U.S. patent application number 17/107762 was filed with the patent office on 2021-07-22 for compounds for the modulation of myc activity.
The applicant listed for this patent is Syros Pharmaceuticals, Inc.. Invention is credited to Francis Beaumier, Lauren Berstler, Stephane Ciblat, Robin Larouche-Gauther, Luce Lepissier, Jason J. Marineau, Peter B. Rahl, Christopher Roberts, Boubacar Sow, Kevin Sprott, Yi Zhang.
Application Number | 20210221820 17/107762 |
Document ID | / |
Family ID | 1000005495341 |
Filed Date | 2021-07-22 |
United States Patent
Application |
20210221820 |
Kind Code |
A1 |
Marineau; Jason J. ; et
al. |
July 22, 2021 |
COMPOUNDS FOR THE MODULATION OF MYC ACTIVITY
Abstract
The present invention provides novel compounds of Formula (I)
and pharmaceutically acceptable salts, solvates, hydrates,
tautomers, stereoisomers, isotopically labeled derivatives, and
compositions thereof. Also provided are methods and kits involving
the compounds or compositions for treating or preventing
proliferative diseases, e.g., cancers (e.g., breast cancer,
prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian
cancer, neuroblastoma, or colorectal cancer), benign neoplasms,
angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic
kidney disease), autoinflammatory diseases, and autoimmune diseases
in a subject. ##STR00001##
Inventors: |
Marineau; Jason J.;
(Franklin, MA) ; Sprott; Kevin; (Needham, MA)
; Ciblat; Stephane; (Montreal, CA) ; Roberts;
Christopher; (Belmont, MA) ; Zhang; Yi;
(Belmont, MA) ; Beaumier; Francis;
(Mont-Saint-Hilaire, CA) ; Lepissier; Luce;
(Montreal, CA) ; Sow; Boubacar; (Saint-Laurent,
CA) ; Rahl; Peter B.; (Natick, MA) ;
Larouche-Gauther; Robin; (Montreal, CA) ; Berstler;
Lauren; (Somerville, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Syros Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005495341 |
Appl. No.: |
17/107762 |
Filed: |
November 30, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15699176 |
Sep 8, 2017 |
|
|
|
17107762 |
|
|
|
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62385610 |
Sep 9, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 495/04 20130101;
A61P 35/00 20180101 |
International
Class: |
C07D 495/04 20060101
C07D495/04; A61P 35/00 20060101 A61P035/00 |
Claims
1.-24. (canceled)
25. A method of treating a patient who has a cancer associated with
deregulated activity of c-Myc, the method comprising administering
to the patient an effective amount of a compound of structural
formula I: ##STR00043## a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition comprising the compound of
structural formula I or the pharmaceutically acceptable salt
thereof, wherein: Y is S; Z is N(R.sup.5); R.sup.1 is optionally
substituted heterocyclyl or optionally substituted heteroaryl;
R.sup.2 is --C(R.sup.2a)(R.sup.2b)(R.sup.2c), wherein: R.sup.2a is
halogen, CN, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 heteroalkyl,
wherein any alkyl or heteroalkyl is optionally substituted; each of
R.sup.2b and R.sup.2c is, independently, hydrogen, halogen, --CN,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl,
C(O)(C.sub.1-C.sub.6 alkyl), C(O)(C.sub.1-C.sub.6 heteroalkyl),
C(O)O(C.sub.1-C.sub.6 alkyl), C(O)O(C.sub.1-C.sub.6 heteroalkyl),
or C(O)N(R.sup.3a)(R.sup.3b), wherein any alkyl or heteroalkyl
portion of R.sup.2b and R.sup.2c is optionally and independently
substituted; each R.sup.3 is, independently, hydrogen,
--C.sub.1-C.sub.6 alkyl, or --C.sub.1-C.sub.6 heteroalkyl, wherein
any alkyl or heteroalkyl is optionally substituted; or two R.sup.3
bound to a common nitrogen atom are optionally taken together with
the nitrogen atom to which they are commonly bound to form a 4-11
member heterocyclyl or heteroaryl; each R.sup.4 is, independently,
hydrogen, halogen, --CN, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
heteroalkyl, N(R.sup.3)(R.sup.3), C(O)(C.sub.1-C.sub.6 alkyl),
C(O)(C.sub.1-C.sub.6 heteroalkyl), C(O)O(C.sub.1-C.sub.6 alkyl),
C(O)N(R.sup.3)(R.sup.3), (C.sub.0-C.sub.6 alkylene)-carbocyclyl,
(C.sub.1-C.sub.6 heteroalkylene)-carbocyclyl, (C.sub.0-C.sub.6
alkylene)-heterocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-heterocyclyl, (C.sub.0-C.sub.6 alkylene)-aryl,
(C.sub.1-C.sub.6 heteroalkylene)-aryl, (C.sub.0-C.sub.6
alkylene)-heteroaryl, or (C.sub.1-C.sub.6
heteroalkylene)-heteroaryl, wherein any alkyl, alkylene,
heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or
heteroaryl portion of R.sup.4 is optionally and independently
substituted; R.sup.5 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 heteroalkyl, (C.sub.0-C.sub.6
alkylene)-carbocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-carbocyclyl, (C.sub.0-C.sub.6
alkylene)-heterocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-heterocyclyl, (C.sub.0-C.sub.6 alkylene)-aryl,
(C.sub.1-C.sub.6 heteroalkylene)-aryl, (C.sub.0-C.sub.6
alkylene)-heteroaryl, (C.sub.1-C.sub.6 heteroalkylene)-heteroaryl,
CH.sub.2C(O)OR.sup.8, CH.sub.2C(O)N(R.sup.10)(R.sup.9), or
CH.sub.2CH.sub.2N(R.sup.10)(R.sup.9), wherein: R.sup.8 is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl,
(C.sub.0-C.sub.3 alkylene)-carbocyclyl, or (C.sub.0-C.sub.3
alkylene)-heterocyclyl; R.sup.9 is hydrogen or C.sub.1-C.sub.4
alkyl; and R.sup.10 is hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 heteroalkyl, (C.sub.0-C.sub.4
alkylene)-carbocyclyl, (C.sub.0-C.sub.4 alkylene)-heterocyclyl,
(C.sub.0-C.sub.4 alkylene)-aryl, (C.sub.0-C.sub.4
alkylene)-heteroaryl, (C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4
alkyl), (C.sub.1-C.sub.4 alkyl)-N--(C.sub.1-C.sub.4 alkyl).sub.2,
(C.sub.1-C.sub.4 alkyl)-NH--(C.sub.1-C.sub.4 alkyl),
C(O)--(C.sub.1-C.sub.4 alkyl), or C(O)--O--(C.sub.1-C.sub.4 alkyl),
or R.sup.10 and R.sup.9 are taken together with the nitrogen atom
to which they are commonly bound to form a 4- to 11-membered
heterocyclyl or heteroaryl; n is 1; m is 1; and p is 0, 1, 2, 3, 4,
5, or 6.
26. The method of claim 25, wherein, in the compound of structural
formula I or the pharmaceutically acceptable salt thereof, R.sup.5
is hydrogen.
27. The method of claim 25, wherein, in the compound of structural
formula I or the pharmaceutically acceptable salt thereof, R.sup.1
is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
3,6-dihydro-2H-pyran-4-yl, 2-oxo-1,2-dihydropyridin-3-yl,
1,2,3,6-tetrahydropyridin-4-yl, pyrimidin-5-yl,
2-methoxypyridin-3-yl, 5-methoxypyridin-3-yl,
pyridin-3-ylaminocarbonyl, 4-methylpyridin-3-yl,
2-methylpyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl,
4-methyl-1H-imidazol-1-yl, 1-methyl-1H-pyrazol-4-yl,
5-fluoropyridin-3-yl, phenylaminocarbonyl, piperidin-1-ylcarbonyl,
4-methylpiperazin-1-ylcarbonyl, or morpholin-4-ylcarbonyl.
28. The method of claim 25, wherein, in the compound of structural
formula I or the pharmaceutically acceptable salt thereof, R.sup.2
is --(CH.sub.2).sub.2--NH--CH(CH.sub.3).sub.2,
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.2--OCH.sub.3, or
--(CH.sub.2).sub.2--NH--CH(CH.sub.3)--CH.sub.2CH.sub.3.
29. The method of claim 25, wherein, in the compound of structural
formula I or the pharmaceutically acceptable salt thereof, R.sup.3
is hydrogen and p is 0.
30. The method of claim 25, wherein the compound of structural
formula I is ##STR00044## ##STR00045## ##STR00046## ##STR00047##
##STR00048## or a pharmaceutically acceptable salt thereof.
31. The method of claim 25, wherein the pharmaceutical composition
comprises a pharmaceutically acceptable carrier.
32. The method of claim 25, wherein the compound is ##STR00049## or
a pharmaceutically acceptable salt thereof.
33. The method of claim 25, wherein, in the compound of structural
formula I or the pharmaceutically acceptable salt thereof, R.sup.1
is an unsubstituted heterocyclyl or heteroaryl; R.sup.2a is
halogen, CN, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 heteroalkyl,
wherein any alkyl or heteroalkyl is unsubstituted; each of R.sup.2b
and R.sup.2c is, independently, hydrogen, halogen, --CN,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl,
C(O)(C.sub.1-C.sub.6 alkyl), C(O)(C.sub.1-C.sub.6 heteroalkyl),
C(O)O(C.sub.1-C.sub.6 alkyl), C(O)O(C.sub.1-C.sub.6 heteroalkyl),
or C(O)N(R.sup.3a)(R.sup.3b), wherein any alkyl or heteroalkyl
portion of R.sup.2b and R.sup.2c is unsubstituted; each R.sup.3 is,
independently, hydrogen, --C.sub.1-C.sub.6 alkyl, or
--C.sub.1-C.sub.6 heteroalkyl, wherein any alkyl or heteroalkyl is
unsubstituted; and/or each R.sup.4 is, independently, hydrogen,
halogen, --CN, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 heteroalkyl,
N(R.sup.3)(R.sup.3), C(O)(C.sub.1-C.sub.6 alkyl),
C(O)(C.sub.1-C.sub.6 heteroalkyl), C(O)O(C.sub.1-C.sub.6 alkyl),
C(O)N(R.sup.3)(R.sup.3), (C.sub.0-C.sub.6 alkylene)-carbocyclyl,
(C.sub.1-C.sub.6 heteroalkylene)-carbocyclyl, (C.sub.0-C.sub.6
alkylene)-heterocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-heterocyclyl, (C.sub.0-C.sub.6 alkylene)-aryl,
(C.sub.1-C.sub.6 heteroalkylene)-aryl, (C.sub.0-C.sub.6
alkylene)-heteroaryl, or (C.sub.1-C.sub.6
heteroalkylene)-heteroaryl, wherein any alkyl, alkylene,
heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or
heteroaryl portion of R.sup.4 is unsubstituted.
34. The method of claim 25, wherein, in the compound of structural
formula I or the pharmaceutically acceptable salt thereof, R.sup.1
is an unsubstituted heterocyclyl or heteroaryl; R.sup.2a is
halogen, CN, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 heteroalkyl,
wherein any alkyl or heteroalkyl is unsubstituted; each of R.sup.2b
and R.sup.2c is, independently, hydrogen, halogen, --CN,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl,
C(O)(C.sub.1-C.sub.6 alkyl), C(O)(C.sub.1-C.sub.6 heteroalkyl),
C(O)O(C.sub.1-C.sub.6 alkyl), C(O)O(C.sub.1-C.sub.6 heteroalkyl),
or C(O)N(R.sup.3a)(R.sup.3b), wherein any alkyl or heteroalkyl
portion of R.sup.2b and R.sup.2c is unsubstituted; each R.sup.3 is,
independently, hydrogen, --C.sub.1-C.sub.6 alkyl, or
--C.sub.1-C.sub.6 heteroalkyl, wherein any alkyl or heteroalkyl is
unsubstituted; and/or each R.sup.4 is, independently, hydrogen,
halogen, --CN, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 heteroalkyl,
N(R.sup.3)(R.sup.3), C(O)(C.sub.1-C.sub.6 alkyl),
C(O)(C.sub.1-C.sub.6 heteroalkyl), C(O)O(C.sub.1-C.sub.6 alkyl),
C(O)N(R.sup.3)(R.sup.3), (C.sub.0-C.sub.6 alkylene)-carbocyclyl,
(C.sub.1-C.sub.6 heteroalkylene)-carbocyclyl, (C.sub.0-C.sub.6
alkylene)-heterocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-heterocyclyl, (C.sub.0-C.sub.6 alkylene)-aryl,
(C.sub.1-C.sub.6 heteroalkylene)-aryl, (C.sub.0-C.sub.6
alkylene)-heteroaryl, or (C.sub.1-C.sub.6
heteroalkylene)-heteroaryl, wherein any alkyl, alkylene,
heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or
heteroaryl portion of R.sup.4 is unsubstituted.
35. The method of claim 27, wherein, in the compound of structural
formula I or the pharmaceutically acceptable salt thereof, R.sup.1
is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
3,6-dihydro-2H-pyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, or
pyrimidin-5-yl.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 15/699,176, filed Sep. 8, 2017, which claims the benefit of the
filing date of U.S. Provisional Application No. 62/385,610, filed
Sep. 9, 2016, the entire content of which is hereby incorporated by
reference herein.
BACKGROUND OF THE INVENTION
[0002] The transcription factor c-Myc plays an important role in
the regulation of cell proliferation, cell growth, apoptosis, the
cell cycle, and oncogenesis. c-Myc, a basic helix-loop-helix (bHLH)
leucine zipper protein, is the most frequently occurring
oncoprotein in a wide range of cancers, including breast, lung, and
prostate cancers, where its deregulation provides growth
factor-independent growth (Tansey, W. P. New J Sci (2014) 2014:
1-27; Dang, C. V. Cell (2012) 149:22-35). Myc proteins arise from
three distinct gene families, c-myc, N-myc, and L-myc, each of
which functions in an analogous manner but exhibits differences in
expression levels and potency (Nesbit, C. E. et al, Oncogene (1999)
13:3004-3016; Tansey, W. P. New J Sci (2014) 2014:1-27; Dang, C. V.
Cell (2012) 149:22-35). c-Myc requires heterodimerization with the
small bHLH leucine zipper protein Max to bind DNA and activate gene
transcription. Interaction of c-Myc with Max occurs at all
c-Myc-bound genes in the genome and is essential for its
oncogencity (Tansey, W. P. New J Sci (2014) 2014: 1-27). Further,
Max is capable of dimerization with additional bHLH proteins that
may influence the c-Myc-Max interaction, such as Mad and Mxl1
(Tansey, W. P. New J Sci (2014) 2014: 1-27; C. Grandori et al, Ann
Rev Cell Dev Biol (2000) 16:653-699)
[0003] The myc gene is deregulated in cancer through multiple
mechanisms including gene amplification, chromosomal translocation,
deregulated upstream signaling, and protein stabilization, where
the end result is increased levels of the resulting Myc protein
(Nesbit, C. E. et al, Oncogene (1999) 13:3004-3016). Transgenic
mouse models studies have demonstrated that genetic inactivation of
myc leads to tumor regression in a range of cancer types (Jain, M.
Science (2002) 297:102-104; Felsher, D. et al, Mol Cell (1999)
4:199-207; Choi, P. S. et al, Proc Natl Acad Sci USA (2011)
108:17432-17437; Murphy, D. et al. Cancer Cell (2008) 14:447-457;
He, T. C. et al, Science (1998) 281:1509-1512). In some models,
even brief inactivation of Myc significantly improves survival
rates (Murphy, D. et al. Cancer Cell (2008) 14:447-457; Chesi, M.
et al. Cancer Cell (2008) 13:167-180; Pelengaris, S. et al, Mol
Cell (1999) 3:565-577). Additional studies have confirmed these
findings in a number of other aggressive tumor models, where the
prediction is that Myc inhibitors would have broad utility across
multiple cancer types (Hermeking, H. Curr Cancer Drug Targets
(2003) 3:163-175; Soucek, L. Nature (2008) 455:679-683;
Konstantinopoulos, P. et al, JAMA (2011) 305:2349-2350; Soucek, L.
et al, Nature (2008) 455:679-683). As such, there is a need to
identify compounds that are capable of modulating Myc activity for
use as therapeutic agents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0004] FIGS. 1A to 1H are a table of exemplary compounds of Formula
I.
SUMMARY OF THE INVENTION
[0005] The present invention provides Myc inhibitors, for example
c-Myc inhibitors, and in particular selective c-Myc inhibitors of
Formula (I), and pharmaceutically acceptable salts, solvates,
hydrates, tautomers, stereoisomers, isotopically labeled
derivatives, and compositions thereof. The present invention
further provides methods of using the compounds of the invention,
and pharmaceutically acceptable salts, solvates, hydrates,
tautomers, stereoisomers, isotopically labeled derivatives, and
compositions thereof, to study the inhibition of c-Myc or other Myc
family members (e.g., N-Myc or L-Myc), as well as the interaction
of c-Myc with DNA or Max. The present invention still further
provides methods of using the compounds of the invention, and
pharmaceutically acceptable salts, solvates, hydrates, tautomers,
stereoisomers, isotopically labeled derivatives, and compositions
thereof, as therapeutics for the prevention and/or treatment of
diseases associated with overexpression and/or aberrant activity of
c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In
certain embodiments, the inventive compounds are used for the
prevention and/or treatment of proliferative diseases (e.g.,
cancers (e.g., breast cancer, prostate cancer, lymphoma, lung
cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or
colorectal cancer), benign neoplasms, angiogenesis, inflammatory
diseases, fibrosis (e.g., polycystic kidney disease),
autoinflammatory diseases, and autoimmune diseases) in a
subject.
[0006] In one aspect, the present invention provides compounds of
Formula (I):
##STR00002##
and pharmaceutically acceptable salts, solvates, hydrates,
tautomers, stereoisomers, and isotopically labeled derivatives
thereof, wherein Y, Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, m, n, p,
and subvariables thereof are as defined herein.
