brown
solid.
[0570] Step B: tert-butyl 4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-y1)-3-
(pyridin-4-y1)-1H-
pyrazol-1-yl)phenyl)piperazine-1-carboxylate
0
0
Nr---\____/N4
..--
N . 0
NI
N ---
[0571] The mixture of tert-butyl 4-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-
1-
yl)phenyl)piperazine-1-carboxylate (2.4 g, 5.0 mmol), 5-(4,4,5,5-tetramethy1-
1,3,2-dioxaborolan-
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2-y1)-2,3-dihydro-1H-inden-1-one (1.3 g, 5.0 mmol), [1,1'-
bis(diphenylphosphino)ferrocene[dichloropalladium (366 mg, 0.5 mmol). tri-tert-
butylphosphine
tetrafluoroborate (145 mg, 0.5 mmol) and cesium fluoride (2.3 g, 15.0 mmol) in
1,4-
dioxane/water (20 mL, 10/1) was stirred at 90 C overnight. The mixture was
poured into water
(30 mL) and extracted with dichloromethane (30 mL x3). The combined organic
phase was
concentrated in vacuo and the residue was purified by column chromatography on
silica gel
(dichloromethane/methanol = 20/1) to give tert-butyl 4-(4-(4-(1-oxo-2,3-
dihydro-1H-inden-5-
y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazine-1-carboxylate (1.6 g,
60% yield) as a
yellow solid. LCMS: m/z 536.3 [M+H]t
[0572] Step C: 5-(1-(4-(piperazin-1-yl)pheny1)-3-(pyridin-4-y1)-1H-pyrazol-
4-y1)-2,3-
dihydro-1H-inden-1-one hydrochloride
0
/--\ ---
HN N . NsNõ....
i N
=HCI I
-- N
[0573] The solution of tert-butyl 4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-y1)-
3-(pyridin-4-
y1)-1H-pyrazol-1-yl)phenyl)piperazine-1-carboxylate (1.6 g, 3.0 mmol) in dry
hydrochloride
acid/methanol (30 mL, 1.0 M.) was stirred at room temperature overnight. The
reaction mixture
was concentrated in vacuo to give 5-(1-(4-(piperazin-1-yl)pheny1)-3-(pyridin-4-
y1)-1H-pyrazol-
4-y1)-2,3-dihydro-1H-inden-1-one hydrochloride (1.0 g, 80% yield) as a white
solid, which was
directly used to the next step without further purification.
[0574] Step D: 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
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00
N) 0
0
/ y
\N
[0575] The mixture of 5-(1-(4-(piperazin-1-yl)pheny1)-3-(pyridin-4-y1)-1H-
pyrazol-4-y1)-
2,3-dihydro-1H-inden-1-one hydrochloride (1.0 g, 2.3 mmol), 2-(2,6-
dioxopiperidin-3-y1)-5-
fluoroisoindoline-1,3-dione (635 mg, 2.3 mmol) and triethylamine (697 mg, 6.9
mmol) in
dimethyl sulfoxide (10 mL) was stirred at 80 C overnight. The mixture was
poured into water
(20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic
phase was
concentrated in vacuo and the residue was purified by column chromatography on
silica gel
(dichloromethane/methanol = 20/1) to give 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 (1.1 g, 70% yield) as a yellow solid. LCMS: m/z 692.3 [M+H]t
[0576] Step E: (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-
yl)isoindoline-1,3-dione
HON
N=
Nr-\N 0
0
Nj.(NH
NV 0
[0577] The mixture of 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 (300 mg,
0.43 mmol) and hydroxylamine hydrochloride (300 mg, 4.3 mmol) in pyridine (10
mL) was
stirred at room temperature overnight. The reaction mixture was concentrated
in vacuo. The
residue was purified by preparative HPLC to give (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-yl)isoindoline-1,3-dione (182 mg, 60% yield) as a yellow solid. LCMS: m/z
707.3 [M+H];
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1H NMR (400 MHz, DMSO-d6) 6 2.01-2.07 (1H, m), 2.54-2.61 (2H, m), 2.80-2.89
(3H, m),
2.98-3.02 (2H, m), 3.39 (4H, brs), 3.66 (4H, brs), 5.06-5.11 (1H, m), 7.16
(2H, d, J = 8.8 Hz),
7.21 (1H, d, J = 7.6 Hz), 7.33-7.35 (1H, m), 7.42 (2H, d, J = 8.0 Hz), 7.47
(2H, dd, J = 5.6, 1.6
Hz), 7.55 (1H, J = 7.6 Hz), 7.72 (1H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.8
Hz), 8.57 (2H, dd, J =
4.4, 1.2 Hz), 8.73 (1H, s), 10.9 (1H, s), 11.0-11.1 (1H. m).
[0578] Compounds 118-132 and 271 may be prepared in an analogous manner.
[0579] Example synthesis of compound 137
00
NH
HO-N
0
/ N
[0580] Step A: tert-butyl (2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethyl)(methyl)carbamate
BocN¨
Br
*0
N
N
[0581] To a solution of tert-butyl methyl(2-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)phenoxy)ethyl)carbamate (3.57 g, 9.47 mmol) and 4-(4-bromo-1H-pyrazol-3-
yl)pyridine (2.12
g, 9.47 mmol) in DCM(20 mL) were added Et2NH(6.91 g, 94.72 mmol),
Cu(0Ac)2(1.72 g, 9.47
mmol).The resulting mixture was stirred at 30 C for 16 hours under the
atmosphere of 02 The
mixture was diluted with DCM (30 mL), and then the mixture was washed with NH3-
1-120 thrice.
The organic phase was evaporated under reduced pressure, The residue was
purified by silica gel
column chromatography on silica gel(DCM/Me0H= 80/1) to afford tert-butyl (2-(4-
(4-bromo-3-
(pyridin-4-y1)-1H-pyrazol-1-y1) phenoxy)ethyl)(methyl)carbamate (3.0 g, 66.9%
yield) as a
brown oil.
[0582] Step B: 2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)-N-
methylethan-1-
amine
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H
Br -/N¨
Or
N
N
[0583] To a solution of tert-butyl (2-(4-(4-bromo-3-(pyridin-4-y1)-1H-
pyrazol-1-
yl)phenoxy)ethyl)(methyl)carbamate (1.56 g, 3.31 mmol) in Me0H (6 mL) was
added
HC1/Dioxane(6 N, 10 mL) at room temperature slowly. The mixture was stirred at
room
temperature for 2 hours .The mixture was evaporated under reduced pressure to
afford 2-(4-(4-
bromo-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)-N-methylethan-1-amine as a
colorless solid
(1.23 g, 100% yield).
[0584] Step C: 5-((2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-
dione
Br 0
of---/ 0
N
N 0
0
[0585] To a solution of 2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)-N-
methylethan-1-amine (400 mg, 1.07 mmol) and 2-(2,6-dioxopiperidin-3-y1)-5-
fluoroisoindoline-
1,3-dione (591.9 mg, 2.14 mmol) in NMP(2 mL) was added DIPEA(1.38 g, 10.7
mmol). The
resulting mixture was stirred at 130 C for 12 hours under the atmosphere of N2
The mixture was
diluted with EA (30 mL), and then the mixture was washed with brine twice. The
organic phase
was evaporated under reduced pressure, The residue was purified by column
chromatography on
silica gel (PE/Et0Ac= 1/3) to afford 5-((2-(4-(4-bromo-3-(pyridin-4-y1)-1H-
pyrazol-1-
yl)phenoxy)ethyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-
dione (500 mg,
74.1% yield).
[0586] Step D: 2-(2,6-dioxopiperidin-3-y1)-5-(methyl(2-(4-(4-(1-oxo-2,3-
dihydro-1H-inden-
5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-y1)phenoxy)ethyl)amino)isoindoline-1,3-
dione
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00
0 NH
ON
0
0
/ N
[0587] To a solution of 5-((2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-
dione (500 mg,
0.79 mmol) and 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-2,3-dihydro-1H-
inden-1-one
(307.6 mg, 1.19 mmol) in 1,4-dioxane/H20(9 mL,8:1) were added t-Bu3PHBF4(92.2
mg, 0.32
mmol), CsF(483.3 mg, 3.18 mmol),Cy2NMe(5 drop) and Pd2(dba)3(145.6 mg, 0.16
mmol). The
resulting mixture was stirred at 100 C for 2 hour under the atmosphere of N2
The solvent was
evaporated under reduced pressure. The residue was diluted with EA (30 mL),
and then the
mixture was washed with brine twice. The organic phase was evaporated under
reduced pressure,
The residue was purified by column chromatography on silica gel (PE/DCM/Me0H,
800/200/25) to afford 2-(2,6-dioxopiperidin-3-y1)-5-(methyl(2-(4-(4-(1-oxo-2,3-
dihydro-1H-
inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)ethyl)amino)isoindoline-
1,3-dione (500
mg, 92.4% yield).
[0588] Step E: (E)-2-(2,6-dioxopiperidin-3-y1)-5-((2-(4-(4-(1-
(hydroxyimino)-2,3-dihydro-
1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethyl)(methyl)amino)isoindoline-1,3-
dione
00
ON NH
N-t
HO-N
0
/ N
[0589] To a solution of 2-(2,6-dioxopiperidin-3-y1)-5-(methyl(2-(4-(4-(1-
oxo-2,3-dihydro-
1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethyl)amino)isoindoline-1,3-dione
(200 mg, 0.294 mmol) in CH3CN/Py(3 mL/3 mL) was added NH2OH-HC1(200 mg, 2.877
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mmol),the mixture was stirred at 40 C for 0.5 hour. The mixture was diluted
with DCM (30
mL),washed with brine twice. The organic layer was evaporated under reduced
pressure. The
residue was purified by TLC(DCM/EA/Me0H=50/100/15) to afford (E)-2-(2,6-
dioxopiperidin-
3-y1)-5-
[0590] ((2-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-y1)-3-(pyridin-4-
y1)-1H-
pyrazol-1-yl)phenoxy)ethyl)(methyl)amino)isoindoline-1,3-dione as a yellow-
green solid (103
mg, 49.9% yield). 1H NMR (400 MHz, CDC13): 6 8.56 (d, J = 4.0 Hz, 2H), 8.16
(s, 1H), 7.94 (s,
1H), 7.66 ¨ 7.72 (m, 4H), 7.50 (d, J = 4.8 Hz, 2H), 7.43 (s, 1H), 7.29 (s,
1H), 7.19 ¨ 7.26 (m,
2H), 6.93 ¨ 6.98 (m, 3H), 4.92 ¨ 4.96 (m, 1H), 4.24 (t, J = 4.8 Hz, 2H), 3.94
(t, J =10 Hz, 2H),
3.23 (s, 3H), 3.00¨ 3.04 (m, 4H), 2.77 ¨2.92 (m, 4H), 2.12 ¨ 2.15 (d, J =8.4
Hz, 1H); LCMS
(ES): m/z 696.2 [M+H] +.
[0591] Compounds 133-136, 138-149, and 273-281 may be prepared in an
analogous
manner.
[0592] Example synthesis of compound 150
/Th
H0 =7......./--Nv_./N
' NI\ 0 -7-
0
/ N =N 0
c*IF-1
\ /
N 0
[0593] Step A: 4-(4-bromo-1-(4-(2-(3-((tert-
butyldimethylsilyl)oxy)propoxy)ethoxy)pheny1)-1H-pyrazol-3-y1)pyridine
Br
---
N = ONOOTBS
----. N
I
N /
[0594] To a solution of 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethy14-
methylbenzene-
esulfonate (420 mg, 1.08 mmol) in dry DMF (10 mL) were added K2CO3 (299 mg,
2.16 mmol)
and 4-(4-bromo-1H-pyrazol-3-yl)pyridine (342 mg, 1.08 mmol) subsequently. The
resulting
solution was stirred at 80 C for 3 hours. The reaction mixture was diluted
with EA (30 mL) and
washed with brine. The organic phase was dried over anhydrous sodium sulfate
and concentrated
under vacuum. The residue was purified to afford the desired product 4-(4-
bromo-1-(4-(2-(3-
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((tert-butyldimethylsilyl)oxy)propoxy) ethoxy) phenyl)-1H-pyrazol-3-
y1)pyridine (DCM:Me0H
= 20:1) (430 mg) as colorless solid. 1H NMR (400 MHz, CDC13): 6 8.66 (br, 2H),
7.89-7.93 (m,
3H), 7.55 (d, J = 8.8 Hz, 2H), 6.96-6.98 (m, 2H), 4.04-4.14 (m, 2H), 3.76 (d,
J = 4.8 Hz, 2H),
3.67 (d, J = 6 Hz, 3H), 3.58 (d, J = 6.4 Hz, 2H), 1.71-1.79 (m, 2H), 0.84 (s,
9H), 0.0 (s, 6H).
[0595] Step B: 3-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)propan-
1-ol
Br
---
N 4I 'OOH
------_ N
I
N Z
[0596] To a solution of 4-(4-bromo-1-(4-(2-(3-((tert-
butyldimethylsilyl)oxy)
propoxy)ethoxy)pheny1)-1H-pyrazol-3-y1)pyridine (430 mg, 0.808 mmol) in 1,4-
dioxane (2 mL)
was added 6 M HC1 in 1,4-dioxane (4 mL). The resulting solution was stirred at
25 C for 1 hour.
The solvent was removed under reduced pressure to afford crude the desired
product 3-(2-(4-(4-
bromo-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)ethoxy)propan-1-ol (270 mg
crude), which
was used in next step without further purification. LCMS (ES): m/z 420.0 [M+H]
+.
[0597] Step C: 3-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)propanal
Br
411 n
N
---...
I
N /
[0598] To a solution of 3-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)propan-1-ol (135 mg, 0.32 mmol), IBX (136 mg, 0.48 mmol) in
CH3CN (4
mL) was added at room temperature. The mixture was stirred at 80 C for 2
hours. After the
reaction was completed, the mixture was filtrated. The filtrate was
concentrated under vacuum to
afford crude desired product 3-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)
ethoxy)propanal (140 mg crude), which was used in next step without further
purification.
LCMS (ES): m/z 416.0 [M+H] +.
[0599] Step D: tert-butyl 4-(2-(2,6-dioxopiperidin-3-y1)-1,3-
dioxoisoindolin-4-
yl)piperazine-1-carboxylate
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0 0
N_Z-NH 0
N C ) N
1
Boc
[0600] To a solution of tert-butyl piperazine-l-carboxylate (1.35 g, 7.25
mmol) in NMP (10
mL) were added 2-(2,6-dioxopiperidin-3-y1)-4-fluoroisoindoline-1,3-dione (1 g,
3.62 mmol) and
DIEA (1.87 g, 14.5 mmol). The resulting solution was stirred at 90 C under N2
for 4 hours. The
reaction mixture was diluted with EA (30 mL) and washed with brine. The
organic phase was
dried over anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified
to afford the desired product tert-butyl 4-(2-(2,6-dioxopiperidin-3-y1)-1,3-
dioxoisoindolin-4-
yl)piperazine-1-carboxylate (DCM:EA = 1:1) (1.4 g) as yellow solid. 1H NMR
(400 MHz,
DMSO-d6): 6 7.73 (d, J = 7.2 Hz, 1H), 7.35-7.41 (m, 2H), 5.09-5.13 (m, 1H),
3.52 (s, 4H),
3.26 (s, 4H), 2.84-2.89 (m, 1H), 2.56-2.63 (m, 2H), 2.00-2.05 (m, 2H), 1.45
(s, 9H).
[0601] Step E: 2-(2,6-Dioxopiperidin-3-y1)-4-(piperazin-1-yl)isoindoline-
1,3-dione
hydrochloride
0 0
N_Z-NH 0
N _____________________________________
EN)
H HCI
[0602] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-y1)-1,3-
dioxoisoindolin-4-
yl)piperazine-1-carboxylate (1.4 g, 3.16 mmol) in 1,4-dioxane (4 mL) was added
6 M HC1 in
1,4-dioxane (6 mL). The resulting solution was stirred at 25 C for 1 hour.
The solution was
concentrated under reduced pressure. The residue afforded the desired product
2-(2,6-
dioxopiperidin-3-y1)-4-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride
(1.4 g crude), which
was used in next step without further purification. LCMS (ES): m/z 343.1 [M+H]
+.
[0603] Step F: 4 (4 (3 (2 (4 (4 bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)propyl)piperazin-l-y1)-2-(2,6-dioxopiperidin-3-
yl)isoindoline-1,3-dione
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NON
. 0 /---C/
0
B rT N N 0
( / cCrIF-I
N 0
[0604] To a solution of 3-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)propanal (140 mg crude, 0.32 mmol), 2-(2,6-dioxopiperidin-3-
y1)-4-
(piperazin- 1-y1) isoindoline-1,3-dione (123 mg, 0.32 mmol), NaBH3CN (41 mg,
0.64 mmol),
acetic acid (3.8 mg, 0.062 mmol) in Me0H. The resulting solution was stirred
atrt for overnight.
The mixture was diluted with EA, washed with water, and brine. The organic
phase was dried
over anhydrous sodium sulfate and concentrated under vacuum. The residue was
purified to
afford the desired product 4-(4-(3-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-
1-
yl)phenoxy)ethoxy)propyl)piperazin-1-y1)-2-(2,6-dioxopiperidin-3-
yl)isoindoline-1,3-dione
(DCM:Me0H = 15:1) (70 mg) as yellow solid. LCMS (ES): m/z 742.1 [M+H] +.
[0605] Step G: 2-(2,6-dioxopiperidin-3-y1)-4-(4-(3-(2-(4-(4-(1-oxo-2,3-
dihydro-1H-inden-5-
y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)piperazin-l-
yl)isoindoline-1,3-
dione
/.........7"-N7¨\
0 *0
¨NI 0
c*CrIF:1
\ /
N 0
[0606] To a solution of 4-(4-(3-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-
1-
yl)phenoxy)ethoxy)propyl)piperazin-1-y1)-2-(2,6-dioxopiperidin-3-
yl)isoindoline-1,3-dione (70
mg, 0.094 mmol), 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-2,3-dihydro-
1H-inden-1-one
(191 mg, 0.74 mmol), Pd2(dba)3 (181 mg, 0.198 mmol), CsF (300 mg, 1.97 mmol).
tri-tert-
butylphosphine tetrafluoroborate (115 mg, 0.39 mmol), N,N-
dicyclohexylmethylamine (9 mg,
0.047 mmol) in 1,4-dioxane/H20 (6 mL, 10/1). The resulting solution was
irradiated at 100 C
with microwave under N2 for 2 hours. After cooling to room temperature, the
mixture was
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diluted with EA, washed with water, and brine. The organic phase was dried
over anhydrous
sodium sulfate and concentrated under vacuum. The residue was purified to
afford the desired
product 2-(2,6-dioxopiperidin-3-y1)-4-(4-(3-(2-(4-(4-(1-oxo-2,3-dihydro-1H-
inden-5-y1)-3-
(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)piperazin-l-
yl)isoindoline-1,3-dione
(DCM:Me0H = 20:1) (33 mg) as yellow solid. LCMS (ES): m/z 795.3 [M-FH] +.
