U.S. patent application number 17/523480 was filed with the patent office on 2022-03-03 for substituted reverse pyrimidine bmi-1 inhibitors.
The applicant listed for this patent is PTC Therapeutics, Inc.. Invention is credited to Ramil Baiazitov, Liangxian Cao, Thomas W. Davis, Wu Du, Chang-Sun Lee, Ronggang Liu, Young-Choon Moon, Steven D. Paget, Hongyu Ren, Nadiya Sydorenko, Richard Gerald Wilde.
Application Number | 20220064150 17/523480 |
Document ID | / |
Family ID | 1000005962493 |
Filed Date | 2022-03-03 |
United States Patent
Application |
20220064150 |
Kind Code |
A1 |
Lee; Chang-Sun ; et
al. |
March 3, 2022 |
SUBSTITUTED REVERSE PYRIMIDINE BMI-1 INHIBITORS
Abstract
Amine substituted reverse pyrimidine compounds and forms thereof
that inhibit the function and reduce the level of B-cell specific
Moloney murine leukemia virus integration site 1 (Bmi-1) protein
and methods for their use to inhibit Bmi-1 function and reduce the
level of Bmi-1 to treat a cancer mediated by Bmi-1 are described
herein.
Inventors: |
Lee; Chang-Sun; (Belle Mead,
NJ) ; Baiazitov; Ramil; (East Brunswick, NJ) ;
Cao; Liangxian; (East Brunswick, NJ) ; Davis; Thomas
W.; (South Orange, NJ) ; Du; Wu; (Cranbury,
NJ) ; Liu; Ronggang; (Berwyn, PA) ; Moon;
Young-Choon; (Belle Mead, NJ) ; Paget; Steven D.;
(Hillsborough, NJ) ; Ren; Hongyu; (Florence,
NJ) ; Sydorenko; Nadiya; (Princeton, NJ) ;
Wilde; Richard Gerald; (Somerville, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PTC Therapeutics, Inc. |
South Plainfield |
NJ |
US |
|
|
Family ID: |
1000005962493 |
Appl. No.: |
17/523480 |
Filed: |
November 10, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16583442 |
Sep 26, 2019 |
11180483 |
|
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17523480 |
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14443911 |
May 19, 2015 |
10428050 |
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PCT/US2013/071132 |
Nov 21, 2013 |
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16583442 |
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61728907 |
Nov 21, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/506 20130101;
A61N 5/10 20130101; A61K 45/06 20130101; C07D 471/04 20130101; C07D
403/04 20130101; Y02A 50/30 20180101; C07D 403/12 20130101; C07D
487/04 20130101 |
International
Class: |
C07D 403/12 20060101
C07D403/12; A61K 31/506 20060101 A61K031/506; A61K 45/06 20060101
A61K045/06; C07D 487/04 20060101 C07D487/04; A61N 5/10 20060101
A61N005/10; C07D 403/04 20060101 C07D403/04; C07D 471/04 20060101
C07D471/04 |
Claims
1-20. (canceled)
21. A compound, wherein the compound is
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl-
)phenyl]pyrimidine-4,6-diamine, or a pharmaceutically acceptable
salt thereof.
22. A pharmaceutical composition comprising the compound, or
pharmaceutically acceptable salt thereof, of claim 21 and at least
one pharmaceutically acceptable excipient.
23. The pharmaceutical composition of claim 22, wherein the
pharmaceutical composition comprises about 0.1 ng to about 3500 mg
of the compound or pharmaceutically acceptable salt thereof.
24. The pharmaceutical composition of claim 23, wherein the
pharmaceutical composition comprises about 5.0 mg to about 1500 mg
of the compound or pharmaceutically acceptable salt thereof.
25. The pharmaceutical composition of claim 22, wherein the
pharmaceutical composition further comprises one or more additional
agents selected from the group consisting of anti-cancer agents,
anti-proliferative agents, chemotherapeutic agents,
immunomodulatory agents, anti-angiogenic agents, anti-inflammatory
agents, alkylating agents, steroidal and non-steroidal
anti-inflammatory agents, pain relievers, leukotriene antagonists,
.beta.2-agonists, anticholinergic agents, hormonal agents,
biological agents, tubulin binding agents, glucocorticoids,
corticosteroid agents, antibacterial agents, antihistamines,
anti-malarial agents, anti-viral agents, and antibiotics.
26. The pharmaceutical composition of claim 22, wherein the
pharmaceutical composition is a solution, emulsion, suspension,
tablet, pill, capsule, troche, lozenge, powder, granule, syrup, or
elixir.
27. The pharmaceutical composition of claim 26, wherein the
pharmaceutical composition is a tablet or a capsule.
28. The compound of claim 21, wherein the compound is
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl-
)phenyl]pyrimidine-4,6-diamine.
29. A pharmaceutical composition comprising the compound of claim
28 and at least one pharmaceutically acceptable excipient.
30. The pharmaceutical composition of claim 29, wherein the
pharmaceutical composition comprises about 0.1 ng to about 3500 mg
of the compound.
31. The pharmaceutical composition of claim 30, wherein the
pharmaceutical composition comprises about 5.0 mg to about 1500 mg
of the compound.
32. The pharmaceutical composition of claim 29, wherein the
pharmaceutical composition further comprises one or more additional
agents selected from the group consisting of anti-cancer agents,
anti-proliferative agents, chemotherapeutic agents,
immunomodulatory agents, anti-angiogenic agents, anti-inflammatory
agents, alkylating agents, steroidal and non-steroidal
anti-inflammatory agents, pain relievers, leukotriene antagonists,
.beta.2-agonists, anticholinergic agents, hormonal agents,
biological agents, tubulin binding agents, glucocorticoids,
corticosteroid agents, antibacterial agents, antihistamines,
anti-malarial agents, anti-viral agents, and antibiotics.
33. The pharmaceutical composition of claim 29, wherein the
pharmaceutical composition is a solution, emulsion, suspension,
tablet, pill, capsule, troche, lozenge, powder, granule, syrup, or
elixir.
34. The pharmaceutical composition of claim 33, wherein the
pharmaceutical composition is a tablet or a capsule.
35. A method of treating a cancer mediated by Bmi-1 in a subject in
need thereof, the method comprising administering to the subject an
effective amount of the compound are pharmaceutically acceptable
salt thereof of claim 21.
36. A method of treating a cancer mediated by Bmi-1 in a subject in
need thereof, the method comprising administering to the subject an
effective amount of the pharmaceutical composition of claim 22.
37. A method of treating a cancer mediated by Bmi-1 in a subject in
need thereof, the method comprising administering to the subject an
effective amount of the pharmaceutical composition of claim 29.
Description
INTRODUCTION
[0001] Substituted reverse pyrimidine compounds that inhibit the
function of the B-cell specific Moloney murine leukemia virus
integration site 1 (Bmi-1) protein and reduce the level thereof and
methods of using such compounds to treat a cancer mediated by Bmi-1
are described. More particularly, amine substituted reverse
pyrimidine compounds that inhibit Bmi-1 function and reduce the
level of Bmi-1 are useful for treating a cancer mediated by
Bmi-1.
BACKGROUND
[0002] Bmi-1 was originally identified by its over-expression in
various leukemias and lymphomas. Subsequently, Bmi-1 has been shown
to have oncogenic activity when overexpressed in normal cells and
to play a role in the maintenance of cancer stem cell populations.
Bmi-1 is elevated in many tumor types and is important in
hematologic cancers and many solid tumors, including brain cancers.
Reduction of Bmi-1 levels in tumor cells by siRNA causes apoptosis
and/or cell senescence and increases susceptibility to cytotoxic
agents. Bmi-1 serves as the key regulatory component of the PRC1
complex (polycomb repressive complex-1), but has no enzymatic
activity. Therefore, targeting Bmi-1 by traditional drug discovery
methods has been problematic.
[0003] Since Bmi-1 levels within cells are tightly regulated
through both transcriptional and post-transcriptional mechanisms,
this regulation can be exploited to target this important protein.
Accordingly, there remains a need to provide compounds that inhibit
Bmi-1 function and reduce the level of Bmi-1 to treat a cancer
mediated by Bmi-1.
SUMMARY
[0004] Certain amine substituted reverse pyrimidine compounds that
inhibit Bmi-1 function and reduce the level of Bmi-1 and methods
for their use to treat a cancer mediated by Bmi-1 are described
herein.
[0005] A compound of Formula (I) is described:
##STR00001##
wherein X, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined
herein, including forms and pharmaceutical compositions thereof,
and methods of using such compounds, forms or compositions thereof
to treat a cancer mediated by Bmi-1 in a human subject in need
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] FIG. 1 demonstrates the dose dependent reduction of a CSC
population in a BXD GBM model as the result of treatment with a
compound of Formula (I), or a form thereof.
[0007] FIG. 2 demonstrates the reduction of a CSC population in a
BXD GBM model as the result of treatment with a compound of Formula
(I), or a form thereof.
[0008] FIG. 3 demonstrates the reduction of monolayer and
neurosphere CSC populations in a tumorosphere assay as the result
of contacting the cells with a compound of Formula (I), or a form
thereof.
[0009] FIG. 4 demonstrates the comparative effect on survival of
mice treated with vehicle, temozolomide or a compound of Formula
(I), or a form thereof, in an orthotopic model of glioblastoma.
DETAILED DESCRIPTION
[0010] Amine substituted reverse pyrimidine compounds for use in
inhibiting Bmi-1 function and reducing the level of Bmi-1 and in
methods for treating a cancer mediated by Bmi-1 are described.
[0011] In one embodiment is a compound of Formula (I):
##STR00002##
or a form thereof, wherein [0012] R.sub.1 is heteroaryl or
heterocyclyl optionally substituted on a carbon atom ring member
with one, two, three or four R.sub.5 substituents, or on a nitrogen
atom ring member with an oxygen atom substituent to form an
N-oxide; [0013] X is N or N substituted with an oxygen atom
substituent to form an N-oxide; [0014] R.sub.2 is hydrogen, cyano,
halo, hydroxyl, nitro, C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl,
C.sub.1-8alkoxy, amino, C.sub.1-8alkyl-amino,
(C.sub.1-8alkyl).sub.2-amino, hydroxyl-amino,
hydroxyl-C.sub.1-8alkyl-amino,
C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-thio,
C.sub.1-8alkyl-carbonyl, C.sub.1-8alkyl-carbonyl-amino,
amino-carbonyl, C.sub.1-8alkyl-amino-carbonyl,
(C.sub.1-8alkyl).sub.2-amino-carbonyl, amino-carbonyl-amino,
C.sub.1-8alkyl-amino-carbonyl-amino,
(C.sub.1-8alkyl).sub.2-amino-carbonyl-amino,
C.sub.1-8alkoxy-carbonyl, C.sub.1-8alkoxy-carbonyl-amino,
amino-sulfonyl, C.sub.1-8alkyl-amino-sulfonyl,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl, amino-sulfonyl-amino,
C.sub.1-8alkyl-amino-sulfonyl-amino,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl-amino,
P(O)(R.sub.7).sub.2-amino or heteroaryl, wherein heteroaryl is
optionally substituted with one, two, three or four C.sub.1-8alkyl
substituents; [0015] R.sub.3 is hydrogen, cyano, halo,
C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino or
(C.sub.1-8alkyl).sub.2-amino; [0016] R.sub.4 is
C.sub.3-14cycloalkyl, aryl, heteroaryl or heterocyclyl, each
optionally substituted with one, two, three or four R.sub.6
substituents; [0017] R.sub.5 is independently selected from cyano,
halo, hydroxyl, nitro, oxo, C.sub.1-8alkyl, cyano-C.sub.1-8alkyl,
halo-C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy,
C.sub.1-8alkoxy-C.sub.1-8alkyl, halo-C.sub.1-8alkoxy,
C.sub.2-8alkenyl, C.sub.1-8alkoxy-C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.1-8alkoxy-C.sub.2-8alkynyl, carboxyl,
amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino,
amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl-amino,
hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino,
C.sub.1-8alkyl-thio, C.sub.1-8alkyl-carbonyl,
C.sub.1-8alkyl-carbonyl-amino, C.sub.1-8alkyl-carbonyl-oxy,
C.sub.1-8alkyl-carbonyl-oxy-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl, C.sub.1-8alkoxy-carbonyl-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl-amino, C.sub.1-8alkyl-sulfonyl,
C.sub.3-14cycloalkyl, aryl, aryl-C.sub.1-8alkyl, aryl-amino,
aryl-C.sub.1-8alky-amino, heteroaryl, heteroaryl-C.sub.1-8alkyl or
heterocyclyl, wherein C.sub.3-14cycloalkyl, aryl, heteroaryl or
heterocyclyl and the aryl and heteroaryl portions of
aryl-C.sub.1-8alkyl, aryl-amino, aryl-C.sub.1-8alky-amino and
heteroaryl-C.sub.1-8alkyl are each optionally substituted with one,
two, three or four halo, C.sub.1-8alkyl, halo-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy,
hydroxyl-C.sub.1-8alkoxy or carboxyl substituents; [0018] R.sub.6
is independently selected from cyano, halo, hydroxyl, nitro,
C.sub.1-8alkyl, halo-C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl,
C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.2-8alkenyl,
C.sub.1-8alkoxy-C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkoxy-C.sub.2-8alkynyl, carboxyl, formyl, formyl-oxy,
C.sub.1-8alkyl-carbonyl, halo-C.sub.1-8alkyl-carbonyl,
C.sub.1-8alkyl-thio, halo-C.sub.1-8alkyl-thio, amino,
C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino,
C.sub.1-8alkyl-carbonyl, C.sub.1-8alkyl-carbonyl-oxy,
C.sub.1-8alkyl-carbonyl-oxy-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl, halo-C.sub.1-8alkoxy-carbonyl,
C.sub.1-8alkoxy-carbonyl-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl-amino,
C.sub.1-8alkoxy-carbonyl-amino-C.sub.1-8alkyl, amino-carbonyl,
C.sub.1-8alkyl-amino-carbonyl,
(C.sub.1-8alkyl).sub.2-amino-carbonyl,
C.sub.1-8alkyl-carbonyl-amino,
C.sub.1-8alkyl-carbonyl-amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl,
C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl,
amino-C.sub.1-8alkyl-amino,
C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino,
(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino,
hydroxyl-C.sub.1-8alkyl-amino,
hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino,
imino-C.sub.1-8alkyl, hydroxyl-imino-C.sub.1-8alkyl,
C.sub.1-8alkoxy-imino-C.sub.1-8alkyl, C.sub.1-8alkyl-sulfonyl,
halo-C.sub.1-8alkyl-sulfonyl, amino-sulfonyl,
C.sub.1-8alkyl-amino-sulfonyl,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl, B(OR.sub.8).sub.2,
C.sub.3-14cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein
C.sub.3-14cycloalkyl, heterocyclyl, aryl, and heteroaryl are each
optionally substituted with one, two, three or four halo or
C.sub.1-8alkyl substituents; [0019] R.sub.7 is independently
hydroxyl or (C.sub.1-8alkoxy).sub.n, wherein n represents an
integer from 1 to 5; and, [0020] R.sub.8 is independently hydrogen
or C.sub.1-8alkyl.
[0021] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl or
heterocyclyl selected from 1H-pyrazolyl, 1H-imidazolyl,
1,2-oxazolyl, pyridinyl, 1H-indolyl, 2H-indazolyl,
4,5,6,7-tetrahydro-2H-indazolyl, 1H-benzimidazolyl,
imidazo[2,1-b][1,3]thiazolyl, pyrazolo[1,5-a]pyridinyl,
pyrazolo[1,5-c]pyrimidinyl, imidazo[1,2-a]pyridinyl,
5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl,
1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl,
imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 7H-purinyl or
quinolinyl.
[0022] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl or
heterocyclyl selected from 1H-pyrazolyl, 1H-imidazolyl,
1,2-oxazolyl, pyridinyl, 1H-indolyl, 2H-indazolyl,
4,5,6,7-tetrahydro-2H-indazolyl, 1H-benzimidazolyl,
imidazo[2,1-b][1,3]thiazolyl, pyrazolo[1,5-a]pyridinyl,
imidazo[1,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl,
1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl,
imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 7H-purinyl or
quinolinyl.
[0023] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl or
heterocyclyl selected from 1H-pyrazol-4-yl, 1H-imidazol-1-yl,
1H-imidazol-5-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, pyridin-4-yl,
1H-indol-1-yl, 1H-indol-3-yl, 1H-indol-4-yl, 2H-indazol-3-yl,
4,5,6,7-tetrahydro-2H-indazol-3-yl, 1H-benzimidazol-1-yl,
imidazo[2,1-b][1,3]thiazol-5-yl, pyrazolo[1,5-a]pyridin-2-yl,
pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-7-yl,
pyrazolo[1,5-c]pyrimidin-3-yl, imidazo[1,2-a]pyridin-2-yl,
imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl,
5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl,
1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl,
imidazo[1,2-a]pyrazin-3-yl, imidazo[1,2-a]pyrimidin-3-yl,
7H-purin-7-yl or quinolin-4-yl.
[0024] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl or
heterocyclyl selected from 1H-pyrazol-4-yl, 1H-imidazol-1-yl,
1H-imidazol-5-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, pyridin-4-yl,
1H-indol-1-yl, 1H-indol-4-yl, 2H-indazol-3-yl,
4,5,6,7-tetrahydro-2H-indazol-3-yl, 1H-benzimidazol-1-yl,
imidazo[2,1-b][1,3]thiazol-5-yl, pyrazolo[1,5-a]pyridin-3-yl,
pyrazolo[1,5-a]pyridin-7-yl, imidazo[1,2-a]pyridin-3-yl,
imidazo[1,2-a]pyridin-5-yl,
5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl,
1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl,
imidazo[1,2-a]pyrazin-3-yl, imidazo[1,2-a]pyrimidin-3-yl,
7H-purin-7-yl or quinolin-4-yl.
[0025] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl or
heterocyclyl selected from 1H-pyrazol-4-yl, 1H-imidazol-1-yl,
1H-imidazol-5-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, pyridin-4-yl,
1H-indol-1-yl, 1H-indol-4-yl, 2H-indazol-3-yl,
4,5,6,7-tetrahydro-2H-indazol-3-yl, 1H-benzimidazol-1-yl,
imidazo[2,1-b][1,3]thiazol-5-yl, pyrazolo[1,5-a]pyridin-3-yl,
pyrazolo[1,5-a]pyridin-7-yl, imidazo[1,2-a]pyridin-3-yl,
imidazo[1,2-a]pyridin-5-yl,
5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl,
1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl, 7H-purin-7-yl or
quinolin-4-yl.
[0026] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazolyl, 1H-imidazolyl, 1,2-oxazolyl, pyridinyl, 1H-indolyl,
2H-indazolyl, 1H-benzimidazolyl, imidazo[2,1-b][1,3]thiazolyl,
pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-c]pyrimidinyl,
imidazo[1,2-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl,
1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyrazinyl,
imidazo[1,2-a]pyrimidinyl, 7H-purinyl or quinolinyl.
[0027] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazolyl, 1H-imidazolyl, 1,2-oxazolyl, pyridinyl, 1H-indolyl,
2H-indazolyl, 1H-benzimidazolyl, imidazo[2,1-b][1,3]thiazolyl,
pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,
1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl,
imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 7H-purinyl or
quinolinyl.
[0028] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazolyl, 1H-imidazolyl, 1,2-oxazolyl, pyridinyl, 1H-indolyl,
2H-indazolyl, 1H-benzimidazolyl, imidazo[2,1-b][1,3]thiazolyl,
pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,
1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 7H-purinyl
or quinolinyl.
[0029] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazolyl, 1H-indolyl, 1H-benzimidazolyl,
pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,
1H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl or
imidazo[1,2-a]pyrimidinyl.
[0030] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazolyl, 1H-indolyl, 1H-benzimidazolyl,
pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl or
1H-imidazo[4,5-b]pyridinyl.
[0031] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
imidazo[1,2-a]pyrazinyl or imidazo[1,2-a]pyrimidinyl.
[0032] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted
imidazo[1,2-a]pyrazinyl.
[0033] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted
imidazo[1,2-a]pyrimidinyl.
[0034] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-5-yl,
1,2-oxazol-4-yl, 1,2-oxazol-5-yl, pyridin-4-yl, 1H-indol-1-yl,
1H-indol-3-yl, 1H-indol-4-yl, 2H-indazol-3-yl,
1H-benzimidazol-1-yl, imidazo[2,1-b][1,3]thiazol-5-yl,
pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl,
pyrazolo[1,5-a]pyridin-7-yl, pyrazolo[1,5-c]pyrimidin-3-yl,
imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl,
imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-1-yl,
1H-imidazo[4,5-c]pyridin-1-yl, imidazo[1,2-a]pyrazin-3-yl,
imidazo[1,2-a]pyrimidin-3-yl, 7H-purin-7-yl or quinolin-4-yl.
[0035] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-5-yl,
1,2-oxazol-4-yl, 1,2-oxazol-5-yl, pyridin-4-yl, 1H-indol-1-yl,
1H-indol-4-yl, 2H-indazol-3-yl, 1H-benzimidazol-1-yl,
imidazo[2,1-b][1,3]thiazol-5-yl, pyrazolo[1,5-a]pyridin-3-yl,
pyrazolo[1,5-a]pyridin-7-yl, imidazo[1,2-a]pyridin-3-yl,
imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-1-yl,
1H-imidazo[4,5-c]pyridin-1-yl, imidazo[1,2-a]pyrazin-3-yl,
imidazo[1,2-a]pyrimidin-3-yl, 7H-purin-7-yl or quinolin-4-yl.
[0036] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-5-yl,
1,2-oxazol-4-yl, 1,2-oxazol-5-yl, pyridin-4-yl, 1H-indol-1-yl,
1H-indol-4-yl, 2H-indazol-3-yl, 1H-benzimidazol-1-yl,
imidazo[2,1-b][1,3]thiazol-5-yl, pyrazolo[1,5-a]pyridin-7-yl,
imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-1-yl,
1H-imidazo[4,5-c]pyridin-1-yl, imidazo[1,2-a]pyrazin-3-yl,
imidazo[1,2-a]pyrimidin-3-yl, 7H-purin-7-yl or quinolin-4-yl.
[0037] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazol-4-yl, 1H-indol-1-yl, 1H-indol-3-yl, 1H-indol-4-yl,
1H-benzimidazol-1-yl, pyrazolo[1,5-a]pyridin-2-yl,
pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-7-yl,
imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl,
imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-b]pyridin-1-yl,
imidazo[1,2-a]pyrazin-3-yl or imidazo[1,2-a]pyrimidin-3-yl.
[0038] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazol-4-yl, 1H-indol-3-yl, 1H-benzimidazol-1-yl,
pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl,
imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl,
1H-imidazo[4,5-b]pyridin-1-yl, imidazo[1,2-a]pyrazin-3-yl or
imidazo[1,2-a]pyrimidin-3-yl.
[0039] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heteroaryl selected from
1H-pyrazol-4-yl, 1H-indol-3-yl, 1H-benzimidazol-1-yl,
pyrazolo[1,5-a]pyridin-3-yl, imidazo[1,2-a]pyridin-3-yl,
1H-imidazo[4,5-b]pyridin-1-yl, imidazo[1,2-a]pyrazin-3-yl or
imidazo[1,2-a]pyrimidin-3-yl.
[0040] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted
imidazo[1,2-a]pyrazin-3-yl.
[0041] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted
imidazo[1,2-a]pyrimidin-3-yl.
[0042] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heterocyclyl selected
from 4,5,6,7-tetrahydro-2H-indazolyl,
5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl or
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl.
[0043] Another embodiment includes a compound of Formula (I),
wherein R.sub.1 is optionally substituted heterocyclyl selected
from 4,5,6,7-tetrahydro-2H-indazol-3-yl,
5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl or
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl.
[0044] Another embodiment includes a compound of Formula (I),
wherein X is N.
[0045] Another embodiment includes a compound of Formula (I),
wherein X is N substituted with an oxygen atom substituent to form
an N-oxide.
[0046] Another embodiment includes a compound of Formula (I),
wherein R.sub.2 is cyano, halo, hydroxyl, nitro, C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy, amino,
C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, hydroxyl-amino,
hydroxyl-C.sub.1-8alkyl-amino,
C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-thio,
C.sub.1-8alkyl-carbonyl, C.sub.1-8alkyl-carbonyl-amino,
amino-carbonyl, C.sub.1-8alkyl-amino-carbonyl,
(C.sub.1-8alkyl).sub.2-amino-carbonyl, amino-carbonyl-amino,
C.sub.1-8alkyl-amino-carbonyl-amino,
(C.sub.1-8alkyl).sub.2-amino-carbonyl-amino,
C.sub.1-8alkoxy-carbonyl, C.sub.1-8alkoxy-carbonyl-amino,
amino-sulfonyl, C.sub.1-8alkyl-amino-sulfonyl,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl, amino-sulfonyl-amino,
C.sub.1-8alkyl-amino-sulfonyl-amino,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl-amino,
P(O)(R.sub.7).sub.2-amino or heteroaryl, wherein heteroaryl is
optionally substituted with one, two, three or four C.sub.1-8alkyl
substituents.
[0047] Another embodiment includes a compound of Formula (I),
wherein R.sub.2 is cyano, halo, nitro, C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy, amino, hydroxyl-amino,
hydroxyl-C.sub.1-8alkyl-amino,
C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-thio,
amino-carbonyl, amino-carbonyl-amino,
C.sub.1-8alkoxy-carbonyl-amino, amino-sulfonyl-amino or heteroaryl,
wherein heteroaryl is optionally substituted with one, two, three
or four C.sub.1-8alkyl substituents.
[0048] Another embodiment includes a compound of Formula (I),
wherein R.sub.2 is cyano, halo, hydroxyl, nitro, C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy, amino,
C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, hydroxyl-amino,
hydroxyl-C.sub.1-8alkyl-amino,
C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-thio,
C.sub.1-8alkyl-carbonyl, C.sub.1-8alkyl-carbonyl-amino,
amino-carbonyl, C.sub.1-8alkyl-amino-carbonyl,
(C.sub.1-8alkyl).sub.2-amino-carbonyl, amino-carbonyl-amino,
C.sub.1-8alkyl-amino-carbonyl-amino,
(C.sub.1-8alkyl).sub.2-amino-carbonyl-amino,
C.sub.1-8alkoxy-carbonyl, C.sub.1-8alkoxy-carbonyl-amino,
amino-sulfonyl, C.sub.1-8alkyl-amino-sulfonyl,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl, amino-sulfonyl-amino,
C.sub.1-8alkyl-amino-sulfonyl-amino,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl-amino or
P(O)(R.sub.7).sub.2-amino.
[0049] Another embodiment includes a compound of Formula (I),
wherein R.sub.2 is cyano, halo, nitro, C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy, amino, hydroxyl-amino,
hydroxyl-C.sub.1-8alkyl-amino,
C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-thio,
amino-carbonyl, amino-carbonyl-amino,
C.sub.1-8alkoxy-carbonyl-amino or amino-sulfonyl-amino.
[0050] Another embodiment includes a compound of Formula (I),
wherein R.sub.2 is heteroaryl, wherein heteroaryl is optionally
substituted with one, two, three or four C.sub.1-8alkyl
substituents.
[0051] Another embodiment includes a compound of Formula (I),
wherein R.sub.2 heteroaryl is optionally substituted
1H-pyrrolyl.
[0052] Another embodiment includes a compound of Formula (I),
wherein R.sub.2 heteroaryl is optionally substituted
1H-pyrrol-1-yl.
[0053] Another embodiment includes a compound of Formula (I),
wherein R.sub.3 is hydrogen.
[0054] Another embodiment includes a compound of Formula (I),
wherein R.sub.3 is cyano, halo, C.sub.1-8alkyl, amino,
C.sub.1-8alkyl-amino or (C.sub.1-8alkyl).sub.2-amino.
[0055] Another embodiment includes a compound of Formula (I),
wherein R.sub.3 is cyano, halo, C.sub.1-8alkyl or amino.
[0056] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted C.sub.3-14cycloalkyl
selected from 2,3-dihydro-1H-indenyl; or, optionally substituted
aryl selected from phenyl or naphthyl; or, optionally substituted
heteroaryl selected from 1,3-thiazolyl, 1,2-oxazolyl, pyridinyl,
pyrimidinyl, 1H-indolyl, benzofuranyl, benzooxazolyl,
1,3-benzothiazolyl, quinolinyl or isoquinolinyl; or, optionally
substituted heterocyclyl selected from 1,3-benzodioxolyl or
2,3-dihydro-1,4-benzodioxinyl.
[0057] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted C.sub.3-14cycloalkyl
selected from 2,3-dihydro-1H-indenyl.
[0058] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted C.sub.3-14cycloalkyl
selected from 2,3-dihydro-1H-inden-2-yl.
[0059] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted aryl selected from phenyl
or naphthyl.
[0060] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted heteroaryl selected from
1,3-thiazolyl, 1,2-oxazolyl, pyridinyl, pyrimidinyl, 1H-indolyl,
benzofuranyl, benzooxazolyl, 1,3-benzothiazolyl, quinolinyl or
isoquinolinyl; or, optionally substituted heterocyclyl selected
from 1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl.
[0061] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted heteroaryl selected from
1,3-thiazol-2-yl, 1,2-oxazol-5-yl, pyridin-2-yl, pyridin-3-yl,
pyrimidin-5-yl, 1H-indol-5-yl, benzofuran-5-yl, benzooxazol-5-yl,
1,3-benzothiazol-2-yl, quinolin-3-yl, quinolin-6-yl or
isoquinolin-3-yl; or, optionally substituted heterocyclyl selected
from 1,3-benzodioxol-5-yl or 2,3-dihydro-1,4-benzodioxin-6-yl.
[0062] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted heteroaryl selected from
1,3-thiazolyl, 1,2-oxazolyl, pyridinyl, pyridinyl, pyrimidinyl,
1H-indolyl, benzofuranyl, benzooxazolyl, 1,3-benzothiazolyl,
quinolinyl or isoquinolinyl.
[0063] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted heteroaryl selected from
1,3-thiazol-2-yl, 1,2-oxazol-5-yl, pyridin-2-yl, pyridin-3-yl,
pyrimidin-5-yl, 1H-indol-5-yl, benzofuran-5-yl, benzooxazol-5-yl,
1,3-benzothiazol-2-yl, quinolin-3-yl, quinolin-6-yl or
isoquinolin-3-yl.
[0064] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted heterocyclyl selected
from 1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl.
[0065] Another embodiment includes a compound of Formula (I),
wherein R.sub.4 is optionally substituted heterocyclyl selected
from 1,3-benzodioxol-5-yl or 2,3-dihydro-1,4-benzodioxin-6-yl.
[0066] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from cyano, halo,
hydroxyl, nitro, C.sub.1-8alkyl, cyano-C.sub.1-8alkyl,
halo-C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy,
C.sub.1-8alkoxy-C.sub.1-8alkyl, halo-C.sub.1-8alkoxy,
C.sub.2-8alkenyl, C.sub.1-8alkoxy-C.sub.2-8alkenyl, carboxyl,
amino, C.sub.1-8alkyl-amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-thio,
C.sub.1-8alkyl-carbonyl,
C.sub.1-8alkyl-carbonyl-oxy-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl, C.sub.1-8alkyl-sulfonyl,
C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl, aryl-amino,
aryl-C.sub.1-8alky-amino, heteroaryl or heteroaryl-C.sub.1-8alkyl,
wherein heteroaryl and the aryl and heteroaryl portions of
aryl-C.sub.1-8alkyl, aryl-amino, aryl-C.sub.1-8alky-amino and
heteroaryl-C.sub.1-8alkyl are each optionally substituted with one,
two, three or four halo or halo-C.sub.1-8alkoxy substituents.
[0067] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from cyano, halo,
hydroxyl, nitro, oxo, C.sub.1-8alkyl, cyano-C.sub.1-8alkyl,
halo-C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy,
C.sub.1-8alkoxy-C.sub.1-8alkyl, halo-C.sub.1-8alkoxy,
C.sub.2-8alkenyl, C.sub.1-8alkoxy-C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.1-8alkoxy-C.sub.2-8alkynyl, carboxyl,
amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino,
amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl-amino,
hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino,
C.sub.1-8alkyl-thio, C.sub.1-8alkyl-carbonyl,
C.sub.1-8alkyl-carbonyl-amino, C.sub.1-8alkyl-carbonyl-oxy,
C.sub.1-8alkyl-carbonyl-oxy-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl, C.sub.1-8alkoxy-carbonyl-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl-amino or C.sub.1-8alkyl-sulfonyl.
[0068] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from cyano, halo,
hydroxyl, nitro, C.sub.1-8alkyl, cyano-C.sub.1-8alkyl,
halo-C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy,
C.sub.1-8alkoxy-C.sub.1-8alkyl, halo-C.sub.1-8alkoxy,
C.sub.2-8alkenyl, C.sub.1-8alkoxy-C.sub.2-8alkenyl, carboxyl,
amino, C.sub.1-8alkyl-amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-thio,
C.sub.1-8alkyl-carbonyl,
C.sub.1-8alkyl-carbonyl-oxy-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl or C.sub.1-8alkyl-sulfonyl.
[0069] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from optionally
substituted C.sub.3-14cycloalkyl selected from cyclopropyl or
cyclobutyl; or, aryl, aryl-C.sub.1-8alkyl, aryl-amino or
aryl-C.sub.1-8alky-amino optionally substituted on aryl and the
aryl portions, wherein aryl is selected from phenyl; and, wherein
the optional substituents on C.sub.3-14cycloalkyl, aryl and the
aryl portions are selected from one, two, three or four halo,
C.sub.1-8alkyl, halo-C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl,
C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, hydroxyl-C.sub.1-8alkyl or
carboxyl substituents; or, heteroaryl or heteroaryl-C.sub.1-8alkyl
optionally substituted on heteroaryl and the heteroaryl portion,
wherein heteroaryl is selected from tetrazolyl or pyridinyl; and,
wherein the optional substituents on heteroaryl and the heteroaryl
portion are selected from one, two, three or four halo,
C.sub.1-8alkyl, halo-C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl,
C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, hydroxyl-C.sub.1-8alkyl or
carboxyl substituents.
[0070] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from optionally
substituted C.sub.3-14cycloalkyl selected from cyclopropyl or
cyclobutyl; or, aryl-C.sub.1-8alkyl, aryl-amino or
aryl-C.sub.1-8alky-amino optionally substituted on the aryl
portions, wherein aryl is selected from phenyl; and, wherein the
optional substituents on C.sub.3-14cycloalkyl and the aryl portions
are selected from one, two, three or four halo or
halo-C.sub.1-8alkoxy substituents; or, heteroaryl or
heteroaryl-C.sub.1-8alkyl optionally substituted on heteroaryl and
the heteroaryl portion, wherein heteroaryl is selected from
tetrazolyl or pyridinyl; and, wherein the optional substituents on
heteroaryl and the heteroaryl portion are selected from one, two,
three or four halo or halo-C.sub.1-8alkoxy substituents.
[0071] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from optionally
substituted C.sub.3-14cycloalkyl selected from cyclopropyl or
cyclobutyl.
[0072] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from aryl,
aryl-C.sub.1-8alkyl, aryl-amino or aryl-C.sub.1-8alky-amino
optionally substituted on aryl and the aryl portions, wherein aryl
is selected from phenyl; and, wherein the optional substituents are
selected from one, two, three or four halo, C.sub.1-8alkyl,
halo-C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy,
halo-C.sub.1-8alkoxy, hydroxyl-C.sub.1-8alkyl or carboxyl
substituents.
[0073] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from aryl-C.sub.1-8alkyl,
aryl-amino or aryl-C.sub.1-8alky-amino optionally substituted on
the aryl portions, wherein aryl is selected from phenyl; and,
wherein the optional substituents are selected from one, two, three
or four halo or halo-C.sub.1-8alkoxy substituents.
[0074] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from heteroaryl or
heteroaryl-C.sub.1-8alkyl optionally substituted on heteroaryl and
the heteroaryl portion, wherein heteroaryl is selected from
tetrazolyl or pyridinyl; and, wherein the optional substituents are
selected from one, two, three or four halo, C.sub.1-8alkyl,
halo-C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy,
halo-C.sub.1-8alkoxy, hydroxyl-C.sub.1-8alkyl or carboxyl
substituents.
[0075] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from heteroaryl or
heteroaryl-C.sub.1-8alkyl optionally substituted on heteroaryl and
the heteroaryl portion, wherein heteroaryl is selected from
tetrazolyl or pyridinyl; and, wherein the optional substituents are
selected from one, two, three or four halo or halo-C.sub.1-8alkoxy
substituents.
[0076] Another embodiment includes a compound of Formula (I),
wherein R.sub.5 is independently selected from heteroaryl or
heteroaryl-C.sub.1-8alkyl optionally substituted on heteroaryl and
the heteroaryl portion, wherein heteroaryl is selected from
2H-tetrazol-2-yl, tetrazol-1-yl, pyridin-2-yl, pyridin-3-yl or
pyridin-4-yl; and, wherein the optional substituents are selected
from one, two, three or four halo or halo-C.sub.1-8alkoxy
substituents.
[0077] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 is independently selected from cyano, halo,
hydroxyl, nitro, C.sub.1-8alkyl, halo-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, formyl, formyl-oxy,
C.sub.1-8alkyl-carbonyl, halo-C.sub.1-8alkyl-carbonyl,
C.sub.1-8alkyl-thio, halo-C.sub.1-8alkyl-thio, amino,
C.sub.1-8alkyl-carbonyl, C.sub.1-8alkoxy-carbonyl, amino-carbonyl,
C.sub.1-8alkyl-amino-carbonyl, amino-C.sub.1-8alkyl,
(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino,
hydroxyl-C.sub.1-8alkyl-amino, hydroxyl-imino-C.sub.1-8alkyl,
C.sub.1-8alkyl-sulfonyl, B(OR.sub.8).sub.2, C.sub.3-14cycloalkyl,
heterocyclyl, aryl or heteroaryl, wherein C.sub.3-14cycloalkyl,
heterocyclyl, aryl and heteroaryl are each optionally substituted
with one, two, three or four halo or C.sub.1-8alkyl
substituents.
[0078] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 is independently selected from cyano, halo,
hydroxyl, nitro, C.sub.1-8alkyl, halo-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy,
C.sub.2-8alkenyl, C.sub.1-8alkoxy-C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.1-8alkoxy-C.sub.2-8alkynyl, carboxyl,
formyl, formyl-oxy, C.sub.1-8alkyl-carbonyl,
halo-C.sub.1-8alkyl-carbonyl, C.sub.1-8alkyl-thio,
halo-C.sub.1-8alkyl-thio, amino, C.sub.1-8alkyl-amino,
(C.sub.1-8alkyl).sub.2-amino, C.sub.1-8alkyl-carbonyl,
C.sub.1-8alkyl-carbonyl-oxy,
C.sub.1-8alkyl-carbonyl-oxy-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl, halo-C.sub.1-8alkoxy-carbonyl,
C.sub.1-8alkoxy-carbonyl-C.sub.1-8alkyl,
C.sub.1-8alkoxy-carbonyl-amino,
C.sub.1-8alkoxy-carbonyl-amino-C.sub.1-8alkyl, amino-carbonyl,
C.sub.1-8alkyl-amino-carbonyl,
(C.sub.1-8alkyl).sub.2-amino-carbonyl,
C.sub.1-8alkyl-carbonyl-amino,
C.sub.1-8alkyl-carbonyl-amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl,
C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, amino-C.sub.1-8
alkyl-amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino,
(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino,
hydroxyl-C.sub.1-8alkyl-amino,
hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino,
imino-C.sub.1-8alkyl, hydroxyl-imino-C.sub.1-8alkyl,
C.sub.1-8alkoxy-imino-C.sub.1-8alkyl, C.sub.1-8alkyl-sulfonyl,
halo-C.sub.1-8alkyl-sulfonyl, amino-sulfonyl,
C.sub.1-8alkyl-amino-sulfonyl,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl or B(OR.sub.8).sub.2.
[0079] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 is independently selected from cyano, halo,
hydroxyl, nitro, C.sub.1-8alkyl, halo-C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, formyl, formyl-oxy,
C.sub.1-8alkyl-carbonyl, halo-C.sub.1-8alkyl-carbonyl,
C.sub.1-8alkyl-thio, halo-C.sub.1-8alkyl-thio, amino,
C.sub.1-8alkyl-carbonyl, C.sub.1-8alkoxy-carbonyl, amino-carbonyl,
C.sub.1-8alkyl-amino-carbonyl, amino-C.sub.1-8alkyl,
(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino,
hydroxyl-C.sub.1-8alkyl-amino, hydroxyl-imino-C.sub.1-8alkyl,
C.sub.1-8alkyl-sulfonyl, C.sub.1-8alkyl-amino-sulfonyl or
B(OR.sub.8).sub.2.
[0080] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 is independently selected from
C.sub.3-14cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein
C.sub.3-14cycloalkyl, heterocyclyl, aryl and heteroaryl are each
optionally substituted with one, two, three or four halo or
C.sub.1-8alkyl substituents.
[0081] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 is independently selected from C.sub.3-14cycloalkyl
or heterocyclyl, wherein C.sub.3-14cycloalkyl and heterocyclyl are
each optionally substituted with two C.sub.1-8alkyl
substituents.
[0082] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 optionally substituted C.sub.3-14cycloalkyl is
selected from cyclopropyl; optionally substituted heterocyclyl is
selected from morpholinyl or 1,3,2-dioxaborolanyl; optionally
substituted aryl is selected from phenyl; or, optionally
substituted heteroaryl is selected from 1H-pyrazolyl.
[0083] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 optionally substituted C.sub.3-14cycloalkyl is
selected from cyclopropyl.
[0084] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 optionally substituted heterocyclyl is selected
from morpholinyl or 1,3,2-dioxaborolanyl.
[0085] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 optionally substituted heterocyclyl is selected
from morpholin-4-yl or 1,3,2-dioxaborolan-2-yl.
[0086] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 optionally substituted aryl is selected from
phenyl.
[0087] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 optionally substituted heteroaryl is selected from
1H-pyrazolyl.
[0088] Another embodiment includes a compound of Formula (I),
wherein R.sub.6 optionally substituted heteroaryl is selected from
1H-pyrazol-1-yl.
[0089] Another embodiment includes a compound of Formula (I),
wherein R.sub.7 is hydroxyl.
[0090] Another embodiment includes a compound of Formula (I),
wherein R.sub.7 is (C.sub.1-8alkoxy).sub.n, wherein n represents an
integer from 1 to 5.
[0091] Another embodiment includes a compound of Formula (I),
wherein R.sub.8 is hydrogen.
[0092] Another embodiment includes a compound of Formula (I),
wherein R.sub.8 is C.sub.1-8alkyl.
[0093] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a free acid, free base, salt, ester, hydrate,
solvate, chelate, clathrate, polymorph, isotopologue, stereoisomer,
racemate, enantiomer, diastereomer or tautomer thereof.
[0094] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a free acid, free base, salt, ester, hydrate, solvate
or polymorph thereof.
[0095] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a salt, ester, hydrate, solvate, chelate, clathrate,
polymorph, isotopologue, stereoisomer, racemate, enantiomer,
diastereomer or tautomer thereof.
[0096] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a free acid, free base, salt, hydrate or polymorph
thereof.
[0097] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a free acid, free base, hydrate, solvate or polymorph
thereof.
[0098] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a salt, hydrate, solvate or polymorph thereof.
[0099] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a free acid, free base or salt thereof.
[0100] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a free acid or free base thereof.
[0101] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a salt thereof.
[0102] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
selected from a polymorph thereof.
[0103] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
pharmaceutically acceptable.
[0104] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the form of the compound of Formula (I) is
isolated.
[0105] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the compound is a compound of Formula (II),
Formula (III) or Formula (IV):
##STR00003##
or a form thereof, wherein [0106] R.sub.9 and R.sub.10 are
independently hydrogen, hydroxyl, C.sub.1-8alkyl,
hydroxyl-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl,
C.sub.1-8alkyl-carbonyl, amino-carbonyl,
C.sub.1-8alkyl-amino-carbonyl,
(C.sub.1-8alkyl).sub.2-amino-carbonyl, C.sub.1-8alkoxy-carbonyl,
amino-sulfonyl, C.sub.1-8alkyl-amino-sulfonyl,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl or P(O)(R.sub.7).sub.2.
[0107] Another embodiment includes a compound of Formula (III),
wherein one of R.sub.9 and R.sub.10 is hydrogen and the other is
hydroxyl, C.sub.1-8alkyl, hydroxyl-C.sub.1-8alkyl,
C.sub.1-8alkoxy-C.sub.1-8alkyl, C.sub.1-8alkyl-carbonyl,
amino-carbonyl, C.sub.1-8alkyl-amino-carbonyl,
(C.sub.1-8alkyl).sub.2-amino-carbonyl, C.sub.1-8alkoxy-carbonyl,
amino-sulfonyl, C.sub.1-8alkyl-amino-sulfonyl,
(C.sub.1-8alkyl).sub.2-amino-sulfonyl or P(O)(R.sub.7).sub.2.
[0108] Another embodiment includes a compound of Formula (I) or a
form thereof, wherein the compound is a compound of Formula (Ia),
Formula (IIa), Formula (Ma) or Formula (IVa):
##STR00004##
or a form thereof, wherein R.sub.2, R.sub.3, R.sub.9, R.sub.10 or
R.sub.11 are independently deuterium.
[0109] Another embodiment includes a compound of Formula (I) or a
form thereof selected from the group consisting of:
##STR00005## ##STR00006## ##STR00007## ##STR00008## ##STR00009##
##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014##
##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019##
##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##
##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033##
##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038##
##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043##
##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048##
##STR00049## ##STR00050## ##STR00051## ##STR00052##
wherein the form of the compound of Formula (I) is selected from a
salt, ester, hydrate, solvate, chelate, clathrate, polymorph,
isotopologue, stereoisomer, racemate, enantiomer, diastereomer or
tautomer thereof.
