U.S. patent application number 15/008994 was filed with the patent office on 2016-05-26 for bromodomain inhibitors.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Yujia Dai, Steven D. Fidanze, Lisa Hasvold, James H. Holms, Warren M. Kati, Dachun Liu, Robert A. Mantei, William J. McClellan, Keith F. McDaniel, John K. Pratt, George S. Sheppard, Carol K. Wada, Le Wang.
Application Number | 20160143916 15/008994 |
Document ID | / |
Family ID | 48696151 |
Filed Date | 2016-05-26 |
United States Patent
Application |
20160143916 |
Kind Code |
A1 |
Wang; Le ; et al. |
May 26, 2016 |
BROMODOMAIN INHIBITORS
Abstract
The present invention provides for compounds of formula (I)
##STR00001## wherein A.sup.1, A.sup.2, A.sup.3, A.sup.4, X.sup.1,
X.sup.2, Y.sup.1, L.sup.1, G.sup.1, R.sup.x, and R.sup.y have any
of the values defined thereof in the specification, and
pharmaceutically acceptable salts thereof, that are useful as
agents in the treatment of diseases and conditions, including
inflammatory diseases, cancer, and AIDS. Also provided are
pharmaceutical compositions comprising one or more compounds of
formula (I).
Inventors: |
Wang; Le; (Vernon Hills,
IL) ; Pratt; John K.; (Kenosha, WI) ;
McDaniel; Keith F.; (Wauconda, IL) ; Dai; Yujia;
(Gurnee, IL) ; Fidanze; Steven D.; (Grayslake,
IL) ; Hasvold; Lisa; (Grayslake, IL) ; Holms;
James H.; (Gurnee, IL) ; Kati; Warren M.;
(Gurnee, IL) ; Liu; Dachun; (Vernon Hills, IL)
; Mantei; Robert A.; (Franklin, WI) ; McClellan;
William J.; (Waukegan, IL) ; Sheppard; George S.;
(Wilmette, IL) ; Wada; Carol K.; (Evanston,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
48696151 |
Appl. No.: |
15/008994 |
Filed: |
January 28, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13828285 |
Mar 14, 2013 |
9296741 |
|
|
15008994 |
|
|
|
|
PCT/CN2012/086357 |
Dec 11, 2012 |
|
|
|
13828285 |
|
|
|
|
PCT/CN2011/002224 |
Dec 30, 2011 |
|
|
|
PCT/CN2012/086357 |
|
|
|
|
Current U.S.
Class: |
514/19.3 ;
514/228.2; 514/234.5; 514/248; 514/300; 514/303; 514/43;
514/49 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 17/06 20180101; A61K 31/437 20130101; A61P 5/40 20180101; A61P
3/10 20180101; A61P 25/00 20180101; A61P 27/02 20180101; A61K
31/541 20130101; A61P 13/00 20180101; A61P 35/00 20180101; A61P
15/16 20180101; A61K 31/5377 20130101; A61P 31/04 20180101; A61P
31/18 20180101; A61P 1/18 20180101; A61P 9/00 20180101; A61P 1/00
20180101; C07D 487/04 20130101; A61P 21/00 20180101; A61P 13/12
20180101; A61P 17/02 20180101; A61P 19/08 20180101; C07D 471/04
20130101; A61K 45/06 20130101; A61P 1/04 20180101; A61P 19/02
20180101; A61P 1/02 20180101; A61P 1/16 20180101; A61P 5/06
20180101; A61P 25/28 20180101; A61K 31/5025 20130101; A61P 17/04
20180101; A61P 25/02 20180101; A61P 19/06 20180101; A61P 29/00
20180101; A61P 25/04 20180101; A61P 35/02 20180101; A61P 17/00
20180101; A61P 37/02 20180101; A61P 37/06 20180101; A61P 5/14
20180101; A61P 19/00 20180101; A61P 37/00 20180101; A61P 31/00
20180101; A61P 39/02 20180101; A61P 43/00 20180101; A61P 9/10
20180101; A61P 11/00 20180101; A61P 3/00 20180101 |
International
Class: |
A61K 31/541 20060101
A61K031/541; A61K 45/06 20060101 A61K045/06; A61K 31/5025 20060101
A61K031/5025; A61K 31/437 20060101 A61K031/437; A61K 31/5377
20060101 A61K031/5377 |
Claims
1-55. (canceled)
56. A method for treating cancer in a subject comprising
administering a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof,
##STR00013## wherein R.sup.x is hydrogen or C.sub.1-C.sub.3 alkyl;
R.sup.y is C.sub.1-C.sub.3 alkyl, --(C.sub.2-C.sub.3 alkylenyl)-OH,
or C.sub.1-C.sub.3 haloalkyl; X.sup.1 is N or CR.sup.x1 wherein
R.sup.x1 is hydrogen, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, --C(O)OR.sup.ax1, --C(O)NR.sup.bx1R.sup.cx1,
--C(O)R.sup.dx1, S(O).sub.2R.sup.dx1,
--S(O).sub.2NR.sup.bx1R.sup.cx1, G.sup.x1, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with one substituent selected from
the group consisting of OR.sup.ax1, SR.sup.ax1, S(O)R.sup.dx1,
S(O).sub.2R.sup.dx1, NR.sup.bx1R.sup.cx1, --C(O)R.sup.ax1,
--C(O)OR.sup.ax1, --C(O)NR.sup.bx1R.sup.cx1,
--S(O).sub.2NR.sup.bx1R.sup.cx1, and G.sup.x1; R.sup.ax1,
R.sup.bx1, and R.sup.cx1, at each occurrence, are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, G.sup.a, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.a;
R.sup.dx1, at each occurrence, are each independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, G.sup.a, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.a; X.sup.2 is N or CR.sup.x2;
wherein R.sup.x2 is hydrogen, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, --C(O)OR.sup.ax2,
--C(O)NR.sup.bx2R.sup.cx2, --C(O)R.sup.dx2, --C(O)H,
S(O).sub.2R.sup.dx2, --S(O).sub.2NR.sup.bx2R.sup.cx2, G.sup.x2,
C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl; wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one
substituent selected from the group consisting of OR.sup.ax2,
SR.sup.ax2, S(O)R.sup.dx2, S(O).sub.2R.sup.dx2,
NR.sup.bx2R.sup.cx2, --C(O)R.sup.ax2, --C(O)OR.sup.ax2,
--C(O)NR.sup.bx2R.sup.cx2, --S(O).sub.2NR.sup.bx2R.sup.cx2, and
G.sup.x2; R.sup.ax2, R.sup.bx2, and R.sup.cx2, at each occurrence,
are each independently hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.b, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.b; R.sup.dx2, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, G.sup.b, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.b; Y.sup.1 is N or CR.sup.u;
wherein R.sup.u is hydrogen, C.sub.1-C.sub.6 alkyl, halogen, or
C.sub.1-C.sub.6 haloalkyl; A.sup.1 is N or CR.sup.1, A.sup.2 is N
or CR.sup.2, A.sup.3 is N or CR.sup.3; and A.sup.4 is N or
CR.sup.4; with the proviso that zero, one, two, or three of
A.sup.1, A.sup.2, A.sup.3, and A.sup.4 are N; R.sup.1, R.sup.3, and
R.sup.4 are each independently hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, CN, or NO.sub.2; R.sup.2 is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN, NO.sub.2,
G.sup.2a, --OR.sup.2a, --OC(O)R.sup.2d, --OC(O)NR.sup.2bR.sup.2c,
--SR.sup.2a, --S(O).sub.2R.sup.2d, --S(O).sub.2NR.sup.2bR.sup.2c,
--C(O)R.sup.2d, --C(O)OR.sup.2a, --C(O)NR.sup.2bR.sup.2c,
--NR.sup.2bR.sup.2c, --N(R.sup.2e)C(O)R.sup.2d,
--N(R.sup.2e)S(O).sub.2R.sup.2d, --N(R.sup.2e)C(O)O(R.sup.2d),
--N(R.sup.2e)C(O)NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.2a,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.2a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)O(R.sup.2a), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, and
--(C.sub.1-C.sub.6 alkylenyl)-CN; R.sup.2a, R.sup.2b, R.sup.2c, and
R.sup.2e, at each occurrence, are each independently hydrogen,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, G.sup.2b, or C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one
substituent selected from the group consisting of --OR.sup.z1,
NR.sup.z1R.sup.z2, --C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2,
--S(O).sub.2R.sup.z1, --S(O).sub.2NR.sup.z1R.sup.z2, and G.sup.2b;
R.sup.2d, at each occurrence, is independently C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl,
G.sup.2b, or C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with one substituent selected from
the group consisting of --OR.sup.z1, NR.sup.z1R.sup.z2,
--C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2, --S(O).sub.2R.sup.z1,
--S(O).sub.2NR.sup.z1R.sup.z2, and G.sup.2b; R.sup.z1 and R.sup.z2,
at each occurrence, are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; G.sup.x1,
G.sup.x2, G.sup.a, G.sup.b, G.sup.2a, and G.sup.2b, at each
occurrence, are each independently aryl, heteroaryl, heterocycle,
cycloalkyl, or cycloalkenyl, and each of which is independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 of R.sup.v;
L.sup.1 is absent, CH.sub.2, C(O), C(H)(OH), (CH.sub.2).sub.mO,
(CH.sub.2).sub.mS(O).sub.n wherein n is 0, 1, or 2; or
(CH.sub.2).sub.mN(R.sup.z) wherein R.sup.z is hydrogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, (C.sub.2-C.sub.3
alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or 1; G.sup.1
is C.sub.1-C.sub.6 alkyl, alkoxyalkyl, G.sup.1a or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.1a; wherein each G.sup.1a is
independently aryl, heteroaryl, heterocycle, cycloalkyl, or
cycloalkenyl, and each G.sup.1a is independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 of R.sup.w; R.sup.v and R.sup.w,
at each occurrence, are each independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, oxo, --OR.sup.h, --OC(O)R.sup.i,
--OC(O)NR.sup.jR.sup.k, --SR.sup.h, --S(O).sub.2R.sup.h,
--S(O).sub.2NR.sup.jR.sup.k, --C(O)R.sup.h, --C(O)-monocyclic
heterocycle, --C(O)-monocyclic heteroaryl, --C(O)OR.sup.h,
--C(O)NR.sup.jR.sup.k, --NR.sup.jR.sup.k, --N(R.sup.h)C(O)R.sup.i,
--N(R.sup.h)S(O).sub.2R.sup.i, --N(R.sup.h)C(O)O(R.sup.i),
--N(R.sup.h)C(O)NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.h, --(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.i,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)NR.sup.jR.sup.k,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.h, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.h, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.h,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.jR.sup.k,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)R.sup.i, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)S(O).sub.2R.sup.i, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)O(R.sup.i), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)NR.sup.jR.sup.k, or --(C.sub.1-C.sub.6
alkylenyl)-CN; R.sup.h, R.sup.j, R.sup.k, at each occurrence, are
each independently hydrogen, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; and R.sup.i, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl,
to a subject in need thereof.
57. The method of claim 56 wherein the cancer is selected from the
group consisting of: acoustic neuroma, acute leukemia, acute
lymphocytic leukemia, acute myelocytic leukemia (monocytic,
myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,
myelomonocytic and promyelocytic), acute t-cell leukemia, basal
cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer,
breast cancer, bronchogenic carcinoma, cervical cancer,
chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,
chronic lymphocytic leukemia, chronic myelocytic (granulocytic)
leukemia, chronic myelogenous leukemia, colon cancer, colorectal
cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell
lymphoma, dysproliferative changes (dysplasias and metaplasias),
embryonal carcinoma, endometrial cancer, endotheliosarcoma,
ependymoma, epithelial carcinoma, erythroleukemia, esophageal
cancer, estrogen-receptor positive breast cancer, essential
thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma,
germ cell testicular cancer, glioma, glioblastoma, gliosarcoma,
heavy chain disease, hemangioblastoma, hepatoma, hepatocellular
cancer, hormone insensitive prostate cancer, leiomyosarcoma,
leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma,
lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and
non-Hodgkin's), malignancies and hyperproliferative disorders of
the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin
and uterus, lymphoid malignancies of T-cell or B-cell origin,
leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma,
meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,
myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC),
non-small cell lung cancer, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,
prostate cancer, rectal cancer, renal cell carcinoma,
retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland
carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid
tumors (carcinomas and sarcomas), small cell lung cancer, stomach
cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma,
thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors,
uterine cancer and Wilms' tumor.
58. The method of claim 56, further comprising administering a
therapeutically effective amount of at least one additional
therapeutic agent, wherein the additional therapeutic agent is
selected from the group consisting of cytarabine, bortezomib, and
5-azacitidine.
59-65. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This present application is a continuation of International
PCT Application No. PCT/CN2012/086357, filed on Dec. 11, 2012,
which claims the benefit of priority to International PCT
Application No. PCT/CN2011/002224, filed on Dec. 30, 2011, the
teachings of which are each herein incorporated by reference in
their entirety
BACKGROUND
[0002] Bromodomains refer to conserved protein structural folds
which bind to N-acetylated lysine residues that are found in some
proteins. The BET family of bromodomain containing proteins is
comprised of four members (BRD2, BRD3, BRD4 and BRDt). Each member
of the BET family employs two bromodomains to recognize
N-acetylated lysine residues found primarily, but not exclusively,
on the amino-terminal tails of histone proteins. These interactions
modulate gene expression by recruiting transcription factors to
specific genome locations within chromatin. For example,
histone-bound BRD4 recruits the transcription factor P-TEFb to
promoters, resulting in the expression of a subset of genes
involved in cell cycle progression (Yang et al., Mol. Cell. Biol.
28: 967-976 (2008)). BRD2 and BRD3 also function as transcriptional
regulators of growth promoting genes (LeRoy et al., Mol. Cell 30:
51-60 (2008)). BET family members were recently established as
being important for the maintenance of several cancer types (Zuber
et al., Nature 478: 524-528 (2011); Mertz et al; Proc. Nat'l. Acad.
Sci. 108: 16669-16674 (2011); Delmore et al., Cell 146: 1-14,
(2011); Dawson et al., Nature 478: 529-533 (2011)). BET family
members have also been implicated in mediating acute inflammatory
responses through the canonical NF-KB pathway (Huang et al., Mol.
Cell. Biol. 29: 1375-1387 (2009)) resulting in the upregulation of
genes associated with the production of cytokines (Nicodeme et al.,
Nature 468: 1119-1123, (2010)). In addition, bromodomain function
has been implicated in kidney disease (Zhang, et al., J. Biol.
Chem. 287: 28840-28851 (2012)). BRD2 function has also been linked
to a predisposition for dyslipidemia or improper regulation of
adipogenesis, elevated inflammatory profiles and increased
susceptibility to autoimmune diseases (Denis, Discovery Medicine
10: 489-499 (2010)). The human immunodeficiency virus utilizes BRD4
to initiate transcription of viral RNA from stably integrated viral
DNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomain
inhibitors have also been shown to reactivate HIV transcription in
models of latent T cell infection and latent monocyte infection
(Banerjee, et al, J. Leukocyte Biol. doi:10.1189/jlb.0312165). BRDt
has an important role in spermatogenesis (Matzuk, et al., Cell 150:
673-684 (2012)). Accordingly, there is an ongoing medical need to
develop new drugs to treat diseases and indications involving
bromodomain function, including BET bromodomain function.
SUMMARY
[0003] In one aspect the present invention provides for compounds
of formula (I) or pharmaceutically acceptable thereof,
##STR00002##
wherein [0004] R.sup.x is hydrogen or C.sub.1-C.sub.3 alkyl; [0005]
R.sup.y is C.sub.1-C.sub.3 alkyl, --(C.sub.2-C.sub.3 alkylenyl)-OH,
or C.sub.1-C.sub.3 haloalkyl; [0006] X.sup.1 is N or CR.sup.x1
wherein [0007] R.sup.x1 is hydrogen, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, --C(O)OR.sup.ax1,
--C(O)NR.sup.bx1R.sup.cx1, --C(O)R.sup.dx1, S(O).sub.2R.sup.dx1,
--S(O).sub.2NR.sup.bx1R.sup.cx1, G.sup.x1, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with one substituent selected from
the group consisting of OR.sup.ax1, SR.sup.ax1, S(O)R.sup.dx1,
S(O).sub.2R.sup.dx1, NR.sup.bx1R.sup.cx1, --C(O)R.sup.ax1,
--C(O)OR.sup.ax1, --C(O)NR.sup.bx1R.sup.cx1,
--S(O).sub.2NR.sup.bx1R.sup.cx1, and G.sup.x1; [0008] R.sup.ax1,
R.sup.bx1, and R.sup.cx1, at each occurrence, are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, G.sup.a, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.a;
[0009] R.sup.dx1, at each occurrence, are each independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, G.sup.a, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.a; [0010] X.sup.2 is N or
CR.sup.x2; wherein [0011] R.sup.x2 is hydrogen, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, --C(O)OR.sup.ax2,
--C(O)NR.sup.bx2R.sup.cx2, --C(O)R.sup.dx2, --C(O)H,
S(O).sub.2R.sup.dx2, --S(O).sub.2NR.sup.bx2R.sup.cx2, G.sup.x2,
C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl; wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one
substituent selected from the group consisting of OR.sup.ax2,
SR.sup.ax2, S(O)R.sup.dx2, S(O).sub.2R.sup.dx2,
NR.sup.bx2R.sup.cx2, --C(O)R.sup.ax2, --C(O)OR.sup.ax2,
--C(O)NR.sup.bx2R.sup.cx2, --S(O).sub.2NR.sup.bx2R.sup.cx2, and
G.sup.x2; [0012] R.sup.ax2, R.sup.bx2, and R.sup.cx2, at each
occurrence, are each independently hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.b, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.b; [0013] R.sup.dx2, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
G.sup.b, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.b; [0014] Y.sup.1
is N or CR.sup.u; wherein R.sup.u is hydrogen, C.sub.1-C.sub.6
alkyl, halogen, or C.sub.1-C.sub.6 haloalkyl; [0015] A.sup.1 is N
or CR.sup.1, A.sup.2 is N or CR.sup.2, A.sup.3 is N or CR.sup.3;
and A.sup.4 is N or CR.sup.4; with the proviso that zero, one, two,
or three of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 are N; [0016]
R.sup.1, R.sup.3, and R.sup.4 are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, CN, or NO.sub.2;
[0017] R.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6
haloalkyl, --CN, NO.sub.2, G.sup.2a, --OR.sup.2a, --OC(O)R.sup.2d,
--OC(O)NR.sup.2bR.sup.2c, --SR.sup.2a, --S(O).sub.2R.sup.2d,
--S(O).sub.2NR.sup.2bR.sup.2c, --C(O)R.sup.2d, --C(O)OR.sup.2a,
--C(O)NR.sup.2bR.sup.2c, --NR.sup.2bR.sup.2c,
--N(R.sup.2e)C(O)R.sup.2d, --N(R.sup.2e)S(O).sub.2R.sup.2d,
--N(R.sup.2e)C(O)O(R.sup.2d), --N(R.sup.2e)C(O)NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.2a,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.2a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)O(R.sup.2a), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, and
--(C.sub.1-C.sub.6 alkylenyl)-CN; [0018] R.sup.2a, R.sup.2b,
R.sup.2c, and R.sup.2e, at each occurrence, are each independently
hydrogen, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.2b, or C.sub.1-C.sub.6 alkyl
wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with
one substituent selected from the group consisting of --OR.sup.z1,
NR.sup.z1R.sup.z2, --C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2,
--S(O).sub.2R.sup.z1, --S(O).sub.2NR.sup.z1R.sup.z2, and G.sup.2b;
[0019] R.sup.2d, at each occurrence, is independently
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, G.sup.2b, or C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one
substituent selected from the group consisting of --OR.sup.z1,
NR.sup.z1R.sup.z2, --C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2,
--S(O).sub.2R.sup.z1, --S(O).sub.2NR.sup.z1R.sup.z2, and G.sup.2b;
[0020] R.sup.z1 and R.sup.z2, at each occurrence, are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl; [0021] G.sup.x1, G.sup.x2, G.sup.a, G.sup.b, G.sup.2a,
and G.sup.2b, at each occurrence, are each independently aryl,
heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of
which is independently unsubstituted or substituted with 1, 2, 3,
4, or 5 of R.sup.v; [0022] L.sup.1 is absent, CH.sub.2, C(O),
C(H)(OH), (CH.sub.2).sub.mO, (CH.sub.2).sub.mS(O).sub.n wherein n
is 0, 1, or 2; or (CH.sub.2).sub.mN(R.sup.z) wherein R.sup.z is
hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
(C.sub.2-C.sub.3 alkylenyl)-OH, or unsubstituted cyclopropyl;
[0023] m is 0 or 1;
[0024] G.sup.1 is C.sub.1-C.sub.6 alkyl, alkoxyalkyl, G.sup.1a or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.1a; wherein each G.sup.1a is
independently aryl, heteroaryl, heterocycle, cycloalkyl, or
cycloalkenyl, and each G.sup.1a is independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 of R.sup.w; [0025] R.sup.v and
R.sup.w, at each occurrence, are each independently C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, oxo, --OR.sup.h, --OC(O)R.sup.i,
--OC(O)NR.sup.jR.sup.k, --SR.sup.h, --S(O).sub.2R.sup.h,
--S(O).sub.2NR.sup.jR.sup.k, --C(O)R.sup.h, --C(O)-monocyclic
heterocycle, --C(O)-monocyclic heteroaryl, --C(O)OR.sup.h,
--C(O)NR.sup.jR.sup.k, --NR.sup.jR.sup.k, --N(R.sup.h)C(O)R.sup.i,
--N(R.sup.h)S(O).sub.2R.sup.i, --N(R.sup.h)C(O)O(R.sup.i),
--N(R.sup.h)C(O)NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.h, --(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.i,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)NR.sup.jR.sup.k,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.h, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.h, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.h,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.jR.sup.k,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)R.sup.i, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)S(O).sub.2R.sup.i, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)O(R.sup.i), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)NR.sup.jR.sup.k, or --(C.sub.1-C.sub.6
alkylenyl)-CN; [0026] R.sup.h, R.sup.j, R.sup.k, at each
occurrence, are each independently hydrogen, C.sub.1-C.sub.6 alkyl,
or C.sub.1-C.sub.6 haloalkyl; and [0027] R.sup.i, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 haloalkyl.
[0028] In one aspect the present invention provides for compounds
of formula (I) or pharmaceutically acceptable thereof,
##STR00003##
wherein [0029] R.sup.x is hydrogen or C.sub.1-C.sub.3 alkyl; [0030]
R.sup.y is C.sub.1-C.sub.3 alkyl, --(C.sub.2-C.sub.3 alkylenyl)-OH,
or C.sub.1-C.sub.3 haloalkyl; [0031] X.sup.1 is N or CR.sup.x1
wherein [0032] R.sup.x1 is hydrogen, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, --C(O)OR.sup.ax1,
--C(O)NR.sup.bx1R.sup.cx1, --C(O)R.sup.dx1, S(O).sub.2R.sup.dx1,
--S(O).sub.2NR.sup.bx1R.sup.cx1, G.sup.x1, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with one substituent selected from
the group consisting of OR.sup.ax1, SR.sup.ax1, S(O)R.sup.dx1,
S(O).sub.2R.sup.dx1, NR.sup.bx1R.sup.cx1, --C(O)R.sup.ax1,
--C(O)OR.sup.ax1, --C(O)NR.sup.bx1R.sup.cx1,
--S(O).sub.2NR.sup.bx1R.sup.cx1, and G.sup.x1; [0033] R.sup.ax1,
R.sup.bx1, and R.sup.cx1, at each occurrence, are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, G.sup.a, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.a;
[0034] R.sup.dx1, at each occurrence, are each independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, G.sup.a, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.a; [0035] X.sup.2 is N or
CR.sup.x2; wherein [0036] R.sup.x2 is hydrogen, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, --C(O)OR.sup.x2,
--C(O)NR.sup.bx2R.sup.cx2, --C(O)R.sup.dx2, S(O).sub.2R.sup.dx2,
--S(O).sub.2NR.sup.bx2R.sup.cx2, G.sup.x2, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with one substituent selected from
the group consisting of OR.sup.ax2, SR.sup.ax2 S(O)R.sup.dx2,
S(O).sub.2R.sup.dx2, NR.sup.bx2R.sup.cx2, --C(O)R.sup.ax2,
--C(O)OR.sup.ax2, --C(O)NR.sup.bx2R.sup.cx2,
--S(O).sub.2NR.sup.bx2R.sup.cx2, and G.sup.x2; [0037] R.sup.ax2,
R.sup.bx2, and R.sup.cx2, at each occurrence, are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, G.sup.b, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.b;
[0038] R.sup.dx2, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, G.sup.b, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.b; [0039] Y.sup.1 is N or
CR.sup.u; wherein R.sup.u is hydrogen, C.sub.1-C.sub.6 alkyl,
halogen, or C.sub.1-C.sub.6 haloalkyl; [0040] A.sup.1 is N or
CR.sup.1, A.sup.2 is N or CR.sup.2, A.sup.3 is N or CR.sup.3; and
A.sup.4 is N or CR.sup.4; with the proviso that zero, one, two, or
three of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 are N; [0041]
R.sup.1, R.sup.3, and R.sup.4 are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, CN, or NO.sub.2;
[0042] R.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6
haloalkyl, --CN, NO.sub.2, G.sup.2a, --OR.sup.2a, --OC(O)R.sup.2d,
--OC(O)NR.sup.2bR.sup.2c, --SR.sup.2a, --S(O).sub.2R.sup.2d,
--S(O).sub.2NR.sup.2bR.sup.2c, --C(O)R.sup.2d, --C(O)OR.sup.2a,
--C(O)NR.sup.2bR.sup.2c, --NR.sup.2bR.sup.2c,
--N(R.sup.2e)C(O)R.sup.2d, --N(R.sup.2e)S(O).sub.2R.sup.2d,
--N(R.sup.2e)C(O)O(R.sup.2d), --N(R.sup.2e)C(O)NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.2a,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.2a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)O(R.sup.2a), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, and
--(C.sub.1-C.sub.6 alkylenyl)-CN; [0043] R.sup.2a, R.sup.2b,
R.sup.2c, and R.sup.2e, at each occurrence, are each independently
hydrogen, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.2b, or C.sub.1-C.sub.6 alkyl
wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with
one substituent selected from the group consisting of --OR.sup.z1,
NR.sup.z1R.sup.z2, --C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2,
--S(O).sub.2R.sup.z1, --S(O).sub.2NR.sup.z1R.sup.z2, and G.sup.2b;
[0044] R.sup.2d, at each occurrence, is independently
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, G.sup.2b, or C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one
substituent selected from the group consisting of --OR.sup.z1,
NR.sup.z1R.sup.z2, --C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2,
--S(O).sub.2R.sup.z1, --S(O).sub.2NR.sup.z1R.sup.z2, and G.sup.2b;
[0045] R.sup.z1 and R.sup.z2, at each occurrence, are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl; [0046] G.sup.x1, G.sup.x2, G.sup.a, G.sup.b, G.sup.2a,
and G.sup.2b, at each occurrence, are each independently aryl,
heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of
which is independently unsubstituted or substituted with 1, 2, 3,
4, or 5 of R.sup.v; [0047] L.sup.1 is absent, CH.sub.2, C(O),
(CH.sub.2).sub.mO, (CH.sub.2).sub.mS(O).sub.n wherein n is 0, 1, or
2; or (CH.sub.2).sub.mN(R.sup.z) wherein R.sup.z is hydrogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, (C.sub.2-C.sub.3
alkylenyl)-OH, or unsubstituted cyclopropyl; [0048] m is 0 or
1;
[0049] G.sup.1 is G.sup.1a or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1a; wherein each G.sup.1a is independently aryl,
heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each
G.sup.1a is independently unsubstituted or substituted with 1, 2,
3, 4, or 5 of R.sup.w; [0050] R.sup.v and R.sup.w, at each
occurrence, are each independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, oxo, --OR.sup.h, --OC(O)R.sup.i,
--OC(O)NR.sup.jR.sup.k, --SR.sup.h, --S(O).sub.2R.sup.h,
--S(O).sub.2NR.sup.jR.sup.k, --C(O)R.sup.h, --C(O)OR.sup.h,
--C(O)NR.sup.jR.sup.k, --NR.sup.jR.sup.k, --N(R.sup.h)C(O)R.sup.i,
--N(R.sup.h)S(O).sub.2R.sup.i, --N(R.sup.h)C(O)O(R.sup.i),
--N(R.sup.h)C(O)NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.h, --(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.i,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)NR.sup.jR.sup.k,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.h, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.h, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.h,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.jR.sup.k,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)R.sup.i, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)S(O).sub.2R.sup.i, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)O(R.sup.i), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)NR.sup.jR.sup.k, or --(C.sub.1-C.sub.6
alkylenyl)-CN; [0051] R.sup.h, R.sup.j, R.sup.k, at each
occurrence, are each independently hydrogen, C.sub.1-C.sub.6 alkyl,
or C.sub.1-C.sub.6 haloalkyl; and [0052] R.sup.i, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 haloalkyl.
[0053] In another aspect, the present invention provides for
methods for treating or preventing disorders that are ameliorated
by inhibition of BET. Such methods comprise of administering to the
subject a therapeutically effective amount of a compound of formula
(I), alone, or in combination with a pharmaceutically acceptable
carrier.
[0054] Some of the methods are directed to treating or preventing
an inflammatory disease or cancer or AIDS.
[0055] In another aspect, the present invention relates to methods
of treating cancer in a subject comprising administering a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof. In certain embodiments, the cancer is selected from the
group consisting of: acoustic neuroma, acute leukemia, acute
lymphocytic leukemia, acute myelocytic leukemia (monocytic,
myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,
myelomonocytic and promyelocytic), acute t-cell leukemia, basal
cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer,
breast cancer, bronchogenic carcinoma, cervical cancer,
chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,
chronic lymphocytic leukemia, chronic myelocytic (granulocytic)
leukemia, chronic myelogenous leukemia, colon cancer, colorectal
cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell
lymphoma, dysproliferative changes (dysplasias and metaplasias),
embryonal carcinoma, endometrial cancer, endotheliosarcoma,
ependymoma, epithelial carcinoma, erythroleukemia, esophageal
cancer, estrogen-receptor positive breast cancer, essential
thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma,
germ cell testicular cancer, glioma, glioblastoma, gliosarcoma,
heavy chain disease, hemangioblastoma, hepatoma, hepatocellular
cancer, hormone insensitive prostate cancer, leiomyosarcoma,
leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma,
lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and
non-Hodgkin's), malignancies and hyperproliferative disorders of
the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin
and uterus, lymphoid malignancies of T-cell or B-cell origin,
leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma,
meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,
myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC),
non-small cell lung cancer, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,
prostate cancer, rectal cancer, renal cell carcinoma,
retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland
carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid
tumors (carcinomas and sarcomas), small cell lung cancer, stomach
cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma,
thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors,
uterine cancer and Wilms' tumor. In certain embodiments, the
methods further comprise administering a therapeutically effective
amount of at least one additional therapeutic agent. In certain
embodiments, the additional therapeutic agent is an anti-cancer
agent. In particular embodiments, the additional therapeutic agents
are selected from the group consisting of cytarabine, bortezomib,
and 5-azacitidine.
[0056] In another aspect, the present invention relates to methods
of treating a disease or condition in a subject comprising
administering a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof, to a
subject in need thereof, wherein said disease or condition is
selected from the group consisting of: Addison's disease, acute
gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's
disease, bullous skin diseases, chronic obstructive pulmonary
disease (COPD), Crohn's disease, dermatitis, eczema, giant cell
arteritis, glomerulonephritis, hepatitis, hypophysitis,
inflammatory bowel disease, Kawasaki disease, lupus nephritis,
multiple sclerosis, myocarditis, myositis, nephritis, organ
transplant rejection, osteoarthritis, pancreatitis, pericarditis,
Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis,
psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis,
sclerosing cholangitis, sepsis, systemic lupus erythematosus,
Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes,
ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's
granulomatosis. In certain embodiments, the methods further
comprise administering a therapeutically effective amount of at
least one additional therapeutic agent. In certain embodiments, the
methods further comprise administering a therapeutically effective
amount of at least one additional therapeutic agent.
[0057] In another aspect, the present invention relates to methods
of treating a chronic kidney disease or condition in a subject
comprising administering a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof, to a subject in need thereof, wherein said disease or
condition is selected from the group consisting of: diabetic
nephropathy, hypertensive nephropathy, HIV-associated nephropathy,
glomerulonephritis, lupus nephritis, IgA nephropathy, focal
segmental glomerulosclerosis, membranous glomerulonephritis,
minimal change disease, polycystic kidney disease and tubular
interstitial nephritis. In certain embodiments, the methods further
comprise administering a therapeutically effective amount of at
least one additional therapeutic agent. In certain embodiments, the
methods further comprise administering a therapeutically effective
amount of at least one additional therapeutic agent.
[0058] In another aspect, the present invention relates to methods
of treating an acute kidney injury or disease or condition in a
subject comprising administering a therapeutically effective amount
of a compound of formula (I) or a pharmaceutically acceptable salt
thereof, to a subject in need thereof, wherein said acute kidney
injury or disease or condition is selected from the group
consisting of: ischemia-reperfusion induced, cardiac and major
surgery induced, percutaneous coronary intervention induced,
radio-contrast agent induced, sepsis induced, pneumonia induced,
and drug toxicity induced. In certain embodiments, the methods
further comprise administering a therapeutically effective amount
of at least one additional therapeutic agent. In certain
embodiments, the methods further comprise administering a
therapeutically effective amount of at least one additional
therapeutic agent.
[0059] In another aspect, the present invention relates to methods
of treating AIDS in a subject comprising administering a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof. In certain embodiments, the methods further comprise
administering a therapeutically effective amount of at least one
additional therapeutic agent.
[0060] In another aspect, the present invention relates to methods
of treating obesity, dyslipidemia, hypercholesterolemia,
Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II
diabetes, insulin resistance, diabetic retinopathy or diabetic
neuropathy in a subject comprising administering a therapeutically
effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof, to a subject in need thereof. In certain
embodiments, the methods further comprise administering a
therapeutically effective amount of at least one additional
therapeutic agent.
[0061] In another aspect, the present invention relates to methods
of preventing conception by inhibiting spermatogenesis in a subject
comprising administering a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof, to a subject in need thereof. In certain embodiments, the
methods further comprise administering a therapeutically effective
amount of at least one additional therapeutic agent.
[0062] A further aspect of the invention provides the use of a
compound of formula (I), alone or in combination with a second
active pharmaceutical agent, in the manufacture of a medicament for
treating or preventing conditions and disorders disclosed herein,
with or without a pharmaceutically acceptable carrier.
[0063] Pharmaceutical compositions comprising a compound of formula
(I), or a pharmaceutically acceptable salt, alone or in combination
with a second active pharmaceutical agent, are also provided.
DETAILED DESCRIPTION
[0064] Disclosed herein are compounds of formula (I)
##STR00004##
wherein A.sup.1, A.sup.2, A.sup.3, A.sup.4, X.sup.1, X.sup.2,
Y.sup.1, L.sup.1, G.sup.1, R.sup.x, and R.sup.y are defined above
in the Summary of the Invention and below in the Detailed
Description. Further, compositions comprising such compounds and
methods for treating conditions and disorders using such compounds
and compositions are also disclosed.
[0065] Compounds disclosed herein may contain one or more
variable(s) that occur more than one time in any substituent or in
the formulae herein. Definition of a variable on each occurrence is
independent of its definition at another occurrence. Further,
combinations of substituents are permissible only if such
combinations result in stable compounds. Stable compounds are
compounds, which can be isolated from a reaction mixture.
a). DEFINITIONS
[0066] It is noted that, as used in this specification and the
intended claims, the singular form "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a compound" includes a single
compound as well as one or more of the same or different compounds,
reference to "optionally a pharmaceutically acceptable carrier"
refers to a single optional pharmaceutically acceptable carrier as
well as one or more pharmaceutically acceptable carriers, and the
like.
[0067] As used in the specification and the appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0068] The term "alkenyl" as used herein, means a straight or
branched hydrocarbon chain containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond, optionally
substituted with 1, 2, or 3 halogen atoms. The term
"C.sub.2-C.sub.6 alkenyl" means an alkenyl group containing 2-6
carbon atoms. Non-limiting examples of alkenyl include
buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl,
3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl,
and 3-decenyl.
[0069] The term "alkenylene" means a divalent group derived from a
straight or branched chain hydrocarbon of 2 to 4 carbon atoms and
contains at least one carbon-carbon double bond. Representative
examples of alkenylene include, but are not limited to,
--CH.dbd.CH-- and --CH.sub.2CH.dbd.CH--.
[0070] The term "alkyl" as used herein, means a saturated, straight
or branched hydrocarbon chain radical. In some instances, the
number of carbon atoms in an alkyl moiety is indicated by the
prefix "C.sub.x-C.sub.y", wherein x is the minimum and y is the
maximum number of carbon atoms in the substituent. Thus, for
example, "C.sub.1-C.sub.6 alkyl" refers to an alkyl substituent
containing from 1 to 6 carbon atoms and "C.sub.1-C.sub.3 alkyl"
refers to an alkyl substituent containing from 1 to 3 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl,
2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,
1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl,
1-ethylpropyl, 1,2,2-trimethylpropyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0071] The term "alkylene" or "alkylenyl" means a divalent radical
derived from a straight or branched, saturated hydrocarbon chain,
for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms
(C.sub.1-C.sub.6 alkylenyl) or of 1 to 4 carbon atoms or of 2 to 3
carbon atoms (C.sub.2-C.sub.3 alkylenyl). Examples of alkylene and
alkylenyl include, but are not limited to, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0072] The term "alkynyl" as used herein, means a straight or
branched chain hydrocarbon radical containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond,
optionally substituted with 1, 2, or 3 halogen atoms. The term
"C.sub.2-C.sub.6 alkynyl" means an alkynyl group of 2 to 6 carbon
atoms. Representative examples of alkynyl include, but are not
limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,
2-pentynyl, and 1-butynyl.
[0073] The term "aryl" as used herein, means phenyl or a bicyclic
aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a
monocyclic cycloalkyl, or a phenyl fused to a monocyclic
cycloalkenyl. Non-limiting examples of the aryl groups include
dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and
tetrahydronaphthalenyl. The bicyclic aryls are attached to the
parent molecular moiety through any carbon atom contained within
the bicyclic ring systems and can be unsubstituted or
substituted.
[0074] The term "cycloalkyl" as used herein, refers to a radical
that is a monocyclic cyclic alkyl, a bicyclic cycloalkyl, or a
spiro cycloalkyl. The monocyclic cycloalkyl is a carbocyclic ring
system containing three to eight carbon atoms, zero heteroatoms and
zero double bonds. Examples of monocyclic ring systems include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. The bicyclic cycloalkyl is a monocyclic cycloalkyl
fused to a monocyclic cycloalkyl ring. The monocyclic and the
bicyclic cycloalkyl groups may contain one or two alkylene bridges,
each consisting of one, two, three, or four carbon atoms in length,
and each bridge links two non-adjacent carbon atoms of the ring
system. Non-limiting examples of bicyclic ring systems include
bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,
bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and
bicyclo[4.2.1]nonane, tricyclo[3.3.1.0.sup.3,7]nonane
(octahydro-2,5-methanopentalene or noradamantane), and
tricyclo[3.3.1.1.sup.3,7]decane (adamantane). A spiro cycloalkyl is
a monocyclic cycloalkyl wherein two substituents on the same carbon
atom of the monocyclic cycloalkyl ring together with said carbon
atom form a second monocyclic cycloalkyl ring. The monocyclic, the
bicyclic, and the spiro cycloalkyl groups can be unsubstituted or
substituted, and are attached to the parent molecular moiety
through any substitutable atom contained within the ring
system.
[0075] The term "cycloalkenyl" as used herein, refers to a
monocyclic or a bicyclic hydrocarbon ring radical. The monocyclic
cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms
and zero heteroatoms. The four-membered ring systems have one
double bond, the five- or six-membered ring systems have one or two
double bonds, and the seven- or eight-membered ring systems have
one, two, or three double bonds. Representative examples of
monocyclic cycloalkenyl groups include, but are not limited to,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and
cyclooctenyl. The bicyclic cycloalkenyl is a monocyclic
cycloalkenyl fused to a monocyclic cycloalkyl group, or a
monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group.
The monocyclic or bicyclic cycloalkenyl ring may contain one or two
alkylene bridges, each consisting of one, two, or three carbon
atoms, and each linking two non-adjacent carbon atoms of the ring
system. Representative examples of the bicyclic cycloalkenyl groups
include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene,
octahydronaphthalenyl, and 1,6-dihydro-pentalene. The monocyclic
and bicyclic cycloalkenyls can be attached to the parent molecular
moiety through any substitutable atom contained within the ring
systems, and can be unsubstituted or substituted.
[0076] The term "halo" or "halogen" as used herein, means Cl, Br,
I, and F.
[0077] The term "haloalkyl" as used herein, means an alkyl group,
as defined herein, in which one, two, three, four, five or six
hydrogen atoms are replaced by halogen. The term "C.sub.1-C.sub.6
haloalkyl" means a C.sub.1-C.sub.6 alkyl group, as defined herein,
in which one, two, three, four, five or six hydrogen atoms are
replaced by halogen. The term "C.sub.1-C.sub.3 haloalkyl" means a
C.sub.1-C.sub.3 alkyl group, as defined herein, in which one, two,
or three hydrogen atoms are replaced by halogen. Representative
examples of haloalkyl include, but are not limited to,
chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl,
pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and
trifluoropropyl.
[0078] The term "heterocycle" or "heterocyclic" as used herein,
means a radical of a monocyclic heterocycle, a bicyclic
heterocycle, and a spiro heterocycle. A monocyclic heterocycle is a
three-, four-, five-, six-, seven-, or eight-membered carbocyclic
ring also containing at least one heteroatom independently selected
from the group consisting of O, N, and S. A three- or four-membered
ring contains zero or one double bond, and one heteroatom selected
from the group consisting of O, N, and S. When two O atoms or one O
atom and one S atom are present in a heterocyclic ring, then the
two O atoms or one O atom and one S atom are not bonded directly to
each other. A five-membered ring contains zero or one double bond
and one, two, or three heteroatoms selected from the group
consisting of O, N, and S. Examples of five-membered heterocyclic
rings include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3
N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N. Examples
of 5-membered heterocyclic groups include tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl,
oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrrolidinyl,
2-pyrrolinyl, and 3-pyrrolinyl. A six-membered ring contains zero,
one, or two double bonds and one, two, or three heteroatoms
selected from the group consisting of O, N, and S. Examples of
six-membered heterocyclic rings include those containing in the
ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and
1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 Q and 1 N; and 1 O
and 2 N. Examples of 6-membered heterocyclic groups include
tetrahydropyranyl, dihydropyranyl, dioxanyl, 1,3-dioxolanyl,
1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl,
piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl,
1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl,
1,1-dioxo-hexahydro-1-thiopyranyl,
1,1-dioxo-I.lamda..sup.6-thiomorpholinyl, thiomorpholinyl,
thioxanyl, and trithianyl. Seven- and eight-membered rings contains
zero, one, two, or three double bonds and one, two, or three
heteroatoms selected from the group consisting of O, N, and S.
Representative examples of monocyclic heterocycles include, but are
not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,
1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,
imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,
isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,
oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl,
piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl,
tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
thiopyranyl, and trithianyl. The bicyclic heterocycle is a
monocyclic heterocycle fused to a phenyl group, or a monocyclic
heterocycle fused to a monocyclic cycloalkyl, or a monocyclic
heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic
heterocycle fused to a monocyclic heterocycle. Representative
examples of bicyclic heterocycles include, but are not limited to,
benzopyranyl, benzothiopyranyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydro-1H-indolyl,
3,4-dihydroisoquinolin-2(1H)-yl,
2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,
hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl. The monocyclic
heterocycle and the bicyclic heterocycle may contain one or two
alkylene bridges or an alkenylene bridge, or mixture thereof, each
consisting of no more than four carbon atoms and each linking two
non adjacent atoms of the ring system. Examples of such bridged
heterocycle include, but are not limited to,
azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),
8-azabicyclo[3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene,
hexahydro-2H-2,5-methanocyclopenta[b]furan,
hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane
(1-azatricyclo[3.3.1.1.sup.3,7]decane), and oxa-adamantane
(2-oxatricyclo[3.3.1.1.sup.3,7]decane). A spiro heterocycle is a
monocyclic heterocycle wherein two substituents on the same carbon
atom of the monocyclic heterocycle ring together with said carbon
atom form a second ring system selected from a monocyclic
cycloalkyl, a bicyclic cycloalkyl, a monocyclic heterocycle, or a
bicyclic heterocycle. Examples of spiro heterocycle include, but
not limited to, 6-azaspiro[2.5]oct-6-yl, 1'H,
4H-spiro[1,3-benzodioxine-2,4'-piperidin]-1'-yl, 1'H,
3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl, and
1,4-dioxa-8-azaspiro[4.5]dec-8-yl. The monocyclic, the bicyclic,
and the spiro heterocycles can be unsubstituted or substituted. The
monocyclic, the bicyclic and the spiro heterocycles are connected
to the parent molecular moiety through any carbon atom or any
nitrogen atom contained within the ring systems. The nitrogen and
sulfur heteroatoms in the heterocycle rings may optionally be
oxidized (e.g. 1,1-dioxidotetrahydrothienyl,
1,1-dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholinyl)) and the
nitrogen atoms may optionally be quarternized.
[0079] The term "heteroaryl" as used herein, means a monocyclic
heteroaryl and a bicyclic heteroaryl. The monocyclic heteroaryl is
a five- or six-membered ring. The five-membered ring contains two
double bonds. The five membered ring may contain one heteroatom
selected from O or S; or one, two, three, or four nitrogen atoms
and optionally one oxygen or one sulfur atom. The six-membered ring
contains three double bonds and one, two, three or four nitrogen
atoms. Representative examples of monocyclic heteroaryl include,
but are not limited to, furanyl, imidazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,
thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. The
bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a
phenyl, or a monocyclic heteroaryl fused to a monocyclic
cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic
cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic
heteroaryl, or a monocyclic heteroaryl fused to a monocyclic
heterocycle. Representative examples of bicyclic heteroaryl groups
include, but are not limited to, benzofuranyl, benzothienyl,
benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl,
2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,
6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,
6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,
indolyl, isoindolyl, isoquinolinyl, naphthyridinyl,
pyridoimidazolyl, quinolinyl,
2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,
thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and
5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic
heteroaryl groups can be substituted or unsubstituted and are
connected to the parent molecular moiety through any substitutable
carbon atom or any substitutable nitrogen atom contained within the
ring systems. The nitrogen atom in the heteroaryl rings may
optionally be oxidized and may optionally be quartemized.
[0080] The term "heteroatom" as used herein, means a nitrogen,
oxygen, and sulfur.
[0081] The term "oxo" as used herein, means a .dbd.O group.
[0082] If a moiety is described as "substituted", a non-hydrogen
radical is in the place of hydrogen radical of any substitutable
atom of the moiety. Thus, for example, a substituted heterocycle
moiety is a heterocycle moiety in which at least one non-hydrogen
radical is in the place of a hydrogen radical on the heterocycle.
It should be recognized that if there are more than one
substitution on a moiety, each non-hydrogen radical may be
identical or different (unless otherwise stated).
[0083] If a moiety is described as being "optionally substituted,"
the moiety may be either (1) not substituted or (2) substituted. If
a moiety is described as being optionally substituted with up to a
particular number of non-hydrogen radicals, that moiety may be
either (1) not substituted; or (2) substituted by up to that
particular number of non-hydrogen radicals or by up to the maximum
number of substitutable positions on the moiety, whichever is less.
Thus, for example, if a moiety is described as a heteroaryl
optionally substituted with up to 3 non-hydrogen radicals, then any
heteroaryl with less than 3 substitutable positions would be
optionally substituted by up to only as many non-hydrogen radicals
as the heteroaryl has substitutable positions. To illustrate,
tetrazolyl (which has only one substitutable position) would be
optionally substituted with up to one non-hydrogen radical. To
illustrate further, if an amino nitrogen is described as being
optionally substituted with up to 2 non-hydrogen radicals, then a
primary amino nitrogen will be optionally substituted with up to 2
non-hydrogen radicals, whereas a secondary amino nitrogen will be
optionally substituted with up to only 1 non-hydrogen radical.
[0084] The terms "treat", "treating", and "treatment" refer to a
method of alleviating or abrogating a disease and/or its attendant
symptoms.
[0085] The terms "prevent", "preventing", and "prevention" refer to
a method of preventing the onset of a disease and/or its attendant
symptoms or barring a subject from acquiring a disease. As used
herein, "prevent", "preventing" and "prevention" also include
delaying the onset of a disease and/or its attendant symptoms and
reducing a subject's risk of acquiring a disease.
[0086] The phrase "therapeutically effective amount" means an
amount of a compound, or a pharmaceutically acceptable salt
thereof, sufficient to prevent the development of or to alleviate
to some extent one or more of the symptoms of the condition or
disorder being treated when administered alone or in conjunction
with another pharmaceutical agent or treatment in a particular
subject or subject population. For example in a human or other
mammal, a therapeutically effective amount can be determined
experimentally in a laboratory or clinical setting, or may be the
amount required by the guidelines of the United States Food and
Drug Administration, or equivalent foreign agency, for the
particular disease and subject being treated.
[0087] The term "subject" is defined herein to refer to animals
such as mammals, including, but not limited to, primates (e.g.,
humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,
mice and the like. In preferred embodiments, the subject is a
human.
b. COMPOUNDS
[0088] Compounds of the invention have the general formula (I) as
described above.
[0089] Particular values of variable groups in compounds of formula
(I) are as follows. Such values may be used where appropriate with
any of the other values, definitions, claims or embodiments defined
hereinbefore or hereinafter.
[0090] In compounds of formula (I), RX is as defined in the
Summary. For example, in certain embodiments, R.sup.x is hydrogen
or methyl. In certain embodiments, R.sup.x is hydrogen.
[0091] R.sup.y, in compounds of formula (I), is as disclosed in the
Summary. For example, in certain embodiments, R.sup.y is
C.sub.1-C.sub.3 alkyl (e.g. methyl, ethyl). In certain embodiments,
R.sup.y is methyl.
[0092] X.sup.1 is as disclosed in the Summary. For example, in
certain embodiments, X.sup.1 is N. In certain embodiments, X.sup.1
is CR.sup.x1. R.sup.x1 is as defined in the Summary or embodiments
herein. In certain embodiments, R.sup.x1 is hydrogen,
C.sub.2-C.sub.6 alkenyl, --C(O)OR.sup.ax1,
--C(O)NR.sup.bx1R.sup.cx1, --C(O)R.sup.dx1, G.sup.x1, or
C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with one substituent selected from the group
consisting of OR.sup.ax1, NR.sup.bx1R.sup.cx1, and G.sup.x1. In
certain embodiments, R.sup.x1 is hydrogen, --C(O)OR.sup.ax1,
--C(O)NR.sup.bx1R.sup.cx1, G.sup.x1, or C.sub.1-C.sub.6 alkyl
wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with
OR.sup.ax1. In certain embodiments, R.sup.x1 is hydrogen,
--C(O)OR.sup.ax1, --C(O)NR.sup.bx1R.sup.cx1, optionally substituted
phenyl, or C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl
is optionally substituted with OR.sup.ax1 In certain embodiments,
R.sup.x1 is hydrogen, --C(O)OR.sup.ax1, or
--C(O)NR.sup.bx1R.sup.cx1. In certain embodiments, R.sup.x1 is
hydrogen or unsubstituted C.sub.1-C.sub.6 alkyl. In certain
embodiments, R.sup.x1 is --C(O)OR.sup.ax1,
--C(O)NR.sup.bx1R.sup.cx1, or C.sub.1-C.sub.6 alkyl substituted
with OR.sup.ax1. In certain embodiments, R.sup.x1 is hydrogen or
--C(O)NR.sup.bx1R.sup.cx1. In certain embodiments, R.sup.x1 is
hydrogen. R.sup.ax1, R.sup.bx1, R.sup.x1, R.sup.dx1, and G.sup.x1,
are as disclosed in the Summary. For example, R.sup.ax1 and
R.sup.bx1, are each independently hydrogen, C.sub.1-C.sub.6 alkyl
(e.g. methyl, ethyl, isopropyl), or C.sub.1-C.sub.6 haloalkyl (e.g.
trifluoromethyl). In certain embodiments, R.sup.ax1 and R.sup.bx1,
are each independently hydrogen or C.sub.1-C.sub.6 alkyl (e.g.
methyl, ethyl, isopropyl). In certain embodiments, R.sup.ax1 and
R.sup.bx1, are each independently hydrogen, methyl, or ethyl.