[0607] Step H: (E)-2-(2,6-dioxopiperidin-3-y1)-4-(4-(3-(2-(4-(4-(1-
(hydroxyimino)-2,3-
dihydro-1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)propyl)piperazin-l-
yl)isoindoline-1,3-dione
7.--\
/___7-N\_____iN
HO -N\ 0..x-0
0
/ N 40 N 0
-IV 0
cCr11:1
\ /
N 0
[0608] To a solution of 2-(2,6-dioxopiperidin-3-y1)-4-(4-(3-(2-(4-(4-(1-oxo-
2,3-dihydro-1H-
inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)ethoxy)propyl)piperazin-l-
yl)isoindoline-
1,3-dione (33 mg, 0.042 mmol) in acetonitrile (2 mL) and pyridine (1.5 mL),
added
hydroxylamine hydrochloride (27 mg, 0.42 mmol). The mixture was stirred at 40
C for 20
minutes, and it was diluted with DCM 20mL, washed with brine (10 mL). The
organic layer was
concentrated and purified by preparative TLC to afford (E)-2-(2,6-
dioxopiperidin-3-y1)-4-(4-(3-
(2-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-y1)-3-(pyridin-4-y1)-1H-
pyrazol-1-
yl)phenoxy)ethoxy)propyl)piperazin-l-yl)isoindoline-1,3-dione (22 mg, 66.6%
yield) as yellow
solid. 1H NMR (400 MHz, CDC13): 6 8.56 (d, J = 5.6 Hz, 2H), 8.37 (s, 1H), 7.94
(s, 1H), 7.68 (d,
J = 9.2 Hz, 3H), 7.55-7.57 (m, 1H), 7.51 (d, J = 5.6 Hz, 2H), 7.38-7.40 (m,
1H), 7.21-7.28
(m, 2H), 7.15 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.91-4.98 (m,
1H), 4.18 (d, J = 4.8
Hz, 2H), 3.82-3.84 (m, 2H), 3.63 (d, J = 6.4 Hz, 2H), 3.49 (s, 2H), 3.36-3.38
(m, 4H), 3.02 (d,
J = 10.8 Hz, 4H), 2.69-2.87 (m, 8H), 2.52-2.56 (m, 2H), 1.85-1.88 (m, 1H);
LCMS (ES):
m/z 810.2 [M-FH] +.
[0609] Compounds 151-172 and 282-284 may be prepared in an analogous
manner.
[0610] Example synthesis of compound 174
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HO-N H o
N
\ 0
N .
0 N
¨NI
, 0
\
N /
[0611] Step A: 4-(benzyloxy)butyl 4-methylbenzenesulfonate
,--............,-.....õ.õ.0
Bn0 Ts
[0612] To a solution of 4-(benzyloxy)butyl 4-methylbenzenesulfonate (5 g,
27.76 mmol),
DMAP (0.34 g, 2.78 mmol) and TEA (8.4 g, 83.28 mmol) in DCM (50 mL) was added
TsC1
(7.94 g, 41.64 mmol) batches. The resulting solution was stirred at 15 C for
2 hours. The
reaction was quenched by addition of saturated NH4C1 (50 mL). The mixture was
extracted with
DCM (50 mL x 2). The combined organic layer was dried over anhydrous sodium
sulfate,
concentrated under vacuum. The residue was purified by silica gel to afford
desired product 4-
(benzyloxy)butyl 4-methylbenzenesulfonate (5.6 g, 60% yield) as a light yellow
oil. 1H NMR
(400 MHz, CDC13): 6 7.77 (d, J = 8.4 Hz, 2H), 7.26-7.33 (m, 7H), 4.45 (s, 2H),
4.05 (t, J = 6.4
Hz, 2H), 3.42 (t, J = 6.4 Hz, 2H), 2.44 (s, 3H), 1.59-1.78 (m, 4H).
[0613] Step B: (S)-tert-butyl 5-amino-4-(4-(4-(benzyloxy)butoxy)-1,3-
dioxoisoindolin-2-
y1)-5-oxopentanoate
0 N H
2
0
Bn0¨\ r0
N,/
\
0
>0
[0614] To a solution of 4-(benzyloxy)butyl 4-methylbenzenesulfonate (0.63
g, 1.87 mmol) in
dry DMF (8.0 mL) was added K2C 03 (0.4 g, 2.88 mmol), tert-butyl (S)-5-amino-4-
(4-hydroxy-
1,3-dioxoisoindolin-2-y1)-5-oxopentanoate (0.5 g, 1.44 mmol) subsequently. The
resulting
solution was stirred at 70 C for 2 hours. After cooling to room temperature,
the reaction was
quenched with water (30 mL), and the mixture was extracted with EA (40 mL x
2). The
combined organic layer was washed with brine, dried over anhydrous sodium
sulfate,
concentrated under vacuum. The residue was purified by silica gel column to
afford (S)-tert-
butyl 5-amino-4-(4-(4-(benzyloxy)butoxy)-1,3-dioxoisoindolin-2-y1)-5-
oxopentanoate (0.4 g,
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55% yield). 1H NMR (400 MHz, CDC13): 6 7.63 (t, J = 8.4 Hz, 1H), 7.43 (m, 1H),
7.25-7.40 (m,
5H), 7.18 (s, 1H), 6.41 (br, 1H), 5.66 (br, 1H), 4.79 (m, 1H), 4.52 (s, 2H),
4.19 (t, J = 6.4 Hz,
2H), 3.58 (t, J = 6.4 Hz, 2H), 3.47 (m, 2H), 2.50 (m, 2H), 2.25 (m, 2H), 2.00
(m, 2H), 1.85 (m,
1H), 1.43 (s, 9H).
[0615] Step C: (S)-2-(2,6-dioxopiperidin-3-y1)-4-(4-
hydroxybutoxy)isoindoline-1,3-dione
HO-0
0 0
N __________________________________________ )-NH
0
[0616] To a solution of (S)-Tert-butyl 5-amino-4-(4-(4-(benzyloxy)butoxy)-
1,3-
dioxoisoindolin-2-y1)-5-oxopentanoate (400 mg, 0.784 mmol) in acetonitrile (5
mL) was added
Ts0H H20 (1.48 g, 7.84 mmol). The resulting solution was stirred at 80 C for
2 hours. The
reaction was quenched by saturated NaHCO3 and extracted with EA. The organic
layer was dried
over anhydrous sodium sulfate, concentrated and purified by column to afford
(S)-4-(4-
(benzyloxy)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (370 mg).
To a solution of
(S)-4-(4-(benzyloxy)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
(370 mg, 0.85
mmol) in THF / Me0H (4 mL / 1 mL) was added Pd(OH)2 (185 mg) and two drops of
concentrated HC1. The resulting mixture was stirred at 20 C for 1 hour under
H2 1 atm. The
resulting solution was filtered and evaporated. The residue was purified by
preparative TLC to
afford the desired product (S)-2-(2,6-dioxopiperidin-3-y1)-4-(4-
hydroxybutoxy)isoindoline-1,3-
dione (250 mg, 92% yield in two steps). LCMS (ES, Neg): m/z 345.0 [M-H]
[0617] Step D: (S)-4-((2-(2,6-Dioxopiperidin-3-y1)-1,3-dioxoisoindolin-4-
yl)oxy)butanal
0
0 0
N
0
[0618] To a solution of (S)-2-(2,6-dioxopiperidin-3-y1)-4-(4-
hydroxybutoxy)isoindoline-1,3-
dione (0.25 g, 0.72 mmol) in CH3CN (5 mL) was added IBX (607 mg, 2.16 mmol).
The resulting
solution was stirred at 75 C for 1 hour. After cooling to room temperature,
the reaction mixture
was filtered and concentrated under vacuum to afford crude desired product
(240 mg crude,
calculated, 100% yield), which was used in next step directly.
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[0619] Step E: (S)-4-(4-(4-(4-(4-Bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenyl)piperazin-
1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Br
, 11 Nn\1 H
N -\
---_, N \--/ \ ONO
I \ 0
N 7 N )
0
[0620] To a solution of (S)-4-((2-(2,6-dioxopiperidin-3-y1)-1,3-
dioxoisoindolin-4-
yl)oxy)butanal (240 mg crude, 0.72 mmol) in Me0H (6 mL) was added 1-(4-(4-
bromo-3-
(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazine (276 mg, 0.72 mmol) and two
drops of AcOH.
Then NaBH3CN (134 mg, 2.16 mmol) was added. The resulting solution was stirred
at 18 C for
2 hours. After quenched with water (30 mL), and the mixture was extracted with
EA (40 mL x
2). The combined organic layer was dried over anhydrous sodium sulfate and
concentrated under
vacuum. The residue was applied onto a silica gel column to afford desired
product (S)-4-(4-(4-
(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)butoxy)-2-
(2,6-
dioxopiperidin-3-yl)isoindoline-1,3-dione (350 mg, 68% yield in two steps).
LCMS (ES): m/z
713.1 [M+H] +.
[0621] Step F: (S)-2-(2,6-Dioxopiperidin-3-y1)-4 (4 (4 (4 (4 (1 oxo-2,3-
dihydro-1H-inden-
5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-1-
yl)butoxy)isoindoline-1,3-dione
0
---
N 41 r-\ H
N ,.,
co N õeu
-----.. N /N -\ __ \ 0
1 \-0
N ,
0
[0622] To a solution of (S)-4-(4-(4-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-
1-
yl)phenyl)piperazin-l-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-
dione (0.35 g, 0.52
mmol) and 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-2,3-dihydro-1H-inden-
1-one (147
mg, 0.57 mmol) in 1,4-dioxane (15 mL)/ H20 (1.5 mL) was added CsF (316 mg,
2.08 mmol),
Pd2(dba)3 (190 mg, 0.21 mmol). tri-tert-butylphosphine tetrafluoroborate (121
mg, 0.42 mmol)
and two drops of N-cyclohexyl-N-methylcyclohexanamine subsequently. The
reaction was
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heated to 100 C for 2 hour under N2 atmosphere. After cooling to room
temperature, the
reaction was quenched with water (20 mL), and the mixture was extracted with
ethyl acetate (30
mL x 2). The combined organic layer was dried over anhydrous sodium sulfate
and concentrated
under vacuum. The residue was applied onto a silica gel column to afford
desired product (S)-2-
(2,6-dioxopiperidin-3-y1)-4-(4-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-y1)-3-
(pyridin-4-y1)-1H-
pyrazol-1-yl)phenyl)piperazin-l-yl)butoxy)isoindoline-1,3-dione (0.3 g, 80%
yield) as yellow
solid. LCMS (ES+): m/z 382.8 [(M+H)/2] .
[0623] Step G: (S,E)-2-(2,6-dioxopiperidin-3-y1)-4 (4 (4 (4 (4 (1
(hydroxyimino)-2,3-
dihydro-1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-1-
yl)butoxy)isoindoline-1,3-dione
HO-N H
=
r'N 0 o
N 0
0
N
[0624] To a solution of (S)-2-(2,6-dioxopiperidin-3-y1)-4-(4-(4-(4-(4-(1-
oxo-2,3-dihydro-1H-
inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenyl)piperazin-l-
yl)butoxy)isoindoline-1,3-
dione (165 mg, 0.22 mmol) in acetonitrile / pyridine (6 ml /3 ml) was added
hydroxylamine
hydrochloride (150 mg, 2.16 mmol). The mixture was stirred at 45 C for 1 hour.
The solvent
was removed under vacuum, and the residue was purified by preparative TLC with
DCM /
Me0H (20 / 1) to afford the desired product (S,E)-2-(2,6-dioxopiperidin-3-y1)-
4-(4-(4-(4-(4-(1-
(hydroxyimino)-2,3-dihydro-1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenyl)piperazin-
1-yl)butoxy)isoindoline-1,3-dione (60 mg, 38% yield) as a white solid. 1H NMR
(400 MHz,
DMSO-d6): 6 11.11 (s, 1H), 10.88 (d, J = 3.6 Hz, 1H), 8.69 (s, 1H), 8.56 (m,
2H), 7.81 (m, 3H),
7.35-7.62 (m, 6H), 7.20 (s, 1H), 7.09 (m, 2H), 5.10 (m, 1H), 4.25 (t, J = 6.4
Hz, 2H), 3.32 (m,
4H), 3.19 (m, 4H), 2.75-3.05 (m, 5H), 2.40 (m, 2H), 1.60-2.10 (m, 8H); LCMS
(ES+): m/z 779.3
[M+H] .
[0625] Compounds 173 and 175-181 may be prepared in an analogous manner.
[0626] Example synthesis of compound 182
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0
0
0
F 0
N)WN\J
Fo
N
[0627] Step A: N-(3-(5-((1-(2-(2,6-dioxopiperidin-3-y1)-1,3-dioxoisoindolin-
4-yl)piperidin-
4-y1)(methyl)amino)-3-(pyrimidin-5- y1)-1H-pyrrolo [3 ,2-b1 pyridin-1- y1)-2,4-
difluorophenyl)propane-1-sulfonamide
0
0
0
F 0
N N
F
0 N
[0628] A mixture of N-(2,4-difluoro-3-(5-(methyl(piperidin-4-yl)amino)-3-
(pyrimidin- 5-y1)-
1H-pyrrolo[3,2-b[pyridin-1-yl)phenyl)propane-1-sulfonamide (100.0 mg,
0.18mmol) (previously
described in W02012/104388), 2-(2,6-dioxopiperidin-3-y1)-4-fluoroisoindoline-
1,3-dione (102
mg, 0.36 mmol), DIEA(239 mg, 1.80 mmol) in anhydrous NMP (2.0 mL) was radiated
at 130 C
with microwave for 1 hour. After cooling to room temperature, the reaction was
quenched with
water, and the mixture was extracted with EA (10 mL x 3). The combined organic
layer was
washed with water (10 mL x 3), brine (20 mL), dried over anhydrous sodium
sulfate and
concentrated under vacuum. The residue was purified by preparative TLC to
afford the desired
product N-(3-(5-((1-(2-(2,6-dioxopiperidin-3-y1)- 1,3-dioxoisoindolin-4-
yl)piperidin-4-
yl)(methyl)amino)-3-(pyrimidin-5-y1)-1H- pyrrolo[3,2-b[pyridin-1-y1)-2,4-
difluorophenyl)propane-1-sulfonamide ( DCM : Me0H = 10:1) (45 mg, yield =
30.6%) as white
solid. 1H NMR (400 MHz, CDC13): 6 9.58 (s, 1H), 9.10 (s, 1H), 8.03 (s, 1H),
7.67-7.59 (m, 2H),
7.42 (d, J =7.2 Hz, 1H), 7.34 (d, J =8 Hz, 1H), 7.23-7.18 (m, 1H), 6.66 (d, J
=12 Hz, 1H), 5.02-
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4.81 (m, 1H), 3.90-3.89 (m, 1H), 3.18-3.14 (m, 3H), 3.05 (s, 2H), 2.96-2.87
(m, 3H), 2.13 (dd, J
=2.8 Hz,4 Hz, 2 H), 2.00-1.90 (m, 3H), 1.30 (s, 8H), 1.09 (t, J =12.0 Hz, 3H),
0.84-.088 (m, 4H);
LCMS (ES): m/z 798.2 [M+H]t
[0629] Compound 183 may be prepared in an analogous manner.
[0630] Example synthesis of compound 184
1
F 1 N
cin = N N N 0 0
N p
0
[0631] Step A: tert-butyl (S)-5-amino-4-(4-(2-(benzyloxy)ethoxy)-1,3-
dioxoisoindolin-2-
y1)-5-oxopentanoate
0 0
\¨NH2
N _____________________________________ ,
:
\ _____________________________________________ Y
0 0 & 0
) 0
Bn0
[0632] A mixture of tert-butyl (S)-5-amino-4-(4-hydroxy-1,3-dioxoisoindolin-
2 -y1)-5-
oxopentanoate (1.22 g, 3.51mmol), 2-(benzyloxy)ethyl methanesulfonate (900 mg,
3.91 mmol),
K2CO3(1.08 g, 7.83 mmol) in DMF (10 mL) was stirred at 70 C for 6 hours.
After quenched
with water, the mixture was extracted with EA. The organic phase was dried
over anhydrous
sodium sulfate and concentrated under vacuum. The residue was purified to
afford the desired
product tert-butyl (S)-5-amino-4-(4-(2- (benzyloxy)ethoxy)-1,3-dioxoisoindolin-
2-y1)-5-
oxopentanoate (PE:Et0Ac = 1:5) (907 mg).
[0633] Step B: (S)-4-(2-(benzyloxy)ethoxy)-2-(2,6-dioxopiperidin-3-
yl)isoindoline-1,3-
dione
0 0
ro
Bnaj
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[0634] To a solution of tert-butyl (S)-5-amino-4-(4-(2-(benzyloxy)ethoxy)-
1,3 -
dioxoisoindolin-2-y1)-5-oxopentanoate (907 mg, 1.88 mmol), p-Ts0H (1.5 g, 7.89
mmol) in
MeCN (10 mL) was stirred with at 80 C for 8 hours. After quenched with water,
the mixture
was diluted with EA, washed with water, brine. The organic phase was dried
over anhydrous
sodium sulfate and concentrated under vacuum. The residue was purified to
afford the desired
product (S)-4-(2-(benzyloxy)ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-
1,3-dione
(PE:Et0Ac = 1:1) (1.23 g, crude).
[0635] Step C: (S)-2-(2,6-dioxopiperidin-3-y1)-4-(2-
hydroxyethoxy)isoindoline-1,3-dione
0 0
N 0
HO'
0 0
HO--/
[0636] To a solution of (S)-4-(2-(benzyloxy)ethoxy)-2-(2,6-dioxopiperidin-3-
y1) isoindoline-
1,3-dione (1.23 g, 3.01 mmol), Pd(OH)2/C(0.7 g), HC1/dioxane (6N, 6 drops) in
Me0H/Et0Ac
(1:1, 40 mL) was stirred with at room temperature for 12 hours under H2 1 atm.
The mixture was
filtered through Celite and the filtrate was concentrated under vacuum to
afford the desired
product (S)-2-(2,6-dioxopiperidin-3-y1)-4-(2- hydroxyethoxy)isoindoline-1,3-
dione (700 mg,
crude).
[0637] Step D: (S)-2-((2-(2,6-dioxopiperidin-3-y1)-1,3-dioxoisoindolin-4-
yl)oxy)acetaldehyde
0 0
NH
r 0 0
0------1
[0638] To a solution of (S)-2-(2,6-dioxopiperidin-3-y1)-4-(2-
hydroxyethoxy)isoindoline -1,3-
dione (200 mg, 0.63 mmol) in CH3CN (10 mL) was added IBX (352 mg, 1.26 mmol).
The
resulting solution was stirred at 80 C for 2 hours. After cooling to room
temperature, the
mixture was filtered, and the filtrate was concentrated under vacuum to afford
crude desired
product (S)-2-((2-(2,6-dioxopiperidin-3-y1)-1,3-dioxoisoindolin-4-yl)oxy)
acetaldehyde (200 mg
crude) as yellow solid, which was used into next reaction without further
purification.
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[0639] Step E: N-(3-(5-((1-(2-((2-(2,6-dioxopiperidin-3-y1)-1,3-
dioxoisoindolin-4-
yl)oxy)ethyl)piperidin-4-y1)(methyl)amino)-3-(pyrimidin-5-y1)-1H-pyrrolo [3 ,2-
111 pyridin-l-y1)-
2,4-difluorophenyl)propane-l-sulfonamide
1
F 1 N
. NNOO
N ,0
0
[0640] To a solution of (S)-2-((2-(2,6-dioxopiperidin-3-y1)-1,3-
dioxoisoindolin- 4-
yl)oxy)acetaldehyde (200 mg crude, 0.631 mmol), N-(2,4-difluoro-3-(5-(methyl
(piperidin-4-
yl)amino)-3-(pyrimidin-5 -y1)-1H-pyrrolo [3 ,2-b] pyridin-l-yl)phenyl)prop ane-
l-sulfonamide
hydrochloride (80 mg, 0.148 mmol), CH3COOH (3.8 mg, 0.062 mmol) in
Et0H/DCM(v/v =1/1,
20 mL) was added NaBH(OAc)3 (400 mg, 1.88 mmol). The resulting solution was
stirred at
room temperature overnight. After quenched with water, the mixture was
extracted with Et0Ac.
The organic phase was dried over anhydrous sodium sulfate and concentrated
under vacuum.
