U.S. patent application number 16/122703 was filed with the patent office on 2019-01-03 for inhibitors of lysine specific demethylase-1.
The applicant listed for this patent is CELGENE QUANTICEL RESEARCH, INC.. Invention is credited to Young K. Chen, Toufike Kanouni, Zhe Nie, Jeffrey Alan Stafford, James Marvin Veal.
Application Number | 20190002456 16/122703 |
Document ID | / |
Family ID | 55019883 |
Filed Date | 2019-01-03 |
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United States Patent
Application |
20190002456 |
Kind Code |
A1 |
Chen; Young K. ; et
al. |
January 3, 2019 |
INHIBITORS OF LYSINE SPECIFIC DEMETHYLASE-1
Abstract
The present invention relates generally to compositions and
methods for treating cancer and neoplastic disease. Provided herein
are substituted heterocyclic derivative compounds and
pharmaceutical compositions comprising said compounds. The subject
compounds and compositions are useful for inhibition of lysine
specific demethylase-1. Furthermore, the subject compounds and
compositions are useful for the treatment of cancer, such as
prostate cancer, breast cancer, bladder cancer, lung cancer and/or
melanoma and the like.
Inventors: |
Chen; Young K.; (San Marcos,
CA) ; Kanouni; Toufike; (La Jolla, CA) ; Nie;
Zhe; (San Diego, CA) ; Stafford; Jeffrey Alan;
(San Diego, CA) ; Veal; James Marvin; (Apex,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CELGENE QUANTICEL RESEARCH, INC. |
San Diego |
CA |
US |
|
|
Family ID: |
55019883 |
Appl. No.: |
16/122703 |
Filed: |
September 5, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15867397 |
Jan 10, 2018 |
10100046 |
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16122703 |
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15323277 |
Dec 30, 2016 |
9902719 |
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PCT/US2015/038345 |
Jun 29, 2015 |
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15867397 |
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62020886 |
Jul 3, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 417/06 20130101; A61P 43/00 20180101; C07D 401/14 20130101;
C07D 487/04 20130101; C07D 519/00 20130101; C07D 417/14 20130101;
C07D 401/04 20130101; C07D 471/10 20130101; C07D 417/04 20130101;
C07D 471/04 20130101 |
International
Class: |
C07D 417/14 20060101
C07D417/14; C07D 519/00 20060101 C07D519/00; C07D 417/04 20060101
C07D417/04; C07D 417/06 20060101 C07D417/06; C07D 401/14 20060101
C07D401/14; C07D 471/10 20060101 C07D471/10; C07D 471/04 20060101
C07D471/04; C07D 401/04 20060101 C07D401/04; C07D 487/04 20060101
C07D487/04 |
Claims
1. A compound having the structure of Formula (I), or a
pharmaceutically acceptable salt thereof, ##STR00218## wherein,
W.sup.1 and W.sup.2 are independently chosen from N, C--H, or C--F;
X is chosen from hydrogen, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted heterocyclyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclylalkyl, optionally substituted aralkyl, optionally
substituted heteroarylalkyl, optionally substituted aryl, or
optionally substituted heteroaryl; Y is chosen from hydrogen,
halogen, optionally substituted alkyl, or optionally substituted
cycloalkylalkyl; and Z is chosen from an optionally substituted
group chosen from N-heterocyclyl, --O-- heterocyclylalkyl,
--N(H)-heterocyclylalkyl, --N(H)-alkyl, --N(Me)-alkyl, or
--N(Me)-heterocyclylalkyl.
2. The compound or pharmaceutically acceptable salt of claim 1,
wherein W.sup.2 is C--H.
3. The compound or pharmaceutically acceptable salt of claim 1,
wherein W.sup.1 is C--F.
4. The compound or pharmaceutically acceptable salt of claim 1,
wherein X is optionally substituted aryl.
5. The compound or pharmaceutically acceptable salt of claim 4,
wherein the optionally substituted aryl is an optionally
substituted phenyl.
6. The compound or pharmaceutically acceptable salt of claim 1,
wherein X is optionally substituted heteroaryl.
7. The compound or pharmaceutically acceptable salt of claim 6,
wherein the optionally substituted heteroaryl is chosen from an
optionally substituted pyridinyl, optionally substituted
pyrimidinyl, optionally substituted pyrazinyl, optionally
substituted pyrazolyl, optionally substituted indazolyl, optionally
substituted azaindazolyl, optionally substituted isoindazolyl,
optionally substituted indolyl, or optionally substituted
azaindolyl.
8. The compound or pharmaceutically acceptable salt of claim 1,
wherein Z is an optionally substituted --O-heterocyclylalkyl,
optionally substituted --N(H)-heterocyclylalkyl, or optionally
substituted --N(Me)-heterocyclylalkyl
9. The compound or pharmaceutically acceptable salt of claim 8,
wherein the heterocyclylalkyl group has the formula
--R.sup.c-heterocyclyl and the R.sup.c is an optionally substituted
C.sub.1-C.sub.3 alkylene chain.
10. The compound or pharmaceutically acceptable salt of claim 8,
wherein the heterocyclylalkyl group has the formula
--R.sup.c-heterocyclyl and the R.sup.c is an optionally substituted
C.sub.1 alkylene chain.
11. The compound or pharmaceutically acceptable salt of claim 8,
wherein the heterocyclylalkyl group has the formula
--R.sup.c-heterocyclyl and the heterocyclyl is an optionally
substituted nitrogen-containing 4-, 5-, 6-, or 7-membered
heterocyclyl.
12. The compound or pharmaceutically acceptable salt of claim 1,
wherein Z is an optionally substituted N-heterocyclyl.
13. The compound or pharmaceutically acceptable salt of claim 12,
wherein the optionally substituted N-heterocyclyl is a 4-, 5-, 6-,
or 7-membered N-heterocyclyl.
14. The compound or pharmaceutically acceptable salt of claim 12,
wherein the optionally substituted N-heterocyclyl is a 6-membered
N-heterocyclyl.
15. The compound or pharmaceutically acceptable salt of claim 12,
wherein the optionally substituted N-heterocyclyl is an optionally
substituted piperidine.
16. The compound or pharmaceutically acceptable salt of claim 15,
wherein the optionally substituted piperidine is an optionally
substituted 4-aminopiperidine.
17. The compound or pharmaceutically acceptable salt of claim 1,
wherein Y is hydrogen.
18. The compound or pharmaceutically acceptable salt of claim 1,
wherein Y is halogen.
19. The compound or pharmaceutically acceptable salt of claim 1,
wherein Y is optionally substituted cycloalkylalkyl.
20. The compound or pharmaceutically acceptable salt of claim 1,
wherein Y is optionally substituted alkyl.
21. The compound or pharmaceutically acceptable salt of claim 20,
wherein the optionally substituted alkyl is an optionally
substituted C.sub.1-C.sub.3 alkyl.
22. The compound or pharmaceutically acceptable salt of claim 20,
wherein the optionally substituted alkyl is an optionally
substituted C.sub.1 alkyl.
23. The compound or pharmaceutically acceptable salt of claim 20,
wherein the optionally substituted alkyl is a methyl group.
24. A pharmaceutical composition comprising a compound of Formula
(I) of claim 1, or a pharmaceutically acceptable salt thereof, and
a pharmaceutically acceptable excipient.
25. A method of regulating gene transcription in a cell comprising
inhibiting lysine-specific demethylase 1 activity by exposing the
lysine-specific demethylase 1 enzyme to a compound of Formula (I)
of claim 1.
26. A method of treating acute myeloid leukemia, breast or prostate
cancer in a patient in need thereof, comprising administering to
the patient a therapeutically effective amount of a compound of
Formula (I) of claim 1, or a pharmaceutically acceptable salt
thereof.
27. A compound having the structure of Formula (II), or a
pharmaceutically acceptable salt thereof, ##STR00219## wherein,
W.sup.1 and W.sup.2 are independently chosen from N, C--H, or C--F;
X is chosen from optionally substituted alkyl, optionally
substituted alkoxy, optionally substituted alkylamino, optionally
substituted alkynyl, optionally substituted cycloalkylalkynyl,
optionally substituted (cycloalkylalkyl)alkynyl, optionally
substituted heterocyclylalkynyl, optionally substituted
(heterocyclylalkyl)alkynyl, optionally substituted aryl, or
optionally substituted heteroaryl; and Z is chosen from an
optionally substituted group chosen from N-heterocyclyl,
--C(O)--N-heterocyclyl, --O-heterocyclylalkyl,
--N(H)-heterocyclylalkyl, --N(H)-alkyl, --N(Me)-alkyl, or
--N(Me)-heterocyclylalkyl.
28. The compound or pharmaceutically acceptable salt of claim 27,
wherein W.sup.2 is C--H.
29. The compound or pharmaceutically acceptable salt of claim 27,
wherein W.sup.1 is C--F.
30. The compound or pharmaceutically acceptable salt of claim 27,
wherein W.sup.1 is C--H.
31. The compound or pharmaceutically acceptable salt of claim 27,
wherein X is optionally substituted aryl.
32. The compound or pharmaceutically acceptable salt of claim 31,
wherein the optionally substituted aryl is an optionally
substituted phenyl.
33. The compound or pharmaceutically acceptable salt of claim 27,
wherein X is optionally substituted heteroaryl.
34. The compound or pharmaceutically acceptable salt of claim 33,
wherein the optionally substituted heteroaryl is chosen from an
optionally substituted pyridinyl, optionally substituted
pyrimidinyl, optionally substituted pyrazinyl, optionally
substituted pyrazolyl, optionally substituted indazolyl, optionally
substituted azaindazolyl, optionally substituted isoindazolyl,
optionally substituted indolyl, optionally substituted azaindolyl,
optionally substituted benzimidazolyl, or optionally substituted
azabenzimidazolyl.
35. The compound or pharmaceutically acceptable salt of claim 27,
wherein X is optionally substituted alkynyl, optionally substituted
cycloalkylalkynyl, optionally substituted (cycloalkylalkyl)alkynyl,
optionally substituted heterocyclylalkynyl, or optionally
substituted (heterocyclylalkyl)alkynyl.
36. The compound or pharmaceutically acceptable salt of claim 27,
wherein Z is an optionally substituted --O-heterocyclylalkyl,
optionally substituted --N(H)-heterocyclylalkyl, or optionally
substituted --N(Me)-heterocyclylalkyl.
37. The compound or pharmaceutically acceptable salt of claim 36,
wherein the heterocyclylalkyl group has the formula
--R.sup.c-heterocyclyl and the R.sup.c is an optionally substituted
C.sub.1-C.sub.3 alkylene chain.
38. The compound or pharmaceutically acceptable salt of claim 36,
wherein the heterocyclylalkyl group has the formula
--R.sup.c-heterocyclyl and the R.sup.c is an optionally substituted
C.sub.1 alkylene chain.
39. The compound or pharmaceutically acceptable salt of claim 36,
wherein the heterocyclylalkyl group has the formula
--R.sup.c-heterocyclyl and the heterocyclyl is an optionally
substituted nitrogen-containing 4-, 5-, 6-, or 7-membered
heterocyclyl.
40. The compound or pharmaceutically acceptable salt of claim 27,
wherein Z is an optionally substituted N-heterocyclyl.
41. The compound or pharmaceutically acceptable salt of claim 40,
wherein the optionally substituted N-heterocyclyl is a 4-, 5-, 6-,
or 7-membered N-heterocyclyl.
42. The compound or pharmaceutically acceptable salt of claim 40,
wherein the optionally substituted N-heterocyclyl is a 6-membered
N-heterocyclyl.
43. The compound or pharmaceutically acceptable salt of claim 40,
wherein the optionally substituted N-heterocyclyl is an optionally
substituted piperidine.
44. The compound or pharmaceutically acceptable salt of claim 43,
wherein the optionally substituted piperidine is an optionally
substituted 4-aminopiperidine.
45. The compound or pharmaceutically acceptable salt of claim 27,
wherein Z is an optionally substituted --C(O)--N-heterocyclyl.
46. The compound or pharmaceutically acceptable salt of claim 45,
wherein the optionally substituted N-heterocyclyl is an optionally
substituted piperidine.
47. A pharmaceutical composition comprising a compound of Formula
(II) of claim 27, or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable excipient.
48. A method of regulating gene transcription in a cell comprising
inhibiting lysine-specific demethylase 1 activity by exposing the
lysine-specific demethylase 1 enzyme to a compound of Formula (II)
of claim 27.
49. A method of treating acute myeloid leukemia, breast or prostate
cancer in a patient in need thereof, comprising administering to
the patient a compound of Formula (II) of claim 27, or a
pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/867,397, filed Jan. 10, 2018, which is a
continuation of U.S. patent application Ser. No. 15/323,277, filed
Dec. 30, 2016, now U.S. Pat. No. 9,902,719, which is a 371 of
International Patent Application No. PCT/US2015/038345, filed Jun.
29, 2015, which claims the benefit of U.S. Provisional Application
No. 62/020,886, filed Jul. 3, 2014, the contents of which are
hereby incorporated by reference in their entireties.
BACKGROUND
[0002] A need exists in the art for an effective treatment of
cancer and neoplastic disease.
BRIEF SUMMARY OF THE INVENTION
[0003] Provided herein are substituted heterocyclic derivative
compounds and pharmaceutical compositions comprising said
compounds. The subject compounds and compositions are useful for
inhibition lysine specific demethylase-1 (LSD-1). Furthermore, the
subject compounds and compositions are useful for the treatment of
cancer, such as prostate cancer, breast cancer, bladder cancer,
lung cancer and/or melanoma and the like. The substituted
heterocyclic derivative compounds described herein are based upon a
central heterocyclic ring system, such as a thiazole or
pyrimidinone, or the like. Said central heterocyclic ring system is
further substituted with additional substituents, such as for
example, a 4-cyanophenyl group and a heterocyclyl group.
[0004] One embodiment provides a compound having the structure of
Formula (I), or a pharmaceutically acceptable salt thereof,
##STR00001## [0005] wherein, [0006] W.sup.1 and W.sup.2 are
independently chosen from N, C--H, or C--F; [0007] X is chosen from
hydrogen, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted heterocyclyl, optionally
substituted cycloalkylalkyl, optionally substituted
heterocyclylalkyl, optionally substituted aralkyl, optionally
substituted heteroarylalkyl, optionally substituted aryl, or
optionally substituted heteroaryl; Y is chosen from hydrogen,
halogen, optionally substituted alkyl, or optionally substituted
cycloalkylalkyl; and [0008] Z is chosen from an optionally
substituted group chosen from N-heterocyclyl, --O--
heterocyclylalkyl, --N(H)-heterocyclylalkyl, --N(H)-alkyl,
--N(Me)-alkyl, or --N(Me)-heterocyclylalkyl.
[0009] One embodiment provides a compound having the structure of
Formula (II), or a pharmaceutically acceptable salt thereof,
##STR00002## [0010] wherein, [0011] W.sup.1 and W.sup.2 are
independently chosen from N, C--H, or C--F; [0012] X is chosen from
hydrogen, optionally substituted alkyl, optionally substituted
alkoxy, optionally substituted alkylamino, optionally substituted
alkynyl, optionally substituted cycloalkylalkynyl, optionally
substituted (cycloalkylalkyl)alkynyl, optionally substituted
heterocyclylalkynyl, optionally substituted
(heterocyclylalkyl)alkynyl, optionally substituted aryl, or
optionally substituted heteroaryl; and [0013] Z is chosen from an
optionally substituted group chosen from N-heterocyclyl,
--C(O)--N-- heterocyclyl, --O-heterocyclylalkyl,
--N(H)-heterocyclylalkyl, --N(H)-alkyl, --N(Me)-alkyl, or
--N(Me)-heterocyclylalkyl.
[0014] One embodiment provides a pharmaceutical composition
comprising a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
excipient.
[0015] One embodiment provides a method of regulating gene
transcription in a cell comprising inhibiting lysine-specific
demethylase 1 activity by exposing the lysine-specific demethylase
1 enzyme to a compound of Formula (I).
[0016] One embodiment provides a method of treating cancer in a
patient in need thereof, comprising administering to the patient a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof.
[0017] One embodiment provides a pharmaceutical composition
comprising a compound of Formula (II), or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
excipient.
[0018] One embodiment provides a method of regulating gene
transcription in a cell comprising inhibiting lysine-specific
demethylase 1 activity by exposing the lysine-specific demethylase
1 enzyme to a compound of Formula (II).
[0019] One embodiment provides a method of treating cancer in a
patient in need thereof, comprising administering to the patient a
compound of Formula (II), or a pharmaceutically acceptable salt
thereof.
INCORPORATION BY REFERENCE
[0020] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
[0021] As used herein and in the appended claims, the singular
forms "a," "and," and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to
"an agent" includes a plurality of such agents, and reference to
"the cell" includes reference to one or more cells (or to a
plurality of cells) and equivalents thereof known to those skilled
in the art, and so forth. When ranges are used herein for physical
properties, such as molecular weight, or chemical properties, such
as chemical formulae, all combinations and subcombinations of
ranges and specific embodiments therein are intended to be
included. The term "about" when referring to a number or a
numerical range means that the number or numerical range referred
to is an approximation within experimental variability (or within
statistical experimental error), and thus the number or numerical
range may vary between 1% and 15% of the stated number or numerical
range. The term "comprising" (and related terms such as "comprise"
or "comprises" or "having" or "including") is not intended to
exclude that in other certain embodiments, for example, an
embodiment of any composition of matter, composition, method, or
process, or the like, described herein, may "consist of" or
"consist essentially of" the described features.
Definitions
[0022] As used in the specification and appended claims, unless
specified to the contrary, the following terms have the meaning
indicated below.
[0023] "Amino" refers to the --NH.sub.2 radical.
[0024] "Cyano" refers to the --CN radical.
[0025] "Nitro" refers to the --NO.sub.2 radical.
[0026] "Oxa" refers to the --O-- radical.
[0027] "Oxo" refers to the .dbd.O radical.
[0028] "Thioxo" refers to the .dbd.S radical.
[0029] "Imino" refers to the .dbd.N--H radical.
[0030] "Oximo" refers to the .dbd.N--OH radical.
[0031] "Hydrazino" refers to the .dbd.N--NH.sub.2 radical.