R.sup.cx1, for example, is hydrogen, C.sub.1-C.sub.6 alkyl (e.g.
methyl, ethyl, isopropyl), or C.sub.1-C.sub.6 haloalkyl (e.g.
trifluoromethyl, 2,2,2 trifluoroethyl), wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with G.sup.x1. In certain
embodiments, R.sup.cx1, for example, is hydrogen or C.sub.1-C.sub.6
alkyl (e.g. methyl, ethyl, isopropyl). In certain embodiments,
R.sup.cx1, for example, is G.sup.x1 or C.sub.1-C.sub.6 alkyl
substituted with G.sup.x1; wherein G.sup.x1 is thiazolyl,
morpholinyl, piperazinyl, tetrahydrofuranyl, or phenyl, each of
which is optionally substituted with 1, 2, or 3 substituents
selected from the group consisting of C.sub.1-C.sub.3 alkyl and
C.sub.1-C.sub.3 haloalkyl.
[0093] X.sup.2 is as disclosed in the Summary. For example, in
certain embodiments, X.sup.2 is N. In certain embodiments, X.sup.2
is CR.sup.x2. R.sup.x2 is as defined in the Summary or embodiments
herein. In certain embodiments, X.sup.2 is C(O)H or C.sub.1-C.sub.6
alkyl substituted with one G.sup.x2. In certain embodiments,
X.sup.2 is C(O)H or C.sub.1-C.sub.3 alkyl substituted with one
G.sup.x2 wherein G.sup.2 is piperidinyl, piperazinyl, or
morpholinyl, each of which is optionally substituted with 1, 2, or
3 C.sub.1-C.sub.3 alkyl. In certain embodiments, R.sup.x2 is
hydrogen or unsubstituted C.sub.1-C.sub.6 alkyl (e.g. methyl). In
certain embodiments, R.sup.x2 is hydrogen.
[0094] Y.sup.1 is N or CR.sup.u. For example, in certain
embodiments, Y.sup.1 is N. In certain embodiments, Y.sup.1 is
CR.sup.u. R.sup.u is as defined in the Summary and embodiments
herein. For example, in certain embodiments, R.sup.u is hydrogen or
C.sub.1-C.sub.6 alkyl (e.g. methyl). In certain embodiments,
R.sup.u is hydrogen or C.sub.1-C.sub.3 alkyl (e.g. methyl). In
certain embodiments, R.sup.u is hydrogen or methyl. In certain
embodiments, R.sup.u is hydrogen.
[0095] A.sup.1, A.sup.2, A.sup.3, and A.sup.4 are as defined in the
Summary. In certain embodiments, A.sup.1 is CR.sup.1, A.sup.2 is
CR.sup.2, A.sup.3 is CR.sup.3, and A.sup.4 is CR.sup.4; or one of
A.sup.1, A.sup.2, A.sup.3, and A.sup.4 is N. In certain
embodiments, A.sup.1 is CR.sup.1, A.sup.2 is CR.sup.2, A.sup.3 is
CR.sup.3, and A.sup.4 is CR.sup.4. In certain embodiments, one of
A.sup.1, A.sup.2, A.sup.3, and A.sup.4 is N. In the embodiments
that one of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 is N, example of
a group of compound includes, but is not limited to, those wherein
A.sup.1 is CR.sup.1, A.sup.2 is CR.sup.2, A.sup.3 is CR.sup.3, and
A.sup.4 is N. In certain embodiments, two of A.sup.1, A.sup.2,
A.sup.3, and A.sup.4 are N, for example, A.sup.1 is N, A.sup.2 is
CR.sup.2, A.sup.3 is N, and A.sup.4 is CR.sup.4; or for example,
A.sup.1 is N, A.sup.2 is CR.sup.2, A.sup.3 is CR.sup.3, and A.sup.4
is N. In certain embodiments, three of A.sup.1, A.sup.2, A.sup.3,
and A.sup.4 are N, for example, A.sup.1 is N, A.sup.2 is CR.sup.2,
A.sup.3 is N, and A.sup.4 is N.
[0096] R.sup.1, R.sup.3, and R.sup.4, are as defined in the
Summary. For example, in certain embodiments, R.sup.1, R.sup.3, and
R.sup.4, are each independently hydrogen, C.sub.1-C.sub.6 alkyl
(e.g. methyl, ethyl), halogen (e.g. Br, F, or Cl), or CN. For
example, in certain embodiments, R.sup.1, R.sup.3, and R.sup.4, are
each independently hydrogen, C.sub.1-C.sub.6 alkyl (e.g. methyl,
ethyl), or C.sub.1-C.sub.6 haloalkyl (e.g. trifluoromethyl). In
certain embodiments, R.sup.1, R.sup.3, and R.sup.4, are each
independently hydrogen or methyl. In certain embodiments, R.sup.1,
R.sup.3, and R.sup.4 are hydrogen.
[0097] R.sup.2 is as disclosed in the Summary. In certain
embodiment, R.sup.2, for example, is halogen, haloalkyl (e.g.
CF.sub.3), or --(C.sub.1-C.sub.3 alkylenyl)-CN. In certain
embodiments, R.sup.2, for example, is hydrogen, C.sub.1-C.sub.6
alkyl, NO.sub.2, G.sup.2a, --S(O).sub.2R.sup.2d,
--S(O).sub.2NR.sup.2bR.sup.2c, --C(O)R.sup.2d, --C(O)OR.sup.2a,
--C(O)NR.sup.2bR.sup.2c, --NR.sup.2bR.sup.2c,
--N(R.sup.2e)C(O)R.sup.2d, --N(R.sup.2e)S(O).sub.2R.sup.2d,
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.2a,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.2d,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2NR.sup.2bR.sup.2c,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.2a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2R.sup.2d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c. In certain
embodiments, R.sup.2, for example, is hydrogen, or NO.sub.2. In
certain embodiments, R.sup.2, for example, is G.sup.2a,
--S(O).sub.2R.sup.2d, --S(O).sub.2NR.sup.2bR.sup.2c,
--C(O)R.sup.2d, --C(O)OR.sup.2a, --C(O)NR.sup.2bR.sup.2c,
--NR.sup.2bR.sup.2c, --N(R.sup.2e)C(O)R.sup.2d,
--N(R.sup.2e)S(O).sub.2R.sup.2d,
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.2a,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.2d,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2NR.sup.2bR.sup.2c,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.2a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2R.sup.2d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c. In certain
embodiments, R.sup.2, for example, is --S(O).sub.2R.sup.2d,
--S(O).sub.2NR.sup.2bR.sup.2c, --C(O)R.sup.2d,
--C(O)NR.sup.2bR.sup.2c, --N(R.sup.2e)C(O)R.sup.2d,
--N(R.sup.2e)S(O).sub.2R.sup.2d,
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2R.sup.2d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c. In certain
embodiments, R.sup.2, for example, is --S(O).sub.2R.sup.2d,
--S(O).sub.2NR.sup.2bR.sup.2c, --N(R.sup.2e)S(O).sub.2R.sup.2d, or
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c. In certain embodiment,
R.sup.2, for example, is --S(O).sub.2R.sup.2d,
--S(O).sub.2NR.sup.2bR.sup.2c, --N(R.sup.2e)S(O).sub.2R.sup.2d, or
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.2d. In certain
embodiment, R.sup.2, for example, is --(C.sub.1-C.sub.3
alkylenyl)-S(O).sub.2R.sup.2d wherein R.sup.2d is C.sub.1-C.sub.3
alkyl. In certain embodiment, R.sup.2, for example, is
--(CH.sub.2)--S(O).sub.2R.sup.2d wherein R.sup.2d is methyl or
ethyl.
[0098] G.sup.2a, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and
R.sup.2e are as disclosed in the Summary and embodiments herein
below.
[0099] In the embodiments wherein R.sup.2 is G.sup.2a, G.sup.2a is
as disclosed in the Summary and embodiments herein. For example, in
certain embodiments, G.sup.2a is an optionally substituted
heterocycle. In certain embodiments, G.sup.2a is an optionally
substituted monocyclic heterocycle. In certain embodiments,
G.sup.2a is 1,2-dioxido-1,2-thiazolidin-2-yl or
tetrahydropyridinyl, each of which is optionally substituted. In
certain embodiments, G.sup.2a is optionally substituted
1,2-dioxido-1,2-thiazolidin-2-yl. In certain embodiment, G.sup.2a
is aryl or heteroaryl, each of which is optionally substituted. In
certain embodiments, G.sup.2a is optionally substituted phenyl. In
certain embodiments, G.sup.2a is pyridinyl or pyrazolyl, each of
which is optionally substituted. In certain embodiments, G.sup.2a
is unsubstituted.
[0100] In the embodiments wherein R.sup.2 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a, G.sup.2a is as disclosed in the Summary and
embodiments herein. For example, in certain embodiments, G.sup.2a
is a heterocycle or a heteroaryl, each of which is optionally
substituted. In certain embodiments, G.sup.2a is a monocyclic
heterocycle or a monocyclic heteroaryl, each of which is optionally
substituted. In certain embodiments, G.sup.2a is
1,1-dioxido-1,2-thiazolidin-2-yl, pyrrolidinyl, morpholinyl, or
pyrazolyl, each of which is optionally substituted. In certain
embodiments, G.sup.2a is unsubstituted. In certain embodiments,
G.sup.2a is optionally substituted phenyl.
[0101] Where G.sup.2a group is optionally substituted, it is, for
example, optionally substituted with 1, 2, 3, 4, or 5 R.sup.v.
R.sup.v is as described in the Summary and herein, for example,
R.sup.v is C.sub.1-C.sub.6 alkyl (e.g. methyl), halogen (e.g. F,
Cl), C.sub.1-C.sub.6 haloalkyl, --CN, --NR.sup.jR.sup.k, or
--C(O)OR.sup.h; or for example, R.sup.v is C.sub.1-C.sub.6 alkyl
(e.g. methyl), halogen (e.g. F, Cl), or C.sub.1-C.sub.6
haloalkyl.
[0102] In the embodiments wherein R.sup.2 is --S(O).sub.2R.sup.2d,
R.sup.2d is as disclosed in the Summary and embodiments herein. In
certain embodiments, R.sup.2d is C.sub.1-C.sub.6 haloalkyl (e.g.
CF.sub.3), G.sup.2b, unsubstituted C.sub.1-C.sub.6 alkyl (e.g.
methyl, ethyl, isopropyl), or C.sub.1-C.sub.6 alkyl substituted
with one G.sup.2b group; wherein G.sup.2b is phenyl, monocyclic
cycloalkyl, or monocyclic heterocycle, each of which is optionally
substituted. In some such embodiments, the G.sup.2b group is
optionally substituted with 1, 2, or 3 R.sup.v groups wherein
R.sup.v is as described in the Summary and herein, for example,
each R.sup.v is independently C.sub.1-C.sub.6 alkyl (e.g. methyl),
halogen (e.g. F, Cl), C.sub.1-C.sub.6 haloalkyl, --OR.sup.h, --CN,
or --NR.sup.jR.sup.k, In certain embodiments, R.sup.2d is
C.sub.1-C.sub.6 haloalkyl or unsubstituted C.sub.1-C.sub.6 alkyl.
In certain embodiments, R.sup.2d is methyl or ethyl.
[0103] In the embodiments wherein R.sup.2 is
--S(O).sub.2NR.sup.2bR.sup.2c, R.sup.2b and R.sup.2c are as
disclosed in the Summary and embodiments herein. For example, in
certain embodiments, R.sup.2b is hydrogen or unsubstituted
C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl), and R.sup.2c is
hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl),
or C.sub.1-C.sub.6 haloalkyl (e.g. 2,2,2-trifluoroethyl,
2-fluoroethyl). In certain embodiments, R.sup.2b is hydrogen, and
R.sup.2c is optionally substituted phenyl, or R.sup.2c is
--C.sub.1-C.sub.3 alkyl substituted with one G.sup.2b group wherein
G.sup.2b is optionally substituted pyridinyl.
[0104] In the embodiments wherein R.sup.2 is --C(O)R.sup.2d,
R.sup.2d is as disclosed in the Summary and embodiments herein. For
example, in certain embodiments, R.sup.2d is G.sup.2b wherein
G.sup.2b is as disclosed in the Summary and embodiments herein. For
example, in certain embodiments, G.sup.2b is an optionally
substituted heterocycle. In certain embodiments, G.sup.2b is an
optionally substituted monocyclic heterocycle. In certain
embodiments, G.sup.2b is 1,1-dioxidothiomorpholin-4-yl,
piperazinyl, piperidinyl, pyrrolidin-1-yl, or morpholin-4-yl, each
of which is optionally substituted. Each G.sup.2b is optionally
substituted as described in the Summary and embodiments herein. For
example, each G.sup.2b is independently unsubstituted or
substituted with 1, 2, or 3 R.sup.v. R.sup.v is as described in the
Summary and embodiments herein. For example, each R.sup.v is
independently C.sub.1-C.sub.6 alkyl (e.g. methyl), oxo,
N(H)C(O)O(C.sub.1-C.sub.6 alkyl), --CH.sub.2--C(O)NR.sup.jR.sup.k,
--C(O)-monocyclic heterocycle, or --C(O)-monocyclic heteroaryl. In
certain embodiments, each R.sup.v is independently C.sub.1-C.sub.6
alkyl (e.g. methyl), oxo, or N(H)C(O)O(C.sub.1-C.sub.6 alkyl).
[0105] In the embodiments wherein R.sup.2 is --C(O)OR.sup.2a,
R.sup.2a is as disclosed in the Summary and embodiments herein. For
example, in certain embodiments, R.sup.2a is hydrogen or
unsubstituted C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl).
[0106] In the embodiments wherein R.sup.2 is
--C(O)NR.sup.2bR.sup.2c, R.sup.2b and R.sup.2c are as disclosed in
the Summary and embodiments herein. For example, in certain
embodiments, R.sup.2b is hydrogen or unsubstituted C.sub.1-C.sub.6
alkyl (e.g. methyl), and R.sup.2c is hydrogen, G.sup.2b,
C.sub.1-C.sub.6 haloalkyl (e.g. 2,2-difluoroethyl), C.sub.1-C.sub.6
alkyl (e.g. methyl, ethyl) wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with one substituent selected from the group
consisting of --OR.sup.z1, NR.sup.z1R.sup.z2, and G.sup.2b.
R.sup.z1, R.sup.z2, and G.sup.2b are as defined in the Summary and
embodiments herein. For example, in certain embodiments, G.sup.2b
is optionally substituted phenyl. In certain embodiments, G.sup.2b
is a cycloalkyl, a heteroaryl, or a heterocycle, each of which is
optionally substituted. In certain embodiments, G.sup.2b is a
monocyclic cycloalkyl, a monocyclic heteroaryl, or a monocyclic
heterocycle, each of which is optionally substituted. In certain
embodiments, G.sup.2b is pyridinyl, pyrimidinyl, indazolyl,
indolyl, cyclopentyl, thiazolyl, 1,1-dioxidotetrahydrothienyl,
tetrahydrofuranyl, piperazinyl, piperidinyl, or pyrrolidinyl, each
of which is optionally substituted. Each G.sup.2b is optionally
substituted as described in the Summary and embodiments herein. For
example, each G.sup.2b is independently unsubstituted or
substituted with 1, 2, or 3 R.sup.v. R.sup.v is as described in the
Summary and embodiments herein. For example, each R.sup.v is
independently C.sub.1-C.sub.6 alkyl (e.g. methyl), C.sub.1-C.sub.6
haloalkyl, --OR.sup.h, --C(O)OR.sup.h, --S(O).sub.2R.sup.h,
halogen, or oxo. In certain embodiments, each R.sup.v is
independently C.sub.1-C.sub.6 alkyl (e.g. methyl) or oxo.
[0107] In the embodiments wherein R.sup.2 is --NR.sup.2bR.sup.2c,
R.sup.2b and R.sup.2c are as disclosed in the Summary and
embodiments herein. For example, in certain embodiments, R.sup.2b
and R.sup.2c are each independently hydrogen or unsubstituted
C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl).
[0108] In the embodiments wherein R.sup.2 is
--N(R.sup.2e)C(O)R.sup.2d, R.sup.2d and R.sup.2e are as disclosed
in the Summary and embodiments herein. For example, in certain
embodiments, R.sup.2e hydrogen or unsubstituted C.sub.1-C.sub.6
alkyl (e.g. methyl, ethyl), and R.sup.2d is unsubstituted
C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl, tert-butyl) or
C.sub.1-C.sub.6 haloalkyl (e.g. 2,2,2-trifluoroethyl).
[0109] In the embodiments wherein R.sup.2 is
--N(R.sup.2e)S(O).sub.2R.sup.2d, R.sup.2d and R.sup.2e are as
disclosed in the Summary and embodiments herein. For example, in
certain embodiments, R.sup.2e is hydrogen or unsubstituted
C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl), and R.sup.2d is
unsubstituted C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl) or
C.sub.1-C.sub.6 haloalkyl (e.g. 2,2,2-trifluoroethyl,
2-fluoroethyl, 2,2-dfluoroethyl). In certain embodiments, R.sup.2e
is hydrogen and R.sup.2d is unsubstituted C.sub.1-C.sub.6 alkyl
(e.g. methyl, ethyl). In certain embodiments, R.sup.2e is
C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl substituted
with one substituent selected from the group consisting of
--OR.sup.z1, --NR.sup.z1R.sup.z2, and G.sup.2b, and R.sup.2d is
unsubstituted C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl). In
certain embodiments, R.sup.2e is C.sub.1-C.sub.6 haloalkyl (e.g.
3,3,3-trifluoropropyl), or C.sub.1-C.sub.3 alkyl substituted with
one substituent selected from the group consisting of --OR.sup.z1,
--NR.sup.z1R.sup.z2, and G.sup.2b, and R.sup.2d is unsubstituted
C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl), wherein G.sup.2b is
monocyclic cycloalkyl (e.g. cyclopropyl), monocyclic heterocycle
(e.g. pyrrolidinyl or tetrahydrofuranyl), or monocyclic heteroaryl
(e.g. pyridinyl), each of which is optionally substituted.
[0110] In the embodiments wherein R.sup.2 is
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, R.sup.2b, R.sup.2c, and
R.sup.2e are as disclosed in the Summary and embodiments herein.
For example, in certain embodiments, R.sup.2b, R.sup.2c, and
R.sup.2e are each independently hydrogen or unsubstituted
C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl).
[0111] In the embodiments wherein R.sup.2 is --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.2a, R.sup.2a is as described in the Summary and
embodiments herein. In certain embodiments R.sup.2a is hydrogen. In
certain embodiments, R.sup.2 is --CH.sub.2--OH or
--CH.sub.2CH.sub.2--OH.
[0112] In the embodiments wherein R.sup.2 is --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.2a, R.sup.2a is as described in the Summary
and embodiments herein. For example, R.sup.2a is hydrogen or
unsubstituted C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl).
[0113] In the embodiments wherein R.sup.2 is --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.2bR.sup.2c, R.sup.2b and R.sup.2c are as
disclosed in the Summary and embodiments herein. For example, in
certain embodiments, R.sup.2b and R.sup.2c are each independently
hydrogen or unsubstituted C.sub.1-C.sub.6 alkyl (e.g. methyl,
ethyl).
[0114] In the embodiments wherein R.sup.2 is --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)R.sup.2d, R.sup.2d and R.sup.2e are as
disclosed in the Summary and embodiments herein. For example, in
certain embodiments, R.sup.2e is hydrogen or unsubstituted
C.sub.1-C.sub.6 alkyl (e.g. methyl, ethyl), and R.sup.2d is
C.sub.1-C.sub.6 alkyl (e.g. methyl) optionally substituted with
C(O)OR.sup.z1.
[0115] In the embodiments wherein R.sup.2 is --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.2d, R.sup.2d is as disclosed in the
Summary and embodiments herein. For example, in certain
embodiments, R.sup.2d is optionally substituted phenyl or
unsubstituted C.sub.1-C.sub.6 alkyl. In certain embodiments,
R.sup.2d is unsubstituted C.sub.1-C.sub.3 alkyl. In certain
embodiments, R.sup.2d is methyl or ethyl. In certain embodiments,
R.sup.2d is optionally substituted phenyl.
[0116] L.sup.1 is as set forth in the Summary and embodiments
herein. For example, in certain embodiments, L.sup.1 is absent,
CH.sub.2, C(H)(OH), C(O), (CH.sub.2).sub.mO, or
(CH.sub.2).sub.mN(R.sup.z). For example, in certain embodiments,
L.sup.1 is CH.sub.2, C(O), (CH.sub.2).sub.mO, or
(CH.sub.2).sub.mN(R.sup.z). In certain embodiments, L.sup.1 is
(CH.sub.2).sub.mO or (CH.sub.2).sub.mN(R.sup.z). In certain
embodiments, L.sup.1 is (CH.sub.2).sub.mO. In certain embodiments,
L.sup.1 is (CH.sub.2).sub.mN(R.sup.z).
[0117] The variable, m, is 0 or 1. In certain embodiments, m is 0.
In certain embodiments, m is 1.
[0118] R.sup.z, is as set forth in the Summary and embodiments
herein. For example, R.sup.z is hydrogen or C.sub.1-C.sub.3 alkyl.
In certain embodiments, R.sup.z is hydrogen.
[0119] G.sup.1 is as set forth in the Summary and embodiments
herein. For example, G.sup.1 is G.sup.1a In certain embodiments,
G.sup.1 is --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1a. In certain
embodiments, G.sup.1 is C.sub.1-C.sub.6 alkyl or alkoxyalkyl. In
certain embodiments, G.sup.1 is C.sub.1-C.sub.6 alkyl (e.g. methyl,
ethyl, isobutyl, or 2,2-dimethylpropyl). In certain embodiments,
G.sup.1 is alkoxyalkyl.
[0120] G.sup.1a is as defined in the Summary and embodiments
herein. For example, in certain embodiments G.sup.1a is aryl,
heterocycle, or cycloalkyl, each of which is optionally
substituted. In certain embodiments G.sup.1a is aryl, heterocycle,
heteroaryl, or cycloalkyl, each of which is optionally substituted.
In certain embodiments G.sup.1a is optionally substituted aryl. In
certain embodiments G.sup.1a is optionally substituted heterocycle.
In certain embodiments G.sup.1a is optionally substituted
heteroaryl. In certain embodiments G.sup.1a is optionally
substituted cycloalkyl.
[0121] In the embodiments wherein G.sup.1a is optionally
substituted aryl, G.sup.1a, for example, is phenyl, naphthyl, or
indanyl, each of which is optionally substituted. In certain
embodiments, G.sup.1a, for example, is optionally substituted
phenyl. In certain embodiments, G.sup.1a, for example, is phenyl
optionally substituted with one or two halogen (e.g. F). In certain
embodiments, G.sup.1a is
##STR00005##
[0122] In certain embodiments G.sup.1a is unsubstituted phenyl
or
##STR00006##
[0123] In the embodiments wherein G.sup.1a is optionally
substituted heterocycle, examples of the heterocycle include, but
are not limited to, oxetanyl, tetrahydrofuranyl (e.g.
tetrahydrofuran-2-yl, tetrahydrofuran-3-yl), pyrrolidinyl,
morpholinyl, piperidinyl, tetrahydrothiopyranyl, and
tetrahydropyranyl (e.g. tetrahydropyran-4-yl,
tetrahydropyran-3-yl), each of which (including the exemplary
rings) is optionally substituted.
[0124] In the embodiments wherein G.sup.1a is optionally
substituted heteroaryl, G.sup.1a, for example, is pyrazolyl,
pyridinyl, pyrimidinyl, 2,1,3-benzothiadiazolyl, quinolinyl, or
isoquinolinyl, each of which is optionally substituted.
[0125] In the embodiments wherein G.sup.1a is optionally
substituted cycloalkyl (e.g. optionally substituted monocyclic
cycloalkyl), examples of the cycloalkyl include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, bicyclo[2.2.1]heptyl, and adamantyl, each of which is
optionally substituted. In certain embodiments, G.sup.1a is
optionally substituted cycloalkyl. In certain embodiments, G.sup.1a
is unsubstituted cycloalkyl. In certain embodiments, G.sup.1a is a
substituted cycloalkyl. In certain embodiments, G.sup.1a is
cyclohexyl optionally substituted with 1 or two substituents
selected from the group consisting of C.sub.1-C.sub.3 alkyl (e.g.
methyl), O(C.sub.1-C.sub.3 alkyl), and halogen. In certain
embodiments, G.sup.1a is cyclohexyl optionally substituted with 1
or two substituents selected from the group consisting of methyl
and O(CH.sub.3). In certain embodiments, G.sup.1a is
4,4-difluorocyclohexyl. In certain embodiments, G.sup.1a is
optionally substituted cyclopropyl. In certain embodiments,
G.sup.1a is unsubstituted cyclopropyl.
[0126] The optional substituents of G.sup.1a are as set forth in
the Summary and embodiments herein. For example, each G.sup.1a is
independently unsubstituted or substituted with 1, 2, 3, 4, or 5
R.sup.w. In certain embodiments, R.sup.w is, for example,
C.sub.1-C.sub.6 alkyl --CN, halogen (e.g. F, Cl), oxo,
C.sub.1-C.sub.6 haloalkyl (e.g. trifluoromethyl), --OR.sup.h,
NR.sup.jR.sup.k, --S(O).sub.2R.sup.h, --C(O)R.sup.h,
--C(O)OR.sup.h, --C(O)NR.sup.jR.sup.k, --(C.sub.1-C.sub.3
alkylenyl)-OR.sup.h, or --(C.sub.1-C.sub.3
alkylenyl)C(O)NR.sup.jR.sup.k. In certain embodiments, R.sup.w is,
for example, C.sub.1-C.sub.6 alkyl, --CN, halogen (e.g. F, Cl), or
C.sub.1-C.sub.6 haloalkyl (e.g. trifluoromethyl). In certain
embodiments, R.sup.w is halogen, --OR.sup.h, or C.sub.1-C.sub.6
alkyl. In certain embodiments, R.sup.w is halogen. In certain
embodiments, R.sup.w is F.
[0127] It is appreciated that compounds of formula (I) with
combinations of the above embodiments, including particular, more
particular and preferred embodiments are contemplated. All
embodiments of compounds of formula (I) formed by combining the
substituent embodiments discussed above are within the scope of
Applicants' invention, and some illustrative embodiments of the
compounds of formula (I) are provided below.
[0128] Accordingly, one aspect of the invention is directed to a
group of compounds of formula (I) wherein L.sup.1 is
(CH.sub.2).sub.mO and G.sup.1 is G.sup.1a and G.sup.1a is as
disclosed in the Summary and embodiments herein above.
[0129] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1; and
X.sup.2 is CR.sup.x2.
[0130] Yet other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, and R.sup.y is methyl.
[0131] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, and L.sup.1 is CH.sub.2,
C(O), (CH.sub.2).sub.mO, or (CH.sub.2).sub.mN(R.sup.z). In certain
embodiments, L.sup.1 is (CH.sub.2).sub.mO. In yet other
embodiments, L.sup.1 is (CH.sub.2).sub.mO and m is 0. In yet other
embodiments, L.sup.1 is (CH.sub.2).sub.mO and m is 1. In certain
embodiments, L.sup.1 is (CH.sub.2).sub.mN(R.sup.z). In certain
embodiments, L.sup.1 is (CH.sub.2).sub.mN(R.sup.z) and m is 0. In
yet other embodiments, L.sup.1 is (CH.sub.2).sub.mN(R.sup.z) and m
is 1. R.sup.z has values as described in the Summary and
embodiments herein above.
[0132] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, and G.sup.1 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1a wherein G.sup.1a is optionally substituted
phenyl.
[0133] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, and G.sup.1 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1a wherein G.sup.1a is optionally substituted
cycloalkyl. In some embodiments, G.sup.1a is unsubstituted
cyclopropyl.
[0134] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, and G.sup.1 is G.sup.1a.
[0135] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, G.sup.1 is G.sup.1a, and G.sup.1a is optionally
substituted aryl.
[0136] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, G.sup.1 is G.sup.1a, and G.sup.1a is optionally
substituted phenyl.
[0137] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, G.sup.1 is G.sup.1a, and G.sup.1a is optionally
substituted cycloalkyl (e.g. optionally substituted monocyclic
cycloalkyl).
[0138] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is N; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, G.sup.1 is G.sup.1a, and G.sup.1a is optionally
substituted heterocycle (e.g. optionally substituted monocyclic
heterocycle).
[0139] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; and X.sup.2 is CR.sup.x2.
[0140] Yet other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, and R.sup.y is methyl.
[0141] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, R.sup.y is methyl, and L.sup.1 is
CH.sub.2, C(O), (CH.sub.2).sub.mO, or (CH.sub.2).sub.mN(R.sup.z).
In certain embodiments, L.sup.1 is (CH.sub.2).sub.mO. In yet other
embodiments, L.sup.1 is (CH.sub.2).sub.mO and m is 0. In yet other
embodiments, L.sup.1 is (CH.sub.2).sub.mO and m is 1. In certain
embodiments, L.sup.1 is (CH.sub.2).sub.mN(R.sup.z). In certain
embodiments, L.sup.1 is (CH.sub.2).sub.mN(R.sup.z) and m is 0. In
yet other embodiments, L.sup.1 is (CH.sub.2).sub.mN(R.sup.z) and m
is 1. R.sup.z has meaning as described in the Summary and
embodiments herein above.
[0142] Other examples of a group of compounds of formula (I) is
directed to those wherein Y is CR.sup.u; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mN(R.sup.z), and G.sup.1 is G.sup.1a or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.1a wherein G.sup.1a is phenyl,
monocyclic heterocycle (e.g. tetrahydrofuranyl), or monocyclic
cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl), each of
which (including the exemplary rings) is optionally
substituted.
[0143] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mN(R.sup.z), m is 0, R.sup.z is hydrogen, and
G.sup.1 is G.sup.1a wherein G.sup.1a is phenyl, monocyclic
heterocycle (e.g. tetrahydrofuranyl), or monocyclic cycloalkyl
(e.g. cyclopropyl, cyclopentyl, cyclohexyl), each of which
(including the exemplary rings) is optionally substituted.
[0144] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mN(R.sup.z), m is 0, R.sup.z is hydrogen, and
G.sup.1 is --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1a wherein G.sup.1a
is monocyclic heterocycle (e.g. tetrahydrofuranyl), or monocyclic
cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl), each of
which (including the exemplary rings) is optionally substituted. In
some embodiments, G.sup.1 is --(C.sub.1-C.sub.3 alkylenyl)-G.sup.1a
wherein G.sup.1a is optionally substituted monocyclic cycloalkyl
(e.g. cyclopropyl, cyclopentyl, cyclohexyl, each of which is
optionally substituted). In some embodiments, G.sup.1 is
--(CH.sub.2)-G.sup.1a wherein G.sup.1a is optionally substituted
monocyclic cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl,
each of which is optionally substituted). In certain embodiments,
G.sup.1a is optionally substituted is monocyclic heterocycle (e.g.
optionally substituted tetrahydrofuranyl). In certain embodiments,
G.sup.1a is optionally substituted cyclopropyl. In some
embodiments, G.sup.1a is unsubstituted cyclopropyl.
[0145] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, and G.sup.1 is C.sub.1-C.sub.6 alkyl or
alkoxyalkyl. In certain embodiments, G.sup.1 is C.sub.1-C.sub.6
alkyl (e.g. methyl, ethyl, isobutyl, or 2,2-dimethylpropyl). In
certain embodiments, G.sup.1 is alkoxyalkyl.
[0146] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, and G.sup.1 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1a wherein G.sup.1a is optionally substituted
phenyl.
[0147] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, and G.sup.1 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1a wherein G.sup.1a is optionally substituted
cycloalkyl. In some embodiments, G.sup.1a is optionally substituted
cyclopropyl. In some embodiments, G.sup.1a is unsubstituted
cyclopropyl.
[0148] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, and G.sup.1 is G.sup.1a Other examples of a
group of compounds of formula (I) is directed to those wherein
Y.sup.1 is CR.sup.u; X.sup.1 is CR.sup.x1; X.sup.2 is CR.sup.x2,
R.sup.y is methyl, L.sup.1 is (CH.sub.2).sub.mO, G.sup.1 is
G.sup.1a, and G.sup.1a is optionally substituted aryl.
[0149] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, G.sup.1 is G.sup.1a, and G.sup.1a is optionally
substituted phenyl.
[0150] Other examples of a group of compounds of formula (I) is
directed to those wherein Y is CR.sup.u; X.sup.1 is CR.sup.x1;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, G.sup.1 is G.sup.1a, and G.sup.1a is optionally
substituted cycloalkyl (e.g. optionally substituted monocyclic
cycloalkyl).
[0151] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is
CR.sup.x1; X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, G.sup.1 is G.sup.1a, and G.sup.1a is optionally
substituted heterocycle (e.g. optionally substituted monocyclic
heterocycle).
[0152] Yet other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is N;
X.sup.2 is CR.sup.x2, and R.sup.y is methyl.
[0153] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is N;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, and L.sup.1 is CH.sub.2,
C(O), (CH.sub.2).sub.mO, or (CH.sub.2).sub.mN(R.sup.z). In certain
embodiments, L.sup.1 is (CH.sub.2).sub.mO. In yet other
embodiments, L.sup.1 is (CH.sub.2).sub.mO and m is 0. In yet other
embodiments, L.sup.1 is (CH.sub.2).sub.mO and m is 1. In certain
embodiments, L.sup.1 is (CH.sub.2).sub.mN(R.sup.z). In certain
embodiments, L.sup.1 is (CH.sub.2).sub.mN(R.sup.z) and m is 0. In
yet other embodiments, L.sup.1 is (CH.sub.2).sub.mN(R.sup.z) and m
is 1. R.sup.z has meaning as described in the Summary and
embodiments herein above.
[0154] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is N;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, and G.sup.1 is G.sup.1a.
[0155] Other examples of a group of compounds of formula (I) is
directed to those wherein Y is CR.sup.u; X.sup.1 is N; X.sup.2 is
CR.sup.x2, R.sup.y is methyl, L.sup.1 is (CH.sub.2).sub.mO, G.sup.1
is G.sup.1a, and G.sup.1a is optionally substituted aryl.
[0156] Other examples of a group of compounds of formula (I) is
directed to those wherein Y is CR.sup.u; X.sup.1 is N; X.sup.2 is
CR.sup.x2, R.sup.y is methyl, L.sup.1 is (CH.sub.2).sub.mO, G.sup.1
is G.sup.1a, and G.sup.1a is optionally substituted phenyl.
[0157] Other examples of a group of compounds of formula (I) is
directed to those wherein Y is CR.sup.u; X.sup.1 is N; X.sup.2 is
CR.sup.x2, R.sup.y is methyl, L.sup.1 is (CH.sub.2).sub.mO, G.sup.1
is G.sup.1a, and G.sup.1a is optionally substituted cycloalkyl
(e.g. optionally substituted monocyclic cycloalkyl).
[0158] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is N;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, G.sup.1 is G.sup.1a, and G.sup.1a is optionally
substituted heterocycle (e.g. optionally substituted monocyclic
heterocycle).
[0159] Other examples of a group of compounds of formula (I) is
directed to those wherein Y.sup.1 is CR.sup.u; X.sup.1 is N;
X.sup.2 is CR.sup.x2, R.sup.y is methyl, L.sup.1 is
(CH.sub.2).sub.mO, and G.sup.1 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1a wherein G.sup.1a is optionally substituted
cycloalkyl. In some embodiments, G.sup.1a is optionally substituted
cyclopropyl. In some embodiments, G.sup.1a is unsubstituted
cyclopropyl.
[0160] Within each group of compounds of formula (I) described
herein above, A.sup.1, A.sup.2, A.sup.3, and A.sup.4 have meanings
as disclosed in the Summary and embodiments herein above.
[0161] For example, within each group of compounds of formula (I)
described herein above, examples of a subgroup include those
wherein A.sup.1 is CR.sup.1, A.sup.2 is CR.sup.2, A.sup.3 is
CR.sup.3, and A.sup.4 is CR.sup.4; or one of A.sup.1, A.sup.2,
A.sup.3, and A.sup.4 is N.
[0162] Other examples of a subgroup include, but are not limited
to, those wherein A.sup.1 is CR.sup.1, A.sup.2 is CR.sup.2, A.sup.3
is CR.sup.3, and A.sup.4 is CR.sup.4.
[0163] Other examples of a subgroup include, but are not limited
to, those wherein one of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 is
N.
[0164] Yet other examples of a subgroup include, but are not
limited to, those wherein A.sup.1 is CR.sup.1, A.sup.2 is CR.sup.2,
A.sup.3 is CR.sup.3, and A.sup.4 is N.
[0165] Yet other examples of a subgroup include, but are not
limited to, those wherein two of A.sup.1, A.sup.2, A.sup.3, and
A.sup.4 are N.
[0166] Yet other examples of a subgroup include, but are not
limited to, those wherein A.sup.1 is N, A.sup.2 is CR.sup.2,
A.sup.3 is N, and A.sup.4 is CR.sup.4.
[0167] Yet other examples of a subgroup include, but are not
limited to, those wherein A.sup.1 is N, A.sup.2 is CR.sup.2,
A.sup.3 is CR.sup.3, and A.sup.4 is N.
[0168] Yet other examples of a subgroup include, but are not
limited to, those wherein three of A.sup.1, A.sup.2, A.sup.3, and
A.sup.4 are N.
[0169] Yet other examples of a subgroup include, but are not
limited to, those wherein A.sup.1 is N, A.sup.2 is CR.sup.2,
A.sup.3 is N, and A.sup.4 is N.
[0170] Of all the groups and subgroups of compounds of formula (I)
disclosed in the preceding paragraphs, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.x, R.sup.u; R.sup.x1, R.sup.x2, m, and the optional
substituents of G.sup.1 are as described in the Summary and
embodiments herein above.
[0171] For example, of all the groups and subgroups of compounds of
formula (I) disclosed in the preceding paragraphs, R.sup.2 is
hydrogen, C.sub.1-C.sub.6 alkyl, NO.sub.2, G.sup.2a,
--S(O).sub.2R.sup.2d, --S(O).sub.2NR.sup.2bR.sup.2c,
--C(O)R.sup.2d, --C(O)OR.sup.2a, --C(O)NR.sup.2bR.sup.2c,
--NR.sup.2bR.sup.2c, --N(R.sup.2e)C(O)R.sup.2d,
--N(R.sup.2e)S(O).sub.2R.sup.2d,
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.2a,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.2d,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2NR.sup.2bR.sup.2c,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.2a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2R.sup.2d, or --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c. In certain
embodiments, R.sup.2 is --S(O).sub.2R.sup.2d,
--S(O).sub.2NR.sup.2bR.sup.2c, --N(R.sup.2e)S(O).sub.2R.sup.2d, or
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c. In some embodiments,
R.sup.2 is --S(O).sub.2R.sup.2d, --S(O).sub.2NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2R.sup.2d, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.2d For example, of all the groups and
subgroups of compounds of formula (I) disclosed in the preceding
paragraphs, R.sup.2 is --S(O).sub.2R.sup.2d,
--S(O).sub.2NR.sup.2bR.sup.2c, --N(R.sup.2e)S(O).sub.2R.sup.2d, or
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, and R.sup.x is hydrogen
or methyl. In certain embodiments, R.sup.x is hydrogen.
[0172] For example, of all the groups and subgroups of compounds of
formula (I) disclosed in the preceding paragraphs, R.sup.2 is
--S(O).sub.2R.sup.2d, --S(O).sub.2NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2R.sup.2d, or
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, R.sup.x is hydrogen, and
R.sup.x1 is hydrogen, --C(O)OR.sup.al, --C(O)NR.sup.bx1R.sup.cx1,
G.sup.x1, or C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with OR.sup.ax1. In certain
embodiments, R.sup.x1 is hydrogen, --C(O)OR.sup.ax1, or
--C(O)NR.sup.bx1R.sup.cx1.
[0173] For example, of all the groups and subgroups of compounds of
formula (I) disclosed in the preceding paragraphs, R.sup.2 is
--S(O).sub.2R.sup.2d, --S(O).sub.2NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2R.sup.2d, or
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, R.sup.x is hydrogen,
R.sup.x1 is hydrogen, --C(O)OR.sup.ax1, or
--C(O)NR.sup.bx1R.sup.cx1, and R.sup.x2 is hydrogen.
[0174] For example, of all the groups and subgroups of compounds of
formula (I) disclosed in the preceding paragraphs, R.sup.2 is
--S(O).sub.2R.sup.2d, --S(O).sub.2NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2R.sup.2d, or --(C.sub.1-C.sub.6
alkylenyl)S(O).sub.2R.sup.2d, R.sup.x is hydrogen, R.sup.x1 is
hydrogen or --C(O)NR.sup.bx1R.sup.cx1, and R.sup.x2 is
hydrogen.
[0175] One aspect of the invention is directed to compounds of
formula (I) or pharmaceutically acceptable salts thereof, wherein
[0176] R.sup.x is hydrogen; [0177] R.sup.y is methyl; [0178]
Y.sup.1 is CR.sup.u wherein R.sup.u is hydrogen; [0179] X.sup.1 is
CR.sup.x1 wherein R.sup.x1 is hydrogen or
--C(O)NR.sup.bx1R.sup.cx1; [0180] X.sup.2 is CR.sup.x2 wherein
R.sup.x2 is hydrogen; [0181] L.sup.1 is (CH.sub.2).sub.mO wherein m
is 0; [0182] G.sup.1 is G.sup.1a or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1a, wherein G.sup.1a is optionally substituted
phenyl or optionally substituted cycloalkyl; and [0183] R.sup.2 is
--S(O).sub.2R.sup.2d, --S(O).sub.2NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2R.sup.2d, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.2d.
[0184] In some such embodiments, A.sup.1 is CR.sup.1, A.sup.2 is
CR.sup.2, A.sup.3 is CR.sup.3, and A.sup.4 is CR.sup.4. In some
further embodiments, A.sup.1 is CR.sup.1, A.sup.2 is CR.sup.2,
A.sup.3 is CR.sup.3, and A.sup.4 is N.
[0185] Another aspect of the invention is directed to compounds of
formula (I) or pharmaceutically acceptable salts thereof, wherein
[0186] R.sup.x is hydrogen; [0187] R.sup.y is methyl; [0188]
Y.sup.1 is CR.sup.u wherein R.sup.u is hydrogen; [0189] X.sup.1 is
CR.sup.x1 wherein R.sup.x1 is hydrogen; [0190] X.sup.2 is CR.sup.x2
wherein R.sup.x2 is hydrogen; [0191] L.sup.1 is
(CH.sub.2).sub.mN(R.sup.z) or wherein m is 0 and R.sup.z is
hydrogen; [0192] G.sup.1 is --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1a,
wherein G.sup.1a is optionally substituted cycloalkyl; and [0193]
R.sup.2 is --S(O).sub.2R.sup.2d, --S(O).sub.2NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2R.sup.2d, or --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.2d.
[0194] In some such embodiments, A.sup.1 is CR.sup.1, A.sup.2 is
CR.sup.2, A.sup.3 is CR.sup.3, and A.sup.4 is CR.sup.4. In some
further embodiments, A.sup.1 is CR.sup.1, A.sup.2 is CR.sup.2,
A.sup.3 is CR.sup.3, and A.sup.4 is N.
[0195] In one aspect the present invention provides for compounds
of formula (I) or pharmaceutically acceptable thereof,
##STR00007##
wherein [0196] R.sup.y is C.sub.1-C.sub.3 alkyl, --(C.sub.2-C.sub.3
alkylenyl)-OH, or C.sub.1-C.sub.3 haloalkyl; [0197] X.sup.1 is N or
CR.sup.x1 wherein [0198] R.sup.x1 is hydrogen, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, --C(O)OR.sup.ax1,
--C(O)NR.sup.bx1R.sup.cx1, --C(O)R.sup.dx1, S(O).sub.2R.sup.dx1,
--S(O).sub.2NR.sup.bx1R.sup.cx1, G.sup.x1, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with one substituent selected from
the group consisting of OR.sup.ax1, SR.sup.ax1, S(O)R.sup.dx1,
S(O).sub.2R.sup.dx1, NR.sup.bx1R.sup.cx1, --C(O)R.sup.ax1,
--C(O)OR.sup.ax1, --C(O)NR.sup.bx1R.sup.cx1,
--S(O).sub.2NR.sup.bx1R.sup.cx1, and G.sup.x1; [0199] R.sup.ax1,
R.sup.bx1, and R.sup.cx1, at each occurrence, are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, G.sup.a, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.a;
[0200] R.sup.dx1, at each occurrence, are each independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, G.sup.a, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.a; [0201] X.sup.2 is N or
CR.sup.x2; wherein [0202] R.sup.x2 is hydrogen, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, --C(O)OR.sup.ax2,
--C(O)NR.sup.bx2R.sup.cx2, --C(O)R.sup.dx2, S(O).sub.2R.sup.dx2,
--S(O).sub.2NR.sup.bx2R.sup.cx2, G.sup.x2, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with one substituent selected from
the group consisting of OR.sup.ax2, SR.sup.ax2, S(O)R.sup.dx2,
S(O).sub.2R.sup.dx2, NR.sup.bx2R.sup.cx2, --C(O)R.sup.ax2,
--C(O)OR.sup.ax2, --C(O)NR.sup.bx2R.sup.cx2,
--S(O).sub.2NR.sup.bx2R.sup.cx2, and G.sup.x2; [0203] R.sup.ax2,
R.sup.bx2, and R.sup.cx2, at each occurrence, are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, G.sup.b, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.b;
[0204] R.sup.dx2, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, G.sup.b, or
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.b; [0205] Y.sup.1 is N or
CR.sup.u; wherein R.sup.u is hydrogen, C.sub.1-C.sub.6 alkyl,
halogen, or C.sub.1-C.sub.6 haloalkyl; [0206] A.sup.1 is N or
CR.sup.1, A.sup.2 is N or CR.sup.2, A.sup.3 is N or CR.sup.3; and
A.sup.4 is N or CR.sup.4; with the proviso that zero, one, two, or
three of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 are N;
[0207] R.sup.1, R.sup.3, and R.sup.4 are each independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, CN, or
NO.sub.2;
[0208] R.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6
haloalkyl, --CN, NO.sub.2, G.sup.2a, --OR.sup.2a, --OC(O)R.sup.2d,
--OC(O)NR.sup.2bR.sup.2c, --SR.sup.2a, --S(O).sub.2R.sup.2d,
--S(O).sub.2NR.sup.2bR.sup.2c, --C(O)R.sup.2d, --C(O)OR.sup.2a,
--C(O)NR.sup.2bR.sup.2c, --NR.sup.2bR.sup.2c,
--N(R.sup.2e)C(O)R.sup.2d, --N(R.sup.2e)S(O).sub.2R.sup.2d,
--N(R.sup.2e)C(O)O(R.sup.2d), --N(R.sup.2e)C(O)NR.sup.2bR.sup.2c,
--N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2a, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.2a,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.2a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2R.sup.2d, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)O(R.sup.2a), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)C(O)NR.sup.2bR.sup.2c, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.2e)S(O).sub.2NR.sup.2bR.sup.2c, and
--(C.sub.1-C.sub.6 alkylenyl)-CN; [0209] R.sup.2a, R.sup.2b,
R.sup.2c, and R.sup.2e, at each occurrence, are each independently
hydrogen, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.2b, or C.sub.1-C.sub.6 alkyl
wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with
one substituent selected from the group consisting of --OR.sup.z1,
NR.sup.z1R.sup.z2, --C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2,
--S(O).sub.2R.sup.z1, --S(O).sub.2NR.sup.z1R.sup.z2, and G.sup.2b;
[0210] R.sup.2d, at each occurrence, is independently
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, G.sup.2b, or C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one
substituent selected from the group consisting of --OR.sup.z,
NR.sup.z1R.sup.z2, --C(O)OR.sup.z1, --C(O)NR.sup.z1R.sup.z2,
--S(O).sub.2R.sup.z1, --S(O).sub.2NR.sup.z1R.sup.z2, and G.sup.2b;
[0211] R.sup.z1 and R.sup.z2, at each occurrence, are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl; [0212] G.sup.x1, G.sup.x2, G.sup.a, G.sup.b, G.sup.2a,
and G.sup.2b, at each occurrence, are each independently aryl,
heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of
which is independently unsubstituted or substituted with 1, 2, 3,
4, or 5 of R.sup.v; [0213] L.sup.1 is absent, CH.sub.2, C(O),
(CH.sub.2).sub.mO, (CH.sub.2).sub.mS(O).sub.n wherein n is 0, 1, or
2; or (CH.sub.2).sub.mN(R.sup.z) wherein R.sup.z is hydrogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, (C.sub.2-C.sub.3
alkylenyl)-OH, or unsubstituted cyclopropyl; [0214] m is 0 or 1;
[0215] G.sup.1 is G.sup.1a or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1a; wherein each G.sup.1a is independently aryl,
heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each
G.sup.1a is independently unsubstituted or substituted with 1, 2,
3, 4, or 5 of R.sup.w; [0216] R.sup.v and R.sup.w, at each
occurrence, are each independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, halogen,
C.sub.1-C.sub.6 haloalkyl, --CN, oxo, --OR.sup.h, --OC(O)R.sup.i,
--OC(O)NR.sup.jR.sup.k, --SR.sup.h, --S(O).sub.2R.sup.h,
--S(O).sub.2NR.sup.jR.sup.k, --C(O)R.sup.h, --C(O)OR.sup.h,
--C(O)NR.sup.jR.sup.k, --NR.sup.jR.sup.k, --N(R.sup.h)C(O)R.sup.i,
--N(R.sup.h)S(O).sub.2R.sup.i, --N(R.sup.h)C(O)O(R.sup.i),
--N(R.sup.h)C(O)NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.h, --(C.sub.1-C.sub.6 alkylenyl)-OC(O)R.sup.i,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)NR.sup.jR.sup.k,
--(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.h, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.h, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.h,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)NR.sup.jR.sup.k,
--(C.sub.1-C.sub.6 alkylenyl)-NR.sup.jR.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)R.sup.i, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)S(O).sub.2R.sup.i, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)O(R.sup.i), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.h)C(O)NR.sup.jR.sup.k, or --(C.sub.1-C.sub.6
alkylenyl)-CN; [0217] R.sup.h, R.sup.j, R.sup.k, at each
occurrence, are each independently hydrogen, C.sub.1-C.sub.6 alkyl,
or C.sub.1-C.sub.6 haloalkyl; and [0218] R.sup.i, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 haloalkyl.