[0007] In another aspect, the present invention provides
pharmaceutical compositions comprising a compound of Formula (I),
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, or isotopically labeled derivative thereof, and
optionally a pharmaceutically acceptable excipient. In certain
embodiments, the pharmaceutical compositions described herein
include a therapeutically effective amount of a compound of Formula
(I), or a pharmaceutically acceptable salt, solvate, hydrate,
tautomer, stereoisomer, or isotopically labeled derivative thereof.
The pharmaceutical composition may be useful for treating and/or
preventing a proliferative or infectious disease.
[0008] In another aspect, the present invention provides methods of
down-regulating the expression of c-Myc or other Myc family members
(e.g., N-Myc or L-Myc) in a cell. In some embodiments, the method
comprises contacting the cell with a compound of Formula (I) or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, or isotopically labeled derivative thereof, and
optionally a pharmaceutically acceptable excipient, or compositions
thereof.
[0009] In another aspect, the present invention provides methods of
inhibiting the activity of c-Myc or other Myc family members (e.g.,
N-Myc or L-Myc) in a cell. In some embodiments, the method
comprises contacting the cell with a compound of Formula (I) or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, or isotopically labeled derivative thereof, and
optionally a pharmaceutically acceptable excipient, or compositions
thereof.
[0010] In another aspect, the present invention provides methods of
reducing Myc-regulated transcription of a gene in a cell (e.g.
reducing transcription regulated by c-Myc, N-Myc, or L-Myc). In
some embodiments, the method comprises contacting the cell with a
compound of Formula (I) or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, stereoisomer, or isotopically labeled
derivative thereof, and optionally a pharmaceutically acceptable
excipient, or compositions thereof.
[0011] In another aspect, the present invention provides methods
for treating and/or preventing proliferative diseases. Exemplary
proliferative diseases include cancers (e.g., breast cancer,
prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian
cancer, neuroblastoma, or colorectal cancer), benign neoplasms,
angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic
kidney disease), autoinflammatory diseases, and autoimmune
diseases. In other embodiments, the present invention provides
methods for treating and/or preventing an infectious disease (e.g.,
a viral infection).
[0012] In another aspect, the present invention provides methods
for treating a proliferative disease (e.g., cancers (e.g., breast
cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer,
ovarian cancer, neuroblastoma, or colorectal cancer), benign
neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g.,
polycystic kidney disease), autoinflammatory diseases, and
autoimmune diseases) characterized by deregulated activity of c-Myc
or other Myc family members (e.g., N-Myc or L-Myc). In some
embodiments, the deregulated activity of c-Myc or other Myc family
members (e.g., N-Myc or L-Myc) comprises deregulation of upstream
signaling, gene amplification, or chromosomal translocation by
c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In some
embodiments, the proliferative disease is characterized by
overexpression of c-Myc or other Myc family members (e.g., N-Myc or
L-Myc). In some embodiments, the method comprises administering to
a subject a compound of Formula (I) or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, stereoisomer, or
isotopically labeled derivative thereof, and optionally a
pharmaceutically acceptable excipient, or compositions thereof.
[0013] In another aspect, the present invention provides methods
for treating a proliferative disease (e.g., cancer (e.g., breast
cancer, prostate cancer, lymphoma, or colorectal cancer), benign
neoplasm, angiogenesis, inflammatory diseases, autoinflammatory
diseases, and autoimmune diseases) characterized by deregulation of
other bHLH transcription factors, e.g., MITF, TWIST1, Max,
E2A/TCF3, and HES1. In some embodiments, the proliferative disease
is characterized by deregulation of the interaction between c-Myc
and other bHLH transcription factors, e.g., Max. In some
embodiments, the method comprises administering to a subject a
compound of Formula (I) or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, stereoisomer, or isotopically labeled
derivative thereof, and optionally a pharmaceutically acceptable
excipient, or compositions thereof.
[0014] In another aspect, the present invention provides methods
for treating a subject determined to exhibit deregulated activity
of c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In
some embodiments, the deregulated Myc activity comprises
overexpression of c-Myc or other Myc family members (e.g., N-Myc or
L-Myc). In some embodiments, the method comprises administering to
a subject a compound of Formula (I) or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, stereoisomer, or
isotopically labeled derivative thereof, and optionally a
pharmaceutically acceptable excipient, or compositions thereof.
[0015] In another aspect, the present invention provides methods of
reducing transcription of a gene upregulated in a proliferative
disease (e.g., cancers (e.g., breast cancer, prostate cancer,
lymphoma, lung cancer, pancreatic cancer, ovarian cancer,
neuroblastoma, or colorectal cancer), benign neoplasms,
angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic
kidney disease), autoinflammatory diseases, and autoimmune
diseases). In some embodiments, the method comprises administering
to a subject a compound of Formula (I) or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, stereoisomer, or
isotopically labeled derivative thereof, and optionally a
pharmaceutically acceptable excipient, or compositions thereof.
[0016] In another aspect, the present invention provides methods of
treating a proliferative disease characterized by Myc addiction
(e.g., addiction to c-Myc or other Myc family members, e.g., N-Myc
or L-Myc). In some embodiments, the method comprises administering
to a subject a compound of Formula (I) or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, stereoisomer, or
isotopically labeled derivative thereof, and optionally a
pharmaceutically acceptable excipient, or compositions thereof.
[0017] In another aspect, the present invention provides methods of
inducing apoptosis of a cell in a biological sample or a subject.
In some embodiments, the apoptosis is triggered by c-Myc or other
Myc family members (e.g., N-Myc or L-Myc). In some embodiments, the
method comprises administering to a subject a compound of Formula
(I) or a pharmaceutically acceptable salt, solvate, hydrate,
tautomer, stereoisomer, or isotopically labeled derivative thereof,
and optionally a pharmaceutically acceptable excipient, or
compositions thereof.
[0018] In another aspect, the present invention provides methods of
inducing terminal differentiation of a cell in a biological sample
or subject. In some embodiments, the terminal differentiation is
triggered by c-Myc or other Myc family members (e.g., N-Myc or
L-Myc). In some embodiments, the method comprises administering to
a subject a compound of Formula (I) or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, stereoisomer, or
isotopically labeled derivative thereof, and optionally a
pharmaceutically acceptable excipient, or compositions thereof.
[0019] In another aspect, the present invention provides methods of
inducing senescence of a cell in a biological sample or subject. In
some embodiments, the senescence is triggered by c-Myc or other Myc
family members (e.g., N-Myc or L-Myc). In some embodiments, the
method comprises administering to a subject a compound of Formula
(I) or a pharmaceutically acceptable salt, solvate, hydrate,
tautomer, stereoisomer, or isotopically labeled derivative thereof,
and optionally a pharmaceutically acceptable excipient, or
compositions thereof.
[0020] In another aspect, the present invention provides methods of
disrupting the interaction of one or more bHLH transcription
factors, e.g., Myc (e.g., c-Myc or other Myc family members (e.g.,
N-Myc or L-Myc)), MITF, TWIST1, Max, E2A/TCF3, or HES1, with DNA in
a cell. In some embodiments, a compound Formula (I) or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, or isotopically labeled derivative thereof may
disrupt the interaction of one or more bHLH transcription factors,
e.g., Myc (e.g., c-Myc or other Myc family members (e.g., N-Myc or
L-Myc)), MITF, TWIST1, Max, E2A/TCF3, or HES1, with DNA in a
cell.
[0021] In another aspect, the present invention provides methods of
disrupting the activity of a complex of bHLH transcription factors,
e.g., Myc (e.g., c-Myc or other Myc family members (e.g., N-Myc or
L-Myc)), MITF, TWIST1, Max, E2A/TCF3, or HES1, in a cell. In some
embodiments, a compound Formula (I) or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, stereoisomer, or
isotopically labeled derivative thereof may disrupt the activity of
a complex of bHLH transcription factors, e.g., Myc (e.g., c-Myc or
other Myc family members (e.g., N-Myc or L-Myc)), MITF, TWIST1,
Max, E2A/TCF3, or HES1, in a cell.
[0022] In yet another aspect, the present invention provides
compounds of Formula (I), and pharmaceutically acceptable salts,
solvates, hydrates, tautomers, stereoisomers, isotopically labeled
derivatives, and compositions thereof, for use in the treatment or
prevention of an infectious disease in a subject. In certain
embodiments, the infectious disease is a viral infection.
[0023] Another aspect of the present invention relates to kits
comprising a container with a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, or isotopically labeled derivative thereof, or a
pharmaceutical composition thereof. In certain embodiments, the
kits described herein further include instructions for
administering the compound of Formula (I), or the pharmaceutically
acceptable salt, solvate, hydrate, tautomer, stereoisomer, or
isotopically labeled derivative thereof, or the pharmaceutical
composition thereof.
[0024] The details of one or more embodiments of the invention are
set forth herein. Other features, objects, and advantages of the
invention will be apparent from the Detailed Description, the
Figures, the Examples, and the Claims.
Definitions
[0025] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge
University Press, Cambridge, 1987.
[0026] It is to be understood that compounds that have the same
molecular formula but differ in the nature or sequence of bonding
of their atoms or the arrangement of their atoms in space are
termed "isomers". Isomers that differ in the arrangement of their
atoms in space are termed "stereoisomers".
[0027] Stereoisomers that are not mirror images of one another are
termed "diastereomers" and those that are non-superimposable mirror
images of each other are termed "enantiomers". When a compound has
an asymmetric center, for example, it is bonded to four different
groups and a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0028] The term "tautomers" refer to compounds that are
interchangeable forms of a particular compound structure, and that
vary in the displacement of hydrogen atoms and electrons. Thus, two
structures may be in equilibrium through the movement of .pi.
electrons and an atom (usually H). For example, enols and ketones
are tautomers because they are rapidly interconverted by treatment
with either acid or base. Another example of tautomerism is the
aci- and nitro-forms of phenylnitromethane that are likewise formed
by treatment with acid or base.
[0029] Tautomeric forms may be relevant to the attainment of the
optimal chemical reactivity and biological activity of a compound
of interest.
[0030] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, Z
and E double bond isomers, and Z and E conformational isomers.
Therefore, single stereochemical isomers as well as enantiomeric,
diastereomeric, and geometric (or conformational) mixtures of the
present compounds are within the scope of the invention. Unless
otherwise stated, all tautomeric forms of the compounds of the
invention are within the scope of the invention. Additionally,
unless otherwise stated, structures depicted herein are also meant
to include compounds that differ only in the presence of one or
more isotopically enriched atoms. For example, compounds having the
present structures including the replacement of hydrogen by
deuterium or tritium, or the replacement of a carbon by a .sup.13C-
or .sup.14C-enriched carbon are within the scope of this invention.
Such compounds are useful, for example, as analytical tools, as
probes in biological assays, or as therapeutic agents in accordance
with the present invention.
[0031] Where a particular enantiomer is preferred, it may, in some
embodiments be provided substantially free of the corresponding
enantiomer, and may also be referred to as "optically enriched."
"Optically-enriched," as used herein, means that the compound is
made up of a significantly greater proportion of one enantiomer. In
certain embodiments the compound is made up of at least about 90%
by weight of a preferred enantiomer. In other embodiments the
compound is made up of at least about 95%, 98%, or 99% by weight of
a preferred enantiomer. Preferred enantiomers may be isolated from
racemic mixtures by any method known to those skilled in the art,
including chiral high pressure liquid chromatography (HPLC) and the
formation and crystallization of chiral salts or prepared by
asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E.
L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962);
Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p.
268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972).
[0032] The term "aliphatic" or "aliphatic group", as used herein,
denotes a hydrocarbon moiety that may be straight-chain (i.e.,
unbranched), branched, or cyclic (including fused, bridging, and
spiro-fused polycyclic) and may be completely saturated or may
contain one or more units of unsaturation, but which is not
aromatic. Unless otherwise specified, aliphatic groups contain 1-6
carbon atoms. In some embodiments, aliphatic groups contain 1-4
carbon atoms, and in yet other embodiments aliphatic groups contain
1-3 carbon atoms. Suitable aliphatic groups include, but are not
limited to, linear or branched, alkyl, alkenyl, and alkynyl groups,
and hybrids thereof such as (carbocyclyl)alkyl, (carbocyclyl)alkyl
or (carbocyclyl)alkenyl.
[0033] The term "alkyl," as used herein, refers to a monovalent
saturated, straight- or branched-chain hydrocarbon such as a
straight or branched group of 1-12, 1-10, or 1-6 carbon atoms,
referred to herein as C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.10
alkyl, and C.sub.1-C.sub.6 alkyl, respectively. Examples of alkyl
groups include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl,
tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, and the
like.
[0034] The terms "alkenyl" and "alkynyl" are art-recognized and
refer to unsaturated aliphatic groups analogous in length and
possible substitution to the alkyls described above, but that
contain at least one double or triple bond, respectively. Exemplary
alkenyl groups include, but are not limited to, --CH.dbd.CH.sub.2
and --CH.sub.2CH.dbd.CH.sub.2.
[0035] The term "alkylene" refers to the diradical of an alkyl
group.
[0036] The terms "halo" or "halogen" refer to fluorine (fluoro,
--F), chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine
(iodo, --I).
[0037] The term "haloalkyl" refers to a monovalent saturated
straight or branched alkyl chain wherein at least one carbon atom
in the chain is substituted with a halogen, e.g., F, Cl, Br, or I.
In some embodiments, a haloalkyl group may comprise, e.g., 1-12,
1-10, or 1-6 carbon atoms, referred to herein as C.sub.1-C.sub.12
haloalkyl, C.sub.1-C.sub.10 haloalkyl, and C.sub.1-C.sub.6
haloalkyl. In certain instances, a haloalkyl group comprises 1, 2,
3, or 4 independently selected halogens substituted on 1, 2, 3, or
4 individual carbon atoms in the alkyl chain. In some embodiments,
more than one halogen may be substituted on a single carbon atom.
Representative haloalkyl groups include --CH.sub.2F, --CF.sub.3,
CH.sub.2CH(C.sub.1)CH.sub.3, and the like.
[0038] The term "heteroalkyl" refers to a monovalent saturated
straight or branched alkyl chain wherein at least one carbon atom
in the chain is replaced with a heteroatom, such as O, S, or N. In
some embodiments, a heteroalkyl group may comprise, e.g., 1-12,
1-10, or 1-6 carbon atoms, referred to herein as C.sub.1-C.sub.12
heteroalkyl, C.sub.1-C.sub.10 heteroalkyl, and C.sub.1-C.sub.6
heteroalkyl. In certain instances, a heteroalkyl group comprises 1,
2, 3, or 4 independently selected heteroatoms in place of 1, 2, 3,
or 4 individual carbon atoms in the alkyl chain. Representative
heteroalkyl groups include --CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2NHCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.3, and the like.
[0039] The term "heteroalkylene" refers to the diradical of a
heteralkyl group.
[0040] The term "carbocyclic ring system", as used herein, means a
monocyclic, or fused, spiro-fused, and/or bridged bicyclic or
polycyclic hydrocarbon ring system, wherein each ring is either
completely saturated or contains one or more units of unsaturation,
but where no ring is aromatic.
[0041] The term "carbocyclyl" refers to a radical of a carbocyclic
ring system. Representative carbocyclyl groups include cycloalkyl
groups (e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and
the like), and cycloalkenyl groups (e.g., cyclopentenyl,
cyclohexenyl, cyclopentadienyl, and the like).
[0042] The term "aromatic ring system" is art-recognized and refers
to a monocyclic, bicyclic or polycyclic hydrocarbon ring system,
wherein at least one ring is aromatic.
[0043] The term "aryl" refers to a radical of an aromatic ring
system. Representative aryl groups include fully aromatic ring
systems, such as phenyl, naphthyl, and anthracenyl, and ring
systems where an aromatic carbon ring is fused to one or more
non-aromatic carbon rings, such as indanyl, phthalimidyl,
naphthimidyl, or tetrahydronaphthyl, and the like.
[0044] The term "heteroaromatic ring system" is art-recognized and
refers to monocyclic, bicyclic or polycyclic ring system wherein at
least one ring is both aromatic and comprises a heteroatom; and
wherein no other rings are heterocyclyl (as defined below). In
certain instances, a ring which is aromatic and comprises a
heteroatom contains 1, 2, 3, or 4 independently selected ring
heteroatoms in such ring.
[0045] The term "heteroaryl" refers to a radical of a
heteroaromatic ring system. Representative heteroaryl groups
include ring systems where (I) each ring comprises a heteroatom and
is aromatic, e.g., imidazolyl, oxazolyl, thiazolyl, triazolyl,
pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl,
pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and
pteridinyl; (ii) each ring is aromatic or carbocyclyl, at least one
aromatic ring comprises a heteroatom and at least one other ring is
a hydrocarbon ring or e.g., indolyl, isoindolyl, benzothienyl,
benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one,
thiazolo-[4,5-c]-pyridinyl,
4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl,
5,6-dihydro-4H-thieno[2,3-c]pyrrolyl,
4,5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl;
and (iii) each ring is aromatic or carbocyclyl, and at least one
aromatic ring shares a bridgehead heteroatom with another aromatic
ring, e.g., 4H-quinolizinyl. In certain embodiments, the heteroaryl
is a monocyclic or bicyclic ring, wherein each of said rings
contains 5 or 6 ring atoms where 1, 2, 3, or 4 of said ring atoms
are a heteroatom independently selected from N, O, and S.
[0046] The term "heterocyclic ring system" refers to monocyclic, or
fused, spiro-fused, and/or bridged bicyclic and polycyclic ring
systems where at least one ring is saturated or partially
unsaturated (but not aromatic) and comprises a heteroatom. A
heterocyclic ring system can be attached to its pendant group at
any heteroatom or carbon atom that results in a stable structure
and any of the ring atoms can be optionally substituted.