[0110] Another embodiment includes a compound of Formula (I) or a
form thereof selected from the group consisting of:
TABLE-US-00001 Cpd Name 1
N-(4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-amine
2
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-methylimidazo[1,2-a]pyridin-3-
yl)pyrimidin-4-amine 3
2-(2-methylimidazo[1,2-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]pyri-
midin- 4-amine 4
N-(4-methoxyphenyl)-2-(2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-am-
ine 5
N-(4-chlorophenyl)-2-(2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-ami-
ne 6
2-(2-methylimidazo[1,2-a]pyridin-3-yl)-N-phenylpyrimidin-4-amine 7
2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluoromethyl)
phenyl]pyrimidin-4-amine 8
N-(4-chlorophenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyri-
midin- 4-amine 9
N-(4-methylphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyri-
midin- 4-amine 10
N-(4-bromophenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyri-
midin- 4-amine 11
N-[4-(difluoromethoxy)phenyl]-2-[2-(trifluoromethyl]imidazo[1,2-a]pyrid-
in- 3-yl]pyrimidin-4-amine 12
N-(4-methoxyphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]
pyrimidin-4-amine 13
2-[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine 14
2-[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethoxy)phenyl]pyrimidin-4-amine 15
N-(4-bromophenyl)-2-[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-
3-yl]pyrimidin-4-amine 16
2-[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(difluoromethoxy)phenyl]pyrimidin-4-amine 17
N-(4-chlorophenyl)-2-[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-
- 3-yl]pyrimidin-4-amine 18
2-[2-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(triflu-
oromethyl) phenyl]pyrimidin-4-amine 19
N-(4-bromophenyl)-2-[2-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-
3-yl]pyrimidin-4-amine 20
N-(4-methylphenyl)-2-[2-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-
- 3-yl]pyrimidin-4-amine 21
2-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-(4-methylp-
henyl) pyrimidin-4-amine 22
2-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-(4-methoxy-
phenyl) pyrimidin-4-amine 23
2-[5-chloro-1-methyl-2-(trifluoromethyl)-1H-indol-3-yl]-N-(4-methoxyphe-
nyl) pyrimidin-4-amine 24
2-[5-chloro-1-methyl-2-(trifluoromethyl)-1H-indol-3-yl]-N-[4-(difluorom-
ethoxy) phenyl]pyrimidin-4-amine 25
N-(4-bromophenyl)-2-[5-chloro-1-methyl-2-(trifluoromethyl)-1H-indol-3-y-
l] pyrimidin-4-amine 26
N-(4-bromophenyl)-2-(6-fluoro-2-phenylimidazo[1,2-a]pyridin-3-yl)
pyrimidin-4-amine 27
2-(6-fluoro-2-phenylimidazo[1,2-a]pyridin-3-yl)-N-(4-methylphenyl)
pyrimidin-4-amine 28
N-(1,3-benzodioxol-5-yl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3--
yl]- pyrimidin-4-amine 29
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[2-(trifluoromethyl)imidazo[1,2--
a] pyridin-3-yl]pyrimidin-4-amine 30
N-(6-methoxypyridin-3-yl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
-yl] pyrimidin-4-amine 31
N.sup.2,N.sup.2-dimethyl-N.sup.5-{2-[2-(trifluoromethyl)imidazo[1,2-a]p-
yridin-3-yl]pyrimidin- 4-yl}pyridine-2,5-diamine 32
2-[6-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluo-
romethyl) phenyl]pyrimidin-4-amine 33
2-[6-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-(4-methoxyp-
henyl) pyrimidin-4-amine 34
N-(3-fluoro-4-methoxyphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridi-
n- 3-yl]pyrimidin-4-amine 35
N-(3-chloro-4-methoxyphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridi-
n- 3-yl]pyrimidin-4-amine 36
N-(3-chloro-4-methylphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-
- 3-yl]pyrimidin-4-amine 37
N-(4-ethoxyphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]
pyrimidin-4-amine 38
N-[4-(propan-2-yl)phenyl]-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
-yl] pyrimidin-4-amine 39
N-[4-(1H-pyrazol-1-yl)phenyl]-2-[2-(trifluoromethyl)imidazo[1,2-a]pyrid-
in- 3-yl]pyrimidin-4-amine 40
N-(3-chloro-4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-
-4-amine 41
2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidi-
n-4-amine 42
N-(3-chloro-4-methoxyphenyl)-2-[2-(trifluoromethyl)-1H-benzimidazol-1-
yl]pyrimidin-4-amine 43
5-fluoro-N-(4-methylphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-
-3- yl]pyrimidin-4-amine 44
5-chloro-N-(4-methylphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-
-3- yl]pyrimidin-4-amine 45
N-(4-methoxyphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl]
pyrimidin-4-amine 46
2-[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine 47
N-(4-chlorophenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyr-
imidin- 4-amine 48
2-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine 49
2-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethoxy)phenyl]pyrimidin-4-amine 50
N-(4-methoxyphenyl)-2-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyrid-
in- 3-yl]pyrimidin-4-amine 51
N-[4-(difluoromethoxy)phenyl]-2-[6-methoxy-2-(trifluoromethyl)imidazo[1-
,2-a] pyridin-3-yl]pyrimidin-4-amine 52
2-{[6-{[4-(difluoromethoxy)phenyl]amino}-2-(2-methyl-1H-benzimidazol-1-
yl)pyrimidin-4-yl]amino}ethanol 53
N-[4-(difluoromethoxy)phenyl]-2-[2-(trifluoromethyl)imidazo[1,2-a]pyraz-
in- 3-yl]pyrimidin-4-amine 54
2-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine 55
N-[4-(difluoromethoxy)phenyl]-2-[6-fluoro-2-(trifluoromethyl)imidazo[1,-
2-a] pyridin-3-yl]pyrimidin-4-amine 56
N-[4-(trifluoromethyl)phenyl]-2-[2-(trifluoromethyl)pyrazolo[1,5-a]pyri-
din- 3-yl]pyrimidin-4-amine 57
2-{[2-(2-methyl-1H-benzimidazol-1-yl)-6-{[4-(trifluoromethyl)phenyl]
amino}pyrimidin-4-yl]amino}ethanol 58
N.sup.4-(2-methoxyethyl)-2-(2-methyl-1H-benzimidazol-1-yl)-N.sup.6-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 59
N.sup.4-[4-(difluoromethoxy)phenyl]-N.sup.6-(2-methoxyethyl)-2-(2-methy-
l-1H- benzimidazol-1-yl)pyrimidine-4,6-diamine 60
N-(4-methoxyphenyl)-2-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]
pyrimidin-4-amine 61
N-[4-(difluoromethoxy)phenyl]-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidin-4-amine 62
N-(4-methylphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl]
pyrimidin-4-amine 63
2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidi-
ne- 4,6-diamine 64
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 65
N-[4-(difluoromethoxy)phenyl]-2-[2-(trifluoromethyl)imidazo[1,2-a]pyrid-
in- 3-yl]pyrimidine-4,6-diamine 66
2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluoromethyl-
)phenyl] pyrimidine-4,6-diamine 67
N-[4-(trifluoromethoxy)phenyl]-2-[2-(trifluoromethy)imidazo[1,2-a]pyrid-
in- 3-yl]pyrimidine-4,6-diamine 68
2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N-[4-(trifluoromethyl)p-
henyl] pyrimidine-4,6-diamine 69
N-[4-(difluoromethoxy)phenyl]-2-(6-fluoro-2-methylimidazo[1,2-a]
pyridin-3-yl)pyrimidine-4,6-diamine 70
N-[4-(trifluoromethyl)phenyl]-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimi-
dine- 4,6-diamine 71
2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl-
] pyrimidine-4,6-diamine 72
N-[4-(difluoromethoxy)phenyl]-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl-
) pyrimidine-4,6-diamine 73
2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(trifluoromethyl)phenyl-
] pyrimidine-4,6-diamine 74
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 75
2-(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)-N-[4-(difluorometh-
oxy)- 3-fluorophenyl]pyrimidine-4,6-diamine 76
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(6-fluoro-2-methyl-1H-benzimid-
azol- 1-yl)pyrimidine-4,6-diamine 77
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-6-fluoro-1H-benzimida-
zol- 1-yl)pyrimidine-4,6-diamine 78
2-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)-
3-fluorophenyl]pyrimidine-4,6-diamine 79
N-[4-(trifluoromethyl)phenyl]-2-(2,5,6-trimethyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 80
N-[3-fluoro-4-(trifluoromethyl)phenyl]-2-(2-methyl-1H-benzimidazol-1-yl-
) pyrimidine-4,6-diamine 81
2-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]
pyrimidine-4,6-diamine 82
2-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 83
2-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 84
[3-(4-amino-6-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)-
6-fluoroimidazo[1,2-a]pyridin-2-yl]methanol 85
2-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine 86
2-(2,6-dimethyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine 87
2-(6-ethyl-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-,4,6-diamine 88
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 89
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 90
2-{[2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-6-{[4-
(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanol 91
2-(6-ethenyl-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 92
2-(2-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 93
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine 94
2-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 95
5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine 96
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 97
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(difluoromethoxy)phenyl]pyrimidine-4,6-diamine 98
2-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 99
2-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(difluoromethoxy)phenyl]pyrimidine-4,6-diamine 100
2-(6-fluoro-2-methylimidazo[1,2-a]pyrimidin-3-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 101
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(5,6-difluoro-2-methyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine 102
N-[4-(difluoromethoxy)phenyl]-2-(5,6-difluoro-2-methyl-1H-benzimidazol-
- 1-yl)pyrimidine-4,6-diamine 103
2-(2-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-
(difluoromethoxy)phenyl]pyrimidine-4,6-diamine 104
2-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 105
2-(6-chloro-2-ethyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 106
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methyl-1H-benzimidazol-
1-yl)pyrimidine-4,6-diamine 107 2-(2-ethyl-1H-benzimidazol-1-yl)-5
fluoro-N-[4-(trifluoromethyl) phenyl]pyrimidine-4,6-diamine 108
5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 109
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 110
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimi-
dazol- 1-yl)pyrimidine-4,6-diamine 111
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(6-fluoro-2-methyl-1-
H- benzimidazol-1-yl)pyrimidine-4,6-diamine 112
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(5-fluoro-2-methyl-1-
H- benzimidazol-1-yl)pyrimidine-4,6-diamine 113
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(5-fluoro-2-methyl-1H-benzimi-
dazol- 1-yl)pyrimidine-4,6-diamine 114
2-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-5-fluoro-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 115
2-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(difluorometh-
oxy) phenyl]-5-fluoropyrimidine-4,6-diamine 116
2-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(difluorometh-
oxy)- 3-fluorophenyl]-5-fluoropyrimidine-4,6-diamine 117
2-(2-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-1-yl)-5-fluoro-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 118
2-(imidazo[1,2-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin--
4-amine 119
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(2-methyl-1H-benzimi-
dazol- 1-yl)pyrimidine-4,6-diamine 120
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 121
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)phenyl]-5-
- fluoropyrimidine-4,6-diamine 122
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)-3-fluoro-
phenyl]- 5-fluoropyrimidine-4,6-diamine 123
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-1H-benzimidazol-1-yl)-5-
fluoropyrimidine-4,6-diamine 124
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-1H-benzimidazol-1-yl-
)- 5-fluoropyrimidine-4,6-diamine 125
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 126
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(5,6-difluoro-2-methyl-1H-ben-
zimidazol- 1-yl)-5-fluoropyrimidine-4,6-diamine 127
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 128
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(4,6-difluoro-2-methyl-1H-
benzimidazol-1-yl)-5-fluoropyrimidine-4,6-diamine 129
2-(2-ethyl-4,6-difluoro-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoro-
methyl) phenyl]pyrimidine-4,6-diamine 130
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-4,6-difluoro-1H-benz-
imidazol- 1-yl)-5-fluoropyrimidine-4,6-diamine 131
N-[4-(difluoromethoxy)phenyl]-2-(4,6-difluoro-2-methyl-1H-benzimidazol-
-1-yl)- 5-fluoropyrimidine-4,6-diamine 132
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-4,6-difluoro-1H-benzimidazol--
1-yl)- 5-fluoropyrimidine-4,6-diamine 133
N-[4-(difluoromethoxy)phenyl]-2-(5,6-difluoro-2-methyl-1H-benzimidazol-
-1-yl)- 5-fluoropyrimidine-4,6-diamine 134
5-fluoro-2-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 135
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(4-fluoro-2-methyl-1H-benzimi-
dazol- 1-yl)pyrimidine-4,6-diamine 136
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(4-fluoro-2-methyl-1-
H- benzimidazol-1-yl)pyrimidine-4,6-diamine 137
5-fluoro-2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(trifluoromet-
hyl) phenyl]pyrimidine-4,6-diamine 138
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methyl-1H-imidazo[4,5-b]py-
ridin- 1-yl)pyrimidine-4,6-diamine 139
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(2-methyl-1H-imidazo
[4,5-b]pyridin-1-yl)pyrimidine-4,6-diamine 140
2-(2-cyclopropyl-4-fluoro-1H-benzimidazol-1-yl)-5-fluoro-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 141
2-(2-cyclopropyl-4-fluoro-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)
phenyl]-5-fluoropyrimidine-4,6-diamine 142
2-(2-cyclopropyl-4-fluoro-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)-
- 3-fluorophenyl]-5-fluoropyrimidine-4,6-diamine 143
2-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)
phenyl]pyrimidine-4,6-diamine 144
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl-
) pyrimidine-4,6-diamine 145
N-[4-(difluoromethoxy)phenyl]-2-[2-(difluoromethyl)-6-fluoro-1H-benzim-
idazol- 1-yl]pyrimidine-4,6-diamine 146
2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(methylsulfanyl)phenyl]
pyrimidine-4,6-diamine 147
2-[2-(1-methylcyclopropyl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromethyl-
) phenyl]pyrimidine-4,6-diamine 148
N-[4-(difluoromethoxy)phenyl]-2-[2-(1-methylcyclopropyl)-1H-benzimidaz-
ol- 1-yl]pyrimidine-4,6-diamine 149
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]
pyrimidine-4,6-diamine 150
2-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine 151
2-[2-(propan-2-yl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromethyl)phenyl]
pyrimidine-4,6-diamine 152
2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromethyl)phen-
yl] pyrimidine-4,6-diamine 153
2-(2-ethyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidi-
ne- 4,6-diamine 154
2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]
pyrimidine-4,6-diamine 155
2-(2-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(difluor-
omethoxy) phenyl-5-fluoropyrimidine-4,6-diamine 156
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 157
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-1H-benzimidazol-1-yl-
) pyrimidine-4,6-diamine 158
2-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoromet-
hyl) phenyl]pyrimidine-4,6-diamine 159
2-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)
phenyl]-5-fluoropyrimidine-4,6-diamine 160
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 161
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)
phenyl]-5-fluoropyrimidine-4,6-diamine 162
2-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)-5-fluoro-
N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 163
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl-
)- 5-fluoropyrimidine-4,6-diamine 164
2-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluorometh-
yl) phenyl]pyrimidine-4,6-diamine 165
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl-
)- 5-fluoropyrimidine-4,6-diamine 166
5-chloro-2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)pheny-
l] pyrimidine-4,6-diamine 167
5-chloro-2-(2-ethyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl-
] pyrimidine-4,6-diamine 168
5-chloro-N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-1H-benzimidazol-1-yl-
) pyrimidine-4,6-diamine 169
5-fluoro-2-(2-methylimidazo[1,2-a]pyridin-3-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine 170
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methylimidazo[1,2-a]pyridi-
n- 3-yl)pyrimidine-4,6-diamine 171
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(2-methylimidazo[1,2-
-a] pyridin-3-yl)pyrimidine-4,6-diamine 172
5-methyl-2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine 173
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methylpyrazolo[1,5-a]
pyridin-3-yl)pyrimidine-4,6-diamine 174
5-fluoro-N-[4-(trifluoromethyl)phenyl]-2-(2,6,8-trimethylimidazo[1,2-a-
] pyrazin-3-yl)pyrimidine-4,6-diamine 175
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2,6,8-trimethylimidazo[1,2-a-
] pyrazin-3-yl)pyrimidine-4,6-diamine 176
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(2,6,8-trimethylimid-
azo [1,2-a]pyrazin-3-yl)pyrimidine-4,6-diamine 177
5-fluoro-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 178
5-fluoro-2-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N--
[4- (trifluoromethyl)phenyl]pyrimidine-4,6-diamine 179
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methoxyphenyl-
) pyrimidine-4,6-diamine 180
2-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(difluoromethoxy)
phenyl]-5-fluoropyrimidine-4,6-diamine 181
[3-(4-amino-6-{[4-(difluoromethoxy)phenyl]amino}-5-fluoropyrimidin-2-y-
l)- 5-fluoropyrazolo[1,5-a]pyridin-2-yl]methanol 182
2-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromethyl)phen-
yl] pyrimidine-4,6-diamine 183
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromet-
hyl) pyridin-3-yl]pyrimidine-4,6-diamine 184
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)
pyrimidine-4,6-diamine 185
N-(4-chlorophenyl)-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 186
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-5-fluoropyrazolo[1,5-a]pyridi-
n-3-yl)- 5-fluoropyrimidine-4,6-diamine 187
2-(2-ethyl-5-fluoropyrazolo[1,5-a]pyridin-3-yl)-5-fluoro-N-[4-(trifluo-
romethyl) phenyl]pyrimidine-4,6-diamine 188
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-5-fluoropyrazolo[1,5-
-a] pyridin-3-yl)-5-fluoropyrimidine-4,6-diamine 189
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(3-methoxyphenyl-
) pyrimidine-4,6-diamine 190
N-(3-chlorophenyl)-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 191
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethoxy)phenyl]pyrimidine-4,6-diamine 192
4-{[6-amino-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimid-
in- 4-yl]amino}benzonitrile 193 methyl
4-{[6-amino-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)
pyrimidin-4-yl]amino}benzoate 194
5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-N-(3-methylphenyl)
pyrimidine-4,6-diamine 195
5-fluoro-N-(3-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 196
2-(2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)pyrimidine-4,6-dia-
mine 197
N-(4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-4,6-di-
amine 198
N-[4-(dimethylamino)phenyl]-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 199
5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)
pyrimidine-4,6-diamine 200
5-fluoro-N-(4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 201
N-(4-chlorophenyl)-5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 202
4-{[6-amino-5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-4-yl]amino}benz-
onitrile 203
N-(1,3-benzodioxol-5-yl)-5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 204
5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethoxy)phenyl]pyrimidine-4,6-diamine 205
N-(1,3-benzodioxol-5-yl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-4-
,6-diamine 206
N-(2,2-difluoro-1,3-benzodioxol-5-yl)-2-(2-methyl-1H-benzimidazol-1-yl-
) pyrimidine-4,6-diamine 207
N-(3-fluoro-4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 208
N-(6-methoxypyridin-3-yl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-
4,6-diamine 209
N-(4-chlorophenyl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-4,6-dia-
mine 210
4-{[6-amino-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]amino}benz-
onitrile 211
2-(2-methyl-1H-benzimidazol-1-yl)-N-(4-nitrophenyl)pyrimidine-4,6-diam-
ine 212
N-(4-bromophenyl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-4,6-diam-
ine 213
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-
methylphenyl)pyrimidine-4,6-diamine 214
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-
methoxyphenyl)pyrimidine-4,6-diamine 215
N-(4-chlorophenyl)-2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-
fluoropyrimidine-4,6-diamine 216
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-[2-(methoxymethyl)-1H-benzimi-
dazol- 1-yl]pyrimidine-4,6-diamine 217
5-fluoro-2-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N-(4-methylphenyl)
pyrimidine-4,6-diamine 218
5-fluoro-2-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N-(4-methoxyphenyl-
) pyrimidine-4,6-diamine 219
N-(4-chlorophenyl)-5-fluoro-2-[2-(methoxymethyl)-1H-benzimidazol-
1-yl]pyrimidine-4,6-diamine 220
5-fluoro-2-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromet-
hyl) phenyl]pyrimidine-4,6-diamine 221
2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethoxy)phenyl]
pyrimidine-4,6-diamine 222
1-(4-amino-5-fluoro-6-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl-
)- 2-methyl-1H-benzimidazole-6-carbonitrile 223
1-(4-amino-6-{[4-(difluoromethoxy)phenyl]amino}-5-fluoropyrimidin-2-yl-
)- 2-methyl-1H-benzimidazole-6-carbonitrile 224
1-{4-amino-5-fluoro-6-[(4-methylphenyl)amino]pyrimidin-2-yl}-2-methyl-
1H-benzimidazole-6-carbonitrile 225
1-{4-amino-5-fluoro-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl}-2-methyl-
- 1H-benzimidazole-6-carbonitrile 226
1-(4-amino-6-{[4-(difluoromethoxy)phenyl]amino}-5-fluoropyrimidin-2-yl-
)- 2-methyl-1H-benzimidazole-5-carbonitrile 227
1-{4-amino-5-fluoro-6-[(4-methylphenyl)amino]pyrimidin-2-yl}-
2-methyl-1H-benzimidazole-5-carbonitrile 228
1-{4-amino-5-fluoro-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl}-
2-methyl-1H-benzimidazole-5-carbonitrile 229
1-(4-amino-5-fluoro-6-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-
2-yl)-2-methyl-1H-benzimidazole-5-carbonitrile 230
1-{4-amino-6-[(4-chlorophenyl)amino]-5-fluoropyrimidin-2-yl}-2-methyl--
1H- benzimidazole-5-carbonitrile 231
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methyl-6-nitro-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine 232
5-fluoro-2-(2-methyl-6-nitro-1H-benzimidazol-1-yl)-N-(4-methylphenyl)
pyrimidine-4,6-diamine 233
5-fluoro-N-(4-methoxyphenyl)-2-(2-methyl-6-nitro-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 234
N-[4-(difluoromethoxy)phenyl]-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 235
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-methyl-1H-benzimidazol-
1-yl)pyrimidine-4,6-diamine 236
5-fluoro-2-(2-methyl-6-nitro-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine 237
N-(4-chlorophenyl)-2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-
5-fluoropyrimidine-4,6-diamine 238
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-
(trifluoromethoxy)phenyl]pyrimidine-4,6-diamine 239
5-fluoro-N-(4-methoxyphenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)
pyrimidine-4,6-diamine 240
N-(1,3-benzodioxol-5-yl)-2-(4,6-difluoro-2-methyl-1H-benzimidazol-
1-yl)-5-fluoropyrimidine-4,6-diamine 241
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methylphe-
nyl) pyrimidine-4,6-diamine 242
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methoxyph-
enyl) pyrimidine-4,6-diamine 243
2-(5,7-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-(trifluor-
omethyl) phenyl]pyrimidine-4,6-diamine 244
5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluorome-
thyl) phenyl]pyrimidine-4,6-diamine 245
N-(4-chlorophenyl)-5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-
1-yl)pyrimidine-4,6-diamine 246
5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluorome-
thoxy) phenyl]pyrimidine-4,6-diamine 247
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(6-methoxy-2-methyl-
1H-benzimidazol-1-yl)pyrimidine-4,6-diamine 248
5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl-
) pyrimidine-4,6-diamine 249
5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-1-yl)-N-(4-methoxypheny-
l) pyrimidine-4,6-diamine 250
N-(1,3-benzodioxol-5-yl)-5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazo-
l- 1-yl)pyrimidine-4,6-diamine 251
N-(4-chlorophenyl)-5-fluoro-2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-
3-yl)pyrimidine-4,6-diamine 252
5-fluoro-2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N-
(4-methoxyphenyl)pyrimidine-4,6-diamine 253
5-fluoro-2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N-
(4-methylphenyl)pyrimidine-4,6-diamine 254
5-fluoro-2-(2-methyl-5-nitro-1H-benzimidazol-1-yl)-N-(4-methylphenyl)
pyrimidine-4,6-diamine 255
5-fluoro-N-(4-methoxyphenyl)-2-(2-methyl-5-nitro-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 256
2-(6-amino-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methoxyphenyl)
pyrimidine-4,6-diamine 257
2-(6-amino-2-methyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)
phenyl]-5-fluoropyrimidine-4,6-diamine 258
2-(6-amino-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methylphenyl)
pyrimidine-4,6-diamine 259
N-(4-chlorophenyl)-5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)
pyrimidine-,46-diamine 260
N-(4-chloro-3-fluorophenyl)-5-fluoro-2-(5-fluoro-2-methyl-1H-benzimida-
zol- y1-l)pyrimidine-4,6-diamine 261
N-(4-chloro-3-fluorophenyl)-5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 262
N-(4-chloro-3-fluorophenyl)-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimida-
zol-1- yl)pyrimidine-4,6-diamine 263
N-(4-chlorophenyl)-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 264
2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)
pyrimidine-4,6-diamine 265
2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methoxyphenyl)
pyrimidine-4,6-diamine 266
N-[4-(dimethylamino)phenyl]-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 267
N-(4-chloro-3-fluorophenyl)-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine 268
2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(3-methylphenyl)pyrimidin-
e- 4,6-diamine 269
N-(2,2-difluoro-1,3-benzodioxol-5-yl)-2-(6-fluoro-2-methyl-1H-benzimid-
azol- 1-yl)pyrimidine-4,6-diamine 270
2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methylphenyl)
pyrimidine-4,6-diamine 271
2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methoxyphenyl)pyrimidin-
e- 4,6-diamine 272
2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoromethoxy)pheny-
l] pyrimidine-4,6-diamine 273
N-(1,3-benzodioxol-5-yl)-2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoropyri-
midine- 4,6-diamine 274
N-(4-chlorophenyl)-2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoropyrimidine-
- 4,6-diamine 275
N-(4-chloro-3-fluorophenyl)-2-(2-ethyl-1H-benzimidazol-1-yl)-5-
fluoropyrimidine-4,6-diamine 276
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methylphenyl)
pyrimidine-4,6-diamine 277
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methoxyphenyl)
pyrimidine-4,6-diamine 278
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoromethoxy-
) phenyl]pyrimidine-4,6-diamine 279
N-(4-chlorophenyl)-2-(2-cyclopropyl-1H-benzimidazol-1-yl)-
5-fluoropyrimidine-4,6-diamine 280
N-(4-chloro-3-fluorophenyl)-2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-
fluoropyrimidine-4,6-diamine 281
5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)
pyrimidine-4,6-diamine 282
5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methoxyphenyl-
) pyrimidine-4,6-diamine 283
5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromet-
hoxy) phenyl]pyrimidine-4,6-diamine, and 284
2-(6-amino-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluorometh-
yl) phenyl]pyrimidine-4,6-diamine;
wherein the form of the compound of Formula (I) is selected from a
salt, ester, hydrate, solvate, chelate, clathrate, polymorph,
isotopologue, stereoisomer, racemate, enantiomer, diastereomer or
tautomer thereof.
Terminology
[0111] The chemical terms used above and throughout the description
herein, unless specifically defined otherwise, shall be understood
by one of ordinary skill in the art to have the following indicated
meanings.
[0112] As used herein, the term "C.sub.1-8alkyl" refers to
saturated hydrocarbon radicals having from one to eight carbon
atoms in a straight or branched chain configuration, including,
without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl,
n-octyl and the like. In some embodiments, C.sub.1-8alkyl includes
C.sub.1-6alkyl, C.sub.1-4alkyl and the like. A C.sub.1-8alkyl
radical may be optionally substituted where allowed by available
valences.
[0113] As used herein, the term "C.sub.2-8alkenyl" refers to
partially unsaturated hydrocarbon radicals having from two to eight
carbon atoms in a straight or branched chain configuration and one
or more carbon-carbon double bonds therein, including, without
limitation, ethenyl, allyl, propenyl and the like. In some
embodiments, C.sub.2-8alkenyl includes C.sub.2-6alkenyl,
C.sub.2-4alkenyl and the like. A C.sub.2-8alkenyl radical may be
optionally substituted where allowed by available valences.
[0114] As used herein, the term "C.sub.2-8alkynyl" refers to
partially unsaturated hydrocarbon radicals having from two to eight
carbon atoms in a straight or branched chain configuration and one
or more carbon-carbon triple bonds therein, including, without
limitation, ethynyl, propynyl and the like. In some embodiments,
C.sub.2-8alkynyl includes C.sub.2-6alkynyl, C.sub.2-4alkynyl and
the like. A C.sub.2-8alkynyl radical may be optionally substituted
where allowed by available valences.
[0115] As used herein, the term "C.sub.1-8alkoxy" refers to
saturated hydrocarbon radicals of from one to eight carbon atoms
having a straight or branched chain configuration of the formula:
--O--C.sub.1-8alkyl, including, without limitation, methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
tert-butoxy, n-pentoxy, n-hexoxy and the like. In some embodiments,
C.sub.1-8alkoxy includes C.sub.1-6alkoxy, C.sub.1-4alkoxy and the
like. A C.sub.1-8alkoxy radical may be optionally substituted where
allowed by available valences.
[0116] As used herein, the term "C.sub.3-14cycloalkyl" refers to a
saturated monocyclic, bicyclic or polycyclic hydrocarbon radical,
including, without limitation, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indanyl,
indenyl, 2,3-dihydro-1H-indenyl, tetrahydro-naphthalenyl and the
like. In some embodiments, C.sub.3-14cycloalkyl includes
C.sub.3-8cycloalkyl, C.sub.5-8cycloalkyl, C.sub.3-10cycloalkyl and
the like. A C.sub.3-14cycloalkyl radical may be optionally
substituted where allowed by available valences.
[0117] As used herein, the term "aryl" refers to a monocyclic,
bicyclic or polycyclic aromatic carbon atom ring structure radical,
including, without limitation, phenyl, naphthyl (also referred to
as naphthalenyl), anthracenyl, fluorenyl, azulenyl, phenanthrenyl
and the like. An aryl radical may be optionally substituted where
allowed by available valences.
[0118] As used herein, the term "heteroaryl" refers to a
monocyclic, bicyclic or polycyclic aromatic carbon atom ring
structure radical in which one or more carbon atom ring members
have been replaced, where allowed by structural stability, with one
or more heteroatoms, such as an O, S or N atom, including, without
limitation, furanyl, thienyl (also referred to as thiophenyl),
pyrrolyl, pyrazolyl (also referred to as 1H-pyrazolyl), imidazolyl
(also referred to as 1H-imidazolyl), isoxazolyl (also referred to
as 1,2-oxazolyl), isothiazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl,
pyridinyl (also referred to as pyridyl), pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, indolyl (also referred to as 1H-indolyl),
azaindolyl, indazolyl (also referred to as 2H-indazolyl),
azaindazolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl,
benzimidazolyl (also referred to as 1H-benzimidazolyl),
benzothiazolyl, benzoxazolyl, imidazo[2,1-b][1,3]thiazolyl,
pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-c]pyrimidinyl,
imidazo[1,2-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl,
1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyrazinyl,
imidazo[1,2-a]pyrimidinyl, 7H-purinyl, 9H-purinyl, quinolinyl,
isoquinolinyl, quinazolinyl, quinoxalinyl, acridinyl and the like
and associated homologs and regioisomers thereof. A heteroaryl
radical may be optionally substituted on a carbon or nitrogen atom
ring member where allowed by available valences.
[0119] As used herein, the term "heterocyclyl" refers to a
saturated or partially unsaturated monocyclic, bicyclic or
polycyclic carbon atom ring structure radical in which one or more
carbon atom ring members have been replaced, where allowed by
structural stability, with a heteroatom, such as an O, S or N atom,
including, without limitation, oxiranyl, oxetanyl, azetidinyl,
dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,
tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl,
pyrazolinyl, pyrazolidinyl, dihydroimidazolyl, imidazolinyl,
imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl,
isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl,
thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl,
oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl,
tetrazolidinyl, 1,3-dioxolanyl, dihydro-2H-pyranyl,
tetrahydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl,
dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, dihydro-pyrazinyl,
tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl,
piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl,
dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl,
1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl,
dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl,
dihydro-benzofuranyl, tetrahydro-benzofuranyl,
dihydro-benzothienyl, tetrahydro-benzothienyl,
dihydro-benzoimidazolyl, tetrahydro-benzoimidazolyl,
dihydro-benzooxazolyl, tetrahydro-benzooxazolyl,
dihydro-benzooxazinyl, tetrahydro-benzooxazinyl, benzo[1,3]dioxolyl
(also referred to as 1,3-benzodioxolyl), benzo[1,4]dioxanyl (also
referred to as 1,4-benzodioxanyl or 2,3-dihydro-1,4-benzodioxinyl),
benzo[1,4]dioxinyl (also referred to as 1,4-benzodioxinyl),
4,5,6,7-tetrahydro-2H-indazolyl,
5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl, dihydro-purinyl,
tetrahydro-purinyl, dihydro-quinolinyl, tetrahydro-quinolinyl,
dihydro-isoquinolinyl, tetrahydro-isoquinolinyl,
dihydro-quinazolinyl, tetrahydro-quinazolinyl,
dihydro-quinoxalinyl, tetrahydro-quinoxalinyl and the like and
associated homologs thereof. A heterocyclyl radical may be
optionally substituted on a carbon or nitrogen atom ring member
where allowed by available valences.
[0120] As used herein, the term "B(OR.sub.8).sub.2" refers to a
radical of the formula: --B[(--OH)(--OH)] when R.sub.8 is hydrogen;
or, --B[(--OH)(--O--C.sub.1-8alkyl)] when R.sub.8 is independently
hydrogen or C.sub.1-8alkyl; or,
--B[(--O--C.sub.1-8alkyl)(--O--C.sub.1-8alkyl)] when R.sub.8 is
C.sub.1-8alkyl.
[0121] As used herein, the term "C.sub.1-8alkoxy-C.sub.1-8alkyl"
refers to a radical of the formula:
--C.sub.1-8alkyl-O--C.sub.1-8alkyl.
[0122] As used herein, the term
"C.sub.1-8alkoxy-C.sub.1-8alkyl-amino" refers to a radical of the
formula: --NH--C.sub.1-8alkyl-O--C.sub.1-8alkyl.
[0123] As used herein, the term "C.sub.1-8alkoxy-C.sub.2-8alkenyl"
refers to a radical of the formula:
--C.sub.2-8alkenyl-O--C.sub.1-8alkyl.
[0124] As used herein, the term "C.sub.1-8alkoxy-C.sub.2-8alkynyl"
refers to a radical of the formula:
--C.sub.2-8alkynyl-O--C.sub.1-8alkyl.
[0125] As used herein, the term "C.sub.1-8alkoxy-carbonyl" refers
to a radical of the formula: --C(O)--O--C.sub.1-8alkyl.
[0126] As used herein, the term
"C.sub.1-8alkoxy-carbonyl-C.sub.1-8alkyl" refers to a radical of
the formula: --C.sub.1-8alkyl-C(O)--O--C.sub.1-8alkyl.
[0127] As used herein, the term "C.sub.1-8alkoxy-carbonyl-amino"
refers to a radical of the formula:
--NH--C(O)--O--C.sub.1-8alkyl.
[0128] As used herein, the term
"C.sub.1-8alkoxy-carbonyl-amino-C.sub.1-8alkyl" refers to a radical
of the formula: --C.sub.1-8alkyl-NH--C(O)--O--C.sub.1-8alkyl.
[0129] As used herein, the term
"C.sub.1-8alkoxy-imino-C.sub.1-8alkyl" refers to a radical of the
formula: --C.sub.1-8alkyl(=N--O--C.sub.1-8alkyl).
[0130] As used herein, the term "C.sub.1-8alkyl-amino" refers to a
radical of the formula: --NH--C.sub.1-8alkyl.
[0131] As used herein, the term "(C.sub.1-8alkyl).sub.2-amino"
refers to a radical of the formula: --N(C.sub.1-8alkyl).sub.2.
[0132] As used herein, the term
"C.sub.1-8alkyl-amino-C.sub.1-8alkyl" refers to a radical of the
formula: --C.sub.1-8alkyl-NH--C.sub.1-8alkyl.
[0133] As used herein, the term
"(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl" refers to a radical
of the formula: --C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2.
[0134] As used herein, the term
"C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino" refers to a radical of
the formula: --NH--C.sub.1-8alkyl-NH--C.sub.1-8alkyl.
[0135] As used herein, the term
"(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino" refers to a
radical of the formula:
--NH--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2.
[0136] As used herein, the term "C.sub.1-8alkyl-amino-carbonyl"
refers to a radical of the formula: --C(O)--NH--C.sub.1-8alkyl.
[0137] As used herein, the term
"(C.sub.1-8alkyl).sub.2-amino-carbonyl" refers to a radical of the
formula: --C(O)--N(C.sub.1-8alkyl).sub.2.
[0138] As used herein, the term
"C.sub.1-8alkyl-amino-carbonyl-amino" refers to a radical of the
formula: --NH--C(O)--NH--C.sub.1-8alkyl.
[0139] As used herein, the term
"(C.sub.1-8alkyl).sub.2-amino-carbonyl-amino" refers to a radical
of the formula: --NH--C(O)--N(C.sub.1-8 alkyl).sub.2.
[0140] As used herein, the term "C.sub.1-8alkyl-amino-sulfonyl"
refers to a radical of the formula: --SO.sub.2--NH--C.sub.1-8
alkyl.
[0141] As used herein, the term
"(C.sub.1-8alkyl).sub.2-amino-sulfonyl" refers to a radical of the
formula: --SO.sub.2--N(C.sub.1-8 alkyl).sub.2.
[0142] As used herein, the term
"C.sub.1-8alkyl-amino-sulfonyl-amino" refers to a radical of the
formula: --NH--SO.sub.2--NH--C.sub.1-8 alkyl.
[0143] As used herein, the term
"(C.sub.1-8alkyl).sub.2-amino-sulfonyl-amino" refers to a radical
of the formula: --NH--SO.sub.2--N(C.sub.1-8 alkyl).sub.2.
[0144] As used herein, the term "C.sub.1-8alkyl-carbonyl" refers to
a radical of the formula: --C(O)--C.sub.1-8 alkyl.
[0145] As used herein, the term "C.sub.1-8alkyl-carbonyl-amino"
refers to a radical of the formula: --NH--C(O)--C.sub.1-8
alkyl.
[0146] As used herein, the term
"C.sub.1-8alkyl-carbonyl-amino-C.sub.1-8alkyl" refers to a radical
of the formula: --C.sub.1-8 alkyl-NH--C(O)--C.sub.1-8 alkyl.
[0147] As used herein, the term "C.sub.1-8alkyl-carbonyl-oxy"
refers to a radical of the formula: --O--C(O)--C.sub.1-8 alkyl.
[0148] As used herein, the term
"C.sub.1-8alkyl-carbonyl-oxy-C.sub.1-8alkyl" refers to a radical of
the formula: --C.sub.1-8 alkyl-O--C(O)--C.sub.1-8 alkyl.
[0149] As used herein, the term "C.sub.1-8alkyl-sulfonyl" refers to
a radical of the formula: --SO.sub.2--C.sub.1-8 alkyl.
[0150] As used herein, the term "C.sub.1-8alkyl-thio" refers to a
radical of the formula: --S--C.sub.1-8 alkyl.
[0151] As used herein, the term "amino" refers to a radical of the
formula: --NH.sub.2.
[0152] As used herein, the term "amino-C.sub.1-8alkyl" refers to a
radical of the formula: --C.sub.1-8 alkyl-NH.sub.2.
[0153] As used herein, the term "amino-C.sub.1-8alkyl-amino" refers
to a radical of the formula: --NH--C.sub.1-8alkyl-NH.sub.2.
[0154] As used herein, the term "amino-carbonyl" refers to a
radical of the formula: --C(O)--NH.sub.2.
[0155] As used herein, the term "amino-carbonyl-amino" refers to a
radical of the formula: --NH--C(O)--NH.sub.2.
[0156] As used herein, the term "amino-sulfonyl" refers to a
radical of the formula: --SO.sub.2--NH.sub.2.
[0157] As used herein, the term "amino-sulfonyl-amino" refers to a
radical of the formula: --NH--SO.sub.2--NH.sub.2.
[0158] As used herein, the term "aryl-C.sub.1-8alkyl" refers to a
radical of the formula: --C.sub.1-8alkyl-aryl.
[0159] As used herein, the term "aryl-C.sub.1-8alkyl-amino" refers
to a radical of the formula: --NH--C.sub.1-8alkyl-aryl.
[0160] As used herein, the term "aryl-amino" refers to a radical of
the formula: --NH-aryl.
[0161] As used herein, the term "carboxyl" refers to a radical of
the formula: --COOH, --C(O)OH or --CO.sub.2H.
[0162] As used herein, the term "formyl" refers to a radical of the
formula: --C(O)--H.
[0163] As used herein, the term "formyl-oxyl" refers to a radical
of the formula: --O--C(O)--H.
[0164] As used herein, the terms "halo" or "halogen" refer to a
halogen atom radical, including fluoro, chloro, bromo and iodo.
[0165] As used herein, the term "halo-C.sub.1-8alkoxy" refers to a
radical of the formula: --O--C.sub.1-8alkyl-halo, wherein
C.sub.1-8alkyl may be partially or completely substituted where
allowed by available valences with one or more halogen atoms. In
some embodiments, halo-C.sub.1-8alkoxy includes
halo-C.sub.1-6alkoxy, halo-C.sub.1-4alkoxy and the like.
[0166] As used herein, the term "halo-C.sub.1-8alkoxy-carbonyl"
refers to a radical of the formula:
--C(O)--O--C.sub.1-8alkyl-halo.
[0167] As used herein, the term "halo-C.sub.1-8alkyl" refers to a
radical of the formula: --C.sub.1-8alkyl-halo, wherein
C.sub.1-8alkyl may be partially or completely substituted where
allowed by available valences with one or more halogen atoms. In
some embodiments, halo-C.sub.1-8alkyl includes halo-C.sub.1-6alkyl,
halo-C.sub.1-4alkyl and the like.
[0168] As used herein, the term "halo-C.sub.1-8alkyl-carbonyl"
refers to a radical of the formula:
--C(O)--C.sub.1-8alkyl-halo.
[0169] As used herein, the term "halo-C.sub.1-8alkyl-sulfonyl"
refers to a radical of the formula:
--SO.sub.2--C.sub.1-8alkyl-halo.
[0170] As used herein, the term "halo-C.sub.1-8alkyl-thio" refers
to a radical of the formula: --S--C.sub.1-8alkyl-halo.
[0171] As used herein, the term "heteroaryl-C.sub.1-8alkyl" refers
to a radical of the formula: --C.sub.1-8alkyl-heteroaryl.
[0172] As used herein, the term "hydroxyl-C.sub.1-8alkoxy" refers
to a radical of the formula: --O--C.sub.1-8alkyl-OH, wherein
C.sub.1-8alkyl may be partially or completely substituted where
allowed by available valences with one or more hydroxyl
radicals.
[0173] As used herein, the term "hydroxyl-C.sub.1-8alkyl" refers to
a radical of the formula: --C.sub.1-8alkyl-OH, wherein
C.sub.1-8alkyl may be partially or completely substituted where
allowed by available valences with one or more hydroxyl
radicals.
[0174] As used herein, the term "hydroxyl-amino" refers to a
radical of the formula: --NH--OH.
[0175] As used herein, the term "hydroxyl-C.sub.1-8alkyl-amino"
refers to a radical of the formula: --NH--C.sub.1-8alkyl-OH.
[0176] As used herein, the term
"hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl" refers to a radical
of the formula: --C.sub.1-8alkyl-NH--C.sub.1-8alkyl-OH.
[0177] As used herein, the term
"hydroxyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino" refers to a
radical of the formula:
--NH--C.sub.1-8alkyl-NH--C.sub.1-8alkyl-OH.
[0178] As used herein, the term "hydroxyl-imino-C.sub.1-8alkyl"
refers to a radical of the formula: --C.sub.1-8alkyl(=N--OH).
[0179] As used herein, the term "imino" refers to a radical of the
formula: .dbd.NH.
[0180] As used herein, the term "imino-C.sub.1-8alkyl" refers to a
radical of the formula: --C.sub.1-8alkyl(=NH).
[0181] As used herein, the term "N-oxide" refers to a moiety of the
formula:
##STR00053##
[0182] As used herein, the term "oxo" refers to a moiety of the
formula:
##STR00054##
[0183] As used herein, the term "P(O)(R.sub.7).sub.2-amino" refers
to a radical of the formulae: --NH--P(O)(--O--C.sub.1-8alkyl)(OH)
when R.sub.7 is independently hydroxyl and (C.sub.1-8alkoxy).sub.n,
where n is 1; or, --NH--P(O)(OH).sub.2 when R.sub.7 is hydroxyl;
or, --NH--P(O)(--O--C.sub.1-8alkyl).sub.2 when R.sub.7 is
(C.sub.1-8alkoxy).sub.n, where n is 1.
[0184] As used herein, the term "substituent" means positional
variables on the atoms of a core molecule that are attached at a
designated atom position, replacing one or more hydrogen atoms on
the designated atom, provided that the atom of attachment does not
exceed the available valence or shared valence, such that the
substitution results in a stable compound. Accordingly,
combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds. Any carbon atom as
well as heteroatom with a valence level that appears to be
unsatisfied as described or shown herein is assumed to have a
sufficient number of hydrogen atom(s) to satisfy the valences
described or shown.
[0185] As used herein, the term "and the like," with reference to
the definitions of chemical terms provided herein, means that
variations in chemical structures that could be expected by one
skilled in the art include, without limitation, isomers (including
chain, branching or positional structural isomers), hydration of
ring systems (including saturation or partial unsaturation of
monocyclic, bicyclic or polycyclic ring structures) and all other
variations where allowed by available valences which result in a
stable compound.
[0186] For the purposes of this description, where one or more
substituent variables for a compound of Formula (I) encompass
functionalities incorporated into a compound of Formula (I), each
functionality appearing at any location within the disclosed
compound may be independently selected, and as appropriate,
independently and/or optionally substituted.
[0187] As used herein, the terms "independently selected," or "each
selected" refer to functional variables in a substituent list that
may be attached more than once on the structure of a core molecule,
where the pattern of substitution at each occurrence is independent
of the pattern at any other occurrence. Further, the use of a
generic substituent variable on a core structure for a compound
described herein is understood to include the replacement of the
generic substituent with specie substituents that are included
within the particular genus, e.g., aryl may be replaced with phenyl
or naphthalenyl and the like, such that the resulting compound is
to be included within the scope of the compounds described
herein.
[0188] As used herein, the term "optionally substituted" means that
the specified substituent variables, groups, radicals or moieties
represent the scope of the genus and may be independently chosen as
needed to replace one or more hydrogen atoms on the designated atom
of attachment of a core molecule.
[0189] As used herein, the terms "stable compound" or "stable
structure" mean a compound that is sufficiently robust to be
isolated to a useful degree of purity from a reaction mixture and
formulations thereof into an efficacious therapeutic agent.
[0190] Compound names used herein were obtained using the ACD Labs
Index Name software provided by ACD Labs and/or ChemDraw Ultra
software provided by CambridgeSoft. When the compound name
disclosed herein conflicts with the structure depicted, the
structure shown will supercede the use of the name to define the
compound intended.
Compound Forms
[0191] As used herein, the terms a "compound of Formula (Ia)," "a
compound of Formula (II)," "compound of Formula (IIa)," "compound
of Formula (III)," "compound of Formula (IIIa)," "compound of
Formula (IV)" or "compound of Formula (IVa)" refer to subgenera of
the compound of Formula (I) or a form thereof, as defined herein.
Rather than repeat the various subgenera of the compound of Formula
(I), in certain embodiments, the term "compound(s) of Formula (I)
or a form thereof" is used inclusively to refer to compound(s) of
Formula (Ia) or a form thereof, compound(s) of Formula (II) or a
form thereof, compound(s) of Formula (IIa) or a form thereof,
compound(s) of Formula (III) or a form thereof, compound(s) of
Formula (Ma) or a form thereof, compound(s) of Formula (IV) or a
form thereof or compound(s) of Formula (IVa) or a form thereof,
either separately or together. Thus, embodiments and references to
"a compound of Formula (I)" are intended to be inclusive of
compounds of Formula (Ia), compounds of Formula (II), compounds of
Formula (IIa), compounds of Formula (III), compounds of Formula
(IIIa), compounds of Formula (IV) and compounds of Formula
(IVa).
[0192] As used herein, the term "form" means a compound of Formula
(I) selected from a free acid, free base, salt, ester, hydrate,
solvate, chelate, clathrate, polymorph, isotopologue, stereoisomer,
racemate, enantiomer, diastereomer, or tautomer thereof.
[0193] In certain embodiments described herein, the form of the
compound of Formula (I) is selected from a salt, isotopologue,
stereoisomer, racemate, enantiomer, diastereomer or tautomer
thereof.
[0194] In certain embodiments described herein, the form of the
compound of Formula (I) is selected from a free acid, isotopologue,
stereoisomer, racemate, enantiomer, diastereomer or tautomer
thereof.
[0195] In certain embodiments described herein, the form of the
compound of Formula (I) is selected from a free base, isotopologue,
stereoisomer, racemate, enantiomer, diastereomer or tautomer
thereof.
[0196] In certain embodiments described herein, the form of the
compound of Formula (I) is a free acid, free base or salt
thereof.
[0197] In certain embodiments described herein, the form of the
compound of Formula (I) is an isotopologue thereof.
[0198] In certain embodiments described herein, the form of the
compound of Formula (I) is a stereoisomer, racemate, enantiomer or
diastereomer thereof.
[0199] In certain embodiments described herein, the form of the
compound of Formula (I) is a tautomer thereof.
[0200] In certain embodiments described herein, the form of the
compound of Formula (I) is a pharmaceutically acceptable form.
[0201] In certain embodiments described herein, the compound of
Formula (I) or a form thereof is isolated for use.
[0202] As used herein, the term "isolated" means the physical state
of a compound of Formula (I) or a form thereof after being isolated
and/or separated and/or purified from a synthetic process (e.g.,
from a reaction mixture) or natural source or combination thereof
according to an isolation, separation or purification process or
processes described herein or which are well known to the skilled
artisan (e.g., chromatography, recrystallization and the like) in
sufficient purity to be characterizable by standard analytical
techniques described herein or well known to the skilled
artisan.
[0203] As used herein, the term "protected" means that a functional
group on a compound of Formula (I) or a form thereof is in a form
modified to preclude undesired side reactions of the functional
group when the compound is subjected to a reaction. Suitable
protecting groups will be recognized by those with ordinary skill
in the art as well as by reference to standard textbooks such as,
for example, T. W. Greene et al, Protective Groups in Organic
Synthesis (2007), Wiley, New York.
[0204] Prodrugs and solvates of the compounds of Formula (I) or a
form thereof described herein are also contemplated.
[0205] As used herein, the term "prodrug" means that a functional
group on a compound of Formula (I) is in a form (e.g., acting as an
active or inactive drug precursor) that is transformed in vivo to
yield an active or more active compound of Formula (I) or a form
thereof. The transformation may occur by various mechanisms (e.g.,
by metabolic and/or non-metabolic chemical processes), such as, for
example, by hydrolysis and/or metabolism in blood, liver and/or
other organs and tissues. A discussion of the use of prodrugs is
provided by V. J. Stella, et. al., "Biotechnology: Pharmaceutical
Aspects, Prodrugs: Challenges and Rewards," American Association of
Pharmaceutical Scientists and Springer Press, 2007.
[0206] In one example, when a compound of Formula (I) or a form
thereof contains a carboxylic acid functional group, a prodrug can
comprise an ester formed by the replacement of the hydrogen atom of
the acid group with a functional group such as alkyl and the like.
In another example, when a compound of Formula (I) or a form
thereof contains an alcohol functional group, a prodrug can be
formed by the replacement of the hydrogen atom of the alcohol group
with a functional group such as alkyl or carbonyloxy and the like.
In another example, when a compound of Formula (I) or a form
thereof contains an amine functional group, a prodrug can be formed
by the replacement of one or more amine hydrogen atoms with a
functional group such as alkyl or substituted carbonyl.
[0207] Pharmaceutically acceptable prodrugs of compounds of Formula
(I) or a form thereof include those compounds substituted with one
or more of the following groups: carboxylic acid esters, sulfonate
esters, amino acid esters, phosphonate esters (e.g., a
phosphoramidic acid used to derive a phosphoramidic acid) and
mono-, di- or triphosphate esters further substituted with alkyl,
where appropriate. As described herein, it is understood by a
person of ordinary skill in the art that one or more of such
substituents may be used to provide a compound of Formula (I) or a
form thereof as a prodrug.
[0208] The compounds of Formula (I) or a form thereof can form
salts, which are intended to be included within the scope of this
description. Reference to a compound of Formula (I) or a form
thereof herein is understood to include reference to salts thereof,
unless otherwise indicated. The term "salt(s)", as employed herein,
denotes acidic salts formed with inorganic and/or organic acids, as
well as basic salts formed with inorganic and/or organic bases. In
addition, when a compound of Formula (I) or a form thereof contains
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
included within the term "salt(s)" as used herein.
[0209] The term "pharmaceutically acceptable salt(s)", as used
herein, means those salts of compounds of Formula (I) or a form
thereof described herein that are safe and effective (i.e.,
non-toxic, physiologically acceptable) for use in mammals and that
possess biological activity, although other salts are also useful.
Salts of the compounds of the Formula (I) may be formed, for
example, by reacting a compound of Formula (I) with an amount of
acid or base, such as an equivalent amount, in a medium such as one
in which the salt precipitates or in an aqueous medium followed by
lyophilization.
[0210] Pharmaceutically acceptable salts include one or more salts
of acidic or basic groups present in compounds of Formula (I) or a
form thereof described herein. Embodiments of acid addition salts
include, and are not limited to, acetate, acid phosphate,
ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate,
borate, butyrate, chloride, citrate, camphorate, camphorsulfonate,
ethanesulfonate, formate, fumarate, gentisinate, gluconate,
glucaronate, glutamate, hydrobromide, hydrochloride,
dihydrochloride, hydroiodide, isonicotinate, lactate, maleate,
methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate,
pantothenate, phosphate, propionate, saccharate, salicylate,
succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also
known as tosylate), trifluoroacetate, trifluoroacetic acid salt and
the like. One or more embodiments of acid addition salts include
chloride, hydrochloride, dihydrochloride, trihydrochloride,
hydrobromide, acetate, diacetate, methanesulfonate, sulfate,
trifluoroacetate, trifluoroacetic acid salt and the like. More
particular embodiments include a chloride, hydrochloride,
dihydrochloride, hydrobromide, methanesulfonate, sulfate,
trifluoroacetate, trifluoroacetic acid salt and the like.
[0211] In certain embodiments of the compounds of Formula (I) or a
form thereof described herein, the compound is isolated as a salt
form, wherein the compound is conjugated with the salt in a ratio
represented as, in a non-limiting example, "compound:salt (A:B),"
wherein "A" and "B" represent the equivalents of compound to salt
in the isolated form.
[0212] Additionally, acids which are considered suitable for the
formation of pharmaceutically useful salts from basic
pharmaceutical compounds are discussed, for example, by P. Stahl et
al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties,
Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al,
Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,
International J. of Pharmaceutics (1986) 33, 201-217; Anderson et
al, The Practice of Medicinal Chemistry (1996), Academic Press, New
York; and in The Orange Book (Food & Drug Administration,
Washington, D.C. on their website). These disclosures are
incorporated herein by reference thereto.
[0213] Suitable basic salts include, but are not limited to,
aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium,
zinc, and diethanolamine salts. Certain compounds of Formula (I) or
a form thereof described herein can also form pharmaceutically
acceptable salts with organic bases (for example, organic amines)
such as, but not limited to, dicyclohexylamines, tert-butyl amines
and the like, and with various amino acids such as, but not limited
to, arginine, lysine and the like. Basic nitrogen-containing groups
may be quarternized with agents such as lower alkyl halides (e.g.,
methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl
sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long
chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides
and iodides), aralkyl halides (e.g., benzyl and phenethyl
bromides), and others.
[0214] All such acid salts and base salts are intended to be
included within the scope of pharmaceutically acceptable salts as
described herein. In addition, all such acid and base salts are
considered equivalent to the free forms of the corresponding
compounds for purposes of this description.
[0215] Compounds of Formula (I), and forms thereof, may further
exist in a tautomeric form. All such tautomeric forms are
contemplated and intended to be included within the scope of the
compounds of Formula (I) or a form thereof as described herein.