[0219] Compounds of formula (I) may contain one or more
asymmetrically substituted atoms. Compounds of formula I may also
exist as individual stereoisomers (including enantiomers and
diastereomers) and mixtures thereof. Individual stereoisomers of
compounds of formula I may be prepared synthetically from
commercially available starting materials that contain asymmetric
or chiral centers or by preparation of racemic mixtures followed by
resolution of the individual stereoisomer using methods that are
known to those of ordinary skill in the art. Examples of resolution
are, for example, (i) attachment of a mixture of enantiomers to a
chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography, followed by
liberation of the optically pure product; or (ii) separation of the
mixture of enantiomers or diastereomers on chiral chromatographic
columns.
[0220] Compounds of formula I may also include the various
geometric isomers and mixtures thereof resulting from the
disposition of substituents around a carbon-carbon double bond, a
carbon-nitrogen double bond, a cycloalkyl group, or a heterocycle
group. Substituents around a carbon-carbon double bond or a
carbon-nitrogen double bond are designated as being of Z or E
configuration and substituents around a cycloalkyl or heterocycle
are designated as being of cis or trans configuration.
[0221] Within the present invention it is to be understood that
compounds disclosed herein may exhibit the phenomenon of
tautomerism and all tautomeric isomers are included in the scope of
the invention.
[0222] Thus, the formula drawings within this specification can
represent only one of the possible tautomeric, geometric, or
stereoisomeric forms. It is to be understood that the invention
encompasses any tautomeric, geometric, or stereoisomeric form, and
mixtures thereof, and is not to be limited merely to any one
tautomeric, geometric, or stereoisomeric form utilized within the
formula drawings.
[0223] Exemplary compounds of formula (I) include, but are not
limited to: [0224]
6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin--
7-one; [0225]
6-methyl-4-(5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-
-7-one; [0226]
4-(5-amino-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-
-7-one; [0227]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-
phenyl]methanesulfonamide; [0228]
2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-
-4-yl)-4-phenoxyphenyl]ethanesulfonamide; [0229]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-
phenyl]acetamide; [0230]
N-methyl-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)--
4-phenoxyphenyl]methanesulfonamide; [0231] ethyl
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyben-
zoate; [0232]
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyben-
zoic acid; [0233]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyridi-
n-3-yloxy)phenyl]methanesulfonamide; [0234]
6-methyl-4-[2-(morpholin-4-ylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]-
pyridin-7-one; [0235]
N-ethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-ph-
enoxybenzamide; [0236]
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N--
(tetrahydrofuran-2-ylmethyl)benzamide; [0237]
N-cyclopentyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl-
)-4-phenoxybenzamide; [0238]
N-(2,2-difluoroethyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)-4-phenoxybenzamide; [0239]
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N--
(1,3-thiazol-2-yl)benzamide; [0240]
N-(1,1-dioxidotetrahydrothiophen-3-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-p-
yrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide; [0241]
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyben-
zamide;
4-[5-(hydroxymethyl)-2-phenoxyphenyl]-6-methyl-1,6-dihydro-7H-pyrr-
olo[2,3-c]pyridin-7-one; [0242]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-
phenyl]ethanesulfonamide; [0243]
N,N-dimethyl-N'-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-
-yl)-4-phenoxyphenyl]sulfuric diamide; [0244]
N-[5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-phenoxy-
pyridin-3-yl]methanesulfonamide; [0245]
N-[3-fluoro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)--
4-phenoxyphenyl]methanesulfonamide; [0246]
N-[4-(2-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)phenyl]methanesulfonamide; [0247]
N-[4-(4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)phenyl]methanesulfonamide; [0248]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]methanesulfonamide; [0249]
N-[3-chloro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)--
4-phenoxyphenyl]methanesulfonamide; [0250]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrah-
ydro-2H-pyran-4-yloxy)phenyl]methanesulfonamide; [0251]
6-methyl-4-[2-phenoxy-5-(1H-pyrazol-1-ylmethyl)phenyl]-1,6-dihydro-7H-pyr-
rolo[2,3-c]pyridin-7-one; [0252]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrah-
ydrofuran-3-yloxy)phenyl]methanesulfonamide; [0253]
N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[2-(tri-
fluoromethyl)phenoxy]phenyl}methanesulfonamide; [0254]
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)phenyl]methanesulfonamide; [0255]
N-[4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[-
2,3-c]pyridin-4-yl)phenyl]methanesulfonamide; [0256]
[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-y-
l)phenyl]acetic acid; [0257]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]ethanesulfonamide; [0258]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]acetamide; [0259]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-3,3,3-trifluoropropanamide; [0260]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-2,2-dimethylpropanamide; [0261] ethyl
4-(cyclopentylamino)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)benzoate; [0262]
4-{5-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-2-phenoxyphenyl}-6-methyl-
-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0263]
4-{[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenox-
ybenzyl]amino}-4-oxobutanoic acid; [0264]
4-[2-(2,4-difluorophenoxy)-5-(1,1-dioxido-1,2-thiazolidin-2-yl)phenyl]-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0265]
4-[2-(benzyloxy)-5-(2-hydroxyethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrol-
o[2,3-c]pyridin-7-one; [0266] methyl
[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-y-
l)phenyl]acetate; [0267]
2-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-
-yl)phenyl]-N-ethylacetamide; [0268]
2-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-
-yl)phenyl]-N,N-dimethylacetamide; [0269]
N-[4-(3,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]methanesulfonamide; [0270]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6--
trifluorophenoxy)phenyl]methanesulfonamide; [0271]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)benzamide; [0272]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-N-(tetrahydrofuran-3-yl)benzamide; [0273]
4-{2-(2,4-difluorophenoxy)-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phe-
nyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0274]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-N-(1-methyl-2-oxopyrrolidin-3-yl)benzamide; [0275]
tert-butyl
{1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)benzoyl]pyrrolidin-3-yl}carbamate; [0276]
4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylcarbonyl)phenyl]-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0277]
4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylcarbonyl)phenyl]-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0278]
N-[4-(cyclohexyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]methanesulfonamide; [0279]
N-[4-(cyclopentyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)phenyl]methanesulfonamide; [0280]
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl}methanesulfonamide; [0281]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrah-
ydro-2H-pyran-3-yloxy)phenyl]methanesulfonamide; [0282]
6-methyl-4-[2-(morpholin-4-ylcarbonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3--
c]pyridin-7-one; [0283]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6--
trifluorophenoxy)phenyl]ethanesulfonamide; [0284]
N-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-
-yl)phenyl]methanesulfonamide; [0285]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-2-fluoroethanesulfonamide; [0286]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-N'-methylsulfuric diamide; [0287]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrah-
ydrofuran-3-yloxy)phenyl]ethanesulfonamide; [0288] methyl
6-methyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine--
2-carboxylate; [0289] methyl
1,6-dimethyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
ine-2-carboxylate; [0290] ethyl
4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]p-
yridine-2-carboxylate; [0291]
6-methyl-4-(5-(methylsulfonamido)-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-p-
yrrolo[2,3-c]pyridine-2-carboxylic acid; [0292] ethyl
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro--
1H-pyrrolo[2,3-c]pyridine-2-carboxylate; [0293]
N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7--
dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide; [0294]
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro--
1H-pyrrolo[2,3-c]pyridine-2-carboxamide; [0295] ethyl
4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]p-
yridazine-2-carboxylate; [0296] ethyl
4-[5-(ethylamino)-2-phenoxyphenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[-
2,3-d]pyridazine-2-carboxylate; [0297] ethyl
4-{5-[ethyl(methylsulfonyl)amino]-2-phenoxyphenyl}-6-methyl-7-oxo-6,7-dih-
ydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate; [0298]
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro--
1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid; [0299]
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro--
1H-pyrrolo[2,3-d]pyridazine-2-carboxamide; [0300]
6-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-4-{5-[(methylsulfonyl)amino]-
-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxam-
ide; [0301]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)-4-pheno-
xyphenyl]methanesulfonamide; [0302]
N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7--
dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide; [0303]
6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one-
; [0304]
N-ethyl-N,6-dimethyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl-
}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide;
[0305]
4-{4-[(ethylsulfonyl)amino]-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)phenoxy}benzamide; [0306]
6-methyl-4-[5-(methylsulfonyl)-2-phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,-
3-c]pyridin-7-one; [0307]
5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydr-
ofuran-3-yloxy)pyridine-3-sulfonamide; [0308]
N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(-
tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide; [0309]
6-methyl-4-(2-phenoxyphenyl)-2-phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridi-
n-7-one; [0310]
N-{3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl]-4-phenoxyphenyl}methanesulfonamide; [0311]
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)phenyl]ethanesulfonamide; [0312]
2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)--
4-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamide; [0313]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrah-
ydrofuran-3-yloxy)phenyl]propane-1-sulfonamide; [0314]
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)phenyl]propane-1-sulfonamide; [0315]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6--
trifluorophenoxy)phenyl]propane-1-sulfonamide; [0316]
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyben-
zenesulfonamide; [0317]
6-(cyclohexylamino)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridi-
n-4-yl)pyridine-3-sulfonamide; [0318]
6-(cyclohexylamino)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-
-c]pyridin-4-yl)pyridine-3-sulfonamide; [0319]
N-methyl-N'-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-
-4-(2,4,6-trifluorophenoxy)phenyl]sulfuric diamide; [0320]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrah-
ydro-2H-pyran-4-yloxy)phenyl]propane-1-sulfonamide; [0321]
2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-
-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide;
[0322]
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide; [0323]
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl}propane-1-sulfonamide; [0324]
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl}-2,2,2-trifluoroethanesulfonamide;
[0325]
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl}-N'-methylsulfuric diamide; [0326]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrah-
ydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide; [0327]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrah-
ydro-2H-pyran-3-yloxy)phenyl]propane-1-sulfonamide; [0328]
2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-
-4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide;
[0329]
N-methyl-N'-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-
-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]sulfuric diamide; [0330]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrah-
ydro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide; [0331]
N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-
-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide; [0332]
5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylami-
no)pyridine-3-sulfonamide; [0333]
N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(-
phenylamino)pyridine-3-sulfonamide; [0334]
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)phenyl]-2-fluoroethanesulfonamide; [0335]
2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)--
4-(2,4,6-trifluorophenoxy)phenyl]ethanesulfonamide; [0336]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]propane-1-sulfonamide; [0337]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-N-(pyrimidin-2-yl)benzamide; [0338]
4-(2,4-difluorophenoxy)-N-(2,6-dimethoxypyridin-3-yl)-3-(6-methyl-7-oxo-6-
,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide; [0339]
4-(2,4-difluorophenoxy)-N-(1H-indazol-6-yl)-3-(6-methyl-7-oxo-6,7-dihydro-
-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide; [0340]
4-[2-(2,4-difluorophenoxy)-5-{[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]-
carbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;
[0341]
4-(2,4-difluorophenoxy)-N-[4-(dimethylamino)phenyl]-3-(6-methyl-7--
oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide; [0342]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-N-(pyridin-4-ylmethyl)benzamide; [0343]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide; [0344]
4-(2,4-difluorophenoxy)-N-(2-hydroxy-2-methylpropyl)-3-(6-methyl-7-oxo-6,-
7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide; [0345]
4-(2,4-difluorophenoxy)-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3-(6-methyl--
7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide; [0346]
N-(3,4-difluorobenzyl)-4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihy-
dro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide; [0347]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide; [0348]
2-{4-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,-
3-c]pyridin-4-yl)benzoyl]piperazin-1-yl}-N,N-dimethylacetamide;
[0349]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzamide; [0350]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-N-(pyridin-2-ylmethyl)benzamide; [0351]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-N-(3,4,5-trimethoxybenzyl)benzamide; [0352]
4-(2,4-difluorophenoxy)-N-[2-(dimethylamino)ethyl]-3-(6-methyl-7-oxo-6,7--
dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide; [0353]
N-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2,4-difluorophenoxy)-3-(6-methyl-7-o-
xo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide; [0354]
4-(2,4-difluorophenoxy)-N-[2-(1H-indol-3-yl)ethyl]-3-(6-methyl-7-oxo-6,7--
dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide; [0355]
4-[2-(2,4-difluorophenoxy)-5-{[4-(furan-2-ylcarbonyl)piperazin-1-yl]carbo-
nyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;
[0356] tert-butyl
{1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)benzoyl]piperidin-4-yl}carbamate; [0357] tert-butyl
4-{[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)benzoyl]amino}piperidine-1-carboxylate; [0358]
4-[2-(2,4-difluorophenoxy)-5-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}p-
henyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0359]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one; [0360]
4-[2-(4-chlorobenzoyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyrid-
in-7-one; [0361]
4-{2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyr-
rolo[2,3-c]pyridin-7-one; [0362]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyrimi-
din-5-yloxy)phenyl]ethanesulfonamide; [0363]
N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[(1-met-
hyl-1H-pyrazol-5-yl)methoxy]phenyl}ethanesulfonamide; [0364]
N-{4-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]-3-(6-methyl-7-oxo-6,7-dihydr-
o-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide; [0365]
N-[4-(2,2-dimethylpropoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]ethanesulfonamide; [0366]
N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]ethanesulfonamide; [0367]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)benzenesulfonamide; [0368]
4-[2-(cyclohexylamino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0369]
4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo-
[2,3-d]pyridazin-7-one; [0370]
4-[2-(2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0371]
4-[2-(3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0372]
4-[2-(4-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0373]
4-[2-(2-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0374]
4-[2-(3-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0375]
4-[2-(4-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0376]
3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methyl-
sulfonyl)phenoxy]benzonitrile; [0377]
4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methyl-
sulfonyl)phenoxy]benzonitrile; [0378]
6-methyl-4-{5-(methylsulfonyl)-2-[3-(trifluoromethyl)phenoxy]phenyl}-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0379]
4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one; [0380]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d-
]pyridazin-4-yl)phenyl]methanesulfonamide; [0381]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d-
]pyridazin-4-yl)phenyl]ethanesulfonamide; [0382]
4-[2-(isoquinolin-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one; [0383]
6-methyl-4-[5-(methylsulfonyl)-2-(quinolin-6-yloxy)phenyl]-1,6-dihydro-7H-
-pyrrolo[2,3-c]pyridin-7-one; [0384]
4-{2-[2-chloro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-me-
thyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0385]
4-{2-[2-fluoro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-me-
thyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0386]
2-{4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(met-
hylsulfonyl)phenoxy]phenyl}acetamide; [0387]
4-[2-(3-aminophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one; [0388]
6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylamino)phenyl]-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0389]
4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one; [0390]
4-{2-[(4,4-difluorocyclohexyl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0391]
4-{5-(ethylsulfonyl)-2-[(1-methylpiperidin-4-yl)oxy]phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0392]
4-[2-(2,1,3-benzothiadiazol-4-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0393]
4-[2-(isoquinolin-7-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one; [0394]
4-[2-(2,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one; [0395]
4-[2-(3,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one; [0396]
6-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]ph-
enyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0397]
4-[2-(3,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one; [0398]
6-methyl-4-[2-(4-methylphenoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0399]
4-[2-(2-methoxyphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-
-pyrrolo[2,3-c]pyridin-7-one; [0400]
6-methyl-4-{2-[(2-methylpyridin-3-yl)oxy]-5-(methylsulfonyl)phenyl}-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0401]
4-{2-[3-(dimethylamino)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0402]
6-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]ph-
enyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0403]
6-methyl-4-{5-(methylsulfonyl)-2-[(3-oxo-2,3-dihydro-1H-inden-5-yl)oxy]ph-
enyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0404]
2-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methyl-
sulfonyl)phenoxy]benzonitrile; [0405]
4-[2-(3-chloro-2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0406]
6-methyl-4-[5-(methylsulfonyl)-2-(naphthalen-1-yloxy)phenyl]-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one; [0407]
4-[2-(2-fluoro-5-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0408]
4-[2-(5-fluoro-2-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0409]
6-methyl-4-[5-(methylsulfonyl)-2-(quinolin-7-yloxy)phenyl]-1,6-dihydro-7H-
-pyrrolo[2,3-c]pyridin-7-one; [0410]
4-[2-(4-chloro-3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0411]
6-methyl-4-[5-(methylsulfonyl)-2-(pyridin-3-yloxy)phenyl]-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0412]
4-[2-(2,3-dihydro-1H-inden-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0413]
6-methyl-4-{5-(methylsulfonyl)-2-[4-(propan-2-yl)phenoxy]phenyl}-1,6-dihy-
dro-7H-pyrrolo[2,3-c]pyridin-7-one; [0414]
4-[2-(isoquinolin-8-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one; [0415]
6-methyl-4-[5-(methylsulfonyl)-2-(3,4,5-trifluorophenoxy)phenyl]-1,6-dihy-
dro-7H-pyrrolo[2,3-c]pyridin-7-one; [0416]
4-(2-benzylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;
[0417]
4-(biphenyl-2-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7--
one; [0418]
4-[2-(1,4-dioxaspiro[4.5]dec-8-yloxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0419]
4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one; [0420]
4-{5-(ethylsulfonyl)-2-[(4-oxocyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one; [0421]
4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0422]
6-methyl-4-{5-(methylsulfonyl)-2-[(tetrahydrofuran-3-ylmethyl)amino]pheny-
l}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0423]
4-{5-(ethylsulfonyl)-2-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0424]
4-{5-(ethylsulfonyl)-2-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0425]
4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-d]pyridazin-7-one; [0426]
6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-yloxy)phenyl]-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0427]
4-{2-[(3-fluorooxetan-3-yl)methoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0428]
6-(cyclopropylmethoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)pyridine-3-sulfonamide; [0429]
6-(cyclopropylmethoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[-
2,3-c]pyridin-4-yl)pyridine-3-sulfonamide; [0430]
6-[(cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-
-c]pyridin-4-yl)pyridine-3-sulfonamide; [0431]
6-[(cyclopropylmethyl)amino]-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide; [0432]
4-{5-(ethylsulfonyl)-2-[(cis-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6-m-
ethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0433]
4-{5-(ethylsulfonyl)-2-[(trans-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6-
-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0434]
4-[2-(cyclobutyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-py-
rrolo[2,3-c]pyridin-7-one; [0435]
4-[2-(cyclopentylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one; [0436]
4-[2-(cyclohexyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-py-
rrolo[2,3-c]pyridin-7-one; [0437]
4-[2-(cyclopentyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one; [0438]
6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylmethoxy)phenyl]-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0439]
6-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxoimidazolidin-1-yl)ethoxy]phenyl-
}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0440]
4-[2-(2-cyclopropylethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one; [0441]
4-[2-(cycloheptyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one; [0442]
6-methyl-4-[2-(2-methylpropoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0443]
6-methyl-4-[2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(methylsulfonyl)p-
henyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0444]
6-methyl-4-{2-[(2-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0445]
4-[2-(cyclohexylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one; [0446]
6-methyl-4-{2-[2-(1-methylpyrrolidin-2-yl)ethoxy]-5-(methylsulfonyl)pheny-
l}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0447]
6-methyl-4-[5-(methylsulfonyl)-2-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}phen-
yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0448]
6-methyl-4-{5-(methylsulfonyl)-2-[2-(morpholin-4-yl)ethoxy]phenyl}-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0449]
6-methyl-4-[5-(methylsulfonyl)-2-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}phen-
yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0450]
4-{2-[(1-tert-butoxypropan-2-yl)oxy]-5-(methylsulfonyl)phenyl}-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0451]
4-{2-[(1S,4R)-bicyclo[2.2.1]hept-2-ylmethoxy]-5-(methylsulfonyl)phenyl}-6-
-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0452]
6-methyl-4-{2-[(1-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0453]
6-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]phenyl}--
1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0454]
6-methyl-4-{2-[(4-methylcyclohexyl)oxy]-5-(methylsulfonyl)phenyl}-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0455]
4-[2-(cyclobutylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one; [0456]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]cyclopropanesulfonamide; [0457]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-2-methoxyethanesulfonamide; [0458]
6-methyl-4-{5-(methylsulfonyl)-2-[tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy]ph-
enyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0459]
4-[(cyclopropylmethyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-
-c]pyridin-4-yl)benzenesulfonamide; [0460]
4-[(cyclopropylmethyl)amino]-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-c]pyridin-4-yl)benzenesulfonamide; [0461]
4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-
-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0462]
4-(4-bromo-2-methoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-
-7-one; [0463]
6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)pyridine-3-sulfonamide; [0464]
4-{2-(cyclopropylmethoxy)-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0465]
4-{2-[(cyclopropylmethyl)amino]-5-[(trifluoromethyl)sulfonyl]phenyl}-6-me-
thyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0466]
6-[(cyclopropylmethyl)amino]-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1-
H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide; [0467]
6-(2,4-difluorophenoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo-
[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide; [0468]
4-[2-(cyclopropylmethoxy)-6-methylphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo-
[2,3-c]pyridin-7-one; [0469]
4-{5-(ethylsulfonyl)-2-[(cis-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0470]
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)benzenesulfonamide; [0471]
4-(cyclopropylmethoxy)-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[-
2,3-c]pyridin-4-yl)benzenesulfonamide; [0472]
N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide; [0473]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-d-
ihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide; [0474]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N-ethyl-6-methyl-7-o-
xo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide; [0475]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-N-(2,-
2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;
[0476]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(m-
orpholin-4-ylcarbonyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;
[0477]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methy-
lpiperazin-1-yl)carbonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;
[0478]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-ox-
o-N-(1,3-thiazol-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-
; [0479] ethyl
4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methyl-
sulfonyl)phenoxy]piperidine-1-carboxylate; [0480]
4-[2-ethoxy-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-
-c]pyridin-7-one; [0481]
4-{5-(ethylsulfonyl)-2-[(trans-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0482]
4-{2-[(cyclopropylmethyl)amino]-5-(propan-2-ylsulfonyl)phenyl}-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0483]
N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide; [0484]
N-[4-(cyclopropylmethoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide; [0485]
4-[5-(ethylsulfonyl)-2-(tetrahydro-2H-thiopyran-4-yloxy)phenyl]-6-methyl--
1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0486]
4-{2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(ethylsulfonyl)phen-
yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0487]
6-(2,4-difluorophenoxy)-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyr-
rolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide; [0488]
4-[2-(cyclopropylamino)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one; [0489]
4-(5-(ethylsulfonyl)-2-(cis-4-methoxy-4-methylcyclohexyloxy)phenyl)-6-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one; [0490]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N,N,6-trimethyl-7-ox-
o-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide; [0491]
6-methyl-4-{5-(methylsulfonyl)-2-[4-(methylsulfonyl)phenoxy]phenyl}-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0492]
4-[2-(2,4-difluorophenoxy)-5-(propan-2-ylsulfonyl)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0493]
6-(cyclopropylmethoxy)-N,N-diethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide; [0494]
4-(cyclopropylmethoxy)-N,N-dimethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrr-
olo[2,3-c]pyridin-4-yl)benzenesulfonamide; [0495]
4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-1,6-dihydro-7H-pyrrolo-
[2,3-c]pyridin-7-one; [0496]
4-[2-(2,4-difluorophenoxy)-5-(trifluoromethyl)phenyl]-6-methyl-1,6-dihydr-
o-7H-pyrrolo[2,3-c]pyridin-7-one; [0497]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(hydroxymethyl)-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0498]
4-[2-(2,3-dihydro-1H-inden-2-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0499]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(1-hydroxyethyl)-6-
-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0500]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-[(dimethylamino)me-
thyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0501]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(morpholi-
n-4-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0502]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methy-
lpiperazin-1-yl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;
[0503]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(phenyla-
mino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0504]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(1,3-thi-
azol-2-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;
[0505]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(tetrahy-
drofuran-3-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;
[0506]
4-[2-(cyclopropylmethoxy)-5-(phenylsulfonyl)phenyl]-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0507]
4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0508]
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0509]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridin-3-yl]-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0510]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(pyridin-
-3-yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0511]
4-[5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0512]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(prop-1-e-
n-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0513]
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(phenoxym-
ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0514]
4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0515]
4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)pyridin-3-yl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0516]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-2-(morpholin-4-yl)ethanesulfonamide; [0517]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-N-[2-(dimethylamino)ethyl]ethanesulfonamide;
[0518]
4-{2-(2,4-difluorophenoxy)-5-[(ethylsulfonyl)methyl]phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0519]
4-{2-(2,4-difluorophenoxy)-5-[2-(ethylsulfonyl)propan-2-yl]phenyl}-6-meth-
yl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0520]
4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0521]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-2-(dimethylamino)ethanesulfonamide; [0522]
ethyl
4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenoxy]piperidine-1-carboxylate; [0523]
4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0524]
4-{2-[(1-acetylpiperidin-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0525]
4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenoxy]benzonitrile; [0526]
4-[2-(cyclopropylmethoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0527]
4-{2-(2,4-difluorophenoxy)-5-[(phenylsulfonyl)methyl]phenyl}-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0528]
4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(pyrrolidin-1-ylsulfonyl)phenyl-
}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0529]
4-{2-(cyclopropylmethoxy)-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]phenyl}--
6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0530]
4-{2-[2-(2-hydroxyethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0531]
4-[2-(cyclopropylmethoxy)-5-{[3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}p-
henyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0532]
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]pyridin-3-yl}-6-meth-
yl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0533] tert-butyl
4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenoxy]piperidine-1-carboxylate; [0534]
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-phenylbenzenesulfonamide; [0535]
4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylmethyl)phenyl]-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0536]
4-[2-(cyclopropylmethoxy)-5-(pyridin-3-yl)phenyl]-6-methyl-1,6-dihydro-7H-
-pyrrolo[2,3-c]pyridin-7-one; [0537]
4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylmethyl)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0538]
4-{5-(ethylsulfonyl)-2-[3-(hydroxymethyl)phenoxy]phenyl}-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0539]
4-[2-(cyclopropylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0540]
4-[2-(2,4-difluorophenoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6-
-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0541]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4--
c]pyridin-4-yl)phenyl]ethanesulfonamide; [0542]
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-
-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one; [0543]
4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrazolo[3,4-c]pyridin-7-one; [0544]
4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrazolo[3,4-c]pyridin-7-one; [0545]
N-[2-cyano-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide; [0546] tert-butyl
4-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate; [0547]
4-[5-(6-aminopyridin-3-yl)-2-(cyclopropylmethoxy)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0548]
4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-
-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-ca-
rboxamide; [0549]
4-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methy-
l-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0550]
4-{2-[(cyclopropylmethyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0551]
4-[5-(ethylsulfonyl)-2-(pyrrolidin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one; [0552]
4-[5-(ethylsulfonyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-methyl-1,6-dihyd-
ro-7H-pyrrolo[2,3-c]pyridin-7-one; [0553]
4-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihyd-
ro-7H-pyrrolo[2,3-c]pyridin-7-one; [0554]
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide; [0555]
4-[4-(cyclopropylmethoxy)-3'-fluorobiphenyl-3-yl]-6-methyl-1,6-dihydro-7H-
-pyrrolo[2,3-c]pyridin-7-one; [0556]
4-{2-[(4-fluorophenyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0557]
[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)phenyl]acetonitrile; [0558]
N-{4-(2,4-difluorophenoxy)-3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydr-
o-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide; [0559]
N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)carbony-
l]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamid-
e; [0560]
N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-y-
l)methyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesul-
fonamide; [0561]
4-[2-(cyclopropylmethoxy)-5-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-6-met-
hyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0562]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-N-(2-methoxyethyl)ethanesulfonamide; [0563]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-N-(pyridin-2-ylmethyl)ethanesulfonamide;
[0564]
N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-di-
hydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;
[0565]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]ethanesulfonamide;
[0566]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl]-N-(tetrahydrofuran-2-ylmethyl)ethanesulfonami-
de; [0567]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyr-
rolo[2,3-c]pyridin-4-yl)phenyl]-N-(3,3,3-trifluoropropyl)ethanesulfonamide-
; [0568]
4-(cyclopropylmethoxy)-N-(4-fluorophenyl)-3-(6-methyl-7-oxo-6,7-d-
ihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide; [0569]
4-[2-(cyclopropylmethoxy)-5-(6-fluoropyridin-3-yl)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0570]
N-[4-(2,4-difluorophenoxy)-3-(3-formyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrr-
olo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide; [0571]
N-{4-(2,4-difluorophenoxy)-3-[6-methyl-3-(morpholin-4-ylmethyl)-7-oxo-6,7-
-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide;
[0572]
N-[4-(2,4-difluorophenoxy)-3-{6-methyl-3-[(4-methylpiperazin-1-yl)methyl]-
-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide;
[0573]
4-{2-[(cyclopropylmethyl)amino]phenyl}-6-methyl-1,6-dihydro-7H-pyr-
rolo[2,3-c]pyridin-7-one; [0574]
4'-(cyclopropylmethoxy)-3'-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]p-
yridin-4-yl)biphenyl-3-carbonitrile; and [0575]
4-{2-(cyclopropylmethoxy)-5-[(4-hydroxypiperidin-1-yl)sulfonyl]phenyl}-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.
[0576] In certain embodiments, a compound of formula I is selected
from the group consisting of: [0577]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]ethanesulfonamide; [0578]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]methanesulfonamide; [0579]
6-methyl-4-[5-(methylsulfonyl)-2-phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,-
3-c]pyridin-7-one; [0580]
N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(-
tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide; [0581]
N-[4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[-
2,3-c]pyridin-4-yl)phenyl]methanesulfonamide; [0582]
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro--
1H-pyrrolo[2,3-c]pyridine-2-carboxamide; [0583]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-
phenyl]methanesulfonamide; [0584]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6--
trifluorophenoxy)phenyl]ethanesulfonamide; [0585]
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl}methanesulfonamide; and [0586]
N-[4-(4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)phenyl]methanesulfonamide; or a pharmaceutically
acceptable salt thereof.
[0587] In certain embodiments, a compound of formula I is selected
from the group consisting of: [0588]
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]pyridin-3-yl}-6-meth-
yl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0589]
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]ethanesulfonamide; [0590]
4-(cyclopropylmethoxy)-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[-
2,3-c]pyridin-4-yl)benzenesulfonamide; [0591]
4-{2-[(4,4-difluorocyclohexyl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0592]
4-(5-(ethylsulfonyl)-2-(cis-4-methoxy-4-methylcyclohexyloxy)phenyl)-6-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one; [0593]
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro--
1H-pyrrolo[2,3-c]pyridine-2-carboxamide; [0594]
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0595]
4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one; [0596]
4-{5-(ethylsulfonyl)-2-[(trans-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0597]
4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one; [0598]
4-[(cyclopropylmethyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-
-c]pyridin-4-yl)benzenesulfonamide; [0599]
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)benzenesulfonamide; [0600]
4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one; [0601]
4-[2-(cyclohexyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-py-
rrolo[2,3-c]pyridin-7-one; and [0602]
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-
phenyl]ethanesulfonamide; [0603] or a pharmaceutically acceptable
salt thereof.
[0604] In certain embodiments, a compound of the present invention
is
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenyl]ethanesulfonamide, or a pharmaceutically
acceptable salt thereof.
[0605] Compounds of formula I can be used in the form of
pharmaceutically acceptable salts. The phrase "pharmaceutically
acceptable salt" means those salts which are, within the scope of
sound medical judgement, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity,
irritation, allergic response and the like and are commensurate
with a reasonable benefit/risk ratio.
[0606] Pharmaceutically acceptable salts have been described in S.
M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.
[0607] Compounds of formula (I) may contain either a basic or an
acidic functionality, or both, and can be converted to a
pharmaceutically acceptable salt, when desired, by using a suitable
acid or base. The salts may be prepared in situ during the final
isolation and purification of the compounds of the invention.
[0608] Examples of acid addition salts include, but are not limited
to acetate, adipate, alginate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate,
malate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Also, the basic
nitrogen-containing groups can be quaternized with such agents as
lower alkyl halides such as, but not limited to, methyl, ethyl,
propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates
like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain
halides such as, but not limited to, decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides; arylalkyl halides like
benzyl and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained. Examples of acids which
may be employed to form pharmaceutically acceptable acid addition
salts include such inorganic acids as hydrochloric acid,
hydrobromic acid, sulfuric acid, and phosphoric acid and such
organic acids as acetic acid, fumaric acid, maleic acid,
4-methylbenzenesulfonic acid, succinic acid and citric acid.
[0609] Basic addition salts may be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as, but not limited to, the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with
ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts include, but are not limited to,
cations based on alkali metals or alkaline earth metals such as,
but not limited to, lithium, sodium, potassium, calcium, magnesium
and aluminum salts and the like and nontoxic quaternary ammonia and
amine cations including ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine and the like. Other
examples of organic amines useful for the formation of base
addition salts include ethylenediamine, ethanolamine,
diethanolamine, piperidine, piperazine and the like.
[0610] The term "pharmaceutically acceptable prodrug" or "prodrug"
as used herein, represents those prodrugs of the compounds of the
present invention which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use.
[0611] The present invention contemplates compounds of formula (I)
formed by synthetic means or formed by in vivo biotransformation of
a prodrug.
[0612] Compounds described herein can exist in unsolvated as well
as solvated forms, including hydrated forms, such as hemi-hydrates.
In general, the solvated forms, with pharmaceutically acceptable
solvents such as water and ethanol among others are equivalent to
the unsolvated forms for the purposes of the invention.
General Synthesis
[0613] The compounds described herein, including compounds of
general formula (I) and specific examples, may be prepared, for
example, through the reaction routes depicted in schemes 1-5. The
variables A.sup.1, A.sup.2, A.sup.3, A.sup.4, X.sup.1, X.sup.2,
Y.sup.1, L.sup.1, G.sup.1, R.sup.x, and R.sup.y used in the
following schemes have the meanings as set forth in the summary and
detailed description sections unless otherwise noted.
[0614] Abbreviations used in the descriptions of the schemes and
the specific examples have the following meanings: n-BuLi or BuLi
for n-butyl lithium, DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene,
DIAD for diisopropyl azodicarboxylate; DME for 1,2-dimethoxyethane,
DMF for dimethylformamide, DMSO for dimethyl sulfoxide, EtOAc for
ethyl acetate; mCPBA for 3-chloroperbenzoic acid, MeOH for
methanol; Pd(PPh.sub.3).sub.4 for
tetrakis(triphenylphosphine)palladium(0), Preparative HPLC for
preparative HPLC; THF for tetrahydrofuran, TFA for trifluoroacetic
acid, and HPLC for high performance liquid chromatography.
[0615] Compounds of general formula (I) may be prepared (a) by
treating an aryl halide, an aryl mesylate, or an aryl triflate with
an aryl boronic acid or derivatives thereof (e.g. boronic esters)
under Suzuki coupling condition (N. Miyama and A. Suzuki, Chem.
Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147-148),
and (b) removal of the protecting group (PG), as illustrated in
Scheme 1. Thus coupling of compounds of formula (1) wherein
R.sup.101 is Br, Cl, mesylate, or triflate with compounds of
formula (2) wherein R.sup.102 is boronic acid or derivatives
thereof (e.g. boronic esters), or coupling of (1) wherein R.sup.101
is boronic acid or derivatives thereof (e.g. boronic esters) with
compounds (2) wherein R.sup.102 is Br, Cl, mesylate, or triflate,
provides intermediates of formula (3). Generally, the coupling
reaction is effected in the presence of a palladium catalyst and a
base, and optionally in the presence of a ligand, and in a suitable
solvent at elevated temperature (for example, at about 80.degree.
C. to about 150.degree. C.). The reaction may be facilitated by
microwave irradiation. Examples of the palladium catalyst include,
but are not limited to, tetrakis(triphenylphosphine)palladium(0),
tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate.
Examples of suitable bases that may be employed include, but are
not limited to, carbonates or phosphates of sodium, potassium, and
cesium; and cesium fluoride. Examples of suitable ligands include,
but are not limited to,
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), and
1,1'-bis(diphenylphosphanyl)ferrocene. Non-limiting examples of
suitable solvent include methanol, dimethoxyethane,
N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydropyran,
and water, or a mixture thereof.
[0616] Alternatively, treatment of formula (1) wherein R.sup.101 is
Br, Cl, or triflate with boronic acid of formula (4), followed by
displacement of the fluoride atom in (4) with an appropriate
alcohol or amine of formula G.sup.1-L.sup.1-H wherein L.sup.1 is O
or NH, provides compounds of formula (3) or formula (I) wherein
R.sup.x is hydrogen.
[0617] Displacement of the fluorine with an alcohol or amine may be
achieved in a solvent such as, but not limited to,
dimethylsulfoxide, dimethylformamide, dioxane, or tetrahydrofuran,
and in the presence of a base such as, but not limited to, cesium
carbonate, potassium carbonate, or sodium hydride and at a
temperature from about 40.degree. C. to about 120.degree. C.
[0618] The protecting group (PG) may be removed in situ during the
displacement reaction or the coupling conditions described
above.
[0619] Alternatively, removal of the protecting group (PG) to
afford compounds of general formula (I) wherein R.sup.x is hydrogen
can be accomplished using reaction conditions known generally to
one skilled in the art, or modifications thereof. For example, the
tosyl protecting group can be removed in the presence of a base
such as, but not limited to, cesium carbonate, sodium hydroxide, or
sodium hydride. The reaction is generally performed in the presence
of a suitable solvent such as, but not limited to,
dimethylsulfoxide, methanol, or tetrahydrofuran, and at a
temperature of about 40.degree. C. to about 120.degree. C. The
benzyl protecting group may be removed by hydrogenation in the
presence of a catalyst such as, but not limited to, palladium on
carbon and under hydrogen atmosphere. The reaction is typically
performed in the presence of a solvent such as, but not limited to,
methanol or ethyl acetate, and at about room temperature.
[0620] Removal of the (trimethylsilyl)ethoxy)methyl protecting
group can be achieved by treatment with a base such as, but not
limited to, cesium carbonate or sodium hydride, or with a fluoride
reagent such as, but not limited to, TBAF (tetrabutylammonium
fluoride). The reaction is generally performed in the presence of a
suitable solvent such as, but not limited to, dimethylsulfoxide,
ethanol, or tetrahydrofuran, and at a temperature of about
40.degree. C. to about 120.degree. C. Removal of the
(trimethylsilyl)ethoxy)methyl protecting group can also be achieved
by treatment with an mild acid such as but not limited to, aqueous
hydrochloric acid. The reaction is generally performed in the
presence of a suitable solvent such as, but not limited to,
ethanol, or methanol, and at a temperature of about 25.degree. C.
to about 80.degree. C.
[0621] Conversion of compounds of formula (I) wherein R.sup.x is
hydrogen to (I) wherein R.sup.x is C.sub.1-C.sub.3 alkyl can be
achieved with an alkylating agent of formula R.sup.xR.sup.103
wherein R.sup.103 is halogen, triflate, or mesylate. Generally, the
reaction may be conducted in the presence of a base such as, but
not limited to, sodium hydride or potassium carbonate, and in a
solvent such as, but not limited to, tetrahydrofuran or
dimethylformamide, and at a temperature of about 40.degree. C. to
about 120.degree. C.
##STR00008##
[0622] Compounds of formula (1) wherein Y.sup.1 is CR.sup.u,
X.sup.1 and X.sup.2 are CH, and R.sup.u is hydrogen, Scheme 2.
[0623] Treatment of compounds of formula (6) wherein halo is Br,
Cl, or I, with 1,1-dimethoxy-N,N-dimethylmethanamine at elevated
temperature (e.g. about 60.degree. C. to about 100.degree. C.), in
the absence or presence of a base, and in a solvent such as, but
not limited to, DMF, provide compounds of formula (7). Examples of
suitable bases include, but not limited to, lithium or sodium
methanolate. Catalytic hydrogenation of (7) in the presence of a
catalyst such as, but not limited to, Raney-Nickel and under
hydrogen atmosphere (about 30 psi) and in a solvent such as, but
not limited to, ethyl acetate, at about room temperature generally
affords compounds of formula (8). Protection of the nitrogen atom
with protecting group such as, but not limited to, benzyl, tosyl,
and (trimethylsilyl)ethoxy)methyl group can be derived from
reaction with an appropriate halide in the presence of a strong
base such as, but not limited to, sodium hydride, to provide
compounds of formula (9).
[0624] Treatment of (9) with an acid such as, but not limited to,
hydrochloric acid or hydrobromic acid and in a solvent such as, but
not limited to, dioxane or water, at about 40.degree. C. to about
100.degree. C., typically provides compounds of formula (10).
[0625] Alkylation of (10) with a halide or mesylate, in the
presence of a base such as, but not limited to, sodium hydride,
cesium carbonate, or potassium carbonate, and in a solvent such as,
but not limited to, dimethylformamide or dimethylsulfoxide at a
temperature of about 0.degree. C. to about 50.degree. C. typically
provides compounds of formula (11).
[0626] Treatment of the compounds of formula (11) with
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
generally affords compounds of formula (12). In general, the
conversion may be facilitated by a palladium catalyst such as, but
not limited to, tetrakis(triphenylphosphine)palladium(0),
tris(dibenzylideneacetone)dipalladium(0), or palladium(II)acetate,
an optional ligand such as, but not limited to,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), or
1,1'-bis(diphenylphosphanyl)ferrocene, and a base such as, but not
limited to, carbonates, acetates, or phosphates of sodium,
potassium, and cesium; and cesium fluoride. Non-limiting examples
of suitable solvents include methanol, dimethoxyethane,
N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydropyran,
and water, or a mixture thereof.
##STR00009##
[0627] An approach to prepare compounds of formula (1) wherein
Y.sup.1 is N, R.sup.101 is Cl, and X.sup.1 and X.sup.2 are CH, is
outlined in Scheme 3.
[0628] Treatment of (13) with ammonium hydroxide at about
100.degree. C. to about 150.degree. C. can afford amines of formula
(14).
[0629] Iodination of (14) with N-iodosuccinimide in a solvent such
as, but not limited to, acetonitrile or acetone, at a temperature
of about 40.degree. C. to about 85.degree. C., typically yields
compounds of formula (15). Subsequent coupling with
(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
utilizing Suzuki coupling reaction conditions as described in
Scheme 1 provides compounds of formula (16). Cyclization of (16)
followed by protection of the nitrogen atom typically affords
compounds of formula (17).
[0630] Cyclization of (16) may be accomplished in the presence of
an acid such as, but not limited to, acetic acid or hydrochloric
acid and at an elevated temperature (e.g. about 50.degree. C. to
about 100.degree. C.).
##STR00010##
[0631] Compounds of formula (1) wherein Y.sup.1 is N, R.sup.101 is
Cl, X.sup.1 is --COOR.sup.ax1 or --C(O)NR.sup.bx1R.sup.cx1,
R.sup.ax1, R.sup.bx1, and R.sup.cx1 are hydrogen or C.sub.1-C.sub.6
alkyl, and X.sup.2 is CH may be prepared using the synthetic route
exemplified in Scheme 4.
[0632] Treatment of (15) with pyruvic acid in the presence of a
palladium catalyst such as, but not limited to,
palladium(II)acetate, and a base such as, but not limited to, DBU,
and in a solvent such as, but not limited to, DMF and at elevated
temperature (e.g. at about 80.degree. C. to about 150.degree. C.)
generally results in acids of formula (18). Esterification of (18)
to (19) may be accomplished by reaction conditions known to one
skilled in the art, for example, by treatment with an alcohol under
acidic condition. Subsequent protection of (19) using reaction
conditions described in Scheme 2 for the conversion of (8) to (9)
can provide for compounds of formula (20). Transformation of (20)
to (21) may be accomplished by step-wise reaction of (a) hydrolysis
of the ester to the corresponding acid and (b) conversion of the
acid to the corresponding amides.
[0633] The acid can be transformed to the appropriate acid chloride
by treatment with oxalyl chloride in the presence of catalytic
amount of DMF at about room temperature, and in a suitable solvent
such as, but not limited to, tetrahydrofuran or
dichloromethane.
[0634] The resulting acid chloride may be converted to amides of
formula (21) by treatment with an amine of formula
HNR.sup.bx1R.sup.cx1 in a solvent such as, but not limited to,
tetrahydrofuran, dimethylformamide, or dichloromethane at a
temperature from about room temperature to about 50.degree. C.,
optionally in the presence of a base such as, but not limited to,
triethylamine, diisopropylethylamine, or potassium carbonate, and
optionally in the presence of a catalyst such as
4-dimethylaminopyridine. Alternatively, the acid can be reacted
with the amine of formula HNR.sup.bx1R.sup.cx1 in a solvent such
as, but not limited to, tetrahydrofuran or dimethylformamide in the
presence of a coupling reagent such as 1,1'-carbonyldiimidazole
(CDI), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),
1,3-dicyclohexylcarbodiimide (DCC), polymer supported
1,3-dicyclohexylcarbodiimide (PS-DCC),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), or
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU), in the presence or absence of a coupling auxiliary such as,
but not limited to, 1-hydroxy-7-azabenzotriazole (HOAT) or
1-hydroxybenzotriazole hydrate (HOBT). The reaction may be
generally conducted in the presence or absence of a base such as,
but not limited to, N-methyl morpholine, triethylamine, or
diisopropylethylamine.
##STR00011##
[0635] Scheme 5 demonstrates a general approach to the preparation
of compounds of formula (1) wherein Y.sup.1 is CR.sup.u, R.sup.101
is halogen, X.sup.1 is --COOR.sup.ax1 or --C(O)NR.sup.bx1R.sup.cx1,
R.sup.ax1, R.sup.bx1, and R.sup.cx1 are hydrogen or C.sub.1-C.sub.6
alkyl, and X.sup.2 is CH.
[0636] An ester of formula (23) may be obtained from (a) treatment
of (6) with diethyl oxalate in the presence of a base such as, but
not limited to, potassium ethoxide or sodium ethoxide, in a solvent
such as, but not limited to, potassium ethoxide or sodium ethoxide,
in a solvent such as, but not limited to, ethanol, dioxane, or
diethyl ether, and at a temperature of about 40.degree. C. to about
80.degree. C.; and (b) cyclization of the resulting (22) in the
presence of iron and in ethanol and acetic acid, at a temperature
of about 80.degree. C. to about 100.degree. C. Conversion of (23)
to (26) can be achieved by employing reaction conditions discussed
above.
[0637] An ethyl ester of formula (26) may subsequently be
hydrolysed to the corresponding acids. The resulting acids may be
transformed to an appropriate ester or amide as described in Scheme
4.
##STR00012##
[0638] Optimum reaction conditions and reaction times for each
individual step may vary depending on the particular reactants
employed and substituents present in the reactants used. Unless
otherwise specified, solvents, temperatures and other reaction
conditions may be readily selected by one of ordinary skill in the
art. Specific procedures are provided in the Synthetic Examples
section. Reactions may be further processed in the conventional
manner, e.g. by eliminating the solvent from the residue and
further purified according to methodologies generally known in the
art such as, but not limited to, crystallization, distillation,
extraction, trituration and chromatography. Unless otherwise
described, the starting materials and reagents are either
commercially available or may be prepared by one skilled in the art
from commercially available materials using methods described in
the chemical literature.
[0639] Routine experimentations, including appropriate manipulation
of the reaction conditions, reagents and sequence of the synthetic
route, protection of any chemical functionality that may not be
compatible with the reaction conditions, and deprotection at a
suitable point in the reaction sequence of the method are included
in the scope of the invention. Suitable protecting groups and the
methods for protecting and deprotecting different substituents
using such suitable protecting groups are well known to those
skilled in the art; examples of which may be found in T. Greene and
P. Wuts, Protecting Groups in Chemical Synthesis (3.sup.rd ed.),
John Wiley & Sons, NY (1999), which is incorporated herein by
reference in its entirety. Synthesis of the compounds of the
invention may be accomplished by methods analogous to those
described in the synthetic schemes described hereinabove and in
specific examples.
[0640] Starting materials, if not commercially available, may be
prepared by procedures selected from standard organic chemical
techniques, techniques that are analogous to the synthesis of
known, structurally similar compounds, or techniques that are
analogous to the above described schemes or the procedures
described in the synthetic examples section.
[0641] When an optically active form of a compound of the invention
is required, it may be obtained by carrying out one of the
procedures described herein using an optically active starting
material (prepared, for example, by asymmetric induction of a
suitable reaction step), or by resolution of a mixture of the
stereoisomers of the compound or intermediates using a standard
procedure (such as chromatographic separation, recrystallization or
enzymatic resolution).
[0642] Similarly, when a pure geometric isomer of a compound of the
invention is required, it may be obtained by carrying out one of
the above procedures using a pure geometric isomer as a starting
material, or by resolution of a mixture of the geometric isomers of
the compound or intermediates using a standard procedure such as
chromatographic separation.
Pharmaceutical Compositions
[0643] This invention also provides for pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt thereof together
with a pharmaceutically acceptable carrier, diluent, or excipient
therefor. The phrase "pharmaceutical composition" refers to a
composition suitable for administration in medical or veterinary
use.
[0644] The pharmaceutical compositions that comprise a compound of
formula (I), alone or or in combination with a second active
pharmaceutical agent, may be administered to the subjects orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments or drops),
bucally or as an oral or nasal spray. The term "parenterally" as
used herein, refers to modes of administration which include
intravenous, intramuscular, intraperitoneal, intrasternal,
subcutaneous and intraarticular injection and infusion.
[0645] The term "pharmaceutically acceptable carrier" as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as, but not
limited to, lactose, glucose and sucrose; starches such as, but not
limited to, corn starch and potato starch; cellulose and its
derivatives such as, but not limited to, sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as, but not
limited to, cocoa butter and suppository waxes; oils such as, but
not limited to, peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; glycols; such a propylene
glycol; esters such as, but not limited to, ethyl oleate and ethyl
laurate; agar; buffering agents such as, but not limited to,
magnesium hydroxide and aluminum hydroxide; alginic acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as, but not limited to, sodium lauryl
sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0646] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions as well as sterile
powders for reconstitution into sterile injectable solutions or
dispersions just prior to use. Examples of suitable aqueous and
nonaqueous carriers, diluents, solvents or vehicles include water,
ethanol, polyols (such as glycerol, propylene glycol, polyethylene
glycol and the like), vegetable oils (such as olive oil),
injectable organic esters (such as ethyl oleate) and suitable
mixtures thereof. Proper fluidity can be maintained, for example,
by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions and by the use of surfactants.
[0647] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms can be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride and the like. Prolonged absorption of the
injectable pharmaceutical form can be brought about by the
inclusion of agents, which delay absorption such as aluminum
monostearate and gelatin.
[0648] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally-administered drug form may be
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0649] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0650] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0651] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In certain embodiments, solid
dosage forms may contain from 1% to 95% (w/w) of a compound of
formula I. In certain embodiments, the compound of formula I may be
present in the solid dosage form in a range of from 5% to 70%
(w/w). In such solid dosage forms, the active compound may be mixed
with at least one inert, pharmaceutically acceptable excipient or
carrier, such as sodium citrate or dicalcium phosphate and/or a)
fillers or extenders such as starches, lactose, sucrose, glucose,
mannitol and silicic acid; b) binders such as
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,
sucrose and acacia; c) humectants such as glycerol; d)
disintegrating agents such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates and sodium
carbonate; e) solution retarding agents such as paraffin; f)
absorption accelerators such as quaternary ammonium compounds; g)
wetting agents such as cetyl alcohol and glycerol monostearate; h)
absorbents such as kaolin and bentonite clay and i) lubricants such
as talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate and mixtures thereof. In the case of
capsules, tablets and pills, the dosage form may also comprise
buffering agents.