[0047] The term "heterocyclyl" refers to a radical of a
heterocyclic ring system. Representative heterocyclyls include ring
systems in which (i) every ring is non-aromatic and at least one
ring comprises a heteroatom, e.g., tetrahydrofuranyl,
tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,
pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,
dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl,
morpholinyl, and quinuclidinyl; (ii) at least one ring is
non-aromatic and comprises a heteroatom and at least one other ring
is an aromatic carbon ring, e.g., 1,2,3,4-tetrahydroquinolinyl; and
(iii) at least one ring is non-aromatic and comprises a heteroatom
and at least one other ring is aromatic and comprises a heteroatom,
e.g., 3,4-dihydro-1H-pyrano[4,3-c]pyridinyl, and
1,2,3,4-tetrahydro-2,6-naphthyridinyl. In certain embodiments, the
heterocyclyl is a monocyclic or bicyclic ring, wherein each of said
rings contains 3-7 ring atoms where 1, 2, 3, or 4 of said ring
atoms are a heteroatom independently selected from N, O, and S.
[0048] "Partially unsaturated" refers to a group that includes at
least one double or triple bond. A "partially unsaturated" ring
system is further intended to encompass rings having multiple sites
of unsaturation, but is not intended to include aromatic groups
(e.g., aryl or heteroaryl groups) as herein defined. Likewise,
"saturated" refers to a group that does not contain a double or
triple bond, i.e., contains all single bonds.
[0049] As described herein, compounds of the invention may contain
"optionally substituted" moieties. In general, the term
"substituted", whether preceded by the term "optionally" or not,
means that one or more hydrogens of the designated moiety are
replaced with a suitable substituent. Unless otherwise indicated,
an "optionally substituted" group may have a suitable substituent
at each substitutable position of the group, and when more than one
position in any given structure may be substituted with more than
one substituent selected from a specified group, the substituent
may be either the same or different at each position. Combinations
of substituents envisioned under this invention are preferably
those that result in the formation of stable or chemically feasible
compounds. The term "stable", as used herein, refers to compounds
that are not substantially altered when subjected to conditions to
allow for their production, detection, and, in certain embodiments,
their recovery, purification, and use for one or more of the
purposes disclosed herein.
[0050] Suitable substituents for an optionally substituted alkyl,
alkylene, haloalkyl, heteroalkyl, heteroalkylene, carbocyclyl,
heterocyclyl, aryl group and heteroaryl group include halogen,
.dbd.O, --CN, --OR.sup.c, --NR.sup.dR.sup.e, --S(O).sub.kR.sup.c,
--NR.sup.cS(O).sub.2R.sup.c, --S(O).sub.2NR.sup.dR.sup.e,
--C(.dbd.O)OR.sup.c, --OC(.dbd.O)OR.sup.c, --OC(.dbd.O)R.sup.c,
--OC(.dbd.S)OR.sup.c, --C(.dbd.S)OR.sup.c, --O(C.dbd.S)R.sup.c,
--C(.dbd.O)NR.sup.dR.sup.e, --NR.sup.cC(.dbd.O)R.sup.c,
--C(.dbd.S)NR.sup.dR.sup.e, --NR.sup.cC(.dbd.S)R.sup.c,
--NR.sup.c(C.dbd.O)OR.sup.c, --O(C.dbd.O)NR.sup.dR.sup.e,
--NR.sup.c(C.dbd.S)OR.sup.c, --O(C.dbd.S)NR.sup.dR.sup.e,
--NR.sup.c(C.dbd.O)NR.sup.dR.sup.e,
--NR.sup.c(C.dbd.S)NR.sup.dR.sup.e, --C(.dbd.S)R.sup.c,
--C(.dbd.O)R.sup.c, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 heteroalkyl, carbocyclyl,
(C.sub.1-C.sub.6-alkylene)-carbocyclyl,
(C.sub.1-C.sub.6-heteroalkylene)-carbocyclyl, heterocyclyl,
(C.sub.1-C.sub.6-alkylene)-heterocyclyl,
(C.sub.1-C.sub.6-heteroalkylene)-heterocyclyl, aryl,
(C.sub.1-C.sub.6-alkylene)-aryl,
(C.sub.1-C.sub.6-heteroalkylene)-aryl, heteroaryl,
(C.sub.1-C.sub.6-alkylene)-heteroaryl, or
(C.sub.1-C.sub.6-heteroalkylene)-heteroaryl, wherein each of said
alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl,
heterocyclyl, aryl and heteroaryl are optionally substituted with
one or more of halogen, --OR.sup.c, --NO.sub.2, --CN,
--NR.sup.cC(.dbd.O)R.sup.c, --NR.sup.dR.sup.e, --S(O).sub.kR.sup.c,
--C(.dbd.O)OR.sup.c, --C(.dbd.O)NR.sup.dR.sup.e,
--C(.dbd.O)R.sup.c, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 heteroalkyl, and wherein R.sup.c is
hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
heteroalkyl, carbocyclyl, (C.sub.1-C.sub.6-alkylene)-carbocyclyl,
(C.sub.1-C.sub.6-heteroalkylene)-carbocyclyl, heterocyclyl,
(C.sub.1-C.sub.6-alkylene)-heterocyclyl,
(C.sub.1-C.sub.6-heteroalkylene)-heterocyclyl, aryl,
(C.sub.1-C.sub.6-alkylene)-aryl,
(C.sub.1-C.sub.6-heteroalkylene)-aryl, heteroaryl,
(C.sub.1-C.sub.6-alkylene)-heteroaryl, or
(C.sub.1-C.sub.6-heteroalkylene)-heteroaryl, each of which is
optionally substituted with one or more of halogen, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
R.sup.d and R.sup.e are each independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 heteroalkyl; and k is 0,
1 or 2.
[0051] These and other exemplary substituents are described in more
detail in the Detailed Description, Figures, Examples, and Claims.
The invention is not intended to be limited in any manner by the
above exemplary listing of substituents.
Other Definitions
[0052] The following definitions are more general terms used
throughout the present application:
[0053] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, Berge et al., describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 1977, 66, 1-19, incorporated herein by reference.
Pharmaceutically acceptable salts of the compounds of this
invention include those derived from suitable inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic
acid addition salts are salts of an amino group formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid, and perchloric acid or with organic
acids such as acetic acid, oxalic acid, maleic acid, tartaric acid,
citric acid, succinic acid, or malonic acid or by using other
methods known in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4.sup.-
salts. Representative alkali or alkaline earth metal salts include
sodium, lithium, potassium, calcium, magnesium, and the like.
Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate,
and aryl sulfonate.
[0054] The term "solvate" refers to forms of the compound that are
associated with a solvent, usually by a solvolysis reaction. This
physical association may include hydrogen bonding. Conventional
solvents include water, methanol, ethanol, acetic acid, DMSO, THF,
diethyl ether, and the like. The compounds of Formula (I) may be
prepared, e.g., in crystalline form, and may be solvated. Suitable
solvates include pharmaceutically acceptable solvates and further
include both stoichiometric solvates and non-stoichiometric
solvates. In certain instances, the solvate will be capable of
isolation, for example, when one or more solvent molecules are
incorporated in the crystal lattice of a crystalline solid.
"Solvate" encompasses both solution-phase and isolable solvates.
Representative solvates include hydrates, ethanolates, and
methanolates.
[0055] The term "hydrate" refers to a compound which is associated
with water. Typically, the number of the water molecules contained
in a hydrate of a compound is in a definite ratio to the number of
the compound molecules in the hydrate. Therefore, a hydrate of a
compound may be represented, for example, by the general formula Rx
H.sub.2O, wherein R is the compound and wherein x is a number
greater than 0. A given compound may form more than one type of
hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x
is a number greater than 0 and smaller than 1, e.g., hemihydrates
(R0.5 H.sub.2O)), and polyhydrates (x is a number greater than 1,
e.g., dihydrates (R2 H.sub.2O) and hexahydrates (R6 H.sub.2O)).
[0056] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g., infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult,
or senior adult)) and/or other non-human animals, for example,
mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys);
commercially relevant mammals such as cattle, pigs, horses, sheep,
goats, cats, and/or dogs) and birds (e.g., commercially relevant
birds such as chickens, ducks, geese, and/or turkeys). In certain
embodiments, the animal is a mammal. The animal may be a male or
female and at any stage of development. A non-human animal may be a
transgenic animal.
[0057] The terms "administer," "administering," or
"administration," as used herein refers to implanting, absorbing,
ingesting, injecting, inhaling, or otherwise introducing an
inventive compound, or a pharmaceutical composition thereof.
[0058] As used herein, the terms "treatment," "treat," and
"treating" refer to reversing, alleviating, delaying the onset of,
or inhibiting the progress of a "pathological condition" (e.g., a
disease, disorder, or condition, or one or more signs or symptoms
thereof) described herein. In some embodiments, "treatment,"
"treat," and "treating" require that signs or symptoms of the
disease disorder or condition have developed or have been observed.
In other embodiments, treatment may be administered in the absence
of signs or symptoms of the disease or condition. For example,
treatment may be administered to a susceptible individual prior to
the onset of symptoms (e.g., in light of a history of symptoms
and/or in light of genetic or other susceptibility factors).
Treatment may also be continued after symptoms have resolved, for
example, to delay or prevent recurrence.
[0059] As used herein, the terms "condition," "disease," and
"disorder" are used interchangeably.
[0060] An "effective amount" of a compound of Formula (I) refers to
an amount sufficient to elicit the desired biological response,
i.e., treating the condition. As will be appreciated by those of
ordinary skill in this art, the effective amount of a compound of
Formula (I) may vary depending on such factors as the desired
biological endpoint, the pharmacokinetics of the compound, the
condition being treated, the mode of administration, and the age
and health of the subject. An effective amount encompasses
therapeutic and prophylactic treatment. For example, in treating
cancer, an effective amount of an inventive compound may reduce the
tumor burden or stop the growth or spread of a tumor.
[0061] A "therapeutically effective amount" of a compound of
Formula (I) is an amount sufficient to provide a therapeutic
benefit in the treatment of a condition or to delay or minimize one
or more symptoms associated with the condition. In some
embodiments, a therapeutically effective amount is an amount
sufficient to provide a therapeutic benefit in the treatment of a
condition or to minimize one or more symptoms associated with the
condition. A therapeutically effective amount of a compound means
an amount of therapeutic agent, alone or in combination with other
therapies, which provides a therapeutic benefit in the treatment of
the condition. The term "therapeutically effective amount" can
encompass an amount that improves overall therapy, reduces or
avoids symptoms or causes of the condition, or enhances the
therapeutic efficacy of another therapeutic agent.
[0062] A "prophylactically effective amount" of a compound of
Formula (I) is an amount sufficient to prevent a condition, or one
or more symptoms associated with the condition or prevent its
recurrence. A prophylactically effective amount of a compound means
an amount of a therapeutic agent, alone or in combination with
other agents, which provides a prophylactic benefit in the
prevention of the condition. The term "prophylactically effective
amount" can encompass an amount that improves overall prophylaxis
or enhances the prophylactic efficacy of another prophylactic
agent.
[0063] A "proliferative disease" refers to a disease that occurs
due to abnormal growth or extension by the multiplication of cells
(Walker, Cambridge Dictionary of Biology; Cambridge University
Press: Cambridge, UK, 1990). A proliferative disease may be
associated with: 1) the pathological proliferation of normally
quiescent cells; 2) the pathological migration of cells from their
normal location (e.g., metastasis of neoplastic cells); 3) the
pathological expression of proteolytic enzymes such as the matrix
metalloproteinases (e.g., collagenases, gelatinases, and
elastases); or 4) the pathological angiogenesis as in proliferative
retinopathy and tumor metastasis. Exemplary proliferative diseases
include cancers (i.e., "malignant neoplasms"), benign neoplasms,
angiogenesis, inflammatory diseases, autoinflammatory diseases, and
autoimmune diseases.
[0064] The terms "neoplasm" and "tumor" are used herein
interchangeably and refer to an abnormal mass of tissue wherein the
growth of the mass surpasses and is not coordinated with the growth
of a normal tissue. A neoplasm or tumor may be "benign" or
"malignant," depending on the following characteristics: degree of
cellular differentiation (including morphology and functionality),
rate of growth, local invasion, and metastasis. A "benign neoplasm"
is generally well differentiated, has characteristically slower
growth than a malignant neoplasm, and remains localized to the site
of origin. In addition, a benign neoplasm does not have the
capacity to infiltrate, invade, or metastasize to distant sites.
Exemplary benign neoplasms include, but are not limited to, lipoma,
chondroma, adenomas, acrochordon, senile angiomas, seborrheic
keratoses, lentigos, and sebaceous hyperplasias. In some cases,
certain "benign" tumors may later give rise to malignant neoplasms,
which may result from additional genetic changes in a subpopulation
of the tumor's neoplastic cells, and these tumors are referred to
as "pre-malignant neoplasms." An exemplary pre-malignant neoplasm
is a teratoma. In contrast, a "malignant neoplasm" is generally
poorly differentiated (anaplasia) and has characteristically rapid
growth accompanied by progressive infiltration, invasion, and
destruction of the surrounding tissue. Furthermore, a malignant
neoplasm generally has the capacity to metastasize to distant
sites.
[0065] As used herein, the term "cancer" refers to a malignant
neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.;
Williams & Wilkins: Philadelphia, 1990). Exemplary cancers
include, but are not limited to, acoustic neuroma; adenocarcinoma;
adrenal gland cancer; anal cancer; angiosarcoma (e.g.,
lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma);
appendix cancer; benign monoclonal gammopathy; biliary cancer
(e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g.,
adenocarcinoma of the breast, papillary carcinoma of the breast,
mammary cancer, medullary carcinoma of the breast); brain cancer
(e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma,
oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid
tumor; cervical cancer (e.g., cervical adenocarcinoma);
choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer
(e.g., colon cancer, rectal cancer, colorectal adenocarcinoma);
connective tissue cancer; epithelial carcinoma; ependymoma;
endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic
hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer,
uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the
esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer
(e.g., intraocular melanoma, retinoblastoma); familiar
hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,
stomach adenocarcinoma); gastrointestinal stromal tumor (GIST);
germ cell cancer; head and neck cancer (e.g., head and neck
squamous cell carcinoma, oral cancer (e.g., oral squamous cell
carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal
cancer, nasopharyngeal cancer, oropharyngeal cancer));
hematopoietic cancers (e.g., leukemia such as acute lymphocytic
leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic
leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic
leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic
lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));
lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL)
and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse
large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma),
follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic
lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone
B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT)
lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal
zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt
lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's
macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large
cell lymphoma, precursor B-lymphoblastic lymphoma and primary
central nervous system (CNS) lymphoma; and T-cell NHL such as
precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell
lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,
mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell
lymphoma, extranodal natural killer T-cell lymphoma, enteropathy
type T-cell lymphoma, subcutaneous panniculitis-like T-cell
lymphoma, and anaplastic large cell lymphoma); a mixture of one or
more leukemia/lymphoma as described above; and multiple myeloma
(MM)), heavy chain disease (e.g., alpha chain disease, gamma chain
disease, mu chain disease); hemangioblastoma; hypopharynx cancer;
inflammatory myofibroblastic tumors; immunocytic amyloidosis;
kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell
carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),
malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma,
small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC),
adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis
(e.g., systemic mastocytosis); muscle cancer; myelodysplastic
syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD)
(e.g., polycythemia vera (PV), essential thrombocytosis (ET),
agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),
chronic idiopathic myelofibrosis, chronic myelocytic leukemia
(CML), chronic neutrophilic leukemia (CNL), hypereosinophilic
syndrome (HES)); neuroblastoma; neurofibroma (e.g.,
neurofibromatosis (NF) type 1 or type 2, schwannomatosis);
neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine
tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone
cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian
embryonal carcinoma, ovarian adenocarcinoma); papillary
adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma,
intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors);
penile cancer (e.g., Paget's disease of the penis and scrotum);
pinealoma; primitive neuroectodermal tumor (PNT); plasma cell
neoplasia; paraneoplastic syndromes; intraepithelial neoplasms;
prostate cancer (e.g., prostate adenocarcinoma); rectal cancer;
rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g.,
squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma,
basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix
cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma
(MFH), liposarcoma, malignant peripheral nerve sheath tumor
(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous
gland carcinoma; small intestine cancer; sweat gland carcinoma;
synovioma; testicular cancer (e.g., seminoma, testicular embryonal
carcinoma); thyroid cancer (e.g., papillary carcinoma of the
thyroid, papillary thyroid carcinoma (PTC), medullary thyroid
cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g.,
Paget's disease of the vulva).
[0066] The term "angiogenesis" refers to the formation and the
growth of new blood vessels. Normal angiogenesis occurs in the
healthy body of a subject for healing wounds and for restoring
blood flow to tissues after injury. The healthy body controls
angiogenesis through a number of means, e.g.,
angiogenesis-stimulating growth factors and angiogenesis
inhibitors. Many disease states, such as cancer, diabetic
blindness, age-related macular degeneration, rheumatoid arthritis,
and psoriasis, are characterized by abnormal (i.e., increased or
excessive) angiogenesis. Abnormal angiogenesis refers to
angiogenesis greater than that in a normal body, especially
angiogenesis in an adult not related to normal angiogenesis (e.g.,
menstruation or wound healing). Abnormal angiogenesis can provide
new blood vessels that feed diseased tissues and/or destroy normal
tissues, and in the case of cancer, the new vessels can allow tumor
cells to escape into the circulation and lodge in other organs
(tumor metastases).
[0067] As used herein, an "inflammatory disease" refers to a
disease caused by, resulting from, or resulting in inflammation.