[0032] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to fifteen carbon atoms (e.g.,
C.sub.1-C.sub.15 alkyl). In certain embodiments, an alkyl comprises
one to thirteen carbon atoms (e.g., C.sub.1-C.sub.13 alkyl). In
certain embodiments, an alkyl comprises one to eight carbon atoms
(e.g., C.sub.1-C.sub.8 alkyl). In other embodiments, an alkyl
comprises one to five carbon atoms (e.g., C.sub.1-C.sub.5 alkyl).
In other embodiments, an alkyl comprises one to four carbon atoms
(e.g., C.sub.1-C.sub.4 alkyl). In other embodiments, an alkyl
comprises one to three carbon atoms (e.g., C.sub.1-C.sub.3 alkyl).
In other embodiments, an alkyl comprises one to two carbon atoms
(e.g., C.sub.1-C.sub.2 alkyl). In other embodiments, an alkyl
comprises one carbon atom (e.g., C.sub.1 alkyl). In other
embodiments, an alkyl comprises five to fifteen carbon atoms (e.g.,
C.sub.5-C.sub.15 alkyl). In other embodiments, an alkyl comprises
five to eight carbon atoms (e.g., C.sub.5-C.sub.8 alkyl). In other
embodiments, an alkyl comprises two to five carbon atoms (e.g.,
C.sub.2-C.sub.5 alkyl). In other embodiments, an alkyl comprises
three to five carbon atoms (e.g., C.sub.3-C.sub.5 alkyl). In other
embodiments, the alkyl group is selected from methyl, ethyl,
1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl),
1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),
1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is
attached to the rest of the molecule by a single bond. Unless
stated otherwise specifically in the specification, an alkyl group
is optionally substituted by one or more of the following
substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a).sub.2,
--N(R.sup.a).sub.2, -- C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--OC(O)--N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
[0033] "Alkoxy" refers to a radical bonded through an oxygen atom
of the formula --O-- alkyl, where alkyl is an alkyl chain as
defined above.
[0034] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one carbon-carbon double bond, and having from
two to twelve carbon atoms. In certain embodiments, an alkenyl
comprises two to eight carbon atoms. In other embodiments, an
alkenyl comprises two to four carbon atoms. The alkenyl is attached
to the rest of the molecule by a single bond, for example, ethenyl
(i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl,
penta-1,4-dienyl, and the like. Unless stated otherwise
specifically in the specification, an alkenyl group is optionally
substituted by one or more of the following substituents: halo,
cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, --OR',
--SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--OC(O)--N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
[0035] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one carbon-carbon triple bond, having from two
to twelve carbon atoms. In certain embodiments, an alkynyl
comprises two to eight carbon atoms. In other embodiments, an
alkynyl comprises two to six carbon atoms. In other embodiments, an
alkynyl comprises two to four carbon atoms. The alkynyl is attached
to the rest of the molecule by a single bond, for example, ethynyl,
propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated
otherwise specifically in the specification, an alkynyl group is
optionally substituted by one or more of the following
substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--OC(O)--N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
[0036] "Alkylene" or "alkylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing no unsaturation and having from one to twelve
carbon atoms, for example, methylene, ethylene, propylene,
n-butylene, and the like. The alkylene chain is attached to the
rest of the molecule through a single bond and to the radical group
through a single bond. The points of attachment of the alkylene
chain to the rest of the molecule and to the radical group can be
through one carbon in the alkylene chain or through any two carbons
within the chain. In certain embodiments, an alkylene comprises one
to eight carbon atoms (e.g., C.sub.1-C.sub.8 alkylene). In other
embodiments, an alkylene comprises one to five carbon atoms (e.g.,
C.sub.1-C.sub.5 alkylene). In other embodiments, an alkylene
comprises one to four carbon atoms (e.g., C.sub.1-C.sub.4
alkylene). In other embodiments, an alkylene comprises one to three
carbon atoms (e.g., C.sub.1-C.sub.3 alkylene). In other
embodiments, an alkylene comprises one to two carbon atoms (e.g.,
C.sub.1-C.sub.2 alkylene). In other embodiments, an alkylene
comprises one carbon atom (e.g., C.sub.1 alkylene). In other
embodiments, an alkylene comprises five to eight carbon atoms
(e.g., C.sub.5-C.sub.8 alkylene). In other embodiments, an alkylene
comprises two to five carbon atoms (e.g., C.sub.2-C.sub.5
alkylene). In other embodiments, an alkylene comprises three to
five carbon atoms (e.g., C.sub.3-C.sub.5 alkylene). Unless stated
otherwise specifically in the specification, an alkylene chain is
optionally substituted by one or more of the following
substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--OC(O)--N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
[0037] "Alkynylene" or "alkynylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one carbon-carbon triple bond, and
having from two to twelve carbon atoms. The alkynylene chain is
attached to the rest of the molecule through a single bond and to
the radical group through a single bond. In certain embodiments, an
alkynylene comprises two to eight carbon atoms (e.g.,
C.sub.2-C.sub.8 alkynylene). In other embodiments, an alkynylene
comprises two to five carbon atoms (e.g., C.sub.2-C.sub.5
alkynylene). In other embodiments, an alkynylene comprises two to
four carbon atoms (e.g., C.sub.2-C.sub.4 alkynylene). In other
embodiments, an alkynylene comprises two to three carbon atoms
(e.g., C.sub.2-C.sub.3 alkynylene). In other embodiments, an
alkynylene comprises two carbon atom (e.g., C.sub.2 alkylene). In
other embodiments, an alkynylene comprises five to eight carbon
atoms (e.g., C.sub.5-C.sub.8 alkynylene). In other embodiments, an
alkynylene comprises three to five carbon atoms (e.g.,
C.sub.3-C.sub.5 alkynylene). Unless stated otherwise specifically
in the specification, an alkynylene chain is optionally substituted
by one or more of the following substituents: halo, cyano, nitro,
oxo, thioxo, imino, oximo, trimethylsilanyl, --OR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--OC(O)--N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
[0038] "Aryl" refers to a radical derived from an aromatic
monocyclic or multicyclic hydrocarbon ring system by removing a
hydrogen atom from a ring carbon atom. The aromatic monocyclic or
multicyclic hydrocarbon ring system contains only hydrogen and
carbon from five to eighteen carbon atoms, where at least one of
the rings in the ring system is fully unsaturated, i.e., it
contains a cyclic, delocalized (4n+2) .pi.-electron system in
accordance with the Huckel theory. The ring system from which aryl
groups are derived include, but are not limited to, groups such as
benzene, fluorene, indane, indene, tetralin and naphthalene. Unless
stated otherwise specifically in the specification, the term "aryl"
or the prefix "ar-" (such as in "aralkyl") is meant to include aryl
radicals optionally substituted by one or more substituents
independently selected from alkyl, alkenyl, alkynyl, halo,
fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted carbocyclyl,
optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.b--OR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--OC(O)--OR.sup.a, --R.sup.b--OC(O)--N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O) R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
[0039] "Aralkyl" refers to a radical of the formula --R.sup.c-aryl
where R.sup.c is an alkylene chain as defined above, for example,
methylene, ethylene, and the like. The alkylene chain part of the
aralkyl radical is optionally substituted as described above for an
alkylene chain. The aryl part of the aralkyl radical is optionally
substituted as described above for an aryl group.
[0040] "Aralkenyl" refers to a radical of the formula
--R.sup.d-aryl where R.sup.d is an alkenylene chain as defined
above. The aryl part of the aralkenyl radical is optionally
substituted as described above for an aryl group. The alkenylene
chain part of the aralkenyl radical is optionally substituted as
defined above for an alkenylene group.
[0041] "Aralkynyl" refers to a radical of the formula
--R.sup.e-aryl, where R.sup.e is an alkynylene chain as defined
above. The aryl part of the aralkynyl radical is optionally
substituted as described above for an aryl group. The alkynylene
chain part of the aralkynyl radical is optionally substituted as
defined above for an alkynylene chain.
[0042] "Aralkoxy" refers to a radical bonded through an oxygen atom
of the formula --O--R.sup.c-aryl where R.sup.c is an alkylene chain
as defined above, for example, methylene, ethylene, and the like.
The alkylene chain part of the aralkyl radical is optionally
substituted as described above for an alkylene chain. The aryl part
of the aralkyl radical is optionally substituted as described above
for an aryl group.
[0043] "Carbocyclyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which includes fused or bridged ring systems,
having from three to fifteen carbon atoms. In certain embodiments,
a carbocyclyl comprises three to ten carbon atoms. In other
embodiments, a carbocyclyl comprises five to seven carbon atoms.
The carbocyclyl is attached to the rest of the molecule by a single
bond. Carbocyclyl may be saturated, (i.e., containing single C--C
bonds only) or unsaturated (i.e., containing one or more double
bonds or triple bonds.) A fully saturated carbocyclyl radical is
also referred to as "cycloalkyl." Examples of monocyclic
cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl
is also referred to as "cycloalkenyl." Examples of monocyclic
cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,
cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals
include, for example, adamantyl, norbornyl (i.e.,
bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise
stated specifically in the specification, the term "carbocyclyl" is
meant to include carbocyclyl radicals that are optionally
substituted by one or more substituents independently selected from
alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted carbocyclyl, optionally substituted
carbocyclylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--OC(O)--N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O) R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
[0044] "Carbocyclylalkyl" refers to a radical of the formula
--R.sup.c-carbocyclyl where R.sup.c is an alkylene chain as defined
above. The alkylene chain and the carbocyclyl radical is optionally
substituted as defined above.
[0045] "Carbocyclylalkynyl" refers to a radical of the formula
--R.sup.c-carbocyclyl where R.sup.c is an alkynylene chain as
defined above. The alkynylene chain and the carbocyclyl radical is
optionally substituted as defined above.
[0046] "Carbocyclylalkoxy" refers to a radical bonded through an
oxygen atom of the formula --O--R.sup.c-carbocyclyl where R.sup.c
is an alkylene chain as defined above. The alkylene chain and the
carbocyclyl radical is optionally substituted as defined above.
[0047] As used herein, "carboxylic acid bioisostere" refers to a
functional group or moiety that exhibits similar physical,
biological and/or chemical properties as a carboxylic acid moiety.
Examples of carboxylic acid bioisosteres include, but are not
limited to,
##STR00003##
and the like.
[0048] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo
substituents.
[0049] "Fluoroalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more fluoro radicals, as defined
above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
The alkyl part of the fluoroalkyl radical may be optionally
substituted as defined above for an alkyl group.
[0050] "Heterocyclyl" refers to a stable 3- to 18-membered
non-aromatic ring radical that comprises two to twelve carbon atoms
and from one to six heteroatoms selected from nitrogen, oxygen and
sulfur. Unless stated otherwise specifically in the specification,
the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, which may include fused or bridged ring
systems. The heteroatoms in the heterocyclyl radical may be
optionally oxidized. One or more nitrogen atoms, if present, are
optionally quaternized. The heterocyclyl radical is partially or
fully saturated. The heterocyclyl may be attached to the rest of
the molecule through any atom of the ring(s). Examples of such
heterocyclyl radicals include, but are not limited to, dioxolanyl,
thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,
imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,
octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,
piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,
quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,
tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated
otherwise specifically in the specification, the term
"heterocyclyl" is meant to include heterocyclyl radicals as defined
above that are optionally substituted by one or more substituents
selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted carbocyclyl,
optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.b--OR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--OC(O)--OR.sup.a, --R.sup.b--OC(O)--N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O)R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
[0051] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a
heterocyclyl radical as defined above containing at least one
nitrogen and where the point of attachment of the heterocyclyl
radical to the rest of the molecule is through a nitrogen atom in
the heterocyclyl radical. An N-heterocyclyl radical is optionally
substituted as described above for heterocyclyl radicals. Examples
of such N-heterocyclyl radicals include, but are not limited to,
1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl,
pyrazolidinyl, imidazolinyl, and imidazolidinyl.
[0052] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a
heterocyclyl radical as defined above containing at least one
heteroatom and where the point of attachment of the heterocyclyl
radical to the rest of the molecule is through a carbon atom in the
heterocyclyl radical. A C-heterocyclyl radical is optionally
substituted as described above for heterocyclyl radicals. Examples
of such C-heterocyclyl radicals include, but are not limited to,
2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or
3-pyrrolidinyl, and the like.
[0053] "Heterocyclylalkyl" refers to a radical of the formula
--R.sup.c-heterocyclyl where R.sup.c is an alkylene chain as
defined above. If the heterocyclyl is a nitrogen-containing
heterocyclyl, the heterocyclyl is optionally attached to the alkyl
radical at the nitrogen atom. The alkylene chain of the
heterocyclylalkyl radical is optionally substituted as defined
above for an alkylene chain. The heterocyclyl part of the
heterocyclylalkyl radical is optionally substituted as defined
above for a heterocyclyl group.
[0054] "Heterocyclylalkoxy" refers to a radical bonded through an
oxygen atom of the formula --O--R.sup.c-heterocyclyl where R.sup.c
is an alkylene chain as defined above. If the heterocyclyl is a
nitrogen-containing heterocyclyl, the heterocyclyl is optionally
attached to the alkyl radical at the nitrogen atom. The alkylene
chain of the heterocyclylalkoxy radical is optionally substituted
as defined above for an alkylene chain. The heterocyclyl part of
the heterocyclylalkoxy radical is optionally substituted as defined
above for a heterocyclyl group.
[0055] "Heteroaryl" refers to a radical derived from a 3- to
18-membered aromatic ring radical that comprises two to seventeen
carbon atoms and from one to six heteroatoms selected from
nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical
may be a monocyclic, bicyclic, tricyclic or tetracyclic ring
system, wherein at least one of the rings in the ring system is
fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)
.pi.-electron system in accordance with the Huckel theory.
Heteroaryl includes fused or bridged ring systems. The
heteroatom(s) in the heteroaryl radical is optionally oxidized. One
or more nitrogen atoms, if present, are optionally quaternized. The
heteroaryl is attached to the rest of the molecule through any atom
of the ring(s). Examples of heteroaryls include, but are not
limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl,
1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl,
benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,
benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,
cyclopenta[d]pyrimidinyl,
6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl,
furo[3,2-c]pyridinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl,
imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, triazinyl,
thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,
thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless
stated otherwise specifically in the specification, the term
"heteroaryl" is meant to include heteroaryl radicals as defined
above which are optionally substituted by one or more substituents
selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted carbocyclyl, optionally substituted carbocyclylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.b--OR.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--OC(O)--OR.sup.a,
--R.sup.b--OC(O)--N(R.sup.a).sub.2, --R.sup.b--N(R.sup.a).sub.2,
--R.sup.b--C(O) R.sup.a, --R.sup.b--C(O)OR.sup.a,
--R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
[0056] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl
radical is optionally substituted as described above for heteroaryl
radicals.
[0057] "C-heteroaryl" refers to a heteroaryl radical as defined
above and where the point of attachment of the heteroaryl radical
to the rest of the molecule is through a carbon atom in the
heteroaryl radical. A C-heteroaryl radical is optionally
substituted as described above for heteroaryl radicals.
[0058] "Heteroarylalkyl" refers to a radical of the formula
--R.sup.c-heteroaryl, where R.sup.c is an alkylene chain as defined
above. If the heteroaryl is a nitrogen-containing heteroaryl, the
heteroaryl is optionally attached to the alkyl radical at the
nitrogen atom. The alkylene chain of the heteroarylalkyl radical is
optionally substituted as defined above for an alkylene chain. The
heteroaryl part of the heteroarylalkyl radical is optionally
substituted as defined above for a heteroaryl group.
[0059] "Heteroarylalkoxy" refers to a radical bonded through an
oxygen atom of the formula --O--R.sup.c-heteroaryl, where R.sup.c
is an alkylene chain as defined above. If the heteroaryl is a
nitrogen-containing heteroaryl, the heteroaryl is optionally
attached to the alkyl radical at the nitrogen atom. The alkylene
chain of the heteroarylalkoxy radical is optionally substituted as
defined above for an alkylene chain. The heteroaryl part of the
heteroarylalkoxy radical is optionally substituted as defined above
for a heteroaryl group.
[0060] The compounds disclosed herein may contain one or more
asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that may be defined,
in terms of absolute stereochemistry, as (R)- or (S)-. Unless
stated otherwise, it is intended that all stereoisomeric forms of
the compounds disclosed herein are contemplated by this disclosure.
When the compounds described herein contain alkene double bonds,
and unless specified otherwise, it is intended that this disclosure
includes both E and Z geometric isomers (e.g., cis or trans.)
Likewise, all possible isomers, as well as their racemic and
optically pure forms, and all tautomeric forms are also intended to
be included. The term "geometric isomer" refers to E or Z geometric
isomers (e.g., cis or trans) of an alkene double bond. The term
"positional isomer" refers to structural isomers around a central
ring, such as ortho-, meta-, and para-isomers around a benzene
ring.
[0061] A "tautomer" refers to a molecule wherein a proton shift
from one atom of a molecule to another atom of the same molecule is
possible. The compounds presented herein may, in certain
embodiments, exist as tautomers. In circumstances where
tautomerization is possible, a chemical equilibrium of the
tautomers will exist. The exact ratio of the tautomers depends on
several factors, including physical state, temperature, solvent,
and pH. Some examples of tautomeric equilibrium include:
##STR00004##
[0062] "Optional" or "optionally" means that a subsequently
described event or circumstance may or may not occur and that the
description includes instances when the event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution.
[0063] "Pharmaceutically acceptable salt" includes both acid and
base addition salts. A pharmaceutically acceptable salt of any one
of the substituted heterocyclic derivative compounds described
herein is intended to encompass any and all pharmaceutically
suitable salt forms.
[0064] Preferred pharmaceutically acceptable salts of the compounds
described herein are pharmaceutically acceptable acid addition
salts and pharmaceutically acceptable base addition salts.
[0065] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, hydroiodic acid, hydrofluoric acid,
phosphorous acid, and the like. Also included are salts that are
formed with organic acids such as aliphatic mono- and dicarboxylic
acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic
acids, etc. and include, for example, acetic acid, trifluoroacetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the like. Exemplary salts thus include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates,
phosphates, monohydrogenphosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, trifluoroacetates, propionates, caprylates, isobutyrates,
oxalates, malonates, succinate suberates, sebacates, fumarates,
maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,
phenylacetates, citrates, lactates, malates, tartrates,
methanesulfonates, and the like. Also contemplated are salts of
amino acids, such as arginates, gluconates, and galacturonates
(see, for example, Berge S. M. et al., "Pharmaceutical Salts,"
Journal of Pharmaceutical Science, 66:1-19 (1997), which is hereby
incorporated by reference in its entirety). Acid addition salts of
basic compounds may be prepared by contacting the free base forms
with a sufficient amount of the desired acid to produce the salt
according to methods and techniques with which a skilled artisan is
familiar.