[0652] The pharmaceutical composition may be a unit dosage form. In
such form the preparation is subdivided into unit doses containing
appropriate quantities of the active component. The unit dosage
form can be a packaged preparation, the package containing discrete
quantities of preparation, such as packeted tablets, capsules, and
powders in vials or ampules. Also, the unit dosage form can be a
capsule, tablet, cachet, or lozenge itself, or it can be the
appropriate number of any of these in packaged form. The quantity
of active component in a unit dose preparation may be varied or
adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to
95% (w/w) of a unit dose, according to the particular application
and the potency of the active component. The composition can, if
desired, also contain other compatible therapeutic agents.
[0653] The dose to be administered to a subject may be determined
by the efficacy of the particular compound employed and the
condition of the subject, as well as the body weight or surface
area of the subject to be treated. The size of the dose also will
be determined by the existence, nature, and extent of any adverse
side-effects that accompany the administration of a particular
compound in a particular subject. In determining the effective
amount of the compound to be administered in the treatment or
prophylaxis of the disorder being treated, the physician can
evaluate factors such as the circulating plasma levels of the
compound, compound toxicities, and/or the progression of the
disease, etc. In general, the dose equivalent of a compound is from
about 1 .mu.g/kg to 100 mg/kg for a typical subject.
[0654] For administration, compounds of the formula I can be
administered at a rate determined by factors that can include, but
are not limited to, the LD.sub.50 of the compound, the
pharmacokinetic profile of the compound, contraindicated drugs, and
the side-effects of the compound at various concentrations, as
applied to the mass and overall health of the subject.
Administration can be accomplished via single or divided doses.
[0655] The compounds utilized in the pharmaceutical method of the
invention can be administered at the initial dosage of about 0.001
mg/kg to about 100 mg/kg daily. In certain embodiments, the daily
dose range is from about 0.1 mg/kg to about 10 mg/kg. The dosages,
however, may be varied depending upon the requirements of the
subject, the severity of the condition being treated, and the
compound being employed. Determination of the proper dosage for a
particular situation is within the skill of the practitioner.
Treatment may be initiated with smaller dosages, which are less
than the optimum dose of the compound. Thereafter, the dosage is
increased by small increments until the optimum effect under
circumstances is reached. For convenience, the total daily dosage
may be divided and administered in portions during the day, if
desired.
[0656] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
carriers as lactose or milk sugar as well as high molecular weight
polyethylene glycols and the like.
[0657] The solid dosage forms of tablets, dragees, capsules, pills
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0658] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
carriers.
[0659] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan and mixtures thereof.
[0660] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
[0661] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth and mixtures thereof.
[0662] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating carriers
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0663] Compounds of formula I may also be administered in the form
of liposomes. Liposomes generally may be derived from phospholipids
or other lipid substances. Liposomes are formed by mono- or
multi-lamellar hydrated liquid crystals which are dispersed in an
aqueous medium. Any non-toxic, physiologically acceptable and
metabolizable lipid capable of forming liposomes can be used. The
present compositions in liposome form may contain, in addition to a
compound of formula (I), stabilizers, preservatives, excipients and
the like. Examples of lipids include, but are not limited to,
natural and synthetic phospholipids and phosphatidyl cholines
(lecithins), used separately or together.
[0664] Methods to form liposomes have been described, see example,
Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press,
New York, N.Y. (1976), p. 33 et seq.
[0665] Dosage forms for topical administration of a compound
described herein include powders, sprays, ointments and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which may be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
Methods of Use
[0666] The compounds of formula I, or pharmaceutically acceptable
salts thereof, and pharmaceutical compositions comprising a
compound of formula I, or a pharmaceutically acceptable salt
thereof, can be administered to a subject suffering from a
bromodomain-mediated disorder or condition. The term
"administering" refers to the method of contacting a compound with
a subject. Thus, the compounds of formula I can be administered by
injection, that is, intravenously, intramuscularly,
intracutaneously, subcutaneously, intraduodenally, parentally, or
intraperitoneally. Also, the compounds described herein can be
administered by inhalation, for example, intranasally.
Additionally, the compounds of formula I can be administered
transdermally, topically, via implantation, transdermally,
topically, and via implantation. In certain embodiments, the
compounds of the formula I may be delivered orally. The compounds
can also be delivered rectally, bucally, intravaginally, ocularly,
andially, or by insufflation. Bromodomain-mediated disorders and
conditions can be treated prophylactically, acutely, and
chronically using compounds of formula I, depending on the nature
of the disorder or condition. Typically, the host or subject in
each of these methods is human, although other mammals can also
benefit from the administration of a compound of formula I.
[0667] A "bromodomain-mediated disorder or condition" is
characterized by the participation of one or more bromodomains
(e.g., BRD4) in the inception, manifestation of one or more
symptoms or disease markers, severity, or progression of a disorder
or condition. Accordingly, compounds of formula I may be used to
treat cancer, including, but not limited to acoustic neuroma, acute
leukemia, acute lymphocytic leukemia, acute myelocytic leukemia
(monocytic, myeloblastic, adenocarcinoma, angiosarcoma,
astrocytoma, myelomonocytic and promyelocytic), acute t-cell
leukemia, basal cell carcinoma, bile duct carcinoma, bladder
cancer, brain cancer, breast cancer, bronchogenic carcinoma,
cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic
leukemia, chronic lymphocytic leukemia, chronic myelocytic
(granulocytic) leukemia, chronic myelogenous leukemia, colon
cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,
diffuse large B-cell lymphoma, dysproliferative changes (dysplasias
and metaplasias), embryonal carcinoma, endometrial cancer,
endotheliosarcoma, ependymoma, epithelial carcinoma,
erythroleukemia, esophageal cancer, estrogen-receptor positive
breast cancer, essential thrombocythemia, Ewing's tumor,
fibrosarcoma, follicular lymphoma, germ cell testicular cancer,
glioma, glioblastoma, gliosarcoma, heavy chain disease,
hemangioblastoma, hepatoma, hepatocellular cancer, hormone
insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma,
lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma,
lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's),
malignancies and hyperproliferative disorders of the bladder,
breast, colon, lung, ovaries, pancreas, prostate, skin and uterus,
lymphoid malignancies of T-cell or B-cell origin, leukemia,
lymphoma, medullary carcinoma, medulloblastoma, melanoma,
meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,
myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC),
non-small cell lung cancer, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,
prostate cancer, rectal cancer, renal cell carcinoma,
retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland
carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid
tumors (carcinomas and sarcomas), small cell lung cancer, stomach
cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma,
thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors,
uterine cancer and Wilms' tumor.
[0668] Further, compounds of formula I may be used to treat
inflammatory diseases, inflammatory conditions, and autoimmune
diseases, including, but not limited to: Addison's disease, acute
gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's
disease, bullous skin diseases, chronic obstructive pulmonary
disease (COPD), Crohn's disease, dermatitis, eczema, giant cell
arteritis, glomerulonephritis, hepatitis, hypophysitis,
inflammatory bowel disease, Kawasaki disease, lupus nephritis,
multiple sclerosis, myocarditis, myositis, nephritis, organ
transplant rejection, osteoarthritis, pancreatitis, pericarditis,
Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis,
psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis,
sclerosing cholangitis, sepsis, systemic lupus erythematosus,
Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes,
ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's
granulomatosis.
[0669] Compounds of formula I, or pharmaceutically acceptable salts
thereof, may be used to treat AIDS.
[0670] Compounds of formula I, or pharmaceutically acceptable salts
thereof, may be used to treat chronic kidney disease or condition
including, but are not limited to: diabetic nephropathy,
hypertensive nephropathy, HIV-associated nephropathy,
glomerulonephritis, lupus nephritis, IgA nephropathy, focal
segmental glomerulosclerosis, membranous glomerulonephritis,
minimal change disease, polycystic kidney disease and tubular
interstitial nephritis.
[0671] Compounds of formula I, or pharmaceutically acceptable salts
thereof, may be used to treat acute kidney injury or disease or
condition including, but are not limited to: ischemia-reperfusion
induced, cardiac and major surgery induced, percutaneous coronary
intervention induced, radio-contrast agent induced, sepsis induced,
pneumonia induced, and drug toxicity induced.
[0672] Compounds of formula I, or pharmaceutically acceptable salts
thereof, may be used to treat obesity, dyslipidemia,
hypercholesterolemia, Alzheimer's disease, metabolic syndrome,
hepatic steatosis, type II diabetes, insulin resistance, diabetic
retinopathy or diabetic neuropathy.
[0673] Compounds of formula I, or pharmaceutically acceptable salts
thereof, may be used to provide for male contraception in a male
subject comprising administering a therapeutically effective amount
of a compound of formula (I) or a pharmaceutically acceptable salt
thereof, to a male subject in need thereof.
[0674] The compounds of formula I can be co-administered to a
subject. The term "co-administered" means the administration of two
or more different pharmaceutical agents or treatments (e.g.,
radiation treatment) that are administered to a subject by
combination in the same pharmaceutical composition or separate
pharmaceutical compositions. Thus co-administration involves
administration at the same time of a single pharmaceutical
composition comprising two or more pharmaceutical agents or
administration of two or more different compositions to the same
subject at the same or different times.
[0675] The compounds of the invention can be co-administered with a
therapeutically effective amount of one or more agents to treat a
cancer, where examples of the agents include, such as radiation,
alkylating agents, angiogenesis inhibitors, antibodies,
antimetabolites, antimitotics, antiproliferatives, antivirals,
aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL,
Bcl-w and Bfl-1) inhibitors, activators of death receptor pathway,
Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager)
antibodies, antibody drug conjugates, biologic response modifiers,
cyclin-dependent kinase inhibitors, cell cycle inhibitors,
cyclooxygenase-2 inhibitors, DVDs (dual variable domain
antibodies), leukemia viral oncogene homolog (ErbB2) receptor
inhibitors, growth factor inhibitors, heat shock protein (HSP)-90
inhibitors, histone deacetylase (HDAC) inhibitors, hormonal
therapies, immunologicals, inhibitors of inhibitors of apoptosis
proteins (IAPs), intercalating antibiotics, kinase inhibitors,
kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin
inhibitors, microRNA's, mitogen-activated extracellular
signal-regulated kinase inhibitors, multivalent binding proteins,
non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine
diphosphate)-ribose polymerase (PARP) inhibitors, platinum
chemotherapeutics, polo-like kinase (Plk) inhibitors,
phosphoinositide-3 kinase (bromodomain) inhibitors, proteosome
inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine
kinase inhibitors, etinoids/deltoids plant alkaloids, small
inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,
ubiquitin ligase inhibitors, and the like, and in combination with
one or more of these agents.
[0676] BiTE antibodies are bi-specific antibodies that direct
T-cells to attack cancer cells by simultaneously binding the two
cells. The T-cell then attacks the target cancer cell. Examples of
BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab
(Micromet MT103) and the like. Without being limited by theory, one
of the mechanisms by which T-cells elicit apoptosis of the target
cancer cell is by exocytosis of cytolytic granule components, which
include perforin and granzyme B. In this regard, Bcl-2 has been
shown to attenuate the induction of apoptosis by both perforin and
granzyme B. These data suggest that inhibition of Bcl-2 could
enhance the cytotoxic effects elicited by T-cells when targeted to
cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani, J. of
Immunology 1997, 158 (12), 5783).
[0677] SiRNAs are molecules having endogenous RNA bases or
chemically modified nucleotides. The modifications do not abolish
cellular activity, but rather impart increased stability and/or
increased cellular potency. Examples of chemical modifications
include phosphorothioate groups, 2'-deoxynucleotide,
2'-OCH.sub.3-containing ribonucleotides, 2'-F-ribonucleotides,
2'-methoxyethyl ribonucleotides, combinations thereof and the like.
The siRNA can have varying lengths (e.g., 10-200 bps) and
structures (e.g., hairpins, single/double strands, bulges,
nicks/gaps, mismatches) and are processed in cells to provide
active gene silencing. A double-stranded siRNA (dsRNA) can have the
same number of nucleotides on each strand (blunt ends) or
asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be
present on the sense and/or the antisense strand, as well as
present on the 5'- and/or the 3'-ends of a given strand.
[0678] Multivalent binding proteins are binding proteins comprising
two or more antigen binding sites. Multivalent binding proteins are
engineered to have the three or more antigen binding sites and are
generally not naturally occurring antibodies. The term
"multispecific binding protein" means a binding protein capable of
binding two or more related or unrelated targets. Dual variable
domain (DVD) binding proteins are tetravalent or multivalent
binding proteins binding proteins comprising two or more antigen
binding sites. Such DVDs may be monospecific (i.e., capable of
binding one antigen) or multispecific (i.e., capable of binding two
or more antigens). DVD binding proteins comprising two heavy chain
DVD polypeptides and two light chain DVD polypeptides are referred
to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD
polypeptide, a light chain DVD polypeptide, and two antigen binding
sites. Each binding site comprises a heavy chain variable domain
and a light chain variable domain with a total of 6 CDRs involved
in antigen binding per antigen binding site. Multispecific DVDs
include DVD binding proteins that bind DLL4 and VEGF, or C-met and
EFGR or ErbB3 and EGFR.
[0679] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, CLORETAZINE.RTM. (laromustine, VNP
40101M), cyclophosphamide, decarbazine, estramustine, fotemustine,
glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,
melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard
N-oxide, ranimustine, temozolomide, thiotepa, TREANDA.RTM.
(bendamustine), treosulfan, rofosfamide and the like.
[0680] Angiogenesis inhibitors include endothelial-specific
receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth
factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor
(IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors,
matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived
growth factor receptor (PDGFR) inhibitors, thrombospondin analogs,
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
[0681] Antimetabolites include ALIMTA.RTM. (pemetrexed disodium,
LY231514, MTA), 5-azacitidine, XELODA.RTM. (capecitabine),
carmofur, LEUSTAT.RTM. (cladribine), clofarabine, cytarabine,
cytarabine ocfosfate, cytosine arabinoside, decitabine,
deferoxamine, doxifluridine, eflornithine, EICAR
(5-ethynyl-1-.beta.-D-ribofuranosylimidazole-4-carboxamide),
enocitabine, ethylcytidine, fludarabine, 5-fluorouracil alone or in
combination with leucovorin, GEMZAR.RTM. (gemcitabine),
hydroxyurea, ALKERAN.RTM.(melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,
raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,
tegafur, TS-1, vidarabine, UFT and the like.
[0682] Antivirals include ritonavir, hydroxychloroquine and the
like.
[0683] Aurora kinase inhibitors include ABT-348, AZD-1152,
MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora
B-specific kinase inhibitors and pan-Aurora kinase inhibitors and
the like.
[0684] Bcl-2 protein inhibitors include AT-101 ((-)gossypol),
GENASENSE.RTM. (G3139 or oblimersen (Bcl-2-targeting antisense
oligonucleotide)), IPI-194, IPI-565,
N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4--
(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobe-
nzenesulfonamide) (ABT-737),
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)pip-
erazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-
)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide
(ABT-263), GX-070 (obatoclax), ABT-199, and the like.
[0685] Bcr-Abl kinase inhibitors include DASATINIB.RTM.
(BMS-354825), GLEEVEC.RTM.(imatinib) and the like.
[0686] CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
[0687] COX-2 inhibitors include ABT-963, ARCOXIA.RTM. (etoricoxib),
BEXTRA.RTM. (valdecoxib), BMS347070, CELEBREX.RTM. (celecoxib),
COX-189 (lumiracoxib), CT-3, DERAMAXX.RTM. (deracoxib), JTE-522,
4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole),
MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125,
SD-8381, SVT-2016, S-2474, T-614, VIOXX.RTM. (rofecoxib) and the
like.
[0688] EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFR
immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX.RTM. (cetuximab),
HR3, IgA antibodies, IRESSA.RTM. (gefitinib), TARCEVA.RTM.
(erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB.RTM.
(lapatinib) and the like.
[0689] ErbB2 receptor inhibitors include CP-724-714, CI-1033
(canertinib), HERCEPTIN.RTM. (trastuzumab), TYKERB.RTM.
(lapatinib), OMNITARG.RTM. (2C4, petuzumab), TAK-165, GW-572016
(ionafamib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine),
APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody,
B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB
AR-209, mAB 2B-1 and the like.
[0690] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[0691] HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101,
CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953,
MYCOGRAB.RTM. (human recombinant antibody to HSP-90), NCS-683664,
PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the
like.
[0692] Inhibitors of inhibitors of apoptosis proteins include
HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
[0693] Antibody drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC,
MEDI-547, SGN-19Am SGN-35, SGN-75 and the like Activators of death
receptor pathway include TRAIL, antibodies or other agents that
target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab,
conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029, LBY-135,
PRO-1762 and trastuzumab.
[0694] Kinesin inhibitors include Eg5 inhibitors such as AZD4877,
ARRY-520; CENPE inhibitors such as GSK923295A and the like.
[0695] JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and
INCB018424 and the like.
[0696] MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901,
PD-98059 and the like.
[0697] mTOR inhibitors include AP-23573, CCI-779, everolimus,
RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2
inhibitors, including PI-103, PP242, PP30, Torin 1 and the
like.
[0698] Non-steroidal anti-inflammatory drugs include AMIGESIC.RTM.
(salsalate), DOLOBID.RTM. (diflunisal), MOTRIN.RTM. (ibuprofen),
ORUDIS.RTM. (ketoprofen), RELAFEN.RTM. (nabumetone), FELDENE.RTM.
(piroxicam), ibuprofen cream, ALEVE.RTM. (naproxen) and
NAPROSYN.RTM. (naproxen), VOLTAREN.RTM. (diclofenac), INDOCIN.RTM.
(indomethacin), CLINORIL.RTM. (sulindac), TOLECTIN.RTM. (tolmetin),
LODINE.RTM. (etodolac), TORADOL.RTM. (ketorolac),
DAYPRO.RTM.(oxaprozin) and the like.
[0699] PDGFR inhibitors include C-451, CP-673, CP-868596 and the
like.
[0700] Platinum chemotherapeutics include cisplatin, ELOXATIN.RTM.
(oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN.RTM.
(carboplatin), satraplatin, picoplatin and the like.
[0701] Polo-like kinase inhibitors include BI-2536 and the
like.
[0702] Phosphoinositide-3 kinase (PI3K) inhibitors include
wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658,
PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
[0703] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[0704] VEGFR inhibitors include AVASTIN.RTM. (bevacizumab),
ABT-869, AEE-788, ANGIOZYME.TM. (a ribozyme that inhibits
angiogenesis (Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron,
(Emeryville, Calif.)), axitinib (AG-13736), AZD-2171, CP-547,632,
IM-862, MACUGEN (pegaptamib), NEXAVAR.RTM. (sorafenib, BAY43-9006),
pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT.RTM.
(sunitinib, SU-11248), VEGF trap, ZACTIMA.TM. (vandetanib,
ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3 specific
antibodies, BSG2 specific antibodies, DLL4 specific antibodies and
C-met specific antibodies, and the like.
[0705] Antibiotics include intercalating antibiotics aclarubicin,
actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE.RTM.
(bleomycin), daunorubicin, CAELYX.RTM. or MYOCET.RTM. (liposomal
doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS.RTM.
(idarubicin), mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
VALSTAR.RTM. (valrubicin), zinostatin and the like.
[0706] Topoisomerase inhibitors include aclarubicin,
9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan,
BN-80915, CAMPTOSAR.RTM. (irinotecan hydrochloride), camptothecin,
CARDIOXANE.RTM. (dexrazoxine), diflomotecan, edotecarin,
ELLENCE.RTM. or PHARMORUBICIN.RTM. (epirubicin), etoposide,
exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,
mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan,
sobuzoxane, SN-38, tafluposide, topotecan and the like.
[0707] Antibodies include AVASTIN.RTM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, ERBITUX.RTM. (cetuximab),
HUMAX-CD4.RTM. (zanolimumab), IGF1R-specific antibodies,
lintuzumab, PANOREX.RTM. (edrecolomab), RENCAREX.RTM. (WX G250),
RITUXAN.RTM. (rituximab), ticilimumab, trastuzimab, CD20 antibodies
types I and II and the like.
[0708] Hormonal therapies include ARIMIDEX.RTM. (anastrozole),
AROMASIN.RTM. (exemestane), arzoxifene, CASODEX.RTM.
(bicalutamide), CETROTIDE.RTM. (cetrorelix), degarelix, deslorelin,
DESOPAN.RTM.(trilostane), dexamethasone, DROGENIL.RTM. (flutamide),
EVISTA.RTM. (raloxifene), AFEMA.TM. (fadrozole), FARESTON.RTM.
(toremifene), FASLODEX.RTM. (fulvestrant), FEMARA.RTM. (letrozole),
formestane, glucocorticoids, HECTOROL.RTM. (doxercalciferol),
RENAGEL.RTM. (sevelamer carbonate), lasofoxifene, leuprolide
acetate, MEGACE.RTM. (megesterol), MIFEPREX.RTM. (mifepristone),
NILANDRON.TM. (nilutamide), NOLVADEX.RTM. (tamoxifen citrate),
PLENAXIS.TM. (abarelix), prednisone, PROPECIA.RTM. (finasteride),
rilostane, SUPREFACT.RTM. (buserelin), TRELSTAR.RTM. (luteinizing
hormone releasing hormone (LHRH)), VANTAS.RTM. (Histrelin implant),
VETORYL.RTM. (trilostane or modrastane), ZOLADEX.RTM. (fosrelin,
goserelin) and the like.
[0709] Deltoids and retinoids include seocalcitol (EB1089, CB1093),
lexacalcitrol (KH1060), fenretinide, PANRETIN.RTM. (aliretinoin),
ATRAGEN.RTM. (liposomal tretinoin), TARGRETIN.RTM. (bexarotene),
LGD-1550 and the like.
[0710] PARP inhibitors include ABT-888 (veliparib), olaparib,
KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231
and the like.
[0711] Plant alkaloids include, but are not limited to,
vincristine, vinblastine, vindesine, vinorelbine and the like.
[0712] Proteasome inhibitors include VELCADE.RTM. (bortezomib),
MG132, NPI-0052, PR-171 and the like.
[0713] Examples of immunologicals include interferons and other
immune-enhancing agents. Interferons include interferon alpha,
interferon alpha-2a, interferon alpha-2b, interferon beta,
interferon gamma-1a, ACTIMMUNE.RTM. (interferon gamma-1b) or
interferon gamma-n1, combinations thereof and the like. Other
agents include ALFAFERONE.RTM., (IFN-.alpha.), BAM-002 (oxidized
glutathione), BEROMUN.RTM. (tasonermin), BEXXAR.RTM. (tositumomab),
CAMPATH.RTM. (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4),
decarbazine, denileukin, epratuzumab, GRANOCYTE.RTM. (lenograstim),
lentinan, leukocyte alpha interferon, imiquimod, MDX-010
(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim,
MYLOTARG.TM. (gemtuzumab ozogamicin), NEUPOGEN.RTM. (filgrastim),
OncoVAC-CL, OVAREX.RTM. (oregovomab), pemtumomab (Y-muHMFG1),
PROVENGE.RTM. (sipuleucel-T), sargaramostim, sizofilan, teceleukin,
THERACYS.RTM. (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN.RTM.
(immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific
Substance of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)),
PROLEUKIN.RTM. (aldesleukin), ZADAXIN.RTM. (thymalfasin),
ZENAPAX.RTM. (daclizumab), ZEVALIN.RTM. (90Y-Ibritumomab tiuxetan)
and the like.
[0714] Biological response modifiers are agents that modify defense
mechanisms of living organisms or biological responses, such as
survival, growth or differentiation of tissue cells to direct them
to have anti-tumor activity and include krestin, lentinan,
sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the
like.
[0715] Pyrimidine analogs include cytarabine (ara C or Arabinoside
C), cytosine arabinoside, doxifluridine, FLUDARA.RTM.
(fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR.RTM.
(gemcitabine), TOMUDEX.RTM. (ratitrexed), TROXATYL.TM.
(triacetyluridine troxacitabine) and the like.
[0716] Purine analogs include LANVIS.RTM. (thioguanine) and
PURI-NETHOL.RTM.(mercaptopurine).
[0717] Antimitotic agents include batabulin, epothilone D
(KOS-862),
N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS 247550), paclitaxel, TAXOTERE.RTM. (docetaxel),
PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine,
ZK-EPO (synthetic epothilone) and the like.
[0718] Ubiquitin ligase inhibitors include MDM2 inhibitors, such as
nutlins, NEDD8 inhibitors such as MLN4924 and the like.
[0719] Compounds of this invention can also be used as
radiosensitizers that enhance the efficacy of radiotherapy.
Examples of radiotherapy include external beam radiotherapy,
teletherapy, brachytherapy and sealed, unsealed source radiotherapy
and the like.
[0720] Additionally, compounds having Formula (I) may be combined
with other chemotherapeutic agents such as ABRAXANE.TM. (ABI-007),
ABT-100 (famesyl transferase inhibitor), ADVEXIN.RTM. (Ad5CMV-p53
vaccine), ALTOCOR.RTM. or MEVACOR.RTM. (lovastatin), AMPLIGEN.RTM.
(poly I:poly C12U, a synthetic RNA), APTOSYN.RTM. (exisulind),
AREDIA.RTM. (pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE.RTM. (tazarotene),
AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or
cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC.RTM.
(cancer vaccine), CELEUK.RTM. (celmoleukin), CEPLENE.RTM.
(histamine dihydrochloride), CERVARIX.RTM. (human papillomavirus
vaccine), CHOP.RTM. (C: CYTOXAN.RTM. (cyclophosphamide); H:
ADRIAMYCIN.RTM. (hydroxydoxorubicin); O: Vincristine
(ONCOVIN.RTM.); P: prednisone), CYPAT.TM. (cyproterone acetate),
combrestatin A4P, DAB(389)EGF (catalytic and translocation domains
of diphtheria toxin fused via a His-Ala linker to human epidermal
growth factor) or TransMID-107R.TM. (diphtheria toxins),
dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid
(DMXAA), eniluracil, EVIZON.TM. (squalamine lactate),
DIMERICINE.RTM. (T4N5 liposome lotion), discodermolide, DX-8951f
(exatecan mesylate), enzastaurin, EP0906 (epithilone B),
GARDASIL.RTM. (quadrivalent human papillomavirus (Types 6, 11, 16,
18) recombinant vaccine), GASTRIMMUNE.RTM., GENASENSE.RTM., GMK
(ganglioside conjugate vaccine), GVAX.RTM. (prostate cancer
vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic
acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox),
IL-13-pseudomonas exotoxin, interferon-.alpha., interferon-.gamma.,
JUNOVAN.TM. or MEPACT.TM. (mifamurtide), lonafamib,
5,10-methylenetetrahydrofolate, miltefosine
(hexadecylphosphocholine), NEOVASTAT.RTM.(AE-941), NEUTREXIN.RTM.
(trimetrexate glucuronate), NIPENT.RTM. (pentostatin),
ONCONASE.RTM. (a ribonuclease enzyme), ONCOPHAGE.RTM. (melanoma
vaccine treatment), ONCOVAX.RTM. (IL-2 Vaccine), ORATHECIN.TM.
(rubitecan), OSIDEM.RTM. (antibody-based cell drug), OVAREX.RTM.
MAb (murine monoclonal antibody), paclitaxel, PANDIMEX.TM.
(aglycone saponins from ginseng comprising 20(S)protopanaxadiol
(aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab,
PANVAC.RTM.-VF (investigational cancer vaccine), pegaspargase, PEG
Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB
(catumaxomab), REVLIMID.RTM. (lenalidomide), RSR13 (efaproxiral),
SOMATULINE.RTM. LA (lanreotide), SORIATANE.RTM.(acitretin),
staurosporine (Streptomyces staurospores), talabostat (PT100),
TARGRETIN.RTM. (bexarotene), TAXOPREXIN.RTM. (DHA-paclitaxel),
TELCYTA.RTM. (canfosfamide, TLK286), temilifene, TEMODAR.RTM.
(temozolomide), tesmilifene, thalidomide, THERATOPE.RTM. (STn-KLH),
thymitaq
(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline
dihydrochloride), TNFERADE.TM. (adenovector: DNA carrier containing
the gene for tumor necrosis factor-.alpha.), TRACLEER.RTM. or
ZAVESCA.RTM. (bosentan), tretinoin (Retin-A), tetrandrine,
TRISENOX.RTM. (arsenic trioxide), VIRULIZIN.RTM., ukrain
(derivative of alkaloids from the greater celandine plant), vitaxin
(anti-alphavbeta3 antibody), XCYTRIN.RTM. (motexafin gadolinium),
XINLAY.TM. (atrasentan), XYOTAX.TM. (paclitaxel poliglumex),
YONDELIS.RTM. (trabectedin), ZD-6126, ZINECARD.RTM. (dexrazoxane),
ZOMETA.RTM. (zolendronic acid), zorubicin and the like.
[0721] The compounds of the invention can also be co-administered
with a therapeutically effective amount of one or more agents to
treat an inflammatory disease or condition, or autoimmune disease,
where examples of the agents include, such as methotrexate,
tofacitinib, 6-mercaptopurine, azathioprine sulphasalazine,
mesalazine, olsalazine chloroquinine/hydroxychloroquine,
pencillamine, aurothiomalate (intramuscular and oral),
azathioprine, cochicine, corticosteroids (oral, inhaled and local
injection), beta-2 adrenoreceptor agonists (salbutamol,
terbutaline, salmeteral), xanthines (theophylline, aminophylline),
cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium,
cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide,
NSAIDs, for example, ibuprofen, corticosteroids such as
prednisolone, phosphodiesterase inhibitors, adensosine agonists,
antithrombotic agents, complement inhibitors, adrenergic agents,
agents which interfere with signalling by proinflammatory cytokines
such as TNF.quadrature. or IL-1 (e.g., NIK, IKK, p38 or MAP kinase
inhibitors), IL-1.quadrature. converting enzyme inhibitors, T-cell
signalling inhibitors such as kinase inhibitors, metalloproteinase
inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin
converting enzyme inhibitors, soluble cytokine receptors and
derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the
derivatives p75TNFRIgG (etanercept) and p55TNFRIgG (Lenercept),
sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines (e.g. IL-4,
IL-10, IL-11, IL-13 and TGF.quadrature.), celecoxib, folic acid,
hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab,
adalimumab, certolizumab, tocilizumab, abatacept, naproxen,
valdecoxib, sulfasalazine, methylprednisolone, meloxicam,
methylprednisolone acetate, gold sodium thiomalate, aspirin,
triamcinolone acetonide, propoxyphene napsylate/apap, folate,
nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,
oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac
sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,
sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate
sodium, prednisolone, cortisone, betamethasone, morphine sulfate,
lidocaine hydrochloride, indomethacin, glucosamine
sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodone
HCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium,
omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG,
IL-18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469, VX-702,
AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists (such
as FTY720), PKC family inhibitors (such as Ruboxistaurin or
AEB-071) and Mesopram. In certain embodiments, combinations include
methotrexate or leflunomide and in moderate or severe rheumatoid
arthritis cases, cyclosporine and anti-TNF antibodies as noted
above.
[0722] Non-limiting examples of therapeutic agents for inflammatory
bowel disease with which a compound of Formula (I) of the invention
may be co-administered include the following: budenoside; epidermal
growth factor; corticosteroids; cyclosporin, sulfasalazine;
aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole;
lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide;
antioxidants; thromboxane inhibitors; IL-1 receptor antagonists;
anti-IL-1.quadrature. monoclonal antibodies; anti-IL-6 monoclonal
antibodies; growth factors; elastase inhibitors;
pyridinyl-imidazole compounds; antibodies to or antagonists of
other human cytokines or growth factors, for example, TNF, LT,
IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II,
GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3,
CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their
ligands; methotrexate; cyclosporine; FK506; rapamycin;
mycophenolate mofetil; leflunomide; NSAIDs, for example, ibuprofen;
corticosteroids such as prednisolone; phosphodiesterase inhibitors;
adenosine agonists; antithrombotic agents; complement inhibitors;
adrenergic agents; agents which interfere with signalling by
proinflammatory cytokines such as TNF.quadrature. or IL-1 (e.g.
NIK, IKK, or MAP kinase inhibitors); IL-1.quadrature. converting
enzyme inhibitors; TNF.quadrature. converting enzyme inhibitors;
T-cell signalling inhibitors such as kinase inhibitors;
metalloproteinase inhibitors; sulfasalazine; azathioprine;
6-mercaptopurines; angiotensin converting enzyme inhibitors;
soluble cytokine receptors and derivatives thereof (e.g. soluble
p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and
antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and
TGF.quadrature.). Preferred examples of therapeutic agents for
Crohn's disease with which a compound of Formula (I) can be
combined include the following: TNF antagonists, for example,
anti-TNF antibodies, D2E7 (adalimumab), CA2 (infliximab), CDP 571,
TNFR-Ig constructs, (p75TNFRIgG (etanercept) and p55TNFRIgG
(LENERCEPT.TM.) inhibitors and PDE4 inhibitors. A compound of
Formula (I) can be combined with corticosteroids, for example,
budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid;
olsalazine; and agents which interfere with synthesis or action of
proinflammatory cytokines such as IL-1, for example,
IL-1.quadrature. converting enzyme inhibitors and IL-1ra; T cell
signaling inhibitors, for example, tyrosine kinase inhibitors;
6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine;
mercaptopurine; infliximab; methylprednisolone sodium succinate;
diphenoxylate/atrop sulfate; loperamide hydrochloride;
methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;
hydrocodone bitartrate/apap; tetracycline hydrochloride;
fluocinonide; metronidazole; thimerosal/boric acid;
cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine
sulfate; meperidine hydrochloride; midazolam hydrochloride;
oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium
phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil;
propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide
disodium; codeine phosphate/apap; colesevelam HCl; cyanocobalamin;
folic acid; levofloxacin; methylprednisolone; natalizumab and
interferon-gamma.
[0723] Non-limiting examples of therapeutic agents for multiple
sclerosis with which a compound of Formula (I) may be
co-administered include the following: corticosteroids;
prednisolone; methylprednisolone; azathioprine; cyclophosphamide;
cyclosporine; methotrexate; 4-aminopyridine; tizanidine;
interferon-.quadrature.1a (AVONEX.RTM.; Biogen);
interferon-.quadrature.1b (BETASERON.RTM.; Chiron/Berlex);
interferon .quadrature.-n3) (Interferon Sciences/Fujimoto),
interferon-.quadrature. (Alfa Wassermann/J&J), interferon
.quadrature.1A-IF (Serono/Inhale Therapeutics), Peginterferon
.quadrature. 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1;
COPAXONE.RTM.; Teva Pharmaceutical Industries, Inc.); hyperbaric
oxygen; intravenous immunoglobulin; cladribine; antibodies to or
antagonists of other human cytokines or growth factors and their
receptors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8,
IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. A
compound of Formula (I) can be combined with antibodies to cell
surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25,
CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A
compound of Formula (I) may also be combined with agents such as
methotrexate, cyclosporine, FK506, rapamycin, mycophenolate
mofetil, leflunomide, an S1P1 agonist, NSAIDs, for example,
ibuprofen, corticosteroids such as prednisolone, phosphodiesterase
inhibitors, adensosine agonists, antithrombotic agents, complement
inhibitors, adrenergic agents, agents which interfere with
signalling by proinflammatory cytokines such as TNF.quadrature. or
IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors),
IL-1.quadrature. converting enzyme inhibitors, TACE inhibitors,
T-cell signaling inhibitors such as kinase inhibitors,
metalloproteinase inhibitors, sulfasalazine, azathioprine,
6-mercaptopurines, angiotensin converting enzyme inhibitors,
soluble cytokine receptors and derivatives thereof (e.g. soluble
p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and
antiinflammatory cytokines (e.g. IL-4, IL-10, IL-13 and
TGF.quadrature.).
[0724] A compound of Formula (I) may also be co-administered with
agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone,
xaliproden hydrochloride, fampridine, glatiramer acetate,
natalizumab, sinnabidol, .quadrature.-immunokine NNSO3, ABR-215062,
AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine,
CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD
(cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor),
MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone
allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide,
TGF-beta2, tiplimotide, VLA-4 antagonists (for example, TR-14035,
VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma
antagonists and IL-4 agonists.
[0725] Non-limiting examples of therapeutic agents for ankylosing
spondylitis with which a compound of Formula (I) can be
co-administered include the following: ibuprofen, diclofenac,
misoprostol, naproxen, meloxicam, indomethacin, diclofenac,
celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine,
minocyclin, prednisone, and anti-TNF antibodies, D2E7
(HUMIRA.RTM.), CA2 (infliximab), CDP 571, TNFR-Ig constructs,
(p75TNFRIgG (ENBREL.RTM.) and p55TNFRIgG (LENERCEPT.RTM.).
[0726] Non-limiting examples of therapeutic agents for asthma with
which a compound of Formula (I) may be co-administered include the
following: albuterol, salmeterol/fluticasone, montelukast sodium,
fluticasone propionate, budesonide, prednisone, salmeterol
xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium,
prednisolone sodium phosphate, triamcinolone acetonide,
beclomethasone dipropionate, ipratropium bromide, azithromycin,
pirbuterol acetate, prednisolone, theophylline anhydrous,
methylprednisolone sodium succinate, clarithromycin, zafirlukast,
formoterol fumarate, influenza virus vaccine, amoxicillin
trihydrate, flunisolide, allergy injection, cromolyn sodium,
fexofenadine hydrochloride, flunisolide/menthol,
amoxicillin/clavulanate, levofloxacin, inhaler assist device,
guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,
doxycycline hyclate, guaifenesin/d-methorphan,
p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine
hydrochloride, mometasone furoate, salmeterol xinafoate,
benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizine
HCl/pseudoephed, phenylephrine/cod/promethazine,
codeine/promethazine, cefprozil, dexamethasone,
guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone,
nedocromil sodium, terbutaline sulfate, epinephrine,
methylprednisolone, anti-IL-13 antibody, and metaproterenol
sulfate.
[0727] Non-limiting examples of therapeutic agents for COPD with
which a compound of Formula (I) may be co-administered include the
following: albuterol sulfate/ipratropium, ipratropium bromide,
salmeterol/fluticasone, albuterol, salmeterol xinafoate,
fluticasone propionate, prednisone, theophylline anhydrous,
methylprednisolone sodium succinate, montelukast sodium,
budesonide, formoterol fumarate, triamcinolone acetonide,
levofloxacin, guaifenesin, azithromycin, beclomethasone
dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium,
amoxicillin trihydrate, gatifloxacin, zafirlukast,
amoxicillin/clavulanate, flunisolide/menthol,
chlorpheniramine/hydrocodone, metaproterenol sulfate,
methylprednisolone, mometasone furoate,
p-ephedrine/cod/chlorphenir, pirbuterol acetate,
p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide,
(R,R)-formoterol, TgAAT, cilomilast and roflumilast.
[0728] Non-limiting examples of therapeutic agents for psoriasis
with which a compound of Formula (I) may be co-administered include
the following: calcipotriene, clobetasol propionate, triamcinolone
acetonide, halobetasol propionate, tazarotene, methotrexate,
fluocinonide, betamethasone diprop augmented, fluocinolone
acetonide, acitretin, tar shampoo, betamethasone valerate,
mometasone furoate, ketoconazole, pramoxine/fluocinolone,
hydrocortisone valerate, flurandrenolide, urea, betamethasone,
clobetasol propionate/emoll, fluticasone propionate, azithromycin,
hydrocortisone, moisturizing formula, folic acid, desonide,
pimecrolimus, coal tar, diflorasone diacetate, etanercept folate,
lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,
methylprednisolone acetate, prednisone, sunscreen, halcinonide,
salicylic acid, anthralin, clocortolone pivalate, coal extract,
coal tar/salicylic acid, coal tar/salicylic acid/sulfur,
desoximetasone, diazepam, emollient, fluocinonide/emollient,
mineral oil/castor oil/na lact, mineral oil/peanut oil,
petroleum/isopropyl myristate, psoralen, salicylic acid,
soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab,
cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus,
PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.
[0729] Non-limiting examples of therapeutic agents for psoriatic
arthritis with which a compound of Formula (I) may be
co-administered include the following: methotrexate, etanercept,
rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen,
leflunomide, methylprednisolone acetate, indomethacin,
hydroxychloroquine sulfate, prednisone, sulindac, betamethasone
diprop augmented, infliximab, methotrexate, folate, triamcinolone
acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac
sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone,
tolmetin sodium, calcipotriene, cyclosporine, diclofenac
sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium
thiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate
sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7
(adalimumab), and efalizumab.
[0730] Preferred examples of therapeutic agents for SLE (Lupus)
with which a compound of Formula (I) may be co-administered include
the following: NSAIDS, for example, diclofenac, naproxen,
ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example,
celecoxib, rofecoxib, valdecoxib; anti-malarials, for example,
hydroxychloroquine; steroids, for example, prednisone,
prednisolone, budenoside, dexamethasone; cytotoxics, for example,
azathioprine, cyclophosphamide, mycophenolate mofetil,
methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for
example Cellcept.RTM.. A compound of Formula (I) may also be
combined with agents such as sulfasalazine, 5-aminosalicylic acid,
olsalazine, Imuran.RTM. and agents which interfere with synthesis,
production or action of proinflammatory cytokines such as IL-1, for
example, caspase inhibitors like IL-1.quadrature. converting enzyme
inhibitors and IL-1ra. A compound of Formula (I) may also be used
with T cell signaling inhibitors, for example, tyrosine kinase
inhibitors; or molecules that target T cell activation molecules,
for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1
family antibodies. A compound of Formula (I) can be combined with
IL-11 or anti-cytokine antibodies, for example, fonotolizumab
(anti-IFNg antibody), or anti-receptor receptor antibodies, for
example, anti-IL-6 receptor antibody and antibodies to B-cell
surface molecules. A compound of Formula (I) may also be used with
LJP 394 (abetimus), agents that deplete or inactivate B-cells, for
example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS
antibody), TNF antagonists, for example, anti-TNF antibodies, D2E7
(adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs,
(p75TNFRIgG (etanercept) and p55TNFRIgG (LENERCEPT.TM.).
[0731] The compounds of the invention can also be co-administered
with a therapeutically effective amount of one or more agents used
in the prevention or treatment of AIDS, where examples of the
agents include, HIV reverse transcriptase inhibitors, HIV protease
inhibitors, immunomodulators, and other retroviral drugs. Examples
of reverse transcriptase inhibitors include, but are not limited
to, abacavir, adefovir, didanosine, dipivoxil delavirdine,
efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine,
stavudine, tenofovir, zalcitabine, and zidovudine. Examples of
protease inhibitors include, but are not limited to, amprenavir,
atazanavir, darunavir, indinavir, fosamprenavir, lopinavir,
nelfinavir, ritonavir, saquinavir, and tipranavir. Examples of
other retroviral drugs include, but are not limited to,
elvitegravir, enfuvirtide, maraviroc and raltegravir.
[0732] The compounds of the invention can be co-administered with a
therapeutically effective amount of one or more agents to prevent
or treat type II diabetes, hepatic steatosis, insulin resistance,
metabolic syndrome and related disorders, where examples of the
agents include, but are not limited to, insulin and insulins that
have been modified to improve the duration of action in the body;
agents that stimulate insulin secretion such as acetohexamide,
chlorpropamide, glyburide, glimepiride, glipizide, glicazide,
glycopyramide, gliquidone, rapaglinide, nataglinide, tolazamide and
tolbutamide; agents that are glucagon-like peptide agonists such as
exanatide, liraglutide and taspoglutide; agents that inhibit
dipeptidyl-peptidase IV such as vildagliptin, sitagliptin,
saxagliptin, linagliptin, allogliptin and septagliptin; agents that
bind to the peroxisome proliferator-activated receptor gamma such
as rosiglitazone and pioglitazone; agents that decrease insulin
resistance such as metformin; agents that reduce glucose absorbance
in the small intestine such as acarbose, miglitol and
voglibose.
[0733] The compounds of the invention can be co-administered with a
therapeutically effective amount of one or more agents to prevent
or treat acute kidney disorders and chronic kidney diseases, where
examples of the agents include, but are not limited to, dopamine,
diuretics such as furosemide, bumetanide, thiazide and the like,
mannitol, calcium gluconate, sodium bicarbonate, albuterol,
paricalcitol, doxercalciferol, cinacalcet and bardoxalone
methyl.
[0734] The compounds of the invention can be co-administered with a
therapeutically effective amount of one or more agents to a male
subject to provide for male contraception.
[0735] The following Examples may be used for illustrative purposes
and should not be deemed to narrow the scope of the invention.
EXAMPLES
Example 1
6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 1a
(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine
[0736] 5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7
mmol) was dissolved in dimethylformamide (300 mL), and lithium
methanolate (6.07 mL, 6.07 mmol, 1 M) was added. The reaction
mixture was heated to 100.degree. C. To this mixture was added
1,1-dimethoxy-N,N-dimethylmethanamine (64.5 mL, 486 mmol) over 10
minutes. The reaction mixture was stirred at 95.degree. C. for 16
hours. The reaction mixture was cooled to room temperature and
water was added carefully (300 mL, exothermic). The resulting
precipitate was collected by vacuum filtration, washed with water,
and dried to provide the title compound (13.9 g, 45.9 mmol, 76%
yield).
Example 1b
4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine
[0737] Example 1a (13.9 g, 45.8 mmol) and ethyl acetate (150 mL)
were added to Ra--Ni 2800 (pre-washed with ethanol), water slurry
(6.9 g, 118 mmol) in a stainless steel pressure bottle and stirred
for 30 minutes at 30 psi and room temperature. The reaction mixture
was filtered, and concentrated. The residue was triturated with
dichloromethane, and the solid filtered to provide the title
compound (5.82 g). The mother liquor was evaporated and the residue
triturated again with dichloromethane and filtered to provide an
additional 1.63 g of the title compound. Total yield=7.45 g, 72%
yield.
Example 1c
4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine
[0738] A solution of Example 1b (7.42 g, 32.7 mmol) in
dimethylformamide (235 mL) was stirred at room temperature. To this
solution was added sodium hydride (1.18 g, 1.96 g of 60% dispersion
in oil, 49.0 mmol), and the reaction mixture was stirred for 10
min. P-toluenesulfonyl chloride (9.35 g, 49.0 mmol) was then added
portion-wise, and the mixture was stirred at room temperature under
nitrogen for 16 hours. The reaction mixture was quenched carefully
with water and the resulting beige solid collected by vacuum
filtration on a Buchner funnel, and washed with water. The solid
was collected and dried in a vacuum oven at 50.degree. C. to
provide 12.4 g (100%) of the title compound.
Example 1d
4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0739] A solution of Example 1c (12.4 g, 32.6 mmol) in dioxane (140
mL) was stirred at room temperature. To this solution was added 4M
HCl in dioxane (140 mL). The reaction mixture was stirred at
40.degree. C. for 16 hours. The reaction mixture was cooled to room
temperature and concentrated. The residue was triturated with
diethylether, filtered, and rinsed with additional diethylether and
dried to provide the title compound (11.23 g, 30.6 mmol, 94% yield)
as a beige solid.
Example 1e
4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0740] Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil
dispersion) was added to a stirring solution of Example 1d (11.2 g,
30.4 mmol) in dimethylformamide (217 mL) under nitrogen. After 30
minutes, iodomethane (2.27 mL, 36.5 mmol) was added and the
solution was stirred at room temperature for 3 h. Upon addition of
water (250 mL) a precipitate formed. The precipitate was collected
by vacuum filtration, rinsed with water (50 mL) and dried in a
vacuum oven at 55.degree. C. overnight to provide 11.2 g of the
title compound (96%).
Example 1F
6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0741] A mixture of Example 1e (152 mg, 0.40 mmol),
2-phenoxyphenylboronic acid (0.111 g, 0.520 mmol, 1.3 equivalents),
Pd(PPh.sub.3).sub.4(0.023 g, 5 mol %) and cesium fluoride (0.182 g,
1.2 mmol) in DME (3 mL) and methanol (1.5 mL) was heated under
microwave condition (120.degree. C., 30 minutes). To this mixture
was added potassium carbonate (0.055 g, 0.40 mmol) and water (1 mL)
and the reaction mixture was reheated in the microwave oven at
120.degree. C. for another 2 hours. The organic layer was separated
and purified by flash chromatography (silica gel, ethyl acetate).
The resulting material was triturated with acetone and filtered to
provide 0.075 g of the title compound (59%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.50 (s, 3H), 6.21-6.23 (m, 1H), 6.88 (d,
J=7.62 Hz, 2H), 6.99-7.04 (m, 2H), 7.24-7.30 (m, 5H), 7.36-7.40 (m,
1H), 7.50 (dd, J=7.48, 1.68 Hz, 1H), 11.98 (s, 1H). MS (ESI+) m/z
317 (M+H).sup.+.
Example 2
6-methyl-4-(5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin--
7-one
Example 2a
4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-
-one
Method A:
[0742] Example 1e (0.687 g, 1.802 mmol),
2-fluoro-5-nitrophenylboronic acid (0.500 g, 2.70 mmol),
Pd(PPh.sub.3).sub.4(0.104 g, 0.090 mmol) and sodium carbonate (2.70
mL, 5.41 mmol) were combined in DME (7 mL) and water (7 mL) in a 20
mL microwave tube, sealed, sparged with nitrogen and heated under
microwave at 120.degree. C. for 30 minutes. The mixture was
partitioned between EtAOc and water. The organic layer was washed
with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated.
The crude product was purified by flash chromatography (silica gel,
0-100% ethyl acetate in hexanes) to provide 0.41 g (52%) of the
title compound.
Method B:
[0743] Example 1e (6.00 g, 15.7 mmol),
2-fluoro-5-nitrophenylboronic acid (5.82 g, 31.5 mmol),
Pd(PPh.sub.3).sub.4(0.909 g, 0.787 mmol) and sodium carbonate (3.34
g, 31.5 mmol) were combined in toluene (60 mL), ethanol (15 mL) and
water (15 mL) and the mixture was degassed and left under nitrogen.
The reaction mixture was heated at 90.degree. C. overnight, and
then cooled to room temperature. The mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
brine, dried (MgSO.sub.4), filtered and concentrated. The crude
product was purified by flash chromatography (silica gel, 20-50%
ethyl acetate in hexanes) to provide 6.95 g (61%) of the title
compound.
Example 2b
6-methyl-4-(5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin--
7-one
[0744] Phenol (0.094 g, 0.997 mmol), Example 2a (0.4 g, 0.906 mmol)
and cesium carbonate (0.325 g, 0.997 mmol) were combined in DMSO
(4.53 mL) and heated at 100.degree. C. for 2 hours. The reaction
mixture was partitioned between ethyl acetate and water and pH was
adjusted to pH 7. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated. Purification by
flash chromatography (silica gel, 0-4% methanol in dichloromethane)
afforded 0.28 g (84%) of the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 3.57 (s, 3H) 6.28-6.34 (m, 1H) 6.98 (d,
J=9.12 Hz, 1H) 7.16 (d, J=7.54 Hz, 2H) 7.21-7.32 (m, 2H) 7.40-7.49
(m, 3H) 8.22 (dd, J=9.12, 2.78 Hz, 1H) 8.32 (d, J=2.78 Hz, 1H)
12.07-12.11 (m, 1H). MS (ESI+) m/z 362 [M+H].sup.+
Example 3
4-(5-amino-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin--
7-one
[0745] Example 2b (0.25 g, 0.692 mmol), iron powder (0.193 g, 3.46
mmol), and ammonium chloride (0.056 g, 1.038 mmol) were combined in
tetrahydrofuran (6 mL), ethanol (6 mL) and water (2 mL). The
mixture was heated at 95.degree. C. with vigorous stirring for 1.5
hours. The reaction mixture was cooled to room temperature and
filtered through a plug of Celite to remove solids. The plug was
rinsed repeatedly with methanol and tetrahydrofuran. The filtrate
was concentrated and the residue partitioned between ethyl acetate
and water. The ethyl acetate layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 1-4% methanol in
dichloromethane) to afford 0.21 g (82%) of the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.43 (s, 3H) 5.07 (s,
2H) 6.22-6.25 (m, 1H) 6.59 (dd, J=8.48, 2.71 Hz, 1H) 6.68 (d,
J=7.80 Hz, 2H) 6.74 (d, J=2.71 Hz, 1H) 6.80-6.88 (m, 2H) 7.11-7.19
(m, 3H) 7.24 (t, J=2.71 Hz, 1H) 11.91 (s, 1H). MS (ESI+) m/z 362
[M+H].sup.+.