The term "inflammatory disease" may also refer to a dysregulated
inflammatory reaction that causes an exaggerated response by
macrophages, granulocytes, and/or T-lymphocytes leading to abnormal
tissue damage and/or cell death. An inflammatory disease can be
either an acute or chronic inflammatory condition and can result
from infections or non-infectious causes. Inflammatory diseases
include, without limitation, atherosclerosis, arteriosclerosis,
autoimmune disorders, multiple sclerosis, systemic lupus
erythematosus, polymyalgia rheumatica (PMR), gouty arthritis,
degenerative arthritis, tendonitis, bursitis, psoriasis, cystic
fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory
arthritis, Sjogren's syndrome, giant cell arteritis, progressive
systemic sclerosis (scleroderma), ankylosing spondylitis,
polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes
(e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis, Graves'
disease, Goodpasture's disease, mixed connective tissue disease,
sclerosing cholangitis, inflammatory bowel disease, Crohn's
disease, ulcerative colitis, pernicious anemia, inflammatory
dermatoses, usual interstitial pneumonitis (UIP), asbestosis,
silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis,
sarcoidosis, desquamative interstitial pneumonia, lymphoid
interstitial pneumonia, giant cell interstitial pneumonia, cellular
interstitial pneumonia, extrinsic allergic alveolitis, Wegener's
granulomatosis and related forms of angiitis (temporal arteritis
and polyarteritis nodosa), inflammatory dermatoses, hepatitis,
delayed-type hypersensitivity reactions (e.g., poison ivy
dermatitis), pneumonia, respiratory tract inflammation, Adult
Respiratory Distress Syndrome (ARDS), encephalitis, immediate
hypersensitivity reactions, asthma, hayfever, allergies, acute
anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,
cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic
injury), reperfusion injury, allograft rejection, host-versus-graft
rejection, appendicitis, arteritis, blepharitis, bronchiolitis,
bronchitis, cervicitis, cholangitis, chorioamnionitis,
conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis,
endometritis, enteritis, enterocolitis, epicondylitis,
epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,
gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis,
nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,
pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis,
phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,
salpingitis, sinusitis, stomatitis, synovitis, testitis,
tonsillitis, urethritis, urocystitis, uveitis, vaginitis,
vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis,
osteomyelitis, optic neuritis, temporal arteritis, transverse
myelitis, necrotizing fasciitis, and necrotizing enterocolitis.
[0068] As used herein, an "autoimmune disease" refers to a disease
arising from an inappropriate immune response of the body of a
subject against substances and tissues normally present in the
body. In other words, the immune system mistakes some part of the
body as a pathogen and attacks its own cells. This may be
restricted to certain organs (e.g., in autoimmune thyroiditis) or
involve a particular tissue in different places (e.g.,
Goodpasture's disease which may affect the basement membrane in
both the lung and kidney). The treatment of autoimmune diseases is
typically with immunosuppression, e.g., medications which decrease
the immune response. Exemplary autoimmune diseases include, but are
not limited to, glomerulonephritis, Goodpasture's syndrome,
necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa,
systemic lupus erythematosis, rheumatoid, arthritis, psoriatic
arthritis, systemic lupus erythematosis, psoriasis, ulcerative
colitis, systemic sclerosis, dermatomyositis/polymyositis,
anti-phospholipid antibody syndrome, scleroderma, pemphigus
vulgaris, ANCA-associated vasculitis (e.g., Wegener's
granulomatosis, microscopic polyangiitis), uveitis, Sjogren's
syndrome, Crohn's disease, Reiter's syndrome, ankylosing
spondylitis, Lyme arthritis, Guillain-Barre syndrome, Hashimoto's
thyroiditis, and cardiomyopathy.
[0069] The term "autoinflammatory disease" refers to a category of
diseases that are similar but different from autoimmune diseases.
Autoinflammatory and autoimmune diseases share common
characteristics in that both groups of disorders result from the
immune system attacking a subject's own tissues and result in
increased inflammation. In autoinflammatory diseases, a subject's
innate immune system causes inflammation for unknown reasons. The
innate immune system reacts even though it has never encountered
autoantibodies or antigens in the subject. Autoinflammatory
disorders are characterized by intense episodes of inflammation
that result in such symptoms as fever, rash, or joint swelling.
These diseases also carry the risk of amyloidosis, a potentially
fatal buildup of a blood protein in vital organs. Autoinflammatory
diseases include, but are not limited to, familial Mediterranean
fever (FMF), neonatal onset multisystem inflammatory disease
(NOMID), tumor necrosis factor (TNF) receptor-associated periodic
syndrome (TRAPS), deficiency of the interleukin-1 receptor
antagonist (DIRA), and Behcet's disease.
[0070] The term "biological sample" refers to any sample including
tissue samples (such as tissue sections and needle biopsies of a
tissue); cell samples (e.g., cytological smears (such as Pap or
blood smears) or samples of cells obtained by microdissection);
samples of whole organisms (such as samples of yeasts or bacteria);
or cell fractions, fragments or organelles (such as obtained by
lysing cells and separating the components thereof by
centrifugation or otherwise). Other examples of biological samples
include blood, serum, urine, semen, fecal matter, cerebrospinal
fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied
tissue (e.g., obtained by a surgical biopsy or needle biopsy),
nipple aspirates, milk, vaginal fluid, saliva, swabs (such as
buccal swabs), or any material containing biomolecules that is
derived from a first biological sample. Biological samples also
include those biological samples that are transgenic, such as
transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor
cell, or cell nucleus.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
Compounds
[0071] In one embodiment of the present invention, provided are
compounds of Formula (I):
##STR00003##
or a pharmaceutically acceptable salt solvate, hydrate, tautomer,
or stereoisomer thereof, wherein:
[0072] Y is selected from O, S and N(R.sup.3);
[0073] Z is selected from C(R.sup.4)(N(R.sup.5)(R.sup.6)) and
N(R.sup.5);
[0074] R.sup.1 is selected from halo, -Q, --C.sub.1-C.sub.4 alkyl,
--N(R.sup.3)--C(O)-Q, --N(R.sup.3)--C(O)--(C.sub.1-C.sub.4 alkyl),
--N(R.sup.3)-Q, --N(R.sup.3).sub.2, --S-Q, --S--(C.sub.1-C.sub.4
alkyl), --C(O)-Q, --C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--N(R.sup.3)-Q, --C(O)--N(R.sup.3).sub.2, --O-Q,
--O--(C.sub.1-C.sub.4 alkyl), --C(O)--O-Q and --C(O)--O--R.sup.3,
wherein:
[0075] Q is selected from a carbocyclyl, heterocyclyl, aryl or
heteroaryl, wherein Q is optionally substituted; and each alkyl in
R.sup.1 is optionally substituted;
[0076] R.sup.2 is selected from --C(R.sup.2a)(R.sup.2b)(R.sup.2c),
carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein any
carbocyclyl, aryl, heterocyclyl and heteroaryl is optionally
substituted, wherein:
[0077] R.sup.2a is selected from hydrogen, halogen, CN,
C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 heteroalkyl, wherein any
alkyl or heteroalkyl is optionally substituted;
[0078] each of R.sup.2b and R.sup.2c is independently selected from
hydrogen, halogen, --CN, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
heteroalkyl, C(O)(C.sub.1-C.sub.6 alkyl), C(O)(C.sub.1-C.sub.6
heteroalkyl), C(O)O(C.sub.1-C.sub.6 alkyl), C(O)O(C.sub.1-C.sub.6
heteroalkyl), C(O)N(R.sup.3a)(R.sup.3b), (C.sub.0-C.sub.6
alkylene)-carbocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-carbocyclyl, (C.sub.0-C.sub.6
alkylene)-heterocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-heterocyclyl, (C.sub.0-C.sub.6 alkylene)-aryl,
(C.sub.1-C.sub.6 heteroalkylene)-aryl, (C.sub.0-C.sub.6
alkylene)-heteroaryl and (C.sub.1-C.sub.6
heteroalkylene)-heteroaryl, wherein any alkyl, alkylene,
heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or
heteroaryl portion of R.sup.2b and R.sup.2c is optionally and
independently substituted;
[0079] each R.sup.3 is independently selected from hydrogen,
--C.sub.1-C.sub.6 alkyl, and --C.sub.1-C.sub.6 heteroalkyl, wherein
any alkyl or heteroalkyl is optionally substituted; or
[0080] two R.sup.3 bound to a common nitrogen atom are optionally
taken together with the nitrogen atom to which they are commonly
bound to form a 4-11 member heterocyclyl or heteroaryl;
[0081] each R.sup.4 is independently selected from hydrogen,
halogen, --CN, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 heteroalkyl,
N(R.sup.3)(R.sup.3), C(O)(C.sub.1-C.sub.6 alkyl),
C(O)(C.sub.1-C.sub.6 heteroalkyl), C(O)O(C.sub.1-C.sub.6 alkyl),
C(O)N(R.sup.3)(R.sup.3), (C.sub.0-C.sub.6 alkylene)-carbocyclyl,
(C.sub.1-C.sub.6 heteroalkylene)-carbocyclyl, (C.sub.0-C.sub.6
alkylene)-heterocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-heterocyclyl, (C.sub.0-C.sub.6 alkylene)-aryl,
(C.sub.1-C.sub.6 heteroalkylene)-aryl, (C.sub.0-C.sub.6
alkylene)-heteroaryl, and (C.sub.1-C.sub.6
heteroalkylene)-heteroaryl, wherein any alkyl, alkylene,
heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or
heteroaryl portion of R.sup.4 is optionally and independently
substituted;
[0082] R.sup.5 is selected from hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 heteroalkyl, (C.sub.0-C.sub.6
alkylene)-carbocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-carbocyclyl, (C.sub.0-C.sub.6
alkylene)-heterocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-heterocyclyl, (C.sub.0-C.sub.6 alkylene)-aryl,
(C.sub.1-C.sub.6 heteroalkylene)-aryl, (C.sub.0-C.sub.6
alkylene)-heteroaryl, (C.sub.1-C.sub.6 heteroalkylene)-heteroaryl,
CH.sub.2C(O)OR.sup.8, CH.sub.2C(O)N(R.sup.10)(R.sup.9), and
CH.sub.2CH.sub.2N(R.sup.10)(R.sup.9), wherein:
[0083] R.sup.8 is selected from hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 heteroalkyl, (C.sub.0-C.sub.3
alkylene)-carbocyclyl, and (C.sub.0-C.sub.3
alkylene)-heterocyclyl;
[0084] R.sup.9 is hydrogen or C.sub.1-C.sub.4 alkyl; and
[0085] R.sup.10 is selected from hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 heteroalkyl, (C.sub.0-C.sub.4
alkylene)-carbocyclyl, (C.sub.0-C.sub.4 alkylene)-heterocyclyl,
(C.sub.0-C.sub.4 alkylene)-aryl, (C.sub.0-C.sub.4
alkylene)-heteroaryl, (C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4
alkyl), (C.sub.1-C.sub.4 alkyl)-N--(C.sub.1-C.sub.4 alkyl).sub.2,
(C.sub.1-C.sub.4 alkyl)-NH--(C.sub.1-C.sub.4 alkyl),
C(O)--(C.sub.1-C.sub.4 alkyl), and C(O)--O--(C.sub.1-C.sub.4
alkyl), or
[0086] R.sup.10 and R.sup.9 are taken together with the nitrogen
atom to which they are commonly bound to form a 4-11 membered
heterocyclyl or heteroaryl;
[0087] each of R.sup.6 and R.sup.7 is independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl,
C(O)(C.sub.1-C.sub.6 alkyl), C(O)O(C.sub.1-C.sub.6 alkyl),
(C.sub.0-C.sub.6 alkylene)-carbocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-carbocyclyl, (C.sub.0-C.sub.6
alkylene)-heterocyclyl, (C.sub.1-C.sub.6
heteroalkylene)-heterocyclyl, (C.sub.0-C.sub.6 alkylene)-aryl,
(C.sub.1-C.sub.6 heteroalkylene)-aryl, (C.sub.0-C.sub.6 alkylene)
heteroaryl, and (C.sub.1-C.sub.6 heteroalkylene)-heteroaryl,
wherein any alkyl, alkylene, heteroalkyl, heteroalkylene,
carbocyclyl, heterocyclyl, aryl or heteroaryl portion of each of
R.sup.5 and R.sup.6 is optionally and independently substituted;
or
[0088] R.sup.6 and R.sup.7 are taken together with the nitrogen
atom to which they are bound to form an optionally substituted
heterocyclyl;
[0089] n is 0, 1 or 2;
[0090] m is 0, 1 or 2;
[0091] n+m=1, 2 or 3; and
[0092] p is 0, 1, 2, 3, 4, 5, or 6; and
[0093] wherein the compound is other than
##STR00004##
[0094] In certain embodiments, Y is S.
[0095] In certain embodiments, Z is N(R.sup.5). In certain
embodiments, Z is N(R.sup.5), and R.sup.5 is hydrogen.
[0096] In certain embodiments, Y is S and Z is N(R.sup.5). In
certain embodiments, Y is S, Z is N(R.sup.5), and R.sup.5 is
hydrogen.
[0097] In certain embodiments, R.sup.1 is selected from halo, -Q,
--N(R.sup.3)--C(O)--(C.sub.1-C.sub.4 alkyl), --N(R.sup.3)-Q,
--N(R.sup.3).sub.2, --C(O)-Q, --C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--N(R.sup.3)-Q, --C(O)--N(R.sup.3).sub.2, --O-Q,
--O--(C.sub.1-C.sub.4 alkyl), and --C(O)--O--R.sup.3.
[0098] In certain embodiments, R.sup.1 is selected from halo, -Q,
--N(R.sup.3)--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkyl), --C(O)--N(R.sup.3)-Q,
--C(O)--N(R.sup.3).sub.2, and --C(O)--O--R.sup.3.
[0099] In certain embodiments, R.sup.1 is selected from bromo,
--NH--C(O)--CH.sub.3, --C(O)N(CH.sub.3).sub.2, --C(O)NH,
--(CH.sub.2).sub.2--OCH.sub.3, --C(O)--OCH.sub.3,
--C(O)--NH--CH.sub.2CH.sub.2 (O)(CH.sub.3),
--C(O)--NH--CH(CH.sub.3).sub.2, --C(O)OH, phenyl, pyridin-2-yl,
pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl,
2-oxo-1,2-dihydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl,
pyrimidin-5-yl, 2-methoxypyridin-3-yl, 5-methoxypyridin-3-yl,
pyridin-3-ylaminocarbonyl, 4-methylpyridin-3-yl,
2-methylpyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl,
4-methyl-1H-imidazol-1-yl, 1-methyl-1H-pyrazol-4-yl,
5-fluoropyridin-3-yl, phenylaminocarbonyl, piperidin-1-ylcarbonyl,
4-methylpiperazin-1-ylcarbonyl, and morpholin-4-ylcarbonyl.
[0100] In certain embodiments, R.sup.1 is halo. In certain
embodiments, R.sup.1 is -Q. In certain embodiments, R.sup.1 is
--N(R.sup.3)--C(O)--(C.sub.1-C.sub.4 alkyl). In certain
embodiments, R.sup.1 is --C(O)--(C.sub.1-C.sub.4 alkyl). In certain
embodiments, R.sup.1 is --C(O)--N(R.sup.3)-Q. In certain
embodiments, R.sup.1 is --C(O)--N(R.sup.3).sub.2. In certain
embodiments, R.sup.1 is --C(O)--O--R.sup.3.
[0101] In certain embodiments, Q is selected from heterocyclyl,
aryl, and heteroaryl, each of which is optionally substituted. In
certain embodiments, Q is a 6-membered ring. In certain
embodiments, Q is selected from phenyl, oxygen-containing
heterocyclyl, and a nitrogen-containing heterocyclyl or heteroaryl,
each of which is optionally substituted. In certain embodiments, Q
is a 6-membered nitrogen-containing ring. In certain embodiments, Q
is pyridinyl, pyrimidinyl, pyridinonyl, or tetrahydropyridinyl,
each of which is optionally substituted. In certain embodiments, Q
is a 6-membered oxygen-containing ring. In some embodiments, Q is
dihydropyranyl, which is optionally substituted.
[0102] In certain embodiments, Q is a 5-membered ring. In certain
embodiments, Q is a nitrogen-containing 5-membered ring. In certain
embodiments, Q is selected from imidazolyl or pyrazolyl, each of
which is optionally substituted.
[0103] In certain embodiments, R.sup.2 is
--C(R.sup.2a)(R.sup.2b)(R.sup.2c). In certain embodiments, R.sup.2
is --C(R.sup.2a)(R.sup.2b)(R.sup.2c), R.sub.2a and R.sup.2b are
simultaneously hydrogen; and R.sup.2c is selected from hydrogen,
optionally substituted C.sub.1-C.sub.6 alkyl, and optionally
substituted C.sub.1-C.sub.6 heteroalkyl.
[0104] In certain embodiments, R.sup.2 is selected from --CH.sub.3,
--(CH.sub.2).sub.2--NH--CH(CH.sub.3).sub.2,
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.2--OCH.sub.3, and
--(CH.sub.2).sub.2--NH--CH(CH.sub.3)--CH.sub.2CH.sub.3.
[0105] In certain embodiments, R.sup.2 is
--C(R.sup.2a)(R.sup.2b)(R.sup.2c), wherein R.sup.2a and R.sup.2b
are simultaneously hydrogen; and R.sup.2c is selected from
optionally substituted C.sub.1-C.sub.6 alkyl and optionally
substituted C.sub.1-C.sub.6 heteroalkyl. In certain embodiments,
R.sup.2 is not CH.sub.3.
[0106] In certain embodiments, R.sup.3 is hydrogen, C.sub.1-C.sub.6
alkyl, or C.sub.1-C.sub.6 heteroalkyl. In certain embodiments,
R.sup.3 is hydrogen. In certain embodiments, R.sup.3 is hydrogen,
methyl, isopropyl, CH.sub.2CH.sub.2OCH.sub.3.
[0107] In certain embodiments, two R.sup.3 bound to a common
nitrogen atom are optionally taken together with the nitrogen atom
to which they are commonly bound to form a 4-11 member heterocyclyl
or heteroaryl. In certain embodiments, two R.sup.3 are taken
together with the nitrogen atom to which they are commonly bound to
form a morphilinyl, piperidinyl, piperazinyl ring, each of which is
optionally substituted.
[0108] In certain embodiments, p is 0. In certain embodiments, n is
1. In certain embodiments, m is 0. In certain embodiments, n is 1
and m is 1. In certain embodiments, p is 0, n is 1, and m is 1.