[0216] The compounds of Formula (I) or a form thereof may contain
asymmetric or chiral centers, and, therefore, may exist in
different stereoisomeric forms. The present description is intended
to include all stereoisomeric forms of the compounds of Formula (I)
as well as mixtures thereof, including racemic mixtures.
[0217] The compounds of Formula (I) or a form thereof described
herein may include one or more chiral centers, and as such may
exist as racemic mixtures (R/S) or as substantially pure
enantiomers and diastereomers. The compounds may also exist as
substantially pure (R) or (S) enantiomers (when one chiral center
is present). In one embodiment, the compounds of Formula (I) or a
form thereof described herein are (S) isomers and may exist as
enantiomerically pure compositions substantially comprising only
the (S) isomer. In another embodiment, the compounds of Formula (I)
or a form thereof described herein are (R) isomers and may exist as
enantiomerically pure compositions substantially comprising only
the (R) isomer. As one of skill in the art will recognize, when
more than one chiral center is present, the compounds of Formula
(I) or a form thereof described herein may also exist as a (R,R),
(R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature
Recommendations.
[0218] As used herein, the term "substantially pure" refers to
compounds of Formula (I) or a form thereof consisting substantially
of a single isomer in an amount greater than or equal to 90%, in an
amount greater than or equal to 92%, in an amount greater than or
equal to 95%, in an amount greater than or equal to 98%, in an
amount greater than or equal to 99%, or in an amount equal to 100%
of the single isomer.
[0219] In one aspect of the description, a compound of Formula (I)
or a form thereof is a substantially pure (S) enantiomer present in
an amount greater than or equal to 90%, in an amount greater than
or equal to 92%, in an amount greater than or equal to 95%, in an
amount greater than or equal to 98%, in an amount greater than or
equal to 99%, or in an amount equal to 100%.
[0220] In one aspect of the description, a compound of Formula (I)
or a form thereof is a substantially pure (R) enantiomer present in
an amount greater than or equal to 90%, in an amount greater than
or equal to 92%, in an amount greater than or equal to 95%, in an
amount greater than or equal to 98%, in an amount greater than or
equal to 99%, or in an amount equal to 100%.
[0221] As used herein, the term "racemate" refers to any mixture of
isometric forms that are not "enantiomerically pure", including
mixtures such as, without limitation, in a ratio of about 50/50,
about 60/40, about 70/30, or about 80/20, about 85/15 or about
90/10.
[0222] In addition, the compounds of Formula (I) or a form thereof
described herein embrace all geometric and positional isomers. For
example, if a compound of Formula (I) or a form thereof
incorporates a double bond or a fused ring, both the cis- and
trans-forms, as well as mixtures thereof, are embraced within the
scope of the compounds of Formula (I) or a form thereof described
herein.
[0223] Diastereomeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as, for example, by chromatography and/or fractional
crystallization. Enantiomers can be separated by use of a chiral
HPLC column or other chromatographic methods known to those skilled
in the art.
[0224] Enantiomers can also be separated by converting the
enantiomeric mixture into a diastereomeric mixture by reaction with
an appropriate optically active compound (e.g., chiral auxiliary
such as a chiral alcohol or Mosher's acid chloride), separating the
diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers.
[0225] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds of Formula (I) or a
form thereof (including salts, solvates, esters and prodrugs and
transformed prodrugs thereof), which may exist due to asymmetric
carbons on various substituents, including enantiomeric forms
(which may exist even in the absence of asymmetric carbons),
rotameric forms, atropisomers, diastereomeric and regioisomeric
forms, are contemplated within the scope of the description herein.
Individual stereoisomers of the compounds of Formula (I) or a form
thereof described herein may, for example, be substantially free of
other isomers, or may be present in a racemic mixture, as described
supra.
[0226] The use of the terms "salt," "solvate," "ester," "prodrug"
and the like, is intended to apply equally to the salt, solvate,
ester and prodrug of enantiomers, stereoisomers, rotamers,
tautomers, positional isomers, racemates, isotopologues or prodrugs
of the instant compounds.
[0227] The term "isotopologue" refers to isotopically-enriched
compounds of Formula (I) or a form thereof which are identical to
those recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of
Formula (I) or a form thereof described herein include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and
chlorine, such as H.sup.2, H.sup.3, C.sup.13, C.sup.14, N.sup.15,
O.sup.18, O.sup.17, P.sup.31, P.sup.32, S.sup.35, F.sup.18,
Cl.sup.35 and Cl.sup.36, respectively, each of which is also within
the scope of this description.
[0228] Certain isotopically-enriched forms of compounds of Formula
(I) or a form thereof described herein (e.g., those labeled with
H.sup.3 and C.sup.14) are useful in compound and/or substrate
tissue distribution assays. Tritiated (i.e., H.sup.3) and carbon-14
(i.e., C.sup.14) isotopes are particularly preferred for their ease
of preparation and detectability. Further, substitution with
isotopes such as deuterium (i.e., "deuterium enriched") may afford
certain therapeutic advantages resulting from greater metabolic
stability (e.g., increased in vivo half-life), increased
solubility, reduced dosage requirements (e.g., increased
bioavailability)) or reduced toxicity (e.g., reduced inhibition of
metabolic enzymes) and hence may be preferred in some
circumstances.
[0229] One or more compounds of Formula (I) or a form thereof
described herein may exist in unsolvated as well as solvated forms
with pharmaceutically acceptable solvents such as water, ethanol,
and the like, and the description herein is intended to embrace
both solvated and unsolvated forms.
[0230] As used herein, the term "solvate" means a physical
association of a compound of Formula (I) or a form thereof
described herein with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. As used herein, "solvate" encompasses both
solution-phase and isolatable solvates. Non-limiting examples of
suitable solvates include ethanolates, methanolates, and the
like.
[0231] One or more compounds of Formula (I) or a form thereof
described herein may optionally be converted to a solvate.
Preparation of solvates is generally known. A typical, non-limiting
process involves dissolving a compound of Formula (I) or a form
thereof in a desired amount of the desired solvent (organic or
water or mixtures thereof) at a higher than ambient temperature,
and cooling the solution at a rate sufficient to form crystals
which are then isolated by standard methods. Analytical techniques
such as, for example infrared spectroscopy, show the presence of
the solvent (or water) in the crystals as a solvate (or
hydrate).
[0232] As used herein, the term "hydrate" means a solvate wherein
the solvent molecule is water.
[0233] Polymorphic crystalline and amorphous forms of the compounds
of Formula (I) or a form thereof, and of the salts, solvates,
esters and prodrugs of the compounds of Formula (I) or a form
thereof, are further intended to be included in the scope of the
compounds of Formula (I) or a form thereof described herein.
Compound Uses
[0234] The Bmi-1 oncogene was first identified as part of a key
insertion/activation region of the Moloney murine leukemia virus in
the early 1990's (1-6). Bmi-1 is a member of the Polycomb group
(PcG) of transcriptional repressors and was identified as a
necessary regulator of hematopoietic stem cell (HSC) self-renewal
(76, 77). Park found that Bmi-1 is highly expressed in purified
mouse and human HSCs and that the absence of Bmi-1, as demonstrated
by Bmi-1 knockout mice, results in the progressive loss of all
hematopoietic lineages (76). Furthermore, the transplantation of
Bmi-1.sup.-/- day 14.5 fetal liver cells into lethally irradiated
normal mice, demonstrated that the cells were unable to
reconstitute myeloid cells, B cells, and T cells because
Bmi-1.sup.-/- HSCs were unable to renew (76).
[0235] In addition to the role of Bmi-1 in HSC self renewal, it was
found that Bmi-1 transgene expression induced lymphoma in mice (2).
Bmi-1 was also found to be overexpressed in many tumor types,
including acute myeloid leukemia, medulloblastoma, neuroblastoma,
colorectal cancer, lung cancer, and prostate cancer, and was found
to increase with malignancy (34, 78, 61, 79, 80, 65, 43). Loss of
Bmi-1 in various human cancer cell lines via Bmi-1 specific RNA
interference (RNAi) was shown to lead to acute cell death and
growth inhibition, whereas loss of Bmi-1 in various normal cell
lines was shown to lead to only moderate growth inhibition and not
significant cell death (69). Thus, Bmi-1 is necessary for the
survival of cancer cells but has minimal effect on the survival of
normal cells.
[0236] Bmi-1 has been subsequently shown to act as an oncogene
experimentally and has proven particularly potent in conjunction
with c-myc to initiate lymphoma in mice (7, 8). The role of Bmi-1
in lymphomagenesis has been attributed partially to transcriptional
repression of the INK4a locus (containing both the p16.sup.INK4A
and p14.sup.ARF genes) leading to maintenance of cancer and tumor
cell proliferation and prevention of differentiation (7, 9). Loss
of expression of the INK4a locus due to promoter silencing has been
extensively studied and is both important for the progression and
prognosis of many types of hematologic cancers (10, 11). The INK4a
locus is occasionally lost by deletion in leukemia and lymphoma
(12, 13).
[0237] However, Bmi-1 has been shown to play a role in
tumorigenesis in models lacking the INK4a locus, indicating that
other loci important in cancer are regulated by this protein (14).
Experimental results have demonstrated further that loss of Bmi-1
induces growth arrest and senescence in fibrosarcoma cells known to
lack INK4a (15). There is also evidence that Bmi-1 is important for
the hedgehog (Hh) pathway in breast cancer. Activation of Hh
signaling increases Bmi-1 expression, while down-regulation of
Bmi-1 (via siRNA) abrogates the effects of Hh signaling on
mammosphere formation in vitro and inhibits ductal/alveolar
development in mice (16). Recent work has demonstrated the role of
Bmi-1 in the regulation of Hox gene expression. Knockdown of Bmi-1
caused a global and loci-specific loss of H2A ubiquitination,
upregulation of the HoxC5 gene, and inhibition of the growth of
HeLa cells (17). Another study demonstrated that E2F6 and Bmi-1
cooperate in the regulation of Hox gene expression (particularly
Hox C10 and B9), and consequently affect axial skeleton
development, but not in the repression of the Ink4a-Arf locus.
These findings underscore the significance of the E2F6-Bmi-1
interaction and suggest that the Hox and Ink4a-Arf loci are
regulated by somewhat different Bmi-1-dependent mechanisms (18).
Current research suggests that Bmi-1 has different roles dependent
upon cell types and/or developmental stages. Other genes regulated
by Bmi-1 remain to be identified.
[0238] Bmi-1 is found to be highly expressed in malignancies, such
as diffuse large B cell lymphomas (DLBCL), B cell non-Hodgkin's
lymphoma, Hodgkin's lymphoma, acute myeloid leukemia, colorectal
carcinoma, liver carcinoma, non-small cell lung cancer, breast
carcinoma and medulloblastoma. The study of Bmi-1 knockout mice has
revealed that Bmi-1 is required for the self-renewal of both
leukemic and normal hematopoietic stem cells.
[0239] Additionally, evidence exists linking Bmi-1 levels to blood
tumor types, particularly Burkitt's lymphoma, mantle cell lymphoma,
Hodgkin's lymphoma (21-23), non-Hodgkin's lymphoma, some T cell
lymphomas (2, 24-31), acute myeloid leukemia and T-ALL (32-35).
Raaphorst et al observed that, in Hodgkin's lymphoma,
Reed-Sternberg cells (HRS) co-express Bmi-1, EZH2, and Mib-1/Ki-67.
Because HRS cells are thought to originate from germinal center
lymphocytes that express Bmi-1, such lymphocytes should lose the
ability to express Bmi-1 (and gain the ability to express EZH2) as
they differentiate. These observations suggest that Hodgkin's
lymphoma is associated with aberrant co-expression of Bmi-1 and
EZH2 in these cells (22). An assessment of acute myeloid leukemia
stem cell populations by van Gosliga et al (36) showed that
CD34.sup.+/CD38.sup.- cells capable of forming leukemic-cobblestone
colonies on a bone marrow substrate through at least two rounds of
expansion represented an extreme minority of the cell population.
Further analysis showed that this cell population expresses high
levels of Bmi-1 mRNA and can establish an aggressive leukemia in
mice, while those cells that have lower levels of Bmi-1 mRNA cannot
(36). Such studies implicate Bmi-1 in tumor growth and cell
survival and suggest a central function in tumor initiation and
maintenance of cancer and tumor stem cells.
[0240] The levels of Bmi-1 have been shown to have prognostic
relevance in a number of tumor types. An example of this is found
in acute myeloid leukemia based on results from a study assessing
the prognostic value of high Bmi-1 levels in 64 patients (32). On
the basis of the median value of Bmi-1 (54.58%), patients were
divided into two groups and monitored for survival. Patients with
lower Bmi-1 positivity (<55%, n=33) had significantly longer
overall survival (P=0.0001), relapse-free survival (P=0.0072) and
remission duration (P=0.0065) when compared to the patients with
higher levels of Bmi-1 (>55%, n=31, respectively), regardless of
age group (32). Similarly, Van Galen et al (37) have shown that
Bmi-1 levels are highly prognostic in diffuse large B cell
lymphomas (DLBCL) (37). Neoplastic cells in DLBCL cases originate
from germinal centre B (GCB) cells or their descendents (38).
Recent microarray analyses have shown that some DLBCL
phenotypically resemble non-neoplastic GCB cells, while some show
an expression profile similar to that of activated B cells (ABC)
(39).
[0241] Furthermore, patients with a GCB-like phenotype have a
considerably better prognosis than those with an ABC-like phenotype
(40). Bmi-1 was identified as one of the genes that distinguish the
ABC-like DLBCL (39),(41). Other groups have linked elevated Bmi-1
levels with poor prognosis in mantle cell lymphoma (MCL),
non-Hodgkin's lymphoma and other leukemias (22, 26, 27, 29, 42-44),
as well as many other tumour types including neuroblastoma,
glioblastoma, hepatocellular carcinoma, and breast, colorectal,
prostate, lung, gastric and salivary gland cancers (45-57). The
loss of expression from the INK4A locus has also been shown to have
prognostic value (12, 13). Taken together, these data strongly
implicate Bmi-1 in cancer and suggest that inhibiting uncontrolled
cell proliferation by inhibiting Bmi-1 function and reducing the
level of Bmi-1 in a cancer cell, tumor cell, cancer stem cell or
tumor stem cell will have a beneficial therapeutic effect in
patients with multiple cancer types, particularly in those
afflicted with hematological cancers.
[0242] For example, MCL is a rare, aggressive and incurable B cell
non-Hodgkin's lymphoma that is refractory (i.e., resistant to
conventional chemotherapy) and is associated with a poor prognosis.
MCL is characterized by the t(11;14)(q13;q32) translocation,
resulting in amplification and overexpression of the polycomb group
gene Bmi-1, which normally functions for self-renewal of
hematopoietic stem cells but has the capacity to induce tumors when
overexpressed.
[0243] Multiple myeloma is another fatal B-cell malignancy
characterized by the accumulation of abnormal plasma cells in the
bone marrow. Standard therapy for multiple myeloma is similar to
the course for MCL and normally consists of combination
chemotherapy that often results in a 60-70% response rate. However,
most patients will eventually relapse, leaving patients with
limited therapeutic options. Recent gene expression profiling of
multiple myeloma cells revealed elevated expression of Bmi-1
compared to that in normal plasma cells, as confirmed by
immunoblotting.
[0244] Bmi-1 has been shown to be regulated transcriptionally by a
number of factors including SALL4, FoxM1, c-Myc, E2F-1 and Mel18.
Bmi-1 and SALL4 are putative oncogenes that modulate stem cell
pluripotency and play a role in leukemigenesis (also referred to as
leukemogenesis). Murine Sall4 also has been shown to play an
essential role in maintaining the properties of ES (embryonic stem)
cells and governing the fate of the primitive inner cell mass. Yang
et al demonstrated that transcription from the Bmi-1 promoter is
markedly activated by SALL4 in a dose-dependent manner (35). The
Forkhead box transcription factor FoxM1 is expressed in
proliferating cells and has been shown to upregulate the levels of
Bmi-1 in transformed NIH 3T3 cells in response to oxidative stress
through c-myc activation (58). The Bmi-1 homologue, Mel18, acts as
a potent repressor on the expression of Bmi-1. The Bmi-1 promoter
region contains a functional E-box through which c-Myc and Mel-18
can regulate Bmi-1 expression. Since Mel18 downregulates c-Myc
expression and Bmi-1 is a c-Myc target, these data suggest that
Mel18 regulates expression of Bmi-1 via repression of c-Myc during
cellular senescence and, thus, link c-Myc and polycomb function
(59). Similarly, a recent report suggests that E2F-1 may also
regulate the levels of Bmi-1 in neuroblastoma (60). The Bmi-1
promoter contains a putative E2F binding site required for the
activation of a Bmi-1 promoter-dependent reporter construct by
E2F-1. Neither post-transcriptional nor post-translational control
of Bmi-1 production has been reported.
[0245] Without being limited by theory, the compounds of Formula
(I) or a form thereof described herein activate the apoptotic
pathway as determined by annexin-V expression, as well as cleavage
of poly (ADP-ribose) polymerase (PARP) and caspase-9 and caspase-7.
Cell cycle analyses of cells treated with these compounds of
Formula (I) or a form thereof have further demonstrated a block at
the G.sub.2/M phase followed by the development of polyploidy.
These findings suggest that Bmi-1 may also play a role in DNA
repair and/or regulation of mitosis. The compounds of Formula (I)
or a form thereof described herein are useful inhibitors of Bmi-1
function and cause a reduction in the level of Bmi-1 protein and
are thus potential therapeutics for any cancer cell, tumor cell,
cancer stem cell or tumor stem cell that overexpresses Bmi-1.
Additionally, the compounds of Formula (I) or a form thereof
described herein inhibit the function of Bmi-1 and reduce Bmi-1
levels in cancer stem cell and tumor stem cell environments and are
thus useful in targeting cancer cell populations that have been
shown to be resistant to current therapies (e.g., such as those
using large and small molecule chemotherapeutic agents and
radiation therapies, as well as targeted therapies that primarily
function by indiscriminately damaging mitotic cells).
[0246] As used herein, the italicized form of "Bmi-1," unless
otherwise specified or clear from the context of the specification,
refers to the Bmi-1 gene. The nonitalicized form of "Bmi-1," the
capitalized form of "BMI-1" or the term "Bmi-1 protein," unless
otherwise specified or clear from the context of the specification,
collectively refer to Bmi-1 protein.
[0247] As used herein, the term "Bmi-1 inhibitor" or the phrase (or
variations thereof) "inhibit Bmi-1 function and reduce the level of
Bmi-1" refer to post-translational inhibition of the function of
Bmi-1 protein and subsequent degradation, resulting in decreased
levels of Bmi-1 protein present in a tumor environment including,
but not limited to, in vitro and in vivo environments comprising
cancer stem cells or tumor stem cells or cancer stem cells and
tumor stem cells.
[0248] In accordance with the present description, compounds of
Formula (I) or a form thereof that inhibit Bmi-1 function and
reduce the level of Bmi-1 also inhibit proliferation of tumor cells
in vitro and in vivo and enhance sensitivity of intrinsically
resistant populations (e.g., either "cancer stem cells," "tumor
stem cells" or both) to chemotherapeutics. Elevated expression of
human Bmi-1 has been reported in multiple cancer samples and cancer
cell lines (2, 42, 51, 56, 61-68). Applicants have identified
compounds of Formula (I) or a form thereof that inhibit Bmi-1
function and reduce the level of Bmi-1 in vitro and in vivo, with
concurrent inhibition of tumor cell growth and xenograft growth in
vivo.
[0249] One embodiment described herein is directed to a method of
inhibiting Bmi-1 function and reducing the level of Bmi-1 to treat
a cancer mediated by Bmi-1 in a subject in need thereof comprising
contacting a cell having elevated Bmi-1 levels from the subject
with an amount of a compound of Formula (I) or a form thereof,
wherein the cell is selected from a cancer cell, tumor cell, cancer
stem cell or tumor stem cell, determining an effective amount of
the compound of Formula (I) or a form thereof that inhibits Bmi-1
function in the cell and subsequently administering the effective
amount of the compound of Formula (I) or a form thereof to the
subject.
[0250] Another embodiment described herein is directed to a method
of inhibiting Bmi-1 function and reducing the level of Bmi-1 to
treat a cancer mediated by Bmi-1 in a subject in need thereof
comprising administering to the subject an effective amount of the
compound of Formula (I) or a form thereof.
[0251] Another embodiment described herein is directed to a method
for treating a cancer mediated by Bmi-1 in a subject in need
thereof comprising contacting a cell having elevated Bmi-1 levels
from the subject with an amount of a compound of Formula (I) or a
form thereof, wherein the cell is selected from a cancer cell,
tumor cell, cancer stem cell or tumor stem cell.
[0252] Another embodiment described herein is directed to a method
further comprising contacting a cell having elevated Bmi-1 levels
from the subject with an amount of the compound of Formula (I) or a
form thereof, wherein the cell is selected from a cancer cell,
tumor cell, cancer stem cell or tumor stem cell, determining an
effective amount of the compound of Formula (I) or a form thereof
that inhibits Bmi-1 function in the cell and subsequently
administering the effective amount of the compound of Formula (I)
or a form thereof to the subject.
[0253] Another embodiment described herein is directed to a method
wherein the effective amount of the compound of Formula (I) or a
form thereof determined to inhibit Bmi-1 function in the contacted
cell reduces Bmi-1 levels in the contacted cell.
[0254] An embodiment of the method described herein comprises
administering an effective amount of a compound of Formula (I) or a
form thereof to inhibit the function of Bmi-1 in a cancer cell in
vivo or in vitro, in a tumor cell in vivo or in vitro, in a cancer
stem cell population in vivo or in vitro, or in a tumor stem
population in vivo or in vitro.
[0255] An embodiment of the method described herein comprises
administering an effective amount of a compound of Formula (I) or a
form thereof to reduce the level of Bmi-1 in a cancer cell in vivo
or in vitro, in a tumor cell in vivo or in vitro, in a cancer stem
cell population in vivo or in vitro, or in a tumor stem population
in vivo or in vitro.
[0256] An embodiment of the method described herein comprises
administering an effective amount of a compound of Formula (I) or a
form thereof to inhibit cancer cell proliferation, tumor cell
proliferation, cancer stem cell proliferation or tumor stem cell
proliferation.
[0257] An embodiment described herein includes the use of a
compound of Formula (I) or a form thereof in the manufacture of a
medicament for inhibiting Bmi-1 function and reducing the level of
Bmi-1 to treat a cancer mediated by Bmi-1 in a subject in need
thereof comprising administering an effective amount of the
medicament to the subject.
[0258] Without being limited by theory, any type of cancer mediated
by or dependent on the presence of overexpressed Bmi-1 can be
treated in accordance with the intended use of the compounds of
Formula (I) or a form thereof described herein.
[0259] As used herein, the term "cancer" refers to cells in which
Bmi-1 is aberrantly expressed or overexpressed and the cell depends
on Bmi-1 for survival or proliferation. Without being limited by
theory, the cells may be either stem-like or more differentiated,
but the cell relies on Bmi-1 to enable uncontrolled cell division
and develop resistance to cytotoxic, chemotherapeutic agents.
[0260] In another embodiment, the term "a cancer mediated by Bmi-1"
refers to a cancer that is characterized by cells or a fraction of
cells from a cancer patient that overexpress Bmi-1 compared to
cells from a cancer-free patient (i.e., a patient with no
detectable cancer as determined by conventional techniques, such as
MRI, CAT scan, etc.). Alternatively, the term refers to cells or a
fraction of cells from a cancer patient that, relative to the
cancer patient's cells from surrounding normal tissues, express a
level of Bmi-1 that differs by at least 2%, 4%, 8%, 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%.
90%, or 95% more, as detected by any method routinely used in the
art, or described herein, e.g., in an ELISA.
[0261] Non-limiting examples of a cancer mediated by Bmi-1 that can
be treated with the intended use described herein: leukemias, such
as but not limited to, acute leukemia, acute lymphocytic leukemia,
acute myelocytic leukemias, such as, myeloblastic, promyelocytic,
myelomonocytic, monocytic, and erythroleukemia leukemias and
myelodysplastic syndrome; chronic leukemias, such as but not
limited to, chronic myelocytic (granulocytic) leukemia, chronic
lymphocytic leukemia, hairy cell leukemia; polycythemia vera;
lymphomas such as but not limited to Hodgkin's lymphoma,
non-Hodgkin's lymphoma; multiple myelomas such as but not limited
to smoldering multiple myeloma, nonsecretory myeloma,
osteosclerotic myeloma, placancer cell leukemia, solitary
placancercytoma and extramedullary placancercytoma; Waldenstrom's
macroglobulinemia; monoclonal gammopathy of undetermined
significance; benign monoclonal gammopathy; heavy chain disease;
bone and connective tissue sarcomas such as but not limited to bone
sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant
giant cell tumor, fibrosarcoma of bone, chordoma, periosteal
sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma),
fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,
lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, synovial
sarcoma; glial brain tumors (i.e., gliomas) such as but not limited
to, astrocytoma, ependymoma, oligodendroglioma, brain stem glioma,
optic glioma, diffuse intrinsic pontine glioma, mixed glioma (i.e.,
oligoastrocytoma), glioblastoma, glioblastoma multiforme, nonglial
tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma,
meningioma, pineocytoma, pineoblastoma, primary brain lymphoma;
breast cancer including but not limited to ductal carcinoma,
adenocarcinoma, lobular (cancer cell) carcinoma, intraductal
carcinoma, medullary breast cancer, mucinous breast cancer, tubular
breast cancer, papillary breast cancer, Paget's disease, and
inflammatory breast cancer; adrenal cancer such as but not limited
to pheochromocytom and adrenocortical carcinoma; thyroid cancer
such as but not limited to papillary or follicular thyroid cancer,
medullary thyroid cancer and anaplastic thyroid cancer; pancreatic
cancer such as but not limited to, insulinoma, gastrinoma,
glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or
islet cell tumor; pituitary cancers such as but limited to
Cushing's disease, prolactin-secreting tumor, acromegaly, and
diabetes insipius; eye cancers such as but not limited to ocular
melanoma such as iris melanoma, choroidal melanoma, and cilliary
body melanoma, and retinoblastoma; vaginal cancers such as squamous
cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as
squamous cell carcinoma, melanoma, adenocarcinoma, basal cell
carcinoma, sarcoma, and Paget's disease; cervical cancers such as
but not limited to, squamous cell carcinoma, and adenocarcinoma;
uterine cancers such as but not limited to endometrial carcinoma
and uterine sarcoma; ovarian cancers such as but not limited to,
ovarian epithelial carcinoma, borderline tumor, germ cell tumor,
and stromal tumor; esophageal cancers such as but not limited to,
squamous cancer, adenocarcinoma, adenoid cystic carcinoma,
mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma,
melanoma, placancercytoma, verrucous carcinoma, and oat cell
(cancer cell) carcinoma; stomach cancers such as but not limited
to, adenocarcinoma, fungating (polypoid), ulcerating, superficial
spreading, diffusely spreading, malignant lymphoma, liposarcoma,
fibrosarcoma, and carcinosarcoma; colon cancers; rectal cancers;
liver cancers such as but not limited to hepatocellular carcinoma
and hepatoblastoma; gallbladder cancers such as adenocarcinoma;
cholangiocarcinomas such as but not limited to papillary, nodular,
and diffuse; lung cancers such as non-small cell lung cancer,
squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma,
large-cell carcinoma and small-cell lung cancer; testicular cancers
such as but not limited to germinal tumor, seminoma, anaplastic,
classic (typical), spermatocytic, nonseminoma, embryonal carcinoma,
teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate
cancers such as but not limited to, prostatic intraepithelial
neoplasia, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma;
penal cancers; oral cancers such as but not limited to squamous
cell carcinoma; basal cancers; salivary gland cancers such as but
not limited to adenocarcinoma, mucoepidermoid carcinoma, and
adenoidcystic carcinoma; pharynx cancers such as but not limited to
squamous cell cancer, and verrucous; skin cancers such as but not
limited to, basal cell carcinoma, squamous cell carcinoma and
melanoma, superficial spreading melanoma, nodular melanoma, lentigo
malignant melanoma, acral lentiginous melanoma; kidney cancers such
as but not limited to renal cell carcinoma, adenocarcinoma,
hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis
and/or uterer); Wilms' tumor; bladder cancers such as but not
limited to transitional cell carcinoma, squamous cell cancer,
adenocarcinoma, carcinosarcoma. In addition, cancers include
myxosarcoma, osteogenic sarcoma, endotheliosarcoma,
lymphangioendotheliosarcoma, mesothelioma, synovioma,
hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,
bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland
carcinoma, papillary carcinoma and papillary adenocarcinomas (for a
review of such disorders, see Fishman et al., 1985, Medicine, 2d
Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997,
Informed Decisions: The Complete Book of Cancer Diagnosis,
Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A.,
Inc., United States of America).
[0262] The compounds of Formula (I) or a form thereof are also
useful in the treatment, prevention and/or management of a variety
of cancers mediated by Bmi-1 or other abnormal proliferative
diseases (where such disease is mediated by overexpressed Bmi-1 or
elevated levels of Bmi-1), including (but not limited to) the
following: carcinoma, including that of the bladder, breast, colon,
kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and
skin; including squamous cell carcinoma; hematopoietic tumors of
lymphoid lineage, including leukemia, acute lymphocytic leukemia,
acute lymphoblastic leukemia, B-cell lymphoma, T cell lymphoma,
Burkitt's lymphoma; hematopoietic tumors of myeloid lineage,
including acute and chronic myelogenous leukemias and promyelocytic
leukemia; tumors of mesenchymal origin, including fibrosarcoma and
rhabdomyoscarcoma; other tumors, including melanoma, seminoma,
tetratocarcinoma, neuroblastoma; tumors of the central and
peripheral nervous system, including astrocytoma, neuroblastoma,
glioma, and Schwannomas; tumors of mesenchymal origin, including
fibrosarcoma, rhabdomyoscarama, and osteosarcoma; and other tumors,
including melanoma, xeroderma pigmentosum, keratoactanthoma,
seminoma, thyroid follicular cancer and teratocarcinoma. In some
embodiments, cancers associated with aberrations in apoptosis are
treated in accordance with the methods described herein. Such
cancers may include, but are not limited to, follicular lymphomas,
carcinomas with p53 mutations, hormone dependent tumors of the
breast, prostate and ovary, and precancerous lesions such as
familial adenomatous polyposis, and myelodysplastic syndromes. In
specific embodiments, malignancy or dysproliferative changes (such
as metaplasias and dysplasias), or hyperproliferative disorders of
the skin, lung, liver, bone, brain, stomach, colon, breast,
prostate, bladder, kidney, pancreas, ovary, and/or uterus are
treated in accordance with the methods described herein. In other
specific embodiments, a sarcoma, or melanoma is treated as
described herein.
[0263] In a specific embodiment, the cancer mediated by Bmi-1 being
treated as described herein is leukemia, lymphoma or myeloma (e.g.,
multiple myeloma). Non-limiting examples of leukemias and other
blood-borne cancers mediated by Bmi-1 that can be treated with the
methods described herein include acute lymphoblastic leukemia
(ALL), acute lymphoblastic B-cell leukemia, acute lymphoblastic
T-cell leukemia, acute myeloblastic leukemia (AML), acute
promyelocytic leukemia (APL), acute monoblastic leukemia, acute
erythroleukemic leukemia, acute megakaryoblastic leukemia, acute
myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute
undifferentiated leukemia, chronic myelocytic leukemia (CML),
chronic lymphocytic leukemia (CLL), and hairy cell leukemia.
[0264] Non-limiting examples of lymphomas mediated by Bmi-1 that
can be treated in accordance with the methods described herein
include Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple
myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and
polycythemia vera.
[0265] In another embodiment, the cancer mediated by Bmi-1 being
treated as described herein is a solid tumor. Examples of solid
tumors that can be treated in accordance with the methods described
herein include, but are not limited to fibrosarcoma, myxosarcoma,
liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,
angiosarcoma, endotheliosarcoma, lymphangiosarcoma,
lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's
tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal
cancer, kidney cancer, pancreatic cancer, bone cancer, breast
cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach
cancer, oral cancer, nasal cancer, throat cancer, squamous cell
carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland
carcinoma, sebaceous gland carcinoma, papillary carcinoma,
papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma,
bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct
carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'
tumor, cervical cancer, uterine cancer, testicular cancer, small
cell lung carcinoma, bladder carcinoma, lung cancer, epithelial
carcinoma, glioma, glioblastoma multiforme, astrocytoma,
medulloblastoma, craniopharyngioma, ependymoma, pinealoma,
hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,
skin cancer, melanoma, neuroblastoma, and retinoblastoma.
[0266] In certain embodiments, a cancer mediated by Bmi-1 includes,
but is not limited to, brain cancer, gastric cancer, hematologic
cancer, lung cancer, non-small cell lung cancer, pancreatic cancer,
prostate cancer, salivary gland cancer, colorectal carcinoma,
hepatocellular carcinoma, liver carcinoma, breast carcinomas or
sarcomas, esophageal carcinomas or sarcomas, stomach carcinomas or
sarcomas, fibrosarcoma, glioblastoma, diffuse intrinsic pontine
glioma, medulloblastoma, neuroblastoma, diffuse large B cell
lymphomas, B cell non-Hodgkin's lymphoma, Hodgkin's lymphoma or
chronic or acute myeloid leukemia.
[0267] In certain embodiments, a cancer mediated by Bmi-1 includes,
but is not limited to, tumors that relapse after therapy despite
improved surgical and irradiation techniques. Tumor relapse may
occur for a number of reasons, with one plausible explanation being
the existence of cancer stem cells (CSC) or tumor stem cells (tumor
initiating cells) in the tumor population. CSCs are defined as a
population of stem cells relative to any type of blood cancer,
solid tumor cancer or metastatic cancer. Tumor stem cells are those
specifically found within a tumor. Both have characteristics
similar to normal stem cells. Like normal stem cells, CSCs and
tumor stem cells have the potential to self renew. Unlike normal
stem cells, though, due to the sustained presence of high levels of
Bmi-1, the CSCs and tumor stem cells fail to terminally
differentiate and proliferate unchecked. Their enhanced DNA repair
capacity also enables them to become resistant to cytotoxic,
chemotherapeutic drugs designed to kill cancer cells and tumor
cells. Therefore, targeting CSCs and tumor stem cells that
overexpress Bmi-1 could be an approach for effective cancer
treatment. One further approach is to target various transcription
factors responsible for maintenance of the self renewal capacity of
CSCs and tumor stem cells.
[0268] As used herein, the term "treat," "treatment" or "treating"
refers to: (i) preventing a disease, disorder and/or condition from
occurring in a subject that may be predisposed to the disease,
disorder and/or condition but has not yet been diagnosed as having
said disease, disorder and/or condition; (ii) inhibiting a disease,
disorder and/or condition, i.e., arresting its development; and/or
(iii) relieving a disease, disorder and/or condition, i.e., causing
regression of the disease, disorder and/or condition.
[0269] As used herein, the term "subject" refers to members of the
human, equine, porcine, bovine, murine, rattus, canine and feline
species. In some embodiments, the subject is a mammal or a
warm-blooded vertebrate animal. In other embodiments, the subject
is a human. As used herein, the term "patient" may be used
interchangeably with "subject" and "human".
[0270] In certain embodiments, the subject is a human that is 0 to
6 months old, 6 to 12 months old, 6 to 18 months old, 18 to 36
months old, 1 to 5 years old, 5 to 10 years old, 10 to 15 years
old, 15 to 20 years old, 20 to 25 years old, 25 to 30 years old, 30
to 35 years old, 35 to 40 years old, 40 to 45 years old, 45 to 50
years old, 50 to 55 years old, 55 to 60 years old, 60 to 65 years
old, 65 to 70 years old, 70 to 75 years old, 75 to 80 years old, 80
to 85 years old, 85 to 90 years old, 90 to 95 years old or 95 to
100 years old. In some embodiments, the subject is a human infant.
In other embodiments, the subject is a human toddler. In other
embodiments, the subject is a human child. In other embodiments,
the subject is human adult. In yet other embodiments, the subject
is an elderly human.
[0271] As used herein, the term "elderly human" refers to a human
65 years or older; the term "human adult" refers to a human that is
18 years or older; the term "human child" refers to a human that is
1 year to 18 years old; the term "human infant" refers to a newborn
to 1 year old year human; and, the term "human toddler" refers to a
human that is 1 year to 3 years old.
[0272] In certain embodiments, the subject is in an
immunocompromised state or immunosuppressed state or at risk for
becoming immunocompromised or immunosuppressed. In certain
embodiments, the subject is receiving or recovering from an
immunosuppressive therapy. In certain embodiments, the subject has
or is at risk of getting cancer, AIDS, or a bacterial infection. In
certain embodiments, the subject is, will or has undergone surgery,
chemotherapy and/or radiation therapy. In certain embodiments, the
subject has cystic fibrosis, pulmonary fibrosis or another
condition affecting the lungs. In certain embodiments, the subject
has, will have or had a tissue transplant.
[0273] In some embodiments, the subject's cancer, due to the
overexpression of Bmi-1 in cancer cells, tumor cells, cancer stem
cells or tumor stem cells thereof, has proven refractory to
conventional "standard of care" therapies (excluding treatment with
a compound of Formula (I) or a form thereof), such that the patient
has discontinued the conventional therapy. In one embodiment,
without being limited by theory, the term "refractory" means that
at least some significant portion of the cancer cells, tumor cells,
cancer stem cells or tumor stem cells continue to proliferate due
to the overexpression of Bmi-1, despite therapy. The determination
of whether the cancer is refractory to a particular therapy can be
made either in vivo or in vitro by any method known in the art for
assaying the effect of a therapy on the cancer cells, tumor cells,
cancer stem cells or tumor stem cells, using the art-accepted
meanings of "refractory" in such a context. In certain embodiments,
a patient having a refractory cancer due to the overexpression of
Bmi-1 is a patient in which the cancer is non-responsive or
resistant to a conventional or "standard of care" therapy. In
certain embodiments, a patient with refractory cancer has a cancer
mediated by Bmi-1 that progresses. Disease progression, as a lack
of clinical response to a therapy, is demonstrated when the tumor
or neoplasm has not been significantly eradicated and/or the
symptoms have not been significantly alleviated. The determination
of whether a patient has a refractory cancer mediated by Bmi-1 can
be made either in vivo or in vitro by any method known in the art
for assaying the effectiveness of the therapy for the treatment of
the cancer, using art-accepted meanings of "refractory" in such a
context.
[0274] In certain embodiments, the patient to be treated in
accordance with the methods described herein is a patient already
being treated with antibiotics, anti-virals, anti-fungals, or other
biological therapy, immunotherapy or anti-cancer therapy. Among
these patients are patients with a refractory cancer mediated by
Bmi-1 or patients too young for conventional therapies. In some
embodiments, the patient being treated is treatment naive, not
having received any prior therapy. In any of the foregoing
embodiments, a patient to be treated may receive a small molecule
therapy.
[0275] In some embodiments, a compound of Formula (I) or a form
thereof may be prophylactically administered to a patient to
prevent the onset of cancer mediated by Bmi-1 in a patient at risk
of developing cancer. In some embodiments, a compound of Formula
(I) or a form thereof may be therapeutically administered to a
patient that is susceptible to adverse reactions to conventional
therapies. In some embodiments, the subject being administered one
or more compounds of Formula (I) or a form thereof has not received
prior therapy. In other embodiments, one or more compounds of
Formula (I) or a form thereof are administered to a subject who has
received a prior therapy. In some embodiments, the subject
administered a compound of Formula (I) or a form thereof has
discontinued a prior therapy due to lack of benefit from the
therapy, adverse effects from the therapy or unacceptable levels of
toxicity.
[0276] In some embodiments, the subject being administered one or
more compounds of Formula (I) or a form thereof, will or has
undergone surgery, chemotherapy, antibody therapy, hormonal therapy
and/or radiation therapy. In certain embodiments, the patient has
undergone surgery to remove the tumor or neoplasm. In certain
embodiments, the subject will have, or has had, or is undergoing a
tissue or organ transplant.
[0277] As used herein, the terms "effective amount,"
"prophylactically effective amount" or "therapeutically effective
amount" mean an amount of a compound of Formula (I) or a form
thereof that is effective in inhibiting Bmi-1 protein function and
reducing the level of Bmi-1 protein, as described herein, and thus
producing the desired prophylactic, therapeutic, ameliorative,
inhibitory or preventative effect in a cancer mediated by Bmi-1 in
a patient in need thereof.
[0278] As used herein, the term "effective amount," in the context
of administering a compound of Formula (I) or a form thereof to a
patient, refers to the amount of a compound of Formula (I) or a
form thereof which is sufficient to achieve at least one or more of
the following effects, as applicable, in a patient or in patient
cell(s): (i) inhibition of Bmi-1 protein function; (ii) reduction
in the level or quantity of Bmi-1 protein; (iii) reduction or
amelioration in the severity of a cancer mediated by Bmi-1 or a
symptom associated therewith; (iv) prevention of the progression of
a cancer mediated by Bmi-1 or a symptom associated therewith; (v)
regression of a cancer mediated by Bmi-1 or a symptom associated
therewith; (vi) prevention of the development or onset of a cancer
mediated by Bmi-1 or a symptom associated therewith; (vii)
prevention of the recurrence of a cancer mediated by Bmi-1 or a
symptom associated with a cancer mediated by Bmi-1; (viii)
reduction of the duration of a symptom associated with a cancer
mediated by Bmi-1; (ix) reduction or elimination of the cancer stem
cell or tumor stem cell population; (x) reduction or elimination of
the growth of a tumor or neoplasm overexpressing Bmi-1; (xi)
reduction or elimination of the proliferation of cancer cells or
tumor cells; (xii) reduction or elimination of the formation of a
tumor or neoplasm overexpressing Bmi-1; (xiii) eradication or
control of a primary, regional and/or metastatic cancer mediated by
Bmi-1; (xiv) reduction in patient mortality; (xv) increased number
of patients in remission; (xvi) increased length of remission in
patients; (xvii) the size of a tumor or neoplasm overexpressing
Bmi-1 is maintained or controlled such that the size does not
increase or increases less than the size of the tumor after
administration of a standard therapy as measured by conventional
methods available to one of skill in the art, such as MRI, X-ray
and CAT scan; (xviii) increased delay in disease progression; (xix)
increased patient survival; (xx) reduction in incidences of patient
hospitalization; (xxi) reduction in the length of patient
hospitalization; (xxii) enhancement or improvement in the
prophylactic or therapeutic effect(s) of another therapy; (xxiii)
reduction in the number of symptoms associated with a cancer
mediated by Bmi-1; (xxiv) increased cancer-free survival of
patients; and/or (xxv) increased symptom-free survival of cancer
patients.
[0279] In general, the term "effective amount" also includes that
amount of a compound of Formula (I) or a form thereof administered
to a patient which is in a range of from about 0.001 mg/Kg/day to
about 500 mg/Kg/day, or about 0.01 mg/Kg/day to about 500
mg/Kg/day, or about 0.1 mg to about 500 mg/Kg/day, or about 1.0
mg/day to about 500 mg/Kg/day, in single, divided, or a continuous
dose for a patient or subject having a weight in a range of between
about 40 to about 200 Kg (which dose may be adjusted for patients
or subjects above or below this range, particularly children under
40 Kg). The typical adult subject is expected to have a median
weight in a range of between about 60 to about 100 Kg. The
effective amount for the subject will also depend upon various
factors, including the body weight, size and health of the subject.
An effective amount for a given patient can be determined according
to the skill and judgment of the clinician.
[0280] In another embodiment, where daily doses are adjusted based
upon the weight of the subject or patient, compounds of Formula (I)
or a form thereof described herein may be formulated for delivery
at about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10,
0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20,
1.25, 1.50, 1.75, 2.0, 5.0, 10, 20 or 50 mg/Kg/day. Daily doses
adjusted based upon the weight of the subject or patient may be
administered as a single, divided, or continuous dose. In
embodiments where a dose of a compound of Formula (I) or a form
thereof is given more than once per day, the dose may be
administered once, twice, three times, or more per day. In another
embodiment, a subject is administered one or more doses of an
effective amount of a compound of Formula (I) or a form thereof,
wherein the effective amount may not be the same for each dose.
[0281] Another embodiment described herein includes an effective
amount of the compound of Formula (I) or a form thereof in a range
of from about 0.001 mg/Kg/day to about 500 mg/Kg/day.
[0282] Within the scope described herein, the "effective amount" of
a compound of Formula (I) or a form thereof for use in the
manufacture of a medicament or in a method for treating a cancer
mediated by Bmi-1 in a subject in need thereof, is intended to
include an amount in a range of from about 0.1 ng to about 3500 mg
administered daily; from about 0.1 .mu.g to about 3500 mg
administered daily; from about 0.1 mg to about 3500 mg administered
daily; from about 1 mg to about 3500 mg administered daily; from
about 1 mg to about 3000 mg administered daily; from about 0.05 mg
to about 1500 mg administered daily; from about 0.5 mg to about
1500 mg administered daily; from about 1 mg to about 1500 mg
administered daily; from about 5 mg to about 1500 mg administered
daily; from about 10 mg to about 600 mg administered daily; from
about 0.5 mg to about 2000 mg administered daily; or, an amount in
a range of from about 5.0 mg to about 1500 mg administered
daily.
[0283] Another embodiment described herein includes an effective
amount of the compound of Formula (I) or a form thereof in a range
of from about 0.1 ng to about 3500 mg.
[0284] For any compound of Formula (I) or a form thereof, the
effective amount can be estimated initially by results from cell
culture assays or from relevant animal models, such as the mouse,
chimpanzee, marmoset or tamarin animal model. Relevant animal
models may also be used to determine the appropriate concentration
range and route of administration. Such information can then be
used to determine useful doses and routes for administration in
humans. Therapeutic efficacy and toxicity may be determined by
standard pharmaceutical procedures in cell cultures or experimental
animals, e.g., ED.sub.50 (the dose therapeutically effective in 50%
of the population) and LD.sub.50 (the dose lethal to 50% of the
population). The dose ratio between the toxic and therapeutic
effect is referred to as the therapeutic index, and can be
expressed as the ratio, LD.sub.50/ED.sub.50. In some embodiments,
the effective amount is such that a large therapeutic index is
achieved. In further embodiments, the dosage is within a range of
plasma concentrations that include an ED.sub.50 with little or no
toxicity. The dosage may vary within this range depending upon the
dosage form employed, sensitivity of the patient, and the route of
administration.
[0285] More specifically, the concentration-biological effect
(pharmacodynamic) relationship observed with regard to a compound
of Formula (I) or a form thereof suggests a target plasma
concentration ranging from about 0.001 .mu.g/mL to about 50
.mu.g/mL, from about 0.01 .mu.g/mL to about 20 .mu.g/mL, from about
0.05 .mu.g/mL to about 10 .mu.g/mL, or from about 0.1 .mu.g/mL to
about 5 .mu.g/mL. To achieve such plasma concentrations, the
compounds of Formula (I) or a form thereof described herein may be
administered at doses that vary from 0.001 .mu.g to 100,000 mg,
depending upon the route of administration in single, divided, or
continuous doses for a patient weighing between about 40 to about
100 kg (which dose may be adjusted for patients above or below this
weight range, particularly for children under 40 kg).
[0286] The exact dosage will be determined by the practitioner, in
light of factors related to the subject. Dosage and administration
may be adjusted to provide sufficient levels of the active agent(s)
or to maintain the desired effect. Administration factors that may
be taken into account include the severity of the disease state,
general health of the subject, ethinicity, age, weight, and gender
of the subject, diet, time and frequency of administration, drug
combination(s), reaction sensitivities, tolerance for toxicity
related to drug metabolites, experience with other cancer therapies
and regimens, and tolerance/response to such therapies and
regimens. Long-acting pharmaceutical compositions may be
administered every 2, 3 or 4 days, once every week, or once every
two weeks depending on half-life and clearance rate of the
particular formulation.
[0287] The compounds of Formula (I) or a form thereof described
herein may be administered to the subject via any drug delivery
route known in the art. Nonlimiting examples include oral, ocular,
rectal, buccal, topical, nasal, ophthalmic, subcutaneous,
intramuscular, intraveneous (bolus and infusion), intracerebral,
transdermal, and pulmonary routes of administration.
Compound Metabolites
[0288] Also falling within the scope described herein are the in
vivo metabolic products of the compounds of Formula (I) or a form
thereof. Such products may result, for example, from the oxidation,
reduction, hydrolysis, amidation, glucuronidation, esterification
and the like of the administered compound of Formula (I) or a form
thereof, primarily due to enzymatic processes. Accordingly, the
compounds of Formula (I) or a form thereof described herein include
those produced by a process comprising contacting a compound of
Formula (I) or a form thereof described herein with a mammalian
tissue or a mammal for a period of time sufficient to yield a
metabolic product thereof.
[0289] Such products typically are identified by preparing a
radio-labeled (e.g. C.sup.14 or H.sup.3) compound of Formula (I) or
a form thereof described herein, administering it in a detectable
dose (e.g., greater than about 0.5 mg/kg) to a mammal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours), and
isolating its conversion products from urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS or
NMR analysis. In general, analysis of metabolites may be done in
the same way as conventional drug metabolism studies well-known to
those skilled in the art. The conversion products, so long as they
are not otherwise found in vivo, are useful in diagnostic assays
for therapeutic dosing of the compounds of Formula (I) or a form
thereof described herein even if they possess no biological
activity of their own.
Combination Therapies
[0290] The methods of treating a cancer mediated by Bmi-1 in a
subject in need thereof, in addition to those previously described
herein, further comprise administering to the subject in need
thereof an effective amount of one or more of the compounds of
Formula (I) or a form thereof alone or in combination with one or
more additional agents selected from anti-cancer agents,
anti-proliferative agents, chemotherapeutic agents,
immunomodulatory agents, anti-angiogenic agents, anti-inflammatory
agents, an alkylating agents, steroidal and non-steriodal
anti-inflammatory agents, pain relievers, leukotriene antagonists,
.beta.2-agonists, anticholinergic agents, hormonal agents,
biological agents, tubulin binding agents, glucocorticoids,
corticosteroid agents, antibacterial agents, antihistamines,
anti-malarial agents, anti-viral agents, antibiotics and the like;
and, optionally with radiation therapy.
[0291] In another embodiment, one or more compounds of Formula (I)
or a form thereof alone or in combination with one or more
additional agents may be administered to the subject in combination
with a supportive therapy, a pain relief therapy, or other therapy
that does not have an effect on a cancer mediated by Bmi-1.
[0292] In some embodiments, one or more compounds of Formula (I) or
a form thereof described herein and one or more additional agents
described herein are administered as the same pharmaceutical
composition. In certain embodiments, one or more compounds of
Formula (I) or a form thereof described herein and one or more
additional agents described herein are administered in different
pharmaceutical compositions. In certain embodiments, one or more
compounds of Formula (I) or a form thereof described herein and one
or more additional agents described herein are administered by the
same route of administration. In certain embodiments, one or more
compounds of Formula (I) or a form thereof described herein and one
or more additional agents described herein are administered by
different routes of administration.