Example 4
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyp-
henyl]methanesulfonamide
Method A:
[0746] To a solution of Example 3 (0.125 g, 0.377 mmol) and
triethylamine (0.131 mL, 0.943 mmol) in dichloromethane (3.0 mL)
was added dropwise methanesulfonyl chloride (0.064 mL, 0.830 mmol).
The reaction mixture was stirred for 2 hours at ambient temperature
and then concentrated. The residue was dissolved in a mixture of
dioxane (5 mL) and 1M sodium hydroxide (2 mL) and heated for 1 hour
at 90.degree. C. The reaction mixture was cooled and diluted with
ethyl acetate, brought to pH 7 with 1 M HCl and partitioned. The
organic layer was washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 0-4% methanol in dichloromethane) to
afford 0.20 g (77%) of the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 3.02 (s, 3H) 3.48 (s, 3H) 6.23-6.30 (m, 1H)
6.85 (d, J=7.46 Hz, 2H) 6.99 (t, J=7.29 Hz, 1H) 7.04 (d, J=8.82 Hz,
1H) 7.20-7.29 (m, 5H) 7.39 (d, J=2.71 Hz, 1H) 9.72 (s, 1H) 12.01
(s, 1H). MS (ESI+) m/z 410 [M+H].sup.+.
Method B:
[0747] The product of Example 7d (1.127 g, 2 mmol), potassium
hydroxide (1.82 g, 52.5 mmol) and cetyltrimethylammonium bromide
(0.036 g, 0.100 mmol) were combined in tetrahydrofuran (15.00 mL)
and water (5.00 mL) and the mixture heated at 100.degree. C. for 14
hours. The reaction mixture was partitioned between equal volumes
of EtOAc and water and the pH was adjusted to pH 7 by careful
addition of concentrated HCl. The organic layer was separated,
washed three times with saturated brine, dried (Na.sub.2SO.sub.4)
and concentrated. Purification by trituration in dichloromethane
afforded the title compound (0.76 g, 93%).
Example 5
2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin--
4-yl)-4-phenoxyphenyl]ethanesulfonamide
[0748] To a solution of Example 3 (0.05 g, 0.151 mmol) and
triethylamine (0.053 mL, 0.377 mmol) in dichloromethane (1.0 mL)
was added dropwise 2,2,2-trifluoroethanesulfonyl chloride (0.036 g,
0.196 mmol). The reaction mixture was stirred for 1 hour at room
temperature and then purified by flash chromatography (silica gel,
0-5% methanol in dichloromethane) to afford 0.050 g (68%) of the
title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.49
(s, 3H) 4.55 (q, J=9.91 Hz, 2H) 6.28 (t, J=2.38 Hz, 1H) 6.86 (d,
J=7.54 Hz, 2H) 6.95-7.07 (m, 2H) 7.20-7.31 (m, 5H) 7.40 (d, J=2.78
Hz, 1H) 10.43 (s, 1H) 12.02 (s, 1H). MS (APCI+) m/z 478
[M+H].sup.+.
Example 6
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyp-
henyl]acetamide
Example 6a
6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrol-
o[2,3-c]pyridin-7(6H)-one
[0749] Example 1e (6.55 g, 17.2 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.73
g, 34.4 mmol), potassium acetate (3.71 g, 37.8 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.393 g, 0.430 mmol) and
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS,
0.819 g, 1.72 mmol) were combined and sparged with argon for 1 hour
with stirring. Dioxane (86 mL) was sparged with nitrogen for 1
hour, transferred via canula under nitrogen to the solid
components, and the mixture was heated under argon at 80.degree. C.
for 5 hours. The reaction mixture was cooled to room temperature,
partitioned between ethyl acetate and water, and filtered through
Celite. The ethyl acetate layer was washed twice with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by chromatography (silica gel, 25-80% ethyl acetate in
hexane). The resulting material from chromatography was triturated
with a minimal amount of hexanes (30 mL) and the particulate solid
was collected by filtration, rinsed with a minimal amount of
hexanes and dried to constant mass to afford the title compound
(5.4 g, 73%).
Example 6b
N-(3-bromo-4-phenoxyphenyl)acetamide
[0750] Example 7b (0.2 g, 0.757 mmol), and acetic anhydride (1 mL,
10.60 mmol) were combined in a 5 mL microwave tube, sealed and
heated under microwave at 100.degree. C. for 30 minutes. The
mixture was concentrated and the residue was purified by
chromatography (silica gel, 0-50% ethyl acetate in hexanes) to
afford the title compound (0.22 g, 95%).
Example 6c
N-(3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4--
phenoxyphenyl)acetamide
[0751] Example 6a (0.07 g, 0.163 mmol), Example 6b (0.075 g, 0.245
mmol), tetrakis(triphenylphosphine)palladium(0) (9.44 mg, 8.17
.mu.mol) and sodium carbonate (2.0 M, 0.245 mL, 0.490 mmol) were
combined in DME (0.817 mL) and water (0.817 mL) in a 5 mL microwave
tube, sealed, sparged with nitrogen and heated under microwave at
120.degree. C. for 30 minutes. The mixture was partitioned between
ethyl acetate and water. The organic layer was washed with brine,
dried (Na.sub.2SO.sub.4), filtered and concentrated. Purification
by chromatography (silica gel, 0-5% methanol in dichloromethane)
afforded the title compound (0.048 g, 56%).
Example 6d
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyp-
henyl]acetamide
[0752] Example 6c (0.048 g, 0.091 mmol) and potassium carbonate
(0.044 g, 0.318 mmol) were combined in methanol (2 mL) and water
(0.200 mL) in a 2 mL microwave tube, sealed, and heated under
microwave at 110.degree. C. for 30 minutes. The reaction mixture
was concentrated and the residue partitioned between ethyl acetate
and water, adjusting the pH to 6 with 1M HCl. The organic layer was
separated and concentrated. Purification by flash chromatography
(silica gel, 0-4% methanol in dichloromethane) afforded 0.018 g
(53%) of the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.05 (s, 3H) 3.48 (s, 3H) 6.25-6.30 (m, 1H) 6.80 (d, J=7.46
Hz, 2H) 6.96 (t, J=7.29 Hz, 1H) 7.01 (d, J=8.82 Hz, 1H) 7.18-7.31
(m, 4H) 7.56 (dd, J=8.65, 2.54 Hz, 1H) 7.79 (d, J=2.71 Hz, 1H)
10.04 (s, 1H) 11.97 (s, 1H). MS (ESI+) m/z 374 [M+H].sup.+.
Example 7
N-(3-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridin-4-yl}-4-phenoxyphenyl)methanesulfonamide
Example 7a
2-bromo-4-nitro-1-phenoxybenzene
[0753] 2-Bromo-1-fluoro-4-nitrobenzene (2.5 g, 11.4 mmol), phenol
(1.28 g, 13.6 mmol), and cesium carbonate (4.44 g, 13.6 mmol) were
combined in dimethylsulfoxide (140 mL) and heated to 110.degree. C.
for 1 hour. The reaction mixture was partitioned between ethyl
acetate and brine. The combined organics were washed with brine,
dried (MgSO.sub.4), filtered and concentrated to afford the title
compound.
Example 7b
3-bromo-4-phenoxyaniline
[0754] Example 7a (3.43 g, 11.7 mmol), iron powder (3.26 g, 58.4
mmol), and ammonium chloride (1.25 g, 23.4 mmol) were combined in
ethanol (50 mL), tetrahydrofuran (50 mL), and water (16.7 mL), and
heated at 100.degree. C. for 2 hour. The reaction mixture was
cooled to just below reflux, vacuum filtered through diatomaceous
earth, the filter cake washed with warm methanol (3.times.35 mL),
and the filtrate concentrated under reduced pressure. The residue
was partitioned between saturated aqueous NaHCO.sub.3 and ethyl
acetate (3.times.125 mL). The combined organics were washed with
brine, dried (MgSO.sub.4), gravity filtered then concentrated to
afford the title compound.
Example 7c
N-(3-bromo-4-phenoxyphenyl)methanesulfonamide
[0755] Example 7b (2.86 g, 10.8 mmol) and triethylamine (6.03 mL,
43.3 mmol) were stirred in dichloromethane (48.1 mL) at ambient
temperature. Methanesulfonyl chloride (2.53 mL, 32.4 mmol) was
added dropwise and the solution stirred at ambient temperature for
1 hour. The reaction mixture was concentrated under reduced
pressure, dioxane (24 mL) and sodium hydroxide (10% w/v, 12 mL,
0.427 mmol) were added, and the solution was heated to 70.degree.
C. for 1 h. The solution was neutralized to a pH of 7 with
saturated aqueous NH.sub.4Cl (200 mL). The aqueous phase was
extracted with ethyl acetate (3.times.125 mL). The combined
organics were washed with brine, dried (MgSO.sub.4), filtered, then
concentrated. The residue was purified by flash chromatography
(silica gel, 0-25% ethyl acetate/hexane gradient) to afford the
title compound.
Example 7d
N-(3-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridin-4-yl}-4-phenoxyphenyl)methanesulfonamide
[0756] Example 6a (0.670 g, 1.564 mmol), Example 7c (0.562 g, 1.643
mmol), tris(dibenzylideneacetone)dipalladium(0) (0.036 g, 0.039
mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante
(0.023 g, 0.078 mmol) and potassium phosphate tribasic (1.03 g,
4.85 mmol) were combined and sparged with argon for 30 minutes. A
solution of 4:1 dioxane/water (10 mL total volume) was sparged with
nitrogen for 30 minutes and transferred by syringe into the
reaction vessel under argon. The reaction mixture was stirred at
60.degree. C. for 2 hours, cooled to room temperature and
partitioned between ethyl acetate and water. The organic layer was
washed with brine, dried (Na.sub.2SO.sub.4), treated with
3-mercaptopropyl functionalized silica gel (Aldrich, 538086-100G)
for 45 minutes, filtered and concentrated. Purification by
chromatography (silica gel, 20-100% ethyl acetate in hexanes)
afforded 0.68 g (74%) of the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.38 (s, 3H) 3.02 (s, 3H) 3.38 (s, 3H) 6.52
(d, J=3.39 Hz, 1H) 6.82 (d, J=7.80 Hz, 2H) 6.96-7.04 (m, 2H)
7.19-7.28 (m, 4H) 7.41 (d, J=8.14 Hz, 2H) 7.48 (s, 1H) 7.89-7.97
(m, 3H) 9.73 (s, 1H). MS (ESI+) m/z 564 [M+H].sup.+.
Example 8
N-methyl-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-
-phenoxyphenyl]methanesulfonamide
[0757] A mixture of Example 7d (0.113 g, 0.2 mmol) and potassium
carbonate (0.111 g, 0.800 mmol) in methanol (0.9 mL) and water (0.1
mL) was heated at 100.degree. C. for 1 hour. The reaction was
partitioned between ethyl acetate and water adjusting the pH to 7.
The organic layer was separated, dried (Na.sub.2SO.sub.4), filtered
and concentrated. The residue was purified by reverse phase HPLC
(C18, 10-100% CH.sub.3CN/water (0.1% TFA)) to afford the title
compound (0.012 g, 14%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.99 (s, 3H) 3.27 (s, 3H) 3.51 (s, 3H) 6.27-6.32 (m, 1H)
6.93 (d, J=7.80 Hz, 2H) 6.99 (d, J=8.82 Hz, 1H) 7.03-7.10 (m, 1H)
7.25-7.34 (m, 4H) 7.40 (dd, J=8.65, 2.88 Hz, 1H) 7.55 (d, J=2.71
Hz, 1H) 12.01 (s, 1H). MS (ESI+) m/z 424 [M+H].sup.+.
Example 9
ethyl
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-pheno-
xybenzoate
Example 9a
ethyl
4-fluoro-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)benzoate
[0758] A mixture of Example 1e (1.33 g, 3.5 mmol),
5-(ethoxycarbonyl)-2-fluorophenylboronic acid (1.04 g, 4.9 mmol),
Pd(PPh.sub.3).sub.4(0.20 g, 5 mol %), and sodium carbonate (0.742
g, 7.0 mmol) in toluene (12 mL), ethanol (3 mL) and water (3 mL)
was degassed and stirred under a nitrogen atmosphere. The reaction
mixture was heated at 90.degree. C. for 24 hours. The reaction
mixture was cooled to room temperature and partitioned between
water and ethyl acetate. The aqueous layer was extracted with
additional ethyl acetate twice. The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 20-50% ethyl acetate in hexanes) to afford 1.43 g
(87%) of the title compound.
Example 9b
ethyl
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-pheno-
xybenzoate
[0759] A mixture of Example 9a (1.43 g, 3.05 mmol), phenol (0.0344
g, 3.66 mmol) and cesium carbonate (0.995, 3.05 mmol), in DMSO (15
mL) was heated at 110.degree. C. for 12 hours. After cooling to
room temperature, the reaction mixture was partitioned between
water and ethyl acetate. The aqueous layer was extracted with
additional ethyl acetate twice. The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 30-80% ethyl acetate/hexane) to afford 0.85 g (72%) of
the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
1.31 (t, J=7.02 Hz, 3H), 3.55 (s, 3H), 4.32 (q, J=7.22 Hz, 2H),
6.23 (t, J=2.29 Hz, 1H), 6.97 (d, J=8.54 Hz, 1H), 7.06 (d, J=8.24
Hz, 2H), 7.17 (t, J=7.32 Hz, 1H), 7.28 (t, J=2.75 Hz, 1H),
7.36-7.51 (m, 3H), 7.94 (dd, J=8.7, 2.29 Hz, 1H), 8.04 (d, J=2.14
Hz, 1H), 12.02 (s, 1H). MS (ESI+) m/z 389.2 (M+H).sup.+.
Example 10
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenz-
oic acid
[0760] A mixture of Example 9b (0.23 g, 0.59 mmol) and sodium
hydroxide (0.89 mL of 2.0 M aqueous solution) in dioxane (10 mL)
was heated at 60.degree. C. for 2 hours. The reaction mixture was
cooled to room temperature and poured into water (100 mL). After
addition of concentrated HCl (5 mL), the mixture was extracted with
ethyl acetate (3.times.40 mL). The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated to afford 0.21 g (98%) of the title compound. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 3.55 (s, 3H), 6.24-6.25 (m,
1H), 6.94 (d, J=8.54 Hz, 1H), 7.05 (d, J=7.63 Hz, 2H), 7.16 (t,
J=7.32 Hz, 1H), 7.27 (t, J=2.9 Hz, 1H), 7.35-7.40 (m, 3H), 7.92
(dd, J=8.7, 2.29 Hz, 1H), 8.04 (d, J=2.14 Hz, 1H), 12.03 (s, 1H).
MS (ESI+) m/z 361.2 (M+H).sup.+.
Example 11
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyridin-
-3-yloxy)phenyl]methanesulfonamide
Example 11a
6-methyl-4-(5-nitro-2-(pyridin-3-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(-
6H)-one
[0761] Example 11a was prepared according to the procedure used for
the preparation of Example 2b, substituting pyridin-3-ol for
phenol, to provide the title compound.
Example 11b
4-(5-amino-2-(pyridin-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(-
6H)-one
[0762] Example 11b was prepared according to the procedure used for
the preparation of Example 3, substituting Example 11a for Example
2b, to provide the title compound.
Example 1c
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyridin-
-3-yloxy)phenyl]methanesulfonamide
[0763] Example 11c was prepared according to the procedure used in
method A of Example 4, substituting Example 11b for Example 3, and
purified by Preparative HPLC (C18, 10-100% acetonitrile in 0.1%
TFA/water) to provide the TFA salt of the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 3.49 (s, 3H), 3.05 (s, 3H),
6.25 (dd, J=2.8, 1.9 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 7.34-7.21 (m,
5H), 7.40 (d, J=2.6 Hz, 1H), 8.23-8.16 (m, 2H), 9.80 (s, 1H), 12.02
(bs, 1H). MS (ESI+) m/z 411.1 (M+H).sup.+.
Example 12
6-methyl-4-[2-(morpholin-4-ylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]p-
yridin-7-one
[0764] Example 12 was prepared according to the procedure used for
the preparation of Example 1f, substituting
2-(morpholinomethyl)phenylboronic acid for 2-phenoxyphenylboronic
acid, followed by purification by preparative HPLC (C18, 10-100%
acetonitrile in 0.1% TFA in water), to provide the TFA salt of the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 2.85
(br, 2H), 3.09 (br, 2H), 3.56 (s, 3H), 3.74 (br, 2H), 4.26 (br,
2H), 5.89-5.90 (m, 1H), 7.20 (s, 1H), 7.29 (t, J=2.75 Hz, 1H),
7.39-7.43 (m, 1H), 7.53-7.55 (m, 2H), 7.75-7.77 (m, 1H), 9.73 (br,
1H), 12.12 (s, 1H). MS (ESI+) m/z 324.0 (M+H).sup.+.
Example 13
N-ethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phe-
noxybenzamide
Example 13a
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenz-
oyl chloride
[0765] A solution of Example 10 (0.24 g, 0.67 mmol) in
dichloromethane (10 mL) was treated with oxalyl chloride (0.17 g,
1.33 mmol) and dimethylformamide (5 mg, 10 mol %). The reaction
mixture was stirred at room temperature for 2 hours. The solvent
was removed under reduced pressure to afford the title compound
(0.25 g, quantitative).
Example 13b
N-ethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phe-
noxybenzamide
[0766] A solution of Example 13a (0.040 g, 0.11 mmol) in
tetrahydrofuran (1 mL) was treated with ethylamine (0.21 mL of a 2
M solution in tetrahydrofuran, 0.42 mmol) for 2 h. The reaction
mixture was concentrated and the residue purified by preparative
HPLC (C18, 10-90% acetonitrile in 0.1% TFA in water) to afford the
title compound (0.025 g, 61%). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.12 (t, J=7.32 Hz, 3H), 3.25-3.32 (m, 2H), 3.54 (s, 3H),
6.23-6.24 (m, 1H), 6.95-6.99 (m, 3H), 7.11 (t, J=7.48 Hz, 1H), 7.27
(t, J=2.75 Hz, 1H), 7.31-7.37 (m, 3H), 7.84 (dd, J=8.54, 2.44 Hz,
1H), 7.98 (d, J=2.44 Hz, 1H), 8.46 (t, J=5.49 Hz, 1H), 11.99 (s,
1H). MS (ESI+) m/z 388.2 (M+H).sup.+.
Example 14
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N-(-
tetrahydrofuran-2-ylmethyl)benzamide
[0767] Example 14 was prepared according to the procedure used for
the preparation of Example 13b, substituting
(tetrahydrofuran-2-yl)methanamine for ethylamine, and
dichloromethane for tetrahydrofuran, respectively, to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
1.56-1.57 (m, 1H), 1.79-1.89 (m, 3H), 3.26-3.32 (m, 3H), 3.53 (s,
3H), 3.58-3.63 (m, 1H), 3.73-3.78 (m, 1H), 3.94-3.97 (m, 1H),
6.21-6.22 (m, 1H), 6.93-6.98 (m, 3H), 7.10 (t, J=7.48 Hz, 1H), 7.25
(t, J=2.9 Hz, 1H), 7.30-7.35 (m, 3H), 7.84 (dd, J=8.54, 2.44 Hz,
1H), 7.98 (d, J=2.14 Hz, 1H), 8.52 (t, J=5.8 Hz, 1H), 12.00 (s,
1H). MS (ESI+) m/z 444.2 (M+H).sup.+.
Example 15
N-cyclopentyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-
-4-phenoxybenzamide
[0768] Example 15 was prepared according to the procedure used for
the preparation of Example 13b, substituting cyclopentylamine for
ethylamine, and dichloromethane for tetrahydrofuran, respectively,
to provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.49-1.66 (m, 4H), 1.65-1.69 (m, 2H), 1.85-1.91 (m, 2H),
3.54 (s, 3H), 4.20-4.26 (m, 1H), 6.20-6.22 (m, 1H), 6.95-6.98 (m,
3H), 7.01 (t, J=7.32 Hz, 1H), 7.26 (t, J=2.75 Hz, 1H), 7.30-7.36
(m, 3H), 7.85 (dd, J=8.54, 2.14 Hz, 1H), 7.99 (d, J=2.44 Hz, 1H),
8.52 (t, J=5.8 Hz, 1H), 12.01 (s, 1H). MS (ESI+) m/z 428.3
(M+H).sup.+.
Example 16
N-(2,2-difluoroethyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)-4-phenoxybenzamide
[0769] Example 16 was prepared according to the procedure used for
the preparation of Example 13b, substituting 2,2-difluoroethanamine
for ethylamine, and dichloromethane for tetrahydrofuran,
respectively, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.55 (s, 3H), 3.62-3.72 (m, 3H), 5.97 (t,
J=3.97 Hz, 0.25H), 6.11 (t, J=4.12 Hz, 0.5H), 6.23-6.26 (m, 1.25H),
6.98 (d, J=8.54 Hz, 1H), 7.01 (d, J=7.63 Hz, 2H), 7.13 (t, J=7.48
Hz, 1H), 7.27 (t, J=2.75 Hz, 1H), 7.33-7.36 (m, 3H), 7.88 (dd,
J=8.54, 2.44 Hz, 1H), 8.03 (d, J=2.14 Hz, 1H), 8.85 (t, J=5.8 Hz,
1H), 12.03 (s, 1H). MS (ESI+) m/z 424.2 (M+H).sup.+.
Example 17
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-N-(-
1,3-thiazol-2-yl)benzamide
[0770] Example 17 was prepared according to the procedure used for
the preparation of Example 13b, substituting thiazol-2-amine for
ethylamine, and dichloromethane for tetrahydrofuran, respectively,
to provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.58 (s, 3H), 6.30-6.31 (m, 1H), 6.23-6.26 (m, 1H), 6.98
(d, J=8.54 Hz, 1H), 7.07 (d, J=7.63 Hz, 2H), 7.17 (t, J=7.32 Hz,
1H), 7.27-7.29 (m, 2H), 7.38-7.42 (m, 3H), 7.56 (d, J=3.36 Hz, 1H),
8.09 (dd, J=8.55, 2.44 Hz, 1H), 8.28 (d, J=2.44 Hz, 1H), 12.04 (s,
1H), 12.61 (s, 1H). MS (ESI+) m/z 443.1 (M+H).sup.+.
Example 18
N-(1,1-dioxidotetrahydrothiophen-3-yl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-c]pyridin-4-yl)-4-phenoxybenzamide
[0771] Example 18 was prepared according to the procedure used for
the preparation of Example 13b, substituting
1,1-dioxidotetrahydrothien-3-ylamine for ethylamine, and
dichloromethane for tetrahydrofuran, respectively, to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
2.20-2.23 (m, 1H), 2.41-2.45 (m, 1H), 3.04-3.09 (m, 1H), 3.19-3.23
(m, 1H), 3.34-3.37 (m, 1H), 3.48-3.53 (m, 1H), 3.55 (s, 3H),
4.66-4.76 (m, 1H), 6.30-6.31 (m, 1H), 6.21-6.22 (m, 1H), 6.99 (dd,
J=8.09, 2.59 Hz, 2H), 7.12 (t, J=7.48 Hz, 1H), 7.27 (t, J=2.75 Hz,
1H), 7.31-7.37 (m, 3H), 7.87 (dd, J=8.54, 2.14 Hz, 1H), 8.02 (d,
J=2.14 Hz, 1H), 8.72 (d, J=7.02 Hz, 1H), 12.03 (s, 1H). MS (ESI+)
m/z 478.2 (M+H).sup.+.
Example 19
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenz-
amide
[0772] Example 19 was prepared according to the procedure used for
the preparation of Example 13b, substituting aqueous ammonium
hydroxide for ethylamine to provide the title compound. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 3.54 (s, 3H), 6.23-6.24 (m, 1H),
6.94 (d, J=8.54 Hz, 1H), 6.98-7.00 (m, 2H), 7.11 (t, J=7.48 Hz,
1H), 7.26 (t, J=2.75 Hz, 1H), 7.31-7.37 (m, 4H), 7.86 (dd, J=8.54,
2.44 Hz, 1H), 7.96 (s, 1H), 8.02 (d, J=2.44 Hz, 1H), 12.01 (s, 1H).
MS (ESI+) m/z 360.2 (M+H).sup.+.
Example 20
4-[5-(hydroxymethyl)-2-phenoxyphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3--
c]pyridin-7-one
Example 20a
ethyl
3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-
-4-phenoxybenzoate
[0773] Example 20a was prepared according to the procedure used for
the preparation of Example 1c, substituting Example 9b for Example
1b to provide the title compound.
Example 20b
4-[5-(hydroxymethyl)-2-phenoxyphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3--
c]pyridin-7-one
[0774] Example 20a (0.32 g, 0.59 mmol) in tetrahydrofuran (5 mL)
was cooled to 0.degree. C. To this solution was added 1.0 N
aluminum lithium hydride (0.59 mL, 0.59 mmol). The reaction mixture
was stirred at room temperature for 1 hour. The reaction mixture
was quenched with 2.0 N HCl (5 mL), and then partitioned between
water and ethyl acetate. The aqueous layer was extracted with
additional ethyl acetate twice. The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel eluting with 50-100% ethyl acetate in hexanes to afford
0.08 g (39%) of the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.49 (s, 3H), 4.54 (d, J=5.49 Hz, 2H), 5.21
(t, J=5.8 Hz, 1H), 6.23-6.24 (m, 1H), 6.94 (d, J=7.93 Hz, 2H),
6.97-7.01 (m, 2H), 7.22-7.28 (m, 4H), 7.32 (dd, J=8.39, 2.29 Hz,
1H), 7.16 (d, J=1.83 Hz, 1H), 11.97 (s, 1H). MS (ESI+) m/z 347.3
(M+H).sup.+.
Example 21
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyp-
henyl]ethanesulfonamide
[0775] Example 21 was prepared according to the procedure used in
method A of Example 4, substituting ethanesulfonyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.24 (t, J=7.3 Hz, 3H), 3.13
(q, J=7.3 Hz, 2H), 3.48 (s, 3H), 6.26 (t, J=2.3 Hz, 1H), 6.88-6.80
(m, 2H), 7.07-6.95 (m, 2H), 7.31-7.18 (m, 5H), 7.40 (d, J=2.7 Hz,
1H), 9.79 (s, 1H), 12.02 (bs, 1H). MS (ESI+) m/z 424.2
(M+H).sup.+.
Example 22
N,N-dimethyl-N'-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4--
yl)-4-phenoxyphenyl]sulfuric diamide
[0776] Example 22 was prepared according to the procedure used in
method A of Example 4, substituting dimethylsulfamoyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 2.74 (s, 6H), 3.48 (s, 3H),
6.28-6.23 (m, 1H), 6.85-6.78 (m, 2H), 7.06-6.93 (m, 2H), 7.31-7.17
(m, 5H), 7.40 (d, J=2.7 Hz, 1H), 9.91 (s, 1H), 12.04-12.00 (m, 1H).
MS (ESI+) m/z 439.1 (M+H).sup.+.
Example 23
N-[5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-phenoxyp-
yridin-3-yl]methanesulfonamide
Example 23a
3-bromo-5-nitro-2-phenoxypyridine
[0777] Phenol (0.416 g, 4.42 mmol),
3-bromo-2-chloro-5-nitropyridine (Combi-Blocks, CAS [5470-17-7], 1
g, 4.21 mmol) and cesium carbonate (1.372 g, 4.21 mmol) were
combined in DMSO (8 mL) and heated at 80.degree. C. for 30 minutes.
The reaction mixture was cooled and partitioned between ethyl
acetate and water. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated. Purification of the
residue by chromatography (silica gel, 0-30% ethyl acetate in
hexanes) afforded the title compound (1.13 g, 91%).
Example 23b
6-methyl-4-(5-nitro-2-phenoxypyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridi-
n-7(6H)-one
[0778] Example 23b was prepared according to the procedure used for
the preparation of Example 7d, substituting the product of Example
23a for the product of Example 7c and stirring at 60.degree. C. for
24 hours, to provide the title compound.
Example 23c
4-(5-amino-2-phenoxypyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridi-
n-7(6H)-one
[0779] Example 23c was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
23b for the product of Example 2, to provide the title
compound.
Example 23d
N-[5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-phenoxyp-
yridin-3-yl]methanesulfonamide
[0780] Example 23d was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 23c for
the product of Example 3, to provide the title compound (0.035 g,
36%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.05 (s, 3H) 3.57
(s, 3H) 6.28-6.36 (m, 1H) 7.10 (d, J=7.54 Hz, 2H) 7.16 (t, J=7.54
Hz, 1H) 7.28-7.41 (m, 3H) 7.48 (s, 1H) 7.78 (d, J=2.78 Hz, 1H) 7.96
(d, J=2.38 Hz, 1H) 9.79 (s, 1H) 12.11 (s, 1H). MS (ESI+) m/z 411.0
(M+H).sup.+.
Example 24
N-[3-fluoro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-
-phenoxyphenyl]methanesulfonamide
Example 24a
4-(2,3-difluoro-5-nitrophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7-
(6H)-one
[0781] Example 24a was prepared according to the procedure used for
the preparation of Example 7d, substituting
1-bromo-2,3-difluoro-5-nitrobenzene (Oakwood Products) for the
product of Example 7c, to provide the title compound.
Example 24b
4-(3-fluoro-5-nitro-2-phenoxyphenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6-
H)-one
[0782] Phenol (0.043 g, 0.457 mmol), Example 24a (0.2 g, 0.435
mmol) and cesium carbonate (0.142 g, 0.435 mmol) were combined in
DMSO (2.177 mL) and heated at 80.degree. C. for 30 minutes. The
reaction mix was cooled and partitioned between ethyl acetate and
water. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated to afford the title
compound.
Example 24c
4-(5-amino-3-fluoro-2-phenoxyphenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6-
H)-one
[0783] Example 24c was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
24b for the product of Example 2, to provide the title
compound.
Example 24d
N-[3-fluoro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-
-phenoxyphenyl]methanesulfonamide
[0784] Example 24d was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 24c for
the product of Example 3, to provide the title compound (0.13 g,
67%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.05 (s, 3H) 3.57
(s, 3H) 6.28-6.36 (m, 1H) 7.10 (d, J=7.54 Hz, 2H) 7.16 (t, J=7.54
Hz, 1H) 7.28-7.41 (m, 3H) 7.48 (s, 1H) 7.78 (d, J=2.78 Hz, 1H) 7.96
(d, J=2.38 Hz, 1H) 9.79 (s, 1H) 12.11 (s, 1H).
Example 25
N-[4-(2-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]methanesulfonamide
Example 25a
2-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophe-
noxy)benzonitrile
[0785] Example 25a was prepared according to the procedure used for
the preparation of Example 2b, substituting 2-hydroxybenzonitrile
for phenol, to provide the title compound.
Example 25b
2-(4-amino-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phe-
noxy)benzonitrile
[0786] Example 25b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
25a for the product of Example 2b, to provide the title
compound.
Example 25c
N-[4-(2-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]methanesulfonamide
[0787] Example 25c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 25b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 3.07 (s, 3H), 3.50 (s, 3H),
6.26 (dd, J=2.8, 1.9 Hz, 1H), 6.73 (dd, J=8.6, 0.9 Hz, 1H), 7.07
(td, J=7.6, 0.9 Hz, 1H), 7.34-7.23 (m, 4H), 7.53-7.40 (m, 2H), 7.71
(dd, J=7.7, 1.7 Hz, 1H), 9.89 (s, 1H), 12.03 (bs, 1H). MS (ESI+)
m/z 435.2 (M+H).sup.+.
Example 26
N-[4-(4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)phenyl]methanesulfonamide
Example 26a
4-(2-(4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(-
6H)-one
[0788] Example 26a was prepared according to the procedure used for
the preparation of Example 2b, substituting 4-fluorophenol for
phenol, to provide the title compound.
Example 26b
4-(5-amino-2-(4-fluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(-
6H)-one
[0789] Example 26b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
26a for the product of Example 2b, to provide the title
compound.
Example 26c
N-[4-(4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)phenyl]methanesulfonamide
[0790] Example 26c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 26b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 3.02 (s, 3H), 3.50 (s, 3H),
6.29-6.23 (m, 1H), 6.94-6.82 (m, 2H), 7.14-6.96 (m, 3H), 7.21 (dd,
J=8.7, 2.7 Hz, 1H), 7.31-7.24 (m, 2H), 7.38 (d, J=2.7 Hz, 1H), 9.71
(s, 1H), 12.02 (bs, 1H). MS (ESI+) m/z 428.1 (M+H).sup.+.
Example 27
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]methanesulfonamide
Example 27a
4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridi-
n-7(6H)-one
[0791] Example 27a was prepared according to the procedure used for
the preparation of Example 2b, substituting 2,4-difluorophenol for
phenol, to provide the title compound.
Example 27b
4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridi-
n-7(6H)-one
[0792] Example 27b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
27a for the product of Example 2b, to provide the title
compound.
Example 27c
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]methanesulfonamide
[0793] Example 27b (50 mg, 0.136 mmol) and triethylamine (0.057 mL,
0.408 mmol) were combined in CH.sub.2Cl.sub.2 (9 mL).
Methanesulfonyl chloride (0.042 mL, 0.544 mmol) was added dropwise
and the solution stirred at ambient temperature for 1 hour. The
solution was concentrated under reduced pressure, dioxane (5 mL)
and sodium hydroxide (10% w/v, 3 mL, 0.136 mmol) were added and the
solution heated at 70.degree. C. for 1 hour. The mixture was cooled
to ambient temperature and then neutralized with saturated
NH.sub.4Cl (100 mL) to a pH of 8. The organic layer was separated
and the aqueous phase was extracted with ethyl acetate (3.times.25
mL). The combined organic layers were washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. Purification by reverse
phase HPLC (C18, 10-100% acetonitrile/water, 0.1% TFA) afforded
27.5 mg (45.4%) of the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 3.01 (s, 3H), 3.53 (s, 3H), 6.29-6.23 (m,
1H), 7.04-6.90 (m, 2H), 7.09 (td, J=9.1, 5.6 Hz, 1H), 7.44-7.14 (m,
5H), 9.70 (s, 1H), 12.04 (bs, 1H). MS (ESI+) m/z 446.1
(M+H).sup.+.
Example 28
N-[3-chloro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-
-phenoxyphenyl]methanesulfonamide
Example 28a
4-(3-chloro-2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyri-
din-7(6H)-one
[0794] Example 28a was prepared according to the procedure used for
the preparation of Example 6c, substituting
1,3-dichloro-2-fluoro-5-nitrobenzene (0.176 g, 0.841 mmol) for the
product of Example 6b, to provide the title compound.
Example 28b
N-[3-chloro-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-
-phenoxyphenyl]methanesulfonamide
[0795] Example 28b was prepared according to the procedures used
for the preparation of Examples 24b-24d, substituting Example 28a
for the product of Example 24a, to provide the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.12 (s, 3H) 3.43 (s,
3H) 6.25-6.29 (m, 1H) 6.63 (d, J=7.93 Hz, 2H) 6.87 (t, J=7.34 Hz,
1H) 7.10-7.18 (m, 2H) 7.27-7.31 (m, 2H) 7.39 (s, 2H) 10.05 (s, 1H)
12.04 (s, 1H). MS (ESI+) m/z 444 (M+H).sup.+.
Example 29
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-4-yloxy)phenyl]methanesulfonamide
Example 29a
6-methyl-4-(5-nitro-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0796] Tetrahydro-2H-pyran-4-ol (0.046 g, 0.453 mmol) in
tetrahydrofuran (2 mL) was treated with sodium hydride (0.022 g,
0.906 mmol, 0.036 g of 60% dispersion in oil) at room temperature.
The reaction mixture was stirred for 10 minutes. To this solution
was added Example 2a (0.1 g. 0.227 mmol). The reaction mixture was
heated at 50.degree. C. for 2 hours. After cooling to room
temperature, the reaction mixture was partitioned between water and
ethyl acetate. The aqueous layer was extracted twice with
additional ethyl acetate. The combined organic layers were washed
with brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel eluting
with ethyl acetate to afford 0.055 g of the title compound.
Example 29b
4-(5-amino-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0797] A mixture of Example 29b (0.055 g) and 10% palladium on
carbon (0.050 g) in ethyl acetate (10 mL) was treated with a
balloon of hydrogen overnight. The solid was removed by filtration.
The filtrate was concentrated under reduced pressure to provide
0.042 g of the title compound.
Example 29c
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-4-yloxy)phenyl]methanesulfonamide
[0798] Example 29c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 29b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 1.45-1.51 (m, 2H), 1.82-1.87
(m, 2H), 2.94 (s, 3H), 3.35-3.41 (m, 2), 3.56 (s, 3H), 3.60-3.68
(m, 2H), 4.45-4.49 (m, 1H), 6.20 (t, J=2.29 Hz, 1H), 7.14-7.16 (m,
2H), 7.28-7.29 (m, 3H), 9.45 (s, 1H), 12.01 (s, 1H). (ESI+) m/z
418.2 (M+H).sup.+.
Example 30
6-methyl-4-[2-phenoxy-5-(1H-pyrazol-1-ylmethyl)phenyl]-1,6-dihydro-7H-pyrr-
olo[2,3-c]pyridin-7-one
[0799] A mixture of Example 20b (0.04 g, 0.115 mmol), 1H-pyrazole
(0.016 g, 0.231 mmol), and triphenylphosphine (0.061 g, 0.231 mmol)
in tetrahydrofuran (1 mL) was stirred for 2 minutes. To this
solution was added di-t-butyl azodicarboxylate (DTBAD, 0.053 g,
0.231 mmol). The reaction mixture was stirred at room temperature
for 3 hours. The solvent was removed under reduced pressure, and
the residue was purified by preparative HPLC (C18, 10-80%
acetonitrile/water with 0.1% TFA) to afford 0.006 g of the title
compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 3.49 (s, 3H),
5.37 (s, 2H), 5.21 (t, J=5.8 Hz, 1H), 6.17-6.18 (m, 1H), 6.28 (t,
J=1.98 Hz, 1H), 6.86 (d, J=7.63 Hz, 2H), 6.97 (d, J=8.24 Hz, 1H),
7.02 (t, J=7.32 Hz, 4H), 7.22-7.29 (m, 5H), 7.39 (d, J=2.14 Hz,
1H), 7.47 (d, J=1.83 Hz, 1H), 7.53-7.46 (m, 3H), 7.86 (d, J=2.44
Hz, 1H), 11.97 (s, 1H). (ESI+) m/z 397.2 (M+H).sup.+.
Example 31
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
drofuran-3-yloxy)phenyl]methanesulfonamide
Example 31a
6-methyl-4-(5-nitro-2-(tetrahydrofuran-3-yloxy)phenyl)-1H-pyrrolo[2,3-c]py-
ridin-7(6H)-one
[0800] Example 31a was prepared according to the procedure used for
the preparation of Example 29a, substituting tetrahydrofuran-3-ol
for tetrahydro-2H-pyran-4-ol, to provide the title compound.
Example 31b
4-(5-amino-2-(tetrahydrofuran-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]py-
ridin-7(6H)-one
[0801] Example 31b was prepared according to the procedure used for
the preparation of Example 29b, substituting the product of Example
31a for the product of Example 29a, to provide the title
compound.
Example 31c
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
drofuran-3-yloxy)phenyl]methanesulfonamide
[0802] Example 31 was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 31b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 1.84-1.90 (m, 1H), 2.08-2.17
(m, 1H), 2.95 (s, 3H), 3.35-3.41 (m, 2), 3.56 (s, 3H), 3.62-3.69
(M, 2H), 3.80-3.84 (m, 1H), 4.96-4.98 (m, 1H), 6.17-6.18 (m, 1H),
7.06-7.08 (m, 1H), 7.16-7.18 (m, 1H), 7.25 (s, 1H), 7.27-7.29 (m,
2H), 9.45 (s, 1H), 12.00 (s, 1H). (ESI+) m/z 404.2 (M+H).sup.+.
Example 32
N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[2-(trif-
luoromethyl)phenoxy]phenyl}methanesulfonamide
Example 32a
6-methyl-4-(5-nitro-2-(2-(trifluoromethyl)phenoxy)phenyl)-1H-pyrrolo[2,3-c-
]pyridin-7(6H)-one
[0803] Example 32a was prepared according to the procedure used for
the preparation of Example 2b, substituting
2-(trifluoromethyl)phenol for phenol, to provide the title
compound.
Example 32b
4-(5-amino-2-(2-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c-
]pyridin-7(6H)-one
[0804] Example 32b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
32a for the product of Example 2b, to provide the title
compound.
Example 32c
N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[2-(trif-
luoromethyl)phenoxy]phenyl}methanesulfonamide
[0805] Example 32c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 32b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 3.05 (s, 3H), 3.44 (s, 3H),
6.32-6.26 (m, 1H), 6.75 (d, J=8.4 Hz, 1H), 7.17-7.07 (m, 2H),
7.34-7.18 (m, 3H), 7.53-7.38 (m, 2H), 7.65 (dd, J=7.8, 1.6 Hz, 1H),
9.84 (s, 1H), 12.09-11.99 (m, 1H). MS (ESI+) m/z 478.1
(M+H).sup.+.
Example 33
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]methanesulfonamide
Example 33a
4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophe-
noxy)benzonitrile
[0806] Example 33a was prepared according to the procedure used for
the preparation of Example 2b, substituting 4-hydroxybenzonitrile
for phenol, to provide the title compound.
Example 33b
4-(4-amino-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phe-
noxy)benzonitrile
[0807] Example 33b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
33a for the product of Example 2b, to provide the title
compound.
Example 33c
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]methanesulfonamide
[0808] Example 33c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 33b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 3.07 (s, 3H), 3.46 (s, 3H),
6.27-6.21 (m, 1H), 6.94-6.87 (m, 2H), 7.32-7.20 (m, 4H), 7.42 (d,
J=2.5 Hz, 1H), 7.70-7.63 (m, 2H), 9.87 (s, 1H), 12.03 (bs, 1H). MS
(ESI+) m/z 435.2 (M+H).sup.+.
Example 34
N-[4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridin-4-yl)phenyl]methanesulfonamide
Example 34a
4-(2-(2-chloro-4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]p-
yridin-7(6H)-one
[0809] Example 34a was prepared according to the procedure used for
the preparation of Example 2b, substituting 2-chloro-4-fluorophenol
for phenol, to provide the title compound.
Example 34b
4-(5-amino-2-(2-chloro-4-fluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]p-
yridin-7(6H)-one
[0810] Example 34b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
34a for the product of Example 2b, to provide the title
compound.
Example 34c
N-[4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridin-4-yl)phenyl]methanesulfonamide
[0811] Example 34c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 34b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 3.02 (s, 3H), 3.52 (s, 3H),
6.29 (t, J=2.3 Hz, 1H), 6.99-6.88 (m, 2H), 7.14-7.03 (m, 1H), 7.21
(dd, J=8.7, 2.7 Hz, 1H), 7.28 (t, J=2.8 Hz, 1H), 7.34 (s, 1H), 7.41
(d, J=2.7 Hz, 1H), 7.49 (dd, J=8.3, 3.0 Hz, 1H), 9.75 (s, 1H),
12.05 (bs, 1H). MS (ESI+) m/z 462.1 (M+H).sup.+.
Example 35
[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl-
)phenyl]acetic acid
Example 35a
ethyl 2-(3-bromo-4-hydroxyphenyl)acetate
[0812] To a solution of ethyl 2-(4-hydroxyphenyl)acetate (Alfa,
2.70 g, 15 mmol) in acetic acid (20 mL) was added drop wise over 15
minutes a solution of bromine (0.773 mL, 15.00 mmol) in acetic acid
(15 mL). The mixture was stirred at ambient temperature for 30
minutes and evaporated. Purification by chromatography (silica gel,
10-20% ethyl acetate in hexane) afforded the title compound (3.66
g, 94%).
Example 35b
ethyl 2-(4-(benzyloxy)-3-bromophenyl)acetate
[0813] A solution of Example 35a (2.011 mL, 16.90 mmol), and
potassium carbonate (5.84 g, 42.3 mmol) in ethanol (100 mL) was
refluxed for 2 hours, cooled, concentrated and the residue was
partitioned with ethyl acetate and water. The organic layer was
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated. Purification of the residue by chromatography (silica
gel, 0-20% ethyl acetate in hexane) afforded the title compound
(4.84 g, 98%).
Example 35c
ethyl
2-(4-(benzyloxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,-
3-c]pyridin-4-yl)phenyl)acetate
[0814] Example 35c was prepared according to the procedure used for
the preparation of Example 7d, substituting the product of Example
35b for the product of Example 7c to provide the title
compound.
Example 35d
[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl-
)phenyl]acetic acid
[0815] Example 35c (0.4 g, 0.701 mmol), potassium hydroxide (0.787
g, 14.02 mmol) and cetyltrimethylammonium bromide (0.013 g, 0.035
mmol) were combined in dioxane (10 mL) and water (5 mL) and heated
at 100.degree. C. for 3 hours, cooled and partitioned between equal
volumes of ethyl acetate and water (20 mL each). The pH was
adjusted to pH 2 by careful addition of concentrated HCl. The
organic layer was separated and washed with saturated brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated. Trituration of the
residue in hexane afforded the title compound (0.27 g, 98%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.52 (s, 3H) 3.55 (s,
2H) 5.09 (s, 2H) 6.14-6.21 (m, 1H) 7.10-7.33 (m, 10H) 11.97 (s, 1H)
12.25 (s, 1H). MS (ESI+) m/z 389.0 (M+H).sup.+.
Example 36
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]ethanesulfonamide
Example 36a
2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene
[0816] A mixture of 2-bromo-1-fluoro-4-nitrobenzene (15 g, 68
mmol), 2,4-difluorophenol (7.82 ml, 82 mmol), and cesium carbonate
(26.7 g, 82 mmol) in dimethylsulfoxide (75 mL) was heated to
110.degree. C. for 1 hour. The reaction mixture was cooled to
ambient temperature and water (1000 mL) and saturated aqueous
sodium chloride (1000 mL) were added. The mixture was extracted
with ethyl acetate (3.times.200 mL). The combined organics were
washed with saturated aqueous sodium chloride, dried (anhydrous
magnesium sulfate), filtered, and concentrated under reduced
pressure to provide the title compound (22.5 g, quantitative).
Example 36b
3-bromo-4-(2,4-difluorophenoxy)aniline
[0817] A mixture of Example 36a (22.5 g, 68.2 mmol), iron powder
(19.04 g, 341 mmol), and ammonium chloride (7.30 g, 136 mmol) in
tetrahydrofuran (117 mL), ethanol (117 mL), and water (39.0 mL) was
heated under reflux at 100.degree. C. for 2 hours. The reaction
mixture was cooled to just below reflux temperature, filtered
through celite, and the filter cake washed with warm methanol
(3.times.50 mL). The resulting solution was concentrated under
reduced pressure and then neutralized to a pH of 8 with saturated
sodium hydrogen carbonate (150 mL). The mixture was extracted with
ethyl acetate (3.times.100 mL). The combined organics were washed
with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, ethyl acetate/hexane
gradient 0-15%) to provide the title compound (16.8 g, 82%
yield).
Example 36c
4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0818] A mixture of Example 6a (5.0 g, 11.67 mmol), Example 36b
(3.85 g, 12.84 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.399 g, 1.366 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.321 g, 0.350 mmol), and potassium phosphate (6.19 g, 29.2 mmol)
in dioxane (50 mL) and water (12.5 mL) was degassed and back-filled
with nitrogen several times. The reaction mixture was heated at
60.degree. C. for 16 hours and then cooled to ambient temperature.
The reaction mixture was partitioned between water and ethyl
acetate. The aqueous layer was extracted with additional ethyl
acetate three times. The combined organic layers were washed with
brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by flash column
chromatography (silica gel, 60% ethyl acetate/hexanes) to provide
the title compound (4.40 g, 72.3% yield)
Example 36d
N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide
[0819] A solution of Example 36c (4.35 g, 8.34 mmol) in
dichloromethane (50 mL) was cooled to 0.degree. C. To this solution
was added ethanesulfonyl chloride (2.37 mL, 25.0 mmol). The
reaction mixture was stirred at room temperature for 2 hours. The
solvent was evaporated, and the residue was partitioned between
ethyl acetate and water. The aqueous layer was extracted with
additional ethyl acetate twice. The combined organic layers were
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 80% ethyl
acetate/hexanes) to provide the title compound (5.34 g, 91%
yield).
Example 36e
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]ethanesulfonamide
[0820] A mixture of Example 36d (5.3 g, 7.5 mmol), potassium
hydroxide (8.43 g, 150 mmol), and
N,N,N-trimethylhexadecan-1-aminium bromide (0.137 g, 0.375 mmol) in
tetrahydrofuran (60 mL) and water (30 mL) was heated at 90.degree.
C. for 16 hours. Tetrahydrofuran was removed under reduced
pressure, and the residue was partitioned between water and ethyl
acetate. The aqueous layer was neutralized to pH=7 using 10% HCl.
The aqueous layer was then extracted with ethyl acetate. The
combined organic layers were washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, ethyl acetate). The desired fractions were combined
and concentrated. The residue was triturated with 20 mL of
acetonitrile to provide the title compound (2.82 g, 82% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.23 (t, J=7.3 Hz, 3H),
3.11 (q, J=7.3 Hz, 2H), 3.53 (s, 3H), 6.27-6.22 (m, 1H), 6.91 (d,
J=8.7 Hz, 1H), 7.13-6.93 (m, 2H), 7.19 (dd, J=8.8, 2.7 Hz, 1H),
7.32-7.25 (m, 2H), 7.42-7.31 (m, 2H), 9.77 (s, 1H), 12.04 (bs, 1H).
MS (ESI+) m/z 460.1 (M+H).sup.+.
Example 37
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]acetamide
[0821] Example 27b (50 mg, 0.136 mmol) and triethylamine (56.9
.mu.L, 0.408 mmol) were combined in CH.sub.2Cl.sub.2 (10 mL).
Acetyl chloride (11.6 .mu.L, 0.163 mmol) was added dropwise and the
solution stirred for 1 hour at ambient temperature. Water (25 mL)
and saturated aqueous sodium bicarbonate (25 mL) were added, and
the mixture was extracted with CH.sub.2Cl.sub.2 (3.times.25 mL).
The combined organics were washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. Purification of the residue by reverse
phase HPLC (C18, 10-100% acetonitrile/water, 0.1% TFA) afforded 15
mg (28%) of the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.04 (s, 3H), 3.52 (s, 3H), 6.29-6.23 (m, 1H), 7.08-6.85
(m, 3H), 7.39-7.25 (m, 3H), 7.53 (dd, J=8.8, 2.6 Hz, 1H), 7.77 (d,
J=2.6 Hz, 1H), 10.00 (s, 1H), 12.07-11.96 (m, 1H). MS (ESI+) m/z
410.3 (M+H).sup.+.