[0109] In certain embodiments, the compound of Formula (I) is
selected from the group consisting of any one of the compounds in
the tables in FIGS. 1A to 1H and pharmaceutically acceptable salts,
solvates, hydrates, tautomers, stereoisomers, and isotopically
labeled derivatives thereof.
[0110] In certain embodiments, the compound of Formula (I) is
selected from the group consisting of any one of the compounds in
the table in FIGS. 1A to 1H and pharmaceutically acceptable salts,
solvates, hydrates, tautomers, stereoisomers, and isotopically
labeled derivatives thereof.
Pharmaceutical Compositions, Kits, and Administration
[0111] The present invention provides pharmaceutical compositions
comprising a compound of Formula (I) or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, stereoisomer, or
isotopically labeled derivative thereof, as described herein, and
optionally a pharmaceutically acceptable excipient. In certain
embodiments, the pharmaceutical composition of the invention
comprises a compound Formula (I) or a pharmaceutically acceptable
salt thereof, and optionally a pharmaceutically acceptable
excipient. In certain embodiments, the compound of Formula (I) or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, or isotopically labeled derivative thereof, is
provided in an effective amount in the pharmaceutical composition.
In certain embodiments, the effective amount is a therapeutically
effective amount. In certain embodiments, the effective amount is a
prophylactically effective amount.
[0112] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include the steps of bringing the compound of
Formula (I) (the "active ingredient") into association with a
carrier and/or one or more other accessory ingredients, and then,
if necessary and/or desirable, shaping and/or packaging the product
into a desired single- or multi-dose unit.
[0113] Pharmaceutical compositions can be prepared, packaged,
and/or sold in bulk, as a single unit dose, and/or as a plurality
of single unit doses. As used herein, a "unit dose" is a discrete
amount of the pharmaceutical composition comprising a predetermined
amount of the active ingredient. The amount of the active
ingredient is generally equal to the dosage of the active
ingredient which would be administered to a subject and/or a
convenient fraction of such a dosage such as, for example, one-half
or one-third of such a dosage.
[0114] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition of the invention will
vary, depending upon the identity, size, and/or condition of the
subject treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between about 0.1% and about 100% (w/w)
active ingredient.
[0115] The term "pharmaceutically acceptable excipient" refers to a
non-toxic carrier, adjuvant, diluent, or vehicle that does not
destroy the pharmacological activity of the compound with which it
is formulated. Pharmaceutically acceptable excipients useful in the
manufacture of the pharmaceutical compositions of the invention are
any of those that are well known in the art of pharmaceutical
formulation and include inert diluents, dispersing and/or
granulating agents, surface active agents and/or emulsifiers,
disintegrating agents, binding agents, preservatives, buffering
agents, lubricating agents, and/or oils. Pharmaceutically
acceptable excipients useful in the manufacture of the
pharmaceutical compositions of the invention 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 protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, cellulose-based substances, polyethylene glycol,
sodium carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, polyethylene glycol
and wool fat.
[0116] Compositions of the present invention may be administered
orally, parenterally (including subcutaneous, intramuscular,
intravenous and intradermal), by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. In some embodiments, provided compounds or compositions
are administrable intravenously and/or orally.
[0117] The term "parenteral" as used herein includes subcutaneous,
intravenous, intramuscular, intraocular, intravitreal,
intra-articular, intra-synovial, intrasternal, intrathecal,
intrahepatic, intraperitoneal intralesional and intracranial
injection or infusion techniques. Preferably, the compositions are
administered orally, subcutaneously, intraperitoneally or
intravenously. Sterile injectable forms of the compositions of this
invention 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.
[0118] Pharmaceutically acceptable compositions of this invention
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 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 cornstarch. 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. In some embodiments, a provided
oral formulation is formulated for immediate release or
sustained/delayed release. In some embodiments, the composition is
suitable for buccal or sublingual administration, including
tablets, lozenges and pastilles. A provided compound can also be in
micro-encapsulated form.
[0119] Alternatively, pharmaceutically acceptable compositions of
this invention may be administered in the form of suppositories for
rectal administration. Pharmaceutically acceptable compositions of
this invention may also be administered topically, especially when
the target of treatment includes areas or organs readily accessible
by topical application, including diseases of the eye, the skin, or
the lower intestinal tract. Suitable topical formulations are
readily prepared for each of these areas or organs.
[0120] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0121] For ophthalmic use, provided pharmaceutically acceptable
compositions may be formulated as micronized suspensions or in an
ointment such as petrolatum.
[0122] Pharmaceutically acceptable compositions of this invention
may also be administered by nasal aerosol or inhalation.
[0123] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This can be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0124] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for administration to humans, it
will be understood by the skilled artisan that such compositions
are generally suitable for administration to animals of all sorts.
Modification of pharmaceutical compositions suitable for
administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design
and/or perform such modification with ordinary experimentation.
[0125] Compounds provided herein are typically formulated in dosage
unit form, e.g., single unit dosage form, for ease of
administration and uniformity of dosage. It will be understood,
however, that the total daily usage of the compositions of the
present invention will be decided by the attending physician within
the scope of sound medical judgment. The specific therapeutically
effective dose level for any particular subject or organism will
depend upon a variety of factors including the disease being
treated and the severity of the disorder; the activity of the
specific active ingredient employed; the specific composition
employed; the age, body weight, general health, sex and diet of the
subject; the time of administration, route of administration, and
rate of excretion of the specific active ingredient employed; the
duration of the treatment; drugs used in combination or
coincidental with the specific active ingredient employed; and like
factors well known in the medical arts.
[0126] The exact amount of a compound required to achieve an
effective amount will vary from subject to subject, depending, for
example, on species, age, and general condition of a subject,
severity of the side effects or disorder, identity of the
particular compound(s), mode of administration, and the like. The
desired dosage can be delivered three times a day, two times a day,
once a day, every other day, every third day, every week, every two
weeks, every three weeks, or every four weeks. In certain
embodiments, the desired dosage can be delivered using multiple
administrations (e.g., two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, or more
administrations).
[0127] In certain embodiments, an effective amount of a compound
for administration one or more times a day to a 70 kg adult human
may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to
about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to
about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to
about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100
mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg,
of a compound per unit dosage form.
[0128] In certain embodiments, the compounds of Formula (I) may be
at dosage levels sufficient to deliver from about 0.001 mg/kg to
about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg,
preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from
about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about
10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more
preferably from about 1 mg/kg to about 25 mg/kg, of subject body
weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0129] It will be appreciated that dose ranges as described herein
provide guidance for the administration of provided pharmaceutical
compositions to an adult. The amount to be administered to, for
example, a child or an adolescent can be determined by a medical
practitioner or person skilled in the art and can be lower or the
same as that administered to an adult.
[0130] It will be also appreciated that a compound or composition,
as described herein, can be administered in combination with one or
more additional pharmaceutical agents. The compounds or
compositions can be administered in combination with additional
pharmaceutical agents that improve their bioavailability, reduce
and/or modify their metabolism, inhibit their excretion, and/or
modify their distribution within the body. It will also be
appreciated that the therapy employed may achieve a desired effect
for the same disorder, and/or it may achieve different effects.
[0131] The compound or composition can be administered concurrently
with, prior to, or subsequent to, one or more additional
pharmaceutical agents, which may be useful as, e.g., combination
therapies. Pharmaceutical agents include therapeutically active
agents. Pharmaceutical agents also include prophylactically active
agents. Each additional pharmaceutical agent may be administered at
a dose and/or on a time schedule determined for that pharmaceutical
agent. The additional pharmaceutical agents may also be
administered together with each other and/or with the compound or
composition described herein in a single dose or administered
separately in different doses. The particular combination to employ
in a regimen will take into account compatibility of the inventive
compound with the additional pharmaceutical agents and/or the
desired therapeutic and/or prophylactic effect to be achieved. In
general, it is expected that the additional pharmaceutical agents
utilized in combination be utilized at levels that do not exceed
the levels at which they are utilized individually. In some
embodiments, the levels utilized in combination will be lower than
those utilized individually.
[0132] Exemplary additional pharmaceutical agents include, but are
not limited to, anti-proliferative agents, anti-cancer agents,
anti-diabetic agents, anti-inflammatory agents, immunosuppressant
agents, and a pain-relieving agent Pharmaceutical agents include
small organic molecules such as drug compounds (e.g., compounds
approved by the U.S. Food and Drug Administration as provided in
the Code of Federal Regulations (CFR)), peptides, proteins,
carbohydrates, monosaccharides, oligosaccharides, polysaccharides,
nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides
or proteins, small molecules linked to proteins, glycoproteins,
steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides,
oligonucleotides, antisense oligonucleotides, lipids, hormones,
vitamins, and cells.
[0133] Also encompassed by the invention are kits (e.g.,
pharmaceutical packs). The inventive kits may be useful for
preventing and/or treating a proliferative disease (e.g., cancer
(e.g., leukemia, melanoma, multiple myeloma), benign neoplasm,
angiogenesis, inflammatory disease, autoinflammatory disease, or
autoimmune disease). The kits provided may comprise an inventive
pharmaceutical composition or compound and a container (e.g., a
vial, ampule, bottle, syringe, and/or dispenser package, or other
suitable container). In some embodiments, provided kits may
optionally further include a second container comprising a
pharmaceutical excipient for dilution or suspension of an inventive
pharmaceutical composition or compound. In some embodiments, the
inventive pharmaceutical composition or compound provided in the
container and the second container are combined to form one unit
dosage form.
[0134] Thus, in one aspect, provided are kits including a first
container comprising a compound described herein, or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, and isotopically labeled derivative, or a
pharmaceutical composition thereof. In certain embodiments, the kit
of the invention includes a first container comprising a compound
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition thereof. In certain embodiments, the
kits are useful in preventing and/or treating a proliferative
disease in a subject. In certain embodiments, the kits further
include instructions for administering the compound, or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
stereoisomer, isotopically and labeled derivative thereof, or a
pharmaceutical composition thereof, to a subject to prevent and/or
treat a proliferative disease.
Methods of Treatment and Uses
[0135] The present invention also provides methods for the
treatment or prevention of a proliferative disease (e.g., cancer,
benign neoplasm, angiogenesis, inflammatory disease,
autoinflammatory disease, or autoimmune disease) or an infectious
disease (e.g., a viral disease) in a subject. Such methods comprise
the step of administering to the subject in need thereof an
effective amount of a compound of Formula (I) or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, stereoisomer, or
isotopically labeled derivative thereof, or a pharmaceutical
composition thereof. In certain embodiments, the methods described
herein include administering to a subject an effective amount of a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition thereof.
[0136] In certain embodiments, the subject being treated is a
mammal. In certain embodiments, the subject is a human. In certain
embodiments, the subject is a domesticated animal, such as a dog,
cat, cow, pig, horse, sheep, or goat. In certain embodiments, the
subject is a companion animal such as a dog or cat. In certain
embodiments, the subject is a livestock animal such as a cow, pig,
horse, sheep, or goat. In certain embodiments, the subject is a zoo
animal. In another embodiment, the subject is a research animal
such as a rodent, dog, or non-human primate. In certain
embodiments, the subject is a non-human transgenic animal such as a
transgenic mouse or transgenic pig.
[0137] The proliferative disease to be treated or prevented using
the compounds of Formula (I) will typically be associated with
deregulated activity of c-Myc. Deregulated activity of c-Myc may
constitute an elevated and/or an inappropriate (e.g., abnormal)
activity of c-Myc. In certain embodiments, c-Myc is not
overexpressed, and the activity of c-Myc is elevated and/or
inappropriate. In certain other embodiments, c-Myc is
overexpressed, and the activity of c-Myc is elevated and/or
inappropriate. The compounds Formula (I) and pharmaceutically
acceptable salts, solvates, hydrates, tautomers, stereoisomers,
isotopically labeled derivatives, and compositions thereof, may
inhibit the activity of c-Myc and be useful in treating and/or
preventing proliferative diseases.
[0138] In other embodiments, the proliferative disease to be
treated or prevented using the compounds of Formula (I) may be
associated with deregulated activity a Myc family member, e.g.,
N-Myc or L-Myc. Deregulated activity of a Myc family member (e.g.,
N-Myc or L-Myc) may constitute an elevated and/or an inappropriate
(e.g., abnormal) activity of one or more Myc family members (e.g.,
N-Myc or L-Myc). In certain embodiments, a Myc family member (e.g.,
N-Myc or L-Myc) is not overexpressed, and the activity of said Myc
family member (e.g., N-Myc or L-Myc) is elevated and/or
inappropriate. In certain other embodiments, a Myc family member
(e.g., N-Myc or L-Myc) is overexpressed, and the activity of said
Myc family member (e.g., N-Myc or L-Myc) is elevated and/or
inappropriate. The compounds of Formula (I) and pharmaceutically
acceptable salts, solvates, hydrates, tautomers, stereoisomers,
isotopically labeled derivatives, and compositions thereof, may
inhibit the activity of a Myc family members (e.g., N-Myc or L-Myc)
and be useful in treating and/or preventing proliferative
diseases.
[0139] A proliferative disease may also be associated with
inhibition of apoptosis of a cell in a biological sample or
subject. All types of biological samples described herein or known
in the art are contemplated as being within the scope of the
invention. Inhibition of the activity of c-Myc or other Myc family
member (e.g., N-Myc or L-Myc) may cause cytotoxicity via induction
of apoptosis. The compounds of Formula (I) and pharmaceutically
acceptable salts, solvates, hydrates, tautomers, stereoisomers,
isotopically labeled derivatives, and compositions thereof, may
induce apoptosis, and therefore, may be useful in treating and/or
preventing proliferative diseases.
[0140] In certain embodiments, the proliferative disease to be
treated or prevented using the compounds of Formula (I) is cancer.
All types of cancers disclosed herein or known in the art are
contemplated as being within the scope of the invention. In certain
embodiments, the proliferative disease is a cancer associated with
dependence on BCL-2 anti-apoptotic proteins (e.g., MCL-1 and/or
XIAP). In certain embodiments, the proliferative disease is a
cancer associated with overexpression of Myc. In certain
embodiments, the proliferative disease is a hematological
malignancy. In certain embodiments, the proliferative disease is a
blood cancer. In certain embodiments, the proliferative disease is
leukemia. In certain embodiments, the proliferative disease is
chronic lymphocytic leukemia (CLL). In certain embodiments, the
proliferative disease is acute lymphoblastic leukemia (ALL). In
certain embodiments, the proliferative disease is T-cell acute
lymphoblastic leukemia (T-ALL). In certain embodiments, the
proliferative disease is chronic myelogenous leukemia (CIVIL). In
certain embodiments, the proliferative disease is acute myelogenous
leukemia (AML). In certain embodiments, the proliferative disease
is lymphoma. In certain embodiments, the proliferative disease is
melanoma. In certain embodiments, the proliferative disease is
multiple myeloma. In certain embodiments, the proliferative disease
is a bone cancer. In certain embodiments, the proliferative disease
is osteosarcoma. In some embodiments, the proliferative disease is
Ewing's sarcoma. In some embodiments, the proliferative disease is
triple-negative breast cancer (TNBC). In some embodiments, the
proliferative disease is a brain cancer. In some embodiments, the
proliferative disease is neuroblastoma. In some embodiments, the
proliferative disease is a lung cancer. In some embodiments, the
proliferative disease is small cell lung cancer (SCLC). In some
embodiments, the proliferative disease is large cell lung cancer.
In some embodiments, the proliferative disease is a benign
neoplasm. All types of benign neoplasms disclosed herein or known
in the art are contemplated as being within the scope of the
invention.
[0141] In some embodiments, the proliferative disease is associated
with angiogenesis. All types of angiogenesis disclosed herein or
known in the art are contemplated as being within the scope of the
invention.
[0142] In certain embodiments, the proliferative disease is an
inflammatory disease. All types of inflammatory diseases disclosed
herein or known in the art are contemplated as being within the
scope of the invention. In certain embodiments, the inflammatory
disease is rheumatoid arthritis. In some embodiments, the
proliferative disease is an autoinflammatory disease. All types of
autoinflammatory diseases disclosed herein or known in the art are
contemplated as being within the scope of the invention. In some
embodiments, the proliferative disease is an autoimmune disease.
All types of autoimmune diseases disclosed herein or known in the
art are contemplated as being within the scope of the
invention.
[0143] The cell described herein may be an abnormal cell. The cell
may be in vitro or in vivo. In certain embodiments, the cell is a
proliferative cell. In certain embodiments, the cell is a blood
cell. In certain embodiments, the cell is a lymphocyte. In certain
embodiments, the cell is a cancer cell. In certain embodiments, the
cell is a leukemia cell. In certain embodiments, the cell is a CLL
cell. In certain embodiments, the cell is a melanoma cell. In
certain embodiments, the cell is a multiple myeloma cell. In
certain embodiments, the cell is a benign neoplastic cell. In
certain embodiments, the cell is an endothelial cell. In certain
embodiments, the cell is an immune cell.
[0144] In another aspect, the present invention provides methods of
down-regulating the expression of c-Myc or other Myc family member
(e.g., N-Myc or L-Myc) in a biological sample or subject. In
certain embodiments, the present invention provides methods of
down-regulating the expression of c-Myc in a biological sample or
subject. In another aspect, the present invention provides methods
of down-regulating the expression of other bHLH transcription
factors, such as MITF, TWIST1, and Max, in a biological sample or
subject.