The residue was purified by prep-TLC (DCM/Et0Ac/Me0H=10/1/1) to afford the
desired
product (S)-N-(3-(5- ((1-(2-((2-(2,6-dioxopiperidin-3-y1)-1,3-dioxoisoindolin-
4-y1)-
oxy)ethyl)piperidin- 4-y1)(methyl)amino)-3-(pyrimidin-5-y1)-1H-pyrrolo[3,2-
b[pyridin-1-y1)-2,4-
difluorophenyl)propane-1-sulfonamide (20.1 mg) as white solid. 1H NMR (400
MHz, DMSO-
d6) 6 11.07 (s, 1H), 9.80¨ 10.02 (m, 1H), 9.66 (s, 1H), 9.01 (s, 1H), 8.40 (s,
1H), 7.80 ¨ 7.89 (m,
1H), 7.61-7.63 (m, 2H), 7.44-7.48 (m, 2H), 6.76 (d, J = 9.3 Hz, 1H), 5.08 (dd,
J = 12.9, 5.2 Hz,
1H), 4.33 ¨ 4.49 (m, 3H), 3.45 (s, 6H), 3.06 ¨ 3.25 (m, 3H), 2.94 (s, 2H),
2.83 (s, 2H), 2.55 ¨
2.73 (m, 4H), 2.29 (d, J = 10.3 Hz, 2H), 1.77 (m, 2H), 1.68 (d, J = 10.1 Hz,
2H), 0.99 (t, J = 7.4
Hz, 3H); LC-MS: (ES): m/z 842.3 [M-FH] +.
[0641] Compounds 185-189 may be prepared in an analogous manner.
[0642] Example synthesis of compound 191
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I OH
z-
F nN 0
--Th it N__N1 N e-0J-1\.µr NI-
TI
-.
Os__N H o 0
z.-
OH F / \ ...._\ N HN
N:-_-.--/
S
N \
[0643] Step A: tert-butyl 2-(2-(2-oxoethoxy)ethoxy)acetate
0
o0-'()')0
[0644] To a solution of tert-butyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate (1
g, 4.55 mmol) in
CH3CN (15 mL) was added IBX (3.8 g, 13.64 mmol). The resulting solution was
stirred at 75 C
for 1 hour. After cooling to room temperature, the mixture was filtered and
the filtrate was
concentrated under vacuum to afford crude desired product tert-butyl 2-(2-(2-
oxoethoxy)ethoxy)acetate (1 g crude, 100% yield), which was used in next step
directly. 1H
NMR (400 MHz, CDC13): 6 9.75 (s, 1H), 4.18 (s, 2H), 4.03 (s, 2H), 3.77 (s,
4H), 1.48 (s, 9H).
[0645] Step B: tert-buty1-2-(2-(2-(4-((1-(2,6-difluoro-3-
(propylsulfonamido)pheny1)-3-
(pyrimidin-5-y1)-1H-pyrrolo[3,2-blpyridin-5-y1)(methyl)amino)piperidin-1-
yl)ethoxy)ethoxy)acetate
1
F 0
N
__'\) 410 N \ N N .e-0j-e=K
0:-..-p_N -
OH F
N-:.---/
[0646] To a solution of tert-butyl 2-(2-(2-oxoethoxy)ethoxy)acetate (181 mg
crude, 0.83
mmol) in Et0H / DCM (1 / 1) was added N-(2,4-difluoro-3-(5-(methyl(piperidin -
4-yl)amino)-3-
(pyrimidin-5-y1)-1H-pyrrolo[3,2-b]pyridin-1-y1)phenyl)propane-1-sulfonamide
hydrochloride
(150 mg, 0.28 mmol) and cat. AcOH. KOAc was added if pH was below 5-6. After
stirring for
30 minutes, NaBH(OAc)3 (235 mg, 1.11 mmol) was added. The resulting solution
was stirred at
30 C for 1 hour. After quenched with water (20 mL), the mixture was extracted
with DCM (30
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mL x 2). The combined organic layer was dried over anhydrous sodium sulfate
and concentrated
under vacuum. The residue was applied onto a silica gel column to afford
desired product 2-(2-
(2-(4-((1-(2,6-difluoro-3-(propylsulfonamido)pheny1)-3-(pyrimidin-5-y1)-1H-
pyrrolo[3,2-
b[pyridin-5-y1)(methyl)amino)piperidin-1-yl)ethoxy)ethoxy)acetate (120 mg, 58%
yield).
LCMS: (ES): m/z 744.3 [M-FH] +.
[0647] Step C: 2-(2-(2-(4-((1-(2,6-difluoro-3-(propylsulfonamido)pheny1)-3-
(pyrimidin-5-
y1)-1H-pyrrolo[3,2-b[pyridin-5-y1)(methyl)amino)piperidin-1-
y1)ethoxy)ethoxy)acetic acid
1
F nN 0
---- . ). N \ N N
0--zs_N
OH F
N--.:j
[0648] To a solution of tert-butyl 2-(2-(2-(4-((1-(2,6-difluoro-3-
(propylsulfonamido)phenyl)
-3-(pyrimidin-5-y1)-1H-pyrrolo[3,2-b[pyridin-5-y1)(methyl)amino)piperidin-1-
yl)ethoxy)ethoxy)acetate (0.12 g, 0.16 mmol) in DCM (3 mL) was added TFA (1
mL). The
resulting solution was stirred at 30 C for 1 hour. The solvent was removed
under vacuum to
afford the desired product 2-(2-(2-(4-((1-(2,6-difluoro-3-
(propylsulfonamido)pheny1)-3-
(pyrimidin-5-y1)-1H-pyrrolo[3,2-b[pyridin-5-y1)(methyl)amino)piperidin-1-
y1)ethoxy)ethoxy)acetic acid (111 mg crude, calculated), which was used into
next reaction
without further purification. LCMS: (ES): m/z 688.2 [M-FH] +.
[0649] Step D: (25,4R)-1-((S)-2 (2 (2 (2 (4 ((1-(2,6-difluoro-3-
(propylsulfonamido)pheny1)-3-(pyrimidin-5-y1)-1H-pyrrolo[3,2-blpyridin-5-
y1)(methyl)amino)piperidin-1-y1)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoy1)-
4-hydroxy-
N-(4-(4-methylthiazol-5-y1)benzyl)pyrrolidine-2-carboxamide
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I OH
z-
F N 0
-Th it N....N___\ \N ()0A1\(.rN TI
I--.
Oz.-s__N H o o
¨
OH F / \ N HN
N:-..-.--/
S
N \
[0650] To a solution of 2-(2-(2-(4-((1-(2,6-difluoro-3-
(propylsulfonamido)pheny1)-3-
(pyrimidin-5-y1)-1H-pyrrolo[3,2-b]pyridin-5-y1)(methyl)amino)piperidin-1-
y1)ethoxy)ethoxy)acetic acid (111 mg crude, 0.16 mmol) in DCM (10 mL) was
added (2S,4R)-1-
((S)-2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-
yl)benzyl)pyrrolidine-
2-carboxamide hydrochloride (150 mg, 0.32 mmol), D1PEA (209 mg, 1.62 mmol) and
PyBOP
(250 mg, 0.48 mmol) subsequently. After stirring at 30 C for 1 hour, the
reaction mixture was
diluted with DCM (30 mL), washed with water (10 mL x 2), brine (10 mL). The
organic phase
was dried over anhydrous sodium sulfate and concentrated under vacuum. The
residue was
purified by column (DCM / Me0H 19/1) first and further purified by prep-HPLC
to afford the
desired product (2S,4R)-1-((S)-2-(2-(2-(2-(4-((1-(2,6-difluoro-3-
(propylsulfonamido)pheny1)-3-
(pyrimidin-5-y1)-1H-pyrrolo[3,2-b]pyridin-5-y1)(methyl)amino)piperidin-1-
y1)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-
methylthiazol-5-
y1)benzyl)pyrrolidine-2-carboxamide (55 mg, 31% yield in two steps) as white
solid. 1H NMR
(400 MHz, DMSO-d6): 6 9.65 (s, 2H), 9.02 (s, 1H), 8.94 (s, 1H), 8.57 (t, J =
4.8 Hz, 1H), 8.40
(m, 1H), 7.55-7.65 (m, 1H), 7.35-7.50 (m, 7H), 6.74 (d, J = 9.2 Hz, 1H), 4.57
(d, J = 9.6 Hz, 1H),
4.20-4.50 (m, 5H), 4.00 (s, 2H), 3.50-3.70 (m, 2H), 3.00-3.20 (m, 7H), 2.93
(s, 3H), 2.50-2.70
(m, 4H), 2.43 (s, 3H), 1.60-2.25 (m, 13H), 0.90-1.05 (m, 12H); LCMS: (ES): m/z
1101.4
[M+H] +.
[0651] Compounds 190 and 192 may be prepared in an analogous manner.
[0652] Example synthesis of compound 195 [(3R) N (3 (5 (4 (2 (2 (2,6
dioxopiperidin-3-
y1)-1,3-dioxoisoindolin-5-yloxy)ethoxy)pheny1)-1H-pyrrolo[2,3-b[pyridine-3-
carbony1)-2,4-
difluoropheny1)-3-fluoropyrrolidine-1-sulfonamidel
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0
,Th
0 0
N
[0653] Step A: ethyl 2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)acetate
o
0
0 0
[0654] To a solution of 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenol (5 g, 22.7
mmol) in N,N-dimethylformamide (50 mL) was added ethyl 2-bromoacetate (4.52 g,
27.2 mmol)
and potassium carbonate (6.27 g, 45.4 mmol). The mixture was stirred overnight
under nitrogen
gas. The reaction mixture was added to water (200 mL), and extracted with
ethyl acetate (150
mL x 3). The organic layer was washed with brine (100 mL x 3). The combined
organic phases
were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo
to give ethyl 2-(4-
(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (5.2 g, 75%) as
colorless oil.
[0655] Step B: methyl 2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)ethanol
o0H
B.
[0656] To a solution of ethyl 2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-
2-
yl)phenoxy)acetate (1 g, 3.27 mmol) in tetrahydrofuran/ethanol (10 mL/10 mL)
was added
sodium borohydride (124 mg, 3.27 mmol) under ice-water bath. The mixture was
allowed to
warm to room temperature and stirred for 2 hours. The mixture was partitioned
between ethyl
acetate (100 mL) and water (50 mL). The organic layer was separated, washed
with brine (20 mL
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x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo
to give methyl 2-
(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenoxy)ethanol (0.8 g, 93%)
as colorless oil.
[0657] Step C: 2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)ethyl
methanesulfonate
00Ms
1.1
,B,
[0658] To a solution of 2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)ethanol
(200 mg, 0.76 mmol) and ehyldiisopropylamine (293 mg, 2.27 mol) in
dichloromethane (10.0
mL) was added methanesulfonyl chloride (105 mg, 0.91 mmol) under cooling, and
the mixture
was stirred at 0 C for 30 minutes. The mixture was quenched with cold water
(10.0 mL), the
organic layer was washed with sodium bicarbonate solution (10.0 mL x 3) and
brine (10.0 mL x
3), dried over anhydrous saturated sodium sulfate, filtered and concentrated
in vacuo to afford
(2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl
methanesulfonate which was
used for next step directly.
[0659] Step D: 2-(2,6-dioxopiperidin-3-y1)-5-(2-(4-(4,4,5,5-tetramethy1-
1,3,2-dioxaborolan-
2-yl)phenoxy)ethoxy)isoindoline-1,3-dione
0 0,
0
0,B 0 10 1\1-¨Nli 0
-)-(!) 0
[0660] The mixture of (2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)ethyl
methanesulfonate (260 mg, 0.76 mmol), potassium carbonate (210 mg, 1.52 mol),
potassium
iodide (126 mg, 0.76 mmol) and 2-(2,6-dioxopiperidin-3-y1)-5-
hydroxyisoindoline-1,3-dione
(208 mg, 0.76 mmol) in dimethyl sulfoxide (10 mL) was stirred at 60 C
overnight. The resulting
mixture was cooled down to room temperature. 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 in vacuo to give the crude product
which was purified
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by pre-TLC(dichloromethane/ methano1=20:1) to give 2-(2,6-dioxopiperidin-3-y1)-
5-(2-(4-
(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)isoindoline-1,3-
dione (140 mg,
36% two steps) as a white solid. LCMS (ES): m/z 521.2 [M+H], 538.2 [M+18] .
[0661] Step E: (3R) N (3 (5 (4 (2 (2 (2,6 dioxopiperidin-3-y1)-1,3-
dioxoisoindolin-5-
yloxy)ethoxy)pheny1)-1H-pyrrolo[2,3-blpyridine-3-carbony1)-2,4-difluoropheny1)-
3-
fluoropyrrolidine-1-sulfonamide
0
F
N- 0
F)----/ N N
H
[0662] To a solution of 2-(2,6-dioxopiperidin-3-y1)-5-(2-(4-(4,4,5,5-
tetramethy1-1,3,2-
dioxaborolan-2-yl)phenoxy)ethoxy)isoindoline-1,3-dione (136 mg, 0.26 mmol),
(R)-N-(3-(5-
bromo-1H-pyrrolo[2,3-b]pyridine-3-carbony1)-2,4-difluoropheny1)-3-
fluoropyrrolidine-1-
sulfonamide (120 mg, 0.24 mmol) and CsF (0.18 mg , 0.012 mmol) in 1,4-dioxane
(10 mL) and
water (2 mL) was added Pd(aMPhos)C12 (17 mg, 0.024 mmol) under argon
atmosphere, and the
mixture was stirred at 100 C for 6 hours. When it was cooled to room
temperature, water (20
mL) was added and the resultant mixture was extracted by EA (20 mL x 3),
washed by brine (10
mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The
residue was
purified by pre-HPLC to give (3R)-N-(3-(5-(4-(2-(2-(2,6-dioxopiperidin-3-y1)-
1,3-
dioxoisoindolin-5-yloxy)ethoxy)pheny1)-1H-pyrrolo[2,3-b]pyridine-3-carbony1)-
2,4-
difluoropheny1)-3-fluoropyrrolidine-1-sulfonamide (8.1 mg, 4% yield) as a
white solid. LCMS
(ES): m/z 817.2 [M+H]; 1H NMR (400 MHz, DMSO-d6) 6 2.06-2.09 (3H, m), 2.55-
2.62 (2H,
m), 2.85-2.93 (1H, m), 3.24-3.27 (1H, m), 3.38-3.50 (3H, m), 4.42-4.46 (2H,
m), 4.58-4.62 (2H,
m), 5.12-5.16 (1H, m), 5.23-5.36 (1H, m), 7.15 (2H, d, J= 8.8 Hz), 7.25 (1H,
t, J= 8.8 Hz),
7.45 (1H, dd, J= 2.4, 8.4 Hz), 7.55 (1H, d, J= 2.0 Hz), 7.59-7.63 (1H, m),
7.70 (2H, d, J= 8.4
Hz), 7.87 (1H, d, J= 8.4 Hz), 8.10 (1H, s), 8.58 (1H, s), 8.68 (1H, d, J=2.4
Hz), 9.89 (1H, brs.),
11.14 (1H, s), 12.96 (1H, brs.).
[0663] Compounds 194 and 195 may be prepared in an analogous manner.
[0664] Example synthesis of compound 2851-(25,4R)-1-((S)-2 (3 (2 (4 (4 (3
(2,6-difluoro-
3-(((R)-3-fluoropyrrolidine)-1-sulfonamido)benzoy1)-1H-pyrrolo[2,3-blpyridin-5-
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yl)phenyl)piperazin-l-yflethoxy)isoxazol-5-y1)-3-methylbutanoy1)-4-hydroxy-N-
(4-(4-
methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidel and compound 286 [(2S,4R)-
14(R)-2-(3-
(2-(4-(4-(3-(2,6-difluoro-3-(((R)-3-fluoropyrrolidine)-1-sulfonamido)benzoy1)-
1H-pyrrolo[2,3-
blpyridin-5-y1)phenyl)piperazin-1-yflethoxy)isoxazol-5-y1)-3-methylbutanoy1)-4-
hydroxy-N-(4-
(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidel
F r N 0c,rµii, .,,OH
0 N NI 4 N
0
0
0N
il I-1 F / 1 NH
F -----/ N N
H S
\\ /
N
and
F r N 0sN
\.01,1 .,,OH
0 N N-0 N
0
0
F-----/ N N
H SOJ
\\ /
N
[0665] Step A: 2-(3-hydroxy-1,2-oxazol-5-y1)-3-methylbutanoic acid
HO 0
/ \
OH
N,0
[0666] Into a 100 mL round-bottom flask, was placed 2-(3-methoxy-1,2-oxazol-
5-y1)-3-
methylbutanoic acid (1.0 g, 5.02 mmol, 1.0 equiv) and a solution of
hydrobromic acid (11.9 g,
147.07 mmol, 29.30 equiv) in acetic acid (20 mL). The resulting solution was
stirred overnight at
60 C in an oil bath. The reaction mixture was concentrated under reduced
pressure. This
resulted in 650.0 mg (crude) of 2-(3-hydroxy-1, 2-oxazol-5-y1)-3-
methylbutanoic acid as a white
solid.
[0667] LCMS (ES): m/z 186.05 [M+H]t
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[0668] Step B: ethyl 2-(3-hydroxy-1,2-oxazol-5-y1)-3-methylbutanoate
HO
0
/ \ /----
N, 0
0
[0669] Into a 50 mL round-bottom flask purged and maintained with an inert
atmosphere of
nitrogen, was placed a solution of 2-(3-hydroxy-1,2-oxazol-5-y1)-3-
methylbutanoic acid (650.0
mg, 3.51 mmol, 1.00 equiv) in ethanol (30 mL), sulfuric acid (1 mL). The
resulting solution was
stirred overnight at 70 C. The reaction mixture was then quenched by the
addition of 20 mL
water and extracted with ethyl acetate (20 mL x 2). The combined organic layer
was dried over
anhydrous sodium sulfate. Filtered and the filtrate was concentrated under
reduced pressure.
This resulted in 720.0 mg (96%) of ethyl 2-(3-hydroxy-1,2-oxazol-5-y1)-3-
methylbutanoate as
light yellow oil.
[0670] Step C: ethyl 2-[3-(2-bromoethoxy)-1,2-oxazol-5-y11-3-
methylbutanoate
BrO \
I \
Ng 0µ
\------
0
[0671] Into a 50 mL round-bottom flask purged and maintained with an inert
atmosphere of
nitrogen, was placed a solution of ethyl 2-(3-hydroxy-1,2-oxazol-5-y1)-3-
methylbutanoate (380.0
mg, 1.78 mmo1,1.00 equiv) in acetone (15 mL), 1,2-dibromoethane (994.8 mg,
5.30 mmol, 3.00
equiv), Cs2CO3(1.17 g, 3.59 mmol, 2.00 equiv). The resulting mixture was
stirred overnight at
room temperature. The reaction mixture was then quenched by the addition of
water (15 mL),
and extracted with ethyl acetate (20 mL x 3). The combined organic layer was
dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue
was applied
onto a silica gel column eluting with ethyl acetate/petroleum ether (1:5).
This resulted in 450.0
mg (79%) of ethyl 243-(2-bromoethoxy)-1,2-oxazol-5-y1]-3-methylbutanoate as a
colorless solid.
[0672] Step D: 1-[4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenylipiperazine
40N IB4100 Nr¨NH
0/ \--/
[0673] Into a 100 mL round-bottom flask purged and maintained with an inert
atmosphere of
nitrogen, was placed a solution of tert-butyl 444-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
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yl)phenyl]piperazine-l-carboxylate (1.6 g, 4.12 mmol, 1.00 equiv) in
dichloromethane (40 mL),
followed by the addition of TMSOTf (1.5 g, 6.75 mmol, 1.60 equiv) dropwise
with stirring at
0 C. To the above solution was added 6-dimethylpyridine (132.5 mg, 1.00 mmol,
0.30 equiv).