Example 38
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-3,3,3-trifluoropropanamide
[0822] Example 38 was prepared according to the procedure used for
the preparation of Example 37, substituting
3,3,3-trifluoropropanoyl chloride for acetyl chloride, to provide
the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
3.54-3.46 (m, 2H), 3.53 (s, 3H), 6.27 (t, J=2.3 Hz, 1H), 7.14-6.87
(m, 3H), 7.28 (t, J=2.7 Hz, 1H), 7.31 (s, 1H), 7.37 (ddd, J=11.3,
8.7, 2.8 Hz, 1H), 7.50 (dd, J=8.8, 2.6 Hz, 1H), 7.76 (d, J=2.6 Hz,
1H), 10.38 (s, 1H), 12.03 (bs, 1H). MS (ESI+) m/z 478.2
(M+H).sup.+.
Example 39
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-2,2-dimethylpropanamide
[0823] Example 39 was prepared according to the procedure used for
the preparation of Example 37, substituting pivaloyl chloride for
acetyl chloride, to provide the title compound. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 1.22 (s, 9H), 3.53 (s, 3H), 6.31-6.25
(m, 1H), 6.88 (d, J=8.8 Hz, 1H), 7.08-6.92 (m, 2H), 7.31-7.24 (m,
2H), 7.40-7.29 (m, 1H), 7.62 (dd, J=8.8, 2.6 Hz, 1H), 7.83 (d,
J=2.6 Hz, 1H), 9.28 (s, 1H), 12.00 (bs, 1H). MS (ESI+) m/z 452.3
(M+H).sup.+.
Example 40
ethyl
4-(cyclopentylamino)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)benzoate
[0824] A mixture of Example 9a (0.094 g, 0.2 mmol),
cyclopentanamine (0.034 g, 0.4 mmol), and triethylamine (0.081 g,
0.8 mmol) in DMSO (2 mL) was heated at 120.degree. C. overnight.
The reaction mixture was purified by preparative HPLC (C18, 10-80%
acetonitrile in 0.1% TFA/water to afford 0.019 g of the title
product. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.27 (t,
J=7.02 Hz, 3H), 1.32-1.36 (m, 2H), 1.47-1.55 (m, 3H), 1.88-1.93 (m,
2H), 3.55 (s, 3H), 3.83-3.88 (m, 1H), 4.22 (q, J=7.02 Hz, 2H), 5.94
(t, J=2.29 Hz, 1H), 6.77 (d, J=8.85 Hz, 1H), 7.22 (s, 1H), 7.28 (t,
J=2.75 Hz, 1H), 7.63 (d, J=1.83 Hz, 1H), 7.82 (dd, J=8.54, 2.14,
1H), 12.01 (s, 1H). MS (ESI+) m/z 380.2 (M+H).sup.+.
Example 41
4-{5-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-2-phenoxyphenyl}-6-methyl--
1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 41a
4-(5-(hydroxymethyl)-2-phenoxyphenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]py-
ridin-7(6H)-one
[0825] Example 41a was isolated as a by-product from the
preparation of Example 20b.
Example 41b
3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phe-
noxybenzyl methanesulfonate
[0826] A mixture of Example 41a (0.15 g, 0.3 mmol), methanesulfonyl
chloride (0.069 g, 0.6 mmol), and triethylamine (0.121 g, 1.2 mmol)
in dichloromethane (5 mL) was stirred at room temperature for 2
hours. The solvent was removed, and the residue was purified by
flash chromatography on silica gel eluting with 20-40% ethyl
acetate in hexanes to afford 0.105 g of the title product.
Example 41c
4-{5-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-2-phenoxyphenyl}-6-methyl--
1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0827] 1,2-thiazolidine 1,1-dioxide (0.031 g, 0.259 mmol) in
dimethylformamide (1 mL) was treated with 60% sodium hydride (0.012
g, 0.518 mmol, 0.021 g of a 60% in oil dispersion). The reaction
mixture was stirred for 5 min. To this solution was added Example
41b (0.05 g, 0.086 mmol). The reaction mixture was stirred at room
temperature for 2 hours. 2 N NaOH (1 mL) was added and the reaction
mixture was heated at 65.degree. C. for 2 hours. After cooling to
room temperature, the reaction mixture was partitioned between
water and ethyl acetate. The aqueous layer was extracted with
additional ethyl acetate twice. The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by preparative HPLC (C18,
10-80% acetonitrile in 0.1% TFA water) to afford 0.025 g (64%) of
the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
2.21-2.25 (m, 2H), 3.15 (t, J=6.97 Hz, 2H), 3.23-3.27 (m, 2H), 3.50
(s, 3H), 4.13 (s, 2H), 6.25-6.26 (m, 1H), 6.88 (d, J=7.63 Hz, 2H),
7.00 (d, J=8.54 Hz, 1H), 7.03-7.05 (m, 1H), 7.25-7.30 (m, 4H), 7.34
(dd, J=8.39, 2.29, 1H), 7.48 (d, J=2.44 Hz, 1H), 12.00 (s, 1H). MS
(ESI+) m/z 450.2 (M+H).sup.+.
Example 42
4-{[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxy-
benzyl]amino}-4-oxobutanoic acid
[0828] Example 42 was prepared according to the procedure used for
the preparation of Example 41c, substituting pyrrolidine-2,5-dione
for 1,2-thiazolidine 1,1-dioxide, to provide the title compound.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 2.37-2.40 (m, 2H),
2.44-2.48 (m, 2H), 3.50 (s, 3H), 4.31 (d, J=5.8 Hz, 2H), 6.23-6.24
(m, 1H), 6.84 (d, J=7.63 Hz, 2H), 6.96 (d, J=8.24 Hz, 1H), 7.00 (t,
J=7.32 Hz, 1H), 7.22-7.29 (m, 5H), 7.40 (d, J=2.14, 1H), 8.40 (t,
J=5.95 Hz, 1H), 11.98 (s, 1H). MS (ESI+) m/z 446.1 (M+H).sup.+.
Example 43
4-[2-(2,4-difluorophenoxy)-5-(1,1-dioxido-1,2-thiazolidin-2-yl)phenyl]-6-m-
ethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 43a
3-chloro-N-(3-chloropropylsulfonyl)-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-
-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)propane-1-sulfonam-
ide
[0829] A mixture of Example 27b (0.1 g, 0.272 mmol),
3-chloropropane-1-sulfonyl chloride (0.145 g, 0.817 mmol), and
triethylamine (0.165 g, 1.633 mmol) in dichloromethane (3 mL) was
stirred for 2 hours. The solvent was removed, and the residue was
used directly for the next reaction.
Example 43b
4-[2-(2,4-difluorophenoxy)-5-(1,1-dioxido-1,2-thiazolidin-2-yl)phenyl]-6-m-
ethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0830] Sodium (0.064 g, 2.78 mmol) was dissolved in ethanol (15
mL). To this solution was added Example 43a (0.18 g, 0.278 mmol) in
ethanol (5 mL). The reaction mixture was heated at 75.degree. C.
for 2 hours. After cooling, the solvent was removed under reduced
pressure, and the residue was purified by preparative HPLC (C18,
10-80% acetonitrile in 0.1% TFA/water) to afford 0.055 g of the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
2.37-2.44 (m, 2H), 3.49-3.53 (m, 2H), 3.54 (s, 3H), 3.76 (t, J=6.56
Hz, 2H), 6.27-6.28 (m, 1H), 6.95 (d, J=8.85 Hz, 1H), 7.00-7.12 (m,
2H), 7.20 (dd, J=8.85, 2.75 Hz, 1H), 7.28 (t, J=2.75 Hz, 1H), 7.32
(s, 1H), 7.35-7.41 (m, 2H), 12.05 (s, 1H). MS (ESI+) m/z 472.2
(M+H).sup.+.
Example 44
4-[2-(benzyloxy)-5-(2-hydroxyethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo-
[2,3-c]pyridin-7-one
[0831] Example 35d (0.039 g, 0.1 mmol) in tetrahydrofuran (2 mL)
was treated dropwise with borane-tetrahydrofuran complex (1M, 0.200
mL, 0.200 mmol), and the mixture was stirred at 40.degree. C. for 1
hour, diluted with 5 mL of methanol, heated at 50.degree. C. for 30
minutes and concentrated. Purification by chromatography (silica
gel, 0.5-4% methanol in dichloromethane) afforded the title
compound (0.03 g, 79%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
2.70 (t, J=6.94 Hz, 2H) 3.52 (s, 3H) 3.57-3.64 (m, 2H) 4.59-4.63
(m, 1H) 5.06 (s, 2H) 6.14-6.18 (m, 1H) 7.08-7.18 (m, 2H) 7.20-7.32
(m, 8H) 11.95 (s, 1H). MS (ESI+) m/z 375.0 (M+H).sup.+.
Example 45
methyl
[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]acetate
Example 45a
2-(4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4--
yl)phenyl)acetyl chloride
[0832] Example 35d (0.18 g, 0.463 mmol) in tetrahydrofuran (4.63
mL) was treated with one drop of dimethylformamide followed by
drop-wise addition of oxalyl chloride (0.122 mL, 1.390 mmol),
stirred for twenty minutes and concentrated.
Example 45b
methyl
[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]acetate
[0833] Example 45a (0.058 g, 0.143 mmol) in tetrahydrofuran (4 mL)
was treated with methanol (5 mL, 124 mmol), stirred for 1 hour at
room temperature and concentrated. Purification by chromatography
(silica gel, 0.5-3% methanol in dichloromethane) afforded the title
compound (0.048 g, 79%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 3.52 (s, 3H) 3.62 (s, 3H) 3.66 (s, 2H) 5.09 (s, 2H)
6.15-6.20 (m, 1H) 7.10-7.37 (m, 10H) 11.97 (s, 1H). MS (ESI+) m/z
403.0 (M+H).sup.+.
Example 46
2-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4--
yl)phenyl]-N-ethylacetamide
[0834] Example 46 was prepared according to the procedure used for
the preparation of Example 45b, substituting ethylamine for
methanol, to provide the title compound (0.039 g, 64%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 1.01 (t, J=7.29 Hz, 3H) 2.99-3.11
(m, 2H) 3.35 (s, 2H) 3.52 (s, 3H) 5.07 (s, 2H) 6.14-6.21 (m, 1H)
7.08-7.35 (m, 10H) 7.98 (t, J=5.43 Hz, 1H) 11.96 (s, 1H). MS (ESI+)
m/z 416.0 (M+H).sup.+.
Example 47
2-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4--
yl)phenyl]-N,N-dimethylacetamide
[0835] Example 47 was prepared according to the procedure used for
the preparation of Example 45b, substituting dimethylamine for
methanol, to provide the title compound (0.058 g, 98%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.83 (s, 3H) 3.02 (s, 3H) 3.52 (s,
3H) 3.66 (s, 2H) 5.08 (s, 2H) 6.12-6.24 (m, 1H) 7.06-7.36 (m, 10H)
11.96 (s, 1H). MS (ESI+) m/z 416.0 (M+H).sup.+.
Example 48
N-[4-(3,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]methanesulfonamide
Example 48a
4-(2-(3,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridi-
n-7(6H)-one
[0836] Example 48a was prepared according to the procedure used for
the preparation of Example 2b, substituting 3,4-difluorophenol for
phenol, to provide the title compound.
Example 48b
4-(5-amino-2-(3,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridi-
n-7(6H)-one
[0837] Example 48b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
48a for the product of Example 2b, to provide the title
compound.
Example 48c
N-[4-(3,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]methanesulfonamide
[0838] Example 48c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 48b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 3.04 (s, 3H), 3.50 (s, 3H),
6.28-6.23 (m, 1H), 6.72-6.62 (m, 1H), 6.97 (ddd, J=11.9, 6.7, 3.0
Hz, 1H), 6.97 (ddd, J=11.9, 6.7, 3.0 Hz, 1H), 7.11 (d, J=8.7 Hz,
1H), 7.41-7.19 (m, 5H), 9.78 (s, 1H), 12.03 (bs, 1H). MS (ESI+) m/z
446.1 (M+H).sup.+.
Example 49
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-t-
rifluorophenoxy)phenyl]methanesulfonamide
Example 49a
6-methyl-4-(5-nitro-2-(2,4,6-trifluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[0839] Example 49a was prepared according to the procedure used for
the preparation of Example 2b, substituting 2,4,6-trifluorophenol
for phenol, to provide the title compound.
Example 49b
4-(5-amino-2-(2,4,6-trifluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[0840] Example 49b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
49a for the product of Example 2b, to provide the title
compound.
Example 49c
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-t-
rifluorophenoxy)phenyl]methanesulfonamide
[0841] Example 49c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 49b for
the product of Example 3, to provide the title compound. 1H.sup.1H
NMR NMR (300 MHz, DMSO-d.sub.6) .delta. 2.99 (s, 3H), 3.57 (s, 3H),
6.23 (t, J=2.3 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 7.15 (dd, J=8.8,
2.7 Hz, 1H), 7.34-7.27 (m, 3H), 7.45-7.34 (m, 2H), 9.66 (s, 1H),
12.07 (bs, 1H). MS (ESI+) m/z 464.1 (M+H).sup.+.
Example 50
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)benzamide
Example 50a
ethyl
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-
-c]pyridin-4-yl)benzoate
[0842] Example 50a was prepared according to the procedure used for
the preparation of Example 9b, substituting 2,4-difluorophenol for
phenol, to provide the title compound.
Example 50b
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)benzoic acid
[0843] Example 50b was prepared according to the procedure used for
the preparation of Example 10, substituting Example 50a for Example
9b, to provide the title compound.
Example 50c
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)benzamide
[0844] Example 50c was prepared according to the procedure used for
the preparation of Example 13a, substituting Example 50b for
Example 10, to provide the title compound.
Example 50d
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)benzamide
[0845] Example 50d was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 50c for
Example 13a, and aqueous ammonium hydroxide for ethylamine,
respectively, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.57 (s, 3H), 6.24-6.25 (m, 1H), 6.83 (d,
J=8.24 Hz, 1H), 7.07-7.13 (m, 1H), 7.27-7.34 (m, 4H), 7.42-7.48 (m,
1H), 7.85 (dd, J=8.54, 2.44, 1H), 7.96 (s, 1H), 8.00 (d, J=2.44 Hz,
1H), 12.04 (s, 1H). MS (ESI+) m/z 396.3 (M+H).sup.+.
Example 51
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-(tetrahydrofuran-3-yl)benzamide
[0846] Example 51 was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 50c for
Example 13a, and tetrahydrofuran-3-amine for ethylamine,
respectively, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.87-1.94 (m, 1H), 2.10-2.19 (m, 1H), 3.57
(s, 3H), 3.67-3.73 (m, 2H), 3.81-3.87 (m, 2H), 4.42-4.49 (m, 1H),
6.22-6.23 (m, 1H), 6.85 (d, J=8.54 Hz, 1H), 7.07-7.13 (m, 1H),
7.25-7.34 (m, 3H), 7.42-7.47 (m, 1H), 7.85 (dd, J=8.85, 2.14, 1H),
7.96 (s, 1H), 8.00 (d, J=2.14 Hz, 1H), 8.50 (d, J=6.41 Hz, 1H),
12.03 (s, 1H). MS (ESI+) m/z 466.3 (M+H).sup.+.
Example 52
4-{2-(2,4-difluorophenoxy)-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phen-
yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0847] Example 52 was prepared according to the procedure used for
the preparation of Example 13b, substituting
1,1-dioxo-1-thiomorpholine for ethylamine and Example 50c for
Example 13a, respectively, to provide the title compound. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 3.25-3.28 (m, 4H), 3.56 (s,
3H), 3.78 (m, 4H), 4.45-4.61 (m, 1H), 3.81-3.87 (m, 2H), 6.26-6.27
(m, 1H), 6.86 (d, J=8.24 Hz, 1H), 7.07-7.12 (m, 1H), 7.27-7.33 (m,
3H), 7.42-7.48 (m, 2H), 7.63 (d, J=2.14, 1H), 12.04 (s, 1H). MS
(ESI+) m/z 514.2 (M+H).sup.+.
Example 53
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-(1-methyl-2-oxopyrrolidin-3-yl)benzamide
[0848] Example 53 was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 50c for
Example 13a, and 3-amino-1-methylpyrrolidin-2-one for ethylamine,
respectively, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.87-1.97 (m, 1H), 2.29-2.38 (m, 1H), 2.76
(s, 3H), 3.30-3.34 (m, 2H), 3.57 (s, 3H), 4.45-4.61 (m, 1H),
3.81-3.87 (m, 2H), 4.42-4.49 (m, 1H), 6.23-6.24 (m, 1H), 6.87 (d,
J=8.54 Hz, 1H), 7.08-7.13 (m, 1H), 7.25-7.34 (m, 3H), 7.43-7.48 (m,
1H), 7.85 (dd, J=8.54, 2.44 Hz, 1H), 7.96 (s, 1H), 7.99 (d, J=2.14
Hz, 1H), 8.73 (d, J=8.85 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z
493.2 (M+H).sup.+.
Example 54
tert-butyl
{1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-c]pyridin-4-yl)benzoyl]pyrrolidin-3-yl}carbamate
[0849] Example 54 was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 50c for
Example 13a, and tert-butyl pyrrolidin-3-ylcarbamate for
ethylamine, respectively, to provide the title compound. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 1.33-1.40 (m, 9H), 1.74-1.83
(m, 1H), 2.01-2.0.3 (m, 1H), 3.27-3.31 (m, 1H), 3.56 (s, 3H),
3.62-3.56 (m, 1H), 3.93-4.07 (m, 1H), 6.24 (d, J=2.29 Hz, 1H), 6.83
(d, J=8.54 Hz, 1H), 7.0-7.13 (m, 1H), 7.20-7.33 (m, 3H), 7.41-7.52
(m, 2H), 7.60 (d, J=16.2 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z
565.2 (M+H).sup.+.
Example 55
4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylcarbonyl)phenyl]-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0850] Example 55 was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 50c for
Example 13a, and pyrrolidine for ethylamine, respectively, to
provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.82-1.86 (m, 4H), 3.45-3.48 (m, 4H), 3.56 (s, 3H),
6.24-6.26 (m, 1H), 6.82 (d, J=8.24 Hz, 1H), 7.06-7.12 (m, 1H),
7.26-7.33 (m, 3H), 7.41-7.46 (m, 1H), 7.52 (dd, J=8.54, 2.14 Hz,
1H), 7.61 (d, J=2.14 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 450.3
(M+H).sup.+.
Example 56
4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylcarbonyl)phenyl]-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0851] Example 56 was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 50c for
Example 13a, and morpholine for ethylamine, respectively, to
provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.56 (s, 3H), 3.60-3.68 (m, 8H), 6.24-6.25 (m, 1H), 6.84
(d, J=8.54 Hz, 1H), 7.06-7.12 (m, 1H), 7.26-7.33 (m, 3H), 7.40 dd,
J=8.54, 2.14 Hz, 1H), 7.44-7.46 (m, 1H), 7.50 (dd, J=2.14 Hz, 1H),
12.03 (s, 1H). MS (ESI+) m/z 466.3 (M+H).sup.+.
Example 57
N-[4-(cyclohexyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridi-
n-4-yl)phenyl]methanesulfonamide
Example 57a
4-(2-(cyclohexyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H-
)-one
[0852] Example 57a was prepared according to the procedure used for
the preparation of Example 29a, substituting cyclohexanol for
tetrahydro-2H-pyran-4-ol, to provide the title compound.
Example 57b
4-(5-amino-2-(cyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H-
)-one
[0853] Example 57b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
57a for the product of Example 2b, to provide the title
compound.
Example 57c
N-[4-(cyclohexyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridi-
n-4-yl)phenyl]methanesulfonamide
[0854] Example 57c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 57b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.47-1.10 (m, 6H), 1.61-1.47
(m, 2H), 1.84-1.69 (m, 2H), 2.94 (s, 3H), 3.55 (s, 3H), 4.31-4.22
(m, 1H), 6.21 (t, J=2.3 Hz, 1H), 7.18-7.06 (m, 2H), 7.31-7.25 (m,
3H), 9.39 (s, 1H), 11.98 (bs, 1H). MS (ESI+) m/z 416.2
(M+H).sup.+.
Example 58
N-[4-(cyclopentyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]methanesulfonamide
Example 58a
4-(2-(cyclopentyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6-
H)-one
[0855] Example 58a was prepared according to the procedure used for
the preparation of Example 29a, substituting cyclopentanol for
tetrahydro-2H-pyran-4-ol, to provide the title compound.
Example 58b
4-(5-amino-2-(cyclopentyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6-
H)-one
[0856] Example 58b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
58a for the product of Example 2b, to provide the title
compound.
Example 58c
N-[4-(cyclopentyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]methanesulfonamide
[0857] Example 58c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 58b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.70-1.43 (m, 6H), 1.88-1.70
(m, 2H), 2.94 (s, 3H), 3.55 (s, 3H), 4.78-4.70 (m, 1H), 6.16 (t,
J=2.3 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 7.16 (dd, J=8.7, 2.7 Hz,
1H), 7.22 (s, 1H), 7.30-7.23 (m, 2H), 9.39 (s, 1H), 11.97 (bs, 1H).
MS (ESI+) m/z 402.1 (M+H).sup.+.
Example 59
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl}methanesulfonamide
Example 59a
4-(2-(4,4-difluorocyclohexyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]-
pyridin-7(6H)-one
[0858] Example 59a was prepared according to the procedure used for
the preparation of Example 29a, substituting
4,4-difluorocyclohexanol for tetrahydro-2H-pyran-4-ol, to provide
the title compound.
Example 59b
4-(5-amino-2-(4,4-difluorocyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]-
pyridin-7(6H)-one
[0859] Example 59b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
59a for the product of Example 2b, to provide the title
compound.
Example 59c
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl}methanesulfonamide
[0860] Example 59c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 59b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.95-1.61 (m, 8H), 2.95 (s,
3H), 3.55 (s, 3H), 4.55-4.46 (m, 1H), 6.22-6.17 (m, 1H), 7.20-7.15
(m, 2H), 7.31-7.25 (m, 3H), 9.47 (s, 1H), 12.01 (bs, 1H). MS (ESI+)
m/z 452.2 (M+H).sup.+.
Example 60
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-3-yloxy)phenyl]methanesulfonamide
Example 60a
6-methyl-4-(5-nitro-2-(tetrahydro-2H-pyran-3-yloxy)phenyl)-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0861] Example 60a was prepared according to the procedure used for
the preparation of Example 29a, substituting
tetrahydro-2H-pyran-3-ol for tetrahydro-2H-pyran-4-ol, to provide
the title compound.
Example 60b
4-(5-amino-2-(tetrahydro-2H-pyran-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0862] Example 60b was prepared according to the procedure used for
the preparation of Example 29b, substituting the product of Example
60a for the product of Example 29a, to provide the title
compound.
Example 60c
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-3-yloxy)phenyl]methanesulfonamide
[0863] Example 60c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 60b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 1.39-1.45 (m, 1H), 1.55-1.70
(m, 2H), 1.89-1.96 (m, 1H), 2.95 (s, 3H), 3.41-3.57 (m, 7H),
3.65-3.69 (m, 1H), 6.24-6.26 (m, 1H), 6.84 (d, J=8.54 Hz, 1H), 7.14
(m, 2H), 7.29-7.31 (m, 2H), 7.38 (s, 1H), 9.45 (s, 1H), 12.03 (s,
1H). MS (ESI+) m/z 418.2 (M+H).sup.+.
Example 61
6-methyl-4-[2-(morpholin-4-ylcarbonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c-
]pyridin-7-one
[0864] Example 61 was prepared according to the procedure used for
the preparation of Example 1f, substituting
morpholino(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanon-
e for 2-phenoxyphenylboronic acid, followed by purification by
preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in water),
to provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 2.80-2.83 (m, 2H), 2.91-2.99 (m, 2H), 3.20-3.25 (m, 2H),
3.54-3.57 (m, 5H), 6.17-6.18 (m, 1H), 7.06 (s, 1H), 7.32 (t, J=2.9
Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.42-7.53 (m, 3H), 1H), 12.15 (s,
1H). MS (ESI+) m/z 338.1 (M+H).sup.+.
Example 62
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-t-
rifluorophenoxy)phenyl]ethanesulfonamide
[0865] Example 62 was prepared according to the procedure used in
method A of Example 4, substituting Example 33b for Example 3 and
substituting ethanesulfonyl chloride for methanesulfonyl chloride
respectively to provide the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.22 (t, J=7.3 Hz, 3H), 3.09 (q, J=7.3 Hz,
2H), 3.56 (s, 3H), 6.22 (t, J=2.3 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H),
7.15 (dd, J=8.8, 2.7 Hz, 1H), 7.44-7.27 (m, 5H), 9.72 (s, 1H),
12.06 (bs, 1H). MS (ESI+) m/z 478.1 (M+H).sup.+.
Example 63
N-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4--
yl)phenyl]methanesulfonamide
Example 63a
4-(2-(benzyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-on-
e
[0866] Example 63a was prepared according to the procedure used for
the preparation of Example 29a, substituting phenylmethanol for
tetrahydro-2H-pyran-4-ol, to provide the title compound.
Example 63b
4-(5-amino-2-(benzyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-on-
e
[0867] Example 63b was prepared according to the procedure used for
the preparation of Example 3, substituting the product of Example
63a for the product of Example 2b, to provide the title
compound.
Example 63c
N-[4-(benzyloxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4--
yl)phenyl]methanesulfonamide
[0868] Example 63c was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 63b for
the product of Example 3, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 2.94 (s, 3H), 3.51 (s, 3H),
5.07 (s, 2H), 6.24-6.18 (m, 1H), 7.22-7.16 (m, 2H), 7.37-7.24 (m,
8H), 9.45 (s, 1H), 12.00 (bs, 1H). MS (ESI+) m/z 424.2
(M+H).sup.+.
Example 64
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-2-fluoroethanesulfonamide
[0869] Example 64 was prepared according to the procedure used for
the preparation of Example 27c, substituting 2-fluoroethanesulfonyl
chloride for methanesulfonyl chloride, and bypassing the sodium
hydroxide hydrolysis step, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 3.52 (s, 3H), 3.63 (t, J=6.0
Hz, 2H), 4.12 (q, J=6.0 Hz, 2H), 6.25-6.19 (m, 1H), 7.08-6.62 (m,
5H), 7.27-7.20 (m, 3H), 11.99-11.92 (m, 1H). MS (ESI+) m/z 478.2
(M+H).sup.+.
Example 65
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-N'-methylsulfuric diamide
[0870] Example 65 was prepared according to the procedure used for
the preparation of Example 27c, substituting methylsulfamoyl
chloride for methanesulfonyl chloride, to provide the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.50 (m, 3H
solvent obscured), 3.52 (s, 3H), 6.28-6.22 (m, 1H), 7.08-6.86 (m,
3H), 7.15 (dd, J=8.8, 2.7 Hz, 1H), 7.39-7.21 (m, 5H), 9.65 (s, 1H),
12.02 (bs, 1H), MS (ESI+) m/z 461.1 (M+H).sup.+.
Example 66
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
drofuran-3-yloxy)phenyl]ethanesulfonamide
[0871] Example 66 was prepared according to the procedure used in
method A of Example 4, substituting the product of Example 31b for
the product of Example 3, and ethanesulfonyl chloride for
methanesulfonyl chloride, respectively, to provide the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.22 (t,
J=7.3 Hz, 3H), 1.93-1.80 (m, 1H), 2.20-2.04 (m, 1H), 3.02 (q, J=7.3
Hz, 2H), 3.55 (s, 3H), 3.65 (m, 3H), 3.82 (dd, J=10.0, 4.5 Hz, 1H),
5.00-4.91 (m, 1H), 6.16 (t, J=2.3 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H),
7.16 (dd, J=8.7, 2.7 Hz, 1H), 7.24 (s, 1H), 7.31-7.25 (m, 3H), 9.53
(s, 1H), 12.01 (bs, 1H), MS (ESI+) m/z 418.1 (M+H).sup.+.
Example 67
methyl
6-methyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idine-2-carboxylate
Example 67a
ethyl
4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-
-2-carboxylate
[0872] Diisopropylamine (0.111 g, 1.102 mmol) in tetrahydrofuran (3
mL) was treated with BuLi (2.5 M, 0.44 mL, 1.102 mmol) at
-78.degree. C. The solution was stirred for 20 minutes at
-78.degree. C., and warmed up to room temperature for 5 minutes,
and cooled down to -78.degree. C. again. To this solution was added
N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethylethane-1,2-diamine
(0.128 g, 1.102 mmol). Then Example 1e (0.30 g, 0.787 mmol) in
tetrahydrofuran (3 mL) was added to the reaction mixture via
cannula under nitrogen. The reaction mixture was stirred at
-78.degree. C. for 1 hour, warmed to 0.degree. C. briefly, and
cooled down to -78.degree. C. To this suspension was added ethyl
carbonochloridate (0.205 g, 1.889 mmol) via a syringe. The reaction
mixture was allowed to warm to room temperature gradually
overnight. The mixture was then partitioned between water and ethyl
acetate. The aqueous layer was extracted with additional ethyl
acetate three times. The combined organic layers were washed with
brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel eluting
with 30-50% ethyl acetate in hexanes to afford 0.074 g of the title
compound.
Example 67b
methyl
6-methyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idine-2-carboxylate
[0873] Example 67b was prepared according to the procedure used for
the preparation of Example 1f, substituting Example 67a for Example
1e, and bypassing the use of potassium carbonate, followed by
purification by preparative HPLC (C18, 10-100% acetonitrile in 0.1%
TFA in water), to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.50 (s, 3H), 3.80 (s, 3H), 6.80-6.82 (m,
3H), 7.00 (t, J=7.32 Hz, 1H), 7.06 (d, J=7.02 Hz, 1H), 7.23-7.32
(m, 4H), 7.40-7.42 (m, 1H), 7.52 (dd, J=7.48, 1.68 Hz, 1H), 12.85
(s, 1H). MS (ESI+) m/z 375 (M+H).sup.+.
Example 68
methyl
1,6-dimethyl-7-oxo-4-(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridine-2-carboxylate
[0874] The title compound was obtained as a by-product from the
preparation of Example 67b. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.48 (s, 3H), 3.81 (s, 3H), 4.38 (s, 3H), 6.81-6.84 (m,
3H), 6.98-7.07 (m, 2H), 7.25-7.31 (m, 3H), 7.34 (s, 1H), 7.41-7.47
(m, 1H), 7.48 (dd, J=7.48, 1.68 Hz, 1H). MS (ESI+) m/z 389
(M+H).sup.+.
Example 69
ethyl
4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,-
3-c]pyridine-2-carboxylate
Example 69a
ethyl
1-benzyl-4-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbo-
xylate
[0875] Example 69a was prepared according to the procedure used for
the preparation of Example 2a (Method B), substituting Example 67a
for Example 1e, to provide the title compound.
Example 69b
ethyl
6-methyl-4-(5-nitro-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,-
3-c]pyridine-2-carboxylate
[0876] Example 69b was prepared according to the procedure used for
the preparation of Example 2b, substituting Example 69a for Example
2a, to provide the title compound.
Example 69c
ethyl
4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,-
3-c]pyridine-2-carboxylate
[0877] Example 69c was prepared according to the procedure used for
the preparation of Example 29b, substituting Example 69b for
Example 29a, and purified by preparative HPLC (C18, 10-100%
acetonitrile in 0.1% TFA/water) to provide the TFA salt of the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.30
(t, J=7.02 Hz, 3H), 3.49 (s, 3H), 4.27 (q, J=7.12 Hz, 2H), 6.77 (d,
J=7.93 Hz, 2H), 6.86 (d, J=2.14 Hz, 1H), 6.93-7.03 (m, 3H), 7.11
(s, 1H), 7.20-7.24 (m, 2H), 7.31 (s, 1H), 12.86 (s, 1H). MS (ESI+)
m/z 404.1 (M+H).sup.+.
Example 70
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1-
H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
Example 70a
(Z)-ethyl
3-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-2-hydroxyacrylate
[0878] To a solution of ethanol (15 mL) and ether (150 mL) were
added 5-bromo-2-methoxy-4-methyl-3-nitropyridine (14.82 g, 60
mmol), diethyl oxalate (13.15 g, 90 mmol), and potassium ethoxide
(6.06 g, 72 mmol). The reaction mixture was heated at 45.degree. C.
for 24 hours. During the reaction, the flask was shaken by hand
several times. After cooling, the reaction mixture was partitioned
between water and ethyl acetate. The aqueous layer was extracted
with additional ethyl acetate three times. The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel eluting with 10-20% ethyl acetate in hexanes to 9.5 g of
the title compound (yield 46%).
Example 70b
ethyl 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[0879] A mixture Example 70a (9.5 g, 27.4 mmol) and iron (7.64 g,
137 mmol) in ethanol (60 mL) and acetic acid (60 mL) was heated at
100.degree. C. for 1 hour. The solution turned from red to gray.
The solid was filtered off, and then washed with additional ethyl
acetate. The solvents were removed under reduced pressure to 20% of
original volume, and it was partitioned between water and ethyl
acetate. The aqueous layer was extracted with additional ethyl
acetate several times. The combined organic layers were washed with
brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel eluting
with 20-40% ethyl acetate in hexanes to afford 6.05 g of the title
compound.
Example 70c
ethyl
1-benzyl-4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[0880] Example 70b (0.88 g, 2.94 mmol) in dimethylformamide (15 mL)
was treated with 60% sodium hydride (0.106 g, 4.41 mmol, 0.117 g of
a 60% in oil dispersion). The solution was stirred at room
temperature for 10 minutes. To this solution was added benzyl
bromide (0.59 g, 3.45 mmol). The reaction mixture was stirred for
another 2 hours. It was partitioned between water and ethyl
acetate. The aqueous layer was extracted with additional ethyl
acetate twice. The combined organic layers were washed with brine,
dried over MgSO.sub.4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel eluting with 20-40%
ethyl acetate in hexanes to afford 1.07 g of the title
compound.
Example 70d
ethyl
1-benzyl-4-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbo-
xylate
[0881] Example 70d was prepared according to the procedure used for
the preparation of Example 1d, substituting Example 70c for Example
1c, to provide the title compound.
Example 70e
ethyl
1-benzyl-4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-
e-2-carboxylat
[0882] Example 70e was prepared according to the procedure used for
the preparation of Example 1e, substituting Example 70d for Example
1d, to provide the title compound.
Example 70f
ethyl
1-benzyl-4-(2-fluoro-5-nitrophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-c]pyridine-2-carboxylate
[0883] Example 70f was prepared according to the procedure used for
the preparation of Example 2a (Method B), substituting Example 70e
for Example 1e, to provide the title compound.
Example 70g
ethyl
1-benzyl-6-methyl-4-(5-nitro-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-p-
yrrolo[2,3-c]pyridine-2-carboxylate
[0884] Example 70g was prepared according to the procedure used for
the preparation of Example 2b, substituting Example 70f for Example
2a, to provide the title compound.
Example 70h
ethyl
4-(5-amino-2-phenoxyphenyl)-1-benzyl-6-methyl-7-oxo-6,7-dihydro-1H-p-
yrrolo[2,3-c]pyridine-2-carboxylate
[0885] Example 70h was prepared according to the procedure used for
the preparation of Example 29b, substituting Example 70g for
Example 29a, to provide the title compound.
Example 70i
ethyl
1-benzyl-6-methyl-4-(5-(N-(methylsulfonyl)methylsulfonamido)-2-pheno-
xyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[0886] Example 70i was prepared according to the procedure used in
method A of Example 4, substituting Example 70h for Example 3,
except the use of 1 M NaOH, to provide the title compound.
Example 70j
ethyl
6-methyl-4-(5-(N-(methylsulfonyl)methylsulfonamido)-2-phenoxyphenyl)-
-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[0887] A mixture of Example 70i (0.53 g, 0.816 mmol), anisole
(0.176 g, 1.631 mmol), and concentrated H.sub.2SO.sub.4 (0.5 mL) in
TFA (10 mL) was heated at 90.degree. C. for 4 hours. Excess TFA was
removed under reduced pressure, and the residue was partitioned
between water and ethyl acetate. The organic layer was separated,
and the aqueous layer was extracted with additional ethyl acetate
several times. The combined organic layers were washed with
saturated aqueous sodium bicarbonate, followed by brine, dried over
MgSO.sub.4, filtered, and concentrated to afford 0.48 g of the
title compound. The crude material was used directly for the next
reaction.
Example 70k
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1-
H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[0888] Example 70j (0.4 g, 0.858 mmol) in dioxane (5 mL) was
treated with 2.0 N NaOH (1.72 mL, 3.43 mmol). The reaction mixture
was heated at 65.degree. C. for 2 hours. The reaction mixture was
cooled to room temperature and poured into water (100 mL). After
addition of concentrated HCl (1 mL), the mixture was extracted with
ethyl acetate three times (3.times.30 mL). The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated to afford 0.36 g (93%) of the title compound. A small
amount of sample was purified by preparative HPLC (C18, 10-70%
acetonitrile in 0.1% TFA/water) to provide the TFA salt of the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 3.03
(s, 3H), 3.49 (s, 3H), 6.81 (d, J=7.63 Hz, 2H), 6.84 (d, J=2.14 Hz,
1H), 6.96-7.00 (m, 1H), 7.08 (d, J=8.85 Hz, 1H), 7.22-7.27 (m, 3H),
7.34 (s, 1H), 7.37 (d, J=2.75 Hz, 1H), 9.77 (s, 1H), 12.62 (d,
J=1.53 Hz, 1H), 13.00 (s, br, 1H). MS (ESI+) m/z 454.1
(M+H).sup.+.
Example 71
ethyl
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dih-
ydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[0889] Example 70k (0.2 g, 0.441 mmol) in ethanol (10 mL) was
treated with concentrated H.sub.2SO.sub.4 (0.5 mL). The reaction
mixture was heated under reflux overnight. The solvent was removed,
and the remaining was partitioned between water and ethyl acetate.
The organic layer was separated, and the aqueous layer was
extracted with additional ethyl acetate several times. The combined
organic layers were washed with sat. NaHCO.sub.3, brine, dried over
MgSO.sub.4, filtered, and concentrated to afford 0.19 g of the
title compound. A small amount of crude product was purified by
preparative HPLC to provide clean product for biological testing.
.sup.1HNMR (500 MHz, DMSO-d.sub.6) .delta. 1.30 (t, J=7.17 Hz, 3H),
3.04 (s, 3H), 3.50 (s, 3H), 4.26 (q, J=7.22 Hz, 2H), 6.80 (d,
J=7.63 Hz, 2H), 6.86 (d, J=2.14 Hz, 1H), 6.96-7.00 (m, 1H), 7.09
(d, J=8.85 Hz, 1H), 7.21-7.28 (m, 3H), 7.35 (s, 1H), 7.36 (d,
J=2.75 Hz, 1H), 9.78 (s, 1H), 12.86 (s, 1H). (ESI+) m/z 482.1
(M+H).sup.+.
Example 72
N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-d-
ihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
Example 72a
6-methyl-4-(5-(methylsulfonamido)-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-c]pyridine-2-carbonyl chloride
[0890] Example 72a was prepared according to the procedure used for
the preparation of Example 13a, substituting Example 70k for
Example 10, to provide the title compound.
Example 72b
N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-d-
ihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[0891] Example 72b was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 72a for
Example 13a, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.12 (t, J=7.17 Hz, 3H), 3.03 (s, 3H),
3.23-3.30 (M, 2H), 3.49 (s, 3H), 6.81 (d, J=7.63 Hz, 2H), 6.86 (d,
J=2.44 Hz, 1H), 6.96-7.00 (m, 1H), 7.07 (d, J=8.54 Hz, 1H),
7.22-7.28 (m, 3H), 7.30 (s, 1H), 7.34 (d, J=2.75 Hz, 1H), 8.34 (t,
J=5.34 Hz, 1H), 9.79 (s, 1H), 12.22 (s, 1H). (ESI+) m/z 481.1
(M+H).sup.+.
Example 73
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1-
H-pyrrolo[2,3-c]pyridine-2-carboxamide
[0892] Example 73 was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 72a for
Example 13a, and aqueous ammonium hydroxide for ethyl amine,
respectively, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.03 (s, 3H), 3.50 (s, 3H), 6.82 (d, J=7.63
Hz, 2H), 6.88 (d, J=2.44 Hz, 1H), 6.97-7.01 (m, 1H), 7.06 (d,
J=8.54 Hz, 1H), 7.22-7.28 (m, 3H), 7.31 (s, 1H), 7.35 (d, J=2.75
Hz, 1H), 7.46 (s, 1H), 7.81 (s, 1H), 9.78 (s, 1H), 12.22 (s, 1H).
MS (ESI+) m/z 453.1 (M+H).sup.+.
Example 74
ethyl
4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,-
3-d]pyridazine-2-carboxylate
Example 74a
4-amino-6-chloro-2-methylpyridazin-3(2H)-one
[0893] A mixture of 4,6-dichloro-2-methylpyridazin-3(2H)-one (5.0
g, 27.9 mmol) and ammonium hydroxide (55 mL, 1412 mmol) was heated
at 150.degree. C. for 2 hours and then cooled to room temperature.
The solvent was removed, and the residue was dissolved in ethyl
acetate and washed with water. The aqueous layer was extracted with
additional ethyl acetate three times. The combined organic layers
were washed with brine, dried and concentrated. The residue was
purified by flash chromatography (silica gel, eluted with 40% ethyl
acetate in hexanes to afford 3.85 g (87%) of the title
compound.
Example 74b
4-amino-6-chloro-5-iodo-2-methylpyridazin-3(2H)-one
[0894] A mixture of Example 74a (2.12 g, 13.3 mmol) and
N-iodosuccinimide (5.38 g, 23.9 mmol) in acetonitrile (30 mL) was
heated under reflux for 6 hours. The reaction mixture was cooled to
room temperature and partitioned between ethyl acetate and water.
The aqueous layer was extracted with additional ethyl acetate
twice. The combined organic layers were washed with brine, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel eluting
with 20-40% ethyl acetate in hexanes to afford 3.27 g (86%) of the
title compound.
Example 74c
4-chloro-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazine-2-carboxyl-
ic acid
[0895] A mixture of Example 74b (0.59 g, 2.1 mmol), pyruvic acid
(0.546 g, 6.2 mmol), 1,4-diazabicyclo[2.2.2]octane (0.695 g, 6.2
mmol), and palladium(II)acetate (0.046 g, 10 mol %) in
dimethylformamide (8 mL) was degassed and back-filled with nitrogen
three times. The reaction mixture was then heated at 105.degree. C.
overnight. The reaction mixture was cooled to room temperature and
partitioned between ethyl acetate and water. The aqueous layer was
extracted with additional ethyl acetate twice. The combined organic
layers were washed with brine, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was triturated in
30% ethyl acetate in hexanes to afford 0.25 g (53%) of the title
compound.
Example 74d
ethyl
4-chloro-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazine-2-ca-
rboxylate
[0896] Example 74c (0.45 g, 2.0 mmol) in ethanol (15 mL) was
treated concentrated sulfuric acid (1 mL). The reaction mixture was
heated under reflux for 16 hours. The reaction mixture was cooled
to room temperature and partitioned between ethyl acetate and
water. The aqueous layer was extracted with additional ethyl
acetate twice. The combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate, filtered, and concentrated
to afford 0.45 g (89%) of the title compound.
Example 74e
ethyl
4-chloro-6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dih-
ydro-1H-pyrrolo[3,2-d]pyridazine-2-carboxylate
[0897] A solution of Example 74d (0.41 g, 1.6 mmol) in
dimethylformamide (15 mL) was treated with 60% sodium hydride
(0.096 g, 2.4 mmol) at room temperature. The reaction mixture was
stirred for 30 min, and then was treated with
(2-(chloromethoxy)ethyl)trimethylsilane (0.40 g, 2.4 mmol). The
reaction mixture was then stirred for 2 hours. It was partitioned
between ethyl acetate and water. The aqueous layer was extracted
with additional ethyl acetate twice. The combined organic layers
were washed with brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel, eluting with 20% ethyl acetate to
afford 0.50 g (81%) of the title compound.
Example 74f
ethyl
4-(2-fluoro-5-nitrophenyl)-6-methyl-7-oxo-1-((2-(trimethylsilyl)etho-
xy)methyl)-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazine-2-carboxylate
[0898] Example 74f was prepared according to the procedure used for
the preparation of Example 2a (Method B), substituting Example 74e
for Example 1e, to provide the title compound
Example 74g
ethyl
6-methyl-4-(5-nitro-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-pyrrolo[3,-
2-d]pyridazine-2-carboxylate
[0899] A mixture of Example 74f (0.26 g, 0.53 mmol), phenol (0.060
g, 0.64 mmol) and cesium carbonate (0.21 g, 0.63 mmol) in
dimethylsulfoxide (5 mL) was heated at 110.degree. C. for 6 hours.
After cooling to room temperature, the reaction mixture was
partitioned between water and ethyl acetate. The aqueous layer was
extracted with additional ethyl acetate three times. The combined
organic layers were washed with brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was then
treated with 15 mL of ethanol and 1 mL of concentrated
H.sub.2SO.sub.4. The mixture was heated under reflux overnight. The
reaction mixture was cooled to room temperature and partitioned
between ethyl acetate and water. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel eluting with 40-80% ethyl acetate to afford 0.14 g (61%)
of the title compound.
Example 74h
ethyl
4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,-
3-d]pyridazine-2-carboxylate
[0900] Example 74h was prepared according to the procedure used for
the preparation of Example 29b, substituting Example 74g for
Example 29a, and ethanol for ethyl acetate, respectively, to
provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.29 (t, J=7.02 Hz, 3H), 3.61 (s, 3H), 4.28 (q, J=7.22 Hz,
2H), 5.22 (s, 2H), 6.65 (d, J=7.33 Hz, 2H), 6.74 (dd, J=8.85, 2.75
Hz, 1H), 6.79 (t, J=2.75 Hz, 1H), 6.87 (d, J=7.32 Hz, 1H),
6.91-6.93 (m, 2H), 7.13-7.17 (m, 2H), 13.37 (br s, 1H). MS (ESI+)
m/z 405.1 (M+H).sup.+.
Example 75
ethyl
4-[5-(ethylamino)-2-phenoxyphenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyr-
rolo[2,3-d]pyridazine-2-carboxylate
[0901] Example 75 was obtained as a by-product from the preparation
of Example 74h .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.19 (t,
J=7.17 Hz, 3H), 1.30 (t, J=7.02 Hz, 3H), 3.03-3.08 (m, 2H), 3.62
(s, 3H), 4.29 (q, J=7.02 Hz, 2H), 5.71 (t, J=5.19 Hz, 1H), 6.65 (d,
J=7.63 Hz, 2H), 6.72-6.74 (m, 2H), 6.87 (t, J=7.32 Hz, 1H), 6.91
(s, 1H), 6.99 (d, J=9.16 Hz, 1H), 7.13-7.17 (m, 2H), 13.47 (br s,
1H). MS (ESI+) m/z 433.1 (M+H).sup.+.
Example 76
ethyl
4-{5-[ethyl(methylsulfonyl)amino]-2-phenoxyphenyl}-6-methyl-7-oxo-6,-
7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate
[0902] Example 76 was prepared according to the procedure used in
method A of Example 4, substituting Example 75 for Example 3,
except the use of NaOH, to provide the title compound. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 1.07 (t, J=7.02 Hz, 3H), 1.30 (t,
J=7.17 Hz, 3H), 3.02 (s, 3H), 3.67-3.72 (m, 5H), 4.23 (q, J=7.22
Hz, 2H), 6.93 (d, J=7.93 Hz, 2H), 6.99 (d, J=2.14 Hz, 1H),
7.07-7.12 (m, 2H), 7.30-7.34 (m, 2H), 7.52-7.55 (m, 1H), 7.85 (d,
J=2.75 Hz, 1H). MS (ESI+) m/z 511.1 (M+H).sup.+.
Example 77
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1-
H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid
[0903] Example 77 was prepared according to the procedure used in
method A of Example 4, substituting Example 74h for Example 3, to
provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.04 (s, 3H), 3.66 (s, 3H), 6.39-6.40 (m, 1H), 6.81-6.83
(m, 2H), 6.93 (d, J=1.53 Hz, 1H), 6.98-7.01 (m, 1H), 7.14 (d,
J=8.85 Hz, 1H), 7.23-7.27 (m, 2H), 7.37-7.42 (m, 1H), 7.43 (d,
J=2.75 Hz, 1H), 9.82 (s, 1H), 13.35 (s, 1H). MS (ESI+) m/z 455.1
(M+H).sup.+.
Example 78
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1-
H-pyrrolo[2,3-d]pyridazine-2-carboxamide
Example 78a
6-methyl-4-(5-(methylsulfonamido)-2-phenoxyphenyl)-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-d]pyridazine-2-carbonyl chloride
[0904] Example 78a was prepared according to the procedure used for
the preparation of Example 13a, substituting Example 77 for Example
10, to provide the title compound.
Example 78b
6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-dihydro-1-
H-pyrrolo[2,3-d]pyridazine-2-carboxamide
[0905] Example 78b was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 78a for
Example 13a, and aqueous ammonium hydroxide for ethylamine,
respectively, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.03 (s, 3H), 3.67 (s, 3H), 6.85 (d, J=7.63
Hz, 2H), 6.99-7.04 (m, 2H), 7.10 (d, J=8.54 Hz, 1H), 7.23-7.28 (m,
2H), 7.37-7.40 (m, 2H), 7.57 (s, 1H), 7.91 (s, 1H), 9.82 (s, 1H),
12.95 (s, 1H). MS (ESI+) m/z 454.1 (M+H).sup.+.
Example 79
6-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-4-{5-[(methylsulfonyl)amino]--
2-phenoxyphenyl}-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxami-
de
[0906] Example 79 was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 78a for
Example 13a, and 2-(4-methylpiperazin-1-yl)ethanamine for
ethylamine, respectively, to provide the TFA salt of the title
compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 2.67-2.80 (m,
6H), 3.04 (s, 3H), 3.49 (br, 8H), 3.67 (s, 3H), 6.82 (d, J=7.63 Hz,
2H), 6.99-7.03 (m, 2H), 7.13 (d, J=8.85 Hz, 1H), 7.24-7.28 (m, 2H),
7.37-7.40 (m, 2H), 8.50-8.52 (m, 1H), 9.85 (s, 1H), 13.03 (s, 1H).
MS (ESI+) m/z 580.2 (M+H).sup.+.
Example 80
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)-4-phenox-
yphenyl]methanesulfonamide
Example 80a
(E)-4-amino-6-chloro-5-(2-ethoxyvinyl)-2-methylpyridazin-3(2H)-one
[0907] Example 80a was prepared according to the procedure used for
the preparation of Example 2a (Method B), substituting Example 74b
for Example 1e, and
(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for
2-fluoro-5-nitrophenylboronic acid, respectively, to provide the
title compound.
Example 80b
4-chloro-6-methyl-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one
[0908] Example 80a (0.1 g, 0.435 mmol) in acetic acid (5 mL) was
heated at 90.degree. C. overnight. The solvent was evaporated under
reduced pressure to afford 0.071 g of the title compound.
Example 80c
4-chloro-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-d]py-
ridazin-7(6H)-one
[0909] Example 80c was prepared according to the procedure used for
the preparation of Example 74e, substituting Example 80b for
Example 74c, to provide the title compound.
Example 80d
4-(2-fluoro-5-nitrophenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1-
H-pyrrolo[3,2-d]pyridazin-7(6H)-one
[0910] Example 80d was prepared according to the procedure used for
the preparation of Example 2a (Method B), substituting Example 80c
for Example 1e, to provide the title compound.
Example 80e
6-methyl-4-(5-nitro-2-phenoxyphenyl)-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one
[0911] Example 80e was prepared according to the procedure used for
the preparation of Example 2b, substituting Example 80d for Example
2a, to provide the title compound.