[0145] In certain embodiments, the methods described herein
comprise the additional step of administering one or more
additional pharmaceutical agents in combination with the compounds
of Formula (I) a pharmaceutically acceptable salt thereof, or
compositions comprising such compound or pharmaceutically
acceptable salt thereof. Such additional pharmaceutical agents
include, but are not limited to, anti-proliferative agents,
anti-cancer agents, anti-diabetic agents, anti-inflammatory agents,
immunosuppressant agents, and a pain-relieving agent. The
additional pharmaceutical agent(s) may synergistically augment
inhibition of c-Myc or other Myc family member (e.g., N-Myc or
L-Myc) induced by the inventive compounds or compositions of this
invention in the biological sample or subject. In certain
embodiments, the additional pharmaceutical agent is flavopiridol,
triptolide, SNS-032 (BMS-387032), PHA-767491, PHA-793887, BS-181,
(S)-CR8, (R)-CR8, ABT-737, or NU6140. In certain embodiments, the
additional pharmaceutical agent is an inhibitor of a
mitogen-activated protein kinase (MAPK). In certain embodiments,
the additional pharmaceutical agent is an inhibitor of a Bcl-2
protein. In certain embodiments, the additional pharmaceutical
agent is an inhibitor of a glycogen synthase kinase 3 (GSK3). In
certain embodiments, the additional pharmaceutical agent is an
inhibitor of an AGC kinase. In certain embodiments, the additional
pharmaceutical agent is an inhibitor of a CaM kinase. In certain
embodiments, the additional pharmaceutical agent is an inhibitor of
a casein kinase 1. In certain embodiments, the additional
pharmaceutical agent is an inhibitor of a STE kinase. In certain
embodiments, the additional pharmaceutical agent is an inhibitor of
a tyrosine kinase. Thus, the combination of the inventive compounds
or compositions and the additional pharmaceutical agent(s) may be
useful in treating proliferative diseases resistant to a treatment
using the additional pharmaceutical agent(s) without the inventive
compounds or compositions.
[0146] In yet another aspect, the present invention provides the
compounds of compounds of Formula (I) and pharmaceutically
acceptable salts, solvates, hydrates, tautomers, stereoisomers,
isotopically labeled derivatives, and compositions thereof, for use
in the treatment of a proliferative disease in a subject. In
certain embodiments, provided by the invention are the compounds
described herein, and pharmaceutically acceptable salts and
compositions thereof, for use in the treatment of a proliferative
disease in a subject. In certain embodiments, provided by the
invention are the compounds described herein, and pharmaceutically
acceptable salts and compositions thereof, for use in inhibiting
cell growth. In certain embodiments, provided by the invention are
the compounds described herein, and pharmaceutically acceptable
salts and compositions thereof, for use in inducing apoptosis in a
cell. In certain embodiments, provided by the invention are the
compounds described herein, and pharmaceutically acceptable salts
and compositions thereof, for use in inhibiting transcription.
EXAMPLES
[0147] In order that the invention described herein may be more
fully understood, the following examples are set forth. The
synthetic and biological examples described in this application are
offered to illustrate the compounds, pharmaceutical compositions,
and methods provided herein and are not to be construed in any way
as limiting their scope.
[0148] The compounds provided herein can be prepared from readily
available starting materials using modifications to the specific
synthesis protocols set forth below that would be well known to
those of skill in the art. It will be appreciated that where
typical or preferred process conditions (i.e., reaction
temperatures, times, mole ratios of reactants, solvents, pressures,
etc.) are given, other process conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvents used, but such conditions can be
determined by those skilled in the art by routine optimization
procedures.
[0149] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in Greene et al., Protecting Groups in Organic Synthesis,
Second Edition, Wiley, New York, 1991, and references cited
therein.
TABLE-US-00001 TABLE 1 Abbreviations Ac acetyl Ac.sub.2O acetic
anyhydride AcOH acetic acid ACN acetonitrile aq. aqueous atm
atmospheres Boc tert-butoxy carbonyl Boc.sub.2O di-t-butyl
dicarbonate Bn benzyl DCM bichloromethane DIPEA N,N-diisopropyl
ethylamine DMF dmethylformamide DMSO dimethylsulfoxide DPPA
diphenoxyphosphoryl azide EDTA ethylenediamine tetraacetic acid
eq(s). equivalent(s) EtOAc ethyl acetate Et ethyl EtOH ethanol
Et.sub.3N, TEA triethylamine g gram(s) h hour(s) Hex hexanes HOBt
1-Hydroxybenzotriazole HPLC high pressure liquid chromatography IPA
isopropanol LCMS; liquid chromatography mass LC-MS spectrometry
MeOH methanol mg milligram(s) MHz megahertz min minute(s) mL; ml
milliliter(s) MS mass spectrometry NMe N-methyl NMR nuclear
magnetic resonance Ph phenyl pyr pyridine r.t.; rt; RT room
temperature S., sat. saturated T.sub.3P propylphosphonic anydride
TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer
chromatography
Example 1. Synthesis of
N-(3-(4-phenylthiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)a-
cetamide (Compound 100)
##STR00005##
[0150] Step 1: 2-(4-phenylthiazol-2-yl)acetonitrile
##STR00006##
[0152] To a stirred solution of 2-cyanoethanethioamide (500 mg,
5.00 mmol) in DMF (3 mL) was added drop wise a solution of
2-bromo-1-phenylethan-1-one (1 g, 5.00 mmol) in DMF (3 mL) at room
temperature, and the reaction was stirred for another 50 min. The
resulting solution was heated at 70.degree. C. for 45 min, and the
reaction was monitored by TLC. After the completion, the reaction
mixture was diluted with EtOAc, washed with water, dried over
anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate obtained was
concentrated under reduced pressure to get a crude residue which
was purified by silica-gel column chromatography eluting with 0-7%
ethyl acetate in n-hexane to afford 1 g of the desired compound.
LCMS: [M+H].sup.+=200.95. .sup.1H NMR (CDCl.sub.3, 400 MHz):
.delta. 7.88 (d, J=7.48 Hz, 2H), 7.48 (s, 1H), 7.41-7.47 (m, 2H),
7.37 (d, J=7.48 Hz, 1H), 4.18 (s, 2H).
Step 2: tert-butyl
2-amino-3-(benzo[d]thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-c-
arboxylate
##STR00007##
[0154] To a solution of 2-(4-phenylthiazol-2-yl)acetonitrile (1 g,
5.00 mmol) in ethanol (10 mL) was added tert-butyl
4-oxopiperidine-1-carboxylate (1.19 g, 6.00 mmol), elemental
sulphur (160 mg, 5.00 mmol) and morpholine (0.51 mL, 5.00 mmol) at
room temperature. After the addition, the resulting mixture was
heated to reflux at 85.degree. C. for 2 h and monitored by TLC. The
reaction mixture was evaporated under vacuum. After removal of
solvent, the crude compound was purified by triturating with
methanol to afford the title compound as a yellow solid (500 mg,
yield 24%). LCMS: [M+H].sup.+=414.02. .sup.1H NMR (DMSO-d.sub.6,
400 MHz): 7.97 (d, J=7.59 Hz, 2H), 7.89 (s, 1H), 7.71 (s, 2H),
7.43-7.51 (m, 2H), 7.33-7.40 (m, 1H), 4.36 (m, 2H), 3.66 (t, J=5.13
Hz, 2H), 2.77-2.81 (m, 2H), 1.44 (s, 9H).
Step 3: tert-butyl
2-acetamido-3-(4-phenylthiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5-
H)-carboxylate
##STR00008##
[0156] To a solution of tert-butyl
2-amino-3-(4-phenylthiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-c-
arboxylate (500 mg, 1.21 mmol) in DCM (5 mL) at 0.degree. C. was
added DIPEA (0.42 mL, 2.42 mmol) and acetyl chloride (0.17 mL, 2.42
mmol). The reaction was by TLC, and after completion, the reaction
mass was diluted with DCM and washed with saturated NaHCO.sub.3
solution and brine. The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to get a crude residue
(550 mg). This crude compound was purified by preparative HPLC to
afford the title compound as a white solid (60 mg, 11% yield).
LCMS: [M+H].sup.+=456.0. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.
12.98 (br. s, 1H), 7.89 (d, J=7.34 Hz, 2H), 7.46-7.53 (m, 2H),
7.40-7.44 (m, 2H), 4.59 (m, 2H), 3.79 (t, J=5.38 Hz, 2H), 2.93-2.97
(m, 2H), 2.36 (s, 3H), 1.50 (s, 9H).
Step 4:
N-(3-(4-phenylthiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-
-2-yl)acetamide (Compound 100)
##STR00009##
[0158] To a solution of tert-butyl
2-acetamido-3-(4-phenylthiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5-
H)-carboxylate (60 mg, 0.13 mmol) in dioxane (1 mL) at 0.degree. C.
was added 4M HCl in dioxane (1 mL). After the addition, the
resulting mixture was stirred at room temperature for 2 h and the
reaction was monitored by TLC. After completion, the reaction
mixture was evaporated to dryness resulting in a crude residue
which was purified by triturating with ether and pentane to afford
the title compound as a pale yellow solid (50 mg HCl salt). LCMS:
[M+H].sup.+=355.95. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 9.47 (br.
s, 2H), 8.24 (s, 1H), 8.03 (d, J=7.34 Hz, 2H), 7.48-7.57 (m, 2H),
7.34-7.48 (m, 1H), 4.33 (s, 2H), 3.49 (t, J=5.87 Hz, 2H), 3.07-3.15
(m, 2H), 2.33 (s, 3H).
Example 2. Synthesis of
3-(Isopropylamino)-N-(3-(4-methylbenzo[d]oxazol-2-yl)-4,5,6,7-tetrahydrot-
hieno[2,3-c]pyridin-2-yl)propanamide (Compound 104)
##STR00010##
[0159] Step 1. 2-(4-(Pyridin-2-yl)thiazol-2-yl)acetonitrile
##STR00011##
[0161] 2-Cyanoethanethioamide (400 mg, 3.99 mmol) was added to a
solution of 2-bromo-1-(pyridin-2-yl)ethanone (1122 mg, 3.99 mmol)
in DMF (8 mL) and the resulting mixture was stirred for 2 h at
70.degree. C. The reaction mixture was cooled to RT, diluted with
water and EtOAc, washed with brine (3.times.), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
SiO.sub.2 chromatography (MeOH in DCM, 0 to 10% gradient) to afford
the title compound (215 mg, 27%) as a brown solid.
Step 2: tert-Butyl
2-amino-3-(4-(pyridin-2-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-
-6(7H)-carboxylate
##STR00012##
[0163] A mixture of 2-(4-(pyridin-2-yl)thiazol-2-yl)acetonitrile
(215 mg, 1.07 mmol), N-Boc-4-piperidone (213 mg, 1.07 mmol), sulfur
(34 mg, 1.07 mmol), morpholine (0.093 mL, 1.07 mmol) in EtOH (4 mL)
was stirred for 17 h at 90.degree. C. The reaction mixture was
cooled to RT, concentrated to half of its initial volume and the
precipitated solid was collected by filtration. The solid was
washed with EtOH and dried under vacuum to afford the title
compound (200 mg, 45%) as a light green solid.
Step 3: tert-Butyl
2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propanamido)-3-(4-(pyridin-2--
yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate
##STR00013##
[0165] A mixture of tert-butyl
2-amino-3-(4-(pyridin-2-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-
-6(7H)-carboxylate (100 mg, 0.241 mmol),
3-((tert-butoxycarbonyl)(isopropyl)amino)propanoic acid (84 mg,
0.362 mmol), T3P (50% in EtOAc, 0.287 mL, 0.482 mmol) and Et.sub.3N
(0.101 mL, 0.724 mmol) in EtOAc (2.4 mL) was stirred for 18 h at
65.degree. C. The reaction mixture was cooled to RT, quenched with
saturated NaHCO.sub.3 and diluted with EtOAc. The layers were
separated, the aqueous phase was extracted with EtOAc, the combined
organic layers were washed with brine, dried over MgSO.sub.4,
filtered and concentrated. The residue was taken in a minimum of
EtOAc, sonicated and the precipitate was filtered off to afford the
title compound (73 mg, 43%) as a light brown solid.
Step 4:
3-(Isopropylamino)-N-(3-(4-(pyridin-2-yl)thiazol-2-yl)-4,5,6,7-tet-
rahydrothieno[2,3-c]pyridin-2-yl)propanamide (Compound 104)
##STR00014##
[0167] A solution of HCl (4 N in dioxane, 1.0 mL) was added to a
solution of tert-butyl
2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propanamido)-3-(4-(pyridin-2--
yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate
(73 mg, 0.116 mmol) in DCM (2.0 mL) at RT. The resulting mixture
was stirred for 2 h at RT and diluted with Et.sub.2O (2.0 mL). The
precipitated solid was collected by filtration, washed with
Et.sub.2O and lyophilized from water/MeCN to afford the title
compound (36 mg, 61%) as a yellow solid. .sup.1H NMR (500 MHz):
.delta. DMSO-d6, .delta. 12.06 (s, 1H), 9.71 (s, 2H), 9.23 (s, 2H),
9.04 (d, J=6.3 Hz, 2H), 8.97 (s, 1H), 8.44 (d, J=5.5 Hz, 2H), 4.34
(s, 2H), 3.47 (t, J=6.0 Hz, 2H), 3.34-3.27 (m, 1H), 3.25 (t, J=6.9
Hz, 2H), 3.12 (t, J=5.7 Hz, 2H), 3.04 (t, J=6.8 Hz, 2H), 1.29 (d,
J=6.5 Hz, 6H). LC-MS: Calcd Mass [M+H]: 428.0; Found Mass
[M+H].sup.+: 428.2.
[0168] The following compounds were prepared using the same method
outlined above for Compound 104:
TABLE-US-00002 Compound Calcd. Mass Found Mass No. .sup.1H NMR (500
MHz) [M + H] [M + H].sup.+ 102 12.37 (s, 1H), 9.66 (s, 428.2 428.3
2H), 9.09 (s, 2H), 8.74 (d, 1H), 8.52 (s, 1H), 8.27-8.16 (m, 2H),
7.53 (t, 1H), 4.34 (s, 2H), 3.49 (s, 2H), 3.30 (d, J = 24.2 Hz,
3H), 3.23-3.11 (m, 4H), 1.28 (d, J = 6.1 Hz, 6H) 103 DMSO-d6 +
D.sub.2O, .delta. 428.2 428.2 9.34 (s, 1H), 8.77- 8.65 (m, 2H),
8.49 (s, 1H), 7.89-7.80 (m, 1H), 4.33 (s, 2H), 3.48 (t, J = 6.1 Hz,
2H), 3.32 (hept, J = 6.5 Hz, 1H), 3.26 (t, J = 6.9 Hz, 2H), 3.13
(t, J = 5.8 Hz, 2H), 3.07 (t, J = 6.9 Hz, 2H), 1.24 (d, J = 6.5 Hz,
6H). 5 NH missing due to D.sub.2O 110 DMSO-d6 .delta. 12.39 (s,
444.2 444.2 1H), 9.64 (s, 2H), 9.08 (s, 2H), 8.79-8.67 (m, 1H),
8.49 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.12 (td, J = 7.7, 1.6 Hz,
1H), 7.53-7.46 (m, 1H), 4.34 (s, 2H), 3.66-3.61 (m, 2H), 3.48 (s,
4H), 3.32 (d, J = 1.8 Hz, 3H), 3.20- 3.12 (m, 4H).
Example 3.
N-(3-(4-(3,6-Dihydro-2H-pyran-4-yl)thiazol-2-yl)-4,5,6,7-tetrah-
ydrothieno[2,3-c]pyridin-2-yl)-3-(isopropylamino)propanamide
(Compound 130)
##STR00015##
[0169] Step 1: 3-((tert-Butoxycarbonyl)(isopropyl)amino)propanoic
anhydride
##STR00016##
[0171] DIC (856 mg, 6.8 mmol) added in one portion to a solution of
3-((tert-butoxycarbonyl)(isopropyl)amino)propanoic acid (3.13 g,
13.6 mmol) in DCM (14 mL) at 0.degree. C. The resulting mixture was
allowed to stir at room temperature for 1.5 h. The solvent was then
evaporated and Et.sub.2O added to the slury and the white solid was
then filtered off, rinsed with cold Et.sub.2O. The filtrate was
washed with a saturated solution of NaHCO.sub.3, the combined
organic layers were dried over anh. Na.sub.2SO.sub.4, filtered and
concentrated to afford the title compound (2.63 g, 87%) as a
colorless oil.
Step 2: tert-Butyl 2-(4-bromothiazol-2-yl)-2-cyanoacetate
##STR00017##
[0173] tert-Butyl 2-cyanoacetate (18.6 g, 131.7 mmol) was added
drop-wise to a solution of 2,4-dibromothiazole (20 g, 82.3 mmol)
and grinded K.sub.2CO.sub.3 (34.1 g, 247.0 mmol) in dry NMP (101
mL) and the resulting mixture was stirred for 16 h at 85.degree. C.
The reaction mixture was cooled to RT and poured in water (900 mL).
A solution of HCl 3N (250 mL) was added drop-wise until pH 2. The
solid formed was filtered off, rinsed with water and hexanes and
then air dried to afford the title compound (25 g, 100%) as a light
brown solid.
Step 3: 2-(4-Bromothiazol-2-yl)acetonitrile
##STR00018##
[0175] AcOH (101 mL, 1770 mmol) was added to a suspension of
tert-butyl 2-(4-bromothiazol-2-yl)-2-cyanoacetate (25.0 g, 82.33
mmol) in a 4N HCl solution in water (103 mL, 411.6 mmol) and the
resulting mixture was stirred at 80.degree. C. for 15 min. The
reaction mixture was cooled to RT, quenched with water and diluted
with EtOAc. The layers were separated, the aqueous phase was
extracted with EtOAc, and the combined organic layers were washed
with brine, dried over MgSO.sub.4, filtered and co-evaporated 2
times with toluene. The residue was taken in a minimum of EtOAc and
hexanes, sonicated and filtered off to afford the titled compound
(6.38 g, 38%).
Step 4: tert-Butyl
2-amino-3-(4-bromothiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-ca-
rboxylate
##STR00019##
[0177] A mixture of 2-(4-bromothiazol-2-yl)acetonitrile (5 g, 24.62
mmol), N-Boc-4-piperidone (4.9 g, 24.62 mmol), sulfur (790 mg,
24.62 mmol), morpholine (3.46 mL, 24.62 mmol), and Et.sub.3N (2.15
mL, 24.62 mmol) in degassed EtOH (82 mL) was stirred for 2 h at
40.degree. C. The reaction mixture was cooled to RT, concentrated
and adsorbed on SiO.sub.2. The residue was purified by SiO.sub.2
chromatography (EtOAc in hexanes, 0 to 20% gradient) to afford the
title compound (2.15 g, 21%) as a yellow solid.