The resulting solution was stirred for 3 hours at room temperature. The
reaction was then
quenched by the addition of 50 mL of saturated sodium bicarbonate aqueous. The
resulting
solution was extracted with ethyl acetate (30 mL x 3). The combined organic
layer was dried
over anhydrous sodium sulfate and concentrated under reduced pressure. The
residue was
applied onto a silica gel column eluting with dichloromethane/methanol (10:1).
This resulted in
854.0 mg (72%) of 144-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenyl]piperazine as off-
white solid. LCMS (ES): m/z 289.15 [M+H]t
[0674] Step E: ethyl 3-methyl-2 [3 (2 [4 [4 (tetramethy1-1,3,2-
dioxaborolan-2-
yl)phenyllpiperazin-l-yllethoxy)-1,2-oxazol-5-yllbutanoate
rNC)
N I \
N-0 0
0 \---
0
[06751 Into a 30 mL sealed tube purged and maintained with an inert
atmosphere of nitrogen,
was placed a solution of ethyl 243-(2-bromoethoxy)-1,2-oxazol-5-y11-3-
methylbutanoate (576.0
mg, 1.80 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL), 1-[4-(tetramethy1-
1,3,2-
dioxaborolan-2-yl)phenyl]piperazine (624.0 mg, 2.17 mmol, 1.20 equiv), DIEA
(17 mL), NaI
(20 mg). The resulting solution was stirred for 16 hours at 130 C. The
reaction mixture was then
quenched by the addition of 30 mL of water. The resulting solution was
extracted with ethyl
acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL x
3), dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue
was applied
onto a silica gel column eluting with ethyl acetate/petroleum ether (1:2).
This resulted in 720.0
mg (76%) of ethyl 3-methy1-2-[3-(2-[4-[4-(tetramethy1-1,3,2-dioxaborolan-2-
yl)phenyl]piperazin-1-yl]ethoxy)-1,2-oxazol-5-yl]butanoate as a light yellow
solid. LCMS (ES):
m/z 528.25 [M+H]t
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[0676] Step F: ethyl 2-(3- [2-[4-(4-
amino] phenyl)carbony11-1H-pyrrolo[2,3-b[pyridin-5-
yllphenyl)piperazin-l-yllethoxyl -1,2-oxazol-5-y1)-3-methylbutanoate
0 N N-0 OEt
0 0
Oz.-s"....N
H
[0677] r
[0678] Into a 30 mL sealed tube purged and maintained with an inert
atmosphere of nitrogen,
was placed a solution of ethyl 3-methy1-2-[3-(2-[4-[4-(tetramethy1-1,3,2-
dioxaborolan-2-
yl)phenyl]piperazin-1-yl]ethoxy)-1,2-oxazol-5-yl]butanoate (527.0 mg, 1.00
mmol, 1.00 equiv)
in 20 mL of 1,4-dioxane/water(4:1), (3R)-N-[3-(5-bromo-1H-pyrrolo[2,3-
b]pyridin-3-
ylcarbony1)-2,4-difluoropheny1]-3-fluoropyrrolidine-1-sulfonamide (503.0 mg,
1.00 mmol, 1.00
equiv), sodium carbonate (318.0 mg, 3.00 mmol, 3.00 equiv), Pd(dppf)C12 (82.0
mg, 0.10 mmol,
0.10 equiv). The reaction mixture was reacted under microwave radiation for 2
hours at 100 C.
The reaction mixture was then quenched by the addition of 20 mL of water. The
resulting
solution was extracted with ethyl acetate (30 mL x 3). The combined organic
layer was dried
over anhydrous sodium sulfate and concentrated under reduced pressure. The
residue was
applied onto a silica gel column eluting with dichloromethane/methanol (10:1).
This resulted in
460.0 mg (56%) of ethyl 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-
fluoropyrrolidine-1-
sulfonyl]amino]phenyl)carbony1]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-
1-yl]ethoxy]-
1,2-oxazol-5-y1)-3-methylbutanoate as a light yellow solid. LCMS (ES): m/z
824.15 [M+H]t
Step G: 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidine-1-
sulfonyllaminolphenyl)carbony11-1H-pyrrolo[2,3-blpyridin-5-yllphenyl)piperazin-
1-yllethoxyl-
1,2-oxazol-5-y1)-3-methylbutanoic acid
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I \
0 N N-0 OH
, P 0
-----./ N N
H
F
[0679] Into a 50 mL round-bottom flask purged and maintained with an inert
atmosphere of
nitrogen, was placed a solution of ethyl 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-
[[(3R)-3-
fluoropyrrolidine-1-sulfonyl]amino]phenyl)carbony1]-1H-pyrrolo[2,3-b]pyridin-5-
yl]phenyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-y1)-3-methylbutanoate (420.0 mg,
0.51 mmol,
1.00 equiv) in methanol (10 mL) and then a solution of sodium hydroxide (102.0
mg, 2.55 mmol,
5.00 equiv) in water (2 mL) was added. The resulting solution was stirred at
40 C for 5 hours.
The pH value of the solution was adjusted to pH 6 with hydrogen chloride (1
mol/L). The solids
were collected by filtration. The solid was dried in an oven under reduced
pressure. This resulted
in 366.0 mg (90%) of 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-
fluoropyrrolidine-1-
sulfonyl]amino]phenyl)carbony1]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-
1-yl]ethoxy]-
1,2-oxazol-5-y1)-3-methylbutanoic acid as a solid. LCMS (ES): m/z 796.10
[M+H]t
[0680] Step H: (25,4R)-1 [2 (3 [2 [4 (4 [3 [(2,6-difluoro-3-[[(3R)-3-
fluoropyrrolidine-1-
sulfonyll aminolphenyl)carbonyll -1H-pyrrolo[2,3-b[pyridin-5-
yllphenyl)piperazin-l-yllethoxyl -
1,2-oxazol-5-y1)-3-methylbutanoy11-4-hydroxy-N-[[4-(4-methy1-1,3-thiazol-5-
yl)phenyl-
methyllpyrrolidine-2-carboxamide
..,OH
0 N N-o N.i
, P
k.).1_N
i 00
F . \
r-- F ' I NH
IL--/ N N S
H
\\ /
N '
[0681] To a solution of 2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-
fluoropyrrolidine- 1-
sulfonyl]amino]phenyl)carbony1]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-
1-yl]ethoxy]-
1,2-oxazol-5-y1)-3-methylbutanoic acid (300.0 mg, 0.38 mmol, 1.00 equiv) and
(25,4R)-4-
hydroxy-N-[4-(4-methy1-1,3-thiazol-5-y1)phenyl]methylpyrrolidine-2-carboxamide
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hydrochloride (199.9 mg, 0.56 mmol, 1.50 equiv) in N,N-dimethylformamide (10
mL), was
added DIEA (3.0 mL) and BOP (200.3 mg, 0.45 mmol, 1.20 equiv). The resulting
mixture was
stirred for 1 hour at room temperature. The reaction was then quenched by the
addition of 20 mL
of water. The resulting solution was extracted with ethyl acetate (30 mL x 3).
The combined
organic layer was washed with brine (30 mL x 3), dried over anhydrous sodium
sulfate and
concentrated under reduced pressure. The residue was applied onto a silica gel
column eluting
with dichloromethane/methanol (10:1). This resulted in 265.0 mg (64%) of
(2S,4R)-1-[2-(3-[2-
[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-fluoropyrrolidine-1-
sulfonyl]amino]phenyl)carbony1]-1H-
pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-y1)-3-
methylbutanoyl]-4-
hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-y1)phenyl]methyl]pyrrolidine-2-
carboxamide as a solid.
LCMS (ES): m/z 1095.30 [M+H]t
[0682] Step I: (2S,4R)-4-hydroxy-N-[[4-(4-methy1-1,3-thiazol-5-
y1)phenyllmethyll-1-(2-[3-
[2-(methylamino)ethoxyl-1,2-oxazol-5-yllbutanoyl)pyrrolidine-2-carboxamide
F r N Ocr i i . .,\OH
0 N NI 4 N
, P 0
0
,..,:si_N
AH F / 1 NH
F -----/ N N
H ,S
\\ /
N
and
0 N N-0 N.i
0
ii 0
0:...¨s_N
0
A
F)----/ N NOJ
H vS
\\ /
N
[0683] (2S,4R)-1-[2-(3-[2-[4-(4-[3-[(2,6-difluoro-3-[[(3R)-3-
fluoropyrrolidine-1-
sulfonyl]amino]phenyl)carbony1]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl)piperazin-
1-yl]ethoxy]-
1,2-oxazol-5-y1)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-
y1)phenyl]methyl]pyrrolidine-2-carboxamide was separated by chiral HPLC
resulting in:
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[0684] 25.7 mg (10%) of (2S,4R)-1-((S)-2-(3-(2-(4-(4-(3-(2,6-difluoro-3-
(((R)-3-
fluoropyrrolidine)-1-sulfonamido)benzoy1)-1H-pyrrolo[2,3-b]pyridin-5-
yl)phenyl)piperazin-1-
yl)ethoxy)isoxazol-5-y1)-3-methylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-
yl)benzyl)pyrrolidine-2-carboxamide. 1H NMR (300 MHz, DMSO-d6): 69.10-8.97 (m,
1H), 8.65
(d, J = 2.0 Hz, 1H), 8.60-8.53 (m, 2H), 8.10-8.07 (m, 1H), 7.70-7.56 (m, 3H),
7.51-7.21 (m, 5H),
7.18-7.07 (m, 2H), 6.18-6.12 (m, 1H), 5.38-5.21 (m, 1H), 4.44-4.31 (m, 6H),
3.78 (d, J = 8.6 Hz,
1H), 3.62-3.45 (m, 4H), 3.32-3.01 (m, 8H), 2.98-2.60 (m, 4H), 2.55-2.43 (m,
3H), 2.34-1.82 (m,
6H), 0.97-0.62 (m, 6H). LCMS (ES): m/z 1095.60 [M+H]t
[0685] 57.5 mg (22%) of (2S,4R)-1-((R)-2-(3-(2-(4-(4-(3-(2,6-difluoro-3-
(((R)-3-
fluoropyrrolidine)-1-sulfonamido)benzoy1)-1H-pyrrolo[2,3-b]pyridin-5-
yl)phenyl)piperazin-1-
yl)ethoxy)isoxazol-5-y1)-3-methylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-
yl)benzyl)pyrrolidine-2-carboxamide. 1H NMR (300 MHz, DMSO-d6): M2.90 (brs,
1H), 9.84
(brs, 1H), 8.99-8.95 (m, 1H), 8.69-8.66 (m, 1H), 8.60-8.53 (m, 2H), 8.07 (s,
1H), 7.70-7.61 (m,
3H), 7.54-7.39 (m, 4H), 7.387.30 (m, 1H), 7.21-7.08 (m, 2H), 6.18-5.80 (m,
1H), 5.40-5.15 (m,
1H), 4.74-4.28 (m, 6H), 3.90-3.62 (m ,6H),3.41-3.22 (m, 7H), 3.21-2.81 (m, 5H)
2.45-2.42 (m,
3H), 2.32-2.20 (m, 1H), 2.17-1.80 (m, 4H), 0.95 (d, J= 6.5 Hz, 3H), 0.81 (d,
J= 6.7 Hz, 3H).
LCMS (ES): m/z 1095.60 [M+H]t
[0686] Exemplary compounds 287 and 288 may be prepared in an analogous
manner.
[0687] Example synthesis of compound 291 [(2S,4R)-4-hydroxy-14(S)-2 (2 (2
(4 (4 ((E)-1-
(hydroxyimino)-2,3-dihydro-1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)acetamido)-3,3-dimethylbutanoy1)-N-(4-(4-methylthiazol-5-
yl)benzyl)pyrrolidine-2-carboxamidel
HO,N OH
I
- . i0---,-- 0 HN
,N /----1
F1
I N 0
N
lik
S
N\
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[0688] Step A: tert-butyl 2-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)acetatethoxy)acetate
Br
¨
0
NI \ \N-N 40
[0689] To a solution of tert-butyl 2-(2-chloroethoxy)acetate (400 mg, 2.06
mmol) and
C S2C 03 in DMF (15 mL) was added tert-butyl 4-(4-bromo-3-(pyridin-4-y1) -1H-
pyrazol-1-
yl)phenol (525 mg, 1.66 mmol). The mixture was stirred at 75 C for 3 hours.
The solution was
diluted with EA (100 mL). The mixture was washed with water, brine. The
organic phase was
dried over anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The
residue was purified by silica gel column chromatography to afford 2-(2-(4-(4-
bromo-3-(pyridin-
4-y1)-1H-pyrazol-1-y1) phenoxy)ethoxy)acetatethoxy)acetate (290 mg, 0.62
mmol). LCMS
(ES): m/z 475.21 [M+H], 476.1 [M+2H]t
[0690] Step B: (2S,4R)-1-((S)-2-(2-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-
pyrazol-1-
yl)phenoxy)ethoxy)acetamido)-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-
methylthiazol-5-
yl)benzyl)pyrrolidine-2-carboxamide
OH
z
Br
¨ ________________________ \
NI \ NN'N 0 o//
0
H 0 CHN 0
S
µN \
[0691] To a solution of 2-(2-(4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-y1)
phenoxy)ethoxy)acetatethoxy)acetate (290 mg, 0.61 mmol) in 1,4-dioxane (5 mL)
was added
HC1 (g) in 1,4-dioxane (3 M, 5 mL). The reaction was stirred at room
temperature for 2 hours.
The solvent was removed under reduced pressure. The residue was dissolved in
DCM (20 mL).
(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4- methylthiazol-
5-
yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (394 mg, 0.92 mmol), DIPEA
(394 mg, 3.05
mmol) and PyBOP (954 g, 1.83 mmol) were added to the solution subsequently.
After stirring 30
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minutes, it was diluted with DCM (50 mL). The mixture was washed with water,
brine. The
organic phase was dried over anhydrous sodium sulfate, filtered and
concentrated under reduced
pressure. The residue was purified by silica gel column chromatography to
afford (2S,4R)-1-
((S)-2-(2-(2- (4-(4-bromo-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)acetamido)-3,3-
dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-
carboxamide
(390 mg, 0.46 mmol). LCMS (ES): m/z 830.2 [M+H]t
[0692] Step C: (25,4R)-1-((S)-3,3-dimethy1-2 (2 (2 (4 (4 (1 oxo-2,3-
dihydro-1H-inden-5-
y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)ethoxy)acetamido)butanoy1)-4-
hydroxy-N-(4-(4-
methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
0 OH
0 )......1cIC
0
=
0----)\--F1 0 HN
x ,N /----/
i N 0
N
S
µN\
[0693] To a solution of (2S,4R)-1-((S)-2-(2-(2-(4-(4-bromo-3-(pyridin-4-y1)-
1H-pyrazol-1-
yl)phenoxy)ethoxy)acetamido)-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-
methylthiazol-5-
yl)benzyl)pyrrolidine-2-carboxamide (390 mg,0.46 mmol) and 5-(4,4,5,5-
tetramethy1-1,3,2-
dioxaborolan-2-y1)-2,3-dihydro-1H-inden-1-one (248 mg, 0.92 mmol) in 1,4-
dioxane/water (20
mL/1 mL) were added Pd(aMPhos)C12 (36 mg, 0.046 mmol), CsF (360 mg, 2.30 mmol)
subsequently. The reaction mixture was stirred at 90 C overnight under
nitrogen atmosphere.
After cooled to room temperature, it was diluted with ethyl acetate (100 mL).
The mixture was
washed with brine (50 mL x 2). The organic phase was dried over anhydrous
sodium sulfate,
filtered and concentrated under vacuum. The residue was purified by silica gel
column
chromatography (DCM/Me0H) to afford (2S,4R)-1-((S)-3,3-dimethy1-2-(2-(2-(4-(4-
(1-oxo-2,3 -
dihydro-1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)acetamido)butanoy1)-
4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (230 mg,
0.26 mmol).
LCMS (ES): m/z 882.3 [M+H] +.
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[0694] Step D: (2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(4-(4-((E)-1-(hydroxyimino)-
2,3-dihydro-
1H-inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)ethoxy)acetamido)-3,3-
dimethylbutanoy1)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
HO,N OH
I
0 >.......,\(10
- 0 ,0----)\-- 0 HN
,N 7-----1
F1
1 N 0
N
lik
S
N\
[0695] To a solution of (25,4R)-14(S)-3,3-dimethy1-2-(2-(2-(4-(4-(1-oxo-2,3-
dihydro-1H-
inden-5-y1)-3-(pyridin-4-y1)-1H-pyrazol-1-
yl)phenoxy)ethoxy)acetamido)butanoy1)-4-hydroxy-
N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (230 mg, 0.26
mmol) in CH3CN
and pyridine (v/v = 1/1, 5 mL) was added NH2OH-HC1 (179 mg, 2.6 mmol). The
solution was
stirred at 20 C for 3 hours. The mixture was filtered through Celite. The
filtrate was concentrated
under vacuum. The residue was purified by silica gel column chromatography
(DCM/Me0H) to
afford (2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(4-(4-((E)-1-(hydroxyimino)-2,3-
dihydro-1H-inden-5-
y1)-3-(pyridin-4-y1)-1H-pyrazol-1-yl)phenoxy)ethoxy)acetamido)-3,3-
dimethylbutanoy1)-N-(4-
(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (21 mg, 0.023 mmol). 1H
NMR (400
MHz, DMSO-d6): 6 10.89 (s, 1H), 8.97 (s, 1H), 8.72 (s, 1H),8.56- 8.58 (m, 3H),
7.86 (d, J = 8.4
Hz, 2H), 7.49-7.57 (m, 3H), 7.39 (m, 6H), 7.22 (s, 1H), 7.09-7.12 (m, 2H),
5.17 (m, 1H), 4.52-
4.65 (m, 1H), 4.32-4.50 (m, 3H), 4.08-4.29 (s, 4H), 3.95-4.05 (m, 2H), 3.73-
3.82 (m, 2H),
3.56-3.70 (m, 2H), 2.95-3.08 (m, 2H), 2.76-2.85 (s, 2H), 2.40-2.51 (m, 3H),
1.87-2.16 (s, 1H),
0.91-1.07 (s, 9H). LCMS (ES): m/z 898.4 [M+H]t
[0696] Exemplary compounds 289, 290, 292, and 293 may be prepared in an
analogous
manner.
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[0697] Example 15-Synthetic Scheme A: Compounds 305, 298, 299, 300, 301,
302, 514,
and 303
Method A
FN1 N Cy P.
>% 47,
, Cs2CO3/ DMF
N
0 OorCh< \
Br 0.3r Br ).riOl<
41111111Y1" OH
2(68%) 1(71%)
0
TFA / DCM
N
N
PyBOP Et3N / DMF
\ FNi HN
0 =
0 HO
3 (quantitative yieOlehl Z-3_40
Compound 305 (57%)
F131\11 0 HN (45
4 IN;
[0698] tert-Butyl 4-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy)butanoate (1).
To a mixture of 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenol (209.12
mg, 0.95 mmol)
and tert-butyl 4-bromobutanoate (212 mg, 0.95 mmol) in N,N-Dimethylformamide
(2 mL) was
added Cs2CO3 (402.47 mg, 1.24 mmol). Reaction mixture was heated at 65 C for
12 hours
(overnight) . By TLC small amounts of starting material (Hex:AcOEt, 7:3).
Crude product was
purified by flash CC (5i02-25g, Hex:AcOEt, gradient 9:1 to 4:6) to give 198 mg
(57% yield) of
product as an oil: 1H NMR (500 MHz, DMSO-d6) 6 7.59 (d, J = 8.2 Hz, 2H), 6.91
(d, J = 7.9 Hz,
2H), 3.99 (t, J = 6.3 Hz, 2H), 2.35 (t, J = 7.3 Hz, 2H), 1.92 (p, J = 6.7 Hz,
2H), 1.39 (s, 9H), 1.27
(s, 12H). 13C NMR (101 MHz, dmso) 6 172.25, 161.56, 136.66, 114.37, 83.77,
80.12, 66.81,
31.72, 28.20, 25.12, 24.71. LC-MS (ESI); m/z [M+Na]: Calcd. for C20I-131B05Na,
385.2162.