Example 80f
4-(5-amino-2-phenoxyphenyl)-6-methyl-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one
[0912] Example 80f was prepared according to the procedure used for
the preparation of Example 29b, substituting Example 80e for
Example 29a, to provide the title compound.
Example 80g
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-4-yl)-4-phenox-
yphenyl]methanesulfonamide
[0913] Example 80g was prepared according to the procedure used in
method A of Example 4, substituting Example 80f for Example 3, to
provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.03 (s, 3H), 3.67 (s, 3H), 6.39-6.40 (m, 1H), 6.87 (d,
J=7.63 Hz, 2H), 7.01 (t, J=7.48 Hz, 1H), 7.08 (d, J=8.54 Hz, 1H),
7.24-7.28 (m, 2H), 7.35 (dd, J=8.85, 2.75 Hz, 1H), 7.42-7.43 (m,
2H), 9.80 (s, 1H), 12.67 (s, 1H). MS (ESI+) m/z 411.1
(M+H).sup.+.
Example 81
N-ethyl-6-methyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6,7-d-
ihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide
[0914] Example 81 was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 78a for
Example 13a, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.12 (t, J=7.17 Hz, 3H), 3.03 (s, 3H),
3.27-3.30 m, 2H), 3.66 (s, 3H), 6.82-6.84 (m, 2H), 6.98-7.02 (m,
2H), 6.97-7.01 (m, 1H), 7.12 (d, J=9.16 Hz, 1H), 7.23-7.28 (m, 2H),
7.37-7.40 (m, 2H), 8.44 (t, J=5.34 Hz, 1H), 9.83 (s, 1H), 12.97 (s,
1H). MS (ESI+) m/z 482.1 (M+H).sup.+.
Example 82
6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one
[0915] Example 82 was prepared according to the procedure used for
the preparation of Example 1f, substituting Example 80b for Example
1e, except for the use of potassium carbonate, followed by
purification by preparative HPLC (C18, 10-100% acetonitrile in 0.1%
TFA in water), to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.70 (s, 3H), 6.36-6.37 (m, 1H), 6.91-6.93
(m, 2H), 7.02-7.07 (m, 2H), 7.27-7.31 (m, 3H), 7.41 (t, J=2.75 Hz,
1H), 7.47-7.52 (m, 1H), 7.56 (dd, J=7.63, 1.83 Hz, 1H), 12.65 (s,
1H). MS (ESI+) m/z 318.1 (M+H).sup.+.
Example 83
N-ethyl-N,6-dimethyl-4-{5-[(methylsulfonyl)amino]-2-phenoxyphenyl}-7-oxo-6-
,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxamide
[0916] Example 83 was prepared according to the procedure used for
the preparation of Example 13b, substituting Example 78a for
Example 13a, and N-methylethanamine for ethylamine, respectively,
to provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.07 (br, 3H), 2.94 (s, 3H), 3.03 (s, 3H), 3.45 (br, 2H),
3.68 (s, 3H), 6.88 (d, J=7.93 Hz, 2H), 7.01 (t, J=7.32 Hz, 1H),
7.12 (d, J=8.85 Hz, 1H), 7.24-7.28 (m, 2H), 7.36 (dd, J=8.85, 2.75
Hz, 1H), 7.43 (d, J=2.75 Hz, 1H), 9.81 (s, 1H), 13.01 (s, 1H). MS
(ESI+) m/z 496.1 (M+H).sup.+.
Example 84
4-{4-[(ethylsulfonyl)amino]-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)phenoxy}benzamide
[0917] To a mixture of Example 33b (50 mg, 0.14 mmol) and
triethylamine (0.043 g, 0.42 mmol) in dichloromethane (4 mL) was
added dropwise ethanesulfonyl chloride (0.072 g, 0.56 mmol), and
the reaction mixture stirred at ambient temperature for 1 hour. The
reaction mixture was concentrated under reduced pressure, dioxane
(4 mL) and sodium hydroxide (10% w/v, 3 mL, 0.14 mmol) were added,
and the reaction mixture was heated at 70.degree. C. for 1 hour.
The mixture was cooled to ambient temperature and then neutralized
with saturated aqueous ammonium chloride (50 mL) to a pH of 7. The
organic layer was separated and the aqueous phase was extracted
with ethyl acetate (3.times.25 mL). The combined organic layers
were washed with saturated aqueous sodium chloride, dried
(anhydrous magnesium sulfate), filtered, and concentrated. The
residue was purified by preparative HPLC (C18, 10-100%
acetonitrile/water, 0.1% TFA) to afford the title compound (22 mg,
35%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .quadrature. ppm 12.01
(s, 1H) 9.86 (s, 1H) 7.77 (s, 1H) 7.74 (d, J=8.82 Hz, 2H) 7.42 (d,
J=2.37 Hz, 1H) 7.22-7.30 (m, 3H) 7.18 (s, 1H) 7.11-7.16 (m, 1H)
6.83 (d, J=8.82 Hz, 2H) 6.23-6.28 (m, 1H) 3.47 (s, 3H) 3.15 (q,
J=7.35 Hz, 2H) 1.21-1.29 (m, 3H). MS (ESI+) m/z 467.2
(M+H).sup.+.
Example 85
6-methyl-4-[5-(methylsulfonyl)-2-phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3-
-c]pyridin-7-one
Example 85a
4-(methylsulfonyl)-2-nitro-1-phenoxybenzene
[0918] Example 85a was prepared according to the procedure used for
the preparation of Example 2b, substituting
1-fluoro-4-(methylsulfonyl)-2-nitrobenzene for Example 2a, to
provide the title compound.
Example 85b
5-(methylsulfonyl)-2-phenoxyaniline
[0919] Example 85b was prepared according to the procedure used for
the preparation of Example 29b, substituting 85a for Example 29a,
to provide the title compound.
Example 85c
2-iodo-4-(methylsulfonyl)-1-phenoxybenzene
[0920] Example 85b (0.27 g, 1.025 mmol) in dioxane (1 mL) was
treated with concentrated HCl (6 mL) at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 10 minutes. To this
solution was added sodium nitrite (0.085 g, 1.23 mmol) in water (1
mL). The reaction was stirred at 0.degree. C. for another 1 hour.
To this solution was added potassium iodide (0.34 g, 1.051 mmol) in
water (2 mL). The reaction was stirred for 1 hour at room
temperature. The reaction mixture was partitioned between water and
ethyl acetate. The organic layer was extracted with additional
ethyl acetate twice. The combined organic layer were washed with
brine, dried over MgSO.sub.4, filtered and concentrated. The
residue was purified by flash chromatography on silica gel eluting
with 10-30% ethyl acetate in hexanes to afford 0.28 g of the title
product.
Example 85d
6-methyl-4-[5-(methylsulfonyl)-2-phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3-
-c]pyridin-7-one
[0921] Example 85d was prepared according to the procedure used for
the preparation of Example 1f, substituting 85c for Example 1e, and
Example 6a for 2-phenoxyphenylboronic acid, followed by
purification by preparative HPLC (C18, 10-100% acetonitril/0.1% TFA
in water), to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.26 (s, 3H), 3.57 (s, 3H), 6.29-6.30 (m,
1H), 7.03 (d, J=8.54 Hz, 1H), 7.11 (d, J=7.63 Hz, 2H), 7.20 (t,
J=7.32 Hz, 1H), 7.30 (t, J=2.75 Hz, 1H), 7.40-7.44 (m, 3H), 7.88
(dd, J=8.54, 2.44 Hz, 1H), 8.00 (d, J=2.44 Hz, 1H), 12.07 (s, 1H).
MS (ESI+) m/z 395.2 (M+H).sup.+.
Example 86
5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydro-
furan-3-yloxy)pyridine-3-sulfonamide
Example 86a
5-bromo-6-chloropyridine-3-sulfonamide
[0922] 5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in
methanol (20 mL) was cooled to 0.degree. C. To this solution was
added 7N NH.sub.3 in methanol (80 mL). The reaction mixture was
stirred over night at room temperature. The solvent was removed at
low temperature, and the residue was partitioned between ethyl
acetate and water. The aqueous layer was extracted with ethyl
acetate three times. The combined organic layers were washed with
brine, dried (MgSO.sub.4), filtered, and concentrated. The solid
was purified by flash column chromatography on silica gel to afford
4.2 g of the clean product.
Example 86b
5-bromo-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide
[0923] Example 86b was prepared according to the procedure used for
the preparation of Example 29a, substituting 86a for Example 2a,
and tetrahydrofuran-3-ol for tetrahydro-2H-pyran-4-ol, to provide
the title compound.
Example 86c
5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(tetrahydro-
furan-3-yloxy)pyridine-3-sulfonamide
[0924] Example 86c was prepared according to the procedure used for
the preparation of Example 1f, substituting 86b for Example 1e, and
Example 6a for 2-phenoxyphenylboronic acid, followed by
purification by preparative HPLC (C18, 10-100% acetonitrile in 0.1%
TFA in water), to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.91-1.97 (m, 1H), 2.18-2.25 (m, 1H), 3.59
(s, 3H), 3.66-3.76 (m, 3H), 3.92-3.95 (m, 1H), 5.63-5.66 (m, 1H),
6.19-6.21 (m, 1H), 7.34 (t, J=2.75 Hz, 1H), 7.41 (s, 1H), 7.47 (s,
2H), 8.14 (d, J=2.44 Hz, 1H), 8.54 (d, J=2.44 Hz, 1H), 12.11 (s,
1H). MS (ESI+) m/z 391.1 (M+H).sup.+.
Example 87
N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(t-
etrahydrofuran-3-yloxy)pyridine-3-sulfonamide
[0925] Example 87 was obtained as a by-product from the preparation
of Example 86c. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
1.93-1.98 (m, 1H), 2.17-2.24 (m, 1H), 2.48 (d, J=5.19 Hz, 3H), 3.57
(s, 3H), 3.67-3.78 (m, 3H), 3.91-3.94 (m, 1H), 5.65-5.67 (m, 1H),
6.19 (t, J=2.29 Hz, 1H), 7.33 (t, J=2.75 Hz, 1H), 7.43 (s, 1H),
7.55 (q, J=4.88 Hz, 1H), 8.06 (d, J=2.44 Hz, 1H), 8.51 (d, J=2.44
Hz, 1H), 12.13 (s, 1H). MS (ESI+) m/z 405.1 (M+H).sup.+.
Example 88
6-methyl-4-(2-phenoxyphenyl)-2-phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-
-7-one
4-bromo-2-iodo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
Example 88a
[0926] To a cold (-78.degree. C., dry ice/acetone bath) solution of
Example 1e (0.2 g, 0.525 mmol) in tetrahydrofuran (6 mL) was added
a freshly prepared solution of lithium di-isopropyl amide (1.2
equivalents). The reaction mixture was stirred at -78.degree. C.
for 45 minutes. A solution of iodine (0.054 ml, 1.049 mmol) in
tetrahydrofuran (0.5 mL) was added at -78.degree. C. The cooling
bath was removed, and the reaction mixture was allowed to warm to
room temperature and stirred for 1 hour. The reaction was quenched
by the addition of saturated aqueous sodium thiosulfate (20 mL).
The reaction mixture was partitioned between water and ethyl
acetate. The layers were separated, and the aqueous layer was
extracted with additional ethyl acetate. The combined organics were
washed with brine, dried with anhydrous MgSO.sub.4, filtered and
concentrated to dryness. The residue was purified by flash
chromatography (silica gel, 1-100% ethyl acetate/hexane). The
recovered material was further purified by reverse phase HPLC (C18,
10-100% acetonitrile in 0.1% TFA/water) to afford the title
compound (55 mg, 21%).
Example 88b
4-bromo-6-methyl-2-phenyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[0927] A mixture of Example 88a (0.1 g, 0.197 mmol), phenylboronic
acid (0.024 g, 0.197 mmol), Pd(PPh.sub.3).sub.4(0.011 g, 0.0096
mmol), and sodium hydrogencarbonate (0.041 g, 0.493 mmol) in
dimethylformamide (2 mL) and water (0.6 mL) was heated at
85.degree. C. for 4 hours. After cooling, the reaction mixture was
partitioned between water and ethyl acetate. The aqueous layer was
extracted with additional ethyl acetate twice. The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel eluting with 30% ethyl acetate to afford 0.084 g of the
title compound.
Example 88c
6-methyl-4-(2-phenoxyphenyl)-2-phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-
-7-one
[0928] Example 88c was prepared according to the procedure used for
the preparation of Example 1f, substituting 88b for Example 1e,
followed by purification by preparative HPLC (C18, 10-100%
acetonitrile in 0.1% TFA in water), to provide the title compound.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 3.53 (s, 3H), 6.67 (d,
J=1.22 Hz, 1H), 6.93 (d, J=7.63 Hz, 2H), 7.01-7.04 (m, 2H),
7.26-7.31 (m, 5H), 7.36-7.43 (m, 3H), 7.56 (dd, J=7.48, 1.68 Hz,
1H), 7.89 (d, J=7.32 Hz, 1H), 12.31 (s, 1H). MS (ESI+) m/z 393.3
(M+H).sup.+.
Example 89
N-{3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridi-
n-4-yl]-4-phenoxyphenyl}methanesulfonamide
[0929] Example 89 was prepared according to the procedure used for
the preparation of Example 20b, substituting Example 71 for Example
20a, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.02 (s, 3H), 3.47 (s, 3H), 4.50 (s, 2H),
6.19 (d, J=1.83 Hz, 1H), 6.82 (d, J=7.63 Hz, 2H), 6.99 (t, J=7.32
Hz, 1H), 7.05 (d, J=8.85 Hz, 1H), 7.21-7.27 (m, 4H), 7.38 (d,
J=2.75 Hz, 1H), 9.75 (s, 1H), 11.60 (s, 1H). MS (ESI+) m/z 440.1
(M+H).sup.+.
Example 90
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]ethanesulfonamide
Example 90a
4-(2-bromo-4-nitrophenoxy)benzonitrile
[0930] Example 90a was prepared according to the procedure used for
the preparation of Example 7a, substituting 4-hydroxybenzonitrile
for phenol, to provide the title compound.
Example 90b
4-(4-amino-2-bromophenoxy)benzonitrile
[0931] To a 250 mL stainless steel pressure bottle were added
Example 90a (3.21 g, 10.1 mmol), platinum (IV) oxide (0.642 g, 2.83
mmol) and tetrahydrofuran (70 mL) under a stream of nitrogen. The
reaction flask was charged with hydrogen to 30 psi and stirred at
ambient temperature for 45 minutes. The mixture was filtered
through a nylon membrane. The filtrate was concentrated. The
residue was purified by flash chromatography (silica gel, 1:1 ethyl
acetate/hexanes) to provide the title compound (1.75 g, 60%
yield).
Example 90c
4-(4-amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonit-
rile
[0932] A mixture of example 90b (1.75 g, 6.05 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.07
g, 12.1 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.159
g, 0.545 mmol), potassium acetate (1.31 g, 13.3 mmol) and
tris(dibenzylideneacetone)dipalladium(0) (0.166 g, 0.182 mmol) in
dioxane (30 mL) was degassed and backfilled with nitrogen. The
reaction mixture was heated at 80.degree. C. for 20 hours and then
cooled to ambient temperature. The mixture was concentrated and the
residue was partitioned between ethyl acetate and water. The
organic layer was separated and washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered,
and concentrated. The residue was purified by flash chromatography
(silica gel, hexane/ethyl acetate) to provide the title compound
(2.0 g, 98% yield).
Example 90d
4-(4-amino-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phe-
noxy)benzonitrile
[0933] Example 90d was prepared according to the procedure used for
the preparation of Example 1f, substituting Example 90c for
2-phenoxyphenylboronic acid, with purification by preparative HPLC
(C18, 10-100% acetonitrile in 0.1% TFA in water), to provide the
title compound.
Example 90e
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]ethanesulfonamide
[0934] Example 90e was prepared according to the procedure used for
the preparation of Example 4, Method A, substituting ethanesulfonyl
chloride for methanesulfonyl chloride, and Example 90d for Example
3, respectively, to provide the title compound. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 12.01-12.05 (m, 1H) 9.94 (s, 1H)
7.62-7.69 (m, 2H) 7.43 (d, J=2.75 Hz, 1H) 7.21-7.33 (m, 4H)
6.86-6.93 (m, 2H) 6.22 (dd, J=2.75, 2.14 Hz, 1H) 3.46 (s, 3H) 3.16
(q, J=7.32 Hz, 2H) 1.25 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 449.1
(M+H).sup.+.
Example 91
2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-
-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamide
Example 91a
6-methyl-4-(5-nitro-2-(tetrahydrofuran-3-yloxy)phenyl)-1H-pyrrolo[2,3-c]py-
ridin-7(6H)-one
[0935] Example 91a was prepared according to the procedure used for
the preparation of Example 29a, substituting tetrahydrofuran-3-ol
for tetrahydro-2H-pyran-4-ol, to provide the title compound.
Example 91b
4-(5-amino-2-(tetrahydrofuran-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]py-
ridin-7(6H)-one
[0936] Example 91b was prepared according to the procedure used for
the preparation of Example 29b, substituting Example 91a for
Example 29a, to provide the title compound.
Example 91c
2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-
-(tetrahydrofuran-3-yloxy)phenyl]ethanesulfonamide
[0937] To a mixture of Example 91b (80.0 mg, 0.246 mmol) and
triethylamine (74.6 mg, 0.738 mmol) in dichloromethane (4 mL) was
added dropwise 2-fluoroethanesulfonyl chloride (144 mg, 0.984
mmol), and the reaction mixture was stirred at about ambient
temperature for about 1 hour. The reaction mixture was neutralized
with saturated aqueous ammonium chloride solution (50 mL) and the
mixture was extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were washed with saturated aqueous sodium
chloride solution, dried (anhydrous magnesium sulfate), filtered,
and concentrated. The residue was purified by preparative HPLC
(C18, 10-80% acetonitrile in 0.1% TFA/water) to provide the title
compound (7.0 mg, 6.5% yield). .sup.1H NMR (300 MHz, CDCl.sub.3)
.quadrature. ppm 11.54 (bs, 1H), 7.45 (t, J=2.8 Hz, 1H), 7.19 (s,
1H), 6.88 (d, J=8.7 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H) 6.67 (dd,
J=3.1, 8.8 Hz, 1H), 6.40 (dd, J=2.0, 2.7 Hz, 1H), 4.76 (m, 1H),
3.82 (s, 3H), 3.85-3.62 (m, 8H), 2.97 (bs, 1H), 2.24-1.85 (m, 2H).
MS (ESI+) m/z 436.2 (M+H).sup.+.
Example 92
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
drofuran-3-yloxy)phenyl]propane-1-sulfonamide
[0938] Example 92 was prepared according to the procedure used for
the preparation of Example 4, (Method A), substituting Example 91b
for Example 3 and substituting propane-1-sulfonyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, CDCl.sub.3) .quadrature. ppm 10.63 (bs, 1H), 7.25 (m,
3H), 6.90 (d, J=8.7 Hz, 1H), 6.46-6.35 (m, 2H), 4.88 (bs, 1H),
4.01-3.66 (m, 7H), 3.12-3.03 (m, 2H), 2.2 (bs, 1H), 2.19-1.80 (m,
4H), 1.06 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 432.2 (M+H).sup.+.
Example 93
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]propane-1-sulfonamide
[0939] Example 93 was prepared according to the procedure used for
the preparation of Example 4, (Method A), substituting Example 33b
for Example 3 and substituting propane-1-sulfonyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .quadrature..quadrature. ppm 12.03 (bs,
1H), 9.91 (s, 1H), 7.70-7.63 (m, 2H), 7.42 (d, J=2.5 Hz, 1H),
7.32-7.17 (m, 4H), 6.93-6.86 (m, 2H), 6.22 (dd, J=2.8, 1.9 Hz, 1H),
3.46 (s, 3H), 3.18-3.09 (m, 2H), 1.92-1.65 (m, 2H), 0.98 (t, J=7.4
Hz, 3H). MS (ESI+) m/z 463.2 (M+H).sup.+.
Example 94
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-t-
rifluorophenoxy)phenyl]propane-1-sulfonamide
Example 94a
6-methyl-4-(5-nitro-2-(2,4,6-trifluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[0940] Example 94a was prepared according to the procedure used for
the preparation of Example 2b, substituting 2,4,6-trifluorophenol
for phenol, to provide the title compound.
Example 94b
4-(5-amino-2-(2,4,6-trifluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[0941] Example 94b was prepared according to the procedure used for
the preparation of Example 3, substituting Example 94a for Example
2b, to provide the title compound.
Example 94c
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(2,4,6-t-
rifluorophenoxy)phenyl]propane-1-sulfonamide
[0942] Example 94c was prepared according to the procedure used for
the preparation of Example 4, (Method A), substituting Example 94b
for Example 3 and substituting propane-1-sulfonyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .quadrature. ppm 12.07 (bs, 1H), 9.72
(s, 1H), 7.44-7.33 (m, 2H), 7.33-7.28 (m, 3H), 7.14 (dd, J=8.8, 2.7
Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.24-6.19 (m, 1H), 3.56 (s, 3H),
3.11 3.02 (m, 2H), 1.78-1.62 (m, 2H), 0.95 (t, J=7.4 Hz, 3H). MS
(ESI+) m/z 492.1 (M+H).sup.+.
Example 95
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenz-
enesulfonamide
Example 95a
3-nitro-4-phenoxybenzenesulfonamide
[0943] Phenol (1.282 g, 13.63 mmol) in dimethylformamide (20 mL)
was treated with 60% sodium hydride (0.545 g, 13.63 mmol). The
reaction mixture was stirred for 10 minutes. To this solution was
added 4-fluoro-3-nitrobenzenesulfonamide (0.75 g, 3.41 mmol). The
reaction mixture was stirred at ambient temperature for 2 hours.
The reaction mixture was partitioned between water and ethyl
acetate. The aqueous layer was neutralized with 10% HCl and
extracted with additional ethyl acetate twice. The combined organic
layers were washed with saturated aqueous sodium chloride, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (1:1 ethyl
acetate/hexanes) on silica gel to give 0.96 g of the title
product.
Example 95b
3-amino-4-phenoxybenzenesulfonamide
[0944] Example 95b was prepared according to the procedure used for
the preparation of Example 29b, substituting 95a for Example 29a,
to provide the title compound.
Example 95c
3-iodo-4-phenoxybenzenesulfonamide
[0945] Example 95c was prepared according to the procedure used for
the preparation of Example 85c, substituting 95b for Example 85b,
to provide the title compound.
Example 95d
3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxybenz-
enesulfonamide
[0946] A mixture of Example 6a (0.086 g, 0.20 mmol), Example 95c
(0.083 g, 0.22 mmol), Pd(PPh.sub.3).sub.4(0.012 g, 5 mol %) and
cesium fluoride (0.091 g, 0.6 mmol) in dimethoxyethane (2 mL) and
methanol (1 mL) was heated under microwave conditions (110.degree.
C., 30 minutes). The reaction mixture was cooled to ambient
temperature and portioned between ethyl acetate and water. The
organic layer was separated and dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to
provide the title compound (48 mg, 61% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 12.08 (s, 1H), 7.95 (d, J=2.14 Hz,
1H), 7.79 (dd, J=8.54, 2.44 Hz, 1H), 7.36-7.39 (m, 5H), 7.16 (t,
J=7.48 Hz, 1H), 7.03-7.05 (m, 3H), 6.28 (t, J=2.29 Hz, 1H), 3.55
(s, 3H). MS (ESI+) m/z 396.2 (M+H).sup.+.
Example 96
6-(cyclohexylamino)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-
-4-yl)pyridine-3-sulfonamide
Example 96a
5-bromo-6-(cyclohexylamino)pyridine-3-sulfonamide
[0947] A mixture of Example 86a (0.136 g, 0.5 mmol) and
cyclohexanamine (0.198 g, 2.0 mmol) in dioxane (2 mL) was heated
under microwave conditions (140.degree. C., 1 hour). The solvent
was removed, and the residue was purified by flash chromatography
(3:2 ethyl acetate/hexanes) on silica gel to give 0.164 g of the
title product.
Example 96b
6-(cyclohexylamino)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-
-4-yl)pyridine-3-sulfonamide
[0948] Example 96b was prepared according to the procedure used for
the preparation of Example 95d, substituting Example 96a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.17 (s, 1H), 8.38 (d, J=2.44 Hz, 1H),
7.69 (d, J=2.44 Hz, 1H), 7.32 (t, J=2.75 Hz, 1H), 7.29 (s, 1H),
7.18 (br s, 2H), 6.04 (t, J=2.29 Hz, 1H), 5.97 (d, J=7.63 Hz, 1H),
3.56 (s, 3H), 1.81-1.82 (m, 2H), 1.54-1.65 (m, 3H), 1.01-1.33 (m,
5H) MS (ESI+) m/z 402.1 (M+H).sup.+.
Example 97
6-(cyclohexylamino)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)pyridine-3-sulfonamide
[0949] Example 97 was isolated as a minor product during the
preparation of Example 96b. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.16 (s, 1H), 8.35 (d, J=2.44 Hz, 1H), 7.69 (d, J=2.44
Hz, 1H), 7.32 (t, J=2.75 Hz, 1H), 7.29 (s, 1H), 7.18 (q, J=4.88 Hz,
1H), 6.02 (t, J=2.29 Hz, 1H), 5.96 (d, J=7.24 Hz, 1H), 3.99-4.05
(m, 1H), 3.55 (s, 3H), 2.42 (d, J=4.88 Hz, 3H), 1.80-1.82 (m, 2H),
1.54-1.65 (m, 3H), 1.01-1.33 (m, 6H) MS (ESI+) m/z 416.1
(M+H).sup.+.
Example 98
N-methyl-N'-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)--
4-(2,4,6-trifluorophenoxy)phenyl]sulfuric diamide
[0950] To a mixture of Example 94b (76.3 mg, 0.198 mmol) and
triethylamine (60.1 mg, 0.594 mmol) in dichloromethane (4 mL) was
added dropwise methylsulfamoyl chloride (103 mg, 0.792 mmol), and
the reaction mixture was stirred at ambient temperature for 1 hour.
The reaction mixture was concentrated under reduced pressure, and
the residue was mixed with dioxane (5 mL) and 1M aqueous sodium
hydroxide (3 mL, 0.2 mmol) and heated at 70.degree. C. for 1 hour.
The reaction mixture cooled to ambient temperate and then
neutralized with saturated aqueous ammonium chloride (50 mL) and
the aqueous extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were washed with saturated aqueous sodium
chloride, dried (anhydrous magnesium sulfate), filtered, and
concentrated. The residue was purified by preparative HPLC (C18,
10-80% acetonitrile in 0.1% TFA/water) to provide the title
compound (11 mg, 11% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.quadrature. ppm 12.04 (bs, 1H), 9.58 (s, 1H), 7.43-7.32 (m, 6H),
7.32-7.16 (m, 1H), 7.10 (dd, J=8.8, 2.7 Hz, 1H), 6.75 (d, J=8.8 Hz,
1H), 6.23 (t, J=2.3 Hz, 1H), 3.57 (bs, 3H), 2.35 (d, J=4.9 Hz, 3H).
MS (ESI+) m/z 479.1 (M+H).sup.+.
Example 99
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-4-yloxy)phenyl]propane-1-sulfonamide
Example 99a
6-methyl-4-(5-nitro-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0951] To a solution of tetrahydro-2H-pyran-4-ol (231 mg, 2.265
mmol) in tetrahydrofuran (10 mL) was added sodium hydride (181 mg,
4.53 mmol) portion wise. After stirring for 10 minutes, Example 2a
(500 mg, 1.133 mmol) was added. The mixture was heated at
50.degree. C. for 2 hours. Upon cooling, the reaction mixture was
quenched with saturated ammonium chloride solution (10 mL), diluted
with 50% aqueous sodium chloride (80 mL) and extracted with ethyl
acetate (75 mL, 2.times.50 mL). The combined organics were dried
over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by flash column chromatography (silica gel,
0.5-4% methanol in dichloromethane) to provide the title compound
(220 mg, 52.6% yield).
Example 99b
4-(5-amino-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0952] Example 99b was prepared according to the procedure used for
the preparation of Example 29b, substituting Example 99a for
Example 29a, to provide the title compound.
Example 99c
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-4-yloxy)phenyl]propane-1-sulfonamide
[0953] Example 99c was prepared according to the procedure used for
the preparation of Example 4 (Method A), substituting Example 99b
for Example 3 and propane-1-sulfonyl chloride for methanesulfonyl
chloride with the exception that the reaction mixture was initially
stirred for 18 hours at ambient temperature and then heated at
50.degree. C. for 1 hour in the presence of sodium hydroxide, to
provide the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.00 (s, 1H), 9.50 (s, 1H), 7.24-7.33 (m, 3H), 7.14
(s, 2H), 6.19 (t, J=2.37 Hz, 1H), 4.39-4.53 (m, 1H), 3.53-3.68 (m,
5H), 3.33-3.45 (m, 2H), 2.96-3.06 (m, 2H), 1.78-1.92 (m, 2H),
1.63-1.78 (m, 2H), 1.39-1.54 (m, 2H), 0.95 (t, J=7.46 Hz, 3H). MS
(ESI+) m/z 446.1 (M+H).sup.+.
Example 100
2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin--
4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide
[0954] To a solution of Example 99b (43.2 mg, 0.127 mmol) in
dichloromethane (2 mL) was added 2,2,2-trifluoroethanesulfonyl
chloride (0.015 mL, 0.140 mmol) and triethylamine (0.053 mL, 0.382
mmol). The mixture was stirred for 18 hours at ambient temperature.
The reaction mixture was concentrated and the residue was purified
by flash column chromatography (silica gel, 0.5-5% methanol in
dichloromethane) to provide the title compound (20.8 mg, 33.7%
yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.00 (s,
1H), 10.16 (s, 1H), 7.25-7.32 (m, 3H), 7.14-7.20 (m, 2H), 6.18-6.24
(m, 1H), 4.36-4.55 (m, 3H), 3.52-3.68 (m, 5H), 3.33-3.45 (m, 2H),
1.79-1.94 (m, 2H), 1.39-1.57 (m, 2H). MS (ESI+) m/z 486.1
(M+H).sup.+.
Example 101
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide
Example 101a
4-(2-(4,4-difluorocyclohexyloxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]-
pyridin-7(6H)-one
[0955] Example 101a was prepared according to the procedure used
for the preparation of Example 99a, substituting
4,4-difluorocyclohexanol for tetrahydro-2H-pyran-4-ol, to provide
the title compound.
Example 101b
4-(5-amino-2-(4,4-difluorocyclohexyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]-
pyridin-7(6H)-one
[0956] Example 101b was prepared according to the procedure used
for the preparation of Example 29b, substituting Example 101a for
Example 29a, to provide the title compound.
Example 101c
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide
[0957] Example 101c was prepared according to the procedure used
for the preparation of Example 4 (Method A), substituting Example
101b for Example 3 and ethanesulfonyl chloride for methanesulfonyl
chloride with the exception that the reaction mixture was initially
stirred for 18 hours at ambient temperature and then heated at
50.degree. C. for 1 hour in the presence of sodium hydroxide to
provide the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.02 (s, 1H), 9.56 (s, 1H), 7.24-7.34 (m, J=4.36 Hz,
3H), 7.17 (s, 2H), 6.15-6.23 (m, 1H), 4.48 (s, 1H), 3.49-3.61 (m,
3H), 3.05 (q, J=7.27 Hz, 2H), 1.62-1.88 (m, 8H), 1.22 (t, J=7.34
Hz, 3H). MS (ESI+) m/z 466.1 (M+H).sup.+.
Example 102
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl}propane-1-sulfonamide
[0958] Example 102 was prepared according to the procedure used for
the preparation of Example 4 (Method A), substituting Example 101b
for Example 3 and propane-1-sulfonyl chloride for methanesulfonyl
chloride with the exception that the reaction mixture was initially
stirred for 18 hours at ambient temperature and then heated at
50.degree. C. for 1 hour in the presence of sodium hydroxide, to
provide the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.02 (s, 1H), 9.54 (s, 1H), 7.25-7.31 (m, 3H), 7.17
(s, 2H), 6.14-6.22 (m, 1H), 4.44-4.56 (m, J=2.78 Hz, 1H), 3.51-3.57
(m, 3H), 2.96-3.08 (m, 2H), 1.61-1.89 (m, 10H), 0.95 (t, J=7.54 Hz,
3H). MS (ESI+) m/z 480.2 (M+H).sup.+.
Example 103
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl}-2,2,2-trifluoroethanesulfonamide
[0959] Example 103 was prepared according to the procedure used for
the preparation of Example 100, substituting Example 101b for
Example 99b, to provide the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 12.00 (s, 1H), 10.19 (s, 1H), 7.25-7.32
(m, 3H), 7.19 (s, 2H), 6.17-6.24 (m, 1H), 4.36-4.60 (m, 3H), 3.55
(s, 3H), 1.60-1.88 (m, J=4.07 Hz, 8H). MS (ESI+) m/z 520.1
(M+H).sup.+.
Example 104
N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl}-N'-methylsulfuric diamide
[0960] Example 104 was prepared according to the procedure used for
the preparation of Example 100, substituting Example 101b for
Example 99b and methylsulfamoyl chloride for
2,2,2-trifluoroethanesulfonyl chloride, to provide the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 11.98 (s,
1H), 9.41 (s, 1H), 7.21-7.30 (m, 3H), 7.06-7.17 (m, 3H), 6.15-6.24
(m, 1H), 4.44 (s, 1H), 3.55 (s, 3H), 2.51 (s, 3H), 1.59-1.86 (m,
8H). MS (ESI+) m/z 467.1 (M+H).sup.+.
Example 105
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide
Example 105a
6-methyl-4-(5-nitro-2-(tetrahydro-2H-pyran-3-yloxy)phenyl)-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0961] Example 105a was prepared according to the procedure used
for the preparation of Example 99a, substituting
tetrahydro-2H-pyran-3-ol for tetrahydro-2H-pyran-4-ol, to provide
the title compound.
Example 105b
4-(5-amino-2-(tetrahydro-2H-pyran-3-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[0962] Example 105b was prepared according to the procedure used
for the preparation of Example 29b, substituting Example 105a for
Example 29a, to provide the title compound.
Example 105c
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide
[0963] Example 105c was prepared according to the procedure used
for the preparation of Example 4 (Method A), substituting Example
105b for Example 3 and ethanesulfonyl chloride for methanesulfonyl
chloride with the exception that the reaction mixture was initially
stirred for 18 hours at ambient temperature and then heated at
50.degree. C. for 1 hour in the presence of sodium hydroxide, to
provide the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.02 (s, 1H), 9.53 (s, 1H), 7.37 (s, 1H), 7.27-7.33
(m, 2H), 7.09-7.17 (m, 2H), 6.23 (t, J=2.18 Hz, 1H), 4.23-4.34 (m,
1H), 3.67 (dd, J=11.70, 2.58 Hz, 1H), 3.37-3.59 (m, 6H), 3.04 (q,
J=7.54 Hz, 2H), 1.85-2.00 (m, 1H), 1.51-1.73 (m, 2H), 1.33-1.49 (m,
1H), 1.21 (t, J=7.34 Hz, 3H). MS (ESI+) m/z 432.2 (M+H).sup.+.
Example 106
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-3-yloxy)phenyl]propane-1-sulfonamide
[0964] Example 106 was prepared according to the procedure used for
the preparation of Example 4 (Method A), substituting Example 105b
for Example 3 and propane-1-sulfonyl chloride for methanesulfonyl
chloride with the exception that the reaction mixture was initially
stirred for 18 hours at ambient temperature and then heated at
50.degree. C. for 1 hour in the presence of sodium hydroxide, to
provide the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.02 (s, 1H), 9.52 (s, 1H), 7.37 (s, 1H), 7.30 (s,
2H), 7.12 (s, 2H), 6.23 (t, J=2.18 Hz, 1H), 4.22-4.34 (m, 1H), 3.67
(dd, J=11.50, 2.78 Hz, 1H), 3.36-3.59 (m, 6H), 2.96-3.07 (m, 2H),
1.85-1.99 (m, 1H), 1.52-1.79 (m, 4H), 1.32-1.50 (m, 1H), 0.95 (t,
J=7.54 Hz, 3H). MS (ESI+) m/z 446.2 (M+H).sup.+.
Example 107
2,2,2-trifluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin--
4-yl)-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]ethanesulfonamide
[0965] Example 107 was prepared according to the procedure used for
the preparation of Example 100, substituting Example 105b for
Example 99b, to provide the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 12.02 (s, 1H), 10.17 (s, 1H), 7.38 (s,
1H), 7.26-7.33 (m, 2H), 7.12-7.18 (m, J=1.59 Hz, 2H), 6.26 (t,
J=2.38 Hz, 1H), 4.43 (q, J=9.92 Hz, 2H), 4.27-4.36 (m, 1H), 3.68
(dd, J=11.50, 2.38 Hz, 1H), 3.39-3.59 (m, 6H), 1.86-2.01 (m, 1H),
1.53-1.73 (m, 2H), 1.36-1.49 (m, 1H). MS (ESI+) m/z 486.1
(M+H).sup.+.
Example 108
N-methyl-N'-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)--
4-(tetrahydro-2H-pyran-3-yloxy)phenyl]sulfuric diamide
[0966] Example 108 was prepared according to the procedure used for
the preparation of Example 100, substituting the Example 105b for
Example 99b and methylsulfamoyl chloride for
2,2,2-trifluoroethanesulfonyl chloride, to provide the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 11.99 (s,
1H), 9.38 (s, 1H), 7.33 (s, 1H), 7.26-7.30 (m, J=2.54, 2.54 Hz,
2H), 7.05-7.13 (m, 3H), 6.22-6.27 (m, 1H), 4.16-4.27 (m, 1H), 3.65
(dd, J=11.53, 2.37 Hz, 1H), 3.37-3.59 (m, 6H), 2.50-2.53 (m, J=1.70
Hz, 3H), 1.84-1.96 (m, 1H), 1.50-1.71 (m, 2H), 1.35-1.47 (m, 1H).
MS (ESI+) m/z 433.1 (M+H).sup.+.
Example 109
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(tetrahy-
dro-2H-pyran-4-yloxy)phenyl]ethanesulfonamide
[0967] Example 109 was prepared according to the procedure used for
the preparation of Example 4 (Method A), substituting Example 99b
for Example 3 and ethanesulfonyl chloride for methanesulfonyl
chloride with the exception that the reaction mixture was initially
stirred for 18 hours at ambient temperature and then heated at
50.degree. C. for 1 hour in the presence of sodium hydroxide, to
provide the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.00 (s, 1H), 9.50 (s, 1H), 7.24-7.33 (m, 3H), 7.14
(s, 2H), 6.19 (t, J=2.37 Hz, 1H), 4.39-4.53 (m, 1H), 3.53-3.68 (m,
5H), 3.33-3.45 (m, 2H), 2.96-3.06 (m, 2H), 1.78-1.92 (m, 2H),
1.63-1.78 (m, 2H), 1.39-1.54 (m, 2H), 0.95 (t, J=7.46 Hz, 3H). MS
(ESI+) m/z 432.1 (M+H).sup.+.
Example 110
N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)--
6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide
Example 110a
5-bromo-6-chloro-N,N-dimethylpyridine-3-sulfonamide
[0968] 5-Bromo-6-chloropyridine-3-sulfonyl chloride (1.455 g, 5
mmol) in methanol (20 mL) was treated with 2.0 N dimethylamine
(6.25 mL, 12.50 mmol). The reaction mixture was stirred at ambient
temperature for 16 hours. The solvent was removed, and the solid
was washed with water several times. The solid was then purified by
chromatography on silica gel eluting with 15% ethyl acetate in
hexanes to give 0.8 g of the title compound.
Example 110b
5-bromo-N,N-dimethyl-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide
[0969] Example 110b was prepared according to the procedure used
for the preparation of Example 29a, substituting 110a for Example
2a, and tetrahydrofuran-3-ol for tetrahydro-2H-pyran-4-ol,
respectively, to provide the title compound.
Example 110c
N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)--
6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide
[0970] Example 110c was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 110b for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.11 (s, 1H), 8.53 (d, J=2.44 Hz, 1H),
8.00 (d, J=2.44 Hz, 1H), 7.43 (s, 1H), 7.32 (d, J=2.75 Hz, 1H),
6.17 (t, J=2.29 Hz, 1H), 5.67 (d, J=1.53 Hz, 1H), 3.93 (dd,
J=10.38, 4.58 Hz, 1H), 3.78 (d, J=10.07 Hz, 1H), 3.68-3.72 (m, 2H),
3.57 (s, 3H), 2.69 (s, 6H), 2.54-2.56 (m, 5H), 2.17-2.24 (m, 1H),
1.94-1.98 (m, 1H). MS (ESI+) m/z 419.2 (M+H).sup.+.
Example 111
5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylamin-
o)pyridine-3-sulfonamide
Example 111a
5-bromo-6-(phenylamino)pyridine-3-sulfonamide
[0971] A mixture of Example 86a (0.136 g, 0.5 mmol), aniline (0.186
g, 2.0 mmol), and 60% sodium hydride (0.12 g, 3.0 mmol) in dioxane
(2 mL) was stirred and heated at 60.degree. C. for 16 hours. After
cooling, the reaction mixture was partitioned between water and
ethyl acetate. The aqueous layer was neutralized with 10% HCl and
extracted with additional ethyl acetate twice. The combined organic
layers were washed with saturated aqueous sodium chloride, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel (2:3
ethyl acetate/hexanes) to give 0.095 g of the title product.
Example 111b
5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(phenylamin-
o)pyridine-3-sulfonamide
[0972] Example 111b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 111a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.17 (s, 1H), 8.49 (d, J=2.44 Hz, 1H),
8.25 (s, 1H), 7.87 (d, J=2.44 Hz, 1H), 7.55 (d, J=7.63 Hz, 2H),
7.42 (s, 1H), 7.24-7.31 (m, 5H), 6.99 (t, J=7.32 Hz, 1H), 6.04 (m,
1H), 3.58 (s, 3H). MS (ESI+) m/z 396.2 (M+H).sup.+.
Example 112
N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-6-(p-
henylamino)pyridine-3-sulfonamide
[0973] Example 112 was isolated as a minor product during the
preparation of Example 111b. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.17 (s, 1H), 8.44 (d, J=2.44 Hz, 1H), 8.31 (s, 1H),
7.78 (d, J=2.44 Hz, 1H), 7.56 (d, J=7.63 Hz, 2H), 7.45 (s, 1H),
7.34-7.37 (m, 1H), 7.25-7.30 (m, 3H), 7.00 (t, J=7.32 Hz, 1H), 6.04
(m, 1H), 3.58 (s, 3H), 2.46 (d, J=4.88 Hz, 3H). MS (ESI+) m/z 410.2
(M+H).sup.+.
Example 113
N-[4-(4-cyanophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)phenyl]-2-fluoroethanesulfonamide
[0974] Example 33b (50 mg, 0.140 mmol) and triethylamine (42.6 mg,
0.421 mmol) were combined in dichloromethane (4 mL).
2-Fluoroethanesulfonyl chloride (82 mg, 0.561 mmol) was added
dropwise and reaction mixture was stirred for 1 hour at ambient
temperature. The reaction mixture was then extracted with saturated
aqueous sodium chloride, separated, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
preparative HPLC (C18, 10-100% acetonitrile/water, 0.1% TFA) to
afford the title compound (1.4 mg, 2% yield). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature..quadrature. ppm 11.98-11.92 (m, 1H),
7.62-7.56 (m, 2H), 7.25 (t, J=2.7 Hz, 1H), 7.17 (s, 1H), 7.05 (d,
J=8.6 Hz, 1H), 6.82-6.70 (m, 4H), 6.24-6.13 (m, 1H), 4.19-4.09 (m,
2H), 3.70-3.62 (m, 2H) 3.45 (s, 3H). MS (ESI+) m/z 467.1
(M+H).sup.+.
Example 114
2-fluoro-N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-
-(2,4,6-trifluorophenoxy)phenyl]ethanesulfonamide
[0975] Example 114 was prepared according to the procedure used for
the preparation of Example 91c, substituting Example 94b for
Example 91b, to provide the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature..quadrature. ppm 12.00-11.94 (m, 1H),
7.33 (d, J=8.8 Hz, 1H), 7.27 (m, 2H), 7.25 (s, 1H), 6.69 (d, J=2.5
Hz, 1H), 6.63-6.47 (m, 2H), 6.22 (dd, J=2.8, 2.0 Hz, 1H), 4.08 (q,
J=6.3, 5.7, 6.0 Hz, 2H), 3.60 (t, J=6.3, 6.0 Hz, 2H), 3.55 (bs,
3H). MS (ESI+) m/z 496.2 (M+H).sup.+.
Example 115
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]propane-1-sulfonamide
[0976] Example 115 was prepared according to the procedure used for
the preparation of Example 27c, substituting propane-1-sulfonyl
chloride for methanesulfonyl chloride, to provide the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.quadrature..quadrature. ppm 12.04 (bs, 1H), 9.76 (s, 1H),
7.42-7.26 (m, 4H), 7.18 (dd, J=8.8, 2.7 Hz, 1H), 7.13-6.94 (m, 2H),
6.91 (d, J=8.7 Hz, 1H), 6.24 (t, J=2.3 Hz, 1H), 3.53 (s, 3H),
3.13-3.04 (m, 2H), 1.79-1.64 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). MS
(ESI+) m/z 474.1 (M+H).sup.+.
Example 116
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-(pyrimidin-2-yl)benzamide
[0977] A solution of Example 50b (24 mg, 0.06 mmol) in a 4 mL vial
was dissolved in anhydrous tetrahydrofuran (1.0 mL), followed by
the addition of 1-chloro-N,N,2-trimethyl-1-propenylamine (65 .mu.L,
0.48 mmol). This was capped and placed to shake for 2 hours at
ambient temperature. Then, a solution of pyrimidin-2-amine (9 mg,
0.09 mmol) in anhydrous tetrahydrofuran (0.3 mL) was added,
followed by a solution of 4-(dimethylamino)pyridine (37 mg, 0.3
mmol) in anhydrous tetrahydrofuran (0.5 mL). The mixture was
stirred at 60.degree. C. for 16 hours, cooled, and concentrated to
dryness. The residues were dissolved in 1:1 DMSO/MeOH and purified
by reverse phase HPLC (10-80% acetonitrile in 0.1% TFA water).
.sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.)
.delta. ppm 8.73 (d, J=4.88 Hz, 2H) 8.09 (d, J=2.44 Hz, 1H) 7.95
(dd, J=8.70, 2.29 Hz, 1H) 7.42-7.48 (m, 1H) 7.41 (s, 1H) 7.32-7.38
(m, 2H) 7.27 (t, J=4.88 Hz, 1H) 7.11-7.17 (m, 1H) 6.90 (d, J=8.85
Hz, 1H) 6.32 (d, J=2.75 Hz, 1H) 3.60 (s, 3H); (ESI) m/z 474
(M+H).sup.+.
Example 117
4-(2,4-difluorophenoxy)-N-(2,6-dimethoxypyridin-3-yl)-3-(6-methyl-7-oxo-6,-
7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide
[0978] Example 117 was prepared according to the procedure used for
the preparation of Example 116, substituting
2,6-dimethoxypyridin-3-amine hydrochloride for pyrimidin-2-amine,
to provide the TFA salt of the title compound. .sup.1H NMR (500
MHz, DMSO-d.sub.6/D.sub.2O Temp=25.degree. C.) .delta. ppm 8.08 (d,
J=1.53 Hz, 1H) 7.94 (dd, J=8.85, 2.14 Hz, 1H) 7.74-7.78 (m, 1H)
7.40-7.47 (m, 1H) 7.38 (s, 1H) 7.28-7.35 (m, 2H) 7.09-7.15 (m, 1H)
6.91 (d, J=8.54 Hz, 1H) 6.43 (d, J=8.24 Hz, 1H) 6.29 (d, J=2.75 Hz,
1H) 3.88 (d, J=9.46 Hz, 6H) 3.60 (s, 3H); (ESI) m/z 533
(M+H).sup.+.
Example 118
4-(2,4-difluorophenoxy)-N-(1H-indazol-6-yl)-3-(6-methyl-7-oxo-6,7-dihydro--
1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide
[0979] Example 118 was prepared according to the procedure used for
the preparation of Example 116, substituting 1H-indazol-6-amine for
pyrimidin-2-amine, to provide the title compound. .sup.1H NMR (500
MHz, DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .delta. ppm 8.22
(s, 1H) 8.12 (d, J=2.44 Hz, 1H) 8.02 (s, 1H) 7.97 (dd, J=8.54, 2.44
Hz, 1H) 7.73 (d, J=8.54 Hz, 1H) 7.42-7.48 (m, 1H) 7.41 (s, 1H)
7.30-7.38 (m, 3H) 7.11-7.16 (m, 1H) 6.93 (d, J=8.54 Hz, 1H) 6.31
(d, J=2.75 Hz, 1H) 3.61 (s, 3H); (ESI) m/z 512 (M+H).sup.+.
Example 119
4-[2-(2,4-difluorophenoxy)-5-{[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]c-
arbonyl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0980] Example 119 was prepared according to the procedure used for
the preparation of Example 116, substituting
piperazin-1-yl(pyrrolidin-1-yl)methanone for pyrimidin-2-amine, to
provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .delta. ppm 7.51 (d,
J=2.14 Hz, 1H) 7.39-7.46 (m, 2H) 7.35 (s, 1H) 7.32-7.34 (m, J=2.90,
2.90 Hz, 1H) 7.25-7.31 (m, 1H) 7.07-7.13 (m, 1H) 6.87 (d, J=8.54
Hz, 1H) 6.28 (d, J=2.75 Hz, 1H) 3.59-3.71 (m, 1H) 3.56-3.58 (m, 4H)
3.40-3.55 (m, 2H) 3.18-3.33 (m, J=6.41, 6.41 Hz, 8H) 1.75 (t,
J=6.26 Hz, 4H); (ESI) m/z 562 (M+H).sup.+.
Example 120
4-(2,4-difluorophenoxy)-N-[4-(dimethylamino)phenyl]-3-(6-methyl-7-oxo-6,7--
dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide
[0981] Example 120 was prepared according to the procedure used for
the preparation of Example 116, substituting
N.sup.1,N.sup.1-dimethylbenzene-1,4-diamine for pyrimidin-2-amine,
to provide the TFA salt of the title compound. .sup.1H NMR (500
MHz, DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .delta. ppm 8.09
(d, J=2.44 Hz, 1H) 7.94 (dd, J=8.70, 2.29 Hz, 1H) 7.76 (d, J=9.16
Hz, 2H) 7.41-7.47 (m, 1H) 7.39 (s, 1H) 7.29-7.36 (m, 2H) 7.26 (d,
J=8.85 Hz, 2H) 7.10-7.16 (m, 1H) 6.92 (d, J=8.54 Hz, 1H) 6.29 (d,
J=3.05 Hz, 1H) 3.60 (s, 3H) 3.06 (s, 6H); (ESI) m/z 515
(M+H).sup.+.
Example 121
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-(pyridin-4-ylmethyl)benzamide
[0982] Example 121 was prepared according to the procedure used for
the preparation of Example 116, substituting
pyridin-4-ylmethanamine for pyrimidin-2-amine, to provide the TFA
salt of the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .delta. ppm 8.79 (d,
J=6.41 Hz, 2H) 8.05 (d, J=2.14 Hz, 1H) 7.87-7.96 (m, 3H) 7.41-7.47
(m, 1H) 7.28-7.38 (m, 3H) 7.09-7.16 (m, 1H) 6.91 (d, J=8.54 Hz, 1H)
6.28 (d, J=2.75 Hz, 1H) 4.73 (s, 2H) 3.59 (s, 3H); (ESI) m/z 487
(M+H).sup.+.