Step 5: tert-Butyl
3-(4-bromothiazol-2-yl)-2-(3-((tert-butoxycarbonyl)(isopropyl)-amino)prop-
an-amido)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate
##STR00020##
[0179] A mixture of tert-butyl
2-amino-3-(4-bromothiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-ca-
rboxylate 2450 mg, 2.88 mmol),
3-((tert-butoxycarbonyl)(isopropyl)-amino)propanoic anhydride (3139
mg, 7.06 mmol), and DMAP (1797 mg, 14.7 mmol), in DCE (50 mL) was
stirred for 16 h at RT. The reaction mixture was quenched with
saturated NaHCO.sub.3 and diluted with DCM. The layers were
separated, the aqueous phase was extracted with DCM, and the
combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
reverse phase chromatography (MeCN in a 10 nM NH.sub.4HCO.sub.2, 40
to 90% gradient) to afford the title compound (1640 mg, 43%) as a
yellow solid.
Step 6: tert-Butyl
2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propanamido)-3-(4-(3,6-dihydr-
o-2H-pyran-4-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carbo-
xylate
##STR00021##
[0181] A 20 mL pressure vessel was charged with tert-butyl
3-(4-bromothiazol-2-yl)-2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propa-
namido)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (1650
mg, 2.63 mmol),
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborol-
ane (1104 mg, 5.25 mmol), potassium tert-butanolate (884 mg, 7.88
mmol) and PCl.sub.2(dppf).sub.2 (214.5 mg, 0.263 mmol). The vial
was flushed with N2 and degassed Dioxane (18 mL) was added. The
tube was sealed and heated at 120.degree. C. under microwave
irradiations for 60 min. The reaction was then filtrated over
celite, washed with EtOAc, and concentrated. The residue was
purified by flash chromatography (EtOAc in hexanes, 15% to 40%
gradient) to afford the title compound (1118 mg, 67%).
Step 7:
N-(3-(4-(3,6-Dihydro-2H-pyran-4-yl)thiazol-2-yl)-4,5,6,7-tetrahydr-
othieno[2,3-c]pyridin-2-yl)-3-(isopropylamino)propanamide
dihydrochloride (Compound 130)
##STR00022##
[0183] A solution of HCl (4 N in dioxane, 10 mL) was added to a
solution of tert-butyl
2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propanamido)-3-(4-(3,6-dihydr-
o-2H-pyran-4-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carbo-
xylate (2618 mg, 4.13 mmol) in DCM (20 mL) at RT. The resulting
mixture was stirred for 2 h at RT and diluted with Et.sub.2O (20
mL). The precipitated solid was collected by filtration, washed
with Et.sub.2O and lyophilized from water to afford the title
compound (1900 mg, 91%) as a pale yellow solid. .sup.1H NMR (500
MHz): .delta. DMSO-d6, .delta. 12.84-12.13 (m, 1H), 9.54-9.10 (m,
2H), 8.77-8.51 (m, 2H), 7.86-7.59 (m, 1H), 6.89-6.57 (m, 1H),
4.37-4.29 (m, 4H), 3.91-3.84 (m, 2H), 3.55-3.44 (m, 2H), 3.28-3.23
(m, 3H), 3.12-3.00 (m, 4H), 2.58-2.53 (m, 2H), 1.29-1.21 (m, 6H).
LC-MS: Calcd Mass [M+H]: 433.2; Found Mass [M+H].sup.+: 433.3.
[0184] The following compounds were prepared using the same method
outlined above for Compound 130:
TABLE-US-00003 Compound Calcd. Mass Found Mass No. .sup.1H NMR (500
MHz) [M + H] [M + H].sup.+ 114 DMSO-d6 + D.sub.2O, .delta. 431.2
431.1 8.20 (s, 1H), 7.95 (d, J = 0.5 Hz, 1H), 7.75 (s, 1H), 4.31
(s, 2H), 3.90 (s, 3H), 3.47 (t, J = 6.1 Hz, 2H), 3.33 (d, J = 6.5
Hz, 1H), 3.26 (t, J = 6.9 Hz, 2H), 3.09 (t, J = 5.9 Hz, 2H), 3.06
(t, J = 6.8 Hz, 2H), 1.23 (d, J = 6.5 Hz, 6H). 5 NH missing due to
D.sub.2O 115 DMSO-d6, .delta. 11.95 (s, 446.1 446.2 1H), 9.65 (br
s, 2H), 9.17 (t, J = 1.6 Hz, 1H), 8.82 (br s, 2H), 8.64 (d, J = 2.7
Hz, 1H), 8.54 (s, 1H), 8.37 (ddd, J = 10.1, 2.7, 1.8 Hz, 1H), 4.33
(s, 2H), 3.48 (t, J = 6.1 Hz, 2H), 3.34- 3.22 (m, 3H), 3.13 (t, J =
6.0 Hz, 2H), 3.09 (t, J = 7.0 Hz, 2H), 1.26 (d, J = 6.5 Hz, 6H).
116 DMSO-d6, .delta. 12.19 (s, 442.2 442.2 1H), 9.62 (br s, 2H),
9.22 (br s, 1H), 8.93 (br s, 2H), 8.57 (br s, 1H), 8.48 (br s, 1H),
7.71 (br s, 1H), 4.34 (s, 2H), 3.48 (t, J = 6.0 Hz, 2H), 3.36-3.31
(m, 1H), 3.27 (t, J = 7.0 Hz, 2H), 3.16- 3.10 (m, 4H), 2.64 (s,
3H), 1.27 (d, J = 6.5 Hz, 6H). 117 DMSO-d6, .delta. 11.47 (s, 431.2
431.1 1H), 9.74 (br s, 2H), 9.57 (br s, 1H), 9.12 (br s, 2H), 8.20
(s, 1H), 8.09 (s, 1H), 4.32 (s, 2H), 3.46 (t, J = 6.1 Hz, 2H),
3.35-3.27 (m, 1H), 3.22 (t, J = 6.9 Hz, 2H), 3.12 (dd, J = 17.8,
6.2 Hz, 4H), 2.36 (s, 3H), 1.27 (d, J = 6.5 Hz, 6H). 118 DMSO-d6,
.delta. 12.25 (s, 408.1 408.1 1H), 11.36 (s, 1H), 9.48 (s, 1H),
8.89 (s, 2H), 7.60 (s, 1H), 4.31 (s, 2H), 3.46 (s, 2H), 3.38- 3.24
(m, 3H), 3.20 (t, J = 6.7 Hz, 2H), 3.06 (t, J = 5.8 Hz, 2H), 2.18
(s, 3H), 1.27 (d, J = 6.5 Hz, 6H). 119 DMSO-d6 + D.sub.2O, .delta.
458.2 458.2 8.83 (s, 1H), 8.39- 8.30 (m, 2H), 8.03 (s, 1H), 4.31
(s, 2H), 3.93 (s, 3H), 3.48 (t, J = 5.9 Hz, 2H), 3.31 (hept, J =
6.6 Hz, 1H), 3.25 (t, J = 6.7 Hz, 2H), 3.13 (t, J = 6.4 Hz, 2H),
3.02 (t, J = 6.6 Hz, 2H), 1.22 (d, J = 6.5 Hz, 6H). 5 NH missing
due to D.sub.2O 120 DMSO-d6, .delta. 11.67 (s, 429.0/431.0
429.0/431.0 1H), 9.63 (s, 2H), 8.88 (s, 2H), 7.99 (s, 1H), 4.30
(br. s, 2H), 3.47- 3.39 (m, 2H), 3.28- 2.97 (m, 4H), 1.26 (d, J =
6.5 Hz, 6H). 1H hidden under water signal 121 DMSO-d6, .delta.
11.94 (s, 442.2 442.3 1H), 9.59 (s, 2H), 8.92 (s, 2H), 8.64 (d, J =
4.4 Hz, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 7.76 (s, 1H), 4.27 (s,
2H), 3.23- 3.18 (m, 1H), 3.18- 3.11 (m, 4H), 3.06 (t, J = 5.4 Hz,
2H), 2.97 (t, J = 6.9 Hz, 2H), 2.80 (s, 3H), 1.18 (d, J = 6.5 Hz,
6H). 122 DMSO-d6, .delta. 12.07 (s, 442.2 442.1 1H), 9.57 (s, 2H),
9.14 (s, 1H), 8.84 (s, 2H), 8.60-8.40 (m, 3H), 4.27 (s, 2H), 3.44-
3.40 (m, 3H), 3.27- 3.23 (m, 2H), 3.22- 3.15 (m, J = 5.8 Hz, 3H),
3.13-3.01 (m, 4H), 1.20 (d, J = 6.5 Hz, 6H). 123 DMSO-d6, .delta.
12.02 (s, 442.2 442.3 1H), 9.06 (s, 1H), 8.65 (d, J = 5.5 Hz, 1H),
8.20 (s, 1H), 7.77 (d, J = 5.6 Hz, 1H), 4.33 (s, 2H), 3.48 (t, J =
6.1 Hz, 2H), 3.33-3.23 (m, 2H), 3.22 (t, J = 7.0 Hz, 3H), 3.12 (t,
J = 6.0 Hz, 2H), 3.08 (t, J = 6.8 Hz, 1H), 2.95 (t, J = 7.0 Hz,
2H), 2.67 (s, J = 6.8 Hz, 3H), 1.23 (d, 6H). 125 DMSO-d6, .delta.
12.55- 427.1 427.1 12.47 (m, 1 H), 9.56- 9.45 (m, 2 H), 8.88- 8.79
(m, 2H), 8.31 (s, 1 H), 8.11-8.07 (m, 2 H), 7.63-7.59 (m, 2 H),
7.52-7.45 (m, 1 H), 4.42-4.36 (m, 2 H), 3.57-3.52 (m, 2 H),
3.35-3.27 (m, 3 H), 3.20-3.13 (m, 4 H), 1.34-1.28 (m, 6 H) 126
DMSO-d6, .delta. 12.40 (s, 432.2 432.4 1 H), 9.48 (br. s., 2 H),
9.21 (br. s., 2 H), 9.14 (br. s., 2 H), 7.85 (s, 1 H), 6.67 (br.
s., 1 H), 4.33 (br. s., 2 H), 3.92 (br. s., 2 H), 3.48 (br. s., 2
H), 3.28-3.23 (m, 2 H), 3.17 (m, 6H), 2.79 (br. s., 2 H), 2.37 (br.
s., 1 H), 1.30-1.24 (m, 7 H) 127 DMSO-d6, .delta. 12.27 (s, 458.2
458.1 1H), 9.27 (br. s, 2H), 8.48 (dd, J = 7.5, 1.9 Hz, 1H), 8.46
(br. s, 2H), 8.29 (s, 1H), 8.27 (dd, J = 4.9, 1.9 Hz, 1H), 7.20
(dd, J = 7.5, 4.9 Hz, 1H), 4.36 (br. s, 2H), 4.07 (s, 3H), 3.51
(br. s, 2H), 3.35-3.23 (m, 2H), 3.12 (t, J = 5.8 Hz, 2H), 3.03 (t,
J = 6.9 Hz, 2H), 1.24 (d, J = 6.5 Hz, 6H). 1H hidden under water
signal 128 DMSO-d6, .delta. 11.99 (s, 429.2 429.0 1H), 9.50-9.41
(m, 4H), 9.25 (s, 1H), 8.63 (br. s, 2H), 8.58 (s, 1H), 4.35 (s,
2H), 3.48 (br. s, 2H), 3.35-3.24 (m, 2H), 3.13 (t, J = 5.7 Hz, 2H),
3.08 (t, J = 7.0 Hz, 2H), 1.25 (d, J = 6.5 Hz, 6H). 1H hidden under
water signal 129 DMSO-d6, .delta. 12.40 (s, 444.1 444.1 1H), 12.12
(br. s, 1H), 9.62 (br. s, 2H), 9.05 (br. s, 2H), 8.64 (s, 1H), 8.37
(dd, J = 7.1, 2.0 Hz, 1H), 7.53 (d, J = 5.6 Hz, 1H), 6.62 (t, J =
6.7 Hz, 1H), 4.33 (s, 2H), 3.35-3.30 (m, 2H), 3.29-3.22 (m, 2H),
3.16 (t, J = 7.0 Hz, 2H), 3.11 (t, J = 5.6 Hz, 2H), 1.28 (t, J =
6.8 Hz, 6H). 1H hidden under water signal
Example 4. Synthesis of
2-(2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyrid-
in-3-yl)thiazole-4-carboxylic acid (Compound 101)
##STR00023##
[0185] Step 1: Ethyl 2-(cyanomethyl)thiazole-4-carboxylate
##STR00024##
[0187] To a solution of 2-cyanoethanethioamide 2 (1 g, 9.98 mmol)
in THF (25 mL) was added ethyl 3-bromo-2-oxopropanoate 1 (1.25 mL,
9.98 mmol) at 0.degree. C. The resulting reaction mixture was
refluxed at 70.degree. C. for 3 h, and the progress of the reaction
was monitored by TLC. After completion, the reaction mixture was
concentrated to dryness under reduced pressure. The crude compound
was purified by column chromatography to afford compound 3 as a
yellow solid (0.86 g, yield 86%). LCMS: [M+1].sup.+=196.96.
Step 2: Step 2: tert-butyl
2-amino-3-(4-(ethoxycarbonyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridi-
ne-6(5H)-carboxylate
##STR00025##
[0189] To a solution of ethyl 2-(cyanomethyl)thiazole-4-carboxylate
3 (0.86 g, 4.38 mmol) in ethanol (20 mL) was added tert-butyl
4-oxopiperidine-1-carboxylate (0.874 g, 4.38 mmol) followed by
morpholine (0.381 g, 4.38 mmol) and sulphur (0.14 g, 4.38 mmol),
and the resulting mixture was heated to 80.degree. C. for 3 h and
monitored by TLC. After completion, the reaction mixture was
evaporated to give a crude residue which was triturated with
methanol to afford compound 4 as a yellow solid (1.3 g, yield
73.86%). LCMS: [M+Na].sup.+=431.85.
Step 3: tert-butyl
2-acrylamido-3-(4-(ethoxycarbonyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]p-
yridine-6(5H)-carboxylate
##STR00026##
[0191] To a solution of tert-butyl
2-amino-3-(4-(ethoxycarbonyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridi-
ne-6(5H)-carboxylate 4 (1.1 g, 2.68 mmol) in DCM (15 mL) at
0.degree. C. was added DIPEA (0.52 g, 4.03 mmol) followed by
3-chloropropanoyl chloride (0.51 g, 4.03 mmol) and the reaction
mixture was stirred at room temperature for 12 h. The progress of
the reaction was monitored by TLC. After completion, the reaction
mass was diluted with 10% MeOH/DCM and washed with NaHCO.sub.3
solution. The combined organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to afford the compound 5 as a
yellow solid (1.4 g, crude). LCMS: [M+H].sup.+=464.14.
Step 4: tert-butyl
3-(4-(ethoxycarbonyl)thiazol-2-yl)-2-(3-(isopropylamino)propanamido)-4,7--
dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
##STR00027##
[0193] To a solution of tert-butyl
2-acrylamido-3-(4-(ethoxycarbonyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]p-
yridine-6(5H)-carboxylate (1.4 g, 3.02 mmol) in MeOH (20 mL),
propan-2-amine (0.26 g, 4.53 mmol) was added. The resulting
reaction mixture was stirred at room temperature for 12 h, and the
progress of the reaction was monitored by TLC. After completion,
the reaction mixture was concentrated to dryness under reduced
pressure. The crude compound was purified by column chromatography
to afford the compound 6 as a yellow solid (1.1 g, yield 70.06%).
LCMS: [M+1].sup.+=523.24.
Step 5:
2-(6-(tert-butoxycarbonyl)-2-(3-(isopropylamino)propanamido)-4,5,6-
,7-tetrahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic
acid
##STR00028##
[0195] To a stirred solution of compound 6 (0.5 g, 0.957 mmol) in
THF: H.sub.2O (1:1, 8 mL) mixture was added LiOH (0.046 g, 1.91
mmol) and the reaction was stirred at rt for 12 h. Progress of the
reaction was monitored by TLC. After completion of the reaction,
the reaction mass was acidified using dilute HCl up to pH 6 and
extracted with DCM. The combined organic layers were dried over
anhydrous sodium sulphate and concentrated to afford the compound 7
as a yellow solid (0.3 g, yield 63.42%). LCMS:
[M+1].sup.+=495.36.
Step 6:
2-(2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3--
c]pyridin-3-yl)thiazole-4-carboxylic acid (Compound 101)
##STR00029##
[0197] To a solution of
2-(6-(tert-butoxycarbonyl)-2-(3-(isopropylamino)propanamido)-4,5,6,7-tetr-
ahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic acid 7 (0.1
g, 0.202 mmol) in dioxane (1 mL) at 0.degree. C., 4M HCl in dioxane
(2 mL) was added. After the addition, the resulting mixture was
stirred at room temperature for 2 h. Progress of the reaction was
monitored by TLC. After completion, the reaction mixture was
evaporated in vacuum resulting in a crude residue which was
purified by trituration with diethyl ether and pentane to afford
the title compound as a yellow solid (0.06 g, yield 63.82%). LCMS:
[M+1].sup.+=394.80. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
13.30 (br. s, 1H), 12.50 (s, 1H), 9.60 (s, 2H), 8.98 (s, 2H), 8.58
(s, 1H), 4.32 (s, 2H), 3.52 (t, J=5.1 Hz, 2H), 3.19-2.98 (m, 5H),
1.23-1.21 (m, 6H).