Found 385.2194.
[0699] tert-Butyl 4-(4-(3-benzoy1-1H-pyrrolo[2,3-b[pyridin-5-
yl)phenoxy)butanoate (2). To
a solution of tert-butyl 4-[4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)phenoxy] -butanoate
(72 mg, 0.2 mmol) and (5-bromo-1H-pyrrolo[2,3-b[pyridin-3-y1)-phenyl- -
methanone (59.85 mg,
0.2 mmol) in Dioxane (6 mL) was de-gassed under vacuum and purged with argon.
Then K2CO3
(82.4 mg, 0.6 mmol) was added, follow by water (2 mL), the reaction mixture
was de-gassed
under vacuum and purged with argon again. Tricyclohexylphosphine (5.57 mg,
0.02 mmol) and
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Pd(dba)2 (5.71 mg, 0.01 mmol) was added into and the reaction mixture and the
reaction mixture
was de-gassed under vacuum and purged with argon again. Then reaction mixture
was heated at
90 C for 2 hours. By TLC some SM (Hex:AcOEt, 3:7), an additional amounts of
Tricyclohexylphosphine (5.57 mg, 0.02 mmol) and Pd(dba)2 (5.71 mg, 0.01 mmol)
was added
twice and reaction mixture stirred for an additional 2 hours. The reaction
mixture was diluted
with AcOEt (20 mL), dried (Na2SO4), and filtered in vacuum over a celite pad,
filtrate was dried
(Na2SO4) and concentrated under vacuum. The crude material was diluted in DCM
and purified
by flash chromatography (5i02-40g, gradient Hex:AcOEt, gradient 9:1 to 100%
AcOEt) to give
69 mg (68%) of product as off-white solid. 1H NMR (500 MHz, DMSO-d6) 6 12.68
(s, 1H), 8.65
(s, 1H), 8.60 (s, 1H), 8.10 (s, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.58 (dt, J =
36.0, 7.9 Hz, 5H), 7.04
(d, J = 8.1 Hz, 2H), 4.16 - 3.83 (m, 2H), 2.37 (t, J = 6.5 Hz, 2H), 1.95 (dd,
J = 11.4, 5.5 Hz, 2H),
1.39 (s, 9H). 13C NMR (126 MHz, dmso) 6 189.81, 171.86, 158.13, 148.26,
143.24, 139.62,
136.43, 131.45, 130.82, 130.66, 128.52, 128.48, 128.16, 127.01, 118.77,
115.13, 113.73, 79.68,
66.63, 31.36, 27.77, 24.37. LC-MS (ESI); m/z: [M+H[ Calcd. for C28H29N204,
457.2127. Found
457.2156.
[0700] 4-(4-(3-Benzoy1-1H-pyrrolo[2,3-b[pyridin-5-yl)phenoxy)butanoic acid
(3). A solution
of tert-butyl 4-(4-(3-(2,6-difluorobenzoy1)-1H-pyrrolo[2,3-b]pyridin-5-y1) -
phenoxy)butanoate
(30 mg, 0.06 mmol) in a mixture of TFA (1 ml, 13.46 mmol) and dichloromethane
(3 ml) was
stirred for 1 hour. Then the solvent was removed under vacuum and crude
product was dried
under high vacuum for 2 hours. Crude product was used in the next step without
any further
purification (26.5 mg, quantitative yield). LC-MS (ESI); m/z: [M+H[ Calcd.
for C24H21N204,
401.1501. Found 401.1420.
[0701] (2S,4R)-1-4S)-2-(4-(4-(3-benzoy1-1H-pyrrolo[2,3-b[pyridin-5-
yl)phenoxy)butanamido)-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-
yl)benzyl)pyrrolidine-2-carboxamide (Compound 305). To a solution of 444-(3-
benzoy1-1H-
pyrrolo[2,3-b[pyridin-5-y1) -phenoxy[butanoic acid (26.5 mg, 0.07 mmol) and
(2S,4R)-1-[(2S)-
2-amino-3,3-dimethyl- butanoy1]-4-hydroxy-N-[[4-(4-methylthiazol-5-
yl)phenyl]methyl]pyrrolidine-2-carboxamide;hydrochloride (30.91 mg, 0.07 mmol)
in DMF(2
ml) was added TEA (0.2 ml, 1.43 mmol) and PyBOP (37.88 mg, 0.07 mmol) at room
temperature. The reaction mixture was stirred for 12 hours (overnight) at the
same temperature.
TLC (DCM:MeOH:NH4OH, 90:9:1) shows no starting materials. The DMF was removed
under
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high vacuum. Crude product was filtered over a silica-carbonate cartridge (1g)
using
DCM:Me0H (9:1) as a eluent. Filtrate was evaporated under vacuum and crude
product was
purified by PTLC (MeOH:DCM, 9:1), to give 31 mg of product (58% yield). 1H NMR
(400
MHz, DMSO-d6) 6 12.70 (s, 1H), 8.97 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.62
(d, J = 2.3 Hz, 1H),
8.60¨ 8.51 (m, 1H), 8.12 (s, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.90 ¨ 7.77 (m,
1H), 7.72 ¨ 7.51 (m,
5H), 7.48 ¨ 7.29 (m, 4H), 7.07 (d, J = 8.7 Hz, 2H), 5.15 (d, J = 3.5 Hz, 1H),
4.59 (d, J = 9.3 Hz,
1H), 4.50 ¨ 4.32 (m, 3H), 4.22 (dd, J = 15.9, 5.4 Hz, 1H), 4.03 (td, J = 6.5,
2.6 Hz, 2H), 3.80 ¨
3.60 (m, 2H), 2.44 (s, 3H), 2.48 ¨2.28 (m, 5H), 2.13 ¨ 1.84 (m, 4H), 0.96 (s,
9H). 13C NMR (101
MHz, dmso) 6 189.87, 172.00, 171.63, 169.69, 158.23, 151.48, 148.29, 147.73,
143.29, 139.64,
139.53, 136.54, 131.52, 131.19, 130.74, 129.65, 128.66, 128.58, 128.55,
128.21, 127.44, 127.05,
118.81, 115.19, 113.74, 68.93, 67.13, 58.75, 56.47, 48.64, 41.68, 38.01,
35.29, 31.33, 26.43,
25.08, 15.99. LC-MS (ESI); m/z [M+H]: Calcd. for C46H49N606S, 813.3434. Found
813.3478.
[0702] (2S,4S)-1-((S)-2-(4-(4-(3-(2,6-difluoro-3-
(propylsulfonamido)benzoy1)-1H-
pyrrolo[2,3-b]- pyridine-5-yl)phenoxy)butanamido)-3,3-dimethylbutanoy1)-4-
hydroxy-N-
(4-(4-methylthiazol-5-y1) -benzyl)pyrrolidine-2-carboxamide (Compound 514).
H F \ I
OSN H r`r FIN
0 (DNO
0
[0703] To a solution of 4-[4-[3-[2,6-difluoro-3-(propyl-
sulfonylamino)benzoy1]-1H-
pyrrolo[2,3-b[pyridin-5-yl[phenoxy[butanoic acid (4.08 mg, 0.00732 mmol) and
(2S,4S)-1-((S)-
2-amino-3,3-dimethylbutanoy1)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzy1)-
pyrrolidine-2-
carboxamide (3.76 mg, 0.00873 mmol) in DMF(1.5 ml) was added TEA (0.200 mL,
1.43
mmol) and PyBOP (4.19 mg, 0.00805 mmol) at room temperature. The reaction
mixture was
stirred for 4 h at the same temperature. TLC (DCM:MB, 1:1) shows no starting
materials. The
DMF was removed under high vacuum (product is partially soluble in water).
Crude product
was filtered over a silica-carbonate cartridge using DCM:Me0H (9:1) as a
eluent. Filtrate was
evaporated under vacuum and crude product was purified by PTLC
(DCM:MeOH:NH4OH,
90:9:1) to give 3.1 mg of product (43% yield). 1H (500 MHz, DMSO-d6) 6 12.83
(bs, 1H), 9.64
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(bs, 1H), 8.96 (s, 1H), 8.77 - 8.41 (m, 3H), 8.18 (s, 1H), 7.97 (d, J = 8.6
Hz, 1H), 7.65 (d, J = 8.5
Hz, 2H), 7.61 - 7.48 (m, 1H), 7.38 (q, J = 8.2 Hz, 4H), 7.26 (t, J = 8.7 Hz,
1H), 7.04 (d, J = 8.7
Hz, 2H), 5.43 (d, J = 7.2 Hz, 1H), 4.54 -4.31 (m, 3H), 4.30 - 4.15 (m, 2H),
4.08 - 3.88 (m, 3H),
3.50 - 3.40 (m, 1H), 3.16 - 3.02 (m, 2H), 2.44 - 2.26 (m, 3H), 2.42 (s, 3H),
2.04 - 1.88 (m, 2H),
1.79 - 1.63 (m, 3H), 0.95 (s, 9H), 0.94 (t, 3H). 13C NMR (151 MHz, DMSO-d6) 6
181.03 ,
172.89, 172.34, 170.35, 158.75, 156.44 (dd, J = 246.1, 6.7 Hz), 152.78 (dd, J
= 249.5, 8.6 Hz),
151.89 , 148.94 , 148.15 , 144.15 , 139.63 , 139.07 , 131.74 , 131.55 ,
130.82, 130.14 , 129.36 -
129.11 (m), 129.08 , 128.68 , 127.86 , 126.85 , 122.35 (dd, J = 13.6, 3.4 Hz),
117.94 , 116.03 ,
115.59 , 69.53 , 67.52, 58.95 , 57.24 , 56.04 , 53.86 , 42.21 , 37.36 , 35.11
, 31.62 , 26.82 , 25.42
, 17.26 , 16.37 , 13.04 . LC-MS (ESI); m/z [M+H]: Calcd. for C49H54F2N708S2,
970.3443.
Found 970.3422
[0704] Example 16-Synthetic Scheme B: 217, 220, 510, and 221
Method B
[21 N N N 1) Cy3P, Pc1Mba)2, K2CO3
Dioxane/water (56%)(5a) H õ
N
F I H F I
THF H \ I
0=S-N Br
0 j<
2.- 0
0
0 NH2 >%9
0
7(78%)
j.) 0 j< F 6(71%) F
0-13
411111Yr NHBoc
2) TFA / DCM,
(quantitative yield)
TFA / DCM
H , N
N HO,
F I PyBOP, Et3N / DMF \ F
J ___________________________________
oH
0 JLNFic, HN
0 H0,2
F
8 (quantitative yield))
N 1-1 N
Compound 217(29%)
= ils1;
4 /N;
[0705] tert-B uty1(4-(3 -(2,6-difluoro-3 -(propylsulfonamido)benzoy1)-1H-
pyrrolo [2,3 -
blpyridin-5-yl)phenyl)carbamate (5a). To a solution of tert-butyl (4-(4,4,5,5-
tetramethy1-1,3,2-
dioxaborolan-2-yl)pheny1)-carbamate (50.99 mg, 0.16 mmol) in Dioxane (3 ml)
was added N-[3-
(5-bromo-1- H-pyrrolo [2,3 -b[pyridine-3 -c arbony1)-2,4-difluoro-phenyll
propane-1- sulfonamide
(0.06 ml, 0.13 mmol), K2C 03 (55.19 mg, 0.4 mmol), Tricyclohexylphosphine
(3.73 mg, 0.01
mmol) and water (1 mL). Then the reaction mixture was de-gassed under vacuum
and purged
with argon, Pd(dba)2 (3.83 mg, 0.01 mmol) was added into and the reaction
mixture was heated
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at 80 C for 3 hours. By TLC small amounts of SM (Hex:AcOEt, 3:7), the
reaction mixture was
filtered in vacuum over a celite pad, filtrate was poured onto an aqueous
saturated solution of
NaCl (20 mL) and the product was extracted with Et0Ac (2x20 mL). The Et0Ac
layers were
combined, dried (Na2SO4) and concentrated in vacuum. The crude material was
diluted in DCM
and purified by flash chromatography (5i02-12g, Hexane:AcOEt, gradient 8:2 to
100% AcOEt)
to give 47 mg (56%) of product as a off-white solid. 1H NMR (400 MHz, DMSO-d6)
6 12.96
(bs, 1H), 9.77 (bs, 1H), 9.49 (s, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.57 (bs,
1H), 8.21 (s, 1H), 7.79 ¨
7.46 (m, 5H), 7.28 (td, J = 8.7, 1.5 Hz, 1H), 3.19 ¨ 3.07 (m, 2H), 1.74 (dq, J
= 14.9, 7.4 Hz, 2H),
1.50 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, dmso) 6 180.61,
156.03 (dd, J =
246.5, 7.1 Hz), 152.77, 152.34 (dd, J = 249.5, 8.5 Hz), 148.60, 143.76,
139.22, 138.64, 131.66,
131.31, 128.79 (d, J = 9.7 Hz), 127.35, 126.38, 121.94 (dd, J = 13.7, 3.6 Hz),
118.66, 118.24 (t, J
= 23.5 Hz), 117.53, 115.63, 112.35 (dd, J = 22.6, 3.9 Hz), 79.19, 53.46,
28.15, 16.85, 12.62. LC-
MS (ESI); m/z: [M+H] Calcd. for C28H29F2N4055, 571.1826. Found 571.1917.
[0706] N-(3 -(5-(4- aminopheny1)- 1H-p yrrolo [2,3 -hi p yridine-3 -c
arbony1)-2,4-
difluorophenyl)propane-l-sulfonamide (6). To a solution of tert-butyl (4-(3-
(2,6-difluoro-3-
(prop ylsulfonamido)benzoy1)-1H-p yrrolo - [2,3 -b] pyridin-5 -yl)phenyl)c arb
amate (30 mg, 0.05
mmol) in TFE (2 mL) was heated at 140 C, for 3 hours under microwave assisted
conditions. The reaction mixture was evaporated to dryness under vacuum, to
give 23 mg of
product in quantitative yields. The crude product was used in the next step
without any further
purification. LC-MS (ESI); m/z: [M+H] Calcd. for C23H21F2N4035, 471.1302.
Found
471.1351.
[0707] tert-B uty1-5-((4-(3 -(2,6-difluoro-3 -(prop ylsulfonamido)benzoy1)-
1H-p yrrolo [2,3 -
blpyridin-5-yl)phenyl)amino)-5-oxopentanoate (7). To a solution of tert-butyl
5-chloro-5-
oxopentanoate (21.96 mg, 0.11 mmol) in THF (2 mL) was added N-(3-(5-(4-
aminopheny1)-1H-
pyrrolo [2,3-b] -pyridine-3 -c arbony1)-2,4-difluorophenyl)prop ane-1-
sulfonamide (10 mg, 0.02
mmol). The resulting suspension was heated to reflux for 12 hours (overnight).
The reaction
mixture was evaporated in vacuum and the crude product was purified by PTLC
(MB:DCM, 4:6)
to give a white powder 10.7 mg (79% yield). 1H NMR (500 MHz, DMSO-d6) 6 12.96
(bs, 1H),
10.04 (s, 1H), 9.76 (bs, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 8.21 (s,
1H), 7.75 (d, J = 8.7
Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.59 (td, J = 9.0, 5.8 Hz, 1H), 7.28 (t, J
= 9.2 Hz, 1H), 3.13
(dd, J = 8.7, 6.7 Hz, 2H), 2.39 (t, J = 7.4 Hz, 2H), 2.28 (t, J = 7.4 Hz, 2H),
1.83 (p, J = 7.4 Hz,
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2H), 1.75 (h, J = 7.5 Hz, 2H), 1.41 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR
(101 MHz, dmso)
6 181.01, 172.37, 171.16, 156.02 (dd, J = 246.3, 7.0 Hz), 152.34 (dd, J =
249.5, 8.5 Hz), 149.05,
144.18, 139.30, 139.05, 133.00, 131.62, 128.77 (d, J = 9.5 Hz), 127.75,
126.88, 121.96 (dd, J =
13.7, 3.5 Hz), 120.04, 118.74¨ 117.84 (m), 117.94, 116.05, 112.34 (dd, J =
22.8, 3.0 Hz). 79.98,
53.89, 35.72, 34.53, 28.20, 20.93, 17.25, 13.02. LC-MS (EST); m/z: [M+H[
Calcd. for
C32H35F2N406S, 641.2245. Found 641.2473.
[0708] 5-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoy1)-1H-pyrrolo[2,3-
b[pyridin-5-
yl)phenyl)amino)-5-oxopentanoic acid (8). A solution oftert-butyl 5-((4-(3-
(2,6-difluoro-3-
(propylsulfonamido)benzoyl) -1H-pyrrolo[2,3-b[pyridin-5-yl)phenyl)amino)-5-
oxopentanoate
(10.7 mg, 0.02 mmol) in a mixture of TFA (1 ml, 13.46 mmol) and
Dichloromethane (2 ml) was
stirred for 2 hours. Then the solvent was removed under vacuum and crude
product was dried
under high vacuum for 2 hours. Crude product was used in the next step without
any further
purification (9.7 mg, quantitative yield). LC-MS (ESI); m/z: [M-FH[ Calcd.
for C28H27F2N406S,
585.1619. Found 585.1636.
[0709] N1-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoy1)-1H-pyrrolo[2,3-
b[pyridin-5-
yl)pheny1)-N5-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-
yl)benzyl)carbamoyl)pyrrolidin-l-y1)-3,3-dimethyl-1-oxobutan-2-y1)glutaramide
(Compound
217). To a solution of 5-((4-(3-(2,6-difluoro-3-(propylsulfonamido) -benzoy1)-
1H-pyrrolo[2,3-
b[pyridin-5-yl)phenyl)amino)-5-oxopentanoic acid (9.7 mg, 0.02 mmol) and
(2S,4R)-1-[(2S)-2-
amino-3,3-dimethyl-butanoy1]-4-hydroxy-N-[[4-(4-methylthiazol-5-
yl)phenyl[methyl[pyrrolidine-2-carboxamide;hydrochloride (8.52 mg, 0.02 mmol)
in DMF (1
ml) was added TEA (0.1 ml, 0.72 mmol) and PyBOP (9.5 mg, 0.02 mmol) at room
temperature.
The reaction mixture was stirred for 4 hours at the same temperature. TLC
(DCM:MeOH:NH4OH, 90:9:1) shows no starting materials. The reaction mixture was
diluted
with Et0Ac (10 mL) and washed with brine (5 mL, 4x), organic phase was dried
(Na2SO4), and
evaporated under vacuum. Crude product was purified by PTLC (DCM:MeOH:NH4OH,
90:9:1)
to give 4.8 mg of product (29% yield). 1H NMR (500 MHz, DMSO-d6) 6 10.02 (s,
1H), 8.97 (s,
1H), 8.68 (d, 1H), 8.64 ¨ 8.52 (m, 2H), 8.21 (s, 1H), 7.95 (d, J = 9.2 Hz,
1H), 7.72 (dd, J = 36.7,
8.5 Hz, 4H), 7.62 ¨ 7.54 (m, 1H), 7.40 (dd, 4H), 7.28 (t, J = 8.7 Hz, 1H),
5.16 (d, 2H), 4.56 (d, J
= 9.3 Hz, 1H), 4.50 ¨ 4.40 (m, 2H), 4.40 ¨ 4.33 (m, 1H), 4.22 (dd, J = 15.8,
5.3 Hz, 1H), 3.76 ¨
3.62 (m, 2H), 3.16 ¨3.05 (m, 2H), 2.44 (s, 3H), 2.41 ¨2.17 (m, 4H), 2.09 ¨
2.01 (m, 1H), 1.98 ¨
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1.80 (m, 3H), 1.74 (dq, J = 14.9, 7.4 Hz, 2H), 0.96 (s, 9H), 0.95 (t, 3H). 13C
NMR (151 MHz,
dmso) 6 181.06, 172.39, 172.17, 171.46, 170.15, 156.37 (dd, J = 246.6, 6.3
Hz), 152.73 (dd, J =
249.4, 8.1 Hz), 151.86, 149.05, 148.13, 144.19, 139.91, 139.37, 139.13,
132.97, 131.64, 131.59,
130.05, 129.22 (d, J = 14.7 Hz), 129.06, 127.84, 127.74, 126.89, 122.47 (d, J
= 14.1 Hz), 120.07,
119.02- 118.20 (m), 117.95, 116.06, 112.75 (dd, J = 23.4, 2.8 Hz), 69.34,
59.15, 56.90, 56.81,
53.87, 42.08, 38.38, 36.36, 35.63, 34.63, 26.85, 21.91, 17.27, 16.37, 13.04.