[0066] "Pharmaceutically acceptable base addition salt" refers to
those salts that retain the biological effectiveness and properties
of the free acids, which are not biologically or otherwise
undesirable. These salts are prepared from addition of an inorganic
base or an organic base to the free acid. Pharmaceutically
acceptable base addition salts may be formed with metals or amines,
such as alkali and alkaline earth metals or organic amines. Salts
derived from inorganic bases include, but are not limited to,
sodium, potassium, lithium, ammonium, calcium, magnesium, iron,
zinc, copper, manganese, aluminum salts and the like. Salts derived
from organic bases include, but are not limited to, salts of
primary, secondary, and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines and
basic ion exchange resins, for example, isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine,
ethanolamine, diethanolamine, 2-dimethylaminoethanol,
2-diethylaminoethanol, dicyclohexylamine, lysine, arginine,
histidine, caffeine, procaine, N,N-dibenzylethylenediamine,
chloroprocaine, hydrabamine, choline, betaine, ethylenediamine,
ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine,
theobromine, purines, piperazine, piperidine, N-ethylpiperidine,
polyamine resins and the like. See Berge et al., supra.
[0067] As used herein, "treatment" or "treating," or "palliating"
or "ameliorating" are used interchangeably herein. These terms
refers to an approach for obtaining beneficial or desired results
including but not limited to therapeutic benefit and/or a
prophylactic benefit. By "therapeutic benefit" is meant eradication
or amelioration of the underlying disorder being treated. Also, a
therapeutic benefit is achieved with the eradication or
amelioration of one or more of the physiological symptoms
associated with the underlying disorder such that an improvement is
observed in the patient, notwithstanding that the patient may still
be afflicted with the underlying disorder. For prophylactic
benefit, the compositions may be administered to a patient at risk
of developing a particular disease, or to a patient reporting one
or more of the physiological symptoms of a disease, even though a
diagnosis of this disease may not have been made.
[0068] "Prodrug" is meant to indicate a compound that may be
converted under physiological conditions or by solvolysis to a
biologically active compound described herein. Thus, the term
"prodrug" refers to a precursor of a biologically active compound
that is pharmaceutically acceptable. A prodrug may be inactive when
administered to a subject, but is converted in vivo to an active
compound, for example, by hydrolysis. The prodrug compound often
offers advantages of solubility, tissue compatibility or delayed
release in a mammalian organism (see, e.g., Bundgard, H., Design of
Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
[0069] A discussion of prodrugs is provided in Higuchi, T., et al.,
"Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series,
Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward
B. Roche, American Pharmaceutical Association and Pergamon Press,
1987, both of which are incorporated in full by reference
herein.
[0070] The term "prodrug" is also meant to include any covalently
bonded carriers, which release the active compound in vivo when
such prodrug is administered to a mammalian subject. Prodrugs of an
active compound, as described herein, may be prepared by modifying
functional groups present in the active compound in such a way that
the modifications are cleaved, either in routine manipulation or in
vivo, to the parent active compound. Prodrugs include compounds
wherein a hydroxy, amino or mercapto group is bonded to any group
that, when the prodrug of the active compound is administered to a
mammalian subject, cleaves to form a free hydroxy, free amino or
free mercapto group, respectively. Examples of prodrugs include,
but are not limited to, acetate, formate and benzoate derivatives
of alcohol or amine functional groups in the active compounds and
the like.
[0071] Substituted Heterocyclic Derivative Compounds
[0072] Substituted heterocyclic derivative compounds are described
herein that are lysine specific demethylase-1 inhibitors. These
compounds, and compositions comprising these compounds, are useful
for the treatment of cancer and neoplastic disease. The compounds
described herein are useful for treating prostate cancer, breast
cancer, bladder cancer, lung cancer and/or melanoma and the
like.
[0073] One embodiment provides a compound having the structure of
Formula (I), or a pharmaceutically acceptable salt thereof,
##STR00005## [0074] wherein, [0075] W.sup.1 and W.sup.2 are
independently chosen from N, C--H, or C--F; [0076] X is chosen from
hydrogen, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted heterocyclyl, optionally
substituted cycloalkylalkyl, optionally substituted
heterocyclylalkyl, optionally substituted aralkyl, optionally
substituted heteroarylalkyl, optionally substituted aryl, or
optionally substituted heteroaryl; [0077] Y is chosen from
hydrogen, halogen, optionally substituted alkyl, or optionally
substituted cycloalkylalkyl; and [0078] Z is chosen from an
optionally substituted group chosen from N-heterocyclyl, --O--
heterocyclylalkyl, --N(H)-heterocyclylalkyl, --N(H)-alkyl,
--N(Me)-alkyl, or --N(Me)-heterocyclylalkyl.
[0079] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein W.sup.2 is C--H. Another
embodiment provides the compound or pharmaceutically acceptable
salt of Formula (I), wherein W.sup.1 is C--F. Another embodiment
provides the compound or pharmaceutically acceptable salt of
Formula (I), wherein W.sup.1 is C--H. Another embodiment provides
the compound or pharmaceutically acceptable salt of Formula (I),
wherein W.sup.1 is N.
[0080] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein X is optionally substituted
aryl, or optionally substituted heteroaryl.
[0081] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein X is optionally substituted
aryl. Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein X is optionally substituted
aryl, and the optionally substituted aryl is an optionally
substituted phenyl.
[0082] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein X is optionally substituted
heteroaryl. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (I), wherein X is
optionally substituted heteroaryl, and the optionally substituted
heteroaryl is chosen from an optionally substituted pyridinyl,
optionally substituted pyrimidinyl, optionally substituted
pyrazinyl, optionally substituted pyrazolyl, optionally substituted
indazolyl, optionally substituted azaindazolyl, optionally
substituted isoindazolyl, optionally substituted indolyl, or
optionally substituted azaindolyl.
[0083] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Z is an optionally
substituted --O-heterocyclylalkyl. Another embodiment provides the
compound or pharmaceutically acceptable salt of Formula (I),
wherein Z is an optionally substituted --O-heterocyclylalkyl, the
heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl, and
the R.sup.c is an optionally substituted C.sub.1-C.sub.3 alkylene
chain. Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Z is an optionally
substituted --O-heterocyclylalkyl, the heterocyclylalkyl group has
the formula --R.sup.c-heterocyclyl, and the R.sup.c is an
optionally substituted C.sub.1 alkylene chain. Another embodiment
provides the compound or pharmaceutically acceptable salt of
Formula (I), wherein Z is an optionally substituted
--O-heterocyclylalkyl, the heterocyclylalkyl group has the formula
--R.sup.c-heterocyclyl, and the heterocyclyl is an optionally
substituted nitrogen-containing 4-, 5-, 6-, or 7-membered
heterocyclyl.
[0084] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Z is an optionally
substituted --N(H)-heterocyclylalkyl. Another embodiment provides
the compound or pharmaceutically acceptable salt of Formula (I),
wherein Z is an optionally substituted --N(H)-heterocyclylalkyl,
the heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl,
and the R.sup.c is an optionally substituted C.sub.1-C.sub.3
alkylene chain. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (I), wherein Z is an
optionally substituted --N(H)-heterocyclylalkyl, the
heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl, and
the R.sup.c is an optionally substituted C.sub.1 alkylene chain.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Z is an optionally
substituted --N(H)-heterocyclylalkyl, the heterocyclylalkyl group
has the formula --R.sup.c-heterocyclyl, and the heterocyclyl is an
optionally substituted nitrogen-containing 4-, 5-, 6-, or
7-membered heterocyclyl.
[0085] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Z is an optionally
substituted --N(Me)-heterocyclylalkyl. Another embodiment provides
the compound or pharmaceutically acceptable salt of Formula (I),
wherein Z is an optionally substituted --N(Me)-heterocyclylalkyl,
the heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl,
and the R.sup.c is an optionally substituted C.sub.1-C.sub.3
alkylene chain. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (I), wherein Z is an
optionally substituted --N(Me)-heterocyclylalkyl, the
heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl, and
the R.sup.c is an optionally substituted C.sub.1 alkylene chain.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Z is an optionally
substituted --N(Me)-heterocyclylalkyl, the heterocyclylalkyl group
has the formula --R.sup.c-heterocyclyl, and the heterocyclyl is an
optionally substituted nitrogen-containing 4-, 5-, 6-, or
7-membered heterocyclyl.
[0086] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Z is an optionally
substituted N-heterocyclyl. Another embodiment provides the
compound or pharmaceutically acceptable salt of Formula (I),
wherein Z is an optionally substituted N-heterocyclyl, and the
optionally substituted N-heterocyclyl is a 4-, 5-, 6-, or
7-membered N-heterocyclyl. Another embodiment provides the compound
or pharmaceutically acceptable salt of Formula (I), wherein Z is an
optionally substituted N-heterocyclyl, and the optionally
substituted N-heterocyclyl is a 6-membered N-heterocyclyl. Another
embodiment provides the compound or pharmaceutically acceptable
salt of Formula (I), wherein Z is an optionally substituted
N-heterocyclyl, and the optionally substituted N-heterocyclyl is an
optionally substituted piperidine.
[0087] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Z is an optionally
substituted N-heterocyclyl, the optionally substituted
N-heterocyclyl is an optionally substituted piperidine, and the
optionally substituted piperidine is an optionally substituted
4-aminopiperidine.
[0088] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Y is hydrogen. Another
embodiment provides the compound or pharmaceutically acceptable
salt of Formula (I), wherein Y is halogen. Another embodiment
provides the compound or pharmaceutically acceptable salt of
Formula (I), wherein Y is optionally substituted
cycloalkylalkyl.
[0089] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Y is optionally substituted
alkyl. Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Y is optionally substituted
alkyl, and the optionally substituted alkyl is an optionally
substituted C.sub.1-C.sub.3 alkyl. Another embodiment provides the
compound or pharmaceutically acceptable salt of Formula (I),
wherein Y is optionally substituted alkyl, and the optionally
substituted alkyl is an optionally substituted C.sub.1 alkyl.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Y is optionally substituted
alkyl, and the optionally substituted alkyl is a methyl group.
[0090] One embodiment provides a compound having the structure of
Formula (II), or a pharmaceutically acceptable salt thereof,
##STR00006## [0091] wherein, [0092] W.sup.1 and W.sup.2 are
independently chosen from N, C--H, or C--F; [0093] X is chosen from
hydrogen, optionally substituted alkyl, optionally substituted
alkoxy, optionally substituted alkylamino, optionally substituted
alkynyl, optionally substituted cycloalkylalkynyl, optionally
substituted (cycloalkylalkyl)alkynyl, optionally substituted
heterocyclylalkynyl, optionally substituted
(heterocyclylalkyl)alkynyl, optionally substituted aryl, or
optionally substituted heteroaryl; and [0094] Z is chosen from an
optionally substituted group chosen from N-heterocyclyl,
--C(O)--N-- heterocyclyl, --O-heterocyclylalkyl,
--N(H)-heterocyclylalkyl, --N(H)-alkyl, --N(Me)-alkyl, or
--N(Me)-heterocyclylalkyl.
[0095] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein W.sup.2 is C--H. Another
embodiment provides the compound or pharmaceutically acceptable
salt of Formula (II), wherein W.sup.1 is C--F. Another embodiment
provides the compound or pharmaceutically acceptable salt of
Formula (II), wherein W.sup.1 is C--H. Another embodiment provides
the compound or pharmaceutically acceptable salt of Formula (II),
wherein W.sup.1 is N.
[0096] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein X is optionally
substituted aryl, or optionally substituted heteroaryl.
[0097] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein X is optionally
substituted aryl. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (II), wherein X is
optionally substituted aryl, and the optionally substituted aryl is
an optionally substituted phenyl.
[0098] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein X is optionally
substituted heteroaryl. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (II), wherein X is
optionally substituted heteroaryl, and the optionally substituted
heteroaryl is chosen from an optionally substituted pyridinyl,
optionally substituted pyrimidinyl, optionally substituted
pyrazinyl, optionally substituted pyrazolyl, optionally substituted
indazolyl, optionally substituted azaindazolyl, optionally
substituted isoindazolyl, optionally substituted indolyl,
optionally substituted azaindolyl, optionally substituted
benzimidazolyl, or optionally substituted azabenzimidazolyl.
[0099] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein X is optionally
substituted alkynyl, optionally substituted cycloalkylalkynyl,
optionally substituted (cycloalkylalkyl)alkynyl, optionally
substituted heterocyclylalkynyl, or optionally substituted
(heterocyclylalkyl)alkynyl.
[0100] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein Z is an optionally
substituted --O-heterocyclylalkyl. Another embodiment provides the
compound or pharmaceutically acceptable salt of Formula (II),
wherein Z is an optionally substituted --O-heterocyclylalkyl, the
heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl, and
the R.sup.c is an optionally substituted C.sub.1-C.sub.3 alkylene
chain. Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein Z is an optionally
substituted --O-heterocyclylalkyl, the heterocyclylalkyl group has
the formula --R.sup.c-heterocyclyl, and the R.sup.c is an
optionally substituted C.sub.1 alkylene chain. Another embodiment
provides the compound or pharmaceutically acceptable salt of
Formula (II), wherein Z is an optionally substituted
--O-heterocyclylalkyl, the heterocyclylalkyl group has the formula
--R.sup.c-heterocyclyl, and the heterocyclyl is an optionally
substituted nitrogen-containing 4-, 5-, 6-, or 7-membered
heterocyclyl.
[0101] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein Z is an optionally
substituted --N(H)-heterocyclylalkyl. Another embodiment provides
the compound or pharmaceutically acceptable salt of Formula (II),
wherein Z is an optionally substituted --N(H)-heterocyclylalkyl,
the heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl,
and the R.sup.c is an optionally substituted C.sub.1-C.sub.3
alkylene chain. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (II), wherein Z is an
optionally substituted --N(H)-heterocyclylalkyl, the
heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl, and
the R.sup.c is an optionally substituted C.sub.1 alkylene chain.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein Z is an optionally
substituted --N(H)-heterocyclylalkyl, the heterocyclylalkyl group
has the formula --R.sup.c-heterocyclyl, and the heterocyclyl is an
optionally substituted nitrogen-containing 4-, 5-, 6-, or
7-membered heterocyclyl.
[0102] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein Z is an optionally
substituted --N(Me)-heterocyclylalkyl. Another embodiment provides
the compound or pharmaceutically acceptable salt of Formula (II),
wherein Z is an optionally substituted --N(Me)-heterocyclylalkyl,
the heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl,
and the R.sup.c is an optionally substituted C.sub.1-C.sub.3
alkylene chain. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (II), wherein Z is an
optionally substituted --N(Me)-heterocyclylalkyl, the
heterocyclylalkyl group has the formula --R.sup.c-heterocyclyl, and
the R.sup.c is an optionally substituted C.sub.1 alkylene chain.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein Z is an optionally
substituted --N(Me)-heterocyclylalkyl, the heterocyclylalkyl group
has the formula --R.sup.c-heterocyclyl, and the heterocyclyl is an
optionally substituted nitrogen-containing 4-, 5-, 6-, or
7-membered heterocyclyl.
[0103] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein Z is an optionally
substituted N-heterocyclyl. Another embodiment provides the
compound or pharmaceutically acceptable salt of Formula (II),
wherein Z is an optionally substituted N-heterocyclyl, and the
optionally substituted N-heterocyclyl is a 4-, 5-, 6-, or
7-membered N-heterocyclyl. Another embodiment provides the compound
or pharmaceutically acceptable salt of Formula (II), wherein Z is
an optionally substituted N-heterocyclyl, and the optionally
substituted N-heterocyclyl is a 6-membered N-heterocyclyl.
[0104] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein Z is an optionally
substituted N-heterocyclyl, and the optionally substituted
N-heterocyclyl is an optionally substituted piperidine. Another
embodiment provides the compound or pharmaceutically acceptable
salt of Formula (II), wherein Z is an optionally substituted
N-heterocyclyl, the optionally substituted N-heterocyclyl is an
optionally substituted piperidine, and the optionally substituted
piperidine is an optionally substituted 4-aminopiperidine.
[0105] Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (II), wherein Z is an optionally
substituted --C(O)--N-heterocyclyl. Another embodiment provides the
compound or pharmaceutically acceptable salt of Formula (II),
wherein Z is an optionally substituted --C(O)--N-heterocyclyl, and
the optionally substituted N-heterocyclyl is an optionally
substituted piperidine.
[0106] In some embodiments, the substituted heterocyclic derivative
compound described herein has the structure provided in Table
1.