[0198] The following compounds were prepared using the same method
outlined above for Compound 101:
TABLE-US-00004 Compound No. .sup.1H NMR (400 MHz) Mass [M +
H].sup.+ 105 DMSO-d.sub.6: .delta. 12.07 (s, 435.9 1H), 9.54 (br.
s, 2H), 8.75 (br. s, 2H), 8.52 (d, J = 7.83 Hz, 1H), 8.36 (s, 1H),
4.32 (br. s, 2H), 4.13 (dt, J = 6.60, 13.57 Hz, 1H), 3.45- 3.50 (m,
2H), 3.28 (d, J = 6.36 Hz, 3H), 3.07 (d, J = 5.87 Hz, 4H), 1.24
(dd, J = 6.85, 9.29 Hz, 12H) 106 DMSO-d.sub.6: .delta. 11.78 (s,
464.30 1H), 9.55 (br. s, 2H), 8.82 (br. s, 2H), 8.25 (s, 1H), 4.32
(br. s, 2H), 3.62-3.79 (m, 8H), 3.42-3.47 (m, 2H), 3.19-3.26 (m,
3H), 3.03-3.08 (m, 2H), 2.99 (t, J = 6.85 Hz, 2H), 1.26 (d, J =
6.36 Hz, 6H). 107 DMSO-d.sub.6: .delta. 8.52 (s, 408.75 1H), 8.24
(s, 2H), 3.90 (s, 3H), 3.83-3.88 (m, 2H), 3.05-3.13 (m, 4H), 2.98
(td, J = 6.36, 12.72 Hz, 2H), 2.79 (br. s, 2H), 2.72 (t, J = 6.85
Hz, 2H), 1.05 (d, J = 6.36 Hz, 6H). 108 DMSO-d.sub.6: .delta. 11.88
(s, 451.85 1H), 9.50 (br. s, 2H), 8.70-8.81 (m, 3H), 8.38 (s, 1H),
4.33 (br. s, 2H), 3.45-3.54 (m, 8H), 3.29 (s, 3H), 3.02-3.11 (m,
5H), 1.25 (d, J = 6.36 Hz, 6H). 109 (DMSO-d.sub.6, 400 MHz): 422.25
.delta. 11.96 (s, 1H), 9.53 (br. s, 2H), 8.84 (br. s, 2H), 8.20 (s,
1H), 4.32 (br. s, 2H), 3.43-3.48 (m, 2H), 3.16-3.26 (m, 5H), 3.06
(br. s, 6H), 2.99 (t, J = 7.09 Hz, 2H), 1.26 (d, J = 6.36 Hz, 6H).
111 DMSO-d.sub.6: .delta. 11.74 (br. 477.25 s, 2H), 9.59 (br. s,
2H), 9.02 (br. s, 2H), 8.31 (s, 1H), 4.32 (br. s, 2H), 3.41-3.54
(m, 4H), 3.15-3.29 (m, 7H), 2.99-3.09 (m, 5H), 2.78 (br. s, 3H),
1.28 (d, J = 6.36 Hz, 6H 112 DMSO-d.sub.6: .delta. 11.88 (s, 462.15
1H), 9.58 (br. s, 2H), 8.91 (br. s, 2H), 8.15 (s, 1H), 4.32 (br. s,
2H), 3.57-3.68 (m, 4H), 3.41-3.47 (m, 2H), 3.30 (d, J = 6.36 Hz,
1H), 3.23 (d, J = 5.87 Hz, 2H), 3.03-3.09 (m, 2H), 2.99 (t, J =
7.09 Hz, 2H), 1.66 (d, J = 4.40 Hz, 2H), 1.50-1.61 (m, 4H), 1.26
(d, J = 6.36 Hz, 6H).
Example 5. Synthesis of
2-(2-(3-(Isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyrid-
in-3-yl)-N-phenylthiazole-4-carboxamide (Compound 113)
##STR00030##
[0199] Step 1: tert-Butyl
2-(3-(isopropylamino)propanamido)-3-(4-(phenylcarbamoyl)thiazol-2-yl)-4,7-
-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
##STR00031##
[0201] To a solution of
2-(6-(tert-butoxycarbonyl)-2-(3-(isopropylamino)propanamido)-4,5,6,7-tetr-
ahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic acid (200 mg,
0.404 mmol) in DMF (5 mL) at 0.degree. C. was added triethyl amine
(0.11 mL, 0.809 mmol), PyBOP (316 mg, 0.607 mmol) and aniline (38
mg, 0.404 mmol). After the addition, the resulting mixture was
stirred at room temperature for 16 h. After completion, the
reaction mixture was washed with water and extracted with 10%
methanol in DCM (thrice). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give crude compound.
The crude compound was purified by preparative HPLC to afford the
desired compound as a yellow solid (25 mg, 11% yield). LCMS:
[M-Boc].sup.+=470.45.
Step 2:
2-(2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3--
c]pyridin-3-yl)-N-phenylthiazole-4-carboxamide (Compound 113)
##STR00032##
[0203] To a solution of tert-butyl
2-(3-(isopropylamino)propanamido)-3-(4-(phenylcarbamoyl)thiazol-2-yl)-4,7-
-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (25 mg, 0.043 mmol)
in dioxane (3 mL) at 0.degree. C. was added 4M HCl in dioxane (2
mL). After the addition, the resulting mixture was stirred at room
temperature for 2 h. After completion, the reaction mixture was
evaporated to dryness resulting in a crude residue was purified by
trituration in diethyl ether and pentane to afford the title
compound as a yellow solid (20 mg HCl salt, 84% yield). LCMS:
[M+H].sup.+=470.25. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
12.03 (s, 1H), 10.56 (s, 1H), 9.58 (br. s, 2H), 8.77 (br. s, 2H),
8.55-8.60 (m, 1H), 7.88 (d, J=7.83 Hz, 2H), 7.39 (t, J=7.83 Hz,
2H), 7.15 (t, J=7.34 Hz, 1H), 4.34 (br. s, 2H), 3.46-3.51 (m, 1H),
3.23-3.31 (m, 4H), 3.12 (d, J=6.36 Hz, 4H), 1.20-1.26 (m, 6H).
Example 6. Synthesis of
2-(2-(3-(Isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyrid-
in-3-yl)-N-(pyridin-3-yl)thiazole-4-carboxamide
##STR00033##
[0204] Step 1: tert-Butyl
2-(3-(isopropylamino)propanamido)-3-(4-(pyridin-3-ylcarbamoyl)thiazol-2-y-
l)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1)
##STR00034##
[0206] To a solution of
2-(6-(tert-butoxycarbonyl)-2-(3-(isopropylamino)propanamido)-4,5,6,7-tetr-
ahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic acid (300 mg,
0.607 mmol) in DMF (15 mL) was added pyridin-3-amine (68 mg, 0.728
mmol), triethyl amine (0.42 mL, 3.036 mmol), and T3P (0.3 mL, 50%
wt solution in ethyl acetate) at room temperature. After the
addition, the resulting mixture was warmed to 40.degree. C. and
stirred for 2 h. After completion, the reaction mixture was
concentrated to give crude compound. The crude compound was
purified by preparative HPLC to afford the desired compound as
yellow solid (50 mg, yield 14%). LCMS: [M+H].sup.+=570.90, 570.85.
.sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 12.14 (br. s, 1H), 10.68
(br. s, 1H), 8.92 (br. s, 1H), 8.49 (d, J=7.34 Hz, 1H), 8.30-8.39
(m, 2H), 8.16 (br. s, 1H), 7.29-7.36 (m, 1H), 4.55 (br. s, 2H),
3.74-3.78 (m, 2H), 3.07-3.29 (m, 5H), 2.87-2.91 (m, 2H), 1.50 (s,
9H), 1.21 (d, J=5.38 Hz, 6H).
Step 2:
2-(2-(3-(Isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3--
c]pyridin-3-yl)-N-(pyridin-3-yl)thiazole-4-carboxamide (Compound
124)
##STR00035##
[0208] To a solution of tert-butyl
2-(3-(isopropylamino)propanamido)-3-(4-(pyridin-3-ylcarbamoyl)thiazol-2-y-
l)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (30 mg, 0.052
mmol) in dioxane (1 mL) at 0.degree. C. was added 4M HCl in dioxane
(1 mL). After the addition, the resulting mixture was stirred at
room temperature for 2 h. After completion, the reaction mixture
was evaporated to dryness and the resulting in a crude residue was
triturated in ether and pentane and purified by preparative HPLC to
afford the title compound as a yellow solid (20 mg HCl salt). LCMS:
[M+H].sup.+=470.90. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
11.96 (s, 1H), 11.30 (br. s, 1H), 9.67 (br. s, 2H), 9.30 (br. s,
1H), 8.95 (br. s, 2H), 8.70-8.72 (m, 1H), 8.68 (d, J=8.80 Hz, 1H),
8.53 (d, J=4.40 Hz, 1H), 7.77 (d, J=4.40 Hz, 1H), 4.32 (br. s, 2H),
3.44-3.49 (m, 2H), 3.21-3.32 (m, 3H), 3.16 (d, J=6.36 Hz, 2H),
3.07-3.14 (m, 2H), 1.24 (d, J=6.36 Hz, 6H).
Example 7. Synthesis of
(S)-3-(sec-butylamino)-N-(3-(4-(pyridin-3-yl)thiazol-2-yl)-4,5,6,7-tetrah-
ydrothieno[2,3-c]pyridin-2-yl)propanamide (Compound 131)
##STR00036##
[0209] Step 1: 2-bromo-1-(pyridin-3-yl)ethan-1-one
##STR00037##
[0211] To a solution of 1-(pyridin-3-yl)ethan-1-one (2 g, 16.52
mmol) in acetic acid (5 mL) at 0.degree. C. was added HBr in acetic
acid (28 mL) followed by dropwise addition of bromine (1 mL). The
resulting reaction mixture was heated to 40.degree. C. for 2 h and
then at 75.degree. C. for 2 h, and the reaction was monitored by
TLC. After completion, the mixture was cooled and diluted with
diethyl ether. The solid precipitated was filtered and washed with
diethyl ether and acetone. The crude compound was purified by
recrystallization in methanol and ether to afford the desired
compound as a brown solid (2 g crude). LCMS:
[M+H].sup.+=199.89.
Step 2: 2-(4-(pyridin-3-yl)thiazol-2-yl)acetonitrile
##STR00038##
[0213] To a solution of 2-bromo-1-(pyridin-3-yl)ethan-1-one 2 (500
mg, 2.50 mmol) in DMF (5 mL) was added 2-cyanoethanethioamide (250
mg, 2.50 mmol) at room temperature and stirred for 16 h, and the
reaction was monitored by TLC. After completion, the mixture was
evaporated to dryness and the residue obtained was washed with
diethyl ether and pentane to afford the title compound as a brown
solid (400 mg crude). LCMS: [M+H].sup.+=201.95.
Step 3: tert-butyl
2-amino-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-
-6(5H)-carboxylate
##STR00039##
[0215] To a solution of
2-(4-(pyridin-3-yl)thiazol-2-yl)acetonitrile (150 mg, 1.243 mmol),
elemental sulphur (40 mg, 1.243 mmol) and morpholine (108 mg, 1.243
mmol) in ethanol (5 mL) was added tert-butyl
4-oxopiperidine-1-carboxylate (247 mg, 1.243 mmol) at room
temperature and the resulting reaction mixture was heated to reflux
at 85.degree. C. for 12 h. The reaction was monitored by TLC and
after completion, the mixture was evaporated to dryness to afford
the desired compound as brown solid (150 mg crude). LCMS:
[M+H].sup.+=415.21.
Step 4: tert-butyl
2-acrylamido-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyr-
idine-6(5H)-carboxylate
##STR00040##
[0217] To a solution of tert-butyl
2-amino-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-
-6(5H)-carboxylate (150 mg, 0.362 mmol) in DCM (10 mL) at 0.degree.
C. was added DIPEA (0.1 mL, 0.724 mmol) followed by
3-chloropropanoyl chloride (55 mg, 0.434 mmol). The reaction
mixture was stirred at room temperature for 12 h and monitored by
TLC. After completion, the reaction mixture was diluted with DCM
and washed with saturated NaHCO.sub.3 solution and brine. The
separated organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuum to afford the title compound as a brown
solid (120 mg crude). LCMS: [M+H].sup.+=469.25,
Step 5: tert-butyl
(S)-2-(3-(sec-butylamino)propanamido)-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,-
7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
##STR00041##
[0219] To a solution of tert-butyl
2-acrylamido-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyr-
idine-6(5H)-carboxylate (300 mg, 0.641 mmol) in MeOH: THF (1:1, 20
mL) was added (S)-butan-2-amine (56 mg, 0.769 mmol). The resulting
reaction mixture was stirred at room temperature for 15 h, and the
progress of the reaction was monitored by TLC. After completion,
the reaction mixture was concentrated to dryness under reduced
pressure. The crude residue was dissolved in DCM and washed with
water. The combined organic layers were dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to get a crude residue.
This crude compound was purified by silica gel column
chromatography eluting with 0-5% methanol in DCM to afford desired
compound as yellow solid (200 mg, yield 58%). LCMS:
[M+H].sup.+=542.38.
Step 6:
(S)-3-(sec-butylamino)-N-(3-(4-(pyridin-3-yl)thiazol-2-yl)-4,5,6,7-
-tetrahydrothieno[2,3-c]pyridin-2-yl)propanamide (Compound 131)
##STR00042##
[0221] To a solution of tert-butyl
(S)-2-(3-(sec-butylamino)propanamido)-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,-
7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (100 mg, 0.184
mmol) in dioxane (5 mL) at 0.degree. C. was added 4M HCl in dioxane
(5 mL). After the addition, the resulting mixture was stirred at
room temperature for 3 h. After completion, the reaction mixture
was evaporated in vacuum resulting in a crude residue which was
purified by triturating with methanol. The solid obtained was
filtered and washed with diethyl ether and n-pentane to afford the
title compound as a yellow solid (30 mg). LCMS: [M+H].sup.+=441.80.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 12.05 (s, 1H), 9.66
(br. s, 2H), 9.34 (br. s, 1H), 8.89-9.07 (m, 2H), 8.72 (d, J=4.40
Hz, 2H), 8.54 (s, 1H), 7.90 (br. s, 1H), 4.26 (br. s, 2H),
3.38-3.42 (m, 2H), 3.03-3.27 (m, 7H), 1.70-1.79 (m, 1H), 1.41-1.53
(m, 1H), 1.18 (d, J=6.36 Hz, 3H), 0.85 (t, J=7.34 Hz, 3H).
Example 8. c-Myc/Max/Ebox DNA AlphaScreen Assay
[0222] Compounds of the invention were assayed for c-Myc/Max/EBox
activity as described in the following protocol. Human
his.sub.6-c-Myc and his.sub.6-Max were used with biotinylated DNA
containing a single Ebox sequence
(biotinGGAAGCAGACCACGTGGTCTGCTTCC) purchased from MWG Operon. Free
c-Myc was generated from his.sub.6-c-Myc through thrombin cleavage
of the his.sub.6 tag. For 384-well plate assays, 10 .mu.L of a
2.times. solution of free c-Myc (20 nM final), Ni.sup.2+ coated
Acceptor Beads (25 .mu.g/ml final), and biotinylated Ebox oligo (10
nM final) were added to 384-well plates with a Biotek EL406 liquid
handler. 50 nL of compounds from stock plates were added by pin
transfer using a Janus Workstation (PerkinElmer), allowing the
compounds to interact with c-Myc prior to c-Myc binding with Max.
In the current assay, DMSO was not allowed to exceed 2% v/v of the
assay. 10 .mu.l of 2.times. master mix containing
streptavidin-coated donor beads (25 .mu.g/ml final) and
his.sub.6-Max (5 nM) were added. AlphaScreen measurements were
performed on an Envision plate reader (PerkinElmer) utilizing the
manufacturer's protocol.
[0223] Both master mixes were made in room temperature assay buffer
(50 mM HEPES, 150 mM NaCl, 0.2% w/v BSA, 0.02% w/v Tween20, 40
.mu.g/ml glycogen, 500 .mu.M DTT, pH 8.0, wherein both DTT and
glycogen were added fresh). Alpha beads were added to respective
master solutions. All subsequent steps were performed in low light
conditions. Solution 1: 2.times. solution of components with final
concentrations of c-Myc Ni-coated Acceptor Beads (25 .mu.g/ml), and
biotinylated Ebox oligo (10 nM). Solution 2: 2.times. solution of
streptavidin-coated donor beads (25 .mu.g/ml final) and
his.sub.6-Max 10 .mu.L. Solution 1 was added to 384-well plate
(AlphaPlate-384, PerkinElmer) with Biotek EL406 liquid handler and
the plates were centrifuged very briefly. 50 nL of compounds from
stock plates were added by pin transfer using a Janus Workstation.
Solution 2 (10 .mu.L) was added with the liquid handler. Plates
were sealed with foil to block light exposure and prevent
evaporation. Plates were very briefly centrifuged followed by 2
hour incubation. AlphaScreen measurements were performed on an
Envision 2104 utilizing the manufacturer's protocol. Excitation was
at 680 nm for donor bead release of singlet oxygen and emission was
read with a bandpass filter from 520-620 nm. Glycogen: Roche
Diagnostics #10901393001. Plate 1536: Perkin Elmer, 6004350. Plate
384: Perkin Elmer, 6005350. Nickel-His Alpha Beads: 6760619R. The
data from this assay are summarized in Table 2 below (Myc/Max/DNA
Activity), where "A" represents a calculated IC.sub.50 of less than
500 nM; "B" represents a calculated IC.sub.50 of between 500 nM and
5 .mu.M; "C" represents a calculated IC.sub.50 of between 5 .mu.M
and 10 .mu.M; "D" represents a value of greater than 10 .mu.M, and
"NT" represents a compound for which an assay result was not
obtained.
TABLE-US-00005 TABLE 2 Compound Myc/Max/DNA # Activity 100 D 101 B
102 A 103 A 104 A 105 C 106 D 107 NT 108 D 109 D 110 B 111 D 112 D
113 D 114 A 115 A 116 A 117 B 118 B 119 A 120 B 121 B 122 A 123 B
124 A 125 B 126 A 127 A 128 A 129 A 130 B 131 NT
EQUIVALENTS
[0224] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0225] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims are introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the invention,
or aspects of the invention, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[0226] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present invention that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the invention can be excluded from any claim, for any
reason, whether or not related to the existence of prior art.
[0227] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
invention, as defined in the following claims.
* * * * *