LC-MS (ESI); m/z
[M+H]: Calcd. for C50H55F2N808S2, 997.3552. Found 997.3524.
[0710] N1-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoy1)-1H-pyrrolo[2,3-
b[pyridin-5-
yl)phenyl) -N4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-
yl)benzyl)carbamoyl)pyrrolidin-l-y1)-3,3-dimethyl-1-oxo -butan-2-y1)-N1-
methylsuccinamide
(Compound 510).
N " HO,,,
F \ I
O'SN 0
N jirliN'----\0 HN
\O
0
I
F 0
/ 3
N
[0711] To a solution of 4-[4-[3-[2,6-difluoro-3-(propylsulfonylamino)-
benzoy1]-1H-
pyrrolo[2,3-b]pyridin-5-y1]-N-methyl-anilino[-4-oxo-butanoic acid (33.7 mg,
0.06 mmol) and
(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoy1]-4-hydroxy-N-[[4-(4-
methylthiazol-5-
yl)phenyl]methyl]pyrrolidine-2-carboxamide;hydrochloride (4) (32.31 mg, 0.07
mmol) in DMF
(2 ml) was added TEA (0.2 ml, 1.43 mmol) and PyBOP (36 mg, 0.07 mmol) at room
temperature. The reaction mixture was stirred for 4 h at the same temperature.
TLC
(DCM:MeOH:NH4OH, 90:9:1) shows some starting material (acid). The reaction
mixture was
evaporated to dryness under high vacuum. Crude product was purified by PTLC
(DCM:MeOH:NH4OH, 90:9:1) to give 4.6 mg of product (8 % yield). 1H NMR (400
MHz,
DMSO-d6) 6 13.01 (bs, 1H), 9.70 (bs, 1H), 8.95 (s, 1H), 8.73 (d, J = 2.3 Hz,
1H), 8.66 (bs, 1H),
8.54 (t, J = 5.9 Hz, 1H), 8.22 (s, 1H), 7.84 (dd, J = 19.4, 8.6 Hz, 2H), 7.57
(td, J = 9.0, 6.1 Hz,
1H), 7.52 - 7.30 (m, 6H), 7.26 (t, J = 8.5 Hz, 1H), 5.08 (d, J = 3.2 Hz, 1H),
4.47 (d, J = 9.2 Hz,
1H), 4.44 - 4.25 (m, 3H), 4.19 (dd, J = 16.0, 5.4 Hz, 1H), 3.66- 3.54 (m, 2H),
3.19 (s, 3H), 3.16
-3.00 (m, 2H), 2.75 -2.16 (m, 4H), 2.42 (s, 3H), 2.06- 1.96 (m, 1H), 1.93 -
1.80 (m, 1H), 1.79
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- 1.64 (m, 2H), 0.94 (t, 3H), 0.90 (s, 9H). 13C NMR (151 MHz, DMSO-d6) 6
181.08, 172.37,
171.90, 171.57, 170.00, 156.45 (dd, J = 246.4, 7.0 Hz), 152.76 (dd, J = 249.3,
8.9 Hz), 151.88,
149.37 , 148.13 , 144.49, 143.73 , 139.91 , 139.34, 137.64, 131.59, 131.11 ,
130.04, 129.53 -
129.16 (m), 129.06, 127.84, 127.55, 122.35 (d, J = 15.0 Hz), 119.06- 118.23
(m), 117.93,
116.13 , 112.77 (d, J = 22.0 Hz), 69.31 , 59.13 , 56.87 , 56.75 , 53.86 ,42.07
, 38.32, 35.76,
30.61 , 29.66 , 26.77 , 22.93, 17.26, 16.37, 13.04 . LC-MS (ESI); m/z [M+H]:
Calcd. for
C50f155F2N808S2, 997.3552. Found 997.3572.
[0712] Example 17-Synthetic Scheme C: Compound 218, 219, and 222
Method C
N N 1) RuPh_mFPX.:00()51)LHOMS
N
\---\ F <')1N; I
PyBOP, Et,N / DMF 1\1") ______ \--\
__________________________________ 0% F O's-N Br
0 LNH
HN"-.1 0
10(68%) HOO 9b (71%) F 5
2) TFA / DCM,
(quantitative yield)
TFA / DCM
H HO
PyBOP, Et3N / DMF
0=S-N N-Th 0 0 0 0 HN
0
F 11 (quantitative yield)) 0_40
Compound 218(29%)
/N;
0 HN
4 )
[0713] tert-Butyl 4-(3 -(2,6-difluoro-3 -(prop ylsulfonamido)benzoy1)-
1H-p yrrolo [2,3 -
blpyridin-5-yl)piperazine- 1-carboxylate (9a). A solution of N43-(5-bromo-1H-
pyrrolo[2,3-
b]pyridine-3-carbony1)-2,4- difluoro-phenyl]propane-l-sulfonamide (61 mg, 0.13
mmol) and
tert-butyl piperazine-l-carboxylate (37.19 mg, 0.2 mmol) in THF (3 mL) was
purged with argon
(5x). RuPhos (18.63 mg, 0.04 mmol) and Pd(OAc)2 (2.99 mg, 0.01 mmol) were
added followed
by 1M LHMDS in THF (0.53 ml) The reaction mixture was heated to 60 C and
stirred for 6
hours. The reaction was cooled and poured into an aqueous solution of oxalic
acid (5%, 2 ml),
then a saturated aqueous NaHCO3 solution was added (5 ml), the product was
extracted with
DCM (3x10 m1). Organic extracts were combined, dried (Na2SO4) and evaporated
under
vacuum. Crude product was purified by PTLC (DCM:MeOH:NH4OH, 90:9:1) (20 mg,
26%). 1H
NMR (400 MHz, DMSO-d6) 6 12.61 (bs, 1H), 9.73 (bs, 1H), 8.27 (d, J = 2.6 Hz,
1H), 8.03 (s,
420
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1H), 7.94 (bs, 1H), 7.57 (td, J = 9.0, 5.9 Hz, 1H), 7.26 (td, J = 8.7, 1.5 Hz,
1H), 3.63 - 3.46 (m,
4H), 3.42 - 3.24 (m, 4H), 3.20 - 3.06 (m, 2H), 1.74 (dq, J = 15.0, 7.4 Hz,
2H), 1.43 (s, 9H), 0.96
(t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, dmso) 6 180.37, 155.96 (dd, J = 246.2,
7.2 Hz), 153.87,
152.31 (dd, J = 249.1, 8.6 Hz), 144.72, 144.31, 138.06, 137.78, 128.59 (d, J =
7.8 Hz), 121.94
(dd, J = 13.6, 3.7 Hz), 119.35 - 117.93 (m), 117.56, 115.58, 115.17, 112.25
(dd, J = 22.7, 3.8
Hz), 79.01, 53.49, 50.03, 43.56, 28.07, 16.84, 12.61. LC-MS (ESI); m/z: [M+H]
Calcd. for
C26H32F2N505S, 564.2092. Found 564.2
[0714] N-(2,4-difluoro-3 -(5-(piperazin-1- y1)- 1H-p yrrolo [2,3 -Kip
yridine-3 -
carbonyl)phenyl)propane-l-sulfonamide (9b). A solution of tert-butyl 4-(3-(2,6-
difluoro-3-
(prop ylsulfonamido)benzoy1)-1H-p yrrolo- [2,3 -b] pyridin-5 -yl)piperazine-1 -
c arboxylate (20 mg,
0.04 mmol) in a mixture of DCM:TFA (3 mL:1 mL) was stirred for 1 hour at room
temperature.
By TLC no more starting material (DCM:MeOH:NH4OH, 90:9:1). 16.4 mg of product
(quantitative yield), crude product was used in the next step without any
further purification. LC-
MS (ESI); m/z [M+H]: Calcd. for C21t124F2N503S, 464.1567. Found 464.1712.
[0715] tert-butyl 5-(4-(3 -(2,6-difluoro-3 -(prop ylsulfonamido)benzoy1)-
1H-p yrrolo [2,3 -
blpyridin-5-yl)piperazin-1-y1)-5-oxopentanoate (10). To a solution of N-(2,4-
difluoro-3-(5-
(piperazin- 1-y1)-1H-p yrrolo [2,3 -b] p yridine-3 -carbonyl) -phenyl)prop ane-
1- sulfonamide (16.4
mg, 0.04 mmol) and 5-(tert-butoxy)-5-oxopentanoic acid (7.99 mg, 0.04 mmol) in
DMF (2 ml)
was added TEA (0.1 ml, 0.72 mmol) and PyBOP (20.25 mg, 0.04 mmol) at room
temperature.
The reaction mixture was stirred for 3 hours at the same temperature. TLC
(DCM:MeOH:NH4OH, 90:9:1) shows no starting materials. The reaction mixture was
dissolved
in Et0Ac (10 mL) and washed with brine/water (3x5mL). Organic extract was
concentrated
under vacuum and crude product was purified by PTLC (DCM:MeOH:NH4OH, 90:9:1)
to give
15.4 mg of product (69% yield). 1H NMR (400 MHz, DMSO-d6) 6 12.67 (bs, 1H),
9.71 (bs, 1H),
8.29 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.56 (q, J = 8.8 Hz, 1H), 7.26 (t, J
= 8.7 Hz, 1H), 3.71 -
3.57 (m, 4H), 3.24 - 3.06 (m, 6H), 2.39 (t, J = 7.3 Hz, 2H), 2.26 (t, J = 7.3
Hz, 2H), 1.84 - 1.66
(m, 4H), 1.40 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, dmso) 6
180.79, 172.52,
170.57, 156.37 (dd, J = 246.4, 7.1 Hz), 152.72 (dd, J = 249.2, 8.7 Hz),
145.03, 144.70, 138.44,
138.20, 129.01 (d, J = 10.4 Hz), 122.34 (dd, J = 13.7, 3.7 Hz), 119.28 -
118.29 (m), 117.97,
115.84, 115.58, 112.66 (dd, J = 22.8, 3.3 Hz), 79.92, 53.89, 50.66, 45.18,
41.39, 34.57, 31.72,
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28.21, 20.83, 17.25, 13.02. LC-MS (ESI); m/z [M+H]: Calcd. for C30H38F2N506S,
634.2510.
Found 634.2621.
[0716] 5-((4-(3 -(2,6-difluoro-3 -(prop ylsulfonamido)benzo y1)-1H-p yrrolo
[2,3 -b] p yridin-5-
yflphenyl)amino)-5-oxopentanoic acid (11). A solution of tert-butyl 5-((4-(3-
(2,6-difluoro-3-
(prop ylsulfonamido)benzoyl) -
1H-p yrrolo [2,3 -b] p yridin-5-yl)phenyl)amino)-5-oxopentanoate
(10.7 mg, 0.02 mmol) in a mixture of TFA (1 ml, 13.46 mmol) and
Dichloromethane (2 ml) was
stirred for 2 hours at room temperature. Then the solvent was removed under
vacuum and crude
product was dried under high vacuum for 2 hours. Crude product was used in the
next step
without any further purification (9.7 mg, quantitative yield). LC-MS (ESI);
m/z: [M+H] Calcd.
for C28H27F2N406S, 585.1619. Found 585.1636.
[0717] (2S ,4R)-1-((S )-2-(5-(4-(3-(2,6-difluoro-3-
(propylsulfonamido)benzoy1)-1H-
pyrrolo [2,3 -b] pyridin-5-yl)piperazin-1- y1)-5-oxopentanamido)-3 ,3 -
dimethylbutano y1)-4-
hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound
218). To a
solution of 5-(4-(3 -(2,6-difluoro-3 -(prop ylsulfonamido)-benzoy1)- 1H-p
yrrolo [2,3 -b] pyridin-5-
yl)piperazin-l-y1)-5-oxopentanoic acid (9.3 mg, 0.02 mmol) and (2S,4R)-1-[(2S)-
2-amino-3,3-
dimethyl-butanoy1]-4-hydroxy-N-[[4-(4-methylthiazol -
5-yl)phenyl]methyl]pyrrolidine-2-
carboxamide;hydrochloride (8.27 mg, 0.018 mmol) in DMF (1 ml) was added TEA
(0.1 ml,
0.72 mmol) and PyBOP (9.22 mg, 0.018 mmol) at room temperature. The reaction
mixture was
stirred for 4 hours at the same temperature. TLC (DCM:MeOH:NH4OH, 90:9:1)
shows no
starting materials. The reaction mixture was diluted with Et0Ac (10 mL) and
washed with brine
(5 mL, 4x), organic phase was dried (Na2SO4), and evaporated under vacuum.
Crude mixture did
not show product by TLC, just some VHL starting material (4) (Product is
soluble in water).
Water extracts were lyophilized for overnight, the solid residue was filtered
using a mixture of
DCM:MeOH:NH4OH (90:9:1, 30 mL). Filtrate was evaporated to dryness and crude
product was
purified by PTLC (DCM:MeOH:NH4OH, 90:9:1) to give 13 mg of product (81%
yield). 1H
NMR (500 MHz, DMSO-d6) 6 12.64 (bs, 1H), 9.74 (bs, 1H), 8.97 (s, 1H), 8.62 ¨
8.52 (m, 3H),
8.28 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 7.95 (bs, 1H), 7.90 (d, J = 9.2 Hz,
1H), 7.59 ¨ 7.49 (m,
1H), 7.47 ¨ 7.27 (m, 4H), 7.20 (t, J = 8.7 Hz, 1H), 5.13 (bs, 1H), 4.56 (d, J
= 9.3 Hz, 1H), 4.48 ¨
4.32 (m, 3H), 4.22 (dd, J = 15.8, 5.3 Hz, 1H), 3.75 ¨ 3.57 (m, 5H), 3.23 ¨
3.02 (m, 7H), 2.44 (s,
3H), 2.41 ¨ 2.17 (m, 4H), 2.07 ¨ 2.01 (m, 1H), 1.96 ¨ 1.87 (m, 1H), 1.81 ¨
1.66 (m, 4H), 0.95 (s,
9H), 0.94 (t, 3H). 13C NMR (151 MHz, dmso) 6 180.70, 171.99, 171.92, 170.44,
169.75, 155.24
422
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(dd, J = 248.1, 5.5 Hz), 152.12 (dd, J = 248.8, 8.5 Hz), 151.47, 147.73,
144.63, 144.31, 139.52,
138.02, 137.75, 131.19, 129.65, 128.65, 127.98 - 127.64 (m), 127.44, 123.91 -
123.09 (m),
118.86- 117.72 (m), 117.60, 115.50, 115.23, 112.02 (dd, J = 22.6, 3.2 Hz),
68.92, 58.74, 56.47,
56.43, 53.44, 50.31, 50.18, 48.63, 44.86, 41.68, 41.00, 37.99, 34.28, 31.80,
26.43, 21.36, 16.99,
15.97, 12.72. LC-MS (ESI); m/z [M+H]: Calcd. for C48H58F2N908S2, 990.3817.
Found
990.3889.
[0718] Example 18-Synthetic Scheme C: compound 304, and 306
Method D
Ers1 N
N N
1.1 F I
N'Th 0 Et3N DMF F I
0 j,0,j< 0
F 12(48%)
9
TFA / DCM
0,0 F N 0
HN
OOH
PyBOP Et3N / DMF
F I HN
N-Th 0 0 0
0
13 (quantitative yield))
N H N Compound 304 (52%)
/\
(4) W
[0719] tert-Butyl
4-[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoy11-1H-pyrrolo[2,3-
b[pyridin-5-yllpiperazin-1-yllbutanoate (12). To a solution of methyl N-[2,4-
difluoro-3-(5-
piperazin-l-y1-1H-pyrrolo [2,3-b] -
pyridine-3 -carbonyl)phenyl]propane-l-sulfonamide;2,2,2-
trifluoroacetic acid (17.4 mg, 0.03 mmol) and tert-butyl 4-iodobutanoate (8.95
mg, 0.03 mmol)
in DMF (1 ml) was added TEA (0.03 ml, 0.15 mmol), the resulting solution
stirred for 16 hours
at 50 C (overnight). The solvent was evaporated under high vacuum and the
residue was filtered
over a silica-carbonate cartridge (1g) using DCM:Me0H (9:1) as a eluent.
Filtrate was
evaporated under vacuum and crude product was purified by PTLC
(DCM:MeOH:NH4OH,
90:9:1), to give 8.8 mg of product (48% yield). 1H NMR (400 MHz, DMSO-d6) 6
12.63 (bs,
1H), 9.73 (bs, 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.00 (s, 1H), 7.89 (bs, 1H),
7.56 (td, J = 9.0, 6.0 Hz,
2H), 7.34 -7.16 (m, 1H), 3.25 - 3.04 (m, 6H), 2.68 -2.52 (m, 4H), 2.34 (t, J =
7.1 Hz, 2H), 2.24
(t, J = 7.2 Hz, 2H), 1.85 - 1.61 (m, 4H), 1.40 (s, 9H), 0.96 (t, J = 7.4 Hz,
3H). 13C NMR (151
423
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MHz, DMSO-d6) 6 180.34 , 172.23 , 155.99 (dd, J = 246.1, 7.0 Hz), 152.31 (dd,
J = 249.3, 8.6
Hz), 144.80 , 143.96 , 137.64 , 137.36 , 128.60 (d, J = 9.9 Hz), 121.91 (dd, J
= 13.6, 3.7 Hz),
118.41 (t, J = 23.8 Hz), 117.63 , 115.12, 114.54 , 112.26 (dd, J = 22.8, 3.7
Hz), 56.95 , 53.47 ,
52.70 , 49.72 , 32.69 , 27.83 , 21.79 , 16.86 , 12.63. LC-MS (ESI); m/z: [M+H]
Calcd. for
C29H38F2N505S, 606.2561. Found 606.2504.
[0720] 4- [4- [3- [2,6-Difluoro-3 -(prop ylsulfonylamino)b enzoyll -1H-p
yrrolo [2,3 -b[pyridin-5-
yllpiperazin-1-yllbutanoic acid (13). A solution of tert-butyl 4-[4-[3-[2,6-
difluoro-3-
(prop ylsulfonylamino)benzo yl] - 1H-p yrrolo [2,3 -b] pyridin-5- yl]
piperazin-1- yl] butanoate (8.8
mg, 0.01 mmol) in a mixture of TFA (1 ml, 13.46 mmol) and Dichloromethane (3
ml) was
stirred for 1 hour. Then the solvent was removed under vacuum and crude
product was dried
under high vacuum for 2 hours. Crude product was used in the next step without
any further
purification (7.9 mg, quantitative yield). LC-MS (ESI); m/z: [M+H]+ Calcd.
for C25H30F2N505S, 550.1936. Found 550.1865.