[0293] In other embodiments are pharmaceutical compositions wherein
one or more compounds of Formula (I) or a form thereof are
administered in a combination product with one or more additional
agents useful in the treatment of a cancer mediated by Bmi-1. The
skilled artisan will recognize that a variety of active ingredients
may be administered in a combination with the compounds of Formula
(I) or a form thereof described herein whereby the product may act
to augment or synergistically enhance the anticancer activity of
either or both the additional agent(s) and the compound(s) of
Formula (I) or a form thereof described herein.
[0294] As used herein, the term "synergistic," refers to the effect
of the administration of a combination product as described herein
which is more effective than the additive effects of any two or
more single agents. In a specific embodiment, a synergistic effect
of a combination product permits the use of lower dosages of one or
more agents and/or less frequent administration of said agents to a
subject with a cancer mediated by Bmi-1. In certain embodiments,
the ability to utilize lower dosages of an agent and/or to
administer said agents less frequently reduces the toxicity
associated with the administration of said agents to a subject
without reducing the efficacy of said agents in the prevention or
treatment of a cancer mediated by Bmi-1. In some embodiments, a
synergistic effect results in improved efficacy of each of the
agents in treating a cancer mediated by Bmi-1. In some embodiments,
a synergistic effect of a combination of agents avoids or reduces
adverse or unwanted side effects associated with the use of any
single agent. The combination of agents in such a product can be
administered to a subject in the same pharmaceutical composition.
Alternatively, the agents can be administered concurrently to a
subject in separate pharmaceutical compositions. The agents may
also be administered to a subject by the same or different routes
of administration. In a specific embodiment, at least one of the
agents is a compound of Formula (I) or a form thereof described
herein.
[0295] It is also possible to combine any compound of Formula (I)
or a form thereof described herein with such additional agents
useful in the treatment of a cancer mediated by Bmi-1, including
compounds of Formula (I) or a form thereof as described herein, in
a unitary dosage form, or in separate dosage forms intended for
simultaneous or sequential administration to a patient in need of
treatment. When administered sequentially, the combination may be
administered in two or more administrations. In an alternative
embodiment, it is possible to administer one or more compounds of
Formula (I) or a form thereof described herein and one or more
additional agents described herein by different routes.
[0296] According to the methods described herein, a combination
product may include a combination of active ingredients that may
be: (1) co-formulated and administered or delivered simultaneously
in a combined formulation; (2) delivered sequentially or in
parallel as separate formulations; or (3) by any other combination
regimen known in the art. When delivered as separate formulations
in alternation therapy, the methods described herein may comprise
administration or delivery, for example, without limitation, in
separate solutions, emulsions, suspensions, tablets, pills or
capsules, or by different injections in separate syringes. In
general, when administered in alternation, an effective dosage of
each active ingredient is administered serially, one dose following
another. In contrast, in parallel or simultaneous administration,
effective dosages of two or more active ingredients are
administered together. Various alternative combinations of
intermittent sequential or in parallel combination administration
may also be used.
[0297] Specific examples of such agents include, but are not
limited to, immunomodulatory agents (e.g., interferon,
penicillamine and the like), anti-angiogenic agent,
anti-inflammatory agents (e.g., adrenocorticoids, corticosteroids
(e.g., beclomethasone, budesonide, flunisolide, fluticasone,
triamcinolone, methylprednisolone, prednisolone, prednisone,
hydrocortisone), glucocorticoids, steroidal and non-steriodal
anti-inflammatory drugs (e.g., aspirin, ibuprofen, diclofenac, and
COX-2 inhibitors)), pain relievers, leukotriene antagonists (e.g.,
montelukast, methyl xanthines, zafirlukast, and zileuton),
.beta.2-agonists (e.g., albuterol, biterol, fenoterol, isoetharie,
metaproterenol, pirbuterol, salbutamol, terbutalin formoterol,
salmeterol, and salbutamol terbutaline), anticholinergic agents
(e.g., ipratropium bromide and oxitropium bromide), antibacterial
agents (e.g., sulphasalazine, dapsone and the like),
antihistamines, anti-malarial agents (e.g., hydroxychloroquine),
anti-viral agents (e.g., nucleoside analogs (e.g., zidovudine,
acyclovir, gangcyclovir, vidarabine, idoxuridine, trifluridine,
ribavirin, foscarnet, amantadine, rimantadine, saquinavir,
indinavir, ritonavir, and AZT) and antibiotics (e.g., dactinomycin
(formerly actinomycin), bleomycin, erythomycin, penicillin,
mithramycin, and anthramycin (AMC)).
[0298] Specific examples of additional agents that may be used in
combination with a compound of Formula (I) or a form thereof
described herein include, but are not limited to: acivicin;
aclarubicin; acodazole hydrochloride; acronine; adozelesin;
aldesleukin; altretamine; ambomycin; ametantrone acetate;
aminoglutethimide; amsacrine; anastrozole; anthracyclin;
anthramycin; asparaginase; asperlin; azacitidine; azetepa;
azotomycin; batimastat; benzodepa; bicalutamide; bisantrene
hydrochloride; bisnafide dimesylate; bisphosphonates (e.g.,
pamidronate (Aredria.RTM.), sodium clondronate (Bonefos.RTM.),
zoledronic acid (Zometa.RTM.), alendronate (Fosamax.RTM.),
etidronate, ibandornate, cimadronate, risedromate, and
tiludromate); bizelesin; bleomycin sulfate; brequinar sodium;
bropirimine; busulfan; cactinomycin; calusterone; caracemide;
carbetimer; carboplatin; carmustine; carubicin hydrochloride;
carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine;
demethylation agents; dexormaplatin; dezaguanine; dezaguanine
mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin
hydrochloride; droloxifene; droloxifene citrate; dromostanolone
propionate; duazomycin; edatrexate; eflornithine hydrochloride;
EphA2 inhibitors; elsamitrucin; enloplatin; enpromate;
epipropidine; epirubicin hydrochloride; erbulozole; esorubicin
hydrochloride; estramustine; estramustine phosphate sodium;
etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole
hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine
phosphate; 5-fluorouracil; fluorocitabine; fosquidone; fostriecin
sodium; gemcitabine; gemcitabine hydrochloride; histone deacetylase
inhibitors; hydroxyurea; idarubicin hydrochloride; ifosfamide;
ilmofosine; imatinib mesylate; interleukin II (including
recombinant interleukin II, or rIL2), interferon alpha-2a;
interferon alpha-2b; interferon alpha-n1; interferon alpha-n3;
interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan
hydrochloride; lanreotide acetate; lenalidomide; letrozole;
leuprolide acetate; liarozole hydrochloride; lometrexol sodium;
lomustine; losoxantrone hydrochloride; masoprocol; maytansine;
mechlorethamine hydrochloride; anti-CD2 antibodies; megestrol
acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; rogletimide; safingol; safingol hydrochloride;
semustine; simtrazene; sparfosate sodium; sparsomycin;
spirogermanium hydrochloride; spiromustine; spiroplatin;
streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan
sodium; tegafur; teloxantrone hydrochloride; temoporfin;
teniposide; teroxirone; testolactone; thiamiprine; thioguanine;
thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone
acetate; triciribine phosphate; trimetrexate; trimetrexate
glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard;
uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine
sulfate; vindesine; vindesine sulfate; vinepidine sulfate;
vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;
vinrosidine sulfate; vinzolidine sulfate; volitinib; vorozole;
zeniplatin; zinostatin; zorubicin hydrochloride and the like.
[0299] Other examples of treating a cancer mediated by Bmi-1
include treatment with an anti-cancer or anti-proliferative agent
wherein the anti-cancer or anti-proliferative agent is selected
from, but not limited to: 20-Epi-1,25-dihydroxyvitamin D3 (MC 1288,
MC 1301, KH 1060); 5-ethynyluracil; abiraterone; aclarubicin;
acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK
antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, antiestrogen; antineoplaston; antisense
oligonucleotides; aphidicolin glycinate; apoptosis gene modulators;
apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA
(0-palmitoyl-1-thioglycerol); arginine deaminase; asulacrine;
atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin
3; azasetron; azatoxin; azatyrosine; baccatin III derivatives;
balanol; batimastat; BCR/ABL antagonists; benzochlorins;
benzoylstaurosporine; beta lactam derivatives; beta-alethine;
betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide;
bisantrene; bisaziridinylspermine; bisnafide; bistratene A;
bizelesin; breflate; bropirimine; budotitane; buthionine
sulfoximine; calcipotriol; calphostin C; camptothecin derivatives;
canarypox IL-2; capecitabine; carboxamide-amino-triazole (CaRest
M3); CARN 700; cartilage derived inhibitor; carzelesin; casein
kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate (YNK01 or
Starasid.RTM.); cytolytic factor; cytostatin; dacliximab;
decitabine; dehydrodidemnin B; deslorelin; dexamethasone;
dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B;
didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol,
dioxamycin; diphenyl spiromustine; docetaxel; docosanol;
dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA;
ebselen; ecomustine; edelfosine; edrecolomab; eflornithine;
elemene; emitefur; epirubicin; epristeride; estramustine analogue;
estrogen agonists; estrogen antagonists; etanidazole; etoposide
phosphate; exemestane; fadrozole; fazarabine; fenretinide;
filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;
fludarabine; fluorodaunorunicin hydrochloride; forfenimex;
formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium
nitrate; galocitabine; ganirelix; gelatinase inhibitors;
gemcitabine; glutathione inhibitors; HMG CoA reductase inhibitors
(e.g., atorvastatin, cerivastatin, fluvastatin, lescol, lupitor,
lovastatin, rosuvastatin, and simvastatin); hepsulfam; heregulin;
hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin;
idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones;
imiquimod; immunostimulant peptides; insulin-like growth factor-1
receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide/estrogen/progesterone combinations; leuprorelin;
levamisole; LFA-3TIP (see, International Publication No. WO93/0686
and U.S. Pat. No. 6,162,432); liarozole; linear polyamine analogue;
lipophilic disaccharide peptide; lipophilic platinum compounds;
lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium
texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;
marimastat; masoprocol; maspin; matrilysin inhibitors; matrix
metalloproteinase inhibitors; menogaril; merbarone; meterelin;
methioninase; metoclopramide; MIF tautomerase inhibitor;
mifepristone; miltefosine; mirimostim; mismatched double stranded
RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide;
mitotoxin fibroblast growth factor-saporin; mitoxantrone;
mofarotene; molgramostim; monoclonal antibody, human chorionic
gonadotrophin; monophosphoryl lipid A/myobacterium cell wall
skeleton (CWS/MPL); mopidamol; multiple drug resistance gene
inhibitor; multiple tumor suppressor 1-based therapy; mustard
anticancer agent; mycaperoxide B; mycobacterial cell wall extract;
myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin;
nagrestip; naloxone/pentazocine combinations; napavin; naphterpin;
nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral
endopeptidase; nilutamide; nisamycin; nitric oxide modulators;
nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide;
okicenone; oligonucleotides; onapristone; oracin; oral cytokine
inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin;
paclitaxel; paclitaxel analogues; paclitaxel derivatives;
palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol;
panomifene; parabactin; pazelliptine; pegaspargase; peldesine
(BCX-34); pentosan polysulfate sodium; pentostatin; pentrozole;
perflubron; perfosfamide; perillyl alcohol dehydrogenase;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitors, microalgal; protein tyrosine phosphatase
inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene
conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl
protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RH retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain antigen
binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
5-fluorouracil; leucovorin; tamoxifen methiodide; tauromustine;
tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase
inhibitors; temoporfin; temozolomide; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin
receptor agonist; thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin;
toremifene; totipotent stem cell factor; translation inhibitors;
tretinoin; triacetyluridine; triciribine; trimetrexate;
triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;
tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived
growth inhibitory factor; urokinase receptor antagonists;
vapreotide; variolin B; vector system, erythrocyte gene therapy;
thalidomide; velaresol; veramine; verdins; verteporfin;
vinorelbine; vinxaltine; volitinib; vorozole; zanoterone;
zeniplatin; zilascorb; zinostatin stimalamer and the like.
[0300] In some embodiments, the additional agent used in
combination with a compound of Formula (I) or a form thereof
described herein is one or more immunomodulatory agent(s).
Non-limiting examples of immunomodulatory agents include
proteinaceous agents such as cytokines, peptide mimetics, and
antibodies (e.g., human, humanized, chimeric, monoclonal,
polyclonal, Fvs, ScFvs, Fab or F(ab).sub.2 fragments or epitope
binding fragments), nucleic acid molecules (e.g., antisense nucleic
acid molecules and triple helices), cancer molecules, organic
compounds, and inorganic compounds.
[0301] In particular, one or more immunomodulatory agents that may
be used in combination with a compound of Formula (I) or a form
thereof described herein include, but are not limited to,
methotrexate, leflunomide, cyclophosphamide, cytoxan, cyclosporine
A, minocycline, azathioprine (Imuran.RTM.), antibiotics (e.g.,
FK506 (tacrolimus)), methylprednisolone (MP), corticosteroids,
steroids, mycophenolate mofetil, rapamycin (sirolimus), mizoribine,
deoxyspergualin, brequinar, malononitriloamindes (e.g.,
leflunamide), T cell receptor modulators, cytokine receptor
modulators, and modulators mast cell modulators.
[0302] In one embodiment, the immunomodulatory agent is a
chemotherapeutic agent. In an alternative embodiment, the
immunomodulatory agent is an immunomodulatory agent other than a
chemotherapeutic agent. In some embodiments, the additional agent
used described herein is not an immunomodulatory agent.
[0303] In some embodiments, the additional agent that may be used
in combination with a compound of Formula (I) or a form thereof
described herein is one or more anti-angiogenic agent(s).
Non-limiting examples of anti-angiogenic agents include proteins,
polypeptides, peptides, fusion proteins, antibodies (e.g., human,
humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab
fragments, F(ab).sub.2 fragments, and antigen-binding fragments
thereof) such as antibodies that immunospecifically bind to
TNF-.alpha., nucleic acid molecules (e.g., antisense molecules or
triple helices), organic molecules, inorganic molecules, and cancer
molecules that reduce or inhibit angiogenesis. In other
embodiments, the additional agent described herein is not an
anti-angiogenic agent.
[0304] In some embodiments, the additional agent that may be used
in combination with a compound of Formula (I) or a form thereof
described herein is one or more anti-inflammatory agent(s).
Non-limiting examples of anti-inflammatory agents include any
anti-inflammatory agent useful in treating inflammatory disorders.
Non-limiting examples of anti-inflammatory agents include
non-steroidal anti-inflammatory drugs (NSAIDs), steroidal
anti-inflammatory drugs, anticholinergics (e.g., atropine sulfate,
atropine methylnitrate, and ipratropium bromide (ATROVENT.RTM.),
.beta.2-agonists (e.g., albuterol (VENTOLIN.RTM. and
PROVENTIL.RTM.), bitolterol (TORNALATE.RTM.), levalbuterol
(XOPONEX.RTM.), metaproterenol (ALUPENT.RTM.), pirbuterol
(MAXAIR.RTM.), terbutlaine (BRETHAIRE.RTM. and BRETHINE.RTM.),
albuterol (PROVENTIL.RTM., REPETABS.RTM., and VOLMAX.RTM.),
formoterol (FORADIL AEROLIZER.RTM.), salmeterol (SEREVENT.RTM. and
SEREVENT DISKUS.RTM.), methylxanthines (e.g., theophylline
(UNIPHYL.RTM., THEO-DUR.RTM., SLO-BID.RTM., AND TEHO-42.RTM.)) and
the like. Examples of NSAIDs include, but are not limited to,
aspirin, ibuprofen, celecoxib (CELEBREX.RTM.), diclofenac
(VOLTAREN.RTM.), etodolac (LODINE.RTM.), fenoprofen (NALFON.RTM.),
indomethacin (INDOCIN.RTM.), ketoralac (TORADOL.RTM.), oxaprozin
(DAYPRO.RTM.), nabumentone (RELAFEN.RTM.), sulindac
(CLINORIL.RTM.), tolmentin (TOLECTIN.RTM.), rofecoxib (VIOXX.RTM.),
naproxen (ALEVE.RTM., NAPROSYN.RTM.), ketoprofen (ACTRON.RTM.),
nabumetone (RELAFEN.RTM.) and the like. Such NSAIDs function by
inhibiting a cyclooxgenase enzyme (e.g., COX-1 and/or COX-2).
Examples of steroidal anti-inflammatory drugs include, but are not
limited to, glucocorticoids, dexamethasone (DECADRON.RTM.),
corticosteroids (e.g., methylprednisolone (MEDROL.RTM.), cortisone,
hydrocortisone, prednisone (PREDNISONE.RTM. and DELTASONE.RTM.),
prednisolone (PRELONE.RTM. and PEDIAPRED.RTM.), triamcinolone,
azulfidine, inhibitors of eicosanoids (e.g., prostaglandins,
thromboxanes, and leukotrienes) and the like.
[0305] In certain embodiments, the additional agent that may be
used in combination with a compound of Formula (I) or a form
thereof described herein is an alkylating agent, a nitrosourea, an
antimetabolite, an anthracyclin, a topoisomerase II inhibitor, a
mitotic inhibitor and the like. Alkylating agents include, but are
not limited to, busulfan, cisplatin, carboplatin, cholormbucil,
cyclophosphamide, ifosfamide, decarbazine, mechlorethamine,
mephalen, themozolomide and the like. Nitrosoureas include, but are
not limited to carmustine (BiCNU.RTM.), lomustine (CeeNU.RTM.) and
the like. Antimetabolites include, but are not limited to,
5-fluorouracil, capecitabine, methotrexate, gemcitabine,
cytarabine, fludarabine and the like. Anthracyclins include but are
not limited to daunorubicin, doxorubicin, epirubicin, idarubicin,
mitoxantrone and the like. Topoisomerase II inhibitors include, but
are not limited to, topotecan, irinotecan, etopiside (VP-16),
teniposide and the like. Mitotic inhibitors include, but are not
limited to taxanes (paclitaxel, docetaxel), and the vinca alkaloids
(vinblastine, vincristine, and vinorelbine) and the like.
[0306] In more specific embodiments, the additional anti-cancer
agent, anti-proliferative agent or chemotherapeutic agent that may
be used in combination with a compound of Formula (I) or a form
thereof described herein includes, and is not limited to
aflibercept, amsacrine, bleomycin, busulfan, capecitabine,
carboplatin, carmustine, chlorambucil, cisplatin, cladribine,
clofarabine, crisantaspase, cyclophosphamide, cytarabine,
dacarbazine, dactinomycin, daunorubicin (IV and liposomal),
docetaxel, doxorubicin (IV and liposomal), enzastaurin, epirubicin,
etoposide, fludarabine, 5-fluorouracil (5-FU), gemcitabine, gliadel
implants, hydroxycarbamide, idarubicin, ifosfamide, imatinib
mesylate, irinotecan, lanreotide, lenalidomide, leucovorin,
lomustine, melphalan, mercaptopurine, mesna, methotrexate,
mitomycin, mitoxantrone, octreotide, oxaliplatin, paclitaxel,
pemetrexed, pentostatin, procarbazine, raltitrexed, satraplatin,
sorafenib, streptozocin, sunitinib, tegafur-uracil, temozolomide,
teniposide, thalidomide, thiotepa, tioguanine, topotecan,
treosulfan, vatalanib, vinblastine, vincristine, vindesine,
vinorelbine, volitinib, ZD6474, monoclonal antibodies (such as
bevacizumab, cetuximab, IMC-A12, IMC-1121B, medi-522, rituximab and
the like), hormonal agents (such as anastrozole, bicalutamide,
buserelin, cyproterone, diethylstilbestrol, exemestane, flutamide,
goserelin (breast and prostrate), letrozole, leuprorelin,
medroxyprogesterone, megestrol acetate, tamoxifen, toremifene,
triptorelin and the like), biological agents (such as interferon,
interleukin-12 and the like), angiogenesis receptor tyrosine kinase
(RTK) inhibitors (such as AE-941, angiostatin,
carboxyamidotriazole, cilengitide, endostatin, halofuginone
hydrobromide, 2-methoxyestradiol, squalamine lactate, SU6668 and
the like), tubulin binding agents (such as combretastatin A4
phosphate and the like), matrix metalloproteinase inhibitors (such
as BMS-275291 and the like) and/or serine/threonine/tyrosine kinase
inhibitors and an optional nonsteroidal or COX-2 anti-inflammatory
agents (such as celecoxib and the like) or corticosteroid (such as
prednisone and the like).
[0307] In more particular embodiments, one or more additional
anti-cancer, anti-proliferative or chemotherapeutic agents that may
be used in combination with a compound of Formula (I) or a form
thereof described herein is selected from bevacizumab, carboplatin,
cisplatin, docetaxel, doxorubicin, exemestane, gemcitabine,
5-fluorouracil, imatinib, irinotecan, sorafenib, sunitinib,
temozolomide, volitinib or combinations thereof.
[0308] In some embodiments, a compound of Formula (I) or a form
thereof described herein and one or more additional anti-cancer,
anti-proliferative or chemotherapeutic agents is used in
combination with radiation therapy comprising the use of x-rays,
gamma rays and other sources of radiation to destroy cancer cells
or tumor cells. In specific embodiments, the radiation therapy is
administered as external beam radiation or teletherapy, wherein the
radiation is directed from a remote source. In other embodiments,
the radiation therapy is administered as internal therapy or
brachytherapy wherein a radioactive source is placed close to
cancer cells, tumor cells and/or a tumor mass.
[0309] Currently available anti-cancer, anti-proliferative or
chemotherapeutic agents, their dosage regimens, routes of
administration and recommended usage alone or in combination are
known in the art and have been described in literature such as the
Physician's Desk Reference.
[0310] Any anti-cancer, anti-proliferative or chemotherapeutic
agent or anti-cancer therapy which is known to be useful, or which
has been used or is currently being used for the treatment of a
cancer mediated by Bmi-1, can be used in combination with compounds
of Formula (I) or a form thereof described herein. See, e.g.,
Gilman et al., Goodman and Gilman's: The Pharmacological Basis of
Therapeutics, 10th ed., McGraw-Hill, New York, 2001; The Merck
Manual of Diagnosis and Therapy, Berkow, M. D. et al. (eds.), 17th
Ed., Merck Sharp & Dohme Research Laboratories, Rahway, N J,
1999; Cecil Textbook of Medicine, 20th Ed., Bennett and Plum
(eds.), W.B. Saunders, Philadelphia, 1996, and Physician's Desk
Reference for information regarding cancer therapies (e.g., using
prophylactic or therapeutic agents) which have been or are
currently being used for preventing, treating and/or managing a
cancer mediated by Bmi-1.
Pharmaceutical Compositions
[0311] The present description is also directed to a pharmaceutical
composition comprising an effective amount of a compound of Formula
(I) or a form thereof in admixture with a pharmaceutically
acceptable excipient.
[0312] An embodiment described herein includes a pharmaceutical
composition made by the process of admixing a compound of Formula
(I) or a form thereof with a pharmaceutically acceptable excipient.
The pharmaceutical composition may also be formulated to achieve a
physiologically compatible pH of about pH 7, ranging from about pH
3 to about pH 11.
[0313] Another embodiment of the present includes the use of a
compound of Formula (I) or a form thereof in a pharmaceutical
composition for use in treating a cancer mediated by Bmi-1
comprising an effective amount of a compound of Formula (I) or a
form thereof in admixture with a pharmaceutically acceptable
excipient.
[0314] As used herein, the term "composition" means a product
comprising the specified ingredients in the specified amounts, as
well as any product which results, directly or indirectly, from
combination of the specified ingredients in the specified
amounts.
[0315] In another embodiment, the pharmaceutical composition may
comprise a combination product of one or more compounds of Formula
(I) or a form thereof described herein and one or more additional
agents useful in the treatment of a cancer mediated by Bmi-1, such
as an anti-cancer, anti-proliferative, chemotherapeutic or
biochemotherapeutic agent.
[0316] The term "pharmaceutically acceptable excipient" refers to a
pharmacologically inactive substance formulated for administration
with an active pharmaceutical agent, such as the compounds of
Formula (I) or a form thereof described herein. The term refers to
any pharmaceutical excipient that may be administered without undue
toxicity. Pharmaceutically acceptable excipients may be determined
in part by the particular composition being administered, as well
as by the particular mode of administration and/or dosage form.
Nonlimiting examples of pharmaceutically acceptable excipients
include carriers, solvents, stabilizers, adjuvants, diluents, etc.
Accordingly, there exists a wide variety of suitable formulations
of pharmaceutical compositions as described herein (see, e.g.,
Remington's Pharmaceutical Sciences).
[0317] Suitable excipients may be carrier molecules that include
large, slowly metabolized macromolecules such as proteins,
polysaccharides, polylactic acids, polyglycolic acids, polymeric
amino acids, amino acid copolymers, and inactive virus particles.
Other exemplary excipients include antioxidants such as ascorbic
acid; chelating agents such as EDTA; carbohydrates such as dextrin,
hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid;
liquids such as oils, water, saline, glycerol and ethanol; wetting
or emulsifying agents; pH buffering substances; and the like.
Liposomes are also included within the definition of
pharmaceutically acceptable excipients.
[0318] The pharmaceutical compositions described herein may be
formulated in any form suitable for the intended method of
administration. Suitable formulations for oral administration
include solids, liquid solutions, emulsions and suspensions, while
suitable inhaleable formulations for pulmonary administration
include liquids and powders. Alternative formulations include
syrups, creams, ointments, tablets, and lyophilized solids which
can be reconstituted with a physiologically compatible solvent
prior to administration.
[0319] When intended for oral use for example, tablets, troches,
lozenges, aqueous or oil suspensions, non-aqueous solutions,
dispersible powders or granules (including micronized particles or
nanoparticles), emulsions, hard or soft capsules, syrups or elixirs
may be prepared. Compositions intended for oral use may be prepared
according to any method known to the art for the manufacture of
pharmaceutical compositions, and such compositions may contain one
or more agents including sweetening agents, flavoring agents,
coloring agents and preserving agents, in order to provide a
palatable preparation.
[0320] Pharmaceutically acceptable excipients suitable for use in
conjunction with tablets include, for example, inert fillers, such
as celluloses, calcium or sodium carbonate, lactose, calcium or
sodium phosphate; disintegrating agents, such as croscarmellose
sodium, cross-linked povidone, maize starch, or alginic acid;
binding agents, such as povidone, starch, gelatin or acacia; and
lubricating agents, such as magnesium stearate, stearic acid or
talc. Tablets may be uncoated or may be coated by known techniques
including microencapsulation to delay disintegration and adsorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period.
[0321] Formulations for oral use may be also presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example celluloses, lactose, calcium phosphate
or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with non-aqueous or oil medium, such as
glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid
paraffin or olive oil.
[0322] In other embodiments, pharmaceutical compositions described
herein may be formulated as suspensions comprising a compound of
Formula (I) or a form thereof described herein in admixture with at
least one pharmaceutically acceptable excipient suitable for the
manufacture of a suspension. In yet other embodiments,
pharmaceutical compositions described herein may be formulated as
dispersible powders and granules suitable for preparation of a
suspension by the addition of one or more excipient(s).
[0323] Excipients suitable for use in connection with suspensions
include suspending agents, such as sodium carboxymethylcellulose,
methylcellulose, hydroxypropyl methylcelluose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or
wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycethanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate); and
thickening agents, such as carbomer, beeswax, hard paraffin or
cetyl alcohol. The suspensions may also contain one or more
preservatives such as acetic acid, methyl and/or n-propyl
p-hydroxy-benzoate; one or more coloring agents; one or more
flavoring agents; and one or more sweetening agents such as sucrose
or saccharin.
[0324] The pharmaceutical compositions described herein may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, such as olive oil or arachis oil, a mineral oil,
such as liquid paraffin, or a mixture of these. Suitable
emulsifying agents include naturally-occurring gums, such as gum
acacia and gum tragacanth; naturally occurring phosphatides, such
as soybean lecithin, esters or partial esters derived from fatty
acids; hexitol anhydrides, such as sorbitan monooleate; and
condensation products of these partial esters with ethylene oxide,
such as polyoxyethylene sorbitan monooleate. The emulsion may also
contain sweetening and flavoring agents. Syrups and elixirs may be
formulated with sweetening agents, such as glycerol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative, a flavoring or a coloring agent.
[0325] Additionally, the pharmaceutical compositions described
herein may be in the form of a sterile injectable preparation, such
as a sterile injectable aqueous emulsion or oleaginous suspension.
Such emulsion or suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally acceptable diluent or
solvent, such as a solution in 1,2-propane-diol. The sterile
injectable preparation may also be prepared as a lyophilized
powder. Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution, isotonic sodium chloride
solution and the like. In addition, sterile fixed oils may be
employed as a solvent or suspending medium. For this purpose any
bland fixed oil may be employed including synthetic mono- or
di-glycerides. In addition, fatty acids such as oleic acid may
likewise be used in the preparation of injectables.
[0326] The compounds of Formula (I) or a form thereof described
herein may be substantially modified by substitutions or additions
of chemical or biochemical moieties which make them more suitable
for delivery (e.g., increase solubility, bioactivity, palatability,
decrease adverse reactions, etc.), for example by esterification,
glycosylation, PEGylation and the like.
[0327] In some embodiments, the compound of Formula (I) or a form
thereof described herein is formulated for oral administration in
formulations that enhance the oral bioavailability of such
compounds of Formula (I) or a form thereof. As such, pharmaceutical
compositions described herein may comprise a effective amount of a
compound of Formula (I) or a form thereof, together with at least
one pharmaceutically acceptable excipient selected from medium
chain fatty acids or propylene glycol esters thereof (e.g.,
propylene glycol esters of edible fatty acids such as caprylic and
capric fatty acids) and pharmaceutically acceptable surfactants,
such as polyoxyl 40 hydrogenated castor oil and the like.
[0328] In other embodiments, the bioavailability of a compound of
Formula (I) or a form thereof may be enhanced by using particle
size optimization techniques including, but not limited to, the
preparation of nanoparticles or nanosuspensions using techniques
known to those skilled in art. The compound forms present in such
preparations include amorphous, partially amorphous, partially
crystalline or crystalline forms.
[0329] In alternative embodiments, the pharmaceutical composition
may further comprise one or more aqueous solubility enhancer(s),
such as a cyclodextrin. Nonlimiting examples of cyclodextrin
include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and
maltotriosyl derivatives of .alpha.-, .beta.-, and
.gamma.-cyclodextrin, and hydroxypropyl-.beta.-cyclodextrin (HPBC).
In some embodiments, the pharmaceutical composition further
comprises HPBC in a range of from about 0.1% to about 20%, from
about 1% to about 15%, or from about 2.5% to about 10%. The amount
of solubility enhancer employed may depend on the amount of the
active pharmaceutical ingredient in the composition.
General Synthetic Examples
[0330] As disclosed herein, the methods for preparing the compounds
of Formula (I) or a form thereof described herein commonly use
standard, well-known synthetic methodology. Many of the starting
materials are commercially available or can be prepared in the
Specific Synthetic Examples that follow using techniques known to
those skilled in the art. Functional transformations to modify
substituents may also be undertaken where chemically feasible and
are considered to be included within the scope of the General
Schemes and the knowledge of a person of ordinary skill in the art.
Compounds of Formula (I) or a form thereof can be prepared as
described in the Schemes below.
##STR00055##
[0331] An amine substituted Compound A1 (wherein X.sub.1 represents
a halogen atom selected from bromo, chloro or iodo) is coupled with
various substituted aryl, heteroaryl or heterocyclyl amines
(wherein PG represents an optionally present protecting group
monosubstituted on the amine) in the presence of a strong base
(such as KOtBu, NaOtBu, NaO.sup.tAm, NaH, NaHMDS and the like) in a
solvent (such as THF, DMF and the like) to provide a Compound
A2.
[0332] When one or both of R.sub.2 and R.sub.3 are optionally
halogen, the product Compound A2 is obtained as a mixture of
regioisomers, wherein the term "Sep" refers to isolating the
desired Compound A2 isomer to be carried forward from the mixture
using separation techniques known to those of ordinary skill in the
art, followed by deprotection.
[0333] Alternatively, Compound A2 may be prepared by reacting
Compound A1 with various substituted aryl, heteroaryl or
heterocyclyl amines (wherein the protecting group is absent) in the
presence of a mixture of a phosphino ligand:palladium source
(wherein the palladium source is selected from Pd.sub.2(dba).sub.3,
PdCl.sub.2(allyl), PdCl.sub.2(ACN), [Pd(OAc).sub.2].sub.3 and the
like and the phosphino ligand is selected from PCy.sub.3, Q-Phos,
XPhos and the like; alternatively, a commercially available
catalyst such as Pd(dppf)Cl.sub.2, Pd(PPh.sub.3).sub.4 and the like
may be used), followed by separation as needed.
[0334] Compound A3 may be prepared by reacting Compound A2 with a
substituted ortho-halo-nitro benzene (wherein X.sub.1 represents a
halogen atom selected from bromo, chloro or iodo) in the presence
of a transition metal catalyst (such as a catalyst containing a
metal selected from copper, palladium and the like).
[0335] Alternatively, Compound A3 may be prepared by reacting
Compound A2 with the substituted ortho-halo-nitro benzene (wherein
X.sub.2 represents a halogen atom selected from bromo, chloro,
fluoro or iodo) in the presence of a strong base (such as KOtBu,
NaOtBu, NaO.sup.tAm, NaH, NaHMDS and the like) in a solvent (such
as THF, DMF and the like).
[0336] Compound A4 is prepared by reacting Compound A3 in the
presence of hydrogen and a catalyst (such as nickel, platinum,
palladium on carbon and the like).
[0337] Compound A6 is prepared by condensation of Compound A4 with
an orthoester Compound A5 (wherein Rb represents an additional
optional R.sub.5 substituent and Rc represents C.sub.1-3alkyl).
Compound A6 may also be prepared by cyclizing Compound A4 with a
variety of reactants to obtain the addition of the optional R.sub.5
substituent. For example, the reactant may be TCDI, wherein the
additional optional R.sub.5 substituent is a thio-carbonyl which
may be further substituted.
##STR00056##
[0338] Alternatively, Compound A3 is prepared by cross-coupling of
Compound A7 (wherein X.sub.1 represents a halogen atom selected
from bromo, chloro or iodo) with a nitro substituted amine Compound
A8 (wherein Ar represents an aromatic or heteroaromatic ring; and,
wherein Ra represents one, two or three optional R.sub.5
substituents) via a palladium catalyzed cross-coupling reaction
using a mixture of a phosphino ligand:palladium source (wherein the
palladium source is selected from Pd.sub.2(dba).sub.3,
PdCl.sub.2(allyl), PdCl.sub.2(ACN), [Pd(OAc).sub.2].sub.3 and the
like and the phosphino ligand is selected from PCy.sub.3, Q-Phos,
XPhos and the like; alternatively, a commercially available
catalyst such as Pd(dppf)Cl.sub.2, Pd(PPh.sub.3).sub.4 and the like
may be used).
[0339] When one or both of R.sub.2 and R.sub.3 are optionally
halogen, the product Compound A3 is obtained as a mixture of
regioisomers, wherein the term "Sep" refers to isolating the
desired Compound A3 isomer to be carried forward from the mixture
using separation techniques known to those of ordinary skill in the
art.
##STR00057##
[0340] Compound B1 is prepared by condensation of a substituted
2-amino-pyridine (wherein Ra represents one, two or three optional
R.sub.5 substituents) with an .alpha.-halogenated ketoester
(wherein Rb represents an additional optional R.sub.5 substituent
and Rc represents C.sub.1-3alkyl).
[0341] Compound B2 is prepared by treating Compound B1 with an
ammonia source (such as NH.sub.4Cl, NH.sub.3 and the like) in the
presence of an organoaluminum reagent (such AlMe.sub.3 in toluene
and the like).
[0342] Compound B3 (wherein X.sub.1 represents a halogen atom
selected from bromo, chloro or iodo) is prepared by condensation of
Compound B2 with a substituted alkyl ester (such as a .beta.-keto
ester or a substituted acrylate in a solvent such as phenyl ether
and the like; wherein X.sub.3 represents a leaving group such as
C.sub.1-3alkoxy, benzoxy or halogen) followed by reflux in the
presence of a halogenation reagent (such as POCl.sub.3, POBr.sub.3
and the like).
[0343] Compound B4 is prepared by coupling Compound B3 with various
substituted aryl, heteroaryl or heterocyclyl amines (wherein PG
represents an optionally present protecting group monosubstituted
on the amine) in the presence of a strong base (such as KOtBu,
NaOtBu, NaO.sup.tAm, NaH, NaHMDS and the like) in a solvent (such
as THF, DMF and the like).
[0344] Alternatively, Compound B4 may be prepared by reacting
Compound B3 with a substituted aryl, heteroaryl or heterocyclyl
amine (wherein the protecting group is absent) via a palladium
catalyzed cross-coupling reaction using a mixture of a phosphino
ligand:palladium source (wherein the palladium source is selected
from Pd.sub.2(dba).sub.3, PdCl.sub.2(allyl), PdCl.sub.2(ACN),
[Pd(OAc).sub.2].sub.3 and the like and the phosphino ligand is
selected from PCy.sub.3, Q-Phos, XPhos and the like; alternatively,
a commercially available catalyst such as Pd(dppf)Cl.sub.2,
Pd(PPh.sub.3).sub.4 and the like may be used).
##STR00058##
[0345] Compound C1 is prepared by condensation of a substituted
2-amino-pyridine (wherein Ra represents one, two or three optional
R.sub.5 substituents) and an .alpha.-halogenated ketone (wherein
X.sub.4 represents a leaving group such as chloro or bromo and Rb
represents an additional optional R.sub.5 substituent) at reflux in
an organic solvent (such as acetonitrile and the like).
[0346] Compound C2 is prepared by reacting Compound C1 with a
substituted pyrimidine compound (wherein X.sub.1 represents a
halogen atom selected from bromo, chloro or iodo) via a palladium
catalyzed cross-coupling reaction using a mixture of a phosphino
ligand:palladium source (wherein the palladium source is selected
from Pd.sub.2(dba).sub.3, PdCl.sub.2(allyl), PdCl.sub.2(ACN),
[Pd(OAc).sub.2].sub.3 and the like and the phosphino ligand is
selected from PCy.sub.3, Q-Phos, XPhos and the like; alternatively,
a commercially available catalyst such as Pd(dppf)Cl.sub.2,
Pd(PPh.sub.3).sub.4 and the like may be used) and at least 2
equivalents of a base (such as cesium acetate and the like) in an
organic solvent (such as dimethylacetamide and the like),
undergoing Heck coupling. The reaction may be carried out at
elevated temperatures up to 100.degree. C.
[0347] Compound C3 is prepared by treating Compound C2 with a
deprotection reagent (such as 20-40% TFA in DCM and the like) at
ambient or elevated temperature.
##STR00059##
[0348] Compound D1 is prepared by a condensation reaction with a
substituted malonate compound and an amidated R.sub.1 group in
solution with a sodium alkoxide-solvent mixture (such as NaOMe in
MeOH or NaOEt in EtOH and the like).
[0349] Compound D2 (wherein X.sub.1 represents a halogen atom
selected from bromo, chloro or iodo) is prepared by refluxing
Compound D1 in the presence of a halogenation reagent (such as
POCl.sub.3, POBr.sub.3 and the like).
[0350] Compound D3 is prepared by mono-amination of Compound D2
with various substituted aryl, heteroaryl or heterocyclyl amines in
a solvent (wherein the solvent is selected from EtOH, THF, DMF,
mixtures thereof and the like).
[0351] Compound D4 is prepared by treating Compound D3 with an
aqueous ammonia source in a mixture with a solvent (wherein the
solvent is selected from CH.sub.3CN, DMSO, mixtures thereof and the
like).
##STR00060## ##STR00061##
[0352] A 2-methylsulfonyl substituted Compound E2 is prepared by
reacting a 2-methylthio substituted pyrimidine Compound E1 (wherein
X.sub.1 represents a halogen atom selected from bromo, chloro or
iodo and Rc represents C.sub.1-3alkyl) with an oxidizing agent
(such as mCPBA, MPS and the like) in a solvent (such as
CH.sub.2Cl.sub.2 and the like) at a suitable temperature.
[0353] Compound E4 is prepared by reacting Compound E2 with a nitro
substituted amine Compound E3 (wherein Ar represents an aromatic or
heteroaromatic ring; and, wherein Ra represents one, two or three
optional R.sub.5 substituents) in the presence of a strong base
(such as KOtBu, NaOtBu, NaO.sup.tAm, NaH, NaHMDS and the like) in a
solvent (such as THF, DMF and the like). The amine substituent on
Compound E3 may be optionally monosubstituted on the amine with a
protecting group.
[0354] Compound E5 is prepared by reacting Compound E4 in the
presence of hydrogen and a catalyst (such as nickel, platinum,
palladium on carbon and the like).
[0355] Compound E6 is prepared by condensation of Compound E5 with
an orthoester Compound A5 (wherein Rb represents an additional
optional R.sub.5 substituent and Rc represents C.sub.1-3alkyl).
Compound E6 may also be prepared by cyclizing Compound E5 with a
variety of reactants to obtain the addition of an optional R.sub.5
substituent. For example, the reactant may be TCDI, wherein the
additional optional R.sub.5 substituent is a thio-carbonyl which
may be further substituted.
[0356] Compound E7 may be prepared by reacting Compound E6 with
various substituted aryl, heteroaryl or heterocyclyl amines in a
solvent (wherein the solvent is selected from EtOH, THF, DMF,
mixtures thereof and the like).
[0357] When R.sub.3 is optionally halogen, the product Compound E7
is obtained as a mixture of regioisomers, wherein the term "Sep"
refers to isolating the desired Compound E7 isomer to be carried
forward from the mixture using separation techniques known to those
of ordinary skill in the art, followed by deprotection.
##STR00062##
[0358] Alternatively, Compound E7 may be prepared by reacting
Compound E6 with a substituted aryl, heteroaryl or heterocyclyl
amine or amide (wherein the protecting group is absent) via a
palladium catalyzed cross-coupling reaction using a mixture of a
phosphino ligand:palladium source (wherein the palladium source is
selected from Pd.sub.2(dba).sub.3, PdCl.sub.2(allyl),
PdCl.sub.2(ACN), [Pd(OAc).sub.2].sub.3 and the like and the
phosphino ligand is selected from PCy.sub.3, Q-Phos, XPhos and the
like; alternatively, a commercially available catalyst such as
Pd(dppf)Cl.sub.2, Pd(PPh.sub.3).sub.4 and the like may be
used).
##STR00063##
[0359] Compound E9 may be prepared directly by reacting Compound E2
with a Compound E8 (such as an R.sub.1 substituent having an acidic
proton group, wherein X.sub.5 represents a reactive hydrogen atom)
in the presence of a strong base (such as KOtBu, NaOtBu,
NaO.sup.tAm, NaH, NaHMDS and the like). Compound E9 may be carried
forward in place to Compound E6 to provide a Compound of Formula
(I).
##STR00064##
[0360] Compound F1 is prepared by reacting Compound E1 (wherein
X.sub.1 represents a halogen atom selected from bromo, chloro or
iodo and Rc represents C.sub.1-3alkyl) with a substituted aryl,
heteroaryl or heterocyclyl amine (wherein PG represents an
optionally present protecting group monosubstituted on the amine)
in the presence of a strong base (such as KOtBu, NaOtBu,
NaO.sup.tAm, NaH, NaHMDS and the like) in a solvent (such as THF,
DMF and the like) at a suitable temperature.
[0361] When R.sub.3 is optionally halogen, the product Compound F1
is obtained as a mixture of regioisomers, wherein the term "Sep"
refers to isolating the desired Compound F1 isomer to be carried
forward from the mixture using separation techniques known to those
of ordinary skill in the art.
[0362] Alternatively, Compound F1 is prepared by reacting Compound
E1 with a substituted aryl, heteroaryl or heterocyclyl amine or
amide (wherein the protecting group is absent) via a palladium
catalyzed cross-coupling reaction using a mixture of a phosphino
ligand:palladium source (wherein the palladium source is selected
from Pd.sub.2(dba).sub.3, PdCl.sub.2(allyl), PdCl.sub.2(ACN),
[Pd(OAc).sub.2].sub.3 and the like and the phosphino ligand is
selected from PCy.sub.3, Q-Phos, XPhos and the like; alternatively,
a commercially available catalyst such as Pd(dppf)Cl.sub.2,
Pd(PPh.sub.3).sub.4 and the like may be used).
[0363] Compound F2 is prepared by reacting Compound F1 with an
oxidizing agent (such as mCPBA, MPS and the like) in a solvent
(such as CH.sub.2Cl.sub.2 and the like).
[0364] Compound F2 may be reacted with a Compound E8 (such as an
R.sub.1 substituent having an acidic proton group, wherein X.sub.5
represents a reactive hydrogen atom) in the presence of a strong
base (such as KOtBu, NaOtBu, NaO.sup.tAm, NaH, NaHMDS and the like)
to provide a Compound F3, representative of a Compound of Formula
(I).
[0365] When R.sub.2 is halogen, Compound F3 may be treated with a
substituted amine in a mixture with a solvent (wherein the solvent
is selected from CH.sub.3CN, DMSO, mixtures thereof and the like)
to provide a Compound F4, representative of a Compound of Formula
(III).
##STR00065##
[0366] Compound G1 may be reacted with an oxidizing agent (such as
mCPBA, MPS and the like) to provide a Compound G2, representative
of a Compound of Formula (IV).
##STR00066##
[0367] A Compound H3 is prepared by reacting a Compound H1 (wherein
X.sub.1 represents a halogen atom selected from bromo, chloro or
iodo) with a Compound H2 (wherein R.sub.1 is a substituted
heteroaromatic or heterocyclic monocyclic or bicyclic ring system
and X.sub.6 represents a reactive group such as a boronic acid,
boronate ester, trialkyltin, zinc chloride and the like attached to
a carbon atom of R.sub.1), in the presence of a mixture of a
phosphino ligand:palladium source (wherein the palladium source is
selected from Pd.sub.2(dba).sub.3, PdCl.sub.2(allyl),
PdCl.sub.2(ACN), [Pd(OAc).sub.2].sub.3 and the like and the
phosphino ligand is selected from PCy.sub.3, Q-Phos, XPhos and the
like; alternatively, a commercially available catalyst such as
Pd(dppf)Cl.sub.2, Pd(PPh.sub.3).sub.4 and the like may be
used).
[0368] When one or both of R.sub.2 and R.sub.3 are optionally
halogen, the product Compound H3 may be obtained as a mixture of
regioisomers, wherein the term "Sep" refers to isolating the
desired Compound H3 isomer to be carried forward from the mixture
using separation techniques known to those of ordinary skill in the
art.
[0369] Compound F3 is prepared by reacting Compound H3 with various
substituted aryl, heteroaryl or heterocyclyl amines in a solvent
(wherein PG represents an optionally present protecting group
monosubstituted on the amine; and, wherein the solvent is selected
from EtOH, THF, DMF, mixtures thereof and the like), followed by
separation and deprotection as needed.
##STR00067##
[0370] Alternatively, Compound F3 is prepared by reacting a
Compound H3 with various substituted aryl, heteroaryl or
heterocyclyl amines or amides in the presence of a mixture of a
phosphino ligand:palladium source (wherein the palladium source is
selected from Pd.sub.2(dba).sub.3, PdCl.sub.2(allyl),
PdCl.sub.2(ACN), [Pd(OAc).sub.2].sub.3 and the like and the
phosphino ligand is selected from PCy.sub.3, Q-Phos, XPhos and the
like; alternatively, a commercially available catalyst such as
Pd(dppf)Cl.sub.2, Pd(PPh.sub.3).sub.4 and the like may be used).
When a Compound H3 is reacted with an amide, the resulting
intermediate product is hydrolyzed under basic conditions with a
reagent (such as NaOH, KOH, LiOH and the like) at a suitable
temperature, followed by separation as needed to obtain product
Compound F3.
##STR00068##
[0371] Alternatively, Compound H3 may be prepared via a Heck
reaction of Compound H1 with Compound E8, followed by separation as
needed.
##STR00069##
[0372] Alternatively, Compound F3 is prepared by reacting Compound
H7 with a substituted Compound H2 (wherein R.sub.1 is a substituted
heteroaromatic or heterocyclic monocyclic or bicyclic ring system
and X.sub.6 represents a reactive group such as a boronic acid,
boronate ester, trialkyltin, zinc chloride and the like attached to
a carbon atom of R.sub.1).
##STR00070##
[0373] Alternatively, Compound F3 may be prepared via a Heck
reaction of Compound H7 with Compound E8 (wherein X.sub.5
represents a reactive hydrogen group), followed by separation as
needed.
##STR00071##
[0374] Compound F3 is prepared by reacting a substituted Compound
I1 with a Compound I2 (such as various substituted aryl, heteroaryl
or heterocyclyl ring systems, wherein X.sub.1 represents a halogen
atom selected from bromo, chloro or iodo) in the presence of a
transition metal catalyst (such as a catalyst containing a metal
selected from copper, palladium and the like).
##STR00072##
[0375] Compound F3 is prepared by reacting a substituted Compound
I1 with a Compound I3 (such as various substituted aryl, heteroaryl
or heterocyclyl ring systems, wherein X.sub.7 represents a ketone
or aldehyde leaving group) in the presence of a borohydride (such
as NaCNBH.sub.3 or NaBH(OAc).sub.3 and the like).
Specific Synthetic Examples
[0376] To assist in understanding the scope of the compounds of
Formula (I) or a form thereof described herein, the following
Specific Examples are included. The experiments relating to the
compounds of Formula (I) or a form thereof described herein should
not, of course, be construed as specifically limiting the scope of
the compounds of Formula (I) or a form thereof described herein and
such variations of the compounds of Formula (I) or a form thereof
as described herein, now known or later developed, which would be
within the purview of one skilled in the art are considered to fall
within the scope as described herein and hereinafter claimed.
[0377] Other than in the working examples, unless indicated to the
contrary, all numbers expressing quantities of ingredients,
reaction conditions, experimental data, and so forth used in the
specification and claims are to be understood as being modified by
the term "about". Accordingly, all such numbers represent
approximations that may vary depending upon the desired properties
sought to be obtained by a reaction or as a result of variable
experimental conditions. Therefore, within an expected range of
experimental reproducibility, the term "about" in the context of
the resulting data, refers to a range for data provided that may
vary according to a standard deviation from the mean. As well, for
experimental results provided, the resulting data may be rounded up
or down to present data consistently, without loss of significant
figures. At the very least, and not as an attempt to limit the
application of the doctrine of equivalents to the scope of the
claims, each numerical parameter should be construed in light of
the number of significant digits and ordinary rounding
techniques.
[0378] While the numerical ranges and parameters setting forth the
characterization of the compounds of Formula (I) or a form thereof
described herein are approximations, the numerical values set forth
in the working examples are reported as precisely as possible. Any
numerical value, however, inherently contains certain errors
necessarily resulting from the standard deviation found in their
respective testing measurements.