TABLE-US-00001 TABLE 1 Chemical Synthesis Example Structure Name 1
##STR00007## 4-[2-(4- aminopiperidin-1-yl)- 5-(1-methyl-1H-
indazol-5-yl)-1,3- thiazol-4- yl]benzonitrile 2 ##STR00008##
cis-4-(2- {decahydropyrrolo[3,4- d]azepin-6-yl}-5-(1-
methyl-1H-indazol-5- yl)-1,3-thiazol-4- yl)benzonitrile 3
##STR00009## 4-[2-(4- aminopiperidin-1-yl)- 5-{1-methyl-1H-
pyrrolo[2,3-b]pyridin- 5-yl}-1,3-thiazol-4- yl]benzonitrile 4
##STR00010## 4-[2-(4- aminopiperidin-1-yl)- 5-{1-methyl-1H-
pyrazolo[3,4-b]pyridin- 5-yl}-1,3-thiazol-4- yl]benzonitrile 5
##STR00011## 4-(2-{2,8- diazaspiro[4.5]decan- 8-yl}-5-(1-methyl-1H-
indazol-5-yl)-1,3- thiazol-4- yl)benzonitrile 6 ##STR00012##
4-[5-(1-methyl-1H- indazol-5-yl)-2- {octahydro-1H-
pyrrolo[3,2-c]pyridin- 5-yl}-1,3-thiazol-4- yl]benzonitrile 7
##STR00013## 4-[5-(1-methyl-1H- indazol-5-yl)-2- {octahydro-1H-
pyrrolo[3,4-c]pyridin- 5-yl}-1,3-thiazol-4- yl]benzonitrile 8
##STR00014## 4-[2-(4- aminopiperidin-1-yl)- 5-(1-methyl-1H-1,3-
benzodiazol-5-yl)-1,3- thiazol-4- yl]benzonitrile 9 ##STR00015##
4-[2-(4- aminopiperidin-1-yl)- 5-{3-methyl-3H-
imidazo[4,5-b]pyridin- 6-yl}-1,3-thiazol-4- yl]benzonitrile 10
##STR00016## cis-4-(2- {decahydropyrrolo[3,4- d]azepin-6-yl}-5-(1-
methyl-1H-1,3- benzodiazol-5-yl)-1,3- thiazol-4- yl)benzonitrile 11
##STR00017## cis-4-(2- {decahydropyrrolo[3,4- d]azepin-6-yl}-5-{1-
methyl-1H- pyrazolo[3,4-b]pyridin- 5-yl}-1,3-thiazol-4-
yl)benzonitrile 12 ##STR00018## 4-[2-(4- aminopiperidin-1-yl)-
5-[1-(2,2,2- trifluoroethyl)-1H- pyrazol-4-yl]-1,3- thiazol-4-
yl]benzonitrile 13 ##STR00019## 4-(2- {decahydropyrrolo[3,4-
d]azepin-6-yl}-5-[1- (2,2,2-trifluoroethyl)- 1H-pyrazol-4-yl]-1,3-
thiazol-4- yl)benzonitrile 14 ##STR00020## 4-[2-(4-
aminopiperidin-1-yl- 5[1- (cyclopropylmethyl)-
1H-pyrazol-4-yl]-1,3- thiazol-4- yl]benzonitrile 15 ##STR00021##
4-{5-[1- (cyclopropylmethyl)- 1H-pyrazol-4-yl]-2-
{decahydropyrrolo[3,4- d]azepin-6-yl}-1,3- thiazol-4-
yl}benzonitrile 16 ##STR00022## 4-{2-[(3R)-3- aminopiperidine-1-
carbonyl]-5-(1-methyl- 1H-1,3-benzodiazol-5- yl)-1,3-thiazol-4-
yl}benzonitrile 17 ##STR00023## 4-{2-[(3S)-3- aminopiperidine-1-
carbonyl]-5-(1-methyl- 1H-1,3-benzodiazol-5- yl)-1,3-thiazol-4-
yl}benzonitrile 18 ##STR00024## 4-[2-(4- aminopiperidine-1-
carbonyl)-5-(1-methyl- 1H-1,3-benzodiazol-5- yl)-1,3-thiazol-4-
yl]benzonitrile 19 ##STR00025## 4-{2-[(3R)-3- aminopiperidine-1-
carbonyl]-5-(4- methylphenyl)-1,3- thiazol-4- yl}benzonitrile 20
##STR00026## 4-{2-[(3R)-3- aminopiperidine-1-
carbonyl]-5-{3-methyl- 3H-imidazo[4,5- b]pyridin-6-yl}-1,3-
thiazol-4- yl}benzonitrile 21 ##STR00027## 4-{2-[(3R)-3-
aminopiperidine-1- carbonyl]-5-[1-(2,2,2- trifluoroethyl)-1H-
pyrazol-4-yl]-1,3- thiazol-4- yl}benzonitrile 22 ##STR00028##
4-{2-[(3R)-3- aminopiperidine-1- carbonyl]-5-[1-
(cyclopropylmethyl)- 1H-pyrazol-4-yl]-1,3- thiazol-4-
yl}benzonitrile 23 ##STR00029## 4-[2-(4- aminopiperidin-1-yl)-
5-(3-hydroxy-3- methylbut-1-yn-1-yl)- 1,3-thiazol-4-
yl]benzonitrile 24 ##STR00030## 4-[2-(4- aminopiperidin-1-yl)-
5-(3-hydroxy-3- cyclopentylprop-1-yn- 1-yl)-1,3-thiazol-4-
yl]benzonitrile 25 ##STR00031## 4-[2-(4- aminopiperidin-1-yl)-
5-{3-methyl-3H- imidazo[4,5-b]pyridin- 6-yl}-1,3-thiazol-4-yl]-
2-fluorobenzonitrile 26 ##STR00032## 4-[4-(4- aminopiperidin-1-yl)-
1-(4- cyclopropylphenyl)-6- oxopyrimidin-2-yl]-2-
fluorobenzonitrile 27 ##STR00033## 4-[4-(1,2,3,3a,4,6,7,7a-
octahydropyrrolo[3,2- c]pyridin-5-yl)-1-(4- cyclopropylphenyl)-6-
oxopyrimidin-2-yl]-2- fluorobenzonitrile 28 ##STR00034##
4-[4-(1,2,3,3a,4,6,7,7a- octahydropyrrolo[3,4-
c]pyridin-5-yl)-1-(4- cyclopropylphenyl)-6- oxopyrimidin-2-yl]-2-
fluorobenzonitrile 29 ##STR00035## 4-[1-(4- cyclopropylphenyl)-4-
(2,8- diazaspiro[4.5]decan- 8-yl)-6-oxopyrimidin- 2-yl]-2-
fluorobenzonitrile 30 ##STR00036## 4-[4-(4- aminopiperidin-1-yl)-
1-(3-fluoro-4- methoxyphenyl)-6- oxopyrimidin-2-yl]-2-
fluorobenzonitrile 31 ##STR00037## 4-[4-(4- aminopiperidin-1-yl)-
1-(2-methylindazol-5- yl)-6-oxopyrimidin-2-
yl]-2-fluorobenzonitrile 32 ##STR00038## 4-[4-(4-
aminopiperidin-1-yl)- 1-(4-methoxyphenyl)- 6-oxopyrimidin-2-yl]-
2-fluorobenzonitrile 33 ##STR00039## 4-[4-(4- aminopiperidin-1-yl)-
1-(4-cyclopropyl-3- fluorophenyl)-6- oxopyrimidin-2-yl]-2-
fluorobenzonitrile 34 ##STR00040## 4-[2-(4- aminopiperidin-1-yl)-
5-{2-methyl-2H- indazol-5-yl)pyrazin-2- yl}-1,3-thiazol-4-
yl]benzonitrile
[0107] In some embodiments, the substituted heterocyclic derivative
compound described herein has the structure provided in Table
2.
TABLE-US-00002 TABLE 2 ##STR00041## ##STR00042## ##STR00043##
##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048##
##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053##
##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058##
##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063##
##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068##
##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078##
##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083##
##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088##
##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093##
##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098##
##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103##
##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108##
##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113##
##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118##
##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123##
##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128##
##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133##
##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138##
##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143##
##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148##
##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153##
##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158##
##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163##
##STR00164##
##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169##
##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174##
##STR00175## ##STR00176##
Preparation of the Substituted Heterocyclic Derivative
Compounds
[0108] The compounds used in the reactions described herein are
made according to organic synthesis techniques known to those
skilled in this art, starting from commercially available chemicals
and/or from compounds described in the chemical literature.
"Commercially available chemicals" are obtained from standard
commercial sources including Acros Organics (Pittsburgh, Pa.),
Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and
Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research
(Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall,
U.K.), Chemservice Inc. (West Chester, Pa.), Crescent Chemical Co.
(Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman Kodak Company
(Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons
Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah),
ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall,
U.K.), Lancaster Synthesis (Windham, N.H.), Maybridge Chemical Co.
Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz
& Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),
Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,
Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI
America (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville,
Md.), and Wako Chemicals USA, Inc. (Richmond, Va.).
[0109] Methods known to one of ordinary skill in the art are
identified through various reference books and databases. Suitable
reference books and treatise that detail the synthesis of reactants
useful in the preparation of compounds described herein, or provide
references to articles that describe the preparation, include for
example, "Synthetic Organic Chemistry", John Wiley & Sons,
Inc., New York; S. R. Sandler et al., "Organic Functional Group
Preparations," 2nd Ed., Academic Press, New York, 1983; H. O.
House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc.
Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry",
2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced
Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed.,
Wiley-Interscience, New York, 1992. Additional suitable reference
books and treatise that detail the synthesis of reactants useful in
the preparation of compounds described herein, or provide
references to articles that describe the preparation, include for
example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts,
Methods, Starting Materials", Second, Revised and Enlarged Edition
(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V.
"Organic Chemistry, An Intermediate Text" (1996) Oxford University
Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations" 2nd
Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure" 4th
Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera,
J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:
3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of
Functional Groups" (1992) Interscience ISBN: 0-471-93022-9;
Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John
Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C.,
"Intermediate Organic Chemistry" 2nd Edition (1993)
Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic
Chemicals: Starting Materials and Intermediates: An Ullmann's
Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in
8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons,
in over 55 volumes; and "Chemistry of Functional Groups" John Wiley
& Sons, in 73 volumes.
[0110] Specific and analogous reactants may also be identified
through the indices of known chemicals prepared by the Chemical
Abstract Service of the American Chemical Society, which are
available in most public and university libraries, as well as
through on-line databases (the American Chemical Society,
Washington, D.C., may be contacted for more details). Chemicals
that are known but not commercially available in catalogs may be
prepared by custom chemical synthesis houses, where many of the
standard chemical supply houses (e.g., those listed above) provide
custom synthesis services. A reference for the preparation and
selection of pharmaceutical salts of the substituted heterocyclic
derivative compounds described herein is P. H. Stahl & C. G.
Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica
Chimica Acta, Zurich, 2002.
[0111] The substituted heterocyclic derivative compounds are
prepared by the general synthetic routes described below in Schemes
1-3.
[0112] The substituted thiazole derivative compounds are prepared
by the general synthetic route described below in Scheme 1.
##STR00177##
[0113] Referring to Scheme 1, bromination of compound A yields
compound B. Compound C is obtained from treatment of compound B
under Sandmayer substitution condition. Displacement of compound C
is carried out with a variety of amines DD'-NH.sub.2 under basic
conditions to form compound E. Compound H is prepared from aryl
halide compound E using palladium-mediated cross coupling
conditions with boronic acids G-(OH).sub.2.
[0114] The substituted thiazole derivative compounds are prepared
by the general synthetic route described below in Scheme 2.
##STR00178##
[0115] Referring to Scheme 2, condensation of BH and BI in
polar-protic solvent at elevated temperature provides the
cyclo-annulation product thiazole BJ. Treatment with electrophilic
halide results in substitution to afford BK. Upon hydrolysis to
provide acid BL, BL is coupled with various amines to give amide BN
using amide coupling reagents. Compound BJ is prepared from aryl
halides compound BN using palladium-mediated cross coupling
conditions with boronic acids BC--B(OH).sub.2.
[0116] The substituted pyrimidinone derivative compounds are
prepared by the general synthetic route described below in Scheme
3.
##STR00179##
[0117] Referring to scheme 3, amidine BM reacts with an activated
malonate such as bis(2,4,6-triphenyl)malonate, in an organic
solvent such as toluene, and heated at an elevated temperature to
give cyclized pyrimidinone intermediate BR. Chlorination of BR by a
chlorinating reagent such as phosphorus oxychloride, provides BS.
Chloro compound BS undergoes SNAr displacement with 1 equivalent of
amine in an organic solvent such as DMF, in the presence of a base
such as diisopropylethyl amine. Final product BU is obtained after
removal of protective groups.
Pharmaceutical Compositions
[0118] In certain embodiments, the substituted heterocyclic
derivative compound as described herein is administered as a pure
chemical. In other embodiments, the substituted heterocyclic
derivative compound described herein is combined with a
pharmaceutically suitable or acceptable carrier (also referred to
herein as a pharmaceutically suitable (or acceptable) excipient,
physiologically suitable (or acceptable) excipient, or
physiologically suitable (or acceptable) carrier) selected on the
basis of a chosen route of administration and standard
pharmaceutical practice as described, for example, in Remington:
The Science and Practice of Pharmacy (Gennaro, 21.sup.st Ed. Mack
Pub. Co., Easton, Pa. (2005)), the disclosure of which is hereby
incorporated herein by reference in its entirety.
[0119] Accordingly, provided herein is a pharmaceutical composition
comprising at least one substituted heterocyclic derivative
compound, or a stereoisomer, pharmaceutically acceptable salt,
hydrate, solvate, or N-oxide thereof, together with one or more
pharmaceutically acceptable carriers. The carrier(s) (or
excipient(s)) is acceptable or suitable if the carrier is
compatible with the other ingredients of the composition and not
deleterious to the recipient (i.e., the subject) of the
composition.
[0120] One embodiment provides a pharmaceutical composition
comprising a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
excipient.
[0121] One embodiment provides a pharmaceutical composition
comprising a compound of Formula (II), or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
excipient.
[0122] In certain embodiments, the substituted heterocyclic
derivative compound as described by Formula (I) or (II) is
substantially pure, in that it contains less than about 5%, or less
than about 1%, or less than about 0.1%, of other organic small
molecules, such as contaminating intermediates or by-products that
are created, for example, in one or more of the steps of a
synthesis method.
[0123] Suitable oral dosage forms include, for example, tablets,
pills, sachets, or capsules of hard or soft gelatin,
methylcellulose or of another suitable material easily dissolved in
the digestive tract. Suitable nontoxic solid carriers can be used
which include, for example, pharmaceutical grades of mannitol,
lactose, starch, magnesium stearate, sodium saccharin, talcum,
cellulose, glucose, sucrose, magnesium carbonate, and the like.
(See, e.g., Remington: The Science and Practice of Pharmacy
(Gennaro, 21.sup.st Ed. Mack Pub. Co., Easton, Pa. (2005)).
[0124] The dose of the composition comprising at least one
substituted heterocyclic derivative compound as described herein
may differ, depending upon the patient's (e.g., human) condition,
that is, stage of the disease, general health status, age, and
other factors that a person skilled in the medical art will use to
determine dose.
[0125] Pharmaceutical compositions may be administered in a manner
appropriate to the disease to be treated (or prevented) as
determined by persons skilled in the medical arts. An appropriate
dose and a suitable duration and frequency of administration will
be determined by such factors as the condition of the patient, the
type and severity of the patient's disease, the particular form of
the active ingredient, and the method of administration. In
general, an appropriate dose and treatment regimen provides the
composition(s) in an amount sufficient to provide therapeutic
and/or prophylactic benefit (e.g., an improved clinical outcome,
such as more frequent complete or partial remissions, or longer
disease-free and/or overall survival, or a lessening of symptom
severity. Optimal doses may generally be determined using
experimental models and/or clinical trials. The optimal dose may
depend upon the body mass, weight, or blood volume of the
patient.
[0126] Oral doses can typically range from about 1.0 mg to about
1000 mg, one to four times, or more, per day.
[0127] Biology
[0128] Epigenetics is the study of heritable changes in gene
expression caused by mechanisms other than the underlying DNA
sequence. Molecular mechanisms that play a role in epigenetic
regulation include DNA methylation and chromatin/histone
modifications.
[0129] The genomes of eukaryotic organisms are highly organized
within the nucleus of the cell. Tremendous compaction is required
to package the 3 billion nucleotides of the human genome into the
nucleus of a cell. Chromatin is the complex of DNA and protein that
makes up chromosomes. Histones are the major protein component of
chromatin, acting as spools around which DNA winds. Changes in
chromatin structure are affected by covalent modifications of
histone proteins and by non-histone binding proteins. Several
classes of enzymes are known which can modify histones at various
sites.
[0130] There are a total of six classes of histones (HI, H2A, H2B,
H3, H4, and H5) organized into two groups: core histones (H2A, H2B,
H3, and H4) and linker histones (HI and H5). The basic unit of
chromatin is the nucleosome, which consists of about 147 base pairs
of DNA wrapped around the core histone octamer, consisting of two
copies each of the core histones H2A, H2B, H3, and H4.
[0131] Basic nucleosome units are then further organized and
condensed by the aggregation and folding of nucleosomes to form a
highly condensed chromatin structure. A range of different states
of condensation are possible, and the tightness of chromatin
structure varies during the cell cycle, being most compact during
the process of cell division.
[0132] Chromatin structure plays a critical role in regulating gene
transcription, which cannot occur efficiently from highly condensed
chromatin. The chromatin structure is controlled by a series of
post translational modifications to histone proteins, notably
histones H3 and H4, and most commonly within the histone tails
which extend beyond the core nucleosome structure. These
modifications acetylation, methylation, phosphorylation,
ribosylation sumoylation, ubiquitination, citrullination,
deimination, and biotinylation. The core of histones H2A and H3 can
also be modified. Histone modifications are integral to diverse
biological processes such as gene regulation, DNA repair, and
chromosome condensation.
[0133] Histone methylation is one of the most important chromatin
marks; these play important roles in transcriptional regulation,
DNA-damage response, heterochromatin formation and maintenance, and
X-chromosome inactivation. A recent discovery also revealed that
histone methylation affects the splicing outcome of pre-mRNA by
influencing the recruitment of splicing regulators. Histone
methylation includes mono-, di-, and tri-methylation of lysines,
and mono-, symmetric di-, and asymmetric di-methylation of
arginines. These modifications can be either an activating or
repressing mark, depending on the site and degree of
methylation.
Histone Demethylases
[0134] A "demethylase" or "protein demethylase," as referred to
herein, refers to an enzyme that removes at least one methyl group
from polypeptide. Demethylases comprise a JmjC domain, and can be a
methyl-lysine or methyl-arginine demethylase. Some demethylases act
on histones, e.g., act as a histone H3 or H4 demethylase. For
example, an H3 demethylase may demethylate one or more of H3K4,
H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4 demethylase may
demethylate histone H4K20. Demethylases are known which can
demethylate either a mono-, di- and/or a tri-methylated substrate.
Further, histone demethylases can act on a methylated core histone
substrate, a mononucleosome substrate, a dinucleosome substrate
and/or an oligonucleosome substrate, peptide substrate and/or
chromatin (e.g., in a cell-based assay).
[0135] The first lysine demethylase discovered was lysine specific
demethylase 1 (LSD1/KDM1), which demethylates both mono- and
di-methylated H3K4 or H3K9, using flavin as a cofactor. A second
class of Jumonji C (JmjC) domain containing histone demthylases
were predicted, and confirmed when a H3K36 demethylase was found
used a formaldehyde release assay, which was named JmjC domain
containing histone demethylase 1 (JHDM1/KDM2A).
[0136] More JmjC domain-containing proteins were subsequently
identified and they can be phylogenetically clustered into seven
subfamilies: JHDM1, JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY,
and JmjC domain only.