[0721] (2S ,4R)-1-((S )-2-(4-(4-(3 -(2,6-difluoro-3 -(prop
ylsulfonamido)benzo y1)-1H-
pyrrolo [2,3 -b[pyridin-5-yl)piperazin-1- yl)butanamido)-3 ,3 -
dimethylbutanoy1)-4 -hydroxy-N-(4-
(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Compound 304). To a
solution of 4-[4-
[3- [2,6-difluoro-3 -(prop ylsulfonyl -amino)benzoyl] - 1H-p yrrolo [2,3 -b]
pyridin-5-yl] piperazin-1-
yl] butanoic acid (7.9 mg, 0.01 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-
butanoy1]-4-
hydroxy-N-[[4-(4-methylthiazo-1-5-yl)phenyl]methyl]pyrrolidine-2-
carboxamide;hydrochloride
(7.38 mg, 0.02 mmol) in DMF (1 ml) was added TEA (0.1 ml, 0.72 mmol) and PyBOP
(8.23
mg, 0.02 mmol) at room temperature. The reaction mixture was stirred for 12
hours (overnight)
at the same temperature. TLC (DCM:MeOH:NH4OH, 90:9:1) shows no starting
materials. The
reaction mixture was evaporated to dryness. Crude product was filtered over a
silica-carbonate
cartridge (1 g) using DCM:Me0H (9:1) as eluent (washed a few times, product
has high affinity
for the stationary phase). Filtrate was evaporated under vacuum and crude
product was purified
by PTLC (DCM:Me0H, 9:1) to give 7.2 mg of product (52% yield). 1H NMR (500
MHz,
DMSO-d6) 6 12.66 (bs, 1H), 9.73 (bs, 1H), 8.96 (s, 1H), 8.61 - 8.50 (m, 1H),
8.25 (s, 1H), 8.00
(s, 1H), 7.93 (bs, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.63 - 7.49 (m, 1H), 7.40
(dd, 4H), 7.25 (t, J =
8.7 Hz, 1H), 5.14 (s, 1H), 4.56 (d, J = 9.1 Hz, 1H), 4.46 - 4.34 (m, 3H), 4.22
(dd, J = 15.8, 4.7
Hz, 1H), 3.75 - 3.60 (m, 2H), 3.23 - 3.14 (m, 4H), 3.13 - 3.08 (m, 2H), 2.65 -
2.53 (m, 4H),
2.43 (s, 3H), 2.38 -2.31 (m, 2H), 2.31 -2.25 (m, 1H), 2.24 - 2.16 (m, 1H),
2.07 - 1.99 (m, 1H),
424
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1.95 - 1.87 (m, 1H), 1.72 (dq, J = 16.3, 10.5, 8.9 Hz, 4H), 0.95 (t, J = 5.3
Hz, 3H), 0.95 (s,
9H). 13C NMR (151 MHz, DMSO-d6) 6 180.77 , 172.43 , 172.39 , 170.12 , 156.38
(dd, J =
246.2, 7.1 Hz), 152.75 (dd, J = 249.8, 9.0 Hz), 151.87 , 148.13 , 145.23 ,
144.35 , 139.92 ,
138.09 , 137.78 , 131.59 , 130.05 , 129.21 - 128.76 (m), 127.84 , 122.32 (d, J
= 13.1 Hz),
119.83 - 118.25 (m), 118.03 , 115.53 , 114.96 , 112.68 (d, J = 22.7 Hz),
69.30, 59.13 , 57.62,
56.79 , 55.33 , 53.88 , 53.06 , 50.11 , 42.07 , 38.38 , 35.68 , 33.27 , 26.83
, 23.09, 17.26, 16.37 ,
13.04. LC-MS (EST); m/z [M+H]: Calcd. for C47H58F2N907S2, 962.3868. Found
962.3986.
[0722] Example 19-Synthetic Scheme E: compound 511, and 513
Method E
o HATU / DIPA
OH + DMF 0-B
0
0
14 (52%)
N N
\--\H F \I; Pd(dba)2 / PCY3
o Br K2003,
Dioxane-water
90 C
0
H F \ I
N N
H H HN 1) TFA / DCM \
H F \ I
0
0 = kIV3E011-P-11/g10
0 0 DMF 0
Compound 511 (73%) 15 (69%)
[0723] tert-butyl 3-(4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)benzamido)propanoate (14).
0 B H
N
0 0
[0724] To a solution of 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)benzoic acid (538 mg,
425
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2.17 mmol) and tert-butyl 3-aminopropanoate (315 mg, 2.17 mmol) in N,N-
Dimethylformamide
(10 ml) was added N,N-Diisopropylethylamine (1.13 mL, 6.51 mmol) and 0-(7-
Azabenzotriazol-1-y1)-N,N,N',N'-tetramethyluronium hexafluorophosphate (825
mg, 2.17 mmol)
at room temperature. The reaction mixture was stirred for 4 h at the same
temperature. TLC
(DCM:MeOH:NH4OH, 90:9:1) shows no starting materials. Reaction mixture was
diluted with
Et0Ac (50 mL), washed with water/brine (4x30 mL), dried (Na2SO4) and
evaporated under
vacuum. Crude product was purified by flash chromatography (SiO2-25g, gradient
Hex:Et0Ac,
1:9 to 100% Et0Ac in 15 min), to give 471 mg of product (-90% pure by NMR, 52
% yield).
This product was used in the next step without any further purification. 1H
NMR (500 MHz,
Chloroform-d) 6 7.86 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 6.87 (t,
1H)z 3.69 (q, J = 5.9
Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 1.45 (s, 9H), 1.35 (s, 12H). LC-MS (ESI);
m/z [M+H]: Calcd.
for C20H31BN05, 376.2295. Found 376.2259.
[0725] tert-butyl 3-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoy1)-1H-
pyrrolo[2,3-
b]pyridin-5-yl)benza-mido)-propanoate (15).
H
N N
\----\ H F \ I
OS.N H
\O
0 N .rol<
F 0 0
[0726] To a solution of N- [3 -(5-bromo-1H-p yrrolo [2,3 -Il] p yridine-3 -
c arbony1)-2,4-difluoro-
phenyl[propane- 1-sulfonamide (5) (87.3 mg, 0.191 mmol) in Dioxane (6 ml) was
added tert-
butyl 2- [2- [2- [2- [444,4,5 ,5-tetramethyl- 1,3 ,2-
diox aborolan-2-
yl)phenoxy] ethoxyl ethoxyl ethoxyl acetate (14) (65.0 mg, 0.173 mmol), K2CO3
(71.8 mg, 0.520
mmol), Tricyclohexyl phosphine (4.86 mg, 0.017 mmol) and water (2 mL). Then
the reaction
mixture was de-gassed under vacuum and purged with argon (5x), Pd(dba)2 (4.98
mg, 0.080
mmol) was added into and the reaction mixture was heated at 90 C for 3 h. By
TLC small
amounts of SM (Hex:Et0Ac, 3:7), the reaction mixture was filtered in vacuum
over a celite pad,
filtrate was poured into an aqueous saturated solution of NaCl (20 mL) and the
product was
extracted with Et0Ac (2x20 mL). The Et0Ac layers were combined, dried (Na2SO4)
and
concentrated in vacuum. The crude material was diluted in CH2C12 and purified
by flash
chromatography (5i02-12g, Hexane:Et0Ac, 9:1 to 100% Et0Ac in 15 min) to give
75 mg (71%)
of product. 13C NMR (101 MHz, DMSO-d6) 6 181.08, 171.05, 166.24, 156.44 (dd, J
= 246.3,
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6.9 Hz), 152.76 (dd, J = 249.7, 8.2 Hz), 149.55 , 144.57 , 141.15 , 139.40 ,
133.71 , 130.98 ,
129.65 - 128.79 (m), 128.43 , 127.64 , 127.55 - 126.10 (m), 122.66 - 122.12
(m), 119.00 -
118.20 (m), 117.93 , 116.15 , 112.78 (dd, J = 22.9, 3.5 Hz), 80.28 , 53.88 ,
36.10 , 35.45 ,28.17 ,
17.25 , 13.03 . 1H NMR (500 MHz, DMSO-d6) 6 13.03 (bs, 1H), 9.76 (bs, 1H),
8.78 (s, 1H),
8.69 (s, 1H), 8.61 (t, J = 4.6 Hz, 1H), 8.26 (s, 1H), 7.98 (d, J = 7.1 Hz,
2H), 7.87 (d, J = 7.2 Hz,
2H), 7.59 (q, J = 7.6 Hz, 1H), 7.29 (t, J = 8.7 Hz, 1H), 3.50 (q, J = 5.7 Hz,
2H), 3.13 (t, 2H), 2.64
- 2.44 (m, 2H), 1.74 (dq, J = 13.9, 7.3 Hz, 2H), 1.40 (s, 9H), 0.96 (t, J =
7.4 Hz, 3H). LC-MS
(ESI); m/z [M+H]: Calcd. for C31t133F2N406S, 627.2088. Found 627.2485.
[0727] (2S ,4R)-1-((S )-2-(3 -(4-(3 -(2,6-difluoro-3 -(prop
ylsulfonamido)benzo y1)-1H-
pyrrolo [2,3 -b[pyridin-5-y1) -benzamido)propanamido)-3,3-dimethylbutanoy1)-4-
hydroxy-N-(4-
(4-methylthiazol-5-yl)benzyl)pyrrole -dine-2-carboxamide (Compound 511).
n-S-N
- - \ H
µ0
0 H nHN
N N 0
F 0 0
/
N
[0728] A solution of tert-butyl 44443 -benzoy1-1H-pyrrolo [2,3 -
b]pyridin-5-
yl)phenoxy]butanoate (15) (26.0 mg, 0.0415 mmol) in a mixture of TFA (1 ml,
13.46 mmol) and
Dichloromethane (3 ml) was stirred for 1.5 h. Then the solvent was removed
under vacuum and
crude product was dried under high vacuum for 2 h. Crude product was used in
the next step
without any further purification (23.5 mg, quantitative yield). LS-MS (ESI);
m/z: [M+H] Calcd.
for C27t125F2N406S, 571.1462. Found 571.1812. To a solution of crude product
from above; 4-
[4- [3- [2,6-difluoro-3-(propylsulfonylamino)benzoyl] -1H-p yrrolo [2,3 -b]
pyridin-5-yl] -N-methyl-
anilino] -4-oxo-butanoic acid (23.5 mg, 0.0402 mmol) and (2S ,4R)- 1- [(2S )-2-
amino-3 ,3 -
dimethyl-butano y1]-4-hydroxy-N-[[4-(4-methylthiazol-5-
yl)phenyl]methyl]pyrrolidine-2-
carboxamide;hydrochloride (4) (21.0 mg, 0.0450 mmol) in DMF (1 ml) was added
TEA (0.139
mL, 1.00 mmol) and PyBOP (23.4 mg, 0.0450 mmol) at room temperature. The
reaction
mixture was stirred for 4 h at the same temperature. TLC (DCM:MB, 1:1) shows
no starting
material (acid). The reaction mixture was evaporated to dryness under high
vacuum (Product
may be soluble in water). Crude product was filtered over a silica-carbonate
cartridge (100 mg)
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using DCM:Me0H (9:1) as a eluent. Filtrate was evaporated under vacuum and
crude product
was purified by PTLC (MBLDCM, 1:1). A second purification was performed by
PTLC
(DCM:MeOH:NH4OH, 90:9:1), to give 27 mg of product (73% yield). 11-1NMR (500
MHz,
DMSO-d6) 6 13.03 (bs, 1H), 9.77 (bs, 1H), 8.96 (s, 1H), 8.77 (s, 1H), 8.69 (s,
1H), 8.57 (t, J =
5.7 Hz, 1H), 8.53 (t, J = 4.9 Hz, 1H), 8.26 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H),
7.98 (d, J = 8.0 Hz,
1H), 7.86 (d, J = 8.0 Hz, 1H), 7.59 (q, J = 8.8 Hz, 1H), 7.40 (dd, 4H), 7.28
(t, J = 8.6 Hz, 1H),
5.16 (d, J = 2.8 Hz, 1H), 4.58 (d, J = 9.1 Hz, 1H), 4.50 - 4.34 (m, 3H), 4.22
(dd, J = 15.8, 5.1 Hz,
1H), 3.80- 3.61 (m, 2H), 3.58 - 3.40 (m, 2H), 3.15 - 3.06 (m, 2H), 2.69 -2.49
(m, 2H), 2.43 (s,
3H), 2.11 - 1.99 (m, 1H), 1.96 - 1.86 (m, 1H), 1.83 - 1.66 (m, 2H), 0.95 (t,
3H), 0.94 (s, 9H).
13C NMR (151 MHz, DMSO-d6) 6 180.69 , 171.95 , 170.40, 169.62, 165.76 , 156.00
(dd, J =
246.6, 6.9 Hz), 152.34 (dd, J = 249.4, 8.3 Hz), 151.42 , 149.13 , 147.71 ,
144.14 , 140.67 ,
139.50 , 138.99 , 133.39 , 131.16 , 130.58 , 129.64 , 128.81 (d, J = 9.8 Hz),
128.64 , 128.03 ,
127.42, 127.23 , 126.91 , 122.26- 121.63 (m), 118.52- 117.80 (m), 117.52,
115.75, 112.77 -
111.89 (m), 68.92 , 58.75 , 56.53 , 56.40, 53.47 , 41.67 , 37.97 , 36.32 ,
35.26 , 34.89 , 26.40,
16.85 , 15.95 , 12.63 . LC-MS (ESI); rniz [M+H]: Calcd. for C49H53F2N808S2,
983.3395.
Found 983.3963.
[0729] Example 20-Synthetic Scheme F: compound 512, 513, and 516
Method F
Pd(dba)2/ P0y3 H N
N N
H F \ I K2CO3, Dioxane-water H F \ I TFA / DCM H F
\ I
0"-r-qcoN Br 90 C 0,voN
0 0 0 N-
Th
1-s)
F 5
B
16(83%) 1
(quantitative yield)
0
Br.jak THF
N
H F \ I
OT'Vo-N HO,
N
0 0 --1 N 1) TFA / DCM
H F \ I
z\ 2) VHL-ligand 0.'"SN
PyBOP / TEA
Compoune 512 (64%) DMF
F 18(68%) 103)(0-j<
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[0730] tert-butyl 4-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoy1)-1H-
pyrrolo[2,3-
b]pyridin-5-yl)phenyl) -piperazine-l-carboxylate (16).
H ,
N 11
0
0 N
F NI,.r0<
\ 0
[0731] To a solution of N43-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbony1)-
2,4-difluoro-
phenyl]propane- 1-sulfonamide (5) (70.8 mg, 0.155 mmol) in Dioxane (6 ml) was
added tert-
butyl 4-(4-(4,4,5 ,5-tetramethyl- 1,3 ,2-diox aborolan-2- yl)phenyl)piperazine-
l-c arboxylate (60.0
mg, 0.155 mmol), K2CO3 (64.2 mg, 0.465 mmol), Tricyclohexyl phosphine (4.33
mg, 0.0155
mmol)and water (2 mL). Then the reaction mixture was de-gassed under vacuum
and purged
with argon (5x), Pd(dba)2 (4.44 mg, 0.00773 mmol) was added into and the
reaction mixture was
heated at 90 C for 3 h. By TLC small amounts of SM (Hex:AcOEt, 3:7), the
reaction mixture
was filtered in vacuum over a celite pad, filtrate was poured into an aqueous
saturated solution of
NaCl (20 mL) and the product was extracted with Et0Ac (2x20 mL). The Et0Ac
layers were
combined, dried (Na2SO4) and concentrated in vacuum. The crude material was
diluted in
CH2C12 and purified by flash chromatography (Si02-12g, Hexane:Et0Ac, 9:1 to
100% Et0Ac in
15 min) to give 82 mg (83%) of product. 13C NMR (151 MHz, DMSO-d6) 6 180.61 ,
156.04 (dd,
J = 246.5, 6.9 Hz), 153.88 , 152.34 (dd, J = 249.4, 8.6 Hz), 150.35 , 148.44 ,
143.61 , 138.60 ,
131.47 , 128.92 - 128.75 (m), 128.19 (d, J = 161.3 Hz), 126.05 , 121.94 (dd, J
= 13.6, 3.6 Hz),
118.96 - 117.87 (m), 117.60 , 116.33 , 115.61 , 112.36 (dd, J = 22.6, 3.2 Hz),
79.03 , 53.42 ,
48.08 , 43.72 , 42.58 , 28.09, 16.87 , 12.64 . 1H NMR (500 MHz, DMSO-d6) 6
12.92 (bs, 1H),
9.76 (bs, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.75 -
7.46 (m, 3H), 7.28 (t, J
= 8.7 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 3.49 (t, 4H), 3.19 (t, J = 5.2 Hz,
4H), 3.16 - 3.05 (m,
2H), 1.74 (h, J = 7.5 Hz, 2H), 1.43 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H). LC-MS
(ESI); m/z [M+H]:
Calcd. for C32H36F2N5055, 640.2405. Found 640.2541.
[0732] N-(2,4-difluoro-3-(5-(4-(piperazin-1-yl)pheny1)-1H-pyrrolo[2,3-
b]pyridine-3-
carbonyl)phenyl)propane-1-sulfonamide (17).
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H
N
H F \
n-S-N
0
0
[0733] A solution of tert-butyl 4-[4-[3-[2,6-difluoro-3-
(propylsulfonylamino)benzoy1]-1H-
pyrrolo[2,3-b]pyridin-5-yl]phenyl]piperazine-1-carboxylate (16) (28.0 mg,
0.0438 mmol) in a
mixture of DCM/TFA (3:1, 4 mL) was stirred for lh at room temperature (by TLC
no SM "A").
The solvent was removed under vacuum and the residue was dried under high
vacuum foe 2h (23
mg of product, quantitative yield). Crude product was used in the next step
without any further
purification. LC-MS (ESI); m/z [M+H]: Calcd. for C27t128F2N5035, 540.1880.
Found 540.1949.
[0734] tert-butyl 2-(4-(4-(3-(2,6-difluoro-3-
(propylsulfonamido)benzoy1)-1H-
pyrrolo[2,3-b]pyridin-5-y1)-phenyl) piperazin-l-yl)acetate (18).
H
N 1"
H F \
n-S-N
0
0 N 0
Nj-Lo<
[0735] To a solution of N- [2,4-difluoro-3- [5-(4-piperazin-1- ylpheny1)-
1H-p yrrolo [2,3 -
b] pyridine-3 -carbonyl] -phenyl] prop ane- 1-sulfonamide (17) (23.0 mg,
0.0426 mmol) and TEA
(0.0594 mL, 0.426 mmol) in DMF (1 ml) was added tert-butyl 2-bromoacetate
(9.15 mg, 0.0469
mmol) and the resulting solution stirred for 3 h at rt. The reaction mixture
was evaporated under
vacuum. Crude product was purified by PTLC (DCM:MeOH:NH4OH, 90:9:1, 2x) to
give 19 mg
of pure product (69% yield). 1H NMR (500 MHz, DMSO-d6) 6 12.92 (bs, 1H), 9.76
(bs, 1H),
8.65 (t, J = 2.6 Hz, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.76 - 7.42 (m, 3H),
7.28 (t, J = 8.3 Hz, 1H),
7.07 (d, J = 6.5 Hz, 2H), 3.33 (s, 2H), 3.30 - 3.16 (m, 4H), 3.16 - 3.04 (m,
2H), 2.81 - 2.55 (m,
4H), 1.84 - 1.67 (m, 2H), 1.43 (s, 9H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (151
MHz, DMSO-d6)
6 180.57 , 169.22 , 156.02 (dd, J = 246.3, 7.0 Hz), 152.33 (dd, J = 249.4, 8.6
Hz), 150.42 ,
148.37 , 143.55 , 138.50, 131.53 , 128.75 (d, J = 9.6 Hz), 128.17 , 127.58 ,
125.93 , 121.92 (dd,
J = 13.6, 3.6 Hz), 118.25 (t, J = 23.6 Hz), 117.58 , 115.80 , 115.58 , 112.33
(dd, J = 21.9, 3.0
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Hz), 80.23 , 59.21 , 53.44 , 51.81 , 47.93 , 27.82 , 16.84 , 12.62 . LC-MS
(ESI); m/z [M+H]:
Calcd. for C33H38F2N505S, 654.2561. Found 654.2675.