[0379] The compounds of Formula (I) or a form thereof provided
herein are described in more detail with reference to the following
non-limiting examples, which are offered to more fully illustrate
the scope of the compounds of Formula (I) or a form thereof
described herein, but are not to be construed as limiting the scope
thereof. The examples illustrate the preparation of compounds of
Formula (I) or a form thereof described herein, and the testing of
these compounds of Formula (I) or a form thereof in vitro and/or in
vivo. Those of skill in the art will understand that the synthesis
techniques described in these examples represent techniques that
fall within the practice of those having ordinary skill in the
chemical arts, and as such constitute preferred modes for the
practice thereof. However, it should be appreciated that those
having skill in the art should, in light of the present disclosure,
appreciate that many changes can be made in the specific methods
that are disclosed herein while still obtaining a like or similar
result without departing from the spirit and scope described
herein.
[0380] The reagents and solvents were used as purchased (from a
variety of vendors), except where noted. Where applicable, the term
"Celite" is used as shown in the following examples to represent
the tradename CELITE.RTM. (brand of diatomaceous earth). Where
applicable, chromatographic separations were performed using
techniques and equipment commonly available such as, for example,
by using an ISCO CombiFlash.RTM. Rf system. Where applicable, NMR
spectra were obtained using techniques and equipment commonly
available such as, for example, by using a Bruker Avance
III.sup.500 spectrometer with deuterated solvents such as, for
example, DMSO-d.sub.6 or residual solvent as standard. Where
applicable, melting points were determined using techniques and
equipment commonly available such as, for example, by using a SRS
OptiMelt.RTM. MPA100 (values as obtained without
correction/calibration). Where applicable, TLC analysis was
performed using techniques and equipment commonly available such
as, for example, by using Aldrich 254 nm glass-backed plates (60
.ANG., 250 .mu.m), visualized using UV and I.sub.2 stains. Where
applicable, ESI mass spectra were obtained using techniques and
equipment commonly available such as, for example, by using an
ACQUITY UPLC.RTM. System, with values shown as [M+H].sup.+ or
[M-H].sup.-, unless otherwise indicated. Where applicable, the
structure of the product was obtained via a 2D NOESY (Nuclear
Overhauser SpectroscopY) experiment.
[0381] The following abbreviations are provided to ensure the terms
used herein are unambiguous to one skilled in the art:
TABLE-US-00002 Abbreviation Meaning AcOH or HOAc acetic acid ACN or
MeCN acetonitrile AlMe.sub.3 trimethylaluminum APC allylpalladium
(II) chloride dimer Boc tert-butoxycarbonyl CsOAc cesium acetate
DCM or CH.sub.2Cl.sub.2 dichloromethane DME dimethyl ether DMF
dimethyl formamide DMA dimethylacetamide DMAP
4-dimethylaminopyridine DMSO dimethylsulfoxide EtOAc ethyl acetate
EtOH ethanol HPLC high performance liquid chromatography h, hr, mm,
s hour (h or hr), minute (min), second (s) iPrMgCl*LiCl
isopropylmagnesium chloride lithium chloride complex iPrOAc
isopropyl acetate K.sub.2CO.sub.3 potassium carbonate
K.sub.3PO.sub.4 potassium phosphate KOtBu or t-BuOK potassium
tert-butoxide LC/MS, LCMS or LC-MS liquid chromatographic mass
spectroscopy MeOH methanol MeNH.sub.2 .times. HCl methanamine
hydrochloride MS mass spectroscopy m.p. melting point (shown in
.degree. Centigrade) MPS potassium peroxymonosulfate
(2KHSO.sub.5.cndot.KHSO.sub.4.cndot.K.sub.2SO.sub.4) NaH sodium
hydride NaHCO.sub.3 sodium bicarbonate NaHMDS sodium
hexamethyldisilazide NaIO.sub.4 sodium periodate NaOH sodium
hydroxide NaOtAm sodium tert-pentoxide NaOMe sodium methoxide NaOEt
sodium ethoxide NaOtBu sodium tert-butoxide NCS N-chlorosuccinimide
NH.sub.4Cl ammonium chloride NH.sub.4OH ammonium hydroxide NIS
N-iodosuccinimide NMP N-methylpyrrolidone NMR nuclear magnetic
resonance Oxone potassium peroxymonosulfate PCl.sub.5 phosphorus
perchloride or phosphorus pentachloride PCy.sub.3
tricyclohexylphosphine [Pd] palladium Pd/C .degree. palladium on
carbon Pd.sub.2(dba).sub.3 or Pd.sub.2dba.sub.3
tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)
PdCl.sub.2(ACN) bis(acetonitrile)dichloropalladium(II)
PdCl.sub.2(allyl) chloroallylpalladium(II) dimer
[Pd(OAc).sub.2].sub.3 palladium (II) acetate Pd(PPh.sub.3).sub.4
tetrakis(triphenylphosphine)palladium POCl.sub.3 phosphorus
oxychloride PPh.sub.3 triphenylphosphine psi pounds per square inch
pressure Pt/C platinum on carbon PTSA p-toluenesulfonic acid Q-Phos
or QPhos 1,2,3,4,5-pentaphenyl-1'-(di-tert-
butylphosphino)ferrocene RT room temperature TBSO or OTBS
tert-butyldimethylsilyloxy TCDI 1,1'-thiocarbonyldiimidazole t-Bu
tert-butyl TEA, NEt.sub.3, Et.sub.3N triethylamine TFA
trifluoroacetic acid TFAA trifluoroacetic anhydride THF
tetrahydrofuran TsOH X H.sub.2O p-toluenesulfonic acid monohydrate
UPLC Ultra Performance Liquid Chromatography Xphos or XPhos
2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl
Example 1
N-(1,3-benzodioxol-5-yl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-
pyrimidin-4-amine (Cpd 28)
##STR00073##
[0383] Step 1. To a solution of ethyl
4,4,4-trifluoro-3-oxobutanoate (9.0 g, 48.9 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was added bromine (2.5 mL, 49 mmol). The
reaction mixture was stirred for 15 hours at room temperature, and
then concentrated under dry nitrogen. To the crude material in
ethanol (30 mL) was added pyridin-2-amine (5.2 g, 55 mmol). The
reaction mixture was heated at 60.degree. C. for 3 hours. The
ethanol was evaporated, and the remainder was partitioned between
EtOAc and water. The organic layer was dried, filtered through a
short plug of silica gel, then concentrated under reduced pressure,
and purified by silica gel chromatography to provide ethyl
2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate as a white
solid (5.3 g, 42%).
[0384] Step 2. To a suspension of NH.sub.4Cl (2.67 g, 50 mmol) in
toluene (20 mL) at 0.degree. C. was added AlMe.sub.3 (2M solution
in toluene, 25 mL, 50 mmol) over about a 5 minute period followed
by gas evolution. The suspension was stirred at 0.degree. C. for 5
minutes, then warmed to room temperature. A solution of ethyl
2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (2.58 g, 10
mmol) in toluene (50 mL) was added to the suspension. The reaction
mixture was heated at 80.degree. C. for 72 hours and then cooled in
an ice-bath, quenched with MeOH (100 mL) and NaOH (2 g, 50 mmol).
The mixture was filtered through Celite, and concentrated to
provide crude
2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboximidamide as a
brownish solid (2.3 g).
[0385] Step 3. A mixture of
2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboximidamide (2.3 g,
10 mmol) and ethyl 3-(dimethylamino)acrylate (7.2 g, 50 mmol) in
diphenyl ether (10 mL) was heated at 160.degree. C. for 1 hour. The
mixture was cooled to room temperature and diluted with hexane (200
mL). The precipitate was filtered and washed with hexanes to
provide
2-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4(3H)-one
as a light brown solid. The solid was dissolved in acetonitrile (10
mL) and to the mixture was added POCl.sub.3 (1.9 mL, 20 mmol). The
reaction mixture was heated to 100.degree. C. for 30 minutes,
cooled in an ice-water bath, then diluted with dichloromethane (100
mL), and washed with an aqueous NaHCO.sub.3 solution. The organic
layer was dried, then filtered through Celite and purified by
silica gel chromatography to provide
3-(4-chloropyrimidin-2-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine
as a light yellow solid material (1.09 g, 37% over 3 steps).
[0386] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.61 (d,
J=6.9 Hz, 1H), 9.00 (d, J=5.0 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.73
(d, J=5.4 Hz, 1H), 7.69 (ddd, J=8.7, 7.1, 1.3 Hz, 1H), 7.37 (td,
J=7.0, 1.1 Hz, 1H).
[0387] Step 4. To a solution of
3-(4-chloropyrimidin-2-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine
(75 mg, 0.25 mmol) and benzo[d][1,3]dioxol-5-amine (69 mg, 0.5
mmol) in THF (1 mL) at 0.degree. C. was added KOtBu (1M solution in
THF, 1 mL, 1 mmol). After 10 minutes, the reaction mixture was
quenched with HOAc, then partitioned between EtOAc and water. The
organic portion was dried, then concentrated, and the remainder was
purified by silica gel chromatography to provide the title compound
as a tan solid (58 mg, 58%).
[0388] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.70 (s,
1H), 9.43 (d, J=6.6 Hz, 1H), 8.43 (d, J=5.7 Hz, 1H), 7.84 (d, J=9.1
Hz, 1H), 7.58 (ddd, J=9.1, 6.9, 1.1 Hz, 1H), 7.37 (br. s., 1H),
7.17 (td, J=6.9, 0.9 Hz, 1H), 6.95 (dd, J=8.2, 1.9 Hz, 1H), 6.91
(d, J=8.5 Hz, 1H), 6.72 (d, J=6.0 Hz, 1H), 6.03 (s, 2H); MS m/z 400
[M+H].sup.+.
[0389] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 1 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00003 Cpd Name & Data 2
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-methylimidazo
[1,2-a]pyridin-3-yl)pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.85 (dt, J = 6.9, 0.9 Hz, 1H), 9.45 (br.
s, 1H), 8.36 (d, J = 5.7 Hz, 1H), 7.60 (dt, J = 8.8, 0.9 Hz, 1H),
7.38 (ddd, J = 8.8, 6.6, 1.3 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H),
6.95-6.98 (m, 2H), 6.87 (dd, J = 4.4, 3.5 Hz, 1H), 6.54 (d, J = 6.0
Hz, 1H), 4.25-4.30 (m, 4H), 2.75 (s, 3H); MS m/z 360 [M + H].sup.+
3 2-(2-methylimidazo[1,2-a]pyridin-3-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 10.06 (br. s, 1H), 9.81 (dt, J = 6.9, 1.1 Hz, 1H), 8.53
(d, J = 5.7 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz,
2H), 7.63 (dt, J = 8.8, 1.1 Hz, 1H), 7.42 (ddd, J = 8.8, 6.6, 1.3
Hz, 1H), 7.03 (td, J = 6.9, 1.3 Hz, 1H), 6.74 (d, J = 5.7 Hz, 1H),
2.78 (s, 3H); MS m/z 370 [M + H].sup.+ 4
N-(4-methoxyphenyl)-2-(2-methylimidazo[1,2-a]pyridin-3-yl)
pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
9.84 (d, J = 6.6 Hz, 1H), 9.44 (br. s, 1H), 8.35 (d, J = 6.0 Hz,
1H), 7.59 (dt, J = 8.8, 0.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.37
(ddd, J = 8.9, 6.9, 1.3 Hz, 1H), 6.97-7.00 (m, 2H), 6.95 (td, J =
6.9, 0.9 Hz, 1H), 6.52 (d, J = 5.7 Hz, 1H), 3.78 (s, 3H), 2.73 (s,
3H); MS m/z 332 [M + H].sup.+ 5
N-(4-chlorophenyl)-2-(2-methylimidazo[1,2-a]pyridin-3-yl)
pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
9.81 (d, J = 6.9 Hz, 1H), 9.78 (br. s, 1H), 8.45 (d, J = 5.7 Hz,
1H), 7.67 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.44 (s,
2H), 7.40 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.01 (td, J = 6.9, 1.3
Hz, 1H), 6.64 (d, J = 6.0 Hz, 1H), 2.74 (s, 3H); MS m/z 336 [M +
H].sup.+ 6
2-(2-methylimidazo[1,2-a]pyridin-3-yl)-N-phenylpyrimidin-4- amine
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.85 (dt, J = 6.9,
0.9 Hz, 1H), 9.65 (br. s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 7.59-7.64
(m, 3H), 7.36-7.43 (m, 3H), 7.11 (tt, J = 7.4, 0.9 Hz, 1H), 6.98
(ddd, J = 7.5, 5.5, 0.9 Hz, 1H), 6.63 (d, J = 6.0 Hz, 1H), 2.75 (s,
3H); MS m/z 302 [M + H].sup.+ 7
2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.25 (br. s, 1H), 9.36 (d, J = 6.9 Hz,
1H), 8.59 (d, J = 5.7 Hz, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.86 (d, J
= 9.1 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.60 (ddd, J = 9.1, 6.9,
1.1 Hz, 1H), 7.21 (td, J = 6.9, 1.3 Hz, 1H), 6.92 (d, J = 5.7 Hz,
1H); MS m/z 424 [M + H].sup.+ 8
N-(4-chlorophenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin- 3-
yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 9.95 (br. s., 1H), 9.37 (d, J = 6.9 Hz, 1H), 8.52 (d, J = 5.7
Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.59
(t, J = 7.6 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.20 (t, J = 6.8 Hz,
1H), 6.83 (d, J = 6.0 Hz, 1H); MS m/z 390 [M + H].sup.+ 9
N-(4-methylphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-
3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 9.75 (br. s, 1H), 9.41 (d, J = 6.6 Hz, 1H), 8.45 (d, J = 6.0
Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.58 (t, J = 6.9 Hz, 1H), 7.53
(d, J = 7.6 Hz, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 6.9 Hz,
2H), 6.77 (d, J = 5.7 Hz, 1H), 2.31 (s, 3H); MS m/z 370 [M +
H].sup.+ 10
N-(4-bromophenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin- 3-
yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 9.97 (br. s, 1H), 9.37 (d, J = 6.9 Hz, 1H), 8.52 (d, J = 6.0
Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.59
(dd, J = 8.0, 6.9 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.20 (t, J =
6.9 Hz, 1H), 6.83 (d, J = 6.0 Hz, 1H); MS m/z 435 [M + H].sup.+ 11
N-[4-(difluoromethoxy)phenyl]-2-[2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. ppm 9.52 (dt, J = 7.3, 0.9 Hz, 1H), 8.38 (d,
J = 6.0 Hz, 1H), 7.72 (dt, J = 9.1, 0.9 Hz, 1H), 7.30-7.37 (m, 3H),
7.11 (d, J = 8.8 Hz, 2H), 6.93 (td, J = 6.9, 1.3 Hz, 1H), 6.87 (br.
s., 1H), 6.54 (d, J = 6.0 Hz, 1H), 6.46 (t, J = 73.8 Hz, 1H); MS
m/z 422 [M + H].sup.+ 12
N-(4-methoxyphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]
pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, CHLOROFORM-d)
.delta. ppm 9.63 (dt, J = 7.3, 0.9 Hz, 1H), 8.40 (d, J = 6.0 Hz,
1H), 7.79 (dt, J = 9.1, 0.9 Hz, 1H), 7.41 (ddd, J = 9.0, 6.8, 1.3
Hz, 1H), 7.24-7.33 (m, 2H), 7.00 (td, J = 6.9, 0.9 Hz, 1H),
6.94-6.98 (m, 2H), 6.91 (br. s, 1H), 6.50 (d, J = 6.0 Hz, 1H), 3.87
(s, 3H); MS m/z 386 [M + H].sup.+ 13
2-[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.24 (br. s., 1H), 9.56- 9.72 (m, 1H),
8.60 (d, J = 5.4 Hz, 1H), 7.83-7.98 (m, 3H), 7.63- 7.74 (m, 3H),
6.90 (d, J = 5.4 Hz, 1H); MS m/z 458 [M + H].sup.+ 14
2-[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethoxy)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. ppm 9.72-9.82 (m, 1H), 8.49 (d, J = 6.0 Hz,
1H), 7.65-7.77 (m, 1H), 7.46 (dd, J = 9.0, 2.7 Hz, 2H), 7.39 (dd, J
= 9.6, 2.0 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 6.84 (br. s, 1H),
6.64 (d, J = 6.0 Hz, 1H); MS m/z 474 [M + H].sup.+ 15
N-(4-bromophenyl)-2-[6-chloro-2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.96 (br. s, 1H), 9.60 (dd, J = 2.0, 0.8
Hz, 1H), 8.52 (d, J = 6.0 Hz, 1H), 7.92 (dd, J = 9.6, 0.8 Hz, 1H),
7.66 (dd, J = 9.6, 2.0 Hz, 1H), 7.61-7.64 (m, 2H), 7.50-7.55 (m,
2H), 6.81 (d, J = 6.0 Hz, 1H); MS m/z 469 [M + H].sup.+ 16
2-[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(difluoromethoxy)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. ppm 9.60-9.78 (m, 1H), 8.40 (dd, J = 6.0, 0.9
Hz, 1H), 7.66 (dd, J = 9.5, 0.6 Hz, 1H), 7.34 (dd, J = 8.8, 2.5 Hz,
2H), 7.31 (dd, J = 9.6, 2.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 6.76
(br. s, 1H), 6.54 (d, J = 6.0 Hz, 1H), 6.46 (t, J = 74.4 Hz, 1H);
MS m/z 456 [M + H].sup.+ 17
N-(4-chlorophenyl)-2-[6-chloro-2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. ppm 9.59-9.75 (m, 1H), 8.41 (dd, J = 6.0, 0.9
Hz, 1H), 7.66 (dd, J = 9.6, 0.8 Hz, 1H), 7.23-7.36 (m, 5H), 6.74
(br. s, 1H), 6.55 (dd, J = 6.0, 1.3 Hz, 1H); MS m/z 425 [M +
H].sup.+ 18
2-[2-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.33 (br. s, 1H), 10.26 (s, 1H), 8.59
(d, J = 6.0 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.88 (d, J = 11.0
Hz, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 6.85
(d, J = 6.0 Hz, 1H), 2.86 (s, 3H); MS m/z 438 [M + H].sup.+ 19
N-(4-bromophenyl)-2-[2-methyl-6-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.30 (s, 1H), 10.07 (br. s, 1H), 8.52
(d, J = 6.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.87-7.96 (m, 1H),
7.60 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 6.78 (d, J =
6.0 Hz, 1H), 2.83 (s, 3H); MS m/z 449 [M + H].sup.+ 20
N-(4-methylphenyl)-2-[2-methyl-6-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.28 (s, 1H), 9.83 (br. s, 1H), 8.44 (d,
J = 6.0 Hz, 1H), 7.92 (d, J = 9.3 Hz, 1H), 7.80 (d, J = 9.3 Hz,
1H), 7.47 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.70 (d, J
= 6.0 Hz, 1H), 2.81 (s, 3H), 2.30 (s, 3H); MS m/z 384 [M + H].sup.+
21 2-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-(4-
methylphenyl)pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.78 (s, 1H), 9.63 (br. s, 1H), 8.44 (d, J = 6.0 Hz,
1H), 7.94 (dd, J = 10.1, 5.4 Hz, 1H), 7.70 (ddd, J = 10.7, 7.9, 2.5
Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.74
(d, J = 8.8 Hz, 1H), 2.30 (s, 3H); MS m/z 388 [M + H].sup.+ 22
2-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-(4-
methoxyphenyl)pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.63 (br. s, 1H), 8.41 (d, J = 5.7 Hz, 1H), 7.94 (dd, J
= 9.9, 5.2 Hz, 1H), 7.69 (ddd, J = 10.0, 7.8, 2.4 Hz, 1H), 7.48 (d,
J = 8.2 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.75-6.82 (m, 1H), 6.68
(d, J = 6.0 Hz, 1H), 3.77 (s, 3H); MS m/z 404 [M + H].sup.+ 23
2-[5chloro-1-methyl-2-(trifluoromethyl)-1H-indol-3-yl]-N-(4-
methoxyphenyl)pyrimidin-4-amine .sup.1H NMR (500 MHz, CHLOROFORM-d)
.delta. ppm 8.27 (d, J = 6.3 Hz, 1H), 7.87 (d, J = 1.9 Hz, 1H),
7.56 (br. s, 1H), 7.26 (dd, J = 8.5, 1.9 Hz, 1H), 7.20 (d, J = 8.8
Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.73-6.80 (m, 2H), 6.42 (d, J =
6.0 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H); MS m/z 433 [M + H].sup.+
24 2-[5-chloro-1-methyl-2-(trifluoromethyl)-1H-indol-3-yl]-N-[4-
(difluoromethoxy)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.47 (br. s, 1H), 8.47 (d, J = 6.6 Hz,
1H), 7.98 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.74 (d, J
= 8.8 Hz, 2H), 7.50 (dd, J = 8.8, 1.9 Hz, 1H), 7.16 (d, J = 8.8 Hz,
2H), 7.18 (t, J = 74.4 Hz, 1H), 6.90 (d, J = 6.3 Hz, 1H), 4.00 (s,
3H); MS m/z 469 [M + H].sup.+ 25
N-(4-bromophenyl)-2-[5-chloro-1-methyl-2-(trifluoromethyl)-
1H-indol-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 10.24 (br. s, 1H), 8.49 (d, J = 6.0 Hz, 1H), 7.98 (d, J
= 2.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H),
7.43-7.52 (m, J = 8.5 Hz, 3H), 6.87 (d, J = 6.0 Hz, 1H), 4.00 (s,
3H); MS m/z 482 [M + H].sup.+ 26
N-(4-bromophenyl)-2-(6-fluoro-2-phenylimidazo[1,2-a]pyridin-
3-yl)pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 9.75 (br. s., 1H), 9.55 (d, J = 3.2 Hz, 1H), 8.49 (d, J = 5.4
Hz, 1H), 7.83 (dd, J = 8.8, 5.0 Hz, 1H), 7.67 (d, J = 7.9 Hz, 2H),
7.57 (td, J = 9.1, 1.6 Hz, 1H), 7.31-7.46 (m, J = 7.6 Hz, 3H),
7.01-7.21 (m, 4H), 6.72 (d, J = 5.7 Hz, 1H); MS m/z 461 [M +
H].sup.+ 27 2-(6-fluoro-2-phenylimidazo[1,2-a]pyridin-3-yl)-N-(4-
methylphenyl)pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.88 (br. s, 1H), 9.49-9.61 (m, 1H), 8.37 (d, J = 6.0
Hz, 1H), 7.90 (dd, J = 9.9, 5.2 Hz, 1H), 7.66-7.75 (m, 3H),
7.39-7.49 (m, 3H), 7.14 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.2 Hz,
2H), 6.74 (d, J = 6.3 Hz, 1H), 2.23 (s, 3H); MS m/z 396 [M +
H].sup.+ 29
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[2-(trifluoromethyl)
imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.63 (s, 1H), 8.42 (d, J = 5.7 Hz, 1H),
7.84 (dt, J = 9.1, 0.9 Hz, 1H), 7.58 (ddd, J = 9.0, 6.8, 1.3 Hz,
1H), 7.22 (br. s., 1H), 7.15 (td, J = 6.9, 1.3 Hz, 0H), 7.01 (dd, J
= 8.5, 2.2 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 6.0 Hz,
1H), 4.20-4.29 (m, 4H); MS m/z 410 [M + H].sup.+ 30
N-(6-methoxypyridin-3-yl)-2-[2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. ppm 9.53 (d, J = 6.9 Hz, 1H), 8.34 (d, J =
5.7 Hz, 1H), 8.10 (d, J = 2.5 Hz, 1H), 7.69 (dt, J = 9.1, 0.9 Hz,
1H), 7.65 (d, J = 7.6 Hz, 1H), 7.32 (ddd, J = 9.0, 6.8, 1.3 Hz,
1H), 6.91 (td, J = 7.0, 1.3 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 6.40
(d, J = 6.0 Hz, 1H), 3.90 (s, 3H); MS m/z 387 [M + H].sup.+ 31
N.sup.2,N.sup.2-dimethyl-N.sup.5-{2-[2-(trifluoromethyl)imidazo[1,2-a]-
pyridin- 3-yl]pyrimidin-4-yl}pyridine-2,5-diamine .sup.1H NMR (500
MHz, CHLOROFORM-d) .delta. ppm 9.55 (d, J = 6.9 Hz, 1H), 8.29 (d, J
= 6.0 Hz, 1H), 8.10 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 9.1 Hz, 1H),
7.51 (br. s, 1H), 7.32 (ddd, J = 9.1, 6.9, 1.1 Hz, 1H), 6.92 (td, J
= 6.9, 0.9 Hz, 1H), 6.81 (br. s, 0H), 6.51 (d, J = 9.1 Hz, 1H),
6.35 (d, J = 5.4 Hz, 1H), 3.08 (s, 6H); MS m/z 400 [M + H].sup.+ 32
2-[6-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.25 (br. s, 1H), 9.66 (dd, J = 1.9, 0.9
Hz, 1H), 8.60 (d, J = 6.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.87
(dd, J = 9.6, 0.8 Hz, 1H), 7.74 (dd, J = 9.5, 1.9 Hz, 1H), 7.69 (d,
J = 8.8 Hz, 2H), 6.90 (d, J = 6.0 Hz, 1H); MS m/z 503 [M + H].sup.+
33 2-[6-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-(4-
methoxyphenyl)pyrimidin-4-amine .sup.1H NMR (500 MHz, CHLOROFORM-d)
.delta. ppm 9.70-9.86 (m, 1H), 8.32 (d, J = 4.7 Hz, 1H), 7.60 (d, J
= 9.5 Hz, 1H), 7.40 (dd, J = 9.6, 1.7 Hz, 1H), 7.22 (d, J = 8.5 Hz,
2H), 6.89 (d, J = 8.8 Hz, 2H), 6.47 (br. s, 1H), 3.78 (s, 3H); MS
m/z 465 [M + H].sup.+ 34
N-(3-fluoro-4-methoxyphenyl)-2-[2-(trifluoromethyl)
imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.77 (s, 1H), 9.35 (d, J = 6.9 Hz, 1H),
8.42 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.68 (d, J =
13.6 Hz, 1H), 7.53 (ddd, J = 9.1, 6.9, 1.3 Hz, 1H), 7.17-7.23 (m,
1H), 7.13 (td, J = 6.9, 1.1 Hz, 1H), 7.13 (td, J = 6.9, 0.9 Hz,
1H), 7.10 (t, J = 9.1 Hz, 1H), 6.70 (d, J = 6.0 Hz, 1H), 3.78 (s,
3H); MS m/z 404 [M + H].sup.+ 35
N-(3-chloro-4-methoxyphenyl)-2-[2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.80 (s, 1H), 9.40 (d, J =
6.9 Hz, 1H), 8.47 (d, J = 6.0 Hz, 1H), 7.88-7.92 (m, 1H), 7.85 (dt,
J = 9.1, 1.0 Hz, 1H), 7.59 (ddd, J = 9.1, 6.6, 1.3 Hz, 1H), 7.43
(dd, J = 8.8, 2.8 Hz, 1H), 7.18 (td, J = 6.9, 1.3 Hz, 1H), 7.15 (d,
J = 9.1 Hz, 1H), 6.74 (d, J = 6.0 Hz, 1H), 3.85 (s, 3H); MS m/z 420
[M + H].sup.+ 36
N-(3-chloro-4-methylphenyl)-2-[2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.92 (s, 1H), 9.38 (d, J = 7.3 Hz, 1H),
8.51 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.86 (dt, J =
9.1, 1.1 Hz, 1H), 7.59 (ddd, J = 9.1, 6.9, 1.3 Hz, 1H), 7.41 (dd, J
= 8.2, 2.2 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.20 (td, J = 6.9,
1.3 Hz, 1H), 6.80 (d, J = 5.7 Hz, 1H), 2.30 (s, 3H); MS m/z 404 [M
+ H].sup.+ 37
N-(4-ethoxyphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-
3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 9.64 (br. s, 1H), 9.43 (br. s, 1H), 8.41 (d, J = 6.0 Hz, 1H),
7.84 (dt, J = 9.1, 1.3 Hz, 1H), 7.57 (ddd, J = 9.1, 6.9, 1.1 Hz,
1H), 7.50 (d, J = 8.5 Hz, 1H), 7.16 (t, J = 6.5 Hz, 1H), 6.93 (d, J
= 8.8 Hz, 2H), 6.69 (d, J = 6.0 Hz, 1H), 4.02 (q,J = 6.9 Hz, 2H),
1.34 (t, J = 6.9 Hz, 3H); MS m/z 400 [M + H].sup.+ 38
N-[4-(propan-2-yl)phenyl]-2-[2-(trifluoromethyl)imidazo[1,2-a]
pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.76 (s, 1H), 9.41 (d, J = 6.9 Hz, 1H), 8.45 (d, J =
6.0 Hz, 1H), 7.85 (dt, J = 9.1, 0.9 Hz, 1H), 7.58 (ddd, J = 8.8,
6.6, 1.3 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz,
2H), 7.16 (td, J = 6.9, 0.9 Hz, 1H), 6.77 (d, J = 6.0 Hz, 1H), 2.89
(spt, J = 6.9 Hz, 1H), 1.21 (d, J = 6.9 Hz, 7H); MS m/z 398 [M +
H].sup.+ 39
N-[4-(1H-pyrazol-1-yl)phenyl]-2-[2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.98 (s, 1H), 9.42 (d, J = 7.3 Hz, 1H),
8.51 (d, J = 5.7 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 7.86 (td, J =
9.1, 1.3 Hz, 1H), 7.76-7.84 (m, J = 3.5 Hz, 4H), 7.73 (d, J = 1.6
Hz, 1H), 7.59 (ddd, J = 9.0, 6.8, 1.3 Hz, 1H), 7.20 (td, J = 6.9,
1.3 Hz, 1H), 6.84 (d, J = 6.0 Hz, 1H), 6.54 (t, J = 1.9 Hz, 1H); MS
m/z 422 [M + H].sup.+ 45
N-(4-methoxyphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]
pyrazin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 9.53 (br. s., 1H), 9.16 (d, J = 1.3
Hz, 1H), 8.81 (s, 1H), 8.38 (d, J = 6.0 Hz, 1H), 8.03 (d, J = 4.7
Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 9.1 Hz, 2H), 6.70
(dd, J = 8.2, 2.5 Hz, 1H), 3.79 (s, 3H); MS m/z 387 [M + H].sup.+
46 2-[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 9.41-9.49 (m, 1H), 9.20 (br. s, 1H),
8.49 (dd, J = 6.0, 2.2 Hz, 1H), 8.02-8.12 (m, 1H), 7.83-7.92 (m,
2H), 7.58 (d, J = 8.5 Hz, 2H), 6.93-7.32 (m, 2H); MS m/z 425 [M +
H].sup.+ 47
N-(4-chlorophenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-
3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 9.53 (dd, J = 4.9, 1.4 Hz, 1H), 9.25 (d, J = 1.3 Hz,
1H), 9.20 (br. s., 1H), 8.55 (d, J = 6.0 Hz, 1H), 8.15 (d, J = 4.7
Hz, 1H), 7.70-7.81 (m, 2H), 7.42 (d, J = 8.8 Hz, 2H), 6.91 (d, J =
6.0 Hz, 1H); MS m/z 391 [M + H].sup.+ 48
2-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-
[4-(trifluoromethyl)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.31 (br. s, 1H), 9.02 (d, J = 2.5 Hz,
1H), 8.65 (d, J = 5.7 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.85 (d, J
= 10.4 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.45 (dd, J = 9.8, 2.5
Hz, 1H), 6.95 (d, J = 6.0 Hz, 1H), 3.66 (s, 3H); MS m/z 454 [M +
H].sup.+ 49
2-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-
[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.65 (br. s, 1H), 8.96-9.06 (m, 1H), 8.42
(d, J = 5.7 Hz, 1H), 7.76 (d, J = 9.8 Hz, 1H), 7.51 (d, J = 8.5 Hz,
2H), 7.36 (dd, J = 9.6, 2.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.69
(d, J = 6.0 Hz, 1H), 3.75 (s, 3H); MS m/z 470 [M + H].sup.+ 50
N-(4-methoxyphenyl)-2-[6-methoxy-2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.04 (br. s, 1H), 8.97 (d, J = 1.9 Hz,
1H), 8.54 (d, J = 5.7 Hz, 1H), 7.75-7.79 (m, 3H), 7.38 (dd, J =
9.1, 2.2 Hz, 1H), 7.34 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 6.0 Hz,
1H), 3.59 (s, 3H), 3.33 (s, 3H); MS m/z 416 [M + H].sup.+ 51
N-[4-(difluoromethoxy)phenyl]-2-[6-methoxy-2-(trifluoromethyl)
imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.90 (br. s, 1H), 8.98 (d, J = 1.9 Hz,
1H), 8.50 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 9.5 Hz, 1H), 7.69 (d, J
= 8.8 Hz, 2H), 7.37 (dd, J = 9.8, 2.5 Hz, 1H), 7.17 (d, J = 8.8 Hz,
2H), 7.19 (t, J = 74.4 Hz, 1H), 6.78 (d, J = 5.7 Hz, 1H), 3.61 (s,
3H); MS m/z 452 [M + H].sup.+ 53
N-[4-(difluoromethoxy)phenyl]-2-[2-(trifluoromethyl)imidazo
[1,2-a]pyrazin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 9.74 (dd, J = 4.9, 1.4 Hz, 1H), 9.44
(d, J = 1.6 Hz, 1H), 9.30 (br. s., 1H), 8.72 (d, J = 6.0 Hz, 1H),
8.32 (d, J = 4.7 Hz, 1H), 7.89-8.00 (m, 2H), 7.42-7.52 (m, 2H),
7.07 (dd, J = 6.0, 1.6 Hz, 1H), 7.20 (t, J = 74.4 Hz, 1H); MS m/z
423 [M + H].sup.+ 54
2-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 10.25 (br. s, 1H), 9.58 (ddd, J = 5.7,
1.9, 0.9 Hz, 1H), 8.59 (d, J = 6.0 Hz, 1H), 7.97 (ddd, J = 9.8,
5.4, 0.9 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.73 (ddd, J = 9.9,
7.7, 2.5 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 6.0 Hz,
1H); MS m/z 442 [M + H].sup.+ 55
N-[4-(difluoromethoxy)phenyl]-2-[6-fluoro-2-(trifluoromethyl)
imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) 6 ppm 9.75 (dd, J = 5.5, 2.0 Hz, 1H), 9.10 (br. s,
1H), 8.51 (d, J = 5.7 Hz, 1H), 7.84 (ddd, J = 9.8, 5.4, 0.9 Hz,
1H), 7.71-7.76 (m, 2H), 7.60 (ddd, J = 10.0, 7.6, 2.5 Hz, 1H),
7.22-7.26 (m, 2H), 6.99 (t, J = 74.1 Hz, 1H), 6.83 (d, J = 6.0 Hz,
1H); MS m/z 440 [M + H].sup.+ 56
N-[4-(trifluoromethyl)phenyl]-2-[2-(trifluoromethyl)pyrazolo
[1,5-a]pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. ppm 10.03 (br. s, 1H), 8.48 (d, J = 6.9 Hz,
1H), 8.21-8.36 (m, 1H), 8.00-8.15 (m, 1H), 7.65-7.73 (m, 2H), 7.52
(d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.06-7.12 (m, 1H),
7.03 (t, J = 6.8 Hz, 1H); MS m/z 424 [M + H].sup.+ 60
N-(4-methoxyphenyl)-2-[2-(trifluoromethyl)pyrazolo[1,5-a]
pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, CHLOROFORM-d)
.delta. ppm 8.49 (d, J = 6.6 Hz, 1H), 8.03-8.31 (m, 2H), 7.30-7.55
(m, 3H), 7.00-7.12 (m, 2H), 6.79-6.87 (m, 3H), 3.76 (s, 3H); MS m/z
386 [M + H].sup.+ 62
N-(4-methylphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-
3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 9.58 (d, J = 3.8 Hz, 1H), 9.23 (d, J = 1.6 Hz, 1H),
8.95 (br. s., 1H), 8.48 (d, J = 6.0 Hz, 1H), 8.10 (d, J = 4.7 Hz,
1H), 7.53 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 6.83 (d, J
= 6.0 Hz, 1H), 2.37 (s, 3H); MS m/z 371 [M + H].sup.+ 118
2-(imidazo[1,2-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]
pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
10.10 (s, 1H), 9.92 (d, J = 7.3 Hz, 1H), 8.51 (app. s, 1H), 8.48
(d, J = 5.7 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.75-7.86 (m, 3H),
7.46 (ddd, J = 9.1, 6.6, 0.9 Hz, 1H), 7.14 (td, J = 6.9, 1.1 Hz,
1H), 6.74 (d, J = 6.0 Hz, 1H); MS m/z 356 [M + H].sup.+
Example 2
N-(3-chloro-4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4--
amine (Cpd 40)
##STR00074##
[0391] Step 1. 3-Chloro-4-methoxyaniline (2.07 g, 13.1 mmol),
2,4-dichloropyrimidine (1.95 g, 13.1 mmol) and triethylamine (2.1
mL, 15 mmol) were mixed in isopropanol (10 mL). The mixture was
heated at 100.degree. C. for 13 hours, then partially concentrated,
diluted with water, and made basic with K.sub.2CO.sub.3. The
precipitate was filtered, then washed with water, followed by
hexane. The major isomer,
2-chloro-N-(3-chloro-4-methoxyphenyl)pyrimidin-4-amine (2.07 g,
59%) was recrystallized from methanol as a white solid.
[0392] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.99 (br. s,
1H), 8.15 (d, J=6.0 Hz, 1H), 7.73 (br. s., 1H), 7.47 (d, J=8.2 Hz,
1H), 7.19 (d, J=8.8 Hz, 1H), 6.69 (d, J=5.7 Hz, 1H), 3.85 (s,
3H).
[0393] Step 2.
2-Chloro-N-(3-chloro-4-methoxyphenyl)pyrimidin-4-amine (84 mg, 0.31
mmol), 2-methyl-1H-benzo[d]imidazole (82 mg, 0.62 mmol) and
K.sub.2CO.sub.3 (86 mg, 0.62 mmol) were mixed in DMF (2 mL). The
reaction mixture was heated at 120.degree. C. for 3 days, then
cooled, partitioned between water and EtOAc, and purified by silica
gel chromatography to provide the title compound as a white solid
(29 mg, 26%).
[0394] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.94 (s,
1H), 8.42 (d, J=5.7 Hz, 1H), 8.03-8.10 (m, 1H), 7.82-7.90 (m, 1H),
7.61 (d, J=7.3 Hz, 1H), 7.40-7.45 (m, 1H), 7.20-7.29 (m, 2H), 7.18
(d, J=8.8 Hz, 1H), 6.73 (d, J=5.7 Hz, 1H), 3.86 (s, 3H), 2.79 (s,
3H); MS m/z 366 [M+H].sup.+.
[0395] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 2 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00004 Cpd Name & Data 1
N-(4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
9.79 (br. s., 1H), 8.36 (d, J = 5.4 Hz, 1H), 7.95-8.17 (m, 1H),
7.59 (d, J = 7.9 Hz, 1H), 7.42-7.54 (m, 2H), 7.17-7.33 (m, 2H),
6.96 (d, J = 8.2 Hz, 2H), 6.68 (d, J = 5.0 Hz, 1H), 3.76 (s, 3H),
2.77 (s, 3H); MS m/z 332 [M + H].sup.+ 41
2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]
pyrimidin-4-amine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
10.37 (s, 1H), 8.55 (d, J = 5.7 Hz, 1H), 8.01-8.06 (m, 1H), 7.90
(d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.61-7.65 (m, 1H),
7.26 (app. quind, J = 7.3, 1.4 Hz, 2H), 6.91 (d, J = 5.7 Hz, 1H),
2.81 (s, 3H); MS m/z 370 [M + H].sup.+ 61
N-[4-(difluoromethoxy)phenyl]-2-(2-methyl-1H-benzimidazol-
1-yl)pyrimidin-4-amine .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. ppm 8.32 (1H, d, J = 5.5 Hz), 8.06 (1H, d, J = 8 Hz), 7.59
(3H, d, J = 8 Hz), 7.26 (2H, m), 7.14 (2H, d, J = 8 Hz), 7.0 (1H,
t, J = 74 Hz), 6.69 (1H, d, J = 6 Hz), 2.82 (3H, s); MS m/z 368 [M
+ H].sup.+
Example 3
N-(3-chloro-4-methoxyphenyl)-2-[2-(trifluoromethyl)-1H-benzimidazol-1-yl]p-
yrimidin-4-amine (Cpd 42)
##STR00075##
[0397] A mixture of
2-chloro-N-(3-chloro-4-methoxyphenyl)pyrimidin-4-amine (280 mg,
1.03 mmol) and benzene-1,2-diamine (540 mg, 5 mmol) in isopropanol
(5 mL) was heated in a microwave oven at 160.degree. C. for 10
minutes. The reaction mixture was diluted with water, extracted
with EtOAc, then filtered through a short plug of silica gel, and
concentrated to provide a first crude intermediate
N.sup.2-(2-aminophenyl)-N.sup.4-(3-chloro-4-methoxyphenyl)pyrimidine-2,4--
diamine. The first crude intermediate was dissolved in
dichloromethane (5 mL), then trifluoroacetic anhydride was added in
two portions (0.5 mL each). The reaction mixture was washed with an
aqueous NaHCO.sub.3 solution, and purified by silica gel
chromatography to provide a second crude intermediate
N-(2-(4-(3-chloro-4-methoxyphenylamino)-pyrimidin-2-ylamino)phenyl)-2,2,2-
-trifluoroacetamide.
[0398] To a solution of the second crude intermediate (71 mg, 0.16
mmol) in acetonitrile (2 mL) was added trifluoroacetic acid (0.5
mL). The mixture was heated in a microwave oven at 180.degree. C.
for 1 hour and 45 minutes after which UPLC showed complete
conversion. The final product was purified by silica gel
chromatography to provide the title compound as a white solid (40
mg, 59%).
[0399] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 10.06-10.18
(m, 1H), 8.45 (d, J=5.7 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.94 (d,
J=7.3 Hz, 1H), 7.83-7.90 (m, 1H), 7.52-7.56 (m, J=8.2, 8.2, 1.3 Hz,
1H), 7.50 (td, J=7.9, 1.3 Hz, 1H), 7.43 (dd, J=9.0, 2.7 Hz, 1H),
7.15 (d, J=8.8 Hz, 1H), 6.86 (d, J=6.0 Hz, 1H), 3.84 (s, 3H); MS
m/z 420 [M+H].sup.+.
Example 4
5-fluoro-N-(4-methylphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3--
yl]pyrimidin-4-amine (Cpd 43)
##STR00076##
[0401] Step 1: A mixture of 2,4-dichloro-5-fluoropyrimidine (1.00
g, 5.99 mmol), 4-toluidine (642 mg, 5.99 mmol) and K.sub.2CO.sub.3
(1.66 g, 12.0 mmol) in EtOH (10 mL) was stirred for 18 hours at
50.degree. C. The mixture was filtered through Celite and purified
by column chromatography to yield
2-chloro-5-fluoro-N-p-tolylpyrimidin-4-amine (1.19 g, 84%).
[0402] Step 2: A mixture of
2-chloro-5-fluoro-N-p-tolylpyrimidin-4-amine (165 mg, 0.69 mmol),
3-(tributylstannyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine (300
mg, 0.63 mmol), Q-Phos (13.5 mg, 0.019 mmol) and PdCl.sub.2(allyl)
(6.9 mg, 0.019 mmol) in dioxane (1.5 mL) was stirred for 2 hours at
90.degree. C. The mixture was purified by column chromatography to
yield the title compound (213 mg, 80%).
[0403] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 9.24-9.29
(1H, m) 8.29 (1H, d, J=2.84 Hz) 7.66-7.71 (1H, m) 7.46 (2H, d,
J=8.51 Hz) 7.31 (1H, ddd, J=9.14, 6.62, 1.26 Hz) 7.14 (2H, d,
J=8.20 Hz) 6.82-6.89 (2H, m) 2.30 (3H, s); MS m/z 388.2
[M+H].sup.+.
[0404] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 4 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00005 Cpd Name & Data 44
5-chloro-N-(4-methylphenyl)-2-[2-(trifluoromethyl)imidazo[1,2-a]
pyridin-3-yl]pyrimidin-4-amine .sup.1H NMR (500 MHz, CHLOROFORM-d)
.delta. ppm 9.34-9.42 (1H, m) 8.51 (1H, s) 7.80 (1H, dd, J = 9.14,
0.95 Hz) 7.49 (2H, d, J = 8.51 Hz) 7.41 (1H, ddd, J = 8.99, 6.78,
1.26 Hz) 7.20-7.27 (3H, m) 6.91 (1H, td, J = 6.94, 1.26 Hz) 2.42
(3H, s); MS m/z 404.2 [M + H].sup.+
Example 5
2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phen-
yl]pyrimidine-4,6-diamine (Cpd 68)
##STR00077##
[0406] Step 1. A mixture of 2,6-dichloropyrimidine-4-amine (3.78 g,
23.05 mmol) and DMAP (cat.) in dichloromethane (20 mL) was treated
with di-tert-butyldicarbonate (11.05 g, 50.71 mmol) at 0.degree. C.
After addition, the resulting mixture was stirred at ambient
temperature overnight. The mixture was poured into ice-water (120
mL) and extracted with dichloromethane (150 mL). The organic phase
was separated, washed with brine (100 mL), dried over MgSO.sub.4,
then filtered and evaporated. The residual material was separated
by filtering through a pad of silica gel (100 g) to afford
di-tert-butyl (2,6-dichloropyrimidin-4-yl)imidodicarbonate as an
oil (7.55 g, 90%).
[0407] Step 2. A solution of di-tert-butyl
(2,6-dichloropyrimidin-4-yl)imidodicarbonate (1.75 g, 4.81 mmol)
and 4-trifluoromethylaniline (775.0 mg, 4.81 mmol) in THF (10 mL)
was treated with potassium tert-butoxide solution (1M in THF, 9.62
mL, 9.62 mmol) at -78.degree. C. The mixture was allowed to stir
and warm to 0.degree. C. over 20 minutes. The mixture was then
poured into ice-water (120 mL) and extracted with dichloromethane
(150 mL). The organic phase was separated, washed with brine (100
mL), dried over MgSO.sub.4, then filtered and evaporated. The
residual material was separated by silica gel column chromatography
(by eluting with hexane then 2% ethyl acetate-hexane) to afford
di-tert-butyl
6-chloro-2-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate
(750.0 mg, 32% yield), and (by eluting with 4% ethyl
acetate-hexane) di-tert-butyl
2-chloro-6-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate
(1.08 g, 46%).
##STR00078##
[0408] Step 3. 4-Fluoropyridin-2-amine (8.57 g, 76.44 mmol) and
chloroacetone (12.99 g, 71.67 mmol) were pre-mixed and stirred in a
250 mL round bottom flask at 0.degree. C. for 15 minutes. The
resulting mixture was diluted with acetonitrile (50 mL) and
refluxed for overnight. The acetonitrile was evaporated, and ethyl
ether (200 mL) was added to produce a precipate, which was
collected by filtration. The solid was partitioned between
dichloromethane (300 mL) and a saturated NaHCO.sub.3 solution (250
mL). The organic layer was separated, dried over MgSO.sub.4, then
filtered and concentrated under the reduced pressure. The residual
material was separated by silica gel column chromatography (1:1
ethyl acetate-hexane) to afford
6-fluoro-2-methylimidazo[1,2-a]pyridine (5.20 g, 46%) as a glassy
solid.
[0409] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.95-7.99
(m, 1H), 7.46 (dd, J=5.04, 9.77 Hz, 1H), 7.34 (s, 1H), 6.99-7.06
(m, 1H), 2.44 (d, J=0.63 Hz, 3H); MS m/z 151.0 (100)
[M+H].sup.+.
[0410] Step 4. A mixture of 6-fluoro-2-methylimidazo[1,2-a]pyridine
(445.0 mg, 2.97 mmol), di-tert-butyl
2-chloro-6-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate
(1.0 g, 5.78 mmol), palladium (II) acetate (33.4 mg, 0.149 mmol),
triphenylphosphine (46.7 mg, 0.178 mmol), cesium acetate (1.14 g,
5.94 mmol) and DMA (5 mL) was degassed by three cycles of vacuum
pumping and N.sub.2 purging, and then was heated to 100.degree. C.
for 1 hour. The solution was cooled and poured into water (50 mL),
and this mixture was extracted with dichloromethane. The extract
was dried over MgSO.sub.4, then filtered and concentrated under the
reduced pressure. The residual material was triturated with ethyl
ether to afford di-tert-butyl
2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-6-(4-(trifluoromethyl)phe-
nylamino)pyrimidin-4-yliminodicarbonate (706.0 mg, 83%).
[0411] Step 5. A solution of di-tert-butyl
2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-6-(4-(trifluoromethyl)phe-
nylamino)pyrimidin-4-yliminodicarbonate (140 mg, 0.24 mmol) in
dichloromethane (2 mL) was treated with TFA (0.4 mL) at 0.degree.
C. The resulting mixture was stirred at ambient temperature for 4
hours. The solvent was concentrated under reduced pressure, and the
residual material was partitioned between ethyl acetate and a
saturated NaHCO.sub.3 solution. The organic layer was separated,
dried over MgSO.sub.4, then filtered and evaporated. The residual
material was triturated with ethyl ether to afford the title
compound as a white solid (87.0 mg, 87%). m.p. 209-211.degree.
C.
[0412] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 10.40
(dd, J=2.21, 5.36 Hz, 1H), 8.88 (s, 1H), 8.11-8.27 (m, 1H),
7.78-7.85 (m, 1H), 7.74 (d, J=8.83 Hz, 2H), 7.69 (d, J=8.83 Hz,
2H), 6.47 (br. s., 2H), 6.03 (s, 1H), 2.93 (s, 3H); MS m/z 403.5
(100) [M+H].sup.+, 404.4 (30).
[0413] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 5 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00006 Cpd Name & Data 65
N-[4-(difluoromethoxy)phenyl)-2-[2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 9.67 (ddd, J = 1.10, 1.26, 7.09 Hz,
1H), 8.40 (s, 1H), 7.73 (td, J = 1.10, 9.14 Hz, 1H), 7.59- 7.66 (d,
J = 9.1 Hz, 2H), 7.51 (ddd, J = 1.26, 6.94, 9.14 Hz, 1H), 7.15-7.23
(d, J = 9.1 Hz, 2H), 6.80-7.10 (t, J = 75.00 Hz, 1H), 7.05-7.12 (m,
1H), 6.11 (br. s., 2H), 5.96 (s, 1H); MS m/z 437.3 [M + H].sup.+ 66
2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine m.p. 203-205.degree.
C.; MS m/z 439.4 [M + H].sup.+ 67
N-[4-(trifluoromethoxy)phenyl]-2-[2-(trifluoromethyl)imidazo
[1,2-a]pyridin-3-yl]pyrimidine-4,6-diamine m.p. 199-202.degree. C.;
MS m/z 455.3 [M + H].sup.+ 69
N-[4-(difluoromethoxy)phenyl]-2-(6-fluoro-2-methylimidazo
[1,2-a]pyridin-3-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 10.41 (dd, J = 2.21, 5.36 Hz, 1H),
8.57 (s, 1H), 8.19 (s, 1H), 7.71-7.89 (m, 1H), 7.53 (d, J = 9.77
Hz, 2H), 7.20-7.26 (d, J = 9.77 Hz, 2H), 6.81-7.11 (t, J = 75.00
Hz, 1H), 6.36 (br, s., 2H), 5.91 (s, 1H), 2.91 (s, 3H); m.p.