LSD-1
[0137] Lysine-specific demethylase 1 (LSD1) is a histone lysine
demethylase that specifically demethylates monomethylated and
dimethylated histone H3 at K4 and also demethylates dimethylated
histone H3 at K9. Although the main target of LSD1 appears to be
mono- and di-methylated histone lysines, specifically H3K4 and
H3K9, there is evidence in the literature that LSD 1 can
demethylate methylated lysines on non-histone proteins like p53,
E2F1, Dnmt1 and STAT3.
[0138] LSD 1 has a fair degree of structural similarity and amino
acid identity/homology to polyamine oxidases and monoamine
oxidases, all of which (i. e., MAO-A, MAO-B and LSD1) are flavin
dependent amine oxidases which catalyze the oxidation of
nitrogen-hydrogen bonds and/or nitrogen-carbon bonds. LSD1 also
includes an N-terminal SWRIM domain. There are two transcript
variants of LSD1 produced by alternative splicing.
Methods of Use
[0139] In some embodiments, the compounds disclosed herein are
capable of inhibiting LSD1 activity in a biological sample by
contacting the biological sample with a substituted heterocyclic
compound as disclosed herein. In some embodiments, a substituted
heterocyclic compound as disclosed herein is capable of modulating
the level of histone 4 lysine 3 methylation in the biological
sample. In some embodiments, a substituted heterocyclic compound as
disclosed herein is capable of modulating histone-3 lysine-9
methylation levels in the biological sample.
[0140] In some embodiments, a substituted heterocyclic compound as
disclosed herein inhibits LSD1 activity to a greater extent than
MAO-A and/or MAO-B.
[0141] One embodiment provides a method of regulating gene
transcription in a cell comprising inhibiting lysine-specific
demethylase 1 activity by exposing the lysine-specific demethylase
1 enzyme to a compound of Formula (I).
[0142] One embodiment provides a method of regulating gene
transcription in a cell comprising inhibiting lysine-specific
demethylase 1 activity by exposing the lysine-specific demethylase
1 enzyme to a compound of Formula (II).
Methods of Treatment
[0143] Disclosed herein are methods of modulating demethylation in
a cell or in a subject, either generally or with respect to one or
more specific target genes. Demethylation can be modulated to
control a variety of cellular functions, including without
limitation: differentiation; proliferation; apoptosis;
tumorigenesis, leukemogenesis or other oncogenic transformation
events; hair loss; or sexual differentiation.
[0144] One embodiment provides a method of treating cancer in a
patient in need thereof, comprising administering to the patient a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof.
[0145] One embodiment provides a method of treating cancer in a
patient in need thereof, comprising administering to the patient a
compound of Formula (II), or a pharmaceutically acceptable salt
thereof.
[0146] In a further embodiment is the method for treating cancer in
a subject wherein the cancer is selected from prostate cancer,
breast cancer, bladder cancer, lung cancer or melanoma.
[0147] Other embodiments and uses will be apparent to one skilled
in the art in light of the present disclosures. The following
examples are provided merely as illustrative of various embodiments
and shall not be construed to limit the invention in any way.
EXAMPLES
I. Chemical Synthesis
[0148] Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Anhydrous solvents and
oven-dried glassware were used for synthetic transformations
sensitive to moisture and/or oxygen. Yields were not optimized.
Reaction times are approximate and were not optimized. Column
chromatography and thin layer chromatography (TLC) were performed
on silica gel unless otherwise noted. Spectra are given in ppm
(.delta.) and coupling constants, J are reported in Hertz. For
proton spectra the solvent peak was used as the reference peak.
Example 1:
4-[2-(4-aminopiperidin-1-yl)-5-(1-methyl-1H-indazol-5-yl)-1,3-t-
hiazol-4-yl]benzonitrile
##STR00180##
[0150] Preparation 1A To a round-bottom flash charged with
4-(2-amino-1,3-thiazol-4-yl)benzonitrile (2.0 g, 10 mmol) in
CCl.sub.4 (50 mL) was added NBS (1.8 g, 10 mmol). The reaction was
allowed to stir at room temperature for 2 hours. The heterogeneous
mixture was filtered and the filter cake was washed with water and
dried in vacuo to afford
4-(2-amino-5-bromo-1,3-thiazol-4-yl)benzonitrile (2.0 g, 71%) as an
off-white solid. [M+H] Calc'd for C.sub.10H.sub.6BrN.sub.3S, 281;
Found, 281.
[0151] Preparation 1B To a round-bottom flask charged with t-BuONO
(712 .mu.L, 6 mmol) in ACN (20 mL) was added CuCl.sub.2 (800 mg, 6
mmol). After 10 min, 2-amino-4-bromo-5-(4-benzonitrile)thiazole
(1.12 g, 4 mmol) was added. The reaction was kept at 70.degree. C.
for 2 hours with vigorous stirring at which time the reaction was
quenched with HCl (1N, 20 mL) followed by water. The heterogeneous
solution was extracted with EtOAc and the combined organic layers
were successively washed with brine, dried over Na.sub.2SO.sub.4,
and concentrated in vacuo. The residue was purified by flash
chromatography (33% EtOAc in hexanes) to give
4-(5-bromo-2-chloro-1,3-thiazol-4-yl)benzonitrile (1.1 g, 90%) as a
beige solid.
[0152] Preparation 1C To a round bottom-flask charged with
4-(5-bromo-2-chloro-1,3-thiazol-4-yl)benzonitrile (1.2 g, 4 mmol)
and piperidin-4-yl-carbamic acid tert-butyl ester (1.0 g, 5 mmol)
in DMF (30 mL) was added DIEA (1.0 g, 8 mmol). The reaction was
allowed to stir at 100.degree. C. for 2 hours under inert
atmosphere. Upon completion, the reaction was concentrated in vacuo
and the residue purified by flash chromatography (30-50% gradient
of EtOAc in hexanes) to afford tert-butyl
N-{1-[5-bromo-4-(4-cyanophenyl)-1,3-thiazol-2-yl]piperidin-4-yl}carbamate
(1.4 g, 80%) as a yellow solid. [M+H] Calc'd for
C.sub.20H.sub.23BrN.sub.4O.sub.2S, 463; Found, 463.
[0153] Preparation 1D A vial was charged with tert-butyl
N-{1-[5-bromo-4-(4-cyanophenyl)-1,3-thiazol-2-yl]piperidin-4-yl}carbamate
(139 mg, 0.3 mmol), 1-methylindazole-5-boronic acid (64 mg, 0.36
mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (25 mg, 0.03 mmol) and 2M
Na.sub.2CO.sub.3 in 1,4-dioxane (10 mL). The mixture was purged
with nitrogen for 2 min and allowed to stir at 120.degree. C. 16
hrs. The crude reaction was concentrated in vacuo and the residue
purified by flash chromatography (PE/EA=1/1.about.1/2) to afford a
yellow solid. The solid was dissolved in DCM (10 mL) followed by
the addition of TFA (1 mL) and allowed to stir at ambient
temperature for 2 hours. The mixture was concentrated in vacuo and
purified by prep-HPLC to afford the title compound as the HCl salt
(25 mg, 31%) as a yellow solid. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. ppm 1.64-1.68 (2H, m), 2.00-2.04 (2H, m), 3.08-3.12 (2H,
m), 3.21-3.22 (1H, m), 3.97 (3H, s), 4.07-4.10 (2H, m), 7.17-7.19
(1H, m), 7.43-7.52 (5H, m), 7.63 (1H, s), 7.89 (1H, s). LCMS
(mobile phase: 5-95% Acetonitrile-Water-0.1% TFA): purity is
>95%, Rt=2.934 min. [M+H] Calc'd for C.sub.23H.sub.22N.sub.6S,
415; Found, 415.
Example 2:
cis-4-(2-{decahydropyrrolo[3,4-d]azepin-6-yl}-5-(1-methyl-1H-in-
dazol-5-yl)-1,3-thiazol-4-yl)benzonitrile
##STR00181##
[0155] The title compound was prepared in 45% yield starting with
cis-2-BOC-octahydropyrrolo[3,4-d]azepine hydrochloride and
1-methylindazole-5-boronic acid according to the procedure for the
preparation of Example 1C and 1D. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. ppm 1.64-1.68 (2H, m), 2.00-2.04 (2H, m),
3.08-3.12 (2H, m), 3.21-3.22 (1H, m), 3.97 (3H, s), 4.07-4.10 (2H,
m), 7.17-7.19 (1H, m), 7.43-7.52 (5H, m), 7.63 (1H, s), 7.89 (1H,
s). LCMS (mobile phase: 5-95% Acetonitrile-Water-0.1% TFA): purity
is >95%, Rt=2.934 min. [M+H] Calc'd for
C.sub.23H.sub.22N.sub.6S, 415; Found, 415.
Example 3:
4-[2-(4-aminopiperidin-1-yl)-5-{1-methyl-1H-pyrrolo[2,3-b]pyrid-
in-5-yl}-1,3-thiazol-4-yl]benzonitrile
##STR00182##
[0157] The title compound was prepared in 15% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.79-1.73 (2H,
m), 2.10-2.13 (2H, m), 3.17-3.24 (2H, m), 3.39-3.43 (1H, m), 3.85
(3H, s), 4.16-4.19 (2H, m), 6.47 (1H, s), 7.41 (1H, s), 7.55-7.60
(4H, m), 7.89 (1H, s), 8.06 (1H, s). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.904 min.
[M+H] Calc'd for C.sub.23H.sub.22N.sub.6S, 414; Found, 414.
Example 4:
4-[2-(4-aminopiperidin-1-yl)-5-{1-methyl-1H-pyrazolo[3,4-b]pyri-
din-5-yl}-1,3-thiazol-4-yl]benzonitrile
##STR00183##
[0159] The title compound was prepared in 23% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 1.62-1.66 (2H,
m), 2.02-2.05 (2H, m), 3.16-3.22 (2H, m), 3.21-3.22 (1H, m),
3.99-4.02 (2H, m), 4.06 (3H, s), 7.55-7.57 (2H, d, J=8.0 Hz),
7.73-7.75 (2H, d, J=8.0 Hz), 7.88-7.95 (2H, bs), 8.16 (1H, s), 8.22
(1H, s), 8.39 (1H, s). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.822 min.
[M+H] Calc'd for C.sub.22H.sub.21N.sub.7S, 415; Found, 415.
Example 5:
4-(2-{2,8-diazaspiro[4.5]decan-8-yl}-5-(1-methyl-1H-indazol-5-y-
l)-1,3-thiazol-4-yl)benzonitrile
##STR00184##
[0161] The title compound was prepared in 23% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. ppm 1.81-1.84 (4H,
m), 2.03-2.08 (2H, m), 3.21-3.22 (2H, m), 3.42-3.47 (2H, m),
3.59-3.64 (4H, m), 4.08 (3H, s), 7.26-7.30 (1H, m), 7.52-7.62 (5H,
m), 7.72 (1H, s), 7.99 (1H, s). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.098 min.
[M+H] Calc'd for C.sub.26H.sub.26N.sub.6S, 454; Found, 454.
Example 6:
4-[5-(1-methyl-1H-indazol-5-yl)-2-{octahydro-1H-pyrrolo[3,2-c]p-
yridin-5-yl}-1,3-thiazol-4-yl]benzonitrile
##STR00185##
[0163] The title compound was prepared in 21% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.98-2.09 (2H,
m), 2.16-2.27 (2H, m), 2.69-2.72 (1H, m), 3.36-3.43 (2H, m),
3.51-3.53 (1H, m), 3.71-3.76 (1H, m), 3.83-3.88 (1H, m), 3.94-3.99
(2H, m), 4.09 (3H, s), 7.29-7.32 (1H, m), 7.55-7.64 (5H, m), 7.75
(1H, s), 8.01 (1H, s). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.02% NH.sub.4OAc): purity is >95%, Rt=3.621
min. [M+H] Calc'd for C.sub.25H.sub.24N.sub.6S, 441; Found,
441.
Example 7:
4-[5-(1-methyl-1H-indazol-5-yl)-2-{octahydro-1H-pyrrolo[3,4-c]p-
yridin-5-yl}-1,3-thiazol-4-yl]benzonitrile
##STR00186##
[0165] The title compound was prepared in 39% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.58-1.61 (1H,
m), 1.84-1.88 (1H, m), 2.52-2.63 (2H, m), 3.05-3.11 (2H, m),
3.14-3.18 (1H, m), 3.29-3.34 (1H, m), 3.37-3.42 (1H, m), 3.50-3.55
(1H, m), 3.72-3.75 (1H, m), 3.81-3.85 (1H, m), 3.97 (3H, s),
7.14-7.17 (1H, m), 7.41-7.49 (5H, m), 7.60 (1H, s), 7.87 (1H, s).
LCMS (mobile phase: 5-95% Acetonitrile-Water-0.1% TFA): purity is
>95%, Rt=3.004 min. [M+H] Calc'd for C.sub.25H.sub.24N.sub.6S,
441; Found, 441.
Example 8:
4-[2-(4-aminopiperidin-1-yl)-5-(1-methyl-1H-1,3-benzodiazol-5-y-
l)-1,3-thiazol-4-yl]benzonitrile
##STR00187##
[0167] The title compound was prepared in 12% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.75-1.84 (2H,
m), 2.15-2.17 (2H, m), 3.23-3.30 (2H, m), 3.43-3.49 (1H, m), 4.16
(3H, s), 4.19-4.23 (2H, m), 7.55-7.58 (1H, dd, J=1.6, 8.8 Hz),
7.60-7.64 (4H, m), 7.74 (1H, d, J=0.4 Hz), 7.89-7.91 (1H, dd,
J=1.6, 8.8 Hz), 9.04 (1H, s). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.380 min.
[M+H] Calc'd for C.sub.23H.sub.22N.sub.6S, 414; Found, 414.
Example 9:
4-[2-(4-aminopiperidin-1-yl)-5-{3-methyl-3H-imidazo[4,5-b]pyrid-
in-6-yl}-1,3-thiazol-4-yl]benzonitrile
##STR00188##
[0169] The title compound was prepared in 49% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.77-1.81 (2H,
m), 2.15-2.18 (2H, m), 3.23-3.33 (2H, m), 3.43-3.48 (1H, m), 4.04
(3H, s), 4.20-4.24 (2H, m), 7.60-7.65 (4H, m), 8.07 (1H, d, J=2.0
Hz), 8.42 (1H, d, J=1.6 Hz), 8.97 (1H, s). LCMS (mobile phase:
5-95% Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.400
min. [M+H] Calc'd for C.sub.22H.sub.21N.sub.7S, 415; Found,
415.
Example 10:
cis-4-(2-{decahydropyrrolo[3,4-d]azepin-6-yl}-5-(1-methyl-1H-1,3-benzodia-
zol-5-yl)-1,3-thiazol-4-yl)benzonitrile
##STR00189##
[0171] The title compound was prepared in 34% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.76-1.79 (4H,
m), 2.63-2.68 (2H, m), 2.93-2.98 (2H, m), 3.47-3.57 (4H, m),
3.75-3.79 (2H, m), 4.18 (3H, s), 7.54-7.57 (1H, m), 7.62 (1H, s),
7.80-7.81 (2H, m), 7.85-7.88 (2H, m), 8.00-9.02 (1H, m), 9.40 (1H,
s). LCMS (mobile phase: 5-95% Acetonitrile-Water-0.1% TFA): purity
is >95%, Rt=2.401 min. [M+H] Calc'd for
C.sub.26H.sub.26N.sub.6S, 454; Found, 454.
Example 11:
cis-4-(2-{decahydropyrrolo[3,4-d]azepin-6-yl}-5-{1-methyl-1H-pyrazolo[3,4-
-b]pyridin-5-yl}-1,3-thiazol-4-yl)benzonitrile
##STR00190##
[0173] The title compound was prepared in 17% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.86-1.91 (2H,
m), 1.95-1.99 (2H, m), 2.55-2.56 (2H, m), 2.64-2.68 (2H, m),
3.28-3.30 (2H, m), 3.45-3.51 (2H, m), 4.02-4.06 (2H, m), 4.11 (3H,
s), 7.59-7.60 (4H, m), 8.07 (1H, s), 8.14 (1H, d, J=2.0 Hz), 8.35
(1H, d, J=2.0 Hz). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.883 min.
[M+H] Calc'd for C.sub.25H.sub.25N.sub.7S, 455; Found, 455.
Example 12:
4-[2-(4-aminopiperidin-1-yl)-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-
-1,3-thiazol-4-yl]benzonitrile
##STR00191##
[0175] The title compound was prepared in 38% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.73-1.77 (2H,
m), 2.11-2.14 (2H, m), 3.18-3.25 (2H, m), 3.41-3.45 (1H, m),
4.15-4.18 (2H, m), 4.94-4.98 (2H, m), 7.49 (1H, d, J=2.0 Hz),
7.67-7.69 (2H, d, J=8.4 Hz), 7.73-7.75 (2H, d, J=8.4 Hz), 7.77 (1H,
d, J=2.0 Hz). LCMS (mobile phase: 5-95% Acetonitrile-Water-0.1%
TFA): purity is >95%, Rt=2.963 min. [M+H] Calc'd for
C.sub.20H.sub.19F.sub.3N.sub.6S, 432; Found, 432.
Example 13:
4-(2-{decahydropyrrolo[3,4-d]azepin-6-yl}-5-[1-(2,2,2-trifluoroethyl)-1H--
pyrazol-4-yl]-1,3-thiazol-4-yl)benzonitrile
##STR00192##
[0177] The title compound was prepared in 41% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.98-2.02 (4H,
m), 2.74-2.76 (2H, m), 3.02-3.06 (2H, m), 4.51-4.57 (4H, m),
3.97-4.01 (2H, m), 4.91-4.93 (2H, m), 7.46 (1H, s), 7.68-7.74 (4H,
m), 7.76 (1H, s). LCMS (mobile phase: 5-95% Acetonitrile-Water-0.1%
TFA): purity is >95%, Rt=2.967 min. [M+H] Calc'd for
C.sub.23H.sub.23F.sub.3N.sub.6S, 472; Found, 472.