[0736] (2S,4R)-1-((S)-2 (2 (4 (4 (3 (2,6-difluoro-3-
(propylsulfonamido)benzoy1)-1H-
pyrrolo [2,3 -b[pyridin-5-yl)phenyl)piperazin- 1-y1) acetamido)-3 ,3 -
dimethylbutanoy1)-4-hydroxy-
N-(4-(4-methylthiazol-5-yl)benz yl)p yrrolidine-2-c arboxamide (Compound 512).
H ,
N 11
n¨S¨N
0
HN
. 0
/7\
/ 3
N
A solution oftert-butyl 2-(4-(4-(3 - (2,6-difluoro-3 - (prop yl s
ulfonamido)benzoy1)-1H-p yrrolo [2,3 -
b]pyridin-5-yl)phenyl)piperazin-1-yl)acetate (18) (20.0 mg, 0.0306 mmol) in a
mixture of TFA
(2 ml, 13.46 mmol) and Dichloromethane (2 ml) was stirred for 5 h. Then the
solvent was
removed under vacuum and crude product was dried under high vacuum for 1 h.
Crude product
was used in the next step without any further purification (18.3 mg,
quantitative yield). LC-MS
(ESI); m/z: [M+H] Calcd. for C29H30F2N505S, 598.1935. Found 598.1953. To a
solution of
crude product from above; 2-(4- (4- (3 -(2,6-difluoro-3 -(prop yl
sulfonamido)benzoy1)- 1H-
pyrrolo [2,3 -b] pyridin-5-yl)phenyl) -piperazin- 1-y1) acetic
acid (18.3 mg, 0.0306
mmol) and(2S ,4R)-1- [(2S )-2-amino-3 ,3 -dimethyl-butanoyl] -4-hydroxy-N- [
[4- (4-methylthiazol-
5-yl)phenyl]methyl]pyrrolidine-2-carboxamide;hydrochloride (4) (17.2 mg,
0.0367 mmol) in
DMF (1 ml) was added TEA (0.106 mL, 0.762 mmol) and PyBOP (19.1 mg, 0.0367
mmol) at
room temperature. The reaction mixture was stirred for 4 h at the same
temperature. TLC
(DCM:MeOH:NH4OH, 90:9:1) shows no starting material (acid). The reaction
mixture was
evaporated to dryness under high vacuum. Crude product was diluted with Et0Ac
(10 mL) and
washed with a saturated-aqueous solution of NaHCO3 (2x5 mL), organic extract
was dried
(Na2SO4), and evaporated under vacuum. Crude product was purified by PTLC
DCM:MeOH:NH4OH, 90:9:1, 2x) to give 20 mg of product (65% yield). 1H NMR (500
MHz,
DMSO-d6) 6 12.92 (bs, 1H), 9.76 (bs, 1H), 8.91 (s, 1H), 8.66 (s, 1H), 8.65 ¨
8.45 (m, 2H), 7.85
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(d, J = 9.1 Hz, 1H), 7.74 - 7.52 (m, 3H), 7.49 - 7.32 (m, 4H), 7.28 (t, J =
8.6 Hz, 1H), 7.09 (d, J
= 8.5 Hz, 2H), 5.16 (d, J = 3.0 Hz, 1H), 4.54 (d, J = 9.6 Hz, 1H), 4.52 - 4.32
(m, 3H), 4.26 (dd, J
= 15.7, 5.4 Hz, 1H), 3.76 - 3.58 (m, 2H), 3.27 (s, 4H), 3.21 - 2.95 (m, 4H),
2.68 (s, 4H), 2.40 (s,
3H), 2.07 (dd, J = 12.9, 7.7 Hz, 1H), 1.92 (ddd, J = 13.1, 9.0, 4.6 Hz, 1H),
1.75 (h, J = 7.5 Hz,
2H), 0.97 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) 6
180.56, 171.77 ,
169.28, 168.48, 156.02 (dd, J = 246.6, 7.0 Hz), 152.37 (dd, J = 240.8, 8.8
Hz), 151.30, 150.27,
148.38 , 147.68 , 143.55 , 139.42 , 138.47 , 131.48 , 131.12 , 129.68 , 129.10
- 128.66 (m),
128.63 , 128.33 , 127.57 , 127.51 , 125.96 , 121.92 (dd, J = 13.7, 3.6 Hz),
118.60- 117.95 (m),
117.57 , 115.84 , 115.59 , 112.32 (dd, J = 23.0, 2.7 Hz), 68.91 , 60.59 ,
58.81 , 56.56 , 55.86 ,
48.16 , 41.67 , 37.87 , 35.80 , 26.26, 16.83 , 15.90, 12.61. LC-MS (ESI); m/z
[M+H]: Calcd.
for C51t158F2N907S2, 1010.3868. Found 1010.4036
[0737] (2S ,4R)-1-((S )-2-(4-(4-(3 -(2,6-difluoro-3 -(prop
ylsulfonamido)benzo y1)-1H-
pyrrolo [2,3 -bi -pyridine-5-yl)benzamido)butanamido)-3,3-dimethylbutanoy1)-4-
hydroxy-N-(4-
(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound 513).
H
N "
µ0 N N[i HN
0 NI-1,
. 0
F 0
....õ---...,..
/
N
[0738] To a solution of crude product from SJF-0633; 4-(4-(3-(2,6-difluoro-3-
(propylsulfonamido)benzoy1)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamido)butanoic
acid (29.0 mg,
0.0496 mmol) and (2S ,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoy1]-4-
hydroxy-N4[4-(4-
methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide;hydrochloride (27.8
mg, 0.0595
mmol) in DMF (2 ml) was added TEA (0.172 mL, 1.23 mmol) and PyBOP (31.0 mg,
0.0595
mmol) at room temperature. The reaction mixture was stirred for 4 h at the
same temperature.
TLC (DCM:MeOH:NH4OH, 90:9:1) shows no starting material (acid). The reaction
mixture was
evaporated to dryness under high vacuum. Crude product was filtered over a
silica-carbonate
cartridge (1g) using DCM:Me0H (9:1) as a eluent. Filtrate was evaporated under
vacuum and
crude product was purified by PTLC (DCM:MeOH:NH4OH, 85:14:1) to give 35 mg of
product
(71% yield). 1t1 NMR (400 MHz, DMSO-d6) 6 12.96 (bs, 1H), 9.70 (bs, 1H), 8.97
(s, 1H), 8.77
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(d, J = 2.0 Hz, 1H), 8.69 (bs, 1H), 8.56 (t, J = 5.6 Hz, 2H), 8.26 (s, 1H),
8.08 - 7.92 (m, 3H),
7.86 (d, J = 8.2 Hz, 2H), 7.65 - 7.53 (m, 1H), 7.40 (dd, J = 8.2 Hz, 4H), 7.29
(t, J = 8.7 Hz, 1H),
5.14 (d, J = 3.5 Hz, 1H), 4.57 (d, J = 9.3 Hz, 1H), 4.51 -4.31 (m, 3H), 4.22
(dd, J = 15.9, 5.4 Hz,
1H), 3.77 - 3.59 (m, 2H), 3.32- 3.21 (m, 2H), 3.17 - 3.05 (m, 2H), 2.44 (s,
3H), 2.42 - 2.14 (m,
2H), 2.08 - 1.98 (m, 1H), 1.97 - 1.84 (m, 1H), 1.88 - 1.61 (m, 4H), 0.96 (s,
9H), 0.95 (t, 3H).
13C NMR (151 MHz, DMSO-d6) 6 181.11 , 172.38 , 172.30, 170.10, 166.19 , 156.45
(dd, J =
246.3, 7.1 Hz), 152.78 (dd, J = 249.6, 8.2 Hz), 151.86 , 149.54 , 148.13 ,
144.57 , 141.04 ,
139.92 , 139.43 , 133.94 , 131.59 , 131.04 , 130.05 , 129.46 - 129.15 (m),
129.06 , 128.49 ,
127.84 , 127.63 , 127.32 , 122.35 (dd, J = 13.4, 3.8 Hz), 118.94 - 118.30 (m),
117.94 , 116.15 ,
112.79 (d, J = 22.6 Hz), 69.32 , 59.14 , 56.87 , 56.82 , 53.87 , 42.08 , 40.46
, 38.39 , 35.69 ,
33.08 , 26.84 , 26.10 , 17.26 , 16.38 , 13.04. LC-MS (ESI); m/z [M+H]: Calcd.
for C50H55F2N808S2, 997.3552. Found 997.2761.
[0739] (2S ,4S )-1-((S )-2-(2-(4-(4-(3-(2,6-difluoro-3-
(propylsulfonamido)benzoy1)- 1H-
pyrrolo I-2,3 -bl pyridin-5-yl)phenyl)piperazin- 1-yl)acetamido)-3 ,3 -
dimethylbutanoy1)-4-hydroxy-
N-(4-(4-methylthiazol-5-yl)benz yl)p yrrolidine-2-c arboxamide (Compound 516).
H ,
N 1"
0
F Nj=LNI-1,
----\HN
- 0 _
z
........--....õ,
/ 3
N
[0740] To a solution of crude product from SJF-0660; 2-(4-(4-(3-(2,6-
difluoro-3-
(prop ylsulfonamido)benzoy1)-1H-p yrrolo [2,3 -b] pyridin-5-yl)phenyl) -
piperazin-l-yl)acetic acid
(5.70 mg, 0.00954 mmol) and (2S,4S)-1-((S)-2-amino-3,3-dimethylbutanoy1)-4-
hydroxy-N-(4-
(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (5.35 mg, 0.0124 mmol)
in DMF (1
ml) was added TEA (0.1 mL, 0.762 mmol) and PyBOP (5.96 mg, 0.0114 mmol) at
room
temperature. The reaction mixture was stirred for 4 h at the same temperature.
TLC
(DCM:MeOH:NH4OH, 85:14:1) shows no starting material (acid). The reaction
mixture was
evaporated to dryness under high vacuum (Product may be soluble in water).
Crude product was
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filtered over a silica-carbonate cartridge (100 mg) using DCM:Me0H (9:1) as a
eluent and
evaporated under vacuum.. Crude product was purified by PTLC (DCM:MeOH:NH4OH,
85:14:1) to give 6.1 mg of product (63% yield). 1t1 NMR (500 MHz, DMSO-d6) 6
12.93 (bs,
1H), 9.76 (bs, 1H), 8.93 (s, 1H), 8.69 (t, J = 5.8 Hz, 1H), 8.66 (s, 1H), 8.56
(bs, 1H), 8.18 (s, 1H),
7.81 (d, J = 8.6 Hz, 1H), 7.65 - 7.50 (m, 3H), 7.51 - 7.32 (m, 4H), 7.28 (t, J
= 8.7 Hz, 1H), 7.09
(d, J = 8.2 Hz, 2H), 5.48 (d, J = 7.2 Hz, 1H), 4.49 (d, J = 9.2 Hz, 1H), 4.46 -
4.33 (m, 2H), 4.32 -
4.18 (m, 2H), 3.96 - 3.88 (m, 1H), 3.54 - 3.42 (m, 1H), 3.30 - 3.19 (m, 4H),
3.17 - 3.00 (m,
4H), 2.78 - 2.56 (m, 4H), 2.41 (s, 3H), 2.39 - 2.30 (m, 1H), 1.82 - 1.68 (m,
3H), 0.98 (s, 9H),
0.95 (t, 3H). 13C NMR (151 MHz, DMSO-d6) 6 180.60, 172.29, 169.55, 168.84,
156.04 (dd, J
= 246.5, 6.9 Hz), 152.38 (dd, J = 249.4, 8.3 Hz), 151.40 , 150.29 , 148.40 ,
147.75 , 143.57 ,
139.16 , 138.53 , 131.50 , 131.12 , 129.79 , 128.78 (d, J = 7.4 Hz), 128.70 ,
128.36 , 127.54 ,
125.99 , 121.93 (dd, J = 13.4, 3.6 Hz), 118.52 - 117.94 (m), 117.59 , 115.87 ,
115.60 , 112.35
(dd, J = 23.0, 3.9 Hz), 69.09 , 60.50 , 58.62 , 56.01 , 55.63 , 53.46 , 52.70
, 48.17 , 41.83 , 36.90,
35.21 , 26.25 , 16.85 , 15.93 , 12.63 . LC-MS (ESI); rniz [M-Ft1] : Calcd.
for C51t158F2N907S2, 1010.3868. Found 1010.3542.
[0741] Example 21-Synthetic Scheme G: compound 515
Method G
Br Br
X-PHOS, KOAc
MgC12, (Boc)2 0 B
OH
t-BuOH 0 0 Pd(OAc)2, Dioxane
0 0 h<
19(20%) _ 0 0
B-Bis In-situ formation
N = N
F \ I Pd(dba)2/
PCY3
o Br
K2CO3, Dioxane-water
0 9 90 C
N = N HO,
=
H F \ N N
NO 0 '2) VHL-ligand 0
PyBOP / TEA 0
0 0
DMF
Compound 515 (64%)
F 20 (32%) 0 0 I
\
[0742] tert-butyl 5-(4-bromopheny1)-5-oxopentanoate (19).
434
CA 03109981 2021-02-17
WO 2020/051564 PCT/US2019/050114
Br
0<
0 0
[0743] In a flask equipped with a magnetic stirring bar, 5-(4-bromopheny1)-
5-oxopentanoic
acid (0.460 g, 1.70 mmol), and Boc Anhydride (0.481 g, 2.21 mmol) were
dissolved in t-Butanol
(1.00 mL, 10.5 mmol) and then Magnesium Chloride (0.0162 g, 0.170 mmol) was
added into.
The mixture was stirred at 40 C for 16 h (overnight). The crude reaction
mixture was diluted
with Et0Ac (100 mL), washed with water (2x100 mL), aqueous NaHCO3 (2x100 mL),
dried
(Na2SO4) and evaporated by rotary evaporation. Crude product was purified by
flash
chromatography (SiO2-25g, Gradient Hex 100% to Hex:Et0Ac, 1:1, in 15 min) to
give 198 mg
of product (35% yield). 1H NMR (500 MHz, Chloroform-d) 6 7.82 (d, J = 8.3 Hz,
2H), 7.60 (d, J
= 8.4 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.33 (t, J = 7.1 Hz, 2H), 2.01 (p, J
= 7.2 Hz, 2H), 1.44 (s,
9H). 13C NMR (101 MHz, cdc13) 6 198.68, 172.67, 135.69, 132.04, 129.72,
128.33, 80.54,
37.64, 34.68, 28.27, 19.68. LC-MS (ESI); m/z [M+Na]: Calcd. for C15tl19BrO3Na,
349.0415.
Found 349.0676, and 351.0609.
[0744] tert-Butyl 5-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoy1)-1H-
pyrrolo[2,3-
b]pyridin-5-yl)pheny1)-5-oxopentanoate (20).
H
N N
,
µ0 I
/ ONic.
0
I \
F 0 0
[0745] To a solution of tert-butyl 5-(4-bromopheny1)-5-oxo-pentanoate (19)
(74.0 mg, 0.226
mmol) in Dioxane (5 mL) was added 4,4,5,5-tetramethy1-2-(4,4,5,5-tetramethy1-
1,3,2-
dioxaborolan-2-y1)-1,3,2-dioxaborolane (63.2 mg, 0.249 mmol), CH3CO2K (66.6
mg, 0.678
mmol), and the reaction mixture was degassed under argon. X-PHOS (16.2 mg,
0.0339
mmol) and Palladium(II) acetate (2.54 mg, 0.0113 mmol) were added and the
reaction mixture
was stirred at 100 C (external temperature) for 1 h. under a argon
atmosphere. After 1 h. the
temperature of the heating bath was turned down to 90 C and the flask was
raised out of the
heating bath, but continued stirring. N- [3 -(5-bro mo-1H-p yrrolo [2,3 -b]
pyridine-3 -c arbony1)-2,4-
difluoro-phenyl[propane-l-sulfonamide (5) (104 mg, 0.226 mmol) and Potassium
carbonate
(93.8 mg, 0.678 mmol) were added, followed by water (2.00 m1). Tricyclohexyl
phosphine (6.34
435
CA 03109981 2021-02-17
WO 2020/051564 PCT/US2019/050114
mg, 0.0226 mmol, 2x) and Pd(dba)2 (6.50 mg, 0.0113 mmol) were added, and the
reaction
mixture was heated with vigorous stirring at 90 C and stirred for 3 h, then
the reaction mixture
was cooled to ambient temperature. The reaction mixture was diluted with Et0Ac
(30 mL) and
poured into brine (20 mL), the organic extract was dried (Na2SO4), and
evaporated under
vacuum. Crude product was purified by flash chromatography (SiO2-40g, gradient
Hex:Et0Ac,
1:9 to 100% Et0Ac in 20 min). Product was about 85% pure, it was purified
again by PTLC
(DCM:MeOH:NH4OH, 90:9:1) to give 45 mg of product (32% yield). 1H NMR (500
MHz,
DMSO-d6) 6 12.98 (bs, 1H), 9.68 (bs, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.26 (s,
1H), 8.07 (d, J =
8.3 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.65 - 7.49 (m, 1H), 7.27 (t, J = 8.7
Hz, 1H), 3.10 (q, J =
7.8, 7.3 Hz, 4H), 2.29 (t, J = 7.4 Hz, 2H), 1.85 (p, J = 7.3, 6.8 Hz, 2H),
1.79 - 1.62 (m, 2H), 1.39
(s, 9H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) 6 199.09 ,
180.72, 172.08 ,
156.04 (dd, J = 246.5, 6.9 Hz), 152.37 (dd, J = 249.6, 8.5 Hz), 149.29, 144.21
, 142.60, 139.11 ,
135.42, 130.30, 128.97 - 128.74 (m), 128.78 , 127.40, 127.35 , 122.00 (dd, J =
13.6, 3.7 Hz),
118.66- 117.86 (m), 117.55, 115.79, 112.38 (dd, J = 22.7, 3.8 Hz), 79.61 ,
53.48 , 37.08 , 34.03
, 27.80 , 19.46 , 16.86 , 12.64.
LC-MS (ES I) ; m/z: [M+H]+ Calcd.
for C32H34F2N306S, 626.2136. Found 626.2191.
[0746] (2S ,4R)-1-((S )-2-(5-(4-(3 -(2,6-difluoro-3 -(prop
ylsulfonamido)benzo y1)-1H-
pyrrolo [2,3 -bi pyridin-5-y1) -
pheny1)-5-oxopentanamido)-3,3-dimethylbutanoy1)-4-hydroxy-N-
(4-(4-methylthiazol-5-yl)benzyl) -pyrrolidine-2-carboxamide (Compound 515).
H m
HO
,,.
µ0 I
HN
0
F 0 0
/ 3
N
[0747]
A solution of tert-butyl 5-(4-(3-(2,6-difluoro-3-(propyl -sulfonamido)benzoy1)-
1H-
pyrrolo[2,3-b]pyridin-5-yl)pheny1)-5-oxopentanoate (20) (22.0 mg, 0.0352 mmol)
in a mixture
of TFA (1.50 mL, 20.2 mmol) and Dichloromethane (3 ml) was stirred for 2 h at
room
temperature. Then the solvent was removed under vacuum and crude product was
dried under
high vacuum for 2 h. Crude product was used in the next step without any
further purification
(19.9 mg, quantitative yield). LC-MS (EST); m/z: [M+H] Calcd. for
C28H26F2N306S, 570.1510.
436
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