136-138.degree. C.; MS m/z 401.5 [M + H].sup.+ 75
2-(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)-N-[4-
(difluoromethoxy)-3-fluorophenyl]pyrimidine-4,6-diamine .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 10.06 (dd, J = 2.21, 5.99 Hz,
1H), 9.28 (s, 1H), 7.70-7.87 (m, 1H), 7.58 (dd, J = 5.52, 9.62 Hz,
1H), 7.41 (ddd, J = 2.68, 7.72, 9.77 Hz, 1H), 6.98-7.28 (t, J =
75.00 Hz, 1H), 7.24-7.32 (m, 1H), 7.18-7.24 (m, 1H), 6.73 (s, 2H),
5.72 (s, 1H), 3.42-3.56 (m, 1H), 0.89-1.11 (m, 4H); m.p.
198-200.degree. C.; MS m/z 445.5 [M + H].sup.+ 84
[3-(4-amino-6-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)-
6-fluoroimidazo[1,2-a]pyridin-2-yl]methanol .sup.1H NMR (500 MHz,
METHANOL-d.sub.4) .delta. ppm 9.36-9.77 (m, 1H), 7.90-7.97 (m, 2H),
7.59-7.69 (m, 1H), 7.50-7.55 (m, 2H), 7.-7.45 (m, 1H), 6.55-6.58
(m, 1H), 4.86 (s, 2H); MS m/z 419.1 [M + H].sup.+ 100
2-(6-fluoro-2-methylimidazo[1,2-a]pyrimidin-3-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 10.45 (dd, J = 2.84, 5.67 Hz, 1H),
9.46 (s, 1H), 8.76 (d, J = 2.84 Hz, 1H), 7.72 (d, J = 8.51 Hz, 2H),
7.64 (d, J = 8.51 Hz, 2H), 6.82 (s, 2H), 5.79 (s, 1H), 2.84 (s,
3H); m.p. 256-258.degree. C.; MS m/z 404.3 [M + H].sup.+
Example 6
2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]py-
rimidine-4,6-diamine (Cpd 71)
##STR00079##
[0415] Step 1: A mixture of 5-fluoro-2-nitroaniline (156.2 mg, 1.00
mmol), di-tert-butyl
2-chloro-6-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate
(480.0 mg, 0.98 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (56.1
mg, 0.1 mmol), tris(dibenzylideneacetone) dipalladium(0) (53.8 mg,
0.05 mmol) and potassium phosphate (625.0 mg, 2.95 mmol) in dioxane
(2 mL) was degassed by three cycles of vacuum pumping and N.sub.2
purging, and then was heated to 100.degree. C. for 2 hours. The
solution was cooled and poured into water (10 mL), and this mixture
was extracted with ethyl acetate (15 mL). The extract was dried
over MgSO.sub.4, then filtered and evaporated. The residual
material was separated by column chromatography (eluting with 1:1
dichloromethane:hexane, then 1:2 ethyl acetate:dichloromethane) to
afford di-tert-butyl
2-(5-fluoro-2-nitrophenylamino)-6-(4-(trifluoromethyl)phenylamino)pyrimid-
in-4-yliminodicarbonate (483.0 mg, 81%).
[0416] Step 2: A pressure reaction vessel charged with
di-tert-butyl
2-(5-fluoro-2-nitrophenylamino)-6-(4-(trifluoromethyl)phenylamino)pyrimid-
in-4-yliminodicarbonate (483.0 mg), Pd/C (10%, wet, 48.0 mg) and
1:1 ethyl acetate:methanol (5 mL) was placed on a Parr shaker. The
mixture was degassed by three cycles of vacuum pumping and N.sub.2
purging. The vessel was pressurized to 40 psi hydrogen and shaken
for 2 hours. The charcoal was removed by filtration, and the
solvent was evaporated to give di-tert-butyl
2-(2-amino-5-fluorophenylamino)-6-(4-(trifluoromethyl)phenylamino)-pyrimi-
din-4-yliminodicarbonate. The residual material was used in the
next step without further purification. MS m/z 579.6 (100)
[M+H].sup.+, 580.6 (40).
[0417] Step 3: A mixture of di-tert-butyl
2-(2-amino-5-fluorophenylamino)-6-(4-(trifluoromethyl)-phenylamino)pyrimi-
din-4-yliminodicarbonate (365.0 mg, 0.63 mmol), triethyl
orthoacetate (306.0 mg, 1.89 mmol), p-toluenesulfonic acid (5.0 mg,
0.025 mmol) and ethanol (2.0 mL) was heated to reflux for 2 hours.
After cooling, the mixture was partitioned between dichloromethane
(20 mL) and a saturated NaHCO.sub.3 solution (10 mL). The organic
phase was washed with brine (10 mL), dried over MgSO.sub.4, then
filtered and evaporated. The residual oil was triturated with ethyl
ether to afford di-tert-butyl
2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-6-(4-(trifluoromethyl)phen-
ylamino)pyrimidin-4-yliminodicarbonate (316.0 mg, 83%). MS m/z
603.6 (100) [M+H].sup.+, 604.6 (40).
[0418] Step 4: A solution of the product (316.0 mg, 0.52 mmol) in
dichloromethane (3 mL) was treated with TFA (1 mL) at 0.degree. C.
The resulting mixture was stirred at ambient temperature for 4
hours. The solvent was evaporated, and the residual material was
triturated with ethyl ether to afford the title compound as a white
solid (152.0 mg, 73%). m.p. 253-255.degree. C.
[0419] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.72 (s,
1H), 8.00 (d, J=8.51 Hz, 2H), 7.52-7.69 (m, 3H), 7.45 (dd, J=1.89,
9.14 Hz, 1H), 7.01-7.24 (m, 3H), 6.20 (s, 1H), 2.66 (s, 3H); MS m/z
403.3 (100) [M+H].sup.+.
[0420] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 6 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00007 Cpd Name & Data 93
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.76 (s, 1H), 8.19 (d, J = 1.9 Hz,
1H), 7.74 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.60 (d, J
= 8.5 Hz, 1H), 7.27 (dd, J = 8.5, 1.9 Hz, 1H), 7.02 (br. s., 2H),
5.90 (s, 1H), 2.83 (s, 3H); MS m/z 419.8 [M + H].sup.+ 72
N-[4-(difluoromethoxy)phenyl]-2-(6-fluoro-2-methyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.25 (s, 1H), 7.99 (dd, J = 2.21, 10.09
Hz, 1H), 7.56 (dd, J = 5.04, 8.83 Hz, 1H), 7.48 (d, J = 8.83 Hz,
2H), 7.00-7.30 (t, J = 75.00 Hz, 1H), 7.12-7.19 (m, 2H), 7.07 (dt,
J = 2.36, 9.06 Hz, 1H), 6.84 (br. s., 2H), 5.74 (s, 1H), 2.80 (s,
3H); m.p. 168-170.degree. C.; MS m/z 401.5 [M + H].sup.+ 76
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(6-fluoro-2-methyl-
1H-benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.47 (s, 1H), 7.96 (d, J = 9.14 Hz, 1H),
7.66 (d, J = 12.93 Hz, 1H), 7.57 (dd, J = 5.04, 8.20 Hz, 1H),
7.00-7.28 (t, J = 70.00 Hz, 1H), 7.27-7.39 (m, 1H), 7.23 (d, J =
8.51 Hz, 1H), 7.08 (t, J = 8.20 Hz, 1H), 6.94 (br. s., 2H), 5.80
(s, 1H), 2.50 (br. s., 3H); m.p. 182-183.degree. C.; MS m/z 419.4
[M + H].sup.+ 77
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-6-fluoro-
1H-benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.47 (br. s., 1H), 7.90 (d, J = 9.14 Hz,
1H), 7.50-7.74 (m, 2H), 7.29 (d, J = 5.04 Hz, 1H), 7.00-7.28 (t, J
= 70.00 Hz, 1H), 7.22 (d, J = 8.20 Hz, 1H), 7.09 (d, J = 7.88 Hz,
1H), 6.93 (br. s., 2H), 5.80 (s, 1H), 3.27 (m, 2H), 1.28 (t, J =
6.62 Hz, 3H); m.p. 156-158.degree. C.; MS m/z 433.5 [M + H].sup.+
81 2-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.64 (s, 1H), 7.89 (dd, J = 2.52,
10.09 Hz, 1H), 7.70 (d, J = 8.20 Hz, 2H), 7.58-7.66 (m, 3H),
7.05-7.13 (m, 1H), 6.98 (br. s., 2H), 5.88 (s, 1H), 3.28 (q, J =
7.46 Hz, 2H), 1.28 (t, J = 7.57 Hz, 3H); m.p. 201-203.degree. C.;
MS m/z 417.2 [M + H].sup.+ 96
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 9.11 (br. s, 1H), 8.27 (d, J =
2.2 Hz, 1H), 7.78 (dd, J = 13.9, 1.6 Hz, 1H), 7.65 (t, J = 8.5 Hz,
1H), 7.56 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.25 (dd,
J = 8.5, 1.9 Hz, 1H), 6.57 (br. s., 2H), 6.07 (s, 1H), 2.87 (s,
3H); MS m/z 437.8 [M + H].sup.+ 97
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(difluoromethoxy)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.56 (br. s, 1H), 8.32 (d, J =
2.2 Hz, 1H), 7.56 (dd, J = 6.6, 2.2 Hz, 2H), 7.53 (d, J = 8.8 Hz,
1H), 7.23 (dd, J = 8.5, 2.2 Hz, 1H), 7.20 (dd, J = 6.6, 2.2 Hz,
2H), 6.94 (t, J = 74.7 Hz, 1H), 6.35 (br. s., 2H), 5.91 (s, 1H),
2.85 (s, 3H); MS m/z 418.0 [M + H].sup.+ 98
2-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.94 (br. s, 1H), 8.10 (d, J = 8.7
Hz, 1H), 7.82 (dd, J = 14.3, 1.4 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H),
7.65 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 8.7, 1.1 Hz, 1H), 7.27 (dd,
J = 8.7, 2.0 Hz, 1H), 7.10 (br. s, 2H), 5.93 (s, 1H), 2.83 (s, 3H);
MS m/z 437.8 [M + H].sup.+ 99
2-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-
(difluoromethoxy)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 8.99 (br. s, 1H), 8.72 (d, J = 8.8
Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 8.00-8.03 (m, 2H), 7.65- 7.67
(m, 2H), 7.64 (dd, J = 8.8, 2.2 Hz, 1H), 7.42 (t, J = 75.0 Hz, 1H),
6.79 (br. s., 2H), 6.38 (s, 1H), 3.32 (s, 3H); MS m/z 417.8 [M +
H].sup.+ 144 N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-6-fluoro-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.25 (s, 1H), 7.84-8.12 (m, 1H), 7.60
(dd, J = 5.04, 8.51 Hz, 1H), 7.49 (d, J = 8.83 Hz, 2H), 7.01-7.31
(t, J = 75.00 Hz, 1H), 7.15 (d, J = 8.20 Hz, 2H), 7.04-7.13 (m,
1H), 6.84 (br. s., 2H), 5.76 (s, 1H), 3.28 (q, J = 7.25 Hz, 2H),
1.28 (t, J = 7.41 Hz, 3H); m.p. 166-168.degree. C.; MS m/z 415.4 [M
+ H].sup.+
Example 7
2-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phen-
yl]pyrimidine-4,6-diamine (Cpd 82)
##STR00080##
[0422] Step 1: To a solution of di-tert-butyl
2-(2-amino-5-fluorophenylamino)-6-(4-(trifluoromethyl)-phenylamino)pyrimi-
din-4-yliminodicarbonate (212.0 mg, 0.37 mmol), triethylamine (42.0
mg, 0.41 mmol) in dichloromethane (2 mL) was added
cyclopropanecarbonyl chloride (38.3 mg, 0.37 mmol) at 0.degree. C.
The mixture was stirred at ambient temperature for 3 hours, then
partitioned between dichloromethane and water. The organic phase
was washed with brine, dried over MgSO.sub.4, then filtered and
evaporated to give di-tert-butyl
2-(2-(cyclopropanecarboxamido)-5-fluorophenylamino)-6-(4-(trifluoromethyl-
)phenylamino)-pyrimidin-4-yliminodicarbonate. The residual solid
was used directly in the next step without further
purification.
[0423] Step 2: A mixture of crude di-tert-butyl
2-(2-(cyclopropanecarboxamido)-5-fluorophenylamino)-6-(4-(trifluoromethyl-
)phenylamino)-pyrimidin-4-yliminodicarbonate, p-toluenesulfonic
acid (7.0 mg, 0.037 mmol) and acetonitrile (3 mL) was heated in a
microwave oven at 180.degree. C. for 30 minutes. The mixture was
partitioned between ethyl acetate and a saturated NaHCO.sub.3
solution. The organic phase was washed with brine, dried over
MgSO.sub.4, then filtered and evaporated. The residual material was
separated by silica gel column chromatography (eluting with 1:1
dichloromethane:hexane, then 1:5 MeOH:50% ethyl acetate in
dichloromethane) to afford the title compound (103.0 mg, 65% for
two steps). m.p. 203-206.degree. C.
[0424] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.49-9.59
(m, 1H), 7.70 (td, J=1.00, 13.24 Hz, 1H), 7.64 (d, J=8.57 Hz, 2H),
7.49 (d, J=8.57 Hz, 2H), 7.36-7.42 (m, 1H), 6.91-6.97 (m, 1H), 6.88
(br. s, 2H), 5.77 (s, 1H), 2.88-3.01 (m, 1H), 0.97-1.05 (m, 2H),
0.86-0.95 (m, 2H); MS m/z 429.2 (100) [M+H].sup.+, 430.2 (20).
[0425] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 7 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00008 Cpd Name & Data 78
2-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-
(difluoromethoxy)-3-fluorophenyl]pyrimidine-4,6-diamine .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 9.53 (s, 1H), 7.70-7.95 (m,
2H), 7.52 (dd, J = 5.04, 8.83 Hz, 1H), 7.28 (d, J = 2.52 Hz, 1H),
6.98-7.26 (t, J = 70.00 Hz, 1H), 7.22 (m, 1H), 7.03-7.09 (m, 1H),
6.98 (br. s, 2H), 5.82 (s, 1H), 3.07 (m, 1H), 1.10-1.15 (m, 2H),
1.01-1.08 (m, 2H); m.p. 186-188.degree. C.; MS m/z 445.5 [M +
H].sup.+ 83 2-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.69 (s, 1H), 7.96 (d, J = 5.04,
8.83 Hz, 1H), 7.79 (d, J = 8.51 Hz, 2H), 7.61 (d, J = 8.51 Hz, 2H),
7.34 (dd, J = 2.52, 9.46 Hz, 1H), 6.93-7.09 (m, 3H), 5.78-5.93 (m,
1H), 3.02 (s, 1H), 1.13-1.19 (m, 2H), 1.04-1.08 (m, 2H); MS m/z
429.2 [M + H].sup.+ 143
2-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-
(difluoromethoxy)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.30 (s, 1H), 7.83-7.90 (m, 1H),
7.54 (d, J = 8.83 Hz, 3H), 7.00-7.30 (t, J = 75.00 Hz, 1H),
7.11-7.18 (m, 2H), 7.02-7.10 (m, 1H), 6.83-6.92 (m, 2H), 5.78 (s,
1H), 3.08-3.20 (m, 1H), 1.09-1.14 (m, 2H), 0.99-1.07 (m, 2H); m.p.
175-177.degree. C.; MS m/z 427.2 [M + H].sup.+ 145
N-[4-(difluoromethoxy)phenyl]-2-[2-(difluoromethyl)-6-fluoro-
1H-benzimidazol-1-yl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.32 (s, 1H), 8.36 (dd, J = 1.89, 10.09
Hz, 1H), 7.95-8.16 (t, J = 52.5 Hz, 1H), 7.85 (dd, J = 5.04, 8.83
Hz, 1H), 7.44 (d, J = 8.83 Hz, 2H), 7.04-7.34 (t, J = 75.00 Hz,
1H), 7.27 (dt, J = 2.36, 9.06 Hz, 1H), 7.20 (d, J = 8.83 Hz, 2H),
6.98 (br. s., 2H), 5.76 (s, 1H); m.p. 114-115.degree. C.; MS m/z
437.4 [M + H].sup.+ 149
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.70 (s, 1H), 7.92-7.97 (m, 1H), 7.81 (d, J = 8.51 Hz,
2H), 7.60 (d, J = 8.51 Hz, 2H), 7.50-7.55 (m, 1H), 7.19 (ddd, J =
1.58, 5.04, 7.25 Hz, 2H), 7.00 (br. s., 2H), 5.90 (s, 1H),
2.94-3.03 (m, 1H), 1.15 (m, 2H), 1.05 (m, 2H); m.p. 199-201.degree.
C.; MS m/z 411.3 [M + H].sup.+ 150
2-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.66 (s, 1H), 8.09-8.20 (m, 1H),
7.73 (d, J = 8.51 Hz, 2H), 7.67-7.71 (m, 1H), 7.63 (d, J = 8.51 Hz,
2H), 7.26-7.31 (m, 2H), 6.97 (br. s., 2H), 5.87 (s, 1H), 5.04 (s,
2H), 3.25 (s, 3H); m.p. 212-213.degree. C.; MS m/z 415.4 [M +
H].sup.+ 151 2-[2-(propan-2-yl)-1H-benzimidazol-1-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.69 (s, 1H), 7.85-7.91 (m, 1H),
7.74 (d, J = 8.83 Hz, 2H), 7.61-7.65 (m, 1H), 7.59 (d, J = 8.83 Hz,
2H), 7.17-7.25 (m, 2H), 6.95 (s, 2H), 5.90 (s, 1H), 3.96- 4.08 (m,
1H), 1.29 (d, J = 6.94 Hz, 6H); m.p. 216-218.degree. C.; MS m/z
413.4 [M + H].sup.+ 152
2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-[4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.71 (s, 1H), 8.36-8.52 (m, 1H),
7.89-8.11 (t, J = 55.00 Hz, 1H), 7.80-7.87 (m, 1H), 7.68 (m, 4H),
7.35-7.48 (m, 2H), 6.92-7.20 (m, 2H), 5.91 (s, 1H); m.p.
187-188.degree. C.; MS m/z 421.4 [M + H].sup.+
Example 8
2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methoxyphenyl)pyrimidine-4-
,6-diamine (Cpd 265)
##STR00081##
[0427] Step 1: To a mixture of 5-fluoro-2-nitroaniline (8.16 g,
35.93 mmol), 4,6-dichloro-2-(methylsulfonyl)pyrimidine (5.06 g,
32.67 mmol), THF (50 mL) and DMF (12 mL) was added sodium
tert-pentoxide (2.5 M in THF, 28.6 mL, 71.5 mmol) dropwise at
-78.degree. C. The mixture was stirred at -78.degree. C. for 30
minutes, then ice/water (300 mL) was added to form a precipitate.
The solid was collected by filtration, then washed with water and
hexane to afford
4,6-dichloro-N-(5-fluoro-2-nitrophenyl)pyrimidin-2-amine (9.32 g,
95%).
[0428] Step 2: A 250 mL flask charged with
4,6-dichloro-N-(5-fluoro-2-nitrophenyl)pyrimidin-2-amine (6.35 g,
21.03 mmol), Pd/C (10%, wet, 635.0 mg) and ethyl acetate (50 mL)
was degassed by three cycles of vacuum pumping and N.sub.2 purging,
and then filled with hydrogen from a hydrogen balloon. The mixture
was stirred at ambient temperature for 16 hours. The charcoal was
removed by filtration, and the solvent was evaporated. The residual
material was washed with hexane to afford
N.sup.1-(4,6-dichloropyrimidin-2-yl)-5-fluorobenzene-1,2-diamine as
a white solid (5.55 g, 97%).
[0429] Step 3: A mixture of
N.sup.1-(4,6-dichloropyrimidin-2-yl)-5-fluorobenzene-1,2-diamine
(2.57 g, 9.47 mmol), triethyl orthoacetate (6.06 g, 37.87 mmol),
acetic acid (6 mL) and acetonitrile (30 mL) was stirred at ambient
temperature for 18 hours. A saturated NaHCO.sub.3 solution was
added to the mixture portionwise at 0.degree. C., with resultant
bubbling of the mixture. The solution was added to the mixture
until the bubbling ceased. The product was then extracted with
ethyl acetate. The organic phase was washed with brine, dried over
MgSO.sub.4, then filtered and evaporated. The residual material was
washed with hexane to afford
1-(4,6-dichloropyrimidin-2-yl)-6-fluoro-2-methyl-1H-benzo[d]imidazole
as a brownish solid (2.41 g, 86%).
[0430] Step 4: A mixture of
1-(4,6-dichloropyrimidin-2-yl)-6-fluoro-2-methyl-1H-benzo[d]imidazole
(150.0 mg, 0.51 mmol), 4-methoxyaniline (125.0 mg, 1.01 mmol) and
acetonitrile (1 mL) was stirred at 80.degree. C. for 18 hours.
After cooling, ethyl ether was added to the mixture to form
6-chloro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(4-methoxypheny-
l)pyrimidin-4-amine as a precipitate, which was isolated by
filtration.
[0431] Step 5: To
6-chloro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(4-methoxypheny-
l)-pyrimidin-4-amine was added DMSO (2 mL) and NH.sub.4OH (27%, 0.1
mL). The reaction mixture was sealed, placed in a microwave oven
and heated at 170.degree. C. for 1 hour. The reaction mixture was
partitioned between ethyl acetate and water. The organic phase was
washed with water (2.times.20 mL) and brine, then dried over
MgSO.sub.4 and filtered through a silica gel pad (10 g). The
solvent was evaporated, and the residual material was triturated
with dichloromethane to afford the title compound as a white solid
(161.0 mg, 88%). m.p. 193-195.degree. C.
[0432] .sup.1H NMR (500 MHz, Acetone-d.sub.6).quadrature. .delta.
ppm 8.74 (s, 1H), 8.11 (dd, J=2.52, 10.40 Hz, 1H), 7.52 (dd,
J=5.20, 8.67 Hz, 1H), 7.34-7.43 (d, J=9.14 Hz, 2H), 7.01 (d, J=2.84
Hz, 1H), 6.94 (d, J=9.14 Hz, 2H), 6.49 (br. s., 2H), 5.76 (s, 1H),
3.79 (s, 3H), 2.84 (s, 3H); MS m/z 365.0 (100) [M+H].sup.+.
[0433] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 8 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00009 Cpd Name & Data 52
2-{[6-{[4-(difluoromethoxy)phenyl]amino}-2-(2-methyl-1H-
benzimidazol-1-yl)pyrimidin-4-yl]amino}ethanol .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. ppm 8.17 (1H, dd, J = 7.2, 1.5 Hz),
7.59 (1H, dd, J = 7.2, 1.5 Hz), 7.51 (2H, d, J = 9 Hz), 7.28 (1H,
m), 7.13 (2H, d, J = 9 Hz), 6.78 (1H, t, J = 75 Hz), 5.81 (1H, s),
3.75 (2H, t, J = 6 Hz), 3.53 (2H, br), 2.89 (3H, s); MS m/z 427.1
[M + H].sup.+ 57
2-{[2-(2-methyl-1H-benzimidazol-1-yl)-6-{[4-(trifluoromethyl)
phenyl]amino}pyrimidin-4-yl]amino}ethanol .sup.1H NMR (500 MHz,
Methanol-d.sub.4) .delta. ppm 8.13 (1H, d, J = 7.5 Hz), 7.71 (2H,
d, J = 7.5 Hz), 7.6 (1H, dd, J = 9, 1 Hz), 7.56 (2H, d, J =9 Hz),
7.27 (1H, m), 7.13 (2H, d, J = 9 Hz), 5.91 (1H, s), 3.76 (2H, t, J
= 6 Hz), 3.55 (2H, br), 2.89 (3H, s); MS m/z 429.2 [M + H].sup.+ 58
N.sup.4-(2-methoxyethyl)-2-(2-methyl-1H-benzimidazol-1-yl)-N.sup.6-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR
(Methanol-d.sub.4) .delta. ppm 8.15 (1H, d, J = 8 Hz), 7.67 (2H, d,
J = 8.5 Hz), 7.59 (1H, d, J = 8 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.26
(1H, m), 5.87 (1H, s), 3.58 (4H, br), 3.38 (3H, s), 2.87 (3H, s);
MS m/z 443.1 [M + H].sup.+ 59
N.sup.4-[4-(difluoromethoxy)phenyl]-N.sup.6-(2-methoxyethyl)-2-(2-
methyl-1H-benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. ppm 8.06 (1H, d, J = 7 Hz), 7.47
(1H, m), 7.38 (2H, d, J = 9 Hz), 7.15 (1H, m), 7.00 (2H, d, J = 9
Hz), 5.68 (1H, s), 3.28 (3H, s), 2.76 (3H, s); MS m/z 441.1 [M +
H].sup.+ 63
2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Methanol-d.sub.4) .delta. ppm 8.13 (1H, m), 7.73 (2H, d, J = 8.5
Hz), 7.61 (1H, m), 7.58 (2H, d, J = 8.5 Hz), 7.29 (2H, m), 5.95
(1H, s), 2.89 (3H, s); MS m/z 385.1 [M + H].sup.+ 64
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. ppm 8.19 (1H, dd, J = 11, 7.5 Hz),
7.67 (2H, d, J = 8.5 Hz), 7.6 (2H, d, J = 8.5 Hz), 7.43 (1H, dd, J
= 11, 7.5 Hz), 5.93 (1H, s), 2.9 (3H, s); MS m/z 421.1 [M +
H].sup.+ 73 2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. ppm 8.61 (1H, dd, J = 8, 1.5 Hz),
8.39 (1H, d, J = 4 Hz), 7.65 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J =
8.5 Hz), 7.28 (1H, dd, J = 8, 4 Hz), 5.91 (1H, s), 2.97 (3H, s); MS
m/z 386.2 [M + H].sup.+ 74
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. ppm 8.04 (1H, dd, J = 11, 7.5 Hz),
7.54 (1H, dd, J = 13.5, 1.5 Hz), 7.44 (1H, t, J = 8.5 Hz), 7.32
(1H, dd, J = 11, 7.5 Hz), 7.24 (1H, dd, J = 13.5, 1.5 Hz), 5.81
(1H, s), 2.78 (3H, s); MS m/z 439.1 [M + H].sup.+ 79
N-[4-(trifluoromethyl)phenyl]-2-(2,5,6-trimethyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.63 (s, 1H), 7.91 (s, 1H), 7.77 (d (AB),
J = 8.8 Hz, 2H), 7.63 (d (AB), J = 7.9 Hz, 2H), 7.34 (s, 1H), 6.92
(br. s., 2H), 5.85 (s, 1H), 2.79 (s, 3H), 2.31 (s, 3H), 2.26 (s,
3H); MS m/z 413.0 [M + H].sup.+ 80
N-[3-fluoro-4-(trifluoromethyl)phenyl]-2-(2-methyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.90 (s, 1H), 8.05-8.10 (m, 1H), 7.89 (d,
J = 14.2 Hz, 1H), 7.65 (t, J = 8.7 Hz, 1H), 7.57- 7.62 (m, 1H),
7.41 (d, J = 8.5 Hz, 1H), 7.20-7.28 (m, 2H), 7.05 (br. s, 1H), 5.91
(s, 1H), 2.82 (s, 3H); MS m/z 403.1 [M + H].sup.+ 85
2-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.68 (s, 1H), 8.31 (d, J = 1.6 Hz,
1H), 7.73 (d (AB), J = 8.2 Hz, 2H), 7.65 (d (AB), J = 8.5 Hz, 2H),
7.55 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 8.5, 1.9 Hz, 1H), 6.97-7.07
(m, 2H), 5.87 (s, 1H), 2.83 (s, 3H); MS m/z 463.0 [M + H].sup.+ 86
2-(2,6-dimethyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)
phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.63 (s, 1H), 7.88 (s, 1H), 7.74 (d (AB), J = 8.5 Hz,
2H), 7.61 (d (AB), J = 8.5 Hz, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.04
(dd, J = 8.2, 1.3 Hz, 1H), 6.93 (br. s., 2H), 5.84 (s, 1H), 2.77
(s, 3H), 2.34 (s, 3H); MS m/z 339.0 [M + H].sup.+ 87
2-(6-ethyl-2-methyl-1H-benzimidazol-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.68 (s, 1H), 7.89 (s, 1H), 7.77 (d
(AB), J = 8.5 Hz, 2H), 7.61 (d (AB), J = 8.8 Hz, 2H), 7.52 (d, J =
8.2 Hz, 1H), 7.10 (dd, J = 8.2, 1.3 Hz, 1H), 6.95 (br. s., 2H),
5.86 (s, 1H), 2.81 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 1.15 (t, J =
7.6 Hz, 3H); MS m/z 413.0 [M + H].sup.+ 88
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.68 (s, 1H), 7.85 (dd, J = 9.6, 2.0
Hz, 1H), 7.68-7.73 (d (AB), J = 8.5 Hz, 2H), 7.61-7.68 (d (AB), J =
8.8 Hz, 2H), 7.14 (td, J = 10.4, 2.2 Hz, 1H), 7.04 (br. s., 2H),
5.89 (s, 1H), 2.83 (s, 3H); MS m/z 421 [M + H].sup.+ 89
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-
(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.92 (s, 1H), 7.80-7.84 (m, J = 9.5,
2.2 Hz, 1H), 7.80 (dd, J = 14.0, 1.1 Hz, 1H), 7.66 (t, J = 8.7 Hz,
1H), 7.38 (dd, J = 8.5, 1.3 Hz, 1H), 7.16 (dd, J = 10.4, 2.2 Hz,
1H), 7.11-7.16 (m, 2H), 5.91 (s, 1H); MS m/z 439 [M + H].sup.+ 90
2-{[2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-6-{[4-
(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanol .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.69 (br. s., 1H), 7.83 (d,
J = 9.1 Hz, 1H), 7.70 (d (AB), J = 7.9 Hz, 2H), 7.64 (d (AB), J =
8.8 Hz, 2H), 7.15 (td, J = 10.3, 2.4 Hz, 1H), 5.96 (br. s, 1H),
4.83 (br. s, 1H), 3.59 (q, J = 5.7 Hz, 2H), 3.38-3.51 (m, 2H), 2.85
(s, 3H); MS m/z 465.0 [M + H].sup.+ 91
2-(6-ethenyl-2-methyl-1H-benzimidazol-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.68 (s, 1H), 8.17 (d, J = 1.6 Hz,
1H), 7.76 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.54 (d, J
= 8.2 Hz, 1H), 7.39 (dd, J = 8.4, 1.4 Hz, 1H), 6.98 (br. s., 1H),
6.75 (dd, J = 17.7, 11.0 Hz, 1H), 5.87 (s, 1H), 5.64 (dd, J = 17.7,
0.6 Hz, 1H), 5.13 (dd, J = 11.0, 0.9 Hz, 1H), 2.82 (s, 1H); MS m/z
399 [M + H].sup.+ 92
2-(2-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. ppm 8.37 (1H, dd, J = 9, 3 Hz), 8.3
(1H, m), 7.72 (2H, d, J = 8.5 Hz), 7.6 (2H, d, J = 8.5 Hz), 5.96
(1H, s), 1.33 (2H, m), 1.19 (2H, m); MS m/z 430.1 [M + H].sup.+ 94
2-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. ppm 8.52 (1H, dd, J = 9, 3 Hz), 8.33
(1H, dd, m), 7.65 (2H, d, J = 9 Hz), 7.60 (2H, d, J = 9 Hz), 5.95
(1H, s), 3.00 (3H, s); MS m/z 404.2 [M + H].sup.+ 101
N-[4-(difluoromethoxy)-3-fluorophenyl)-2-(5,6-difluoro-2-
methyl-1H-benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. ppm 8.19 (1H, dd, J = 11, 7.5 Hz),
7.53 (1H, dd, J = 13, 2.5 Hz), 7.44 (1H, dd, J = 10, 7.5 Hz), 7.23
(2H, m), 5.86 (1H, s), 2.89 (3H, s); MS m/z 437.1 [M + H].sup.+ 102
N-[4-(difluoromethoxy)phenyl]-2-(5,6-difluoro-2-methyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR
(Methanol-d.sub.4) .delta. ppm 8.18 (1H, dd, J = 11.5, 7.5 Hz),
7.44 (2H, d, J = 9 Hz), 7.40 (1H, dd, J = 11.5, 7.5 Hz), 7.14 (2H,
d, 9 Hz), 6.77 (1H, t, J = 75 Hz), 5.79 (1H, s), 2.87 (1H, s); MS
m/z 419.1 [M + H].sup.+ 103
2-(2-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-1-yl)-N-
[4-(difluoromethoxy)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Methanol-d.sub.4) .delta. ppm 8.38 (1H, dd, J = 9, 3 Hz), 8.29
(1H, m), 7.5 (2H, d, J = 9 Hz), 7.14 (2H, d, J = 7 Hz), 6.78 (1H,
t, J = 75 Hz), 3.4 (1H, m), 1.3 (2H, m), 1.17 (2H, m); MS m/z 428.1
[M + H].sup.+ 104
2-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, METHANOL-d.sub.4) .delta. ppm 8.77 (d, J = 2.21 Hz, 1H), 8.43
(d, J = 2.21 Hz, 1H), 7.60 (d, J = 6.94 Hz, 4H), 5.91 (s, 1H) 3.05
(s, 3H); MS m/z 420.1 [M + H].sup.+ 105
2-(6-chloro-2-ethyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, METHANOL-d.sub.4) .delta. ppm 8.66 (d, J = 2.52 Hz, 1H), 8.38
(d, J = 2.21 Hz, 1H), 7.62 (dd, J = 19.50, 9.50 Hz, 4H), 5.92 (s,
1H), 3.48 (q, J = 7.60 Hz, 2H), 1.39 (t, J = 7.41 Hz, 3H); MS m/z
434.1 [M + H].sup.+ 146
2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(methylsulfanyl)
phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.45-8.50 (1H, s) 8.25- 8.30 (1H, m)
7.55-7.59 (1H, m) 7.50 (2H, s) 7.32 (2H, s) 7.17- 7.25 (2H, m)
6.24-6.33 (2H, m) 5.92 (1H, s) 2.51 (3H, s) 2.07 (3H, s); MS m/z
363.2 [M + H].sup.+ 147
2-[2-(1-methylcyclopropyl)-1H-benzimidazol-1-yl]-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.72-8.80 (1H, s) 7.66- 7.76 (3H,
m) 7.46 (3H, d, J = 0.63 Hz) 7.08 (2H, s) 6.18-6.28 (2H, m) 5.97
(1H, s) 1.30 (3H, s) 1.10 (2H, s) 0.61 (2H, d, J = 2.21 Hz); MS m/z
425.2 [M + H].sup.+ 148
N-[4-(difluoromethoxy)phenyl]-2-[2-(1-methylcyclopropyl)-1H-
benzimidazol-1-yl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. .quadrature.ppm 8.49 (1H, s) 8.16-8.20
(1H, m) 7.55-7.60 (3H, m) 7.15-7.23 (4H, m) 6.94 (1H, t, J = 75.00
Hz) 6.27 (2H, br. s.) 5.92 (1H, s) 3.32 (2H, q, J = 7.57 Hz) 1.34
(3H, t, J = 6.90 Hz); MS m/z 423.3 [M + H].sup.+ 153
2-(2-ethyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 9.66 (s, 1H), 7.96-8.10 (m, 1H), 7.73 (d, J = 8.83 Hz, 2H),
7.58-7.64 (m, 3H), 7.18-7.26 (m, 2H), 6.96 (br. s, 2H), 5.88 (s,
1H), 3.22-3.29 (m, 2H), 1.29 (t, J = 7.41 Hz, 3H); m.p. 183-185; MS
m/z 415.4 (100) [M + H].sup.+ 416.4 (30) 156
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-1H-benzimidazol-1-
yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.49 (1H, s) 8.16-8.20, (1H, m) 7.55-7.60 (3H, m)
7.15-7.23 (4H, m) 6.94 (1H, t, J = 75.00 Hz) 6.27 (2H, br. s.) 5.92
(1H, s) 3.32 (2H, q, J = 7.57 Hz) 1.34 (3H, t, J = 6.90 Hz); MS m/z
397.2 [M + H].sup.+ 157
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.71 (1H, s) 8.13-8.18 (1H, m)
7.68-7.75 (1H, m) 7.57-7.62 (1H, m) 7.26-7.35 (2H, m) 7.16-7.25
(2H, m) 6.94 (1H, t, J = 73.80 Hz) 6.36 (2H, s) 5.98 (1H, s) 3.33
(2H, q, J = 7.60 Hz) 1.35 (3H, t, J = 7.90 Hz); MS m/z 415.2 [M +
H].sup.+ 182 2-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-N-
[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.85 (br. s., 1H) 8.38 (d, J =
7.88 Hz, 1H), 7.83 (d, J = 8.51 Hz, 2H), 7.66 (d, J = 8.51 Hz, 2H),
7.56 (d, J = 7.57 Hz, 1H), 7.23 (td, J = 7 .57, 1.26 Hz, 1H),
7.13-7.19 (m, 1H), 6.41 (br. s., 2H), 6.02 (s, 1H), 2.63 (s, 3H);
MS m/z 418.3 [M + H].sup.+ 196
2-(2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. ppm 8.13 (1H, m), 7.58 (1H, m), 7.3-7.25 (4H, m), 7.13 (1H,
d, J = 8 Hz), 5.81 (1H, s), 2.86 (3H, s), 2.31 (3H, s); MS m/z
331.1 [M + H].sup.+ 197
N-(4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. ppm 8.13 (1H, m), 7.58 (1H, m), 7.33 (2H, d, J = 9 Hz),
7.27 (2H, m), 6.94 (2H, d, J = 9 Hz), 5.72 (1H, s), 3.81 (3H, s),
2.86 (3H, s); MS m/z 347.1 [M + H].sup.+ 198
N-[4-(dimethylamino)phenyl)-2-(2-methyl-1H-benzimidazol-1-
yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. ppm 8.12 (1H, m), 7.58 (1H, m), 7.27 (2H, m), 7.22 (2H, d,
J = 9 Hz), 6.81 (2H, d, J = 9 Hz), 5.67 (1H, s), 2.92 (6H, s), 2.86
(3H, s); MS m/z 360.4 [M + H].sup.+ 205
N-(1,3-benzodioxol-5-yl)-2-(2-methyl-1H-benzimidazol-1-
yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta. ppm 9.04 (1H, s), 8.20-8.17 (1H, m), 7.61-7.58 (1H, m),
7.27-7.21 (2H, m), 7.15 (1H, d, J = 1.8 Hz), 6.91 (1H, d, J = 8.2
Hz), 6.86 (1H, dd, J = 8.2, 1.8 Hz), 6.76 (2H, br s), 6.03 (2H, s),
5.72 (1H, s), 2.84 (3H, s); m.p. 166- 167; MS m/z 359.1 [M +
H].sup.+
206 N-(2,2-difluoro-1,3-benzodioxol-5-yl)-2-(2-methyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. ppm 9.40 (1H, s), 8.13 (1H, dd, J = 7.0, 1.2
Hz), 7.71 (1H, d, J = 2.1 Hz), 7.61 (1H, dd, J = 7.0, 1.2 Hz), 7.38
(1H, d, J = 8.6 Hz), 7.28-7.20 (3H, m), 6.88 (2H, br s), 5.79 (1H,
s), 2.83 (3H, s); m.p.: 141-142; MS m/z 397.1 [M + H].sup.+ 207
N-(3-fluoro-4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-
yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta. ppm 9.19 (1H, s), 8.18-8.15 (1H, m), 7.62-7.59 (1H, m),
7.50 (1H, dd, J = 13.6, 2.2 Hz), 7.28- 7.13 (4H, m), 6.82 (2H, br
s), 5.76 (1H, s), 3.85 (3H, s), 2.84 (3H, s); m.p.: 233-234; MS m/z
365.2 [M + H].sup.+ 208
N-(6-methoxypyridin-3-yl)-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta.
ppm 9.10 (1H, s), 8.24 (1H, d, J = 2.6 Hz), 8.14 (1H, dd, J = 8.4,
1.2 Hz), 7.84 (1H, dd, J = 8.8, 2.7 Hz), 7.59 (1H, dd, J = 8.4, 1.5
Hz), 7.27-7.20 (2H, m), 6.85 (1H, d, J = 8.8 Hz), 6.80 (2H, br s),
5.69 (1H, s), 3.87 (3H, s), 2.80 (3H, s); m.p.: 118-119; MS m/z
348.2 [M + H].sup.+ 209
N-(4-chlorophenyl)-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. ppm 8.11 (1H, m), 7.58 (1H, m), 7.45 (2H, d, J = 9 Hz),
7.28-7.23 (4H, m), 5.83 (1H, s), 2.85 (3H, s); MS m/z 351.6 [M +
H].sup.+ 210
4-{[6-amino-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]
amino}benzonitrile .sup.1H NMR (500 MHz, Methanol-d.sub.4) .delta.
ppm 8.1 (1H, m), 7.75 (2H, d, J = 9 Hz), 7.61 (3H, m), 7.28 (2H,
m), 5.95 (1H, s), 2.88 (3H, s); MS m/z 342.3 [M + H].sup.+ 211
2-(2-methyl-1H-benzimidazol-1-yl)-N-(4-nitrophenyl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. ppm 8.16 (2H, m), 8.12 (1H, m), 7.79 (2H, m), 7.62 (1H, m),
7.29 (2H, m), 5.99 (1H, s), 2.90 (3H, s); MS m/z 362.3 [M +
H].sup.+ 212 N-(4-bromophenyl)-2-(2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. ppm 8.11 (1H, m), 7.59 (1H, m), 7.42 (4H, m), 7.27 (2H, m),
5.84 (1H, s), 2.86 (3H, s); MS m/z 397.0 [M + H].sup.+ 221
2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethoxy)
phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Methanol-d.sub.4) .delta. ppm 8.11 (1H, m), 7.57 (1H, m), 7.54 (2H,
d, 9 Hz), 7.24 (2H, m), 7.19 (2H, d, J = 9 Hz), 5.84 (1H, S), 2.85
(3H, s); MS m/z 401.0 [M + H].sup.+ 234
N-[4-(difluoromethoxy)phenyl]-2-(2-methyl-1H-benzimidazol-1-
yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Methanol-d.sub.4)
.delta. ppm 8.11 (1H, m), 7.57 (1H, m), 7.45 (2H, d, 7 Hz), 7.25
(2H, m), 7.09 (2H, d, J = 9 Hz), 5.48 (1H, S), 2.85 (3H, s); MS m/z
383.1 [M + H].sup.+ 235
N-[4-(difluoromethoxy)-3-fluorophenyl)-2-(2-methyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Methanol-d.sub.4) .delta. ppm 8.10 (1H, m), 7.58-7.54 (2H, m),
7.27-7.14 (4H, m), 5.47 (1H, s), 2.85 (3H, s); MS m/z 401.0 [M +
H].sup.+ 263
N-(4-chlorophenyl)-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.59 (s, 1H), 8.05 (dd, J = 2.52, 10.40 Hz, 1H),
7.47-7.61 (m, 4H), 7.31-7.42 (m, 2H), 6.92-7.08 (m, 1H), 6.37 (br.
s., 1H), 5.93 (s, 1H), 2.77-2.88 (m, 3H); m.p.: 183-185; MS m/z
369.0 [M + H].sup.+ 264
2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.37 (br. s., 1H), 8.10 (dd, J = 2.52, 10.40 Hz, 1H),
7.52 (dd, J = 5.04, 8.83 Hz, 1H), 7.34 (d, J = 8.20 Hz, 2H), 7.18
(d, J = 8.20 Hz, 2H), 6.94-7.07 (m, 1H), 6.27 (br. s., 2H),
5.82-5.96 (m, 1H), 2.85 (s, 3H), 2.32 (s, 3H); m.p.: 210-212; MS
m/z 349.0 [M + H].sup.+ 266
N-[4-(dimethylamino)phenyl]-2-(6-fluoro-2-methyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.11-8.16 (m, 1H), 8.07- 8.10 (m, 1H),
7.47-7.56 (m, 1H), 7.23 (d, J = 9.77 Hz, 2H), 6.94- 7.05 (m, 1H),
6.79 (d, J = 8.83 Hz, 2H), 6.09-6.25 (br, s, 2H), 5.67 (s, 1H),
2.94 (s, 6H), 2.85 (s, 3H); m.p.: 122-125; MS m/z 378.0 [M +
H].sup.+ 267 N-(4-chloro-3-fluorophenyl)-2-(6-fluoro-2-methyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.80 (s, 1H), 8.03 (dd, J = 2.52,
10.09 Hz, 1H), 7.67 (dd, J = 2.36, 11.82 Hz, 1H), 7.54 (dd, J =
5.04, 8.51 Hz, 1H), 7.44 (t, J = 8.67 Hz, 1H), 7.27-7.37 (m, 1H),
6.95-7.09 (m, 1H), 6.46 (br. s., 2H), 5.99 (s, 1H), 2.85 (s, 3H);
m.p.: 225-227; MS m/z 387.0 [M + H].sup.+ 268
2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(3-methylphenyl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.37-8.52 (m, 1H), 8.14 (dd, J = 2.68, 10.25 Hz, 1H),
7.55 (dd, J = 5.20, 8.67 Hz, 1H), 7.40 (br. s., 1H), 7.22-7.30 (m,
2H), 7.00-7.11 (m, 1H), 6.94 (d, J = 6.62 Hz, 1H), 6.27-6.40 (s,
2H), 5.91-6.06 (s, 1H), 2.89 (s, 3H), 2.34 (s, 3H); m.p.: 203-205;
MS m/z 349.0 [M + H].sup.+ 269
N-(2,2-difluoro-1,3-benzodioxol-5-yl)-2-(6-fluoro-2-methyl-1H-
benzimidazol-1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.62 (s, 1H), 8.04 (dd, J = 2.52,
10.40 Hz, 1H), 7.56 (d, J = 1.89 Hz, 1H), 7.53 (dd, J = 5.04, 8.83
Hz, 1H), 7.21-7.29 (m, 2H), 6.97-7.05 (m, 1H), 6.38 (br. s., 2H),
5.91 (s, 1H), 2.83 (s, 3H); m.p.: 212-215; MS m/z 415.0 [M +
H].sup.+
Example 9
2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]pyrim-
idine-4,6-diamine (Cpd 154)
##STR00082##
[0435] A mixture of
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]py-
ridine (53 mg, 0.205 mmol), di-tert-butyl
2-chloro-6-(4-(trifluoromethyl)phenylamino)pyrimidin-4-yliminodicarbonate
(110 mg, 0.225 mmol), tris(dibenzylideneacetone) dipalladium(0) (18
mg, 0.02 mmol) tricyclohexylphosphine (14 mg, 0.051 mmol), and
potassium phosphate (87.0 mg, 0.41 mmol) in dioxane (3.5 mL) and
water (0.1 mL) was degassed by purging with argon, and then was
heated at 85.degree. C. for 3 hours. The solution was cooled and
filtered via plug of Celite. The filtrate was concentrated and
purified by silica gel column chromatography giving tert-butyl
3,3-dimethylbutanoyl(2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6-(4-(triflu-
oromethyl)phenylamino)-pyrimidin-4-yl)carbamate (25 mg, 21%) as a
clear oil, which was dissolved in dichloromethane (1 mL) and
treated with TFA (0.1 mL) at 0.degree. C. The resulting mixture was
stirred at room temperature for 4 hours. The solvent was
concentrated, and the residual material was partitioned between
ethyl acetate and a saturated NaHCO.sub.3 solution. The organic
layer was separated, dried over Na.sub.2SO.sub.4, then filtered and
evaporated. The residual material was triturated with ethyl ether
to afford the title compound as a yellow solid (8 mg, 50%).
[0436] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 8.55 (d,
J=8.8 Hz, 1H), 8.42 (br. s., 1H), 8.37 (d, J=6.6 Hz, 1H), 7.70 (d,
J=8.8 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H), 7.13 (ddd, J=8.4, 7.3, 0.8
Hz, 1H), 6.77 (td, J=6.6, 1.6 Hz, 1H), 5.82 (br. s., 2H), 5.77 (s,
1H), 2.66 (s, 3H); MS m/z 385.3 [M+H].sup.+.
[0437] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 9 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00010 Cpd Name & Data 70
N-[4-(trifluoromethyl)phenyl]-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimi-
dine-4,6-diamine .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.54
(2H, d, J = 8.7 Hz), 7.48 (2H, d, J = 8.7 Hz), 5.86 (1H, s), 5.60
(2H, v br), 3.73 (3H, s), 2.53 (3H, s), 2.50 (3H, s); m.p.
270-271.degree. C.; MS m/z 363.0 [M + H].sup.+
Example 10
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methoxyphenyl)pyr-
imidine-4,6-diamine (Cpd 179)
##STR00083##
[0439] Step 1. To a solution of methyl
carbamimidothioate-(H.sub.2SO.sub.4).sub.1/2 salt (45.90 g, 0.33
mol) and dimethyl 2-fluoromalonate (45.03 g, 0.30 mol) in MeOH (450
mL) at 0.degree. C. was slowly added sodium methoxide (4.37 M in
MeOH, 226 mL, 0.99 mol). The mixture was stirred for 16 hours at
room temperature. The solution was concentrated under reduced
pressure. The resulting slurry was diluted with water (50 mL) and
acidified to about pH 2 by using a 6N HCl solution. The resulting
precipitate was collected, washed with water and dried under vacuum
to give 5-fluoro-2-(methylthio)pyrimidine-4,6-diol (46.85 g,
88%).
[0440] To a solution of 5-fluoro-2-(methylthio)pyrimidine-4,6-diol
(13.2 g, 74.9 mmol) in POCl.sub.3 (60 mL) was added a catalytic
amount of PCl.sub.5 (60 mg). The mixture was heated at 100.degree.
C. for 16 hours and then concentrated under reduced pressure. To
the mixture was carefully added ice water (150 mL). The resulting
precipitate was removed by filtration, washed with water, then
dried under nitrogen to give
4,6-dichloro-5-fluoro-2-(methylthio)pyrimidine (13.5 g, 85%).
[0441] To a solution of
4,6-dichloro-5-fluoro-2-(methylthio)pyrimidine (12.4 g, 58.8 mmol)
in MeOH (150 mL) was added potassium peroxymonosulfate
(2KHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4) (108.7 g, 176.4 mmol) and
water (70 mL). The mixture was stirred for 6 hours at room
temperature. The salt was removed by filtration, then washed with
MeOH until no more product was observed. The combined organic
mixture was concentrated then ice water was added to the mixture to
provide a precipitate, which was filtered and washed by water. The
solid was dried under nitrogen to yield
4,6-dichloro-5-fluoro-2-(methylsulfonyl)pyrimidine as a white solid
(14.6 g, 99%).