Example 14:
4-[2-(4-aminopiperidin-1-yl)-5-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1,-
3-thiazol-4-yl]benzonitrile
##STR00193##
[0179] The title compound was prepared in 18% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 0.37-0.40 (2H,
m), 0.60-0.63 (2H, m), 1.27-1.31 (1H, m), 1.54-1.58 (2H, m),
1.98-2.01 (2H, m), 3.01-3.06 (1H, m), 3.12-3.18 (2H, m), 3.98-4.00
(2H, m), 4.04-4.07 (2H, m), 7.38 (1H, d, J=2.0 Hz), 7.67-7.69 (3H,
m), 7.75-7.77 (2H, d, J=8.4 Hz). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.937 min.
[M+H] Calc'd for C.sub.22H.sub.24N.sub.6S, 404; Found, 404.
Example 15:
4-{5-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-2-{decahydropyrrolo[3,4-d]az-
epin-6-yl}-1,3-thiazol-4-yl}benzonitrile
##STR00194##
[0181] The title compound was prepared in 13% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 0.37-0.40 (2H,
m), 0.60-0.63 (2H, m), 1.27-1.31 (1H, m), 1.98-2.08 (4H, m),
2.73-2.77 (2H, m), 3.04-3.08 (2H, m), 3.52-3.62 (4H, m), 3.97-4.02
(4H, m), 7.37 (1H, s), 7.70 (1H, s), 7.75 (4H, m). LCMS (mobile
phase: 5-95% Acetonitrile-Water-0.1% TFA): purity is >95%,
Rt=2.906 min. [M+H] Calc'd for C.sub.25H.sub.28N.sub.6S, 444;
Found, 444.
Example 16:
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5-(1-methyl-1H-1,3-benzodiazol-5-
-yl)-1,3-thiazol-4-yl}benzonitrile
##STR00195##
[0183] Preparation 16A. A mixture containing
4-(2-bromoacetyl)benzonitrile (4.48 g, 20 mmol), ethyl
carbamothioylformate (2.66 g, 20 mmol) in absolute ethanol (50 mL)
was allowed to stir at 80.degree. C. for 16 hrs under N.sub.2
atmosphere. The resulting slurry was poured into saturated
NaHCO.sub.3. The precipitate was filtered, washed with water, and
dried in vacuo afford ethyl
4-(4-cyanophenyl)-1,3-thiazole-2-carboxylate (4.6 g, 88%) as a
white solid. [M+H] Calc'd for C.sub.13H.sub.10N.sub.2O.sub.2S, 259;
Found, 259.
[0184] Preparation 16B. A mixture containing ethyl
4-(4-cyanophenyl)-1,3-thiazole-2-carboxylate (2.58 g, 10 mmol) in
AcOH (50 mL), potassium acetate (4.9 g, 50 mmol), was added
Br.sub.2 (8.0 g, 50 mmol) at ambient temperature. The reaction was
heated 100.degree. C. for 12 hours. Upon completion, the slurry was
poured into saturated NaHSO.sub.3. The heterogeneous solution was
filtered, and the filter cake washed water, and dried in vacuo to
afford ethyl 5-bromo-4-(4-cyanophenyl)-1,3-thiazole-2-carboxylate
(1.8 g, 70%). [M+H] Calc'd for C.sub.13H9BrN.sub.2O.sub.2S, 338;
Found, 338.
[0185] Preparation 16C. To a round-bottom flask charged with ethyl
5-bromo-4-(4-cyanophenyl)-1,3-thiazole-2-carboxylate (1.3 g, 3.9
mmol) in THF (20 mL) was added LiOH (1.6 g, 39 mmol) in water (5
mL). The mixture was then heated to 40.degree. C. for 2 hours. The
pH was adjusted to 3-4 with HCl (1N) and filtered. The solid was
washed with dichloromethane, dried in vacuo to afford compound
5-bromo-4-(4-cyanophenyl)-1,3-thiazole-2-carboxylic acid (1.1 g,
91%). [M+H] Calc'd for C.sub.1H5BrN.sub.2O.sub.2S, 310; Found,
310.
[0186] Preparation 16D. To a mixture containing
5-bromo-4-(4-cyanophenyl)-1,3-thiazole-2-carboxylic acid (150 mg,
0.5 mmol) in DMF (30 mL), N-((3R)(3-piperidyl))(tert-butoxy)
carboxamide (150 mg, 0.75 mmol), DIEA (390 mg, 3 mmol) was added
HATU (190 mg, 0.5 mmol). The reaction was stirred under nitrogen
atmosphere for 4 hours. The reaction mixture was poured into water
and filtered. The filter cake was washed with water and dried in
vacuo to give tert-butyl
N-[(3R)-1-[5-bromo-4-(4-cyanophenyl)-1,3-thiazole-2-carbonyl]piperidin-3--
yl]carbamate (150 mg, 51%). [M+H] Calc'd for
C.sub.21H.sub.23BrN.sub.4O.sub.3S, 492; Found, 492.
[0187] Preparation 16E. A vial charged with tert-butyl
N-[(3R)-1-[5-bromo-4-(4-cyanophenyl)-1,3-thiazole-2-carbonyl]piperidin-3--
yl]carbamate (147 mg, 0.3 mmol)) in 1,4-dioxane (10 mL),
1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,3-benzodiazole
(93 mg, 0.36 mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (25 mg, 0.03
mmol) and Na.sub.2CO.sub.3 (1 mL, 2M) was purged with nitrogen for
2 min. The mixture was sealed and allowed to stir at 120.degree. C.
for 16 hrs. Upon completion, the reaction was concentrated in vacuo
and the residue purified by flash chromatography
(PE/EA=1/1.about.1/2) to afford compound tert-butyl
N-[(3R)-1-[4-(4-cyanophenyl)-5-(1-methyl-1H-1,3-benzodiazol-5-yl)-1,3-thi-
azole-2-carbonyl]piperidin-3-yl]carbamate (130 mg, 80%) as a yellow
solid. [M+H] Calc'd for C.sub.29H.sub.30N.sub.6O.sub.3S, 543;
Found, 543.
[0188] Preparation 16F. To a round-bottom flask charge with
tert-butyl
N-[(3R)-1-[4-(4-cyanophenyl)-5-(1-methyl-1H-1,3-benzodiazol-5-yl)-1,3-thi-
azole-2-carbonyl]piperidin-3-yl]carbamate (130 mg, 0.24 mmol) in
DCM (10 mL) was added TFA (1 mL). The reaction was allowed to stir
at ambient temperature for 2 hours. The mixture was concentrated in
vacuo and the residue purified by prep-HPLC to afford the title
compound as the trifluoroacetic acid salt (102 mg, 76%) as a light
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
1.61-1.68 (2H, m), 1.83-1.88 (1H, m), 2.05-2.08 (1H, m), 3.32-3.39
(2H, m), 3.80-3.83 (1H, m), 3.84 (3H, s), 4.33-4.35 (1H, m),
4.77-4.80 (1H, m), 7.43-7.47 (1H, m), 7.60-7.69 (2H, m), 7.81-7.88
(4H, m), 8.14 (3H, br), 9.01 (1H, s). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.364 min.
[M+H] Calc'd for C.sub.24H.sub.22N.sub.6OS, 443; Found, 443.
Example 17:
4-{2-[(3S)-3-aminopiperidine-1-carbonyl]-5-(1-methyl-1H-1,3-benzodiazol-5-
-yl)-1,3-thiazol-4-yl}benzonitrile
##STR00196##
[0190] The title compound was prepared as the TFA salt in 25%
overall yield according to the general procedure for the
preparation of Example 16. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.61-1.68 (2H, m), 1.83-1.88 (1H, m), 2.05-2.08 (1H, m),
3.32-3.39 (2H, m), 3.80-3.83 (1H, m), 3.84 (3H, s), 4.33-4.35 (1H,
m), 4.77-4.80 (1H, m), 7.43-7.47 (1H, m), 7.60-7.69 (2H, m),
7.81-7.88 (4H, m), 8.14 (3H, br), 9.01 (1H, s). LCMS (mobile phase:
5-95% Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.360
min. [M+H] Calc'd for C.sub.24H.sub.22N.sub.6OS, 443; Found,
443.
Example 18:
4-[2-(4-aminopiperidine-1-carbonyl)-5-(1-methyl-1H-1,3-benzodiazol-5-yl)--
1,3-thiazol-4-yl]benzonitrile
##STR00197##
[0192] The title compound was prepared as the TFA salt in 20%
overall yield according to the general procedure for the
preparation of Example 16. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. ppm 1.68-1.80 (2H, m), 2.20-2.23 (2H, m), 2.89-3.11 (1H,
m), 3.39-3.57 (2H, m), 4.17 (3H, s), 4.75-4.78 (1H, m), 5.69-5.73
(1H, m), 7.64-7.70 (5H, m), 7.91 (1H, s), 7.97 (1H, d, J=8.8 Hz)
9.34 (1H, s). LCMS (mobile phase: 10-80% Acetonitrile-Water-0.1%
TFA): purity is >95%, Rt=2.214 min. [M+H] Calc'd for
C.sub.24H.sub.22N.sub.6OS, 443; Found, 443.
Example 19:
4-{2-[3R)-3-aminopiperidine-1-carbonyl]-5-(4-methylphenyl)-1,3-thiazol-4--
yl}benzonitrile
##STR00198##
[0194] The title compound was prepared as the TFA salt in 21%
overall yield according to the general procedure for the
preparation of Example 16. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.62-1.67 (2H, m), 1.83-1.87 (1H, m), 2.02-2.04 (1H, m),
2.35 (3H, s), 3.31-3.35 (2H, m), 3.80-3.83 (1H, m), 4.33-4.35 (1H,
m), 4.80-4.85 (1H, m), 7.12-7.13 (1H, m), 7.26-7.31 (3H, m),
7.61-7.63 (1H, m), 7.67-7.70 (1H, m), 7.85 (2H, d, J=8.4 Hz), 8.04
(3H, br). LCMS (mobile phase: 5-95% Acetonitrile-Water-0.1% TFA):
purity is >95%, Rt=3.311 min. [M+H] Calc'd for
C.sub.23H.sub.22N.sub.40S, 403; Found, 403.
Example 20:
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5-{3-methyl-3H-imidazo[4,5-b]pyr-
idin-6-yl}-1,3-thiazol-4-yl}benzonitrile
##STR00199##
[0196] The title compound was prepared as the TFA salt in 18%
overall yield according to the general procedure for the
preparation of Example 16. .sup.1H NMR (400 MHz, DMSO-d6): .delta.
1.61-1.68 (2H, m), 1.84-1.89 (1H, m), 2.04-2.08 (1H, m), 3.29-3.38
(2H, m), 3.80-3.83 (4H, m), 4.30-4.35 (1H, m), 4.74-4.80 (1H, m),
7.61-7.77 (2H, m), 7.82 (2H, d, J=8.0 Hz), 8.14 (3H, br), 8.18-8.20
(1H, m), 8.36-8.38 (1H, m), 8.61 (1H, s). LCMS (mobile phase:
10-80% Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.456
min. [M+H] Calc'd for C.sub.23H.sub.21N.sub.7OS, 444; Found,
444.
Example 21:
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5-[1-(2,2,2-trifluoroethyl)-1H-p-
yrazol-4-yl]-1,3-thiazol-4-yl}benzonitrile
##STR00200##
[0198] The title compound was prepared as the TFA salt in 22%
overall yield according to the general procedure for the
preparation of Example 16. .sup.1H NMR (400 MHz, DMSO-d6): .delta.
1.58-1.65 (2H, m), 1.80-1.85 (1H, m), 2.02-2.05 (1H, m), 3.30-3.32
(2H, m), 3.78-3.83 (1H, m), 4.28-4.31 (1H, m), 4.71-4.89 (1H, m),
5.14-5.21 (2H, m), 7.73-7.75 (2H, m), 7.80-7.82 (1H, m), 7.91 (2H,
d, J=8.4 Hz), 8.07 (4H, br). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=2.982 min.
[M+H] Calc'd for C.sub.21H.sub.19F.sub.3N.sub.6OS, 461; Found,
461.
Example 22:
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5-[1-(cyclopropylmethyl)-1H-pyra-
zol-4-yl]-1,3-thiazol-4-yl}benzonitrile
##STR00201##
[0200] The title compound was prepared as the TFA salt in 26%
overall yield according to the general procedure for the
preparation of Example 16. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 0.40-0.41 (2H, m), 0.63-0.65 (2H, m), 1.35-1.40 (1H, m),
1.59-1.64 (2H, m), 1.80-1.84 (1H, m), 2.03-2.06 (1H, m), 3.33-3.35
(2H, m), 4.02-4.04 (3H, m), 4.28-4.40 (1H, m), 4.71-4.89 (1H, m),
7.51-7.53 (1H, m), 7.79-7.88 (5H, m). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.002 min.
[M+H] Calc'd for C.sub.23H.sub.24N.sub.6OS, 433; Found, 433.
Example 23:
4-[2-(4-aminopiperidin-1-yl)-5-(3-hydroxy-3-methylbut-1-yn-1-yl)-1,3-thia-
zol-4-yl]benzonitrile
##STR00202##
[0202] To a vial charged with tert-butyl
N-{1-[5-bromo-4-(4-cyanophenyl)-1,3-thiazol-2-yl]piperidin-4-yl}carbamate
(463 mg, 1 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture
was stirred at ambient temperature for 2 hrs. The reaction was
concentrated in vacuo and the crude
4-[2-(4-aminopiperidin-1-yl)-5-bromo-1,3-thiazol-4-yl]-2-fluorobenzonitri-
le, TFA salt was used in the next step without further
purification. To a vial charged with the crude
4-[2-(4-aminopiperidin-1-yl)-5-bromo-1,3-thiazol-4-yl]-2-fluorobenzonitri-
le, TFA salt in acetonitrile (10 mL) was added
2-methyl-but-3-yn-2-ol (252 mg, 3 mmol), PdCl.sub.2(ACN).sub.2 (7
mg, 0.025 mmol), X-Phos (24 mg, 0.05 mmol), and K.sub.2CO.sub.3
(552 mg, 4 mmol). The reaction was purged with nitrogen and stirred
at 80.degree. C. overnight. Upon completion, the reaction was
filtered, and the filtrate concentrated in vacuo. The residue was
purified by prep-HPLC to afford the title compound (41 mg, 11%) as
a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
1.28-1.31 (2H, m), 1.48 (6H, s), 1.70-1.78 (2H, m), 1.81-1.82 (2H,
m), 2.83 (1H, m), 3.13-3.19 (2H, m), 3.84-3.88 (2H, m), 5.58 (1H,
s), 7.89 (2H, d, J=8.4 Hz), 8.29 (2H, d, J=8.0 Hz). LCMS (mobile
phase: 30-95% Acetonitrile-Water-0.1% NH.sub.4OH): purity is
>95%, Rt=3.744 min. [M+H] Calc'd for C.sub.20H.sub.22N.sub.4OS,
367; Found, 367.
Example 24:
4-[2-(4-aminopiperidin-1-yl)-5-(3-hydroxy-3-cyclopentylprop-1-yn-1-yl)-1,-
3-thiazol-4-yl]benzonitrile
##STR00203##
[0204] The title compound was prepared in 21% yield according to
the procedure for the preparation of Example 23. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 1.28-1.29 (2H, m), 1.61-1.81 (8H, m),
1.85-1.92 (4H, m), 2.83 (1H, m), 3.13-3.19 (2H, m), 3.84-3.89 (2H,
m), 5.44 (1H, s), 7.89 (2H, d, J=8.4 Hz), 8.29 (2H, d, J=8.8 Hz).
LCMS (mobile phase: 40-95% Acetonitrile-Water-0.1% NH.sub.4OH):
purity is >95%, Rt=3.838 min. [M+H] Calc'd for
C.sub.22H.sub.24N.sub.40S, 393; Found, 393.
Example 25:
4-[2-(4-aminopiperidin-1-yl)-5-{3-methyl-3H-imidazo[4,5-b]pyridin-6-yl}-1-
,3-thiazol-4-yl]-2-fluorobenzonitrile
##STR00204##
[0206] The title compound was prepared as the TFA salt in 76%
overall yield according to the general procedure for the
preparation of Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.77-1.81 (m, 2H), 2.18 (d, J=10.4 Hz, 2H), 3.27-3.36 (m,
2H), 3.44-3.51 (m, 1H), 4.17 (s, 3H), 4.24 (d, J=13.6 Hz, 2H), 7.38
(dd, J=8.0 Hz, 1.6 Hz, 1H), 7.50 (dd, J=10.4 Hz, 1.6 Hz, 1H),
7.66-7.63 (m, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H),
9.61 (s, 1H). LCMS (mobile phase: 5-95% Acetonitrile-Water-0.1%
TFA): purity is >95%. [M+H] Calc'd for
C.sub.22H.sub.20N.sub.7FS, 434; Found, 434.
Preparation 26A:
4-Bromo-N-(4-cyclopropylphenyl)-3-fluorobenzenecarboximidamide
##STR00205##
[0208] To EtMgBr (20 mL, 1M in THF) in THF (20 mL), under nitrogen,
was carefully added 4-cyclopropylaniline (1.3 g, 10 mmol). After 30
minutes of stirring at rt, 4-bromo-3-fluorobenzonitrile (2 g, 10
mmol) in THF (5 mL) was added dropwise. The mixture was stirred at
rt for 20 h, at which time ice-water (10 mL) was carefully added
while maintaining vigorous stirring. The reaction mixture was
separated between water and EtOAc. Organic extract was dried and
concentrated to an orange suspension which was trituated with EtOAc
and hexane, solid filtered, dried and concentrated to give the
product as light yellow solid (1.37 g, 41%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 0.61 (2H, d, J=3.8 Hz), 0.90 (2H, d, J=6.6
Hz), 1.88 (1H, m), 6.44 (2H, br s), 6.74 (2H, d, J=6.4 Hz), 7.02
(2H, d, J=8.1 Hz), 7.77 (2H, s), 7.89 (1H, d, J=10.6 Hz). [M+H]
Calc'd for C.sub.16H.sub.14BrFN.sub.2, 334; Found, 334.
Preparation 26B:
2-(4-Bromo-3-fluorophenyl)-3-(4-cyclopropylphenyl)-6-hydroxypyrimidin-4-o-
ne
##STR00206##
[0210] A solution of
4-bromo-N-(4-cyclopropylphenyl)-3-fluorobenzenecarboximidamide (1.1
g, 3.3 mmol) and bis(2,4,6-trichlorophenyl)malonate (1.5 g, 3.3
mmol) in toluene (10 ml) was heated in a microwave oven at
160.degree. C. for 1 h. The reaction mixture was then concentrated
and purified by ISCO flash column (MeOH/CH.sub.2Cl.sub.2) to give
500 mg of the product (35%) as light yellow solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 0.62 (2H, d, J=4.7 Hz), 0.93 (2H, d,
J=6.5 Hz), 1.87 (1H, m), 5.50 (1H, s), 7.00 (2H, d, J=8.3 Hz), 7.12
(3H, d&s, J=8.1 Hz), 7.38 (1H, d, J=9.8 Hz), 7.60 (1H, t, J=7.8
Hz). [M+H] Calc'd for C.sub.19H.sub.14BrFN.sub.2O.sub.2, 402;
Found, 402.
Preparation 26C:
2-(4-Bromo-3-fluorophenyl)-6-chloro-3-(4-cyclopropylphenyl)pyrimidin-4-on-
e
##STR00207##
[0212] A suspension of
2-(4-bromo-3-fluorophenyl)-3-(4-cyclopropylphenyl)-6-hydroxypyrimidin-4-o-
ne (960 mg, 2.4 mmol) in phosphorus oxychloride (10 mL) was heated
at 100.degree. C. for 4 h. The mixture was cooled to rt,
concentrated, quenched with water (100 mL) and extracted with
EtOAc. The organic layers were combined, washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
purified by ISCO flash column (EtOAc/Hexane) to afford 700 mg (70%)
of the desired product. [M+H] Calc'd for
C.sub.19H.sub.13BrClFN.sub.2O, 420; Found, 420.
Preparation 26D: tert-butyl
N-[1-[2-(4-bromo-3-fluorophenyl)-1-(4-cyclopropylphenyl)-6-oxopyrimidin-4-
-yl]piperidin-4-yl]carbamate
##STR00208##
[0214] A mixture of
2-(4-bromo-3-fluorophenyl)-6-chloro-3-(4-cyclopropylphenyl)pyrimidin-4-on-
e (200 mg, 0.5 mmol), 4-boc-aminopiperidine (100 mg, 0.5 mmol) and
DIEA (154 .mu.L, 1.0 mmol) in DMF was heated at 90.degree. C. for 1
h. The reaction mixture was concentrated and purified by ISCO flash
column (EtOAc/Hexane) to give the product which was used for next
step. [M+H] Calc'd for C.sub.29H.sub.32BrFN.sub.4O.sub.3, 584;
Found, 584.
Example 26:
4-[4-(4-Aminopiperidin-1-yl)-1-(4-cyclopropylphenyl)-6-oxopyrimidin-2-yl]-
-2-fluorobenzonitrile
##STR00209##
[0216] In a microwave vessel was added tert-butyl
N-[1-[2-(4-bromo-3-fluorophenyl)-1-(4-cyclopropylphenyl)-6-oxopyrimidin-4-
-yl]piperidin-4-yl]carbamate (80 mg, 0.14 mmol), zinc cyanide (82
mg, 0.7 mmol) and Pd(PPh.sub.3).sub.4 (12 mg, 0.01 mmol) in 3 mL
DMF. The reaction mixture was heated at 120.degree. C. for 1 h in a
microwave oven. It was then purified by ISCO flash column
(EtOAc/Hexane). The fractions were concentrated to a residue, which
was dissolved in CH.sub.2Cl.sub.2 (5 mL) and treated with TFA (2
mL). After 2 h, the reaction mixture was concentrated and purified
by prep-HPLC to afford the title compound as the formic acid salt
(35 mg, 58%) as a light yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 0.61 (2H, m), 0.92 (2H, m), 1.33 (2H, m),
1.81-1.89 (3H, m), 2.96 (2H, t, J=12.7 Hz), 3.18 (1H, m), 4.23 (2H,
m), 5.57 (1H, s), 6.98 (2H, d, J=8.4 Hz), 7.07 (2H, d, J=8.4 Hz),
7.33 (1H, dd, J=8.0 and 1.2 Hz), 7.56 (1H, d, J=10.1 Hz), 7.82 (1H,
t, J=7.8 Hz), 8.33 (1H, br s). [M+H] Calc'd for
C.sub.25H.sub.24FN.sub.5O, 430; Found, 430.
Example 27:
4-[4-(1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridin-5-yl)-1-(4-cyclopr-
opylphenyl)-6-oxopyrimidin-2-yl]-2-fluorobenzonitrile
##STR00210##
[0218] The title compound was prepared as the TFA salt in 37%
overall yield according to the general procedure for the
preparation of Example 26 starting from
2-(4-bromo-3-fluorophenyl)-6-chloro-3-(4-cyclopropylphenyl)pyrimidin-4-on-
e. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.61 (2H, m), 0.93
(2H, m), 1.67-1.85 (3H, m), 2.02-2.32 (2H, m), 3.17 (1H, m), 3.29
(2H, m), 3.48 (2H, m), 3.65 (1H, m), 3.80 (2H. m), 5.52 (1H, s),
6.98 (2H, d, J=7.0 Hz), 7.07 (2H, m), 7.33 (1H, dd, J=8.0 and 1.2
Hz), 7.54 (1H, d, J=10.2 Hz), 7.83 (1H, t, J=7.7 Hz), 8.64 (1H, br
s), 8.97 (1H, br s). [M+H] Calc'd for C.sub.27H.sub.26FN.sub.5O,
456; Found, 456.
Example 28:
4-[4-(1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,4-c]pyridin-5-yl)-1-(4-cyclopr-
opylphenyl)-6-oxopyrimidin-2-yl]-2-fluorobenzonitrile
##STR00211##
[0220] The title compound was prepared as the TFA salt in 34%
overall yield according to the general procedure for the
preparation of Example 26 starting from
2-(4-bromo-3-fluorophenyl)-6-chloro-3-(4-cyclopropylphenyl)pyrimidin-4-on-
e. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.61 (2H, m), 0.93
(2H, m), 1.55 (1H, m), 1.77-1.88 (3H, m), 2.85 (1H, m), 3.07 (1H,
m), 3.30 (2H, m), 3.45 (2H, m), 3.80 (2H. m), 5.53 (1H, s), 6.99
(2H, m), 7.09 (2H, m), 7.33 (1H, d, J=7.3 Hz), 7.55 (1H, d, J=10.1
Hz), 7.83 (1H, t, J=7.7 Hz), 8.73 (2H, br s). [M+H] Calc'd for
C.sub.27H.sub.26FN.sub.5O, 456; Found, 456.
Example 29:
4-[1-(4-cyclopropylphenyl)-4-(2,8-diazaspiro[4.5]decan-8-yl)-6-oxopyrimid-
in-2-yl]-2-fluorobenzonitrile
##STR00212##
[0222] The title compound was prepared as the TFA salt in 49%
overall yield according to the general procedure for the
preparation of Example 26 starting from
2-(4-bromo-3-fluorophenyl)-6-chloro-3-(4-cyclopropylphenyl)pyrimidin-4-on-
e. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.62 (2H, m), 0.93
(2H, m), 1.58 (4H, m), 1.86 (3H, m), 3.06 (2H, t, J=5.5 Hz), 3.27
(2H, m), 3.57 (5H, m), 5.59 (1H, s), 6.98 (2H, d, J=8.4 Hz), 7.07
(2H, d, J=8.4 Hz), 7.33 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=10.1 Hz),
7.83 (1H, t, J=7.6 Hz), 8.83 (2H, br s). [M+H] Calc'd for
C.sub.28H.sub.28FN.sub.5O, 470; Found, 470.
Example 30:
4-[4-(4-aminopiperidin-1-yl)-1-(3-fluoro-4-methoxyphenyl)-6-oxopyrimidin--
2-yl]-2-fluorobenzonitrile
##STR00213##
[0224] The title compound was prepared as the formic acid salt in
4% overall yield according to the general procedure for the
preparation of Example 26. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.39 (2H, m), 1.92 (2H, d, J=11.1 Hz), 2.97 (2H, t, J=11.7
Hz), 3.21 (1H, m), 3.79 (3H, s), 4.27 (2H, m), 5.59 (1H, s), 6.97
(1H, dd, J=8.8 and 1.9 Hz), 7.05 (1H, t, J=8.9 Hz), 7.30 (1H, dd,
J=11.9 and 2.2 Hz), 7.39 (1H, d, J=8.1 Hz), 7.61 (1H, d, J=10.0
Hz), 7.86 (1H, t, J=7.5 Hz), 8.33 (1H, br s). [M+H] Calc'd for
C.sub.23H.sub.21F.sub.2N.sub.5O.sub.2, 438; Found, 438.
Example 31:
4-[4-(4-aminopiperidin-1-yl)-1-(2-methylindazol-5-yl)-6-oxopyrimidin-2-yl-
]-2-fluorobenzonitrile
##STR00214##
[0226] The title compound was prepared as the formic acid salt in
2% overall yield according to the general procedure for the
preparation of Example 26. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.38 (2H, m), 1.89 (2H, d, J=11.6 Hz), 2.98 (2H, t, J=12.7
Hz), 3.17 (1H, m), 4.11 (3H, s), 4.27 (2H, m), 5.60 (1H, s), 7.10
(1H, dd, J=9.1 and 1.6 Hz), 7.37 (1H, d, J=9.1 Hz), 7.50 (1H, s),
7.51 (1H, d, J=8.8 Hz), 7.61 (1H, d, J=10.4 Hz), 7.77 (1H, t, J=7.3
Hz), 8.28 (1H, s), 8.33 (1H, s). [M+H] Calc'd for
C.sub.24H.sub.22FN.sub.7O, 444; Found, 444.
Example 32:
4-[4-(4-aminopiperidin-1-yl)-1-(4-methoxyphenyl)-6-oxopyrimidin-2-yl]-2-f-
luorobenzonitrile
##STR00215##
[0228] The title compound was prepared as the formic acid salt in
12% overall yield according to the general procedure for the
preparation of Example 26. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.39 (2H, m), 1.90 (2H, d, J=12.0 Hz), 2.96 (2H, t, J=12.5
Hz), 3.16 (1H, m), 3.70 (3H, s), 4.25 (2H, m), 5.57 (1H, s), 6.83
(2H, d, J=8.9 Hz), 7.13 (2H, d, J=8.8 Hz), 7.36 (1H, dd, J=8.0 and
1.2 Hz), 7.57 (1H, d, J=10.1 Hz), 7.83 (1H, t, J=7.8 Hz), 8.34 (1H,
s). [M+H] Calc'd for C.sub.23H.sub.22FN.sub.5O.sub.2, 420; Found,
420.
Example 33:
4-[4-(4-aminopiperidin-1-yl)-1-(4-cyclopropyl-3-fluorophenyl)-6-oxopyrimi-
din-2-yl]-2-fluorobenzonitrile
##STR00216##
[0230] The title compound was prepared as the formic acid salt in
5% overall yield according to the general procedure for the
preparation of Example 26. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 0.67 (2H, m), 0.95 (3H, m), 1.16 ((1H, m), 1.46 (2H, m),
1.97 (3H, m), 2.92 (2H, m), 3.31 (1H, m), 4.30 (2H, m), 5.60 (1H,
s), 6.93 (2H, m), 7.19 (1H, m), 7.38 (1H, m), 7.62 (1H, m), 7.85
(1H, m), 8.04 (2H,$). [M+H] Calc'd for
C.sub.25H.sub.23F.sub.2N.sub.5O, 448; Found, 448.
Example 34:
4-[2-(4-aminopiperidin-1-yl)-5-{2-methyl-2H-indazol-5-yl)pyrazin-2-yl}-1,-
3-thiazol-4-yl]benzonitrile
##STR00217##
[0232] The title compound was prepared as the HCl salt in 56%
overall yield according to the general procedure for the
preparation of Example 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.52-1.80 (m, 2H), 1.92-2.11 (m, 2H), 3.03-3.25 (m,
2H), 3.25-3.40 (m, 1H), 3.90-4.05 (m, 2H), 4.17 (s, 3H), 5.21-5.89
(m, 7H), 6.95-7.17 (m, 1H), 7.52-7.65 (m, 3H), 7.65-7.76 (m, 3H),
and 8.13 (br. s., 3H) 8.34 (s, 1H). LCMS (mobile phase: 5-95%
Acetonitrile-Water-0.1% TFA): purity is >95%. [M+H] Calc'd for
C.sub.23H.sub.22N.sub.6S, 415; Found, 415.
II. Biological Evaluation
Example 1: In Vitro Enzyme Inhibition Assay--LSD-1
[0233] This assay determines the ability of a test compound to
inhibit LSD1 demethylase activity. E. coli expressed full-length
human LSD1 (Accession number 060341) was purchased from Active
Motif (Cat#31334).
[0234] The enzymatic assay of LSD1 activity is based on Time
Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)
detection. The inhibitory properties of compounds to LSD1 were
determined in 384-well plate format under the following reaction
conditions: 0.1-0.5 nM LSD1, 50 nM H3K4me1-biotin labeled peptide
(Anaspec cat #64355), 2 .mu.M FAD in assay buffer of 50 mM HEPES,
pH7.3, 10 mM NaCl, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA.
Reaction product was determined quantitatively by TR-FRET after the
addition of detection reagent Phycolink
Streptavidin-allophycocyanin (Prozyme) and Europium-anti-unmodified
histone H3 lysine 4 (H3K4) antibody (PerkinElmer) in the presence
of LSD1 inhibitor such as 1.8 mM of Tranylcypromine hydrochloride
(2-PCPA) in LANCE detection buffer (PerkinElmer) to final
concentration of 12.5 nM and 0.25 nM respectively.
[0235] The assay reaction was performed according to the following
procedure: 2 .mu.L of the mixture of 150 nM H3K4me1-biotin labeled
peptide with 2 .mu.L of 11-point serial diluted test compound in 3%
DMSO were added to each well of plate, followed by the addition of
2 .mu.L of 0.3 nM LSD1 and 6 .mu.M of FAD to initiate the reaction.
The reaction mixture was then incubated at room temperature for one
hour, and terminated by the addition of 6 .mu.L of 1.8 mM 2-PCPA in
LANCE detection buffer containing 25 nM Phycolink
Streptavidin-allophycocyanin and 0.5 nM Europium-anti-unmodified
H3K4 antibody. Enzymatic reaction is terminated within 15 minutes
if 0.5 LSD1 enzyme is used in the plate. Plates were read by
EnVision Multilabel Reader in TR-FRET mode (excitation at 320 nm,
emission at 615 nm and 665 nm) after 1 hour incubation at room
temperature. A ratio was calculated (665/615) for each well and
fitted to determine inhibition constant (IC.sub.50).
[0236] The ability of the compounds disclosed herein to inhibit
LSD1 activity was quantified and the respective IC.sub.50 value was
determined. Table 3 provides the IC.sub.50 values of various
substituted heterocyclic compounds disclosed herein.