##STR00084##
[0442] Step 2. A solution of 4-fluorobenzene-1,2-diamine (3.78 g,
30 mmol) in acetic acid (10.0 mL) was microwaved for 1 hour at
180.degree. C. The mixture was concentrated under reduced pressure
and triturated with ether to yield
6-fluoro-2-methyl-1H-benzo[d]imidazole as a brownish solid (4.31 g,
88%).
[0443] To a solution of 6-fluoro-2-methyl-1H-benzo[d]imidazole
(2.31 g, 15.4 mmol) in THF (50 mL) and DMF (10 mL) at -78.degree.
C. was added 60% NaH (648 mg, 16.2 mmol). The mixture was stirred
for about 10 minutes at room temperature. To the mixture at
-78.degree. C. was added
4,6-dichloro-5-fluoro-2-(methylsulfonyl)pyrimidine (3.74 g, 15.3
mmol) in one portion, then the mixture was stirred at -78.degree.
C. for 15 minutes. The reaction mixture was quenched with a 1M HCl
solution (18 mL) and a crude mixture was extracted with EtOAc (200
mL). The organic layer was concentrated under reduced pressure, and
purified by column chromatography (5-30% EtOAc/hexanes) to give
1-(4,6-dichloro-5-fluoropyrimidin-2-yl)-6-fluoro-2-methyl-1H-benzo[d]imid-
azole as a white solid (1.83 g, 38%).
##STR00085##
[0444] Step 3. The mixture of
1-(4,6-dichloro-5-fluoropyrimidin-2-yl)-6-fluoro-2-methyl-1H-benzo[d]-imi-
dazole (63 mg, 0.2 mmol) and 4-methoxyaniline (49 mg, 0.4 mmol) in
EtOH (1 mL) was stirred for 1 hour at 60.degree. C. The precipitate
was obtained by adding water (10 mL). The product
(6-chloro-5-fluoro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(4-me-
thoxyphenyl)-pyrimidin-4-amine) was removed by filtration and
washed with water several times. The resulting crude
6-chloro-5-fluoro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N-(4-met-
hoxyphenyl)pyrimidin-4-amine was used in the next step without
further purification.
[0445] To the crude product in DMSO (5 mL) was added 14 M aqueous
NH.sub.4OH (3 mL). The suspended mixture was heated for 18 hours at
100.degree. C. until all the starting material was consumed. After
cooling to room temperature, water (10 mL) was added to the mixture
to form a precipitate. The precipitate was isolated by filtration
and washed with water several times. The resulting product was
dried under nitrogen to give the title compound as an off-white
solid (72 mg, 94%).
[0446] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 8.30 (1H,
br. s.) 7.94 (1H, dd, J=9.93, 2.36 Hz) 7.48-7.56 (3H, m) 6.93-7.05
(3H, m) 6.48 (2H, br. s.) 3.83 (3H, s) 2.75 (3H, s); MS m/z 383.2
[M+H].sup.+.
[0447] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 10 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00011 Cpd Name & Data 95
5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)pheny-
l]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.60 (1H, s) 8.02 (1H, dd, J = 7.25, 2.21 Hz) 7.86 (2H,
d, J = 8.51 Hz) 7.65 (2H, d, J = 8.51 Hz) 7.56-7.60 (1H, m) 7.29
(2H, 2) 7.17-7.26 (2H, m) 2.75 (3H, s); MS m/z 403.2 [M + H].sup.+
106
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methyl-1H-benzimidazol-1-y-
l)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.39 (1H, s) 7.97 (1H, d, J = 7.88 Hz) 7.59-7.64 (2H,
m) 7.42 (1H, d, J = 7.25 Hz) 7.01-7.11 (4H, m) 6.83 (1H, t, J =
74.56 Hz) 6.40 (2H, br. s.) 2.63 (3H, s); MS m/z 401.1 [M +
H].sup.+ 107
2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoromethyl)phenyl-
]pyrimidine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.69 (1H, br. s.) 7.91 (1H, d, J = 7.88 Hz) 7.85 (2H,
d, J = 8.51 Hz) 7.53 (2H, d, J = 8.51 Hz) 7.47 (1H, d, J = 6.94 Hz)
7.02-7.13 (2H, m) 6.54 (2H, br. s.) 3.14 (2H, q, J = 7.36 Hz) 1.20
(3H, t); MS m/z 417.1 [M + H].sup.+ 108
5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromet-
hyl)phenyl]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.85 (1H, br. s.) 8.13 (1H, dd, J =
9.46, 5.04 Hz) 7.98 (2H, d, J = 8.51 Hz) 7.71 (2H, d, J = 8.51 Hz)
7.31 (1H, dd, J = 9.62, 2.36 Hz) 6.96-7.04 (1H, m) 6.72 (2H, br.
s.) 2.82 (3H, s); MS m/z 421.1 [M + H].sup.+ 109
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromet-
hyl)phenyl]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.85 (1H, br. s.) 7.89-8.00 (3H, m)
7.71 (2H, d, J = 8.51 Hz) 7.56 (1H, dd, J = 8.83, 5.04 Hz)
7.02-7.08 (1H, m) 6.76 (2h, br. s.) 2.82 (3H, s); MS m/z 421.1 [M +
H].sup.+ 110
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimi-
dazol-1-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.01 (1H, dd, J = 10.40, 2.21 Hz) 7.81
(1H, br. s.) 7.68-7.72 (2H, m) 7.65 (1H, dd, J = 8.83, 5.04 Hz)
7.26-7.31 (2H, m) 7.12-7.18 (1H, m) 6.87 (1H, t, J = 74.56 Hz) 5.87
(2H, br. s.) 2.87 (3H, s); MS m/z 419.1 [M + H].sup.+ 111
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(6-fluoro-2-methyl-1-
H-benzimidazol- 1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.73 (1H, s) 7.93 (1H, dd, J = 9.93,
2.36 Hz) 7.80 (1H, dd, J = 1 2.93, 2.52 Hz) 7.51-7.59 (2H, m) 7.36
(1H, t, J = (1H, t, J = 8.99 Hz) 7.01-7.08 (1H, m) 6.98 (1H, t, J =
73.77 Hz) 6.71 (2H, br. s.) 2.81 (3H, s); MS m/z 437.1 [M +
H].sup.+ 112
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(5-fluoro-2-methyl-1-
H-benzimidazol- 1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.19 (1H, dd, J = 9.46, 5.04 Hz) 7.94
(1H, br. s.) 7.79 (1H, dd, J = 12.93, 2.52 Hz) 7.35-7.50 (3H, m)
7.09-7.16 (1H, m) 6.87 (1H, t, J = 73.77 Hz) 5.91 (2H, s) 2.90 (3H,
s); MS m/z 437.2 [M + H].sup.+ 113
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(5-fluoro-2-methyl-1H-benzimi-
dazol-1-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.19 (1H, dd, J = 9.46, 5.04 Hz) 7.81
(1H, br. s.) 7.67-7.74 (2H, m) 7.42 (1H, dd, J = 9.46, 2.84 Hz)
7.25-7.32 (2H, m) 7.07-7.16 (1H, m) 6.88 (1H, t, J = 74.56 Hz) 5.84
(2H, s) 2.88 (3H, s); MS m/z 419.1[M + H].sup.+ 114
2-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-5-fluoro-N-[4-(tri-
fluoromethyl) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.91 (1H, s) 8.57-8.58 (1H, m) 8.39
(1H, d, J = 2.21 Hz) 7.93 (2H, d, J = 8.51 Hz) 7.75 (2H, d, J =
8.51 Hz) 6.83 (2H, br. s.) 2.93 (3H, s); MS m/z 438.3 [M + H].sup.+
115
2-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(difluorometh-
oxy)phenyl]-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.47 (1H, br. s.) 8.41 (1H, d, J =
2.21 Hz) 8.23 (1H, d, J = 2.52 Hz) 7.55 (2H, d, J = 8.83 Hz) 7.11
(2H, d, J = 9.14 Hz) 6.85 (1H, t, J = 74.10 Hz) 6.55 (2H, br. s.)
2.74 (3H, s); MS m/z 436.2 [M + H].sup.+ 116
2-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(difluorometh-
oxy)-3- fluorophenyl]-5-fluoropyrimidine-4,6-diamine .sup.1H NMR
(500 MHz, Acetone-d.sub.6) .delta. ppm 8.77 (1H, s) 8.56 (1H, d, J
= 2.21 Hz) 7.73 (1H, dd, J = 12.61, 2.52 Hz) 7.50-7.56 (1H, m) 7.39
(1H, t, J = 8.99 Hz) 7.00 (1H, t, J = 73.61 Hz) 6.79 (2H, br. s.)
2.91 (3H, s); MS m/z 454.1 [M + H].sup.+ 117
2-(2-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-1-yl)-5-fluoro-N-[4-
- (trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.90 (1H, s) 8.22-8.34 (2H, m)
7.99 (2H, d, J = 8.20 Hz) 7.71 (2H, d, J = 8.20 Hz) 6.84 (2H, br.
s.) 3.20-3.29 (1H, m) 1.26-1.34 (2H, m) 1.06-1.12 (2H, m); MS m/z
448.1 [M + H].sup.+ 119
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(2-methyl-1H-benzimi-
dazol-1-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.71 (1H, br. s.) 8.12 (1H, d, J =
8.51 Hz) 7.87 (1H, dd, J = 13.08, 2.68 Hz) 7.52-7.62 (2H, m) 7.34
(1H, t, J = 8.99 Hz) 7.17-7.27 (2H, m) 6.98 (1H, t, J = 73.93 Hz)
6.6 (2H, br. s.) 2.81 (3H, s); MS m/z 419.3 [M + H].sup.+ 120
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoromethyl)-
phenyl]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.85 (1H, br. s.) 8.06 (2H, d, J =
8.51 Hz) 8.00 (1H, dd, J = 7.25, 1.26 Hz) 7.67 (2H, d, J = 8.51 Hz)
7.50-7.56 (1H, m) 7.14-7.25 (2H, m) 6.70 (2H, br. s.) 2.96-3.05
(1H, m) 1.20-1.26 (2H, m) 1.00-1.06 (2H, m); MS m/z 429.2 [M +
H].sup.+ 121
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)phenyl]-5-
- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.40 (1H, s) 7.86 (1H, dd, J = 7.72,
1.73 Hz) 7.63-7.70 (2H, m) 7.36 (1H, d, J = 9.14 Hz) 6.98-7.08 (4H,
m) 6.64-6.97 (1H, m) 6.41 (2H, s) 2.83-2.91 (1H, m) 1.01-1.07 (2H,
m) 0.80-0.87 (2H, m); MS m/z 427.2 [M + H].sup.+ 122
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)-3-fluoro-
phenyl]-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.73 (1H, s) 7.96-8.03 (2H, m)
7.50-7.60 (2H, m) 7.32 (1H, t, J = 8.83 Hz) 7.20 (2H, dtd, J =
19.70, 7.33, 7.33, 1.26 Hz) 6.80-7.13 (2H, m) 6.66 (2H, s)
2.97-3.05 (1H, m) 1.23 (2H, dd, J = 5.04, 2.84 Hz) 1.01-1.08 (2H,
m); MS m/z 445.2 [M + H].sup.+ 123
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluor-
opyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.52-8.56 (1H, s) 8.04-8.09 (1H, m) 7.76 (2H, d, J =
9.14 Hz) 7.57-7.61 (1H, m) 7.19 (4H, d, J = 8.83 Hz) 6.97 (1H, m)
6.49-6.58 (2H, s) 3.25 (2H, d, J = 7.57 Hz) 1.29-1.34 (3H, m); MS
m/z 415.3[M + H].sup.+ 124
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-1H-benzimidazol-1-yl-
)-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.72 (1H, s) 8.05-8.09 (1H, m) 7.87
(1H, dd, J = 12.93, 2.52 Hz) 7.59-7.63 (1H, m) 7.54 (1H, ddd, J =
8.91, 2.60, 1.42 Hz) 7.33 (1H, t, J = 8.83 Hz) 7.18-7.27 (2H, m)
6.98 (1H, t, J = 74.70 Hz) 6.64 (2H, 2) 3.28 (2H, q, J = 7.36 Hz)
1.35 (3H, t, J = 7.90 Hz); Ms m/z 433.3 [M + H].sup.+ 125
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluor-
omethyl) - phenyl] pyrimidine4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.69-8.75 (1H, m) 7.97-8.04 (1H, m)
7.76-7.83 (2H, m) 7.55-7.61 (2H, m) 7.30-7.37 (1H, m) 6.59-6.69
(2H, m) 2.68 (3H, s); MS m/z 439.2 [M + H].sup.+ 126
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(5,6-difluoro-2-methyl-1H-ben-
zimidazol-1-yl)- 5-fluoropyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.72-8.76 (1H, m) 8.12-8.18 (1H,
m) 7.74-7.80 (1H, m) 7.45-7.55 (2H, m) 7.34-7.40 (1H, m) 6.90-7.05
(1H, m) 6.69-6.78 (2H, m) 2.82 (3H, s); MS m/z 455.2 [M + H].sup.+
127
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluor-
omethyl) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.85-8.90 (1H, m) 7.93-7.99 (2H, m)
7.77-7.82 (1H, m) 7.72 (2H, s) 6.90-6.97 (1H, m) 6.73-6.84 (2H, m)
2.83 (3H, s); MS m/z 439.2 [M + H].sup.+ 128
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(4,6-difluoro-2-methyl-1H-ben-
zimidazol-1- yl)-5-fluoropyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.71-8.79 (1H, m) 7.74-7.82 (2H,
m) 7.48-7.55 (1H, m) 7.33-7.40 (1H, m) 6.83-7.15 (3H, m) 6.70-6.79
(2H, m) 2.82 (3H, s); MS m/z 455.2 [M + H].sup.+ 129
2-(2-ethyl-4,6-difluoro-1H-benzimidazol-1-yl)-5
-fluoro-N-[4-(trifluoromethyl] phenyl]pyrimidine-4,6-diamine
.sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 8.89 (1H, s)
7.95 (2H, d, J = 8.51 Hz) 7.66-7.77 (3H, m) 6.90-6.98 (1H, m) 6.79
(2H, br. s.) 3.30 (2H, q, J = 7.57 Hz) 1.34 (3H, t, J = 7.41 Hz);
MS m/z 453.2 [M + H].sup.+ 130
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-4,6-difluoro-1H-benz-
imidazol-1-yl)- 5-fluoropyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.75 (1H, s) 7.72-7.81 (2H, m)
7.51 (1H, ddd, J = 8.91, 2.60, 1.42 Hz) 7.35 (1H, t, J = 8.83 Hz)
6.81-7.14 (2H, m) 6.74 (2H, br. s.) 3.28 (2H, q, J = 7.25 Hz) 1.34
(3H, t, J = 7.41 Hz); MS m/z 469.2 [M + H].sup.+ 131
N-[4-(difluoromethoxy)phenyl]-2-(4,6-difluoro-2-methyl-1H-benzimidazol-
-1-yl)-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.59 (1H, s) 7.79 (1H, ddd, J = 9.85,
2.44, 0.95 Hz) 7.69-7.74 (2H, m) 7.20-7.24 (2H, m) 6.81-7.13 (2H,
m) 6.65 (2H, br. s.) 2.78 (3H, s); MS m/z 437.2 [M + H].sup.+ 132
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-4,6-difluoro-1H-benzimidazol--
1-yl)-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.59 (1H, s) 7.75 (1H, ddd, J = 9.77,
2.21, 0.95 Hz) 7.68-7.72 (2H, m) 7.18-7.25 (2H, m) 6.81-7.13 (2H,
m) 6.65 (2H, s) 3.25 (2H, q, J = 7.57 Hz) 1.28-1.33 (3H, m); MS m/z
451.2 [M + H].sup.+ 133
N-[4-(difluoromethoxy)phenyl]-2-(5,6-difluoro-2-methyl-1H-benzimidazol-
-1-yl)-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.57 (1H, br. s.) 8.15 (1H, dd, J =
11.82, 7.72 Hz) 7.68-7.74 (2H, m) 7.46 (1H, dd, J = 10.72, 7.57 Hz)
7.21-7.26 (2H, m) 7.05 (2H, t, J = 76.30 Hz) 6.65 (2H, s) 2.78 (3H,
s); MS m/z 437.3 [M + H].sup.+ 134
5-fluoro-2-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromet-
hyl) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.87 (1H, br. s.) 7.99 (2H, d, J =
8.51 Hz) 7.92 (1H, d, J = 8.20 Hz) 7.69 (2H, d, J = 8.51 Hz) 7.19
(1H, td, J = 8.20, 5.04 Hz) 7.01 (1H, dd, J = 10.72, 7.25 Hz) 6.74
(2H, br. s.) 2.83 (3H, s); MS m/z 421.2 [M + H].sup.+ 135
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(4-fluoro-2-methyl-1H-benzimi-
dazol-1-yl)
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.57 (1H, s) 7.92 (1H, d, J = 9.14 Hz) 7.72-7.78 (2H,
m) 6.80-7.24 (5H, m) 6.59 (2H, br. s.) 2.79 (3H, s); MS m/z 418.2
[M + H].sup.+ 136
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(4-fluoro-2-methyl-1-
H-benzimidazol- 1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.74 (1H, s) 7.93 (1H, d, J = 7.57 Hz)
7.85 (1H, dd, J = 12.93, 2.52 Hz) 7.51-7.57 (1H, m) 7.34 (1H, t, J
= 8.99 Hz) 6.82-7.23 (3H, m) 6.69 (2H, s) 2.86 (3H, s); MS m/z
437.2 [M + H].sup.+ 137
5-fluoro-2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(trifluoromet-
hyl)phenyl]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.88 (1H, br. s.) 8.47 (1H, dd, J =
8.04, 1.73 Hz) 8.40-8.44 (1H, m) 7.92-8.00 (2H, m) 7.72 (2H, d, J =
8.51 Hz) 7.18-7.23 (1H, m) 6.70-6.80 (2H, m) 2.90 (3H, s); MS m/z
404.2 [M + H].sup.+ 138
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methyl-1H-imidazo[4,5-b]py-
ridin-1-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.58 (1H, s) 8.46 (1H, dd, J = 8.20,
1.58 Hz) 8.40 (1H, dd, J = 4.73, 1.58 Hz) 7.70-7.76 (2H, m)
7.21-7.25 (2H, m) 7.15-7.19 (1H, m) 6.99 (2H, s) 6.56-6.66 (2H, m)
2.86 (3H, s); MS m/z 402.2 [M + H].sup.+ 139
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(2-methyl-1H-imidazo-
[4,5-b]pyridin- 1-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.75 (1H, br. s.) 8.45-8.50 (1H, m)
8.42 (1H, dd, J = 4.73, 1.58 Hz) 7.80 (1H, dd, J = 12.61, 2.52 Hz)
7.53 (1H, dt, J = 9.06, 1.93 Hz) 7.37 (1H, t, J = 8.83 Hz) 7.20
(1H, dd, J = 8.20, 4.73 Hz) 6.83-7.16 (2H, m) 6.72 (2H, br. s.)
2.89 (3H, s); MS m/z 420.2 [M + H].sup.+ 140
2-(2-cyclopropyl-4-fluoro-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluo-
romethyl)- phenyl]pyrimidine4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.88 (1H, s) 8.05 (2H, d, J = 8.51 Hz)
7.81 (1H, dd, J = 8.20, 0.63 Hz) 7.67 (2H, d, J = 8.51 Hz) 7.16
(1H, td, J = 8.12, 4.89 Hz) 6.95-7.02 (1H, m) 6.74 (2H, s)
2.96-3.03 (1H, m) 1.24-1.29 (2H, m) 1.03-1.08 (2H, m); MS m/z 447.2
[M + H].sup.+ 141
2-(2-cyclopropyl-4-fluoro-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)-
phenyl]-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.59 (1H, s) 7.77-7.84 (3H, m)
7.16-7.20 (2H, m) 7.12-7.16 (1H, m) 6.81-7.11 (2H, m) 6.61 (2H, s)
3.01 (1H, tt, J = 8.28, 4.97 Hz) 1.20-1.24 (2H, m) 1.03 (2H, dq, J
= 8.32, 3.43 Hz); MS m/z 445.2 [M + H].sup.+ 142
2-(2-cyclopropyl-4-fluoro-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)-
-3- fluorophenyl]-5-fluoropyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.77 (1H, s) 7.99 (1H, dd, J =
12.93, 2.52 Hz) 7.83 (1H, dd, J = 8.20, 0.95 Hz) 7.57 (1H, ddd, J =
9.06, 2.60, 1.58 Hz) 7.33 (1H, t, J = 8.99 Hz) 7.18 (1H, td, J =
8.12, 4.89 Hz) 6.83-7.13 (2H, m) 6.72 (2 H, s) 3.01 (1H, tt, J =
8.28, 4.97 Hz) 1.23-1.30 (2H, m) 1.08 (2H, dq, J = 8.32, 3.43 Hz);
MS m/z 463.2 [M + H].sup.+ 155
2-(2-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(difluor-
omethoxy)phenyl]- 5-fluoropyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.62 (1H, s) 8.23-8.32 (2H, m)
7.72-7.78 (2H, m) 7.18-7.24 (2H, m) 6.98 (1H, t, J = 75.30 Hz) 6.71
(2H, br. s.) 3.27 (1H, tt, J = 8.28, 4.97 Hz) 1.25 (2H, dd, J =
4.89, 3.00 Hz) 1.05 (2H, dd, J = 8.20, 3.15 Hz); MS m/z 446.2 [M +
H].sup.+ 158
2-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoromet-
hyl) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.82 (1H, d, J = 1.58 Hz) 8.11 (1H, d,
J = 8.20 Hz) 7.92-7.99 (2H, m) 7.69 (2H, d, J = 8.51 Hz) 7.58 (1H,
d, J = 2.21 Hz) 7.19 (1H, dd, J = 8.83, 2.21 Hz) 6.70 (2H, br. s.)
2.82 (3H, s); MS m/z 437.2 [M + H].sup.+ 159
2-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)pheny-
l]-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.42 (1H, s) 7.95-8.00 (1H, m)
7.55-7.62 (2H, m) 7.43 (1H, d, J = 1.58 Hz) 7.01-7.10 (3H, m) 6.84
(1H, t, J = 75.30 Hz) 6.44 (2H, br. s.) 2.64 (3H, s); MS m/z 435.2
[M + H].sup.+ 160
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoromet-
hyl) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.83 (1H, br. s.) 8.19 (1H, d, J =
1.58 Hz) 7.94 (2H, d, J = 8.20 Hz) 7.70 (3H, d, J = 8.51 Hz) 7.55
(1H, d, J = 8.51 Hz) 7.21-7.27 (1H, m) 6.72 (2H, br. s.) 2.82 (3H,
s); MS m/z 437.2 [M + H].sup.+ 161
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)pheny-
l]-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.57 (1H, s) 8.17-8.22 (1H, m)
7.70-7.77 (2H, m) 7.55 (1H, d, J = 8.20 Hz) 7.20-7.26 (3H, m) 6.97
(1H, t, J = 74.70 Hz) 6.62 (2H, br. s.) 2.80 (3H, s); MS m/z 435.2
[M + H].sup.+ 162
2-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluorometh-
yl) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.85 (1H, br. s.) 8.08 (1H, dd, J =
8.67, 5.20 Hz) 7.97 (2H, d, J = 8.20 Hz) 7.64-7.73 (2H, m) 7.33
(1H, d, J = 6.62 Hz) 6.98-7.04 (1H, m) 6.72 (2H, br. s.) 3.29 (2H,
q, J = 7.36 Hz) 1.34 (3H, t, J = 8.20 Hz); MS m/z 435.3 [M +
H].sup.+ 163 N-
[4-(difluoromethoxy)phenyl]-2-(2-ethyl-5-fluoro-1H-benzimidazol-1-y-
l)-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.56 (1H, s) 8.09 (1H, dd, J = 9.46,
5.04 Hz) 7.69-7.75 (2H, m) 7.31 (1H, dd, J = 9.30, 2.68 Hz)
7.18-7.24 (2H, m) 6.81-7.14 (2H, m) 6.57 (2H, br. s.) 3.22-3.29
(2H, m) 1.27-1.34 (3H, m); MS m/z 433.3 [M + H].sup.+ 164
2-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluorometh-
yl) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.85 (1H, s) 7.96 (2H, d, J = 8.51 Hz)
7.89 (1H, dd, J = 10.09, 2.52 Hz) 7.70 (2H, d, J = 8.51 Hz) 7.59
(1H, dd, J = 8.51, 5.04 Hz) 7.01-7.09 (1H, m) 6.75 (2H, br. s.)
3.29 (2H, q, J = 7.46 Hz) 1.33 (3H, t, J = 14.80 Hz); MS m/z 435.3
[M + H].sup.+ 165
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl-
)-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.56 (1H, s) 7.90 (1H, dd, J = 10.40,
2.52 Hz) 7.68-7.75 (2H, m) 7.56 (1H, dd, J = 8.83, 5.04 Hz)
7.18-7.26 (2H, m) 6.81-7.12 (2H, m) 6.61 (2H, br. s.) 3.25 (2H, q,
J = 7.46 Hz) 1.26-1.34 (3H, m); MS m/z 433.3 [M + H].sup.+ 172
5-methyl-2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)pheny-
l]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.19 (1H, s) 8.14 (1H, dt, J = 8.20, 0.95 Hz) 7.87 (2H,
d, J = 8.51 Hz) 7.64 (2H, d, J = 8.51 Hz) 7.55-7.60 (1H, m) 7.22
(1H, ddd, J = 8.04, 7.09, 1.26 Hz) 7.15 (1H, ddd, J = 8.28, 7.17,
1.26 Hz) 6.31 (2H, br. s.) 2.80 (3H, s) 2.22 (3H, s); MS m/z 399.2
[M + H].sup.+ 183
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromet-
hyl)pyridin-3- yl]pyrimidine-4,6-diamine .sup.1H NMR
(Methanol-d.sub.4) .delta. ppm 8.92 (1H, d, J = 2.5 Hz), 8.34 (1H,
dd, J = 8.5, 2.4 Hz), 7.81 (1H, dd, J = 9.8, 2.5 Hz), 7.75 (1H, d,
J = 8.7 Hz), 7.54 (1H, dd, J = 8.7, 5 Hz), 7.06 (1H, td, J = 9.2,
2.5 Hz), 2.82 (3H, s); MS m/z 422.3 [M + H].sup.+ 184
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)-
pyrimidine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.37 (br. s., 1H), 7.94 (dd, J = 10.4, 2.5 Hz, 1H),
7.50-7.58 (m, 3H), 7.20 (d, J = 8.2 Hz, 2H), 7.01 (ddd, J = 9.8,
8.8, 2.5 Hz, 1H), 6.52 (br. s., 2H), 2.78 (s, 3H), 2.34 (s, 3H); MS
m/z 367.2 [M + H].sup.+ 185
N-(4-chlorophenyl)-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-
pyrimidine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.58 (br. s., 7H), 7.93 (dd, J = 10.2, 2.7 Hz, 1H),
7.70-7.76 (m, 2H), 7.54 (dd, J = 8.7, 5.2 Hz, 1H), 7.37-7.42 (m,
2H), 7.03 (ddd, J = 9.8, 8.8, 2.5 Hz, 1H), 6.63 (br. s., 2H), 2.79
(s, 3H); MS m/z 387.2 [M + H].sup.+ 189
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(3-methoxyphenyl-
)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.43 (br. s., 1H), 7.97 (dd, J = 10.1, 2.5 Hz, 1H),
7.54 (dd, J = 8.8, 5.0 Hz, 1H), 7.32-7.37 (m, 1H), 7.23-7.31 (m,
2H), 7.03 (ddd, J = 9.5, 8.7, 2.8 Hz, 1H), 6.68-6.75 (m, 1H), 6.57
(br. s., 2H), 3.77 (s, 3H), 2.81 (s, 3H); MS m/z 383.2 [M +
H].sup.+ 190
N-(3-chlorophenyl)-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-
pyrimidine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.63 (br. s., 1H), 7.96 (dd, J = 10.1, 2.5 Hz, 1H),
7.91 (t, J = 2.0 Hz, 1H), 7.62 (ddd, J = 8.3, 2.0, 0.8 Hz, 1H),
7.55 (dd, J = 8.8, 5.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.14
(ddd, J = 8.2, 2.2, 0.9 Hz, 1H), 7.04 (ddd, J = 9.5, 8.5, 2.5 Hz,
1H), 6.68 (br. s., 2H), 2.82 (s, 3H); MS m/z 387.2 [M + H].sup.+
191
5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromet-
hoxy) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 9.21 (br. s., 1H), 8.49 (dd, J = 10.2,
2.7 Hz, 1H), 8.32-8.42 (m, 2H), 8.10 (dd, J = 8.7, 5.2 Hz, 1H),
7.91 (dd, J = 9.1, 0.9 Hz, 2H), 7.59 (ddd, J = 9.5, 8.5, 2.5 Hz,
1H), 7.21 (br. s., 2H), 3.34 (s, 3H); MS m/z 437.2 [M + H].sup.+
192
4-{[6-amino-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimid-
in-4-yl] amino}benzonitrile .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.79 (br. s., 1H), 7.80-7.86 (m, 2H), 7.78 (dd, J =
10.1, 2.5 Hz, 1H), 7.61 (dt, J = 8.8, 2.5 Hz, 2H), 7.42 (dd, J =
8.8, 5.0 Hz, 1H), 6.91 (ddd, J = 9.5, 8.5, 2.6 Hz, 1H), 6.65 (br.
s., 2H), 2.67 (s, 3H); MS m/z 378.2 [M + H].sup.+ 193 methyl
4-{[6-amino-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-
pyrimidin-4- yl]amino}benzoate .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.82 (br. s., 1H), 7.99-8.04 (m, 2H),
7.96 (dd, J = 10.1, 2.5 Hz, 1H), 7.85-7.90 (m, 2H), 7.56 (dd, J =
8.8, 5.0 Hz, 1H), 7.05 (ddd, J = 9.5, 8.5, 2.5 Hz, 1H), 6.73 (br.
s., 2H), 3.88 (s, 3H), 2.83 (s, 3H); MS m/z 411.2 [M + H].sup.+ 194
5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-N-(3-methylphenyl)pyrimidin-
e-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm
8.36 (1H, br. s.) 8.19 (1H, d, J = 8.51 Hz) 7.64 (1H, s) 7.57 (1H,
d, J = 7.57 Hz) 7.46 (1H, dd, J = 8.20, 2.21 Hz) 7.16-7.26 (3H, m)
6.94 (1H, d, J 6.49 (2H, br. s.) 2.81 (3H, s) 2.33 (3H, s); MS m/z
439.2 [M + H].sup.+ 195
5-fluoro-N-(3-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidi-
ne-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm
8.42 (1H, br. s.) 8.13-8.18 (1H, m) 7.58 (1H, d, J = 7.25 Hz) 7.40
(1H, t, J = 2.21 Hz) 7.16-7.32 (4H, m) 6.67-6.71 (1H, m) 6.52 (2H,
br. s.) 3.75 (3H, s) 2.82 (3H, s); MS m/z 365.2 [M + H].sup.+ 199
5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)pyrimidin-
e-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm
8.35 (1H, br. s.) 8.13 (1H, d, J = 8.20 Hz) 7.54-7.61 (3H, m)
7.12-7.24 (4H, m) 6.45 (2H, br. s.) 2.78 (3H, s) 2.33 (3H, s); MS
m/z 349.2 [M + H].sup.+
200
5-fluoro-N-(4-methoxyphenyl)-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidi-
ne-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm
8.28 (1H, br. s.) 8.12 (1H, d, J = 8.20 Hz) 7.52-7.60 (3H, m)
7.12-7.24 (2H, m) 6.93-6.98 (2H, m) 6.41 (2H, br. s.) 3.82 (3H, s)
2.76 (3H, s); MS m/z 365.2 [M + H].sup.+ 201
N-(4-chlorophenyl)-5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-
e-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm
8.57 (1H, br. s.) 8.07-8.14 (1H, m) 7.73-7.80 (2H, m) 7.58 (1H, d,
J = 6.94 Hz) 7.35-7.42 (2H, m) 7.15-7.26 (2H, m) 6.56 (2H, br. s.)
2.79 (3H, s); MS m/z 369.2 [M + H].sup.+ 202
4-{[6-amino-5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]a-
mino}benzonitrile .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta.
ppm 8.92 (1H, br. s.) 8.08-8.13 (1H, m) 7.97-8.03 (2H, m) 7.71-7.77
(2H, m) 7.56-7.62 (1H, m) 7.24 (2H, quind, J = 7.33, 7.33, 7.33,
7.33, 1.58 Hz) 6.73 (2H, br. s.) 2.80-2.83 (3H, m); MS m/z 360.2 [M
+ H].sup.+ 203
N-(1,3-benzodioxol-5-yl)-5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)pyr-
imidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta.
ppm 8.33 (1H, br. s.) 8.15 (1H, d, J = 6.62 Hz) 7.56 (1H, d, J =
7.25 Hz) 7.28 (1H, d, J = 2.21 Hz) 7.16-7.25 (2H, m) 7.09 (1H, dd,
J = 8.51, 2.21 Hz) 6.85 (1H, d, J = 8.51 Hz) 6.45 (2H, br. s.) 6.02
(2H, s) 2.79 (3H, s); MS m/z [M + H].sup.+ 204
5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethoxy)phen-
yl]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.63 (1H, br. s.) 8.11 (1H, d, J = 7.57 Hz) 7.80- 7.89
(2H, m) 7.57 (1H, d, J = 7.88 Hz) 7.31-7.38 (2H, m) 7.15-7.26 (2H,
m) 6.58 (2H, br. s.) 2.79 (3H, s); MS m/z 419.1 [M + H].sup.+ 213
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methylphe-
nyl)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.40 (1H, br. s.) 8.15 (1H, dd, J = 11.98, 7.88 Hz)
7.49-7.55 (2H, m) 7.44 (1H, dd, J = 10.72, 7.57 Hz) 7.21 (2H, d, J
= 8.20 Hz) 6.55 (2H, br. s.) 2.79 (3H, s) 2.35 (3H, s); MS m/z
385.2 [M + H].sup.+ 214
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methoxyph-
enyl)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.30 (1H, br. s.) 8.12 (1H, dd, J = 11.98, 7.88 Hz)
7.46-7.51 (2H, m) 7.41 (1H, dd, J = 10.72, 7.57 Hz) 6.93-6.98 (2H,
m) 6.48 (2H, br. s.) 3.81 (3H, s) 2.75 (3H, s); MS m/z 401.3 [M +
H].sup.+ 215
N-(4-chlorophenyl)-2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fl-
uoropyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.61 (1H, br. s.) 8.15 (1H, dd, J = 11.82, 7.72 Hz)
7.68-7.73 (2H, m) 7.38-7.50 (3H, m) 6.66 (2H, br. s.) 2.80 (3H, s);
MS m/z 405.2 [M + H].sup.+ 216
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-[2-(methoxymethyl)-1H-benzimi-
dazol-1-yl] pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.53 (1H, s) 8.13-8.17 (1H, m)
7.73-7.79 (2H, m) 7.64-7.69 (1H, m) 7.19-7.30 (4H, m) 6.82-7.13
(1H, m) 6.54 (2H, br. s.) 5.02 (2H, s) 3.28 (3H, s); MS m/z 431.3
[M + H].sup.+ 217
5-fluoro-2-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N-(4-methylphenyl)-
pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.36 (1H, br. s.) 8.18 (1H, dd, J = 6.78, 1.73 Hz) 7.66
(1H, dd, J = 6.62, 1.89 Hz) 7.54-7.60 (2H, m) 7.17-7.30 (4H, m)
6.46 (2H, br. s.) 4.99-5.04 (2H, m) 3.28 (3H, s) 2.34 (3H, s); MS
m/z 379.3 [M + H].sup.+ 218
5-fluoro-2-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N-(4-methoxyphenyl-
)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.31 (1H, br. s.) 8.14-8.19 (1H, m) 7.65 (1H, dd, J =
6.78, 1.73 Hz) 7.53-7.59 (2H, m) 7.25 (2H, quind, J = 7.41, 7.41,
7.41, 7.41, 1.58 Hz) 6.93-6.99 (2H, m) 6.43 (2H, br. s.) 4.97-5.02
(2H, m) 3.82 (3H, s); MS m/z 395.3 [M + H].sup.+ 219
N-(4-chlorophenyl)-5-fluoro-2-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-
pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.58 (1H, br. s.) 8.12-8.17 (1H, m) 7.73-7.79 (2H, m)
7.65-7.70 (1H, m) 7.37-7.41 (2H, m) 7.24-7.32 (2H, m) 6.58 (2H, br.
s.) 5.03 (2H, s) 3.29 (3H, s); MS m/z 399.2 [M + H].sup.+ 220
5-fluoro-2-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromet-
hyl) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.83 (1H, br. s.) 8.11-8.18 (1H, m)
7.96-8.03 (2H, m) 7.66-7.73 (3H, m) 7.25-7.33 (2H, m) 6.68 (2H, br.
s.) 5.05 (2H, s) 3.29 (3H, s); MS m/z 433.2 [M + H].sup.+ 222
1-(4-amino-5-fluoro-6-[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)-
-2-methyl-1H- benzimidazole-6-carbonitrile .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.91 (1H, s) 8.63 (1H, d, J = 1.58 Hz)
7.92-7.99 (2H, m) 7.74 (3H, t, J = 8.51 Hz) 7.61 (1H, dd, J = 8.20,
1.58 Hz) 6.84 (2H, br. s.) 2.90 (3H, s); MS m/z 428.3 [M + H].sup.+
223
1-(4-amino-6-[4-(difluoromethoxy)phenyl]amino}-5-fluoropyrimidin-2-yl)-
-2-methyl- 1H-benzimidazole-6-carbonitrile .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.58-8.63 (2H, m) 7.68-7.75 (3H, m)
7.57-7.62 (1H, m) 7.22-7.27 (2H, m) 6.84-7.16 (1H, m) 6.68 (2H, br.
s.) 2.87 (3H, s); MS m/z 426.3 [M + H].sup.+ 224
1-{4-amino-5-fluoro-6-[(4-methylphenyl)amino]pyrimidin-2-
yl]-2-methyl-1H- benzimidazole-6-carbonitrile .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.61 (1H, s) 8.42 (1H, br. s.) 7.71
(1H, d, J = 8.20 Hz) 7.49-7.60 (3H, m) 7.24 (2H, d, J = 7.88 Hz)
6.58 (2H, br. s.) 2.87 (3H, s) 2.36 (3H, s); MS m/z 374.3 [M +
H].sup.+ 225
1-{4-amino-5-fluoro-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl]-2-methyl-
-1H- benzimidazole-6-carbonitrile .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.62 (1H, s) 8.37 (1H, s) 7.71 (1H, d,
J = 8.20 Hz) 7.49-7.60 (3H, m) 6.98-7.03 (2H, m) 6.57 (2H, br. s.)
3.84 (3H, s) 2.84 (3H, s); MS m/z 390.3 [M + H].sup.+ 226
1-(4-amino-6-{[4-(difluoromethoxy)phenyl]amino}-5-fluoropyrimidin-2-yl-
)-2-methyl- 1H-benzimidazole-5-carbonitrile .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.60 (1H, s) 8.28 (1H, dd, J = 8.51,
0.63 Hz) 8.00 (1H, dd, J = 1.58, 0.63 Hz) 7.70-7.77 (2H, m) 7.55
(1H, dd, J = 8.51, 1.58 Hz) 7.19-7.25 (2H, m) 6.98 (1H, t, J =
75.00 Hz) 6.63 (2H, br. s.) 2.83 (3H, s); MS m/z 426.3 [M +
H].sup.+ 227
1-{4-amino-5-fluoro-6-[(4-methylphenyl)amino]pyrimidin-2-yl}-2-methyl--
1H- benzimidazole-5-carbonitrile .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.42 (1H, br. s.) 8.31 (1H, s) 7.99
(1H, s) 7.50- 7.57 (3H, m) 7.20 (2H, d, J = 8.20 Hz) 6.55 (2H, br.
s.) 2.83 (3H, s) 2.34 (3H, s); MS m/z 374.3 [M + H].sup.+ 228
1-{4-amino-5-fluoro-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl}-2-methyl-
-1H- benzimidazole-5-carbonitrile .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.33-8.39 (1H, m) 8.29 (1H, d, J =
8.51 Hz) 7.98 (1H, s) 7.49-7.56 (3H, m) 6.95-7.00 (2H, m) 6.51 (2H,
br. s.) 3.83 (3H, s) 2.81 (3H, s); MS m/z 390.4 [M + H].sup.+ 229
1-(4-amino-5-fluoro-6-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl-
)-2-methyl-1H- benzimidazole-5-carbonitrile .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.90 (1H, s) 8.28 (1H, d, J = 8.51 Hz)
8.02 (1H, s) 7.97 (2H, d, J = 8.51 Hz) 7.71 (2H, d, J = 8.20 Hz)
7.58 (1H, dd, J = 8.51, 1.58 Hz) 6.78 (2H, br. s.) 2.87 (3H, s); MS
m/z 428.3 [M + H].sup.+ 230
1-{4-amino-6-[(4-chlorophenyl)amino]-5-fluoropyrimidin-2-yl}-2-methyl--
1H- benzimidazole-5-carbonitrile .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.64 (1H, br. s.) 8.28 (1H, dd, J =
8.51, 0.63 Hz) 8.01 (1H, d, J = 1.58 Hz) 7.70-7.77 (3H, m) 6.94
(1H, t, J = 75.00 Hz) 6.68 (2H, s) 2.88 (2H, m) 6.67 (2H, br. s.)
2.84 (3H, s); MS m/z 394.2 [M + H].sup.+ 231
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methyl-6-nitro-1H-benzimid-
azol-1-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 9.02 (1H, d, J = 2.84 Hz) 8.62 (1H,
br. s.) 8.19 (1H, dd, J = 8.83, 2.52 Hz) 7.71-7.77 (3H, m) 6.94
(1H, t, J = 75.00 Hz) 6.68 (2H, s) 2.88 (3H, s); MS m/z 446.2 [M +
H].sup.+ 232
5-fluoro-2-(2-methyl-6-nitro-1H-benzimidazol-1-yl)-N-(4-methylphenyl)p-
yrimidine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 9.03 (1H, d, J = 2.84 Hz) 8.45 (1H, br. s.) 8.18 (1H,
dd, J = 8.83, 2.21 Hz) 7.74 (1H, d, J = 8.83 Hz) 7.53-7.59 (2H, m)
7.18 (2H, d, J = 7.88 Hz) 6.61 (2H, br. s.) 2.87 (3H, s) 2.32 (3H,
s); MS m/z 394.2 [M + H].sup.+ 233
5-fluoro-N-(4-methoxyphenyl)-2-(2-methyl-6-nitro-1H-benzimidazol-1-yl)-
pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 9.03 (1H, d, J = 1.89 Hz) 8.38 (1H, br. s.) 8.17 (1H,
dd, J = 8.83, 2.21 Hz) 7.73 (1H, d, J = 8.83 Hz 7.52-7.60 (2H, m)
6.92-6.99 (2H, m) 6.57 (2H, br. s.) 3.80 (3H, s) 2.54 (3H, s); MS
m/z 410.2 [M + H].sup.+ 236
5-fluoro-2-(2-methyl-6-nitro-1H-benzimidazol-1-yl)-N-[4-(trifluorometh-
yl)phenyl]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 9.04 (1H, d, J = 2.52 Hz) 8.90 (1H,
br. s.) 8.21 (1H, dt, J = 8.83, 1.42 Hz) 7.99 (2H, dd, J = 8.35,
3.31 Hz) 7.77 (1H, d, J = 8.83 Hz) 7.70 (2H, d, J = 8.51 Hz) 6.83
(2H, br. s.) 2.92 (3H, s); MS m/z 448.2 [M + H].sup.+ 237
N-(4-chlorophenyl)-2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fl-
uoropyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.62 (1H, br. s.) 7.79 (1H, dd, J = 10.25, 2.05 Hz)
7.69-7.74 (2H, m) 7.37-7.44 (2H, m) 6.92 (1H, td, J = 10.25, 2.21
Hz) 6.67 (2H, br. s.) 2.79-2.80 (3H, m); MS m/z 405.2 [M + H].sup.+
238
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluor-
omethoxy) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.69 (1H, s) 7.75-7.85 (3H, m) 7.36
(2H, d, J = 8.20 Hz) 6.92 (1H, td, J = 10.25, 2.52 Hz) 6.69 (2H,
br. s.) 2.79 (3H, s); MS m/z 456.1 [M + H].sup.+ 240
N-(1,3-benzodioxol-5-yl)-2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl-
)-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.37 (1H, br. s.) 7.80 (1H, dd, J =
9.46, 1.89 Hz) 7.20 (1H, d, J = 2.21 Hz) 7.05 (1H, dd, J = 8.35,
2.05 Hz) 6.84-6.92 (2H, m) 6.55 (2H, br. s.) 6.02 (2H, s) 2.79 (3H,
s); MS m/z 416.2 [M + H].sup.+ 241
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methylphe-
nyl)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.41 (1H, br. s.) 7.80 (1H, dd, J = 9.93, 2.36 Hz)
7.50-7.56 (2H, m) 7.20 (2H, d, J = 8.20 Hz) 6.90 (1H, td, J =
10.25, 2.52 Hz) 6.56 (2H, br. s.) 2.79 (3H, s) 2.34 (3H, s); MS m/z
386.2 [M + H].sup.+ 242
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methoxyph-
enyl)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.34 (1H, br. s.) 7.76-7.83 (1H, m) 7.47-7.55 (2H, m)
6.94-7.00 (2H, m) 6.89 (1H, td, J = 10.25, 2.21 Hz) 6.52 (2H, br.
s.) 3.82 (3H, s) 2.76 (3H, s); MS m/z 402.2 [M + H].sup.+ 243
2-(5,7-difluoro-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluor-
omethyl)phenyl]
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.86 (1H, br. s.) 8.15 (1H, dd, J = 11.66, 7.88 Hz)
7.91-7.98 (2H, m) 7.72 (2H, d, J = 8.51 Hz) 7.48 (1H, dd, J =
10.72, 7.57 Hz) 6.78 (2H, br. s.) 2.83 (3H, s); MS m/z 439.3 [M +
H].sup.+ 244
5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluorome-
thyl)phenyl] pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.82 (1H, br. s.) 8.00 (2H, d, J =
8.51 Hz) 7.65-7.73 (3H, m) 7.45 (1H, d, J = 8.51 Hz) 6.83-6.89 (1H,
m) 6.67 (2H, br. s.) 3.64-3.69 (3H, m) 2.78 (3H, s); MS m/z 434.2
[M + H].sup.+ 245
N-(4-chlorophenyl)-5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-1-yl-
)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.57 (1H, br. s.) 7.74-7.79 (2H, m) 7.68 (1H, d, J =
2.52 Hz) 7.44 (1H, d, J = 8.51 Hz) 7.35-7.41 (2H, m) 6.85 (1H, dd,
J = 8.83, 2.52 Hz) 6.57 (2H, br. s.) 3.69 (3H, s) 2.75 (3H, s); MS
m/z 399.2 [M + H].sup.+ 246
5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluorome-
thoxy)phenyl] pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.64 (1H, s) 7.84-7.89 (2H, m) 7.69
(1H, d, J = 2.21 Hz) 7.44 (1H, d, J = 8.83 Hz) 7.34 (2H, d, J =
8.20 Hz) 6.85 (1H, dd, J = 8.51, 2.52 Hz) 6.58 (2H, br. s.) 3.68
(3H, s) 2.75 (3H, s); MS m/z 449.2 [M + H].sup.+ 247
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(6-methoxy-2-methyl-1H-benzim-
idazol-1-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.52 (1H, s) 7.74-7.79 (2H, m) 7.69
(1H, d, J = 2.51 Hz) 7.43 (1H, d, J = 8.51 Hz) 7.17-7.23 (2H, m)
6.81-7.12 (2H, m) 6.53 (2H, br. s.) 3.69 (3H, s) 2.74 (3H, s); MS
m/z 432.2 [M + H].sup.+ 248
5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl-
)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.34 (1H, br, s) 7.70 (1H, d, J = 2.52 Hz) 7.56-7.60
(2H, m) 7.42 (1H, d, J = 8.83 Hz) 7.17 (2H, d, J = 8.20 Hz) 6.83
(1H, dd, J = 8.83, 2.52 Hz) 6.45 (2H, br. s.) 3.65 (3H, s) 2.75
(3H, s) 2.33 (3H, s); MS m/z 380.2 [M + H].sup.+ 249
5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazol-1-yl)-N-(4-methoxypheny-
l) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.27 (1H, br. s.) 7.70 (1H, d, J = 2.52 Hz) 7.54- 7.60
(2H, m) 7.38-7.43 (1H, m) 6.92-6.97 (2H, m) 6.82 (1H, dd, J = 8.51,
2.52 Hz) 6.41 (2H, br. s.) 3.82 (3H, s) 3.67 (3H, s) 2.72 (3H, s);
MS m/z 396.2 [M + H].sup.+ 250
N-(1,3-benzodioxo1-5-yl)-5-fluoro-2-(6-methoxy-2-methyl-1H-benzimidazo-
l-1-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.32 (1H, br. s.) 7.71 (1H, d, J =
2.52 Hz) 7.42 (1H, d, J = 8.51 Hz) 7.30-7.33 (1H, m) 7.09 (1H, dd,
J = 8.35, 2.05 Hz) 6.81-6.87 (2H, m) 6.44 (2H, br. s.) 6.01 (2H, s)
3.72 (3H, s) 2.74 (3H, s); MS m/z 409.2 [M + H].sup.+ 254
5-fluoro-2-(2-methyl-5-nitro-1H-benzimidazol-1-yl)-N-(4-methylphenyl)p-
yrimidine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.45-8.49 (1H, m) 8.44 (1H, d, J = 1.89 Hz) 8.31 (1H,
d, J = 9.14 Hz) 8.11 (1H, dd, J = 8.98, 2.36 Hz) 7.54-7.57 (2H, m)
7.21 (2H, d, J = 8.20 Hz) 6.59 (2H, br. s.) 2.85 (3H, s) 2.34 (3H,
s); MS m/z 394.2 [M + H].sup.+ 255
5-fluoro-N-(4-methoxyphenyl)-2-(2-methyl-5-nitro-1H-benzimidazol-1-yl)-
pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.43 (1H, d, J = 1.89 Hz) 8.40 (1H, br. s.) 8.30 (1H,
d, J = 9.14 Hz) 8.10 (1H, dd, J = 8.99, 2.36 Hz) 7.52-7.57 (2H, m)
6.96-7.01 (2H, m) 6.55 (2H, br. s.) 3.83 (3H, s) 2.83 (3H, s); MS
m/z 410.2 [M + H].sup.+ 256
2-(6-amino-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methoxyphenyl)-
pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.25 (1H, s) 7.53-7.59 (2H, m) 7.42 (1H, d, J = 1.58
Hz) 7.24 (1H, d, J = 8.83 Hz) 6.93-6.99 (2H, m) 6.61 (1H, dd, J =
8.20, 2.21 Hz) 6.33 (2H, s) 4.30 (2H, br. s.) 3.81 (3H, s) 2.67
(3H, s); MS m/z 380.3 [M + H].sup.+ 257
2-(6-amino-2-methyl-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)phenyl-
]-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.48 (1H, br. s.) 7.75-7.82 (2H, m)
7.42 (1H, d, J = 2.21 Hz) 7.25 (1H, d, J = 8.20 Hz) 7.04 (2H, d, J
= 8.20 Hz) 6.47 (1H, dd, J = 75.00 Hz) 6.64 (1H, dd, J = 8.51, 2.21
Hz) 6.44 (2H, br. s.) 4.36 (2H, s) 2.68 (3H, s); MS m/z 416.2 [M +
H].sup.+ 258
2-(6-amino-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methylphenyl)p-
yrimidine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.15 (1H, br. s.) 7.39-7.46 (2H, m) 7.28 (1H, d, J =
2.21 Hz) 7.09 (1H, d, J = 8.20 Hz) 7.04 (2H, d, J = 8.20 Hz) 6.47
(1H, dd, J = 8.51, 2.21 Hz) 6.22 (2H, br. s.) 4.16 (2H, s) 2.54
(3H, s) 2.18 (3H, s); MS m/z 364.3 [M + H].sup.+ 259
N-(4-chlorophenyl)-5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-
pyrimidine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.60 (1H, br. s.) 8.13 (1H, dd, J = 9.46, 5.04 Hz)
7.71-7.78 (2H, m) 7.36-7.43 (2H, m) 7.29 (1H, dd, J = 9.30, 2.36
Hz) 6.99 (1H, td, J = 9.30, 2.52 Hz) 6.60 (2H, br. s.) 2.80 (3H,
s); MS m/z 387.2 [M + H].sup.+ 260
N-(4-chloro-3-fluorophenyl)-5-fluoro-2-(5-fluoro-2-methyl-1H-benzimida-
zol-1-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.76 (1H, br. s.) 8.13 (1H, dd, J =
8.83, 5.04 Hz) 7.86 (1H, dd, J = 11.98, 2.52 Hz) 7.54-7.59 (1H, m)
7.45-7.51 (1H, m) 7.30 (1H, dd, J = 9.30, 2.36 Hz) 7.02 (1H, td, J
= 9.22, 2.68 Hz) 6.69 (2H, br. s.) 2.84 (3H, s); MS m/z 405.2 [M +
H].sup.+ 261
N-(4-chloro-3-fluorophenyl)-5-fluoro-2-(2-methyl-1H-benzimidazol-1-yl)-
pyrimidine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.74 (1H, br. s.) 8.11 (1H, dd, J = 7.57, 1.89 Hz) 7.90
(1H, dd, J = 11.98, 2.52 Hz) 7.58 (2H, td, J = 7.88, 2.21 Hz) 7.47
(1H, t, J = 7.57, 1.89 Hz) 7.18-7.28 (2H, m) 6.65 (2H, br. s.) 2.82
(3H, s); MS m/z 387.2 [M + H].sup.+ 262
N-(4-chloro-3-fluorophenyl)-5-fluoro-2-(6-fluoro-2-methyl-1H-benzimida-
zol-1-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.77 (1H, br. s.) 7.93 (1H, dd, J =
10.09, 2.21 Hz) 7.83 (1H, dd, J = 11.82, 2.36 Hz) 7.53-7.59 (2H, m)
7.46-7.51 (1H, m) 7.05 (1H, td, J = 9.14, 2.52 Hz) 6.72 (2H, br.
s.) 2.82 (3H, s); MS m/z 405.2 [M + H].sup.+ 270
2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methylphenyl)pyrimidine-
-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm
8.36 (1H, br. s.) 8.07-8.11 (1H, m) 7.54-7.62 (3H, m) 7.15-7.24
(4H, m) 6.46 (2H, br. s.) 3.26 (2H, q, J = 7.46 Hz) 2.33 (3H, s)
1.30-1.33 (3H, m); MS m/z 363.3 [M + H].sup.+ 271
2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methoxyphenyl)pyrimidin-
e-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm
8.15 (1H, br. s.) 7.93-7.97 (1H, m) 7.39-7.46 (3H, m) 6.99-7.10
(2H, m) 6.78-6.83 (2H, m) 6.28 (2H, s) 3.68 (3H, s) 3.10 (2H, q, J
= 7.36 Hz) 1.14-1.17 (3H, m); MS m/z 379.3 [M + H].sup.+ 272
2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoromethoxy)pheny-
l)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.67 (1H, s) 8.04-8.10 (1H, m) 7.80-7.87 (2H, m)
7.58-7.64 (1H, m) 7.33 (2H, d, J = 8.20 Hz) 7.14-7.26 (2H, m) 6.60
(2H, 2) 3.26 (2H, q, J = 7.36 Hz) 1.31-1.34 (3H, m); MS m/z 433.2
[M + H].sup.+ 273
N-(1,3-benzodioxo1-5-yl)-2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoropyri-
midine-4,6- diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta.
ppm 8.32 (1H, br. s.) 8.08-8.13 (1H, m) 7.58 (1H, d, J = 7.57 Hz)
7.28 (1H, d, J = 1.89 Hz) 7.15-7.24 (2H, m) 7.07 (1H, dd, J = 8.67,
2.05 Hz) 6.85 (1H, d, J = 8.51 Hz) 6.40-6.48 (2H, m) 6.01 (2H, s)
3.25 (2H, q, J = 7.57 Hz) 1.30-1.33 (3H, m); MS m/z 393.2 [M +
H].sup.+ 274
N-(4-chlorophenyl)-2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoropyrimidine-
-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm
8.57 (1H, br. s.) 8.03-8.09 (1H, m) 7.72-7.79 (2H, m) 7.60 (1H, d,
J = 7.57 Hz) 7.34-7.40 (2H, m) 7.16-7.26 (2H, m) 6.56 (2H, br. s.)
3.26 (2H, q, J = 7.57 Hz) 1.33 (3H, t, J = 7.57 Hz); MS m/z 383.4
[M + H].sup.+ 275
N-(4-chloro-3-fluorophenyl)-2-(2-ethyl-1H-benzimidazol-1-yl)-5-fluorop-
yrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.75 (1H, br. s.) 8.06 (1H, d, J = 6.94 Hz) 7.90 (1H,
dd, J = 11.98, 2.52 Hz) 7.62 (1H, dd, J = 6.94, 1.58 Hz) 7.54-7.58
(1H, m) 7.42-7.49 (1H, m) 7.18-7.29 (2H, m) 6.65 (2H, br. s.) 3.29
(2H, q, J = 7.36 Hz) 1.36 (3H, t, J = 7.41 Hz); MS m/z 401.4 [M +
H].sup.+ 276
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methylphenyl)pyri-
midine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta.
ppm 8.36 (1H, br. s.) 8.02-8.06 (1H, m) 7.61-7.67 (2H, m) 7.46-7.53
(1H, m) 7.12-7.23 (4H, m) 6.47 (2H, br. s.) 3.01-3.10 (1H, m) 2.32
(3H, s) 1.16-1.21 (2H, m) 0.98 (2H, dq, J = 8.47, 3.38 Hz); MS m/z
375.4 [M + H].sup.+ 277
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-fluoro-N-(4-methoxyphenyl)pyr-
imidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta.
ppm 8.29 (1H, br. s.) 8.04 (1H, d, J = 8.83 Hz) 7.58-7.65 (2H, m)
7.46-7.51 (1H, m) 7.10-7.21 (2H, m) 6.89-6.96 (2H, m) 6.43 (2H, br.
s.) 3.81 (3H, s) 3.02-3.10 (1H, m) 1.13-1.18 (2H, m) 0.96 (2H, dq,
J = 8.35, 3.42 Hz); MS m/z 391.3 [M + H].sup.+ 278
2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluoromethoxy-
)phenyl]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.65 (1H, s) 7.98-8.03 (1H, m)
7.87-7.93 (2H, m) 7.49-7.54 (1H, m) 7.31 (2H, d, J = 8.20 Hz)
7.12-7.24 (2H, m) 6.60 (2H, br. s.) 2.98-3.05 (1H, m) 1.17-1.23
(2H, m) 0.95-1.02 (2H, m); MS m/z 445.3 [M + H].sup.+ 279
N-(4-chlorophenyl)-2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-fluoropyri-
midine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta.
ppm 8.59 (1H, br. s.) 7.97-8.04 (1H, m) 7.80-7.86 (2H, m) 7.47-7.55
(1H, m) 7.32-7.38 (2H, m) 7.12-7.23 (2H, m) 6.58 (2H, br. s.)
2.96-3.05 (1H, m) 1.17-1.25 (2H, m) 0.97-1.04 (2H, m); MS m/z 395.3
[M + H].sup.+ 280
N-(4-chloro-3-fluorophenyl)-2-(2-cyclopropyl-1H-benzimidazol-1-yl)-5-
fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.77 (1H, br. s.) 7.96-8.06 (2H, m) 7.60 (1H, dd, J =
7.88, 2.52 Hz) 7.53 (1H, d, J = 6.94 Hz) 7.45 (1H, t, J = 8.67 Hz)
7.16-7.25 (2H, m) 6.68 (2H, br. s.) 2.96-3.03 (1H, m) 1.21-1.26
(2H, m) 1.02-1.07 (2H, m); MS m/z 413.3 [M + H].sup.+ 281
5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methylphenyl)-
pyrimidine-4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.39 (1H, br. s.) 8.15 (1H, dd, J = 8.51, 5.04 Hz)
7.53-7.58 (2H, m) 7.27 (1H, dd, J = 9.62, 2.36 Hz) 7.19 (2H, d, J =
8.51, 5.04 Hz) (1H, m) 6.51 (2H, br. s.) 2.79 (3H, s) 2.34 (3H, s);
MS m/z 367.3 [M + H].sup.+ 282
5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-(4-methoxyphenyl-
)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.30 (1H, br. s.) 8.14 (1H, dd, J = 9.30, 4.89 Hz)
7.51-7.58 (2H, m) 7.26 (1H, dd, J = 9.46, 2.52 Hz) 6.91-7.00 (3H,
m) 6.44 (2H, br. s.)
3.83 (3H, s) 2.76 (3H, s); MS m/z 383.3 [M + H].sup.+ 283
5-fluoro-2-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromet-
hoxy)phenyl]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.66 (1H, s) 8.12 (1H, dd, J = 8.67,
4.89 Hz) 7.80-7.86 (2H, m) 7.35 (2H, d, J = 8.20 Hz) 7.29 (1H, dd,
J = 8.83, 2.52 Hz) 6.97 (1H, td, J = 9.30, 2.52 Hz) 6.62 (2H, s)
2.79 (3H, s); MS m/z 437.3 [M + H].sup.+ 284
2-(6-amino-2-methyl-1H-benzimidazol-1-yl)-5-fluoro-N-[4-(trifluorometh-
yl)phenyl]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 7.86 (2H, d, J = 8.51 Hz) 7.53 (2H, d,
J = 8.51 Hz) 7.28 (1H, d, J = 2.21 Hz) 7.13 (1H, d, J = 8.51 Hz)
6.50 (1H, dd, J = 8.51, 2.21 Hz) 6.42 (2H, br. s.) 4.26 (2H, s)
2.56 (3H, s) MS m/z 418.3 [M + H].sup.+
Example 11
5-fluoro-N-(4-methoxyphenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimi-
dine-4,6-diamine (Cpd 239)
##STR00086##
[0449] Step 1. To a mixture of 1-aminopyridinium iodide (9.59 g,
43.2 mmol) and methyl but-2-ynoate (5.2 mL, 51.83 mmol) in DMF (50
mL) at 0.degree. C. was added K.sub.2CO.sub.3 (11.94 g, 86.4 mmol).
The reaction mixture was warmed to room temperature and stirred for
3 days until UPLC showed complete conversion to product. The
reaction mixture was partitioned between water and EtOAc. The
organic phase was concentrated, then MeOH (50 mL) and NaOH (6 mL,
50% in H.sub.2O) were added and the reaction mixture was heated at
70.degree. C. for 1 hour. The MeOH was evaporated and the remaining
mixture was acidified with 1N HCl to about pH 4. A crude
2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid was isolated on a
filter and dried under vacuum, then dissolved in MeOH (50 mL) and
CHCl.sub.3 (100 mL) and N-iodosuccinimide (7.3 g, 32.4 mmol) were
added in one portion. The reaction mixture was stirred for 20
minutes at room temperature. The MeOH was evaporated and the
remainder was washed three times with an aqueous NaHCO.sub.3
solution. The organic phase was dried over Na.sub.2SO.sub.4, the
solvent was removed under reduced pressure, and the crude product
was purified by silica gel chromatography to give
3-iodo-2-methylpyrazolo[1,5-a]pyridine (4.2 g, 38% for 3 steps) as
an off-white solid.
[0450] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 8.51 (dt,
J=6.8, 1.3 Hz, 1H), 7.41 (dt, J=8.8, 1.3 Hz, 1H), 7.31 (ddd, J=8.8,
6.8, 1.3 Hz, 1H), 6.90 (td, J=6.8, 1.3 Hz, 1H), 2.42 (s, 3H); MS
m/z 298.1 [M+H].sup.+.
[0451] Step 2. To a solution of
3-iodo-2-methylpyrazolo[1,5-a]pyridine (340 mg, 1.32 mmol) in dry
THF (10 mL) at 0.degree. C. was added an isopropylmagnesium
chloride lithium chloride complex solution (iPrMgCl.LiCl) (1.5 mL,
1.97 mL). The reaction mixture was stirred at 0.degree. C. for 30
minutes and 4,6-dichloro-5-fluoro-2-(methylsulfonyl)pyrimidine (484
mg, 1.97 mmol) in dry THF (20 mL) was added. The reaction mixture
was stirred at 0.degree. C. for 1 hour, and the reaction was
quenched with water. The crude product was extracted with
CH.sub.2Cl.sub.2 three times. The combined organic extracts were
washed with brine, then dried over Na.sub.2SO.sub.4, concentrated,
and triturated in CH.sub.3CN (10 mL). The resulting precipitate was
filtered and dried providing
3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine
(270 mg, 68%) isolated as a tan solid.
[0452] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 8.79 (d,
J=6.9 Hz, 1H), 8.34 (d, J=8.8 Hz, 1H), 7.61 (ddd, J=8.8, 6.9, 0.9
Hz, 1H), 7.13 (td, J=6.9, 1.1 Hz, 1H), 2.70 (s, 3H). MS m/z 298.1
[M+H].sup.+.
[0453] Step 3.
3-(4,6-Dichloro-5-fluoropyrimidin-2-yl)-2-methylpyrazolo[1,5-a]pyridine
(65 mg, 0.21 mmol) and 4-methoxyaniline (52 mg, 0.42 mmol) were
mixed in EtOH (1 mL) and heated in a sealed tube at 100.degree. C.
until UPLC showed complete conversion (3 hours). After the starting
materials were consumed, the reaction was cooled to room
temperature and diluted with water (5 mL) to precipitate the
product. The product was collected by filtration, washed with water
and subsequently washed with hexanes. The crude product, without
drying, was dissolved in iPrOAc (2 mL), then saturated ammonia in
water (150 .mu.L) was added. The reaction mixture was heated at
100.degree. C. in a sealed tube for 24 hours until UPLC showed
complete consumption of starting material. A crude product was
precipitated by addition of water (10 mL), then filtered and
purified by chromatography on silica gel to provide the title
compound (26 mg, 34% in two steps).
[0454] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 8.54 (dt,
J=8.9, 1.2 Hz, 1H), 8.47 (dt, J=6.9, 1.1 Hz, 1H), 7.93 (br. s.,
1H), 7.59 (dd, J=6.6, 2.2 Hz, 2H), 7.21 (ddd, J=9.0, 6.8, 0.9 Hz,
1H), 6.98 (dd, J=6.6, 2.2 Hz, 2H), 6.87 (td, J=6.8, 1.3 Hz, 1H),
5.96 (br. s., 2H), 2.84 (s, 3H), 2.70 (s, 3H); MS m/z 383.2
[M+H].sup.+.
[0455] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 11 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00012 Cpd Name & Data 173
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methylpyrazolo[1,5-a]pyrid-
in- 3-yl)pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.55 (dt, J = 8.9, 1.2 Hz, 1H), 8.49
(dt, J = 6.9, 1.0 Hz, 1H), 8.20 (hr. s., 1H), 7.76-7.81 (m, 2H),
7.20-7.27 (m, 3H), 6.98 (t, J = 75 Hz, 1H) 6.89 (td, J = 6.9, 1.4
Hz, 1H), 6.08 (br. s, 2H), 2.72 (s, 3H); MS m/z 401.2 [M + H].sup.+
177
5-fluoro-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(trifluoromethyl-
) phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.44 (dt, J = 9.1, 1.1 Hz, 1H), 8.37
(dt, J = 6.9, 0.9 Hz, 1H), 8.39 (br. s., 1H), 7.87 (d, J = 8.5 Hz,
2H), 7.55 (d, J = 8.5 Hz, 2H), 7.13 (ddd, J = 9.1, 6.7, 1.3 Hz,
1H), 6.77 (td, J = 6.8, 1.6 Hz, 1H), 6.09 (br. s., 2H), 2.62 (s,
3H); MS m/z 403.4 [M + H].sup.+ 178
5-fluoro-2-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N--
[4- (trifluoromethyl)phenyl]pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.76-8.81 (m, 1H), 8.70 (br. s.,
1H), 7.91 (d, J = 8.5 Hz, 2H), 7.68 (dd, J = 10.1, 4.7 Hz, 1H),
7.47 (d, J = 8.5 Hz, 2H), 7.45 (t, J = 9.8 Hz, 1H), 6.52 (hr. s.,
2H); MS m/z 475.3 [M + H].sup.+
Example 12
2-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(difluoromethoxy)phenyl]-
-5-fluoropyrimidine-4,6-diamine (Cpd 180)
##STR00087##
[0457] Step 1. To a solution of cyclopropylacetylene (777.0 mg,
9.82 mmol) in THF (5 mL) at -78.degree. C. was added an
isopropylmagnesium chloride lithium chloride complex solution (9.0
mL, 1.3 M in THF) dropwise. The mixture was warmed to 0.degree. C.
and stirred for 30 minutes. To the mixture at -78.degree. C. was
added 4,6-dichloro-5-fluoro-2-(methylsulfonyl)pyrimidine (4.80 g,
19.6 mmol), then the mixture was warmed to 0.degree. C. and stirred
for 1 hour. The mixture was partitioned between ethyl acetate and
water. The organic phase was washed with brine, dried over
MgSO.sub.4, then filtered and evaporated. The residual material was
separated by silica gel column chromatography (eluting with 1:9
ethyl acetate-hexane) to afford
4,6-dichloro-2-(cyclopropylethynyl)-5-fluoropyrimidine (1.17 g,
45%).
[0458] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 1.53-1.67
(m, 1H), 0.98-1.10 (m, 2H), 0.83-0.94 (m, 2H); MS m/z 231.1 (100)
[M+H].sup.+.
[0459] Step 2. A mixture of
4,6-dichloro-2-(cyclopropylethynyl)-5-fluoropyrimidine (241.0 mg,
1.04 mmol) and 4-difluoromethoxy aniline (707.0 mg, 4.45 mmol) in
EtOH (2 mL) was stirred at reflux for 1 hour. After cooling, the
mixture was partitioned between ethyl acetate and water. The
organic phase was washed with brine, dried over MgSO.sub.4, then
filtered and evaporated. The residual material was separated by
silica gel column chromatography (eluting with 1:20 and 1:10 ethyl
acetate-hexane) to afford
6-chloro-2-(cyclopropylethynyl)-N-(4-(difluoromethoxy)phenyl)-5-fluoropyr-
imidin-4-amine (258.0 mg, 70%); MS m/z 354.2 (100) [M+H].sup.+,
356.2 (40).
[0460] Step 3. To
6-chloro-2-(cyclopropylethynyl)-N-(4(difluoromethoxy)phenyl)-5-fluoropyri-
midin-4-amine was added DMSO (2 mL) and NH.sub.4OH (27%, 0.1 mL).
The reaction mixture was sealed and stirred at 100.degree. C. for 2
days. The reaction mixture was partitioned between ethyl acetate
and water. The organic phase was washed with water (2.times.20 mL)
and brine, dried over MgSO.sub.4, then filtered and evaporated. The
residual material was separated by silica gel column chromatography
(eluting with 1:4 ethyl acetate-hexane) to afford
2-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(difluoromethoxy)phenyl-
]-5-fluoropyrimidine-4,6-diamine (149.0 mg, 64%). MS m/z 335.5 (80)
[M+H].sup.+, 336.2 (100).
[0461] Step 4. A mixture of
2-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(difluoromethoxy)phenyl-
]-5-fluoropyrimidine-4,6-diamine (100.0 mg, 0.30 mmol),
pyridinium-1-ylazanide (74.0 mg, 0.30 mmol), K.sub.2CO.sub.3 (43.0
mg, 0.31 mmol) and DMF (2 mL) was stirred at room temperature for 1
day, and then at 80.degree. C. for 1 day. The reaction mixture was
partitioned between ethyl acetate and water. The organic phase was
washed with water and brine, dried over MgSO.sub.4, then filtered
and evaporated. The residual material was separated by silica gel
column chromatography (eluting with 1:1 dichloromethane:hexane,
then 1:3 ethyl acetate:dichloromethane) to afford the title
compound (32.0 mg, 28% yield): m.p. 53-55.degree. C.
[0462] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 8.55 (d,
J=8.83 Hz, 1H), 8.41 (d, J=6.94 Hz, 1H). 8.20 (br. s., 1H),
7.63-7.91 (m, 2H), 7.21 (ddd, J=0.95, 6.78, 8.98 Hz, 1H), 7.17 (d,
J=8.83 Hz, 2H), 6.80-7.10 (t, J=75.00 Hz, 1H), 6.86 (dt, J=1.26,
6.78 Hz, 1H), 6.10 (br. s., 2H), 3.44 (m, 1H), 0.53-1.13 (m, 4H);
MS m/z 427.3 (100) [M+11].sup.+, 428.3 (50).
Example 13
[3-(4-amino-6-{[4-(difluoromethoxy)phenyl]amino}-5-fluoropyrimidin-2-yl)-5-
-fluoropyrazolo[1,5-a]pyridin-2-yl]methanol (Cpd 181)
##STR00088## ##STR00089##
[0464] Step 1. A mixture of 2-chloro-4-fluoropyridine (2.19 g,
16.65 mmol), prop-2-yn-1-ol (1.86 g, 33.29 mmol),
bis(acetonitrile)dichloropalladium(II) (215.6 mg, 0.83 mmol) and
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos)
(794.3 mg, 0.17 mmol) in NMP (15 mL) was degassed by three cycles
of vacuum pumping and N.sub.2 purging, and then triethylamine (4.7
mL, 33.3 mmol) was added. The mixture was degassed and purged with
N.sub.2, then heated at 60.degree. C. overnight. The solution was
cooled and poured into water (100 mL), and the product was
extracted with ethyl acetate (150 mL). The extract was dried over
MgSO.sub.4, then filtered and concentrated under the reduced
pressure. The residual material was separated by column
chromatography (eluting with 0 to 10% dichloromethane-hexane) to
yield 3-(4-fluoropyridin-2-yl)prop-2-yn-1-ol as an oil (2.40 g,
96%).
[0465] Step 2-4. To a solution of
3-(4-fluoropyridin-2-yl)prop-2-yn-1-ol (820.0 mg, 5.43 mmol) in
dichloromethane (10 mL) was added
2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (1.5 g, 6.98 mmol)
portion wise at 0.degree. C. The resulting mixture was stirred at
ambient temperature for 2 days. The solvent removed under a blowing
N.sub.2 stream to give a crude mixture. To the crude mixture in DMF
(3 mL) was added K.sub.2CO.sub.3 (825.0 mg, 5.97 mmol) at 0.degree.
C. The resulting mixture was stirred at room temperature for 24
hours, and then partitioned between ethyl acetate and water. The
organic phase was washed with water and brine, dried over
MgSO.sub.4, then filtered and evaporated. The residual material was
used in the next step without further purification.
[0466] A mixture of crude material, N-iodosuccinimide (1.2 g, 5.33
mmol) in chloroform (10 mL) was stirred at ambient temperature for
2 hours, and then partitioned between ethyl acetate and water. The
organic phase was washed with water and brine, dried over
MgSO.sub.4, then filtered and evaporated. The residual material was
separated by silica gel column chromatography (eluting with 1:1
dichloromethane:hexane, then 1% methanol in 1:4 ethyl
acetate:dichloromethane to afford
(5-fluoro-3-iodopyrazolo[1,5-a]pyridin-2-yl)methanol as an oil (1.4
g, 50%).
[0467] Step 5. To a solution of
(5-fluoro-3-iodopyrazolo[1,5-a]pyridin-2-yl)methanol (500.0 mg,
1.71 mmol) in dichloromethane (3 mL) was added imidazole (139.5 mg,
2.05 mmol), followed by tert-butyldimethylsilyl chloride (384.0 mg,
2.55 mmol) in dichloromethane (5 mL) added dropwise at 0.degree. C.
The resulting mixture was stirred at ambient temperature for 30
minutes, then filtered through a pad of silica gel/selite, washing
with dichloromethane to provide
2-[(tert-butyldimethylsilyloxy)methyl]-5-fluoro-3-iodopyrazolo[1,-
5-a]pyridine (470.0 mg, 72%).
[0468] Step 6. To a solution of
2-[(tert-butyldimethylsilyloxy)methyl]-5-fluoro-3-iodopyrazolo[1,5-a]pyri-
dine (470.0 mg, 1.15 mmol) in THF (5 mL) was added an
isopropylmagnesium chloride lithium chloride complex solution (1.07
mL, 1.3 M in THF) at -78.degree. C. dropwise. The mixture was
warmed to 0.degree. C. and stirred for 30 minutes, and then
4,6-dichloro-5-fluoro-2-(methylsulfonyl)pyrimidine (4.80 g, 19.6
mmol) was added in one portion at -78.degree. C. The mixture was
stirred at 0.degree. C. for 1 hour and then partitioned between
ethyl acetate and water. The organic phase was washed with brine,
dried over MgSO.sub.4, then filtered and evaporated. The residual
material was separated by silica gel column chromatography (eluting
with 1:9 ethyl acetate:hexane) to afford
2-[(tert-butyldimethylsilyloxy)methyl]-3-(4,6-dichloro-5-fluoro-
pyrimidin-2-yl)-5-fluoropyrazolo[1,5-a]pyridine (205.0 mg,
40%).
[0469] Steps 7-8. A mixture of
2-[(tert-butyldimethylsilyloxy)methyl]-3-(4,6-dichloro-5-fluoropyrimidin--
2-yl)-5-fluoropyrazolo[1,5-a]pyridine (102.0 mg, 0.23 mmol),
4-difluoromethoxy aniline (145.0 mg, 0.92 mmol) and ethanol (1 mL)
was heated at 90.degree. C. overnight. After cooling, the mixture
was poured into ice-water to afford a solid. The solid was
collected by filtration, followed by washing with water and hexane.
The solid was dried under the vacuum to provide
2-[2-[(tert-butyldimethylsilyloxy)methyl]-5-fluoropyrazolo[1,5-a]pyridin--
3-yl]-6-chloro-N-(4-difluoromethoxy)phenyl]-5-fluoropyrimidin-4-amine
(a mixture of TBS protected and unprotected product).
[0470] To the dried solid was added DMSO (3 mL) and NH.sub.4OH (0.3
mL). The reaction mixture was sealed and stirred at 100.degree. C.
for 2 days. The mixture was partitioned between ethyl acetate and
water and the organic phase was washed with water (2.times.10 mL)
and brine, dried over MgSO.sub.4, then filtered and evaporated. The
residual material was separated by silica gel column chromatography
(eluting with 1-5% methanol in dichloromethane) to provide the
title compound as a white solid (25.0 mg, 25% for two steps); m.p.
198-200.degree. C.
[0471] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 8.50-8.64
(m, 1H), 8.35 (s, 1H), 8.06-8.21 (m, 1H), 7.64 (d, J=8.83 Hz, 2H),
7.24 (d, J=8.83 Hz, 2H), 6.80-7.10 (t, J=75.00 Hz, 1H), 6.86-6.93
(m, 1H), 6.23-6.41 (m, 2H), 5.46-5.66 (m, 1H), 4.68-4.83 (m, 2H);
MS m/z 435.2 (100) [M+H].sup.+, 436.2 (20).
[0472] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 13 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00013 Cpd Name & Data 186
N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-5-fluoropyrazolo[1,5-a]pyridi-
n-3-yl)-5- fluoropyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.54 (dd, J = 5.20, 7.41 Hz, 1H), 8.25
(dd, J = 2.68, 10.88 Hz, 1H), 8.18 (br. s., 1H), 7.71 (d, J = 9.14
Hz, 2H), 7.21 (d, J = 9.14 Hz, 2H), 6.80-7.10 (t, J = 75.00 Hz,
1H), 6.76-6.88 (m, 1H), 6.14 (br. s., 2H), 3.24 (q, J = 7.57 Hz,
2H), 1.20-1.35 (m, 3H); m.p. 103-105.degree. C.; MS m/z 433.6 [M +
H].sup.+ 187
2-(2-ethyl-5-fluoropyrazolo[1,5-alpyridin-3-yl)-5-fluoro-N-[4-(trifluo-
romethyl)phenyl] pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 8.53-8.59 (m, 1H), 8.50 (br. s., 1H),
8.28 (dd, J = 2.68, 10.25 Hz, 1H), 7.93 (d, J = 8.51 Hz, 2H), 7.69
(d, J = 8.51 Hz, 2H), 6.83 (dt, J = 2.99, 7.33 Hz, 1H), 6.28 (br.
s., 2H), 3.28 (q, J = 7.46 Hz, 2H), 1.28 (t, J = 7.57 Hz, 3H); m.p.
164-166.degree. C.; MS m/z 435.2 [M + H].sup.+ 188
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-5-fluoropyrazolo[1,5-
-a]pyridin-3-yl)- 5-fluoropyrimidine-4,6-diamine .sup.1H NMR (500
MHz, Acetone-d.sub.6) .delta. ppm 8.49-8.64 (m, 1H), 8.33-8.40 (m,
1H), 8.24-8.32 (m, 1H), 7.77-7.85 (m, 1H), 7.44-7.50 (m, 1H),
7.29-7.38 (m, 1H), 6.80-7.10 (t, J = 75.00 Hz, 1H), 6.81-6.87 (m,
1H), 6.17-6.34 (m, 2H), 3.27 (d, J = 7.57 Hz, 2H), 1.28 (t, J =
7.57 Hz, 3H); m.p. 150-152.degree. C.; MS m/z 452. [M +
H].sup.+
Example 14
5-fluoro-2-(2-methylimidazo[1,2-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phen-
yl]pyrimidine-4,6-diamine (Cpd 169)
##STR00090##
[0474] Step 1. To a solution of
2-methylimidazo[1,2-a]pyridine-3-carboximidamide pivaloate (250 mg,
0.905 mmol) and dimethyl 2-fluoromalonate (272 mg, 1.81 mmol) in
MeOH (5 mL) was added 30% NaOMe in MeOH (0.2 mL). The mixture was
heated at 85.degree. C. in a sealed tube for 72 hours until UPLC
showed complete consumption of the starting material. The reaction
mixture was concentrated under reduced pressure, then diluted with
water (5 mL), and acidified with 1N HCl to about pH 7. A tan
precipitate was collected by filtration giving
5-fluoro-2-(2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-4,6-diol.
5-fluoro-2-(2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-4,6-diol
(180 mg, 76%). The product (180 mg, 0.69 mmol) was mixed with
phosphorus oxychloride (3 mL) in a microwave vial, then the vial
was sealed and microwaved for 15 minutes at 150.degree. C. The
reaction mixture was transferred into a 25 mL round-bottom flask
and concentrated under reduced pressure. The remainder was
redissolved in EtOAc (10 mL) and washed with an aqueous NaHCO.sub.3
solution three times. The organic phase was dried over
Na.sub.2SO.sub.4, then filtered and evaporated to afford
3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-2-methylimidazo[1,2-a]pyri-
dine (164 mg, 80%) as a yellow solid.
[0475] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.59 (dt,
J=6.9, 0.9 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H),
7.32 (t, J=6.9 Hz, 1H), 2.77 (s, 3H); MS m/z 298.1 [M+H].sup.+.
[0476] Step 2.
3-(4,6-Dichloro-5-fluoropyrimidin-2-yl)-2-methylimidazo[1,2-a]pyridine
(50 mg, 0.168 mmol) and 4-trifluoromethyl aniline (54 mg, 0.336
mmol) were mixed in EtOH (2 mL) and heated in a sealed tube at
100.degree. C. until UPLC showed complete consumption of the
starting material (48 hours). The reaction mixture was cooled to
room temperature and diluted with water (5 mL) to form a
precipitate. The product was collected by filtration, then washed
with hexanes. The crude product, without drying, was dissolved in
CH.sub.3CN (2 mL), then saturated ammonia (4 mL) in water was
added. The reaction mixture was heated at 100.degree. C. in a
sealed tube for 16 hours until UPLC showed complete consumption of
starting material. A crude product was precipitated by addition of
water (10 mL). The precipitate was filtered, then washed with
hexanes and dried to yield the title compound (32 mg, 47% over two
steps) as a light tan solid.
[0477] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 9.76 (dt,
J=7.1, 1.0 Hz, 1H), 8.50 (br. s., 1H), 7.85 (d, J=8.5 Hz, 2H), 7.57
(d, J=8.5 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H), 7.19 (ddd, J=8.5, 6.5,
1.8 Hz, 1H), 6.74 (td, J=6.9, 1.3 Hz, 1H), 6.27 (br. s., 2H), 2.64
(s, 3H); MS m/z 403.3 [M+H].sup.+.
[0478] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 14 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00014 Cpd Name & Data 170
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2-methylimidazo[1,2-a]pyridi-
n-3-yl) pyrimidine-4,6-diamine MS m/z 401.3 [M + H].sup.+ 171
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(2-methylimidazo[1,2-
-a]pyridin-3-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.83 (d, J = 6.9 Hz, 1H), 9.25 (br. s,
1H), 7.80 (dd, J = 13.4, 2.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H),
7.44 (d, J = 8.5 Hz, 1H), 7.31-7.39 (m, 2H), 7.18 (t, J = 73.1 Hz,
1H), 6.88-6.97 (m, 3H), 3.31 (s, 3H); MS m/z 419.3 [M + H].sup.+
174
5-fluoro-N-[4-(trifluoromethyl)phenyl]-2-(2,6,8-trimethylimidazo[1,2-a-
]pyrazin-3-yl) pyrimidine-4,6-diamine .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 9.48 (s, 1H), 9.39 (s, 1H), 7.83 (d, J =
8.51 Hz, 2H), 7.68 (d, J = 8.83 Hz, 2H), 7.11 (s, 2H), 2.75 (s,
3H), 2.72 (s, 3H), 2.55 (s, 3H); m.p. 166-168.degree. C.; MS m/z
432.3 [M + H].sup.+ 175
N-[4-(difluoromethoxy)phenyl]-5-fluoro-2-(2,6,8-trimethylimidazo[1,2-a-
]pyrazin-3-yl) pyrimidine-4,6-diamine m.p. 141-143.degree. C.; MS
m/z 430.4 [M + H].sup.+ 176
N-[4-(difluoromethoxy)-3-fluorophenyl]-5-fluoro-2-(2,6,8-trimethylimid-
azo[1,2-a] pyrazin-3-yl)pyrimidine-4,6-diamine .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 9.40 (s, 1H), 9.32 (s, 1H),
7.71-7.83 (m, 1H), 7.40-7.45 (m, 1H), 7.31-7.37 (m, 1H), 7.04-7.32
(t, J = 70.00 Hz, 1H), 7.07 (s, 2H), 2.74 (s, 3H), 2.72 (s, 3H),
2.38 (s, 3H); m.p. 140-141.degree. C.; MS m/z 448.4 [M + H].sup.+
251
N-(4-chlorophenyl)-5-fluoro-2-(6-fluoro-2-methylimidazo[1,2-a]pyridin--
3-yl)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. .quadrature. ppm 9.88-10.04 (m, 1H), 8.33-8.46 (m, 1H),
7.72 (d, J = 8.83 Hz, 2H), 7.48-7.59 (m, 1H), 7.39 (d, J = 8.83 Hz,
2H), 7.27-7.34 (m, 1H), 6.34-6.45 (br., s, 2H), 2.73 (s, 3H); m.p.
226-229.degree. C.; MS m/z 388.2 [M + H].sup.+ 252
5-fluoro-2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N-(4-methoxyp-
henyl)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz,
Acetone-d.sub.6) .delta. ppm 9.91 (dd, J = 2.52, 5.99 Hz, 1H), 8.10
(br. s., 1H), 7.45-7.58 ( d, J = 8.83 Hz, 2H), 7.26 (d, J = 1.89
Hz, 1H), 6.96 (d, J = 8.83 Hz, 2H), 6.23 (br. s., 2H), 3.81 (s,
3H), 2.70 (s, 3H); m.p. 204-206.degree. C.; MS m/z 384.2 [M +
H].sup.+ 253
5-fluoro-2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N-(4-methylph-
enyl)pyrimidine- 4,6-diamine m.p. 210-212.degree. C.; MS m/z 368.2
[M + H].sup.+
Example 15
5-chloro-2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]py-
rimidine-4,6-diamine (Cpd 166)
##STR00091##
[0480] To a solution of
2-(2-methyl-1H-benzo[d]imidazol-1-yl)-N4-(4-(trifluoromethyl)-phenyl)pyri-
midine-4,6-diamine (76 mg, 0.20 mmol) in DMF (1.5 mL) was added
N-chlorosuccinimide (29 mg, 0.22 mmol). The mixture was stirred for
2 hours at room temperature. Ice water (5 mL) and a saturated
NaHCO.sub.3 solution (2 mL) was added to the mixture. The resulting
precipitate was filtered, washed by water, and dried under nitrogen
to yield the title compound (77 mg, 92%) as an off-white solid.
[0481] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 8.40 (1H,
s) 7.95-8.00 (1H, m) 7.76-7.83 (2H, m) 7.57 (2H, d, J=8.51 Hz)
7.40-7.45 (1H, m) 7.06-7.11 (1H, m) 6.98-7.04 (1H, m) 6.52-6.75
(2H, m) 2.68 (3H, s); MS m/z 419.1 [M+H].sup.+.
[0482] Additional compounds of Formula (I) or a form thereof
described herein may be prepared according to the procedure of
Example 15 by substituting the appropriate starting materials,
reagents and reaction conditions.
TABLE-US-00015 Cpd Name & Data 167
5-chloro-2-(2-ethyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl-
]pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.55 (1H, s) 8.07-8.12 (1H, m) 7.91-7.96 (2H, m) 7.71
(2H, d, J = 8.51 Hz) 7.58-7.63 (1H, m) 7.13-7.26 (2H, m) 6.80 (2H,
br. s.) 3.23-3.30 (2H, m) 1.31 (3H, t, J = 7.41 Hz); MS m/z 433.2
[M + H].sup.+ 168
5-chloro-N-[4-(difluoromethoxy)phenyl]-2-(2-ethyl-1H-benzimidazol-1-yl-
)pyrimidine- 4,6-diamine .sup.1H NMR (500 MHz, Acetone-d.sub.6)
.delta. ppm 8.31 (1H, s) 8.09-8.13 (1H, m) 7.65-7.71 (2H, m)
7.55-7.60 (1H, m) 7.13-7.25 (4H, m) 6.99 (1H, t, J = 74.40 Hz) 6.68
(2H, br. s.) 3.19-3.25 (2H, m) 1.28 (3H, t, J = 7.41 Hz); MS m/z
431.2 [M + H].sup.+
BIOLOGICAL EXAMPLES
[0483] The following biological examples demonstrate the usefulness
of the compounds described herein to inhibit Bmi-1 function and
reduce the level of Bmi-1 protein.
Example 1
Sandwich ELISA Assay
Cell Seeding and Compound Treatment (Day 1):
[0484] HT-1080 cells were seeded at 8000 cells/well (50 .mu.L) in
96-well tissue culture plates. After the cells became adherent (3-4
hours), 2.times. diluted stocks of test compounds in 50 .mu.L DMEM
containing 1% DMSO (final DMSO concentration was 0.5%) were added
and the plates were incubated at 37.degree. C. under 5% CO.sub.2
for 40-48 hours.
ELISA Plate First Antibody Preparation (Day 2):
[0485] The First Antibody (Millipore Mouse, monoclonal to mouse
Bmi-1, clone F6, catalog #05-637) diluted to 2 .mu.g/mL in PBS was
added (100 .mu.L) to each well of a Nunc MaxiSorp 96-well ELISA
plate. The plate was covered with a plate seal and allowed to stand
overnight.
Cell Lysate Preparation (Day 3):
[0486] Fresh 1.times. Lysis buffer was prepared on the day of the
assay as follows: 1 mM EDTA, 150 mM NaCl, 0.5% Triton-X 100, 10 mM
NaF, 20 mM B-Glycerophosphate, 1 mM DTT (in PBS, pH 7.2-7.4) and
1.times.HALT protease inhibitor cocktail (Pierce #78410).
[0487] The 1.times. Lysis Buffer (40 .mu.L) was added to each well
and the plate was shaken for 5-10 minutes on an orbital shaker to
allow cell lysis, then diluent (1% BSA in PBS in 0.5% NP40) (100
.mu.L) was added to each well.
[0488] A standard curve was prepared at the following Bmi-1
concentrations: 8000, 4000, 2000, 1000, 500, 250, 125, 0 pg/mL The
Bmi-1 Recombinant Protein Standard (Novus Biologicals PCGF4
Recombinant Protein (P01), catalog #H00000648-P01) used to prepare
the standard curve was stored at -80.degree. C. On first thaw, the
Bmi-1 Recombinant Protein Standard was diluted to 10 .mu.g/.mu.L in
Blocking Buffer (1% BSA in PBS; BSA: Fisher Scientific Catalog
#1600-100). Aliquots were taken and refrozen at -80.degree. C. The
aliquots may be kept at 4.degree. C. and reused after first thaw,
but only within 1-2 weeks. The Bmi-1 Recombinant Protein Standard
contains a GST-fusion tag that appears around 70 Kda on Western
Blot.
ELISA Assay (Day 3):
[0489] The prepared ELISA plate was washed 3.times. with Wash
Buffer (0.05% Tween-20 in PBS). The final wash was removed from the
plate and the plate was blotted dry. Blocking Buffer (300 .mu.L)
(1% BSA in PBS) was added to each well. The plate was covered with
a plate seal and incubated at room temperature for 1 hour. The
blocked plate was washed 3.times. with Wash Buffer, then the final
wash was removed and the plate was blotted dry. The previously
prepared samples and standards were added (100 .mu.L/well) and the
plate was covered with a plate seal and incubated at 4.degree. C.
overnight.
ELISA Assay (Day 4):
[0490] The prepared ELISA plate was removed from 4.degree. C.,
incubated at room temperature for 30 minutes, then washed and
blotted dry as previously described for Day 3. The Second Antibody
(Cell Signaling Rabbit anti-Bmi-1, Cat #2830) diluted to 1:600 in
Blocking Buffer was added (100 .mu.L) to each well, except as
needed for background control wells. The plate was covered with a
plate seal and incubated for 1.5 hrs at room temperature.
[0491] The ELISA plate was washed and blotted dry as previously
described. The Third Antibody (Cell Signaling HRP conjugated
anti-rabbit IgG (CellSignaling, Cat #: 7074) diluted to 1:300 in
Blocking Buffer was added (100 .mu.L) to each well, except as
needed for background control wells. The plate was incubated for 1
hr at room temperature.
[0492] The plate was washed and blotted dry as previously
described, then prepared TMB substrate (TMB substrate kit, Pierce
catalog #34021) (prepared by mixing kit reagents 1:1) (100 .mu.L)
was added per well. The plate was incubated for 20-30 minutes at
room temperature in the dark, then Stop Solution (2 M sulfuric acid
in water) (50 .mu.L) was added per well. The plates were read at
OD450 (experimental) and OD570 (reference).
[0493] As shown in Table 1, test compounds described herein had
Bmi-1 ELISA EC.sub.50 values between >0.1 .mu.M to .ltoreq.3
.mu.M (one star), an EC.sub.50 value between >0.01 .mu.M to
.ltoreq.0.1 .mu.M (two stars), an EC.sub.50 value between >0.001
.mu.M to .ltoreq.0.01 .mu.M (three stars) or an EC.sub.50 value of
.ltoreq.0.001 .mu.M (four stars).
TABLE-US-00016 TABLE 1 Cpd EC.sub.50 1 ** 2 * 3 ** 4 ** 5 * 6 ** 7
* 8 * 9 *** 10 ** 11 * 12 ** 13 * 14 * 15 ** 16 ** 17 * 18 * 19 *
20 * 21 *** 22 ** 23 * 24 * 25 * 26 * 27 * 28 * 29 ** 30 * 31 ** 32
* 33 ** 34 *** 35 * 36 ** 37 ** 38 * 39 * 40 * 41 * 42 ** 43 ** 44
* 45 * 46 * 47 * 48 * 49 * 50 ** 51 * 52 * 53 * 54 * 55 * 56 * 57 *
58 * 59 * 60 ** 61 * 62 ** 63 ** 64 ** 65 ** 66 ** 67 * 68 ** 69 **
70 * 71 ** 72 ** 73 ** 74 * 75 * 76 ** 77 ** 78 ** 79 * 80 ** 81 **
82 ** 83 ** 84 * 85 * 86 ** 87 * 88 ** 89 * 90 * 91 * 92 ** 93 **
94 ** 95 ** 96 * 97 ** 98 * 99 * 100 * 101 ** 102 ** 103 ** 104 **
105 ** 106 ** 107 ** 108 * 109 ** 110 ** 111 ** 112 ** 113 ** 114
** 115 ** 116 ** 117 ** 118 * 119 ** 120 ** 121 *** 122 ** 123 ***
124 ** 125 * 126 ** 127 ** 128 ** 129 ** 130 ** 131 ** 132 ** 133
** 134 ** 135 ** 136 ** 137 ** 138 ** 139 * 140 ** 141 ** 142 **
143 *** 144 ** 145 *** 146 ** 147 * 148 * 149 ** 150 ** 151 ** 152
** 153 ** 154 * 155 ** 156 *** 157 ** 158 * 159 * 160 ** 161 ** 162
** 163 ** 164 ** 165 *** 166 * 167 ** 168 * 169 * 170 * 171 * 172 *
173 * 174 * 175 * 176 * 177 * 178 * 179 *** 180 * 181 ** 182 * 183
** 184 *** 185 ** 186 * 187 * 188 * 189 * 190 * 191 ** 192 * 193 **
194 * 195 * 196 *** 197 *** 198 *** 199 *** 200 *** 201 ** 202 *
203 *** 204 ** 205 *** 206 ** 207 *** 208 *** 209 ** 210 * 211 *
212 ** 213 *** 214 ** 215 * 216 ** 217 ** 218 *** 219 * 220 ** 221
* 222 * 223 * 224 ** 225 ** 226 * 227 ** 228 ** 229 * 230 * 231 *
232 ** 233 ** 234 ** 235 ** 236 * 237 ** 238 * 239 ** 240 *** 241
** 242 *** 243 ** 244 ** 245 ** 246 **
247 ** 248 ** 249 ** 250 ** 251 * 252 ** 253 *** 254 ** 255 * 256
** 257 ** 258 *** 259 * 260 * 261 ** 262 ** 263 ** 264 *** 265 ***
266 ** 267 * 268 * 269 * 270 *** 271 *** 272 ** 273 *** 274 ** 275
** 276 *** 277 **** 278 * 279 ** 280 ** 281 *** 282 *** 283 * 284
**
Example 2
In Vitro Cancer Stem Cell Assay
[0494] The effect on inhibition of Bmi-1 function and reduction in
the level of Bmi-1 protein by a compound of Formula (I) or a form
thereof was tested in the in vitro pediatric Baylor Xenograft
Derived (BXD) brain tumor model and in cells from primary patient
cultures (PPC).
[0495] Cells were grown under conditions to measure either general
cell growth (such as in fetal bovine serum (FBS) containing media
in conventional tissue culture plates) or in conditions
specifically for cancer stem cell (CSC) growth (low serum,
nonadherent plates) to assess the effect of Bmi-1 inhibition and
reduction in the level of Bmi-1 protein by a compound of Formula
(I) on these populations. The cells were treated with a
predetermined dose range of Compound 109 at fixed time points over
a time period of from 24 hours to 13 days. The effect of inhibition
on cell growth viability was quantitated using conventional 2D
growth and neurosphere growth using a cell-counting kit (CCK)
(supplied by Dojindo Molecular Technologies, Inc.).
[0496] FIG. 1 demonstrates the effect of Compound 109 in a BXD GBM
model where the CSC population (as measured by number of
neurospheres) was dose dependently reduced over a period of 13 days
in the presence of the stated concentrations of Compound 109.
[0497] FIG. 2 demonstrates the effect of Compound 109 in a BXD GBM
model where the CSC population (as measured by number of
neurospheres) was universally reduced over a period of 13 days in
the presence of the stated concentrations of Compound 109.
[0498] FIG. 3 demonstrates the effect of Compound 109 in a
tumorosphere assay where 2000 PPC CSCs per well were cultured
either under standard 2D tissue culture conditions (with FBS) or
conditions selective for CSC growth (attachment-free, serum-free)
for 13 days in the presence of the stated concentrations of
Compound 109. Both the monolayer and neurosphere CSC populations
were reduced as the result of contacting the PPC CSCs with Compound
109, representative of a compound of Formula (I) or a form thereof,
at concentrations of 62.5 nm and 15.6 nm, respectively.
[0499] Taken together, the data from FIGS. 1-3 demonstrate the
preferential reduction of cancer stem cell populations compared to
general cell populations as a result of inhibition of Bmi-1
function and reduction in the level of Bmi-1 protein by a compound
of Formula (I) or a form thereof.
Example 3
In Vivo Survival Assay
[0500] A glioblastoma animal model was developed in which U87-MG
tumor cells were injected intracranially into nu/nu mice and a
tumor was allowed to become established over a 10 day period. The
mice were dosed daily with vehicle, Compound 109 or temozolomide (a
standard-of-care agent), as indicated. The comparative results for
survival for each treatment group (n=10) from administration of
vehicle, Compound 109 and temozolomide are shown in FIG. 4.
[0501] FIG. 4 demonstrates the effect of daily dosing of Compound
109 compared to temozolomide, at the indicated dose levels, on
survival over a 40 day time period in an orthotopic model of
glioblastoma. Cells were implanted intracranially into nude mice
and dosing was begun 10 days later with either vehicle, Compound
109 or temozolomide. Compound 109 demonstrated extended survival of
these tumor bearing mice over both vehicle and temozolomide
(p<0.0001).
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[0575] Without regard to whether a document cited herein was
specifically and individually indicated as being incorporated by
reference, all documents referred to herein are incorporated by
reference into the present application for any and all purposes to
the same extent as if each individual reference was fully set forth
herein.
[0576] Although certain embodiments have been described in detail
above, those having ordinary skill in the art will clearly
understand that many modifications are possible in the embodiments
without departing from the teachings thereof. All such
modifications are intended to be encompassed within the scope of
the claims presented herein.
* * * * *