TABLE-US-00003 TABLE 3 Chemical Synthesis LSD1 IC.sub.50 Example
Name (.mu.M) 1 4-[2-(4-aminopiperidin-1-yl)-5-(1-methyl-1H- A
indazol-5-yl)-1,3-thiazol-4-yl]benzonitrile 2
cis-4-(2-{decahydropyrrolo[3,4-d]azepin-6-yl}-5- A
(1-methyl-1H-indazol-5-yl)-1,3-thiazol-4- yl)benzonitrile 3
4-[2-(4-aminopiperidin-1-yl)-5-{1-methyl-1H- A
pyrrolo[2,3-b]pyridin-5-yl}-1,3-thiazol-4- yl]benzonitrile 4
4-[2-(4-aminopiperidin-1-yl)-5-{1-methyl-1H- A
pyrazolo[3,4-b]pyridin-5-yl}-1,3-thiazol-4- yl]benzonitrile 5
4-(2-{2,8-diazaspiro[4.5]decan-8-yl}-5-(1-methyl- A
1H-indazol-5-yl)-1,3-thiazol-4-yl)benzonitrile 6
4-[5-(1-methyl-1H-indazol-5-yl)-2-{octahydro- A
1H-pyrrolo[3,2-c]pyridin-5-yl}-1,3-thiazol-4- yl]benzonitrile 7
4-[5-(1-methyl-1H-indazol-5-yl)-2-{octahydro- A
1H-pyrrolo[3,4-c]pyridin-5-yl}-1,3-thiazol-4- yl]benzonitrile 8
4-[2-(4-aminopiperidin-1-yl)-5-(1-methyl-1H-1,3- A
benzodiazol-5-yl)-1,3-thiazol-4-yl]-benzonitrile 9
4-[2-(4-aminopiperidin-1-yl)-5-{3-methyl-3H- A
imidazo[4,5-b]pyridin-6-yl}-1,3-thiazol-4- yl]benzonitrile 10
cis-4-(2-{decahydropyrrolo[3,4-d]azepin-6-yl}-5- A
(1-methyl-1H-1,3-benzodiazol-5-yl)-1,3-thiazol-4- yl)benzonitrile
11 cis-4-(2-{decahydropyrrolo[3,4-d]azepin-6-yl}-5- A
{1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}-1,3-
thiazol-4-yl)benzonitrile 12
4-[2-(4-aminopiperidin-1-yl)-5-[1-(2,2,2- A
trifluoroethyl)-1H-pyrazol-4-yl]-1,3-thiazol-4- yl]benzonitrile 13
4-(2-{decahydropyrrolo[3,4-d]azepin-6-yl}-5-[1- A
(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1,3-
thiazol-4-yl)benzonitrile 14
4-{5-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-2- A
{decahydropyrrolo[3,4-d]azepin-6-yl}-1,3-thiazol- 4-yl}benzonitrile
15 4-{5-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-2- A
{decahydropyrrolo[3,4-d]azepin-6-yl}-1,3-thiazol- 4-yl}benzonitrile
16 4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5-(1- A
methyl-1H-1,3-benzodiazol-5-yl)-1,3-thiazol-4- yl}benzonitrile 17
4-{2-[(3S)-3-aminopiperidine-1-carbonyl]-5-(1- A
methyl-1H-1,3-benzodiazol-5-yl)-1,3-thiazol-4- yl}benzonitrile 18
4-[2-(4-aminopiperidine-1-carbonyl)-5-(1-methyl- A
1H-1,3-benzodiazol-5-yl)-1,3-thiazol-4- yl]benzonitrile 19
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5-(4- A
methylphenyl)-1,3-thiazol-4-yl}benzonitrile 20
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5-{3- A
methyl-3H-imidazo[4,5-b]pyridin-6-yl}-1,3-
thiazol-4-yl}benzonitrile 21
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5-[1- A
(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1,3-
thiazol-4-yl}benzonitrile 22
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5-[1- A
(cyclopropylmethyl)-1H-pyrazol-4-yl]-1,3-thiazol- 4-yl}benzonitrile
23 4-[2-(4-aminopiperidin-1-yl)-5-(3-hydroxy-3- --
methylbut-1-yn-1-yl)-1,3-thiazol-4-yl]benzonitrile 24
4-[2-(4-aminopiperidin-1-yl)-5-(3-hydroxy-3- --
methylbut-1-yn-1-yl)-1,3-thiazol-4-yl]benzonitrile 25
4-[2-(4-aminopiperidin-1-yl)-5-{3-methyl-3H- --
imidazo[4,5-b]pyridin-6-yl}-1,3-thiazol-4-yl]-2- fluorobenzonitrile
26 4-[4-(4-aminopiperidin-1-yl)-1-(4- A
cyclopropylphenyl)-6-oxopyrimidin-2-yl]-2- fluorobenzonitrile 27
4-[4-(1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2- A
c]pyridin-5-yl)-1-(4-cyclopropylphenyl)-6-
oxopyrimidin-2-yl]-2-fluorobenzonitrile 28
4-[4-(1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,4- A
c]pyridin-5-yl)-1-(4-cyclopropylphenyl)-6-
oxopyrimidin-2-yl]-2-fluorobenzonitrile 29
4-[1-(4-cyclopropylphenyl)-4-(2,8- A
diazaspiro[4.5]decan-8-yl)-6-oxopyrimidin-2-yl]-
2-fluorobenzonitrile 30 4-[4-(4-aminopiperidin-1-yl)-1-(3-fluoro-4-
A methoxyphenyl)-6-oxopyrimidin-2-yl]-2- fluorobenzonitrile 31
4-[4-(4-aminopiperidin-1-yl)-1-(2-methylindazol- A
5-yl)-6-oxopyrimidin-2-yl]-2-fluorobenzonitrile 32
4-[4-(4-aminopiperidin-1-yl)-1-(4- A
methoxyphenyl)-6-oxopyrimidin-2-yl]-2- fluorobenzonitrile 33
4-[4-(4-aminopiperidin-1-yl)-1-(4-cyclopropyl-3- A
fluorophenyl)-6-oxopyrimidin-2-yl]-2- fluorobenzonitrile 34
4-[2-(4-aminopiperidin-1-yl)-5-{2-methyl-2H- A
indazol-5-yl)pyrazin-2-yl}-1,3-thiazol-4- yl]benzonitrile Note:
Biochemical assay IC.sub.50 data are designated within the
following ranges: A: .ltoreq.0.10 .mu.M B: >0.10 .mu.M to
.ltoreq.1.0 .mu.M C: >1.0 .mu.M to .ltoreq.10 .mu.M D: >10
.mu.M
Example 2: In Vitro Enzyme Inhibition Assay--MAO Selectivity
[0237] Human recombinant monoamine oxidase proteins MAO-A and MAO-B
are obtained. MAOs catalyze the oxidative deamination of primary,
secondary and tertiary amines. In order to monitor MAO enzymatic
activities and/or their inhibition rate by inhibitor(s) of
interest, a fluorescent-based (inhibitor)-screening assay is
performed. 3-(2-Aminophenyl)-3-oxopropanamine (kynuramine
dihydrobromide, Sigma Aldrich), a non-fluorescent compound is
chosen as a substrate. Kynuramine is a non-specific substrate for
both MAOs activities. While undergoing oxidative deamination by MAO
activities, kynuramine is converted into 4-hydroxyquinoline (4-HQ),
a resulting fluorescent product.
[0238] The monoamine oxidase activity is estimated by measuring the
conversion of kynuramine into 4-hydroxyquinoline. Assays are
conducted in 96-well black plates with clear bottom (Corning) in a
final volume of 100 The assay buffer is 100 mM HEPES, pH 7.5. Each
experiment is performed in triplicate within the same
experiment.
[0239] Briefly, a fixed amount of MAO (0.25 .mu.g for MAO-A and 0.5
.mu.g for AO-B) is incubated on ice for 15 minutes in the reaction
buffer, in the absence and/or in the presence of various
concentrations of compounds as disclosed herein (e.g., from 0 to 50
.mu.M, depending on the inhibitor strength). Tranylcypromine
(Biomol International) is used as a control for inhibition.
[0240] After leaving the enzyme(s) interacting with the test
compound, 60 to 90 .mu.M of kynuramine is added to each reaction
for MAO-B and MAO-A assay respectively, and the reaction is left
for 1 hour at 37.degree. C. in the dark. The oxidative deamination
of the substrate is stopped by adding 50 .mu.l of 2N NaOH. The
conversion of kynuramine to 4-hydroxyquinoline, is monitored by
fluorescence (excitation at 320 nm, emission at 360 nm) using a
microplate reader (Infinite 200, Tecan). Arbitrary units are used
to measure levels of fluorescence produced in the absence and/or in
the presence of test compound.
[0241] The maximum of oxidative deamination activity is obtained by
measuring the amount of 4-hydroxyquinoline formed from kynuramine
deamination in the absence of test compound and corrected for
background fluorescence. The Ki (IC.sub.50) of each inhibitor is
determined at Vmax/2.
Example 3: LSD1 CD11b Cellular Assay
[0242] To analyze LSD1 inhibitor efficacy in cells, a CD11b flow
cytometry assay was performed. LSD1 inhibition induces CD11b
expression in THP-1 (AML) cells which can be measured by flow
cytometry. THP-1 cells were seeded at 100,000 cells/well in 10%
Fetal Bovine Serum containing RPMI 1640 media in a 24 well plate
with a final volume of 500 .mu.L per well. LSD1 test compounds were
serially diluted in DMSO. The dilutions were added to each well
accordingly to a final concentration of 0.2% DMSO. The cells were
incubated at 37 degrees Celsius in 5% CO.sub.2 for 4 days. 250
.mu.L of each well was transferred to a well in a 96 well round
bottom plate. The plate was centrifuged at 1200 rpm at 4 degrees
Celsius in a Beckman Coulter Alegra 6KR centrifuge for 5 minutes.
The media was removed leaving the cells at the bottom of the wells.
The cells were washed in 100 .mu.L cold HBSS (Hank's Balanced Salt
Solution) plus 2% BSA (Bovine Serum Albumin) solution and
centrifuged at 1200 rpm at 4 degrees Celsius for 5 minutes. The
wash was removed. The cells were resuspended in 100 .mu.L HBSS plus
2% BSA containing 1:15 dilution of APC conjugated mouse anti-CD11b
antibody (BD Pharmingen Cat#555751) and incubated on ice for 25
minutes. The cells were centrifuged and washed two times in 100
.mu.l HBSS plus 2% BSA. After the final spin the cells were
resuspended in 100 .mu.L HBSS plus 2% BSA containing 1 ug/mL DAPI
(4',6-diamidino-2-phenylindole). The cells were then analyzed by
flow cytometry in a BD FACSAria machine. Cells were analyzed for
CD11b expression. The percent of CD11b expressing cells for each
inhibitor concentration was used to determine an IC.sub.50 curve
for each compound analyzed.
[0243] Table 4 provides the cellular IC.sub.50 values of various
substituted heterocyclic compounds disclosed herein.
TABLE-US-00004 TABLE 4 Chemical Cellular Synthesis IC.sub.50
Example Name (.mu.M) 1 4-[2-(4-aminopiperidin-1-yl)-5-(1-methyl-1H-
A indazol-5-yl)-1,3-thiazol-4-yl]benzonitrile 2
cis-4-(2-{decahydropyrrolo[3,4-d]azepin-6- A
yl}-5-(1-methyl-1H-indazol-5-yl)-1,3-thiazol-4- yl)benzonitrile 3
4-[2-(4-aminopiperidin-1-yl)-5-{1-methyl-1H- A
pyrrolo[2,3-b]pyridin-5-yl}-1,3-thiazol-4- yl]benzonitrile 4
4-[2-(4-aminopiperidin-1-yl)-5-{1-methyl-1H- A
pyrazolo[3,4-b]pyridin-5-yl}-1,3-thiazol-4- yl]benzonitrile 5
4-(2-{2,8-diazaspiro[4.5]decan-8-yl}-5-(1- B
methyl-1H-indazol-5-yl)-1,3-thiazol-4- yl)benzonitrile 6
4-[5-(1-methyl-1H-indazol-5-yl)-2- A
{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}-1,3-
thiazol-4-yl]benzonitrile 7 4-[5-(1-methyl-1H-indazol-5-yl)-2- A
{octahydro-1H-pyrrolo[3,4-c]pyridin-5-yl}-1,3-
thiazol-4-yl]benzonitrile 8
4-[2-(4-aminopiperidin-1-yl)-5-(1-methyl-1H- A
1,3-benzodiazol-5-yl)-1,3-thiazol-4- yl]benzonitrile 9
4-[2-(4-aminopiperidin-1-yl)-5-{3-methyl-3H- A
imidazo[4,5-b]pyridin-6-yl}-1,3-thiazol-4- yl]benzonitrile 10
cis-4-(2-{decahydropyrrolo[3,4-d]azepin-6- A
yl}-5-(1-methyl-1H-1,3-benzodiazol-5-yl)-1,3-
thiazol-4-yl)benzonitrile 11
cis-4-(2-{decahydropyrrolo[3,4-d]azepin-6- A
yl}-5-{1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}-
1,3-thiazol-4-yl)benzonitrile 12
4-[2-(4-aminopiperidin-1-yl)-5-[1-(2,2,2- A
trifluoroethyl)-1H-pyrazol-4-yl]-1,3-thiazol-4- yl]benzonitrile 13
4-[2-{decahydropyrrolo[3,4-d]azepin-6-yl}-5- A
[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1,3-
thiazol-4-yl)benzonitrile 14
4-{5-[1-(cyclopropylmethyl)-1H-pyrazol-4- B
yl]-2-{decahydropyrrolo[3,4-d]azepin-6-yl}-1,3-
thiazol-4-yl}benzonitrile 15
4-{5-[1-(cyclopropylmethyl)-1H-pyrazol-4- B
yl]-2-{decahydropyrrolo[3,4-d]azepin-6-yl}-1,3-
thiazol-4-yl}benzonitrile 16
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5- A
(1-methyl-1H-1,3-benzodiazol-5-yl)-1,3-thiazol-4- yl}benzonitrile
17 4-{2-[(3S)-3-aminopiperidine-1-carbonyl]-5- A
(1-methyl-1H-1,3-benzodiazol-5-yl)-1,3-thiazol-4- yl}benzonitrile
18 4-[2-(4-aminopiperidine-1-carbonyl)-5-(1- A
methyl-1H-1,3-benzodiazol-5-yl)-1,3-thiazol-4- yl]benzonitrile 19
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5- A
(4-methylphenyl)-1,3-thiazol-4-yl}benzonitrile 20
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5- B
{3-methyl-3H-imidazo[4,5-b]pyridin-6-yl}-1,3-
thiazol-4-yl}benzonitrile 21
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5- A
[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1,3-
thiazol-4-yl}benzonitrile 22
4-{2-[(3R)-3-aminopiperidine-1-carbonyl]-5- B
[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1,3-
thiazol-4-yl}benzonitrile 23
4-[2-(4-aminopiperidin-1-yl)-5-(3-hydroxy-3- --
methylbut-l-yn-1-yl)-1,3-thiazol-4-yl]benzonitrile 24
4-[2-(4-aminopiperidin-1-yl)-5-(3-hydroxy-3- --
methylbut-l-yn-1-yl)-1,3-thiazol-4-yl]benzonitrile 25
4-[2-(4-aminopiperidin-1-yl)-5-{3-methyl-3H- --
imidazo[4,5-b]pyridin-6-yl}-1,3-thiazol-4-yl]-2- fluorobenzonitrile
26 4-[4-(4-aminopiperidin-1-yl)-1-(4- A
cyclopropylphenyl)-6-oxopyrimidin-2-yl]-2- fluorobenzonitrile 27
4-[4-(1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2- A
c]pyridin-5-yl)-1-(4-cyclopropylphenyl)-6-
oxopyrimidin-2-yl]-2-fluorobenzonitrile 28
4-[4-(1,2,3,3a,4,6,7,7a-octahydropyrrolo[3,4- A
c]pyridin-5-yl)-1-(4-cyclopropylphenyl)-6-
oxopyrimidin-2-yl]-2-fluorobenzonitrile 29
4-[1-(4-cyclopropylphenyl)-4-(2,8- A
diazaspiro[4.5]decan-8-yl)-6-oxopyrimidin-2-yl]-
2-fluorobenzonitrile 30 4-[4-(4-aminopiperidin-1-yl)-1-(3-fluoro-4-
B methoxyphenyl)-6-oxopyrimidin-2-yl]-2- fluorobenzonitrile 31
4-[4-(4-aminopiperidin-1-yl)-1-(2- B
methylindazol-5-yl)-6-oxopyrimidin-2-yl]-2- fluorobenzonitrile 32
4-[4-(4-aminopiperidin-1-yl)-1-(4- --
methoxyphenyl)-6-oxopyrimidin-2-yl]-2- fluorobenzonitrile 33
4-[4-(4-aminopiperidin-1-yl)-1-(4- A
cyclopropyl-3-fluorophenyl)-6-oxopyrimidin-2-
yl]-2-fluorobenzonitrile 34
4-[2-(4-aminopiperidin-1-yl)-5-{2-methyl-2H- A
indazol-5-yl)pyrazin-2-yl}-1,3-thiazol-4- yl]benzonitrile Note:
Cellular assay IC.sub.50 data are designated within the following
ranges: A: .ltoreq.0.10 .mu.M B: >0.10 .mu.M to .ltoreq.1.0
.mu.M C: >1.0 .mu.M to .ltoreq.10 .mu.M D: >10 .mu.M
Example 4: In Vivo Xenograph Study--MCF-7 Xenograph
[0244] Time release pellets containing 0.72 mg 1713 Estradiol are
subcutaneously implanted into nu/nu mice. MCF-7 cells are grown in
RPMI containing 10% FBS at 5% CO.sub.2, 37.degree. C. Cells are
spun down and re-suspended in 50% RPMI (serum free) and 50%
Matrigel at 1.times.10.sup.7 cells/mL. MCF-7 cells are
subcutaneously injected (100 .mu.L/animal) on the right flank 2-3
days post pellet implantation and tumor volume
(length.times.width.sup.2/2) is monitored bi-weekly. When tumors
reach an average volume of .about.200 mm.sup.3 animals are
randomized and treatment is started. Animals are treated with
vehicle or compound daily for 4 weeks. Tumor volume and body weight
are monitored bi-weekly throughout the study. At the conclusion of
the treatment period, plasma and tumor samples are taken for
pharmacokinetic and pharmacodynamic analyses, respectively.
Example 5: In Vivo Xenograph Study--LNCaP Xenograph
[0245] LNCaP cells with a stable knockdown of LSD1 (shLSD1 cells)
or control cells (such as shNTC cells) are inoculated in the dorsal
flank of nude mice by subcutaneous injection (such as
3.times.10.sup.6 cells in 100 .mu.l of 50% RPMI 1640/BD Matrigel).
Mouse weight and tumor size are measured once per week and tumor
volume is estimated using the formula (7i/6)(L.times.W), where
L=length of tumor and W=width of tumor. A two sample t-test is
performed to determine statistical differences in mean tumor volume
between the two groups.
[0246] Unmodified LNCaP cells are inoculated by subcutaneous
injection into the dorsal flank of nude mice (such as
3.times.10.sup.6 cells in 100 .mu.l of 50% RPMI 1640/BD Matrigel).
After three weeks, mice are injected intraperitoneally once per day
with water (control), pargyline (0.53 mg or 1.59 mg; 1 or 3 mM
final concentration, assuming 70% bioavailability), or XB154 (4 or
20 .mu.g; 1 or 5 .mu.M final concentration, assuming 70%
bioavailability) or treated with a test compound (5 mg/kg each week
or 10 mg/kg each week). Treatment continues for three weeks, during
which time mouse weight and tumor volume are measured as above.
[0247] shLSD1 LNCaP cells or control cells are injected in nude
mice as above. After three weeks, mice are treated with 2.6 .mu.g
mitomycin C (predicted final concentration of 1 .mu.M assuming 40%
bioavailability), olaparib (for example, about 0.5 mg/kg to 25
mg/kg), or vehicle intraperitoneally once per day for three weeks.
In other examples, unmodified LNCaP cells are injected in nude mice
as above.
[0248] After three weeks, mice are treated with test compounds, or
vehicle as above, plus MMC or olaparib. Treatment continues for
three weeks, during which time mouse weight and tumor volume are
measured as above.
[0249] A decrease in tumor volume compared to control in mice
injected with shLSD1 cells indicates that LSD1 inhibition decreases
tumor growth in vivo.
[0250] Similarly, a decrease in tumor volume compared to control in
mice injected with LNCaP cells and treated with a compound
disclosed herein indicates that LSD1 inhibition decreases tumor
growth in vivo. Finally, a decrease in tumor volume in mice
injected with LNCaP cells and treated with a compound disclosed
herein plus olaparib as compared to mice treated with a compound
disclosed herein alone indicates that inhibition of LSD1 plus
inhibition of PARP decreases tumor growth in vivo.
[0251] The harvested xenograft tissue is examined for evidence of
LSD1 inhibition. This is assessed with Western blots to examine
global levels of the 2MK4 and 2MK9 histone marks, expression of
FA/BRcA genes, FANCD2 ubiquitination, and LSD1 protein levels in
the cases of the shRNA cells. A decrease in one or more of these
parameters indicates the effective inhibition of LSD 1.
Additionally, effects on DNA damage repair are assessed with
staining for H2AX foci.
III. Preparation of Pharmaceutical Dosage Forms
Example 1: Oral Tablet
[0252] A tablet is prepared by mixing 48% by weight of a compound
of Formula (I) or a pharmaceutically acceptable salt thereof, 45%
by weight of microcrystalline cellulose, 5% by weight of
low-substituted hydroxypropyl cellulose, and 2% by weight of
magnesium stearate. Tablets are prepared by direct compression. The
total weight of the compressed tablets is maintained at 250-500
mg.
* * * * *