Example 122
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-[2-(2-oxopyrrolidin-1-yl)ethyl]benzamide
[0983] Example 122 was prepared according to the procedure used for
the preparation of Example 116, substituting
1-(2-aminoethyl)pyrrolidin-2-one for pyrimidin-2-amine, to provide
the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O,
Temp=25.degree. C.) .delta. ppm 7.91 (d, J=2.44 Hz, 1H) 7.77 (dd,
J=8.70, 2.29 Hz, 1H) 7.38-7.47 (m, 1H) 7.32-7.36 (m, 2H) 7.26-7.31
(m, 1H) 7.07-7.13 (m, 1H) 6.86 (d, J=8.54 Hz, 1H) 6.27 (d, J=2.75
Hz, 1H) 3.59 (s, 3H) 3.33-3.46 (m, 6H) 2.19 (t, J=8.09 Hz, 2H)
1.86-1.95 (m, 2H); (ESI) m/z 507 (M+H).sup.+.
Example 123
4-(2,4-difluorophenoxy)-N-(2-hydroxy-2-methylpropyl)-3-(6-methyl-7-oxo-6,7-
-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide
[0984] Example 123 was prepared according to the procedure used for
the preparation of Example 116, substituting
1-amino-2-methylpropan-2-ol for pyrimidin-2-amine, to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O
Temp=25.degree. C.) .delta. ppm 7.98 (d, J=2.14 Hz, 1H) 7.85 (dd,
J=8.70, 2.29 Hz, 1H) 7.39-7.45 (m, 1H) 7.35 (s, 1H) 7.32 (d, J=3.05
Hz, 1H) 7.25-7.31 (m, 1H) 7.07-7.13 (m, 1H) 6.86 (d, J=8.54 Hz, 1H)
6.26 (d, J=2.75 Hz, 1H) 3.58-3.60 (m, 3H) 3.27 (s, 2H) 1.11 (s,
6H); (ESI) m/z 468 (M+H).sup.+.
Example 124
4-(2,4-difluorophenoxy)-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3-(6-methyl-7-
-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide
[0985] Example 124 was prepared according to the procedure used for
the preparation of Example 116, substituting
2-(5-methoxy-1H-indol-3-yl)ethanamine for pyrimidin-2-amine, to
provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .delta. ppm 7.93 (d,
J=2.14 Hz, 1H) 7.83 (dd, J=8.54, 2.14 Hz, 1H) 7.39-7.45 (m, 1H)
7.30-7.33 (m, 2H) 7.26-7.30 (m, 1H) 7.24 (d, J=8.85 Hz, 1H) 7.14
(s, 1H) 7.07-7.13 (m, 1H) 7.03 (d, J=2.44 Hz, 1H) 6.86 (d, J=8.54
Hz, 1H) 6.72 (dd, J=8.85, 2.44 Hz, 1H) 6.24 (d, J=2.75 Hz, 1H) 3.67
(s, 3H) 3.59 (s, 3H) 3.53 (t, J=7.32 Hz, 2H) 2.92 (t, J=7.32 Hz,
2H); (ESI) m/z 569 (M+H).sup.+.
Example 125
N-(3,4-difluorobenzyl)-4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihyd-
ro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide
[0986] Example 125 was prepared according to the procedure used for
the preparation of Example 116, substituting
(3,4-difluorophenyl)methanamine for pyrimidin-2-amine, to provide
the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O,
Temp=25.degree. C.) .delta. ppm 8.00 (d, J=2.14 Hz, 1H) 7.87 (dd,
J=8.54, 2.14 Hz, 1H) 7.26-7.46 (m, 6H) 7.15-7.20 (m, 1H) 7.08-7.13
(m, 1H) 6.88 (d, J=8.54 Hz, 1H) 6.26 (d, J=2.75 Hz, 1H) 4.45 (s,
2H) 3.58 (s, 3H); (ESI) m/z 522 (M+H).sup.+.
Example 126
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide
[0987] Example 126 was prepared according to the procedure used for
the preparation of Example 116, substituting
(4-(trifluoromethoxy)phenyl)methanamine for pyrimidin-2-amine, to
provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .quadrature. ppm 8.01
(d, J=2.44 Hz, 1H) 7.88 (dd, J=8.54, 2.14 Hz, 1H) 7.39-7.47 (m, 3H)
7.35 (s, 1H) 7.26-7.34 (m, 4H) 7.08-7.14 (m, 1H) 6.88 (d, J=8.54
Hz, 1H) 6.26 (d, J=2.75 Hz, 1H) 4.50 (s, 2H) 3.58 (s, 3H); (ESI)
m/z 570 (M+H).sup.+.
Example 127
2-{4-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-
-c]pyridin-4-yl)benzoyl]piperazin-1-yl}-N,N-dimethylacetamide
[0988] Example 127 was prepared according to the procedure used for
the preparation of Example 116, substituting
N,N-dimethyl-2-(piperazin-1-yl)acetamide for pyrimidin-2-amine, to
provide the TFA salt of the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .quadrature. ppm 7.56
(d, J=2.14 Hz, 1H) 7.40-7.48 (m, 2H) 7.35 (s, 1H) 7.33 (d, J=2.75
Hz, 1H) 7.26-7.32 (m, 1H) 7.08-7.13 (m, 1H) 6.88 (d, J=8.24 Hz, 1H)
6.28 (d, J=2.75 Hz, 1H) 4.26 (s, 2H) 2.99-3.71 (m, 11H) 2.92 (d,
J=5.49 Hz, 6H); (ESI) m/z 550 (M+H).sup.+.
Example 128
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-(pyridin-3-ylmethyl)benzamide
[0989] Example 128 was prepared according to the procedure used for
the preparation of Example 116, substituting
pyridin-3-ylmethanamine for pyrimidin-2-amine, to provide the TFA
salt of the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .quadrature. ppm 8.78
(s, 1H) 8.72 (d, J=5.19 Hz, 1H) 8.36 (d, J=7.93 Hz, 1H) 8.01 (d,
J=2.14 Hz, 1H) 7.85-7.92 (m, 2H) 7.40-7.46 (m, 1H) 7.35 (s, 1H)
7.33 (t, J=3.36 Hz, 1H) 7.27-7.31 (m, 1H) 7.09-7.14 (m, 1H) 6.89
(d, J=8.54 Hz, 1H) 6.26 (d, 1H) 4.63 (s, 2H) 3.59 (s, 3H); (ESI)
m/z 487 (M+H).sup.+.
Example 129
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-(pyridin-2-ylmethyl)benzamide
[0990] Example 129 was prepared according to the procedure used for
the preparation of Example 116, substituting
pyridin-2-ylmethanamine for pyrimidin-2-amine, to provide the TFA
salt of the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .quadrature. ppm 8.68
(d, J=5.49 Hz, 1H) 8.23-8.29 (m, 1H) 8.04 (d, J=2.44 Hz, 1H) 7.90
(dd, J=8.70, 2.29 Hz, 1H) 7.75 (d, J=7.93 Hz, 1H) 7.69-7.73 (m, 1H)
7.39-7.47 (m, 1H) 7.36 (s, 1H) 7.33 (d, J=2.75 Hz, 1H) 7.26-7.32
(m, 1H) 7.09-7.15 (m, 1H) 6.90 (d, J=8.85 Hz, 1H) 6.27 (d, J=2.75
Hz, 1H) 4.73 (s, 2H) 3.59 (s, 3H); (ESI) m/z 487 (M+H).sup.+.
Example 130
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N-(3,4,5-trimethoxybenzyl)benzamide
[0991] Example 130 was prepared according to the procedure used for
the preparation of Example 116, substituting
(3,4,5-trimethoxyphenyl)methanamine for pyrimidin-2-amine, to
provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .quadrature. ppm 8.00
(d, J=2.14 Hz, 1H) 7.87 (dd, J=8.70, 2.29 Hz, 1H) 7.39-7.45 (m, 1H)
7.35 (s, 1H) 7.32 (d, J=2.75 Hz, 1H) 7.26-7.31 (m, 1H) 7.11 (m, 1H)
6.87 (d, J=8.54 Hz, 1H) 6.66 (s, 2H) 6.26 (d, J=2.75 Hz, 1H) 4.41
(s, 2H) 3.75 (s, 6H) 3.63 (s, 3H) 3.58 (s, 3H); (ESI) m/z 576
(M+H).sup.+.
Example 131
4-(2,4-difluorophenoxy)-N-[2-(dimethylamino)ethyl]-3-(6-methyl-7-oxo-6,7-d-
ihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide
[0992] Example 131 was prepared according to the procedure used for
the preparation of Example 116, substituting
N.sup.1,N.sup.1-dimethylethane-1,2-diamine for pyrimidin-2-amine,
to provide the TFA salt of the title compound. .sup.1H NMR (500
MHz, DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .quadrature. ppm
7.97 (d, J=2.14 Hz, 1H) 7.85 (dd, J=8.70, 2.29 Hz, 1H) 7.39-7.46
(m, 1H) 7.31-7.35 (m, 2H) 7.25-7.31 (m, 1H) 7.09-7.15 (m, 1H) 6.90
(d, J=8.55 Hz, 1H) 6.25 (d, J=2.75 Hz, 1H) 3.62 (t, J=5.95 Hz, 2H)
3.59 (s, 3H) 3.26 (t, J=5.95 Hz, 2H) 2.84 (s, 6H); (ESI) m/z 467
(M+H).sup.+.
Example 132
N-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2,4-difluorophenoxy)-3-(6-methyl-7-ox-
o-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide
[0993] Example 132 was prepared according to the procedure used for
the preparation of Example 116, substituting
2-(benzo[d][1,3]dioxol-5-yl)ethanamine for pyrimidin-2-amine, to
provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .quadrature. ppm 7.92
(d, J=2.14 Hz, 1H) 7.79 (dd, J=8.70, 2.29 Hz, 1H) 7.39-7.45 (m, 1H)
7.31-7.34 (m, 2H) 7.25-7.31 (m, 1H) 7.06-7.14 (m, 1H) 6.80-6.87 (m,
3H) 6.70 (d, J=7.02 Hz, 1H) 6.25 (d, J=3.05 Hz, 1H) 5.94 (s, 2H)
3.59 (s, 3H) 3.44 (t, J=7.32 Hz, 2H) 2.76 (t, J=7.32 Hz, 2H); (ESI)
m/z 544 (M+H).sup.+.
Example 133
4-(2,4-difluorophenoxy)-N-[2-(1H-indol-3-yl)ethyl]-3-(6-methyl-7-oxo-6,7-d-
ihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide
[0994] Example 133 was prepared according to the procedure used for
the preparation of Example 116, substituting
2-(1H-indol-3-yl)ethanamine for pyrimidin-2-amine, to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O,
Temp=25.degree. C.) .quadrature. ppm 8.65 (t, J=5.49 Hz, 1H) 7.94
(d, J=2.14 Hz, 1H) 7.83 (dd, J=8.70, 2.29 Hz, 1H) 7.58 (d, J=7.93
Hz, 1H) 7.39-7.45 (m, 1H) 7.36 (d, J=7.93 Hz, 1H) 7.32-7.34 (m, 2H)
7.25-7.31 (m, 1H) 7.18 (s, 1H) 7.05-7.13 (m, 2H) 6.98 (t, J=7.32
Hz, 1H) 6.86 (d, J=8.54 Hz, 1H) 6.25 (d, J=2.75 Hz, 1H) 3.59 (s,
3H) 3.48-3.58 (m, 2H) 2.96 (t, J=7.48 Hz, 2H); (ESI) m/z 539
(M+H).sup.+.
Example 134
4-[2-(2,4-difluorophenoxy)-5-{[4-(furan-2-ylcarbonyl)piperazin-1-yl]carbon-
yl}phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0995] Example 134 was prepared according to the procedure used for
the preparation of Example 116, substituting
furan-2-yl(piperazin-1-yl)methanone for pyrimidin-2-amine, to
provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6/D.sub.2O, Temp=25.degree. C.) .quadrature. ppm 7.82
(s, 1H) 7.55 (d, J=2.14 Hz, 1H) 7.39-7.48 (m, 2H) 7.25-7.37 (m, 3H)
7.07-7.13 (m, 1H) 7.05 (d, J=3.36 Hz, 1H) 6.88 (d, J=8.24 Hz, 1H)
6.64 (dd, J=3.36, 1.83 Hz, 1H) 6.29 (d, J=2.75 Hz, 1H) 3.74-3.89
(m, 4H) 3.41-3.70 (m, 7H); (ESI) m/z 559 (M+H).sup.+.
Example 135
tert-butyl
{1-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-c]pyridin-4-yl)benzoyl]piperidin-4-yl}carbamate
[0996] Example 135 was prepared according to the procedure used for
the preparation of Example 116, substituting tert-butyl
piperidin-4-ylcarbamate for pyrimidin-2-amine, to provide the title
compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O,
Temp=25.degree. C.) .quadrature. ppm 7.45 (d, J=1.83 Hz, 1H)
7.36-7.44 (m, 2H) 7.34 (s, 1H) 7.32 (d, J=2.75 Hz, 1H) 7.25-7.31
(m, 1H) 7.06-7.13 (m, 1H) 6.86 (d, J=8.54 Hz, 1H) 6.27 (d, J=2.75
Hz, 1H) 4.31 (s, 1H) 3.42-3.69 (m, 5H) 2.85-3.24 (m, 2H) 1.77 (s,
2H) 1.21-1.47 (m, 11H); (ESI) m/z 579 (M+H).sup.+.
Example 136
tert-butyl
4-{[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-py-
rrolo[2,3-c]pyridin-4-yl)benzoyl]amino}piperidine-1-carboxylate
[0997] Example 136 was prepared according to the procedure used for
the preparation of Example 116, substituting tert-butyl
4-aminopiperidine-1-carboxylate for pyrimidin-2-amine, to provide
the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O,
Temp=25.degree. C.) .quadrature. ppm 7.95 (d, J=2.14 Hz, 1H) 7.83
(dd, J=8.54, 2.14 Hz, 1H) 7.43 (d, J=8.54 Hz, 1H) 7.31-7.35 (m, 2H)
7.24-7.51 (m, 1H) 7.10 (d, J=1.83 Hz, 1H) 6.86 (d, J=8.54 Hz, 1H)
6.24 (d, J=2.75 Hz, 1H) 3.87-4.08 (m, 3H) 3.58 (s, 3H) 2.91 (d,
J=85.75 Hz, 2H) 1.78 (d, 2H) 1.34-1.45 (m, 11H); (ESI) m/z 579
(M+H).sup.+.
Example 137
4-[2-(2,4-difluorophenoxy)-5-{[4-(ethylsulfonyl)piperazin-1-yl]carbonyl}ph-
enyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[0998] Example 137 was prepared according to the procedure used for
the preparation of Example 116, substituting
1-(ethylsulfonyl)piperazine for pyrimidin-2-amine, to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6/D.sub.2O,
Temp=25.degree. C.) .quadrature. ppm 7.53 (d, J=2.14 Hz, 1H)
7.38-7.47 (m, 2H) 7.35 (s, 1H) 7.33 (d, J=3.05 Hz, 1H) 7.26-7.32
(m, 1H) 7.07-7.13 (m, 1H) 6.87 (d, J=8.54 Hz, 1H) 6.28 (d, J=2.75
Hz, 1H) 3.43-3.70 (m, 7H) 3.25 (s, 4H) 3.07 (q, J=7.43 Hz, 2H) 1.22
(t, J=7.32 Hz, 3H); (ESI) m/z 557 (M+H).sup.+.
Example 138
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
Example 138a
4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]py-
ridin-7(6H)-one
[0999] A mixture of Example 6a (0.642 g, 1.5 mmol),
2-bromo-1-fluoro-4-(methylsulfonyl)benzene (0.380 g, 1.500 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.051 g, 0.176 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.041 g, 0.045 mmol), and potassium phosphate (0.796 g, 3.75 mmol)
in dioxane (10 mL) and water (2.500 mL) was degassed and
back-filled with nitrogen several times. The reaction was heated at
60.degree. C. for 16 hours. The reaction mixture was partitioned
between water and ethyl acetate. The aqueous layer was extracted
with additional ethyl acetate three times. The combined organic
layers were washed with saturated aqueous sodium chloride, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel
eluting with 30% ethyl acetate in hexanes to give the title
compound (0.63 g, 1.328 mmol, 89% yield).
Example 138b
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
[1000] A mixture of Example 138a (0.05 g, 0.105 mmol),
2,4-difluorophenol (0.016 g, 0.126 mmol), and cesium carbonate
(0.069 g, 0.211 mmol) in DMSO (1 mL) was heated at 120.degree. C.
for 16 hours. The reaction mixture was partitioned between water
and ethyl acetate. The aqueous layer was extracted with additional
ethyl acetate three times. The combined organic layers were washed
with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by reverse phase Preparative HPLC (10-80% acetonitrile in
0.1% TFA/water) to give the title compound (0.036 g, 0.084 mmol,
79% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.10
(s, 1H), 7.99 (d, J=2.44 Hz, 1H), 7.86 (dd, J=8.54, 2.44 Hz, 1H),
7.40-7.56 (m, 3H), 7.31 (t, J=2.9 Hz, 1H), 7.14-7.20 (m, 1H), 6.98
(d, J=8.54 Hz, 1H), 6.28-6.30 (m, 1H), 3.59 (s, 3H), 3.26 (s, 3H).
MS (ESI+) m/z 431.1 (M+H).sup.+.
Example 139
4-[2-(4-chlorobenzoyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridi-
n-7-one
[1001] Example 139 was prepared according to the procedure used for
the preparation of Example 95d, substituting
(2-bromophenyl)(4-chlorophenyl)methanone for Example 95c, to
provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 11.96 (s, 1H), 7.86-7.73 (m, 1H), 7.55-7.62 (m, 3H),
7.39-7.43 (m, 2H), 7.25-7.29 (m, 2H), 7.21 (t, J=2.75 Hz, 1H), 6.88
(s, 1H), 6.05-6.06 (m, 1H), 3.39 (s, 3H). MS (DCI+) m/z 363.0
(M+H).sup.+.
Example 140
4-{2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrr-
olo[2,3-c]pyridin-7-one
[1002] A mixture of Example 139 (0.05 g, 0.138 mmol) and sodium
tetrahydroborate (2) (5.21 mg, 0.138 mmol) in tetrahydrofuran (2
mL) was heated at 60.degree. C. for 3 hours. The solvent was
removed, and the residue was purified by reverse phase Preparative
HPLC (10-80% acetonitrile in 0.1% TFA/water) to give the title
compound (0.042 g, 0.115 mmol, 84% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 11.70 (s, 1H), 7.56 (d, J=7.63 Hz, 1H),
7.35-7.39 (m, 1H), 7.27-7.31 (m, 1H), 7.21-7.23 (m, 4H), 7.00 (d,
J=8.54 Hz, 2H), 6.79 (s, 1H), 5.94 (t, J=2.29 Hz, 1H), 5.75 (s,
1H), 3.47 (s, 3H). MS (DCI+) m/z 365.0 (M+H).sup.+. Example 141
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyrimid-
in-5-yloxy)phenyl]ethanesulfonamide
Example 141a
6-methyl-4-(5-nitro-2-(pyrimidin-5-yloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin--
7(6H)-one
[1003] Example 141a was prepared according to the procedure used
for the preparation of Example 2b, substituting pyrimidin-5-ol for
phenol, to provide the title compound.
Example 141b
4-(5-amino-2-(pyrimidin-5-yloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin--
7(6H)-one
[1004] Example 141b was prepared according to the procedure used
for the preparation of Example 3, substituting Example 141a for
Example 2b, to provide the title compound.
Example 141c
N-[3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(pyrimid-
in-5-yloxy)phenyl]ethanesulfonamide
[1005] Example 141c was prepared according to the procedure used
for the preparation of Example 4 (Method A), substituting Example
141b for Example 3 and substituting ethanesulfonyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .quadrature. ppm 12.03 (bs, 1H), 9.90
(s, 1H), 8.35 (s, 2H), 7.40 (d, J=2.3 Hz, 1H), 7.31-7.22 (m, 4H),
6.25-6.20 (m, 1H), 3.49 (s, 3H), 3.17 (q, J=7.3 Hz, 2H), 1.24 (t,
J=7.3 Hz, 3H). MS (ESI+) m/z 462.2 (M+H).sup.+.
Example 142
N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[(1-meth-
yl-1H-pyrazol-5-yl)methoxy]phenyl}ethanesulfonamide
Example 142a
6-methyl-4-(2-((1-methyl-1H-pyrazol-5-yl)methoxy)-5-nitrophenyl)-1H-pyrrol-
o[2,3-c]pyridin-7(6H)-one
[1006] Example 142a was prepared according to the procedure used
for the preparation of Example 29a, substituting
(1-methyl-1H-pyrazol-5-yl)methanol for tetrahydro-2H-pyran-4-ol, to
provide the title compound.
Example 142b
4-(5-amino-2-((1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-6-methyl-1H-pyrrol-
o[2,3-c]pyridin-7(6H)-one
[1007] Example 142b was prepared according to the procedure used
for the preparation of Example 3, substituting Example 142a for
Example 2b, to provide the title compound.
Example 142c
N-{3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-[(1-meth-
yl-1H-pyrazol-5-yl)methoxy]phenyl}ethanesulfonamide
[1008] Example 142c was prepared according to the procedure used
for the preparation of Example 4 (Method A), substituting Example
142b for Example 3 and substituting ethanesulfonyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .quadrature. ppm 12.01 (bs, 1H), 9.58
(s, 1H), 7.32-7.14 (m, 6H), 6.20 (d, J=1.8 Hz, 1H), 6.10 (dd,
J=2.8, 1.9 Hz, 1H), 5.10 (s, 2H), 3.63 (s, 3H), 3.50 (s, 3H), 3.04
(q, J=7.4 Hz, 2H), 1.21 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 442.1
(M+H).sup.+.
Example 143
N-{4-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]-3-(6-methyl-7-oxo-6,7-dihydro-
-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide
Example 143a
4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)-5-nitrophenyl)-6-methyl-1H-py-
rrolo[2,3-c]pyridin-7(6H)-one
[1009] Example 143a was prepared according to the procedure used
for the preparation of Example 29a, substituting
(1,3-dimethyl-1H-pyrazol-5-yl)methanol for
tetrahydro-2H-pyran-4-ol, to provide the title compound.
Example 143b
4-(5-amino-2-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)phenyl)-6-methyl-1H-py-
rrolo[2,3-c]pyridin-7(6H)-one
[1010] Example 143b was prepared according to the procedure used
for the preparation of Example 3, substituting Example 143a for
Example 2b, to provide the title compound.
Example 143c
N-{4-[(1,3-dimethyl-1H-pyrazol-5-yl)methoxy]-3-(6-methyl-7-oxo-6,7-dihydro-
-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide
[1011] Example 143c was prepared according to the procedure used
for the preparation of Example 4 (Method A), substituting Example
143b for Example 3 and substituting ethanesulfonyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .quadrature. ppm 12.04-11.99 (m, 1H),
9.57 (s, 1H), 7.29-7.13 (m, 5H), 6.12-6.07 (m, 1H), 5.98 (s, 1H),
5.03 (s, 2H), 3.54 (s, 3H), 3.50 (s, 3H), 3.04 (q, J=7.3 Hz, 2H),
2.05 (s, 3H), 1.21 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 456.2
(M+H).sup.+.
Example 144
N-[4-(2,2-dimethylpropoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]ethanesulfonamide
Example 144a
6-methyl-4-(2-(neopentyloxy)-5-nitrophenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-
-one
[1012] Example 144a was prepared according to the procedure used
for the preparation of Example 29a, substituting
2,2-dimethylpropan-1-ol for tetrahydro-2H-pyran-4-ol, to provide
the title compound.
Example 144b
4-(5-amino-2-(neopentyloxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-
-one
[1013] Example 144b was prepared according to the procedure used
for the preparation of Example 3, substituting Example 144a for
Example 2b, to provide the title compound.
Example 144c
[1014] Example 144c was prepared according to the procedure used
for the preparation of Example 4 (Method A), substituting Example
144b for Example 3 and substituting ethanesulfonyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .quadrature. ppm 12.00 (s, 1H) 9.50 (s,
1H) 7.26-7.33 (m, 3H) 7.15 (dd, J=2.71, 8.82 Hz, 1H) 7.06 (d,
J=9.16 Hz, 1H) 6.17-6.22 (m, 1H) 3.59 (s, 2H) 3.54 (s, 3H) 3.03 (q,
J=7.23 Hz, 2H) 1.21 (t, J=7.29 Hz, 3H) 0.84 (s, 9H). MS (ESI+) m/z
416.5 (M-H).sup.+.
Example 145
N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]p-
yridin-4-yl)phenyl]ethanesulfonamide
Example 145a
4-(2-(cyclopropylmethoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-
-7(6H)-one
[1015] Example 145a was prepared according to the procedure used
for the preparation of Example 29a, substituting
cyclopropylmethanol for tetrahydro-2H-pyran-4-ol, to provide the
title compound.
Example 145b
4-(5-amino-2-(cyclopropylmethoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-
-7(6H)-one
[1016] Example 145b was prepared according to the procedure used
for the preparation of Example 3, substituting Example 145a for
Example 2b, to provide the title compound.
Example 145c
N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]p-
yridin-4-yl)phenyl]ethanesulfonamide
[1017] Example 145c was prepared according to the procedure used
for the preparation of Example 4 (Method A), substituting Example
145b for Example 3 and substituting ethanesulfonyl chloride for
methanesulfonyl chloride, to provide the title compound. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .quadrature. ppm 12.02-11.97 (m, 1H),
9.49 (s, 1H), 7.32-7.24 (m, 3H), 7.14 (dd, J=8.7, 2.7 Hz, 1H), 7.05
(d, J=8.8 Hz, 1H), 6.21-6.16 (m, 1H), 3.80 (d, J=6.7 Hz, 2H), 3.56
(s, 3H), 3.02 (q, J=7.3 Hz, 2H), 1.21 (t, J=7.3 Hz, 3H), 1.08 (m,
1H), 0.50-0.39 (m, 2H), 0.27-0.18 (m, 2H). MS (ESI+) m/z 402.1
(M+H).sup.+.
Example 146
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)benzenesulfonamide
Example 146a
4-(2,4-difluorophenoxy)-3-nitrobenzenesulfonamide
[1018] A solution of 2,4-difluorophenol (5.39 g, 41.4 mmol) in
N,N-dimethylformamide (34.5 mL) was cooled to 10.degree. C. and
treated portionwise with sodium hydride (1.66 g, 41.4 mmol). After
stirring 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (2.28 g,
10.36 mmol) was added portionwise. The reaction mixture was stirred
at ambient temperature for 1.5 hours, diluted into ethyl acetate
and quenched with 0.5 M HCl to pH 6. The organic layer was washed
with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated to provide the title
compound (3.24 g, 95%).
Example 146b
3-amino-4-(2,4-difluorophenoxy)benzenesulfonamide
[1019] Example 146a (3.24 g, 9.81 mmol), iron (2.74 g, 49.1 mmol),
and ammonium chloride (0.787 g, 14.72 mmol) were stirred in a
mixture of tetrahydrofuran (21 mL), ethanol (21 mL) and water (7
mL) at 95 OC for 3 hours. The mixture was filtered through a nylon
membrane and concentrated. The residue partitioned between ethyl
acetate and water. The organic layer was washed with saturated
aqueous sodium chloride, dried over anhydrous sodium sulfate,
filtered, and concentrated to provide the title compound (2.81 g,
95%).
Example 146c
4-(2,4-difluorophenoxy)-3-iodobenzenesulfonamide
[1020] To a solution of Example 146b (2.8 g, 9.32 mmol) in dioxane
(20 mL) at 0.degree. C. was added concentrated hydrochloric acid
(40 mL, 9.32 mmol). The mixture was stirred 15 minutes and a
solution of sodium nitrite (0.772 g, 11.19 mmol) in water (10 mL)
was added. The mixture was stirred for 1 hour at 0.degree. C. A
solution of potassium iodide (3.10 g, 18.7 mmol) in water (10 mL)
was added and stirring was continued 1 hour at ambient temperature.
The mixture was partitioned between ethyl acetate and water. The
organic layer was washed with saturated sodium thiosulfate, water,
and saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash column chromatography (silica gel, 0-60% ethyl
acetate in hexane) to provide the title compound (2.24 g, 58.4%
yield).
Example 146d
4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)benzenesulfonamide
[1021] A suspension of Example 146c (111 mg, 0.270 mmol), Example
6a (150 mg, 0.351 mmol), tetrakis(triphenylphosphine)palladium (0)
(31.2 mg, 0.027 mmol) and cesium fluoride (123 mg, 0.810 mmol) in a
mixture of 1,2 dimethoxyethane (4.6 mL) and methanol (2.3 mL) was
heated under microwave conditions at 150.degree. C. for 5 minutes.
The reaction mixture was partitioned between ethyl acetate (75 mL)
and 50% aqueous sodium chloride (75 mL). The organic layer was
dried over anhydrous sodium sulfate, filtered, and concentrated. To
a solution of the residue in dioxane (4 mL) was added a solution of
lithium hydroxide hydrate (113 mg, 2.7 mmol) in water (1 mL) and
the mixture was heated under microwave conditions at 120.degree. C.
for 30 minutes. The reaction mixture was partitioned between ethyl
acetate (75 mL) and water (75 mL). The organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by flash column chromatography (silica gel, 0.5-10%
methanol in dichloromethane) to provide the title compound (74 mg,
63.5% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.09
(s, 1H), 7.92 (d, J=2.37 Hz, 1H), 7.76 (dd, J=8.82, 2.37 Hz, 1H),
7.43-7.53 (m, 1H), 7.28-7.40 (m, 5H), 7.08-7.18 (m, 1H), 6.95 (d,
J=8.82 Hz, 1H), 6.27 (d, J=2.71 Hz, 1H), 3.58 (s, 3H). MS (ESI+)
m/z 432.2 (M+H).sup.+.
Example 147
4-[2-(cyclohexylamino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
Example 147a
2-bromo-N-cyclohexyl-4-(methylsulfonyl)aniline
[1022] A mixture of 2-bromo-1-fluoro-4-(methylsulfonyl)benzene
(0.05 g, 0.198 mmol) and cyclohexanamine (0.059 g, 0.593 mmol) in
dioxane (1 mL) in a vial was capped and heated at 110.degree. C.
for three days. The reaction mixture was partitioned between water
and ethyl acetate. The aqueous layer was extracted with additional
ethyl acetate twice. The combined organic layers were washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
flash column chromatography on silica gel eluting with 40% ethyl
acetate in hexanes to afford the title compound (0.044 g, 0.132
mmol, 67.0% yield).
Example 147b
4-[2-(cyclohexylamino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1023] Example 147b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 147a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.13 (s, 1H), 7.66 (dd, J=8.7, 2.29 Hz,
1H), 7.51 (d, J=2.14 Hz, 1H), 7.30 (t, J=2.75 Hz, 1H), 7.26 (s,
1H), 6.86 (d, J=8.85 Hz, 1H), 6.00-6.01 (m, 1H), 4.83 (br, s, 1H),
3.56 (s, 3H), 3.35-3.44 (m, 1H), 1.84-1.87 (m, 2H), 1.53-1.62 (m,
3H), 1.27-1.37 (m, 2H), 1.03-1.12 (m, 3H). MS (APCI+) m/z 400.1
(M+H).sup.+.
Example 148
4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[-
2,3-d]pyridazin-7-one
Example 148a
[1024] Example 148a was prepared according to the procedure used
for the preparation of Example 2b, substituting
2-bromo-1-fluoro-4-nitrobenzene for Example 2a, and
2,4-difluorophenol for phenol, respectively, to provide the title
compound.
Example 148b
3-bromo-4-(2,4-difluorophenoxy)aniline
[1025] Example 148b was prepared according to the procedure used
for the preparation of Example 3, substituting Example 148a for
Example 2b, to provide the title compound.
Example 148c
4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani-
line
[1026] Example 148c was prepared according to the procedure used
for the preparation of Example 6a, substituting Example 148b for
Example 1e, to provide the title compound.
Example 148d
4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[-
2,3-d]pyridazin-7-one
[1027] Example 148d was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 80b for
Example 95c and Example 148c for Example 6a, respectively, to
provide the TFA salt of the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.69 (s, 1H), 7.44 (t, J=2.59 Hz, 1H),
7.32-7.37 (m, 2H), 7.16 (d, J=2.75 Hz, 1H), 7.05-7.12 (m, 1H),
6.97-7.02 (m, 1H), 6.92 (d, J=8.54 Hz, 1H), 3.37-6.39 (m, 1H), 3.70
(s, 3H). MS (ESI+) m/z 369.4 (M+H).sup.+.
Example 149
4-[2-(2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-,6-dihydro-7H-py-
rrolo[2,3-c]pyridin-7-one
[1028] Example 149 was prepared according to the procedure used for
the preparation of Example 138b, substituting 2-fluorophenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.99 (d, J=2.4 Hz, 1H),
7.89 (dt, J=7.7, 3.9 Hz, 1H), 7.50-7.38 (m, 2H), 7.35-7.24 (m, 4H),
6.98 (d, J=8.6 Hz, 1H), 6.32 (d, J=2.8 Hz, 1H), 3.60 (s, 3H), 3.26
(s, 3H). MS (ESI+) m/z 413(M+H).sup.+.
Example 150
4-[2-(3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1029] Example 150 was prepared according to the procedure used for
the preparation of Example 138b, substituting 3-fluorophenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.01 (t, J=3.4 Hz, 1H),
7.93 (dt, J=7.1, 3.5 Hz, 1H), 7.47-7.37 (m, 2H), 7.34 (t, J=3.3 Hz,
1H), 7.21 (t, J=6.3 Hz, 1H), 6.96 (dddd, J=26.2, 21.5, 8.3, 2.2 Hz,
3H), 6.30 (d, J=2.8 Hz, 1H), 3.57 (s, 3H), 3.27 (s, 3H). MS (ESI+)
m/z 413(M+H).sup.+.
Example 151
4-[2-(4-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1030] Example 151 was prepared according to the procedure used for
the preparation of Example 138b, substituting 4-fluorophenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.98 (d, J=2.4 Hz, 1H),
7.89 (dd, J=8.7, 2.4 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J=2.8 Hz, 1H),
7.31-7.22 (m, 2H), 7.22-7.10 (m, 2H), 7.04 (d, J=8.7 Hz, 1H), 6.31
(d, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.25 (s, 3H). MS (ESI+) m/z
413(M+H).sup.+.
Example 152
4-[2-(2-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1031] Example 152 was prepared according to the procedure used for
the preparation of Example 138b, substituting 2-chlorophenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.02 (dd, J=7.0, 1.6 Hz,
1H), 7.96-7.85 (m, 1H), 7.65-7.57 (m, 1H), 7.47 (s, 1H), 7.44-7.34
(m, 2H), 7.33-7.21 (m, 2H), 6.92 (d, J=8.7 Hz, 1H), 6.37 (d, J=2.8
Hz, 1H), 3.59 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z
429(M+H).sup.+.
Example 153
4-[2-(3-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1032] Example 153 was prepared according to the procedure used for
the preparation of Example 138b, substituting 3-chlorophenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.01 (d, J=2.4 Hz, 1H),
7.99-7.88 (m, 1H), 7.43-7.37 (m, 2H), 7.35 (t, J=3.3 Hz, 1H),
7.27-7.19 (m, 2H), 7.16 (dd, J=10.2, 8.1 Hz, 1H), 7.08-6.93 (m,
1H), 6.30 (d, J=2.8 Hz, 1H), 3.57 (s, 3H), 3.27 (s, 3H). MS (ESI+)
m/z 429(M+H).sup.+.
Example 154
4-[2-(4-chlorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1033] Example 154 was prepared according to the procedure used for
the preparation of Example 138b, substituting 4-chlorophenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.00 (d, J=2.4 Hz, 1H),
7.91 (dd, J=8.3, 2.0 Hz, 1H), 7.56-7.38 (m, 3H), 7.34 (t, J=3.3 Hz,
1H), 7.19-7.07 (m, 3H), 6.29 (d, J=2.8 Hz, 1H), 3.58 (s, 3H), 3.26
(s, 3H). MS (ESI+) m/z 429(M+H).sup.+.
Example 155
3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methyls-
ulfonyl)phenoxy]benzonitrile
[1034] Example 155 was prepared according to the procedure used for
the preparation of Example 138b, substituting 3-cyanophenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.02 (d, J=2.4 Hz, 1H),
7.99-7.91 (m, 1H), 7.68-7.49 (m, 3H), 7.46-7.38 (m, 2H), 7.38-7.32
(m, 1H), 7.24 (d, J=8.6 Hz, 1H), 6.30 (d, J=2.8 Hz, 1H), 3.56 (s,
3H), 3.28 (s, 3H). MS (ESI+) m/z 420(M+H).sup.+.
Example 156
4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methyls-
ulfonyl)phenoxy]benzonitrile
[1035] Example 156 was prepared according to the procedure used for
the preparation of Example 138b, substituting 4-cyanophenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.05 (d, J=2.4 Hz, 1H),
8.02-7.94 (m, 1H), 7.80-7.73 (m, 2H), 7.38 (t, J=4.3 Hz, 2H), 7.33
(t, J=3.3 Hz, 1H), 7.17-7.03 (m, 2H), 6.25 (d, J=2.8 Hz, 1H), 3.54
(s, 3H), 3.29 (s, 3H). MS (ESI+) m/z 420(M+H).sup.+.
Example 157
6-methyl-4-{5-(methylsulfonyl)-2-[3-(trifluoromethyl)phenoxy]phenyl}-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1036] Example 157 was prepared according to the procedure used for
the preparation of Example 138b, substituting
3-trifluoromethylphenol for 2,4-difluorophenol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 8.03 (d, J=2.4 Hz, 1H), 7.95 (dd, J=8.6, 2.4 Hz, 1H),
7.62-7.56 (m, 1H), 7.54-7.48 (m, 1H), 7.42 (d, J=7.1 Hz, 1H),
7.37-7.31 (m, 3H), 7.25 (d, J=8.6 Hz, 1H), 6.30 (d, J=2.8 Hz, 1H),
3.55 (s, 3H), 3.28 (s, 3H). MS (ESI+) m/z 463(M+H).sup.+.
Example 158
4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one
[1037] Cyclopropylmethanol (0.014 g, 0.19 mmol) in tetrahydrofuran
(2 mL) was treated with 60% sodium hydride (10.11 mg, 0.253 mmol).
The reaction mixture was stirred at ambient temperature for 5
minutes. To this solution was added Example 138a (0.03 g, 0.063
mmol). The reaction mixture was heated at 60.degree. C. for 16
hours. The solvent was removed, and the residue was purified by
Preparative HPLC (C18, 10-80% CH.sub.3CN/water (0.1% TFA)) to give
the title compound (0.012 g, 0.032 mmol, 51.0% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) 8 ppm 7.88 (dd, J=8.6, 2.5 Hz,
1H), 7.84 (d, J=2.4 Hz, 1H), 7.37 (s, 1H), 7.34 (d, J=2.4 Hz, 2H),
7.32 (d, J=3.5 Hz, 2H), 6.17 (d, J=2.8 Hz, 1H), 3.99 (d, J=6.8 Hz,
2H), 3.20 (s, 3H), 1.17-1.06 (m, 1H), 0.52-0.41 (m, 2H), 0.34-0.24
(m, 2H). MS (ESI+) m/z 373 (M+H).sup.+.
Example 159
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]-
pyridazin-4-yl)phenyl]methanesulfonamide
[1038] Example 159 was prepared according to the procedure used for
the preparation of Example 4 (Method A), substituting Example 148d
for Example 3, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.72 (s, 1H), 9.79 (s, 1H), 7.45 (t,
J=2.59 Hz, 1H), 7.40 (t, J=2.44 Hz, 1H), 7.31-7.38 (m, 2H),
7.11-7.17 (m, 1H), 6.89-7.03 (m, 1H), 6.39-6.40 (m, 1H), 3.70 (s,
3H), 3.02 (s, 3H). MS (ESI+) m/z 447.1 (M+H).sup.+.
Example 160
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]-
pyridazin-4-yl)phenyl]ethanesulfonamide
[1039] Example 160 was prepared according to the procedure used for
the preparation of Example 4 (Method A), substituting Example 148d
for Example 3, and ethanesulfonyl chloride for methanesulfonyl
chloride, respectively, to provide the title compound. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.72 (s, 1H), 9.86 (s, 1H),
7.45 (t, J=2.75 Hz, 1H), 7.41 (d, J=2.75 Hz, 1H), 7.31-7.40 (m,
2H), 7.10-7.16 (m, 1H), 6.98-7.03 (m, 1H), 6.38-6.39 (m, 1H), 3.70
(s, 3H), 3.11 (q, J=7.43 Hz, 2H), 1.23 (t, J=7.32 Hz, 3H). MS
(ESI+) m/z 461.1 (M+H).sup.+.
Example 161
4-[2-(isoquinolin-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
[1040] Example 161 was prepared according to the procedure used for
the preparation of Example 138b, substituting isoquinolin-5-ol for
2,4-difluorophenol, to provide the TFA salt of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 9.68 (s,
1H), 8.58 (d, J=6.4 Hz, 1H), 8.30 (d, J=6.4 Hz, 1H), 8.11 (t, J=4.9
Hz, 2H), 8.00 (dd, J=8.6, 2.4 Hz, 1H), 7.78 (t, J=8.1 Hz, 1H),
7.55-7.46 (m, 2H), 7.40 (d, J=8.6 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H),
6.39 (d, J=2.8 Hz, 1H), 3.97 (s, 1H), 3.47 (s, 3H), 3.31 (s, 3H).
MS (ESI+) m/z 445 (M+H).sup.+.
Example 162
6-methyl-4-[5-(methylsulfonyl)-2-(quinolin-6-yloxy)phenyl]-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one
[1041] Example 162 was prepared according to the procedure used for
the preparation of Example 138b, substituting quinolin-6-ol for
2,4-difluorophenol, to provide the TFA salt of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 9.03 (dd,
J=4.8, 1.4 Hz, 1H), 8.71 (d, J=8.1 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H),
8.08 (d, J=2.4 Hz, 1H), 7.99 (dd, J=8.6, 2.4 Hz, 1H), 7.88-7.80 (m,
1H), 7.74 (dt, J=3.7, 2.5 Hz, 2H), 7.45 (s, 1H), 7.37 (d, J=8.6 Hz,
1H), 7.32 (t, J=3.3 Hz, 1H), 6.34 (d, J=2.8 Hz, 1H), 3.53 (d, J=6.8
Hz, 3H), 3.30 (s, 3H). MS (ESI+) m/z 446 (M+H).sup.+.
Example 163
4-{2-[2-chloro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-met-
hyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1042] Example 163 was prepared according to the procedure used for
the preparation of Example 138b, substituting
2-chloro-5-trifluoromethylphenol for 2,4-difluorophenol, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 8.03 (d, J=2.4 Hz, 1H), 7.94 (dd, J=8.7, 2.4 Hz, 1H),
7.79 (d, J=8.3 Hz, 1H), 7.58 (dd, J=16.2, 8.4 Hz, 1H), 7.49 (d,
J=1.8 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.27-7.13 (m,
2H), 6.33 (d, J=2.9 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H). MS (ESI+)
m/z 496 (M+H).sup.+.
Example 164
4-{2-[2-fluoro-5-(trifluoromethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-met-
hyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1043] Example 164 was prepared according to the procedure used for
the preparation of Example 138b, substituting
2-fluoro-5-trifluoromethylphenol for 2,4-difluorophenol, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 8.01 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.6, 2.4 Hz, 1H),
7.67-7.55 (m, 3H), 7.43 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.23-7.15
(m, 2H), 6.29 (d, J=2.8 Hz, 1H), 3.57 (s, 3H), 3.27 (s, 3H). MS
(ESI+) m/z 480 (M+H).sup.+.
Example 165
2-{4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(meth-
ylsulfonyl)phenoxy]phenyl}acetamide
[1044] Example 165 was prepared according to the procedure used for
the preparation of Example 138b, substituting
2-(4-hydroxyphenyl)acetamide for 2,4-difluorophenol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.97 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.6, 2.4 Hz, 1H),
7.43 (s, 1H), 7.36-7.30 (m, 3H), 7.09-7.00 (m, 3H), 6.31 (d, J=2.8
Hz, 1H), 3.59 (s, 3H), 3.39 (s, 2H), 3.24 (s, 3H). MS (ESI+) m/z
452(M+H).sup.+.
Example 166
4-[2-(3-aminophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-py-
rrolo[2,3-c]pyridin-7-one
[1045] Example 166 was prepared according to the procedure used for
the preparation of Example 138b, substituting 3-aminophenol for
2,4-difluorophenol, to provide the TFA salt of the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.00 (d,
J=2.4 Hz, 1H), 7.92 (dd, J=8.6, 2.4 Hz, 1H), 7.40 (s, 1H),
7.36-7.24 (m, 2H), 7.15 (d, J=8.6 Hz, 1H), 6.78 (dd, J=8.0, 1.9 Hz,
1H), 6.70-6.62 (m, 2H), 6.27 (d, J=2.8 Hz, 1H), 3.96 (s, 1H), 3.58
(s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 410(M+H).sup.+.
Example 167
6-methyl-4-[5-(methylsulfonyl)-2-(tetrahy
drofuran-3-ylamino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 167a
N-(2-bromo-4-(methylsulfonyl)phenyl)tetrahydrofuran-3-amine
[1046] Example 167a was prepared according to the procedure used
for the preparation of Example 147a, substituting
tetrahydrofuran-3-amine for cyclohexanamine, to provide the title
compound.
Example 167b
6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylamino)phenyl]-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1047] Example 167b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 167a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.12 (s, 1H), 7.70 (dd, J=8.7, 2.29 Hz,
1H), 7.54 (d, J=2.44 Hz, 1H), 7.29 (t, J=2.75 Hz, 1H), 7.27 (s,
1H), 6.87 (d, J=8.85 Hz, 1H), 6.00 (t, J=2.29 Hz, 1H), 5.25 (br s,
1H), 4.17 (br s, 1H), 3.68 (q, J=7.32, Hz, 2H), 3.56 (s, 3H), 3.49
(dd, J=9, 3.51 Hz, 1H), 3.12 (s, 3H), 2.12-2.19 (m, 1H), 1.74-1.77
(m, 1H). MS (ESI+) m/z 388.2 (M+H).sup.+.
Example 168
4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one
Example 168a
(3-bromo-4-fluorophenyl)(ethyl)sulfane
[1048] A mixture of 3-bromo-4-fluorobenzenethiol (3.89 g, 18.79
mmol) and sodium hydroxide (3.95 mL, 19.73 mmol) in MeOH was
stirred at 0.degree. C. for 10 minutes. To this solution was added
iodoethane (1.803 mL, 22.54 mmol). The reaction mixture was stirred
at ambient temperature for 6 hours. The solvent was removed, and
the residue was partitioned between water and ethyl acetate. The
aqueous layer was extracted with addition ethyl acetate three
times. The combined organic layers were washed with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered, and concentrated to give the title compound (4.35 g,
18.50 mmol, 98% yield). It was used directly for the next
reaction.
Example 168b
2-bromo-4-(ethylsulfonyl)-1-fluorobenzene
[1049] Example 168a (4.4 g, 18.71 mmol) in dichloromethane (250 mL)
was cooled to 0.degree. C. To this solution was treated with mCPBA
(10.15 g, 41.2 mmol) portionwise. The reaction was stirred at
ambient temperature for 6 hours. The solid from the reaction
mixture was removed by filtration. The filtrate was washed with
saturated aqueous sodium bicarbonate several times. The aqueous
layer was then extracted with additional dichloromethane three
times. The combined organic layers were washed with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel eluting with 15% ethyl acetate/hexanes
to afford the title compound (4.4 g, 16.47 mmol, 88% yield).
Example 168c
4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[1050] Example 168c was prepared according to the procedure used
for the preparation of Example 138a, substituting Example 168b for
2-bromo-1-fluoro-4-(methylsulfonyl)benzene, to provide the title
compound.
Example 168d
4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one
[1051] Example 168d was prepared according to the procedure used
for the preparation of Example 138b, substituting Example 168c for
Example 138a, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.31 (s, 1H), 7.93 (d, J=2.44 Hz, 1H),
7.83 (dd, J=8.54, 2.44 Hz, 1H), 7.52-7.54 (m, 1H), 7.42-7.46 (m,
2H), 7.32 (t, J=2.75 Hz, 1H), 7.16-7.19 (m, 1H), 6.99 (d, J=8.54
Hz, 1H), 6.27-6.28 (m, 1H), 3.59 (s, 3H), 3.38 (q, J=7.32, Hz, 2H),
1.15 (t, J=7.32 Hz, 1H). MS (ESI+) m/z 445.2 (M+H).sup.+.
Example 169
4-{2-[(4,4-difluorocyclohexyl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1052] Example 169 was prepared according to the procedure used for
the preparation of Example 158, substituting Example 168c for
Example 138a, and 4,4-difluorocyclohexanol for cyclopropylmethanol,
respectively, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.05 (s, 1H), 7.81-7.85 (m, 2H), 7.45
(d, J=8.85 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J=2.75 Hz, 1H),
6.12-6.13 (m, 1H), 4.81 (s, 1H), 3.56 (s, 3H), 3.29 (q, J=7.32, Hz,
2H), 1.70-1.87 (m, 8H), 1.14 (t, J=7.32 Hz, 1H). MS (ESI+) m/z
451.2 (M+H).sup.+.
Example 170
4-{5-(ethylsulfonyl)-2-[(1-methylpiperidin-4-yl)oxy]phenyl}-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1053] Example 170 was prepared according to the procedure used for
the preparation of Example 158, substituting Example 168c for
Example 138a, and 1-methylpiperidin-4-ol for cyclopropylmethanol,
respectively, to provide the TFA salt of the title compound.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.13 (s, 1H),
7.81-7.87 (m, 2H), 7.46 (d, J=8.85 Hz, 1H), 7.34 (s, 1H), 7.32 (t,
J=2.75 Hz, 1H), 6.11-6.12 (m, 1H), 4.86 (s, 1H), 3.56 (s, 3H), 3.30
(s, 3H), 3.29 (q, J=7.32, Hz, 2H), 3.24-3.29 (m, 1H), 3.04-3.10 (m,
1H), 2.25-2.29 (m, 2H), 1.91-2.05 (m, 2H), 1.14 (t, J=7.32 Hz, 1H).
MS (ESI+) m/z 430.2 (M+H).sup.+.
Example 171
4-[2-(2,1,3-benzothiadiazol-4-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1054] Example 171 was prepared according to the procedure used for
the preparation of Example 138b, substituting
benzo[c][1,2,5]thiadiazol-5-ol for 2,4-difluorophenol, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 8.04 (d, J=2.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.84
(dd, J=8.6, 2.4 Hz, 1H), 7.69 (dd, J=8.8, 7.5 Hz, 1H), 7.50 (s,
1H), 7.36 (d, J=7.1 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.09 (d, J=8.7
Hz, 1H), 6.49 (d, J=2.8 Hz, 1H), 3.55 (s, 3H), 3.27 (s, 3H). MS
(ESI.sup.+) m/z 453(M+H).sup.+.
Example 172
4-[2-(isoquinolin-7-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
[1055] Example 172 was prepared according to the procedure used for
the preparation of Example 138b, substituting isoquinolin-7-ol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.65 (s, 1H), 8.39 (s, 1H),
8.24 (d, J=8.9 Hz, 1H), 8.16-8.04 (m, 1H), 8.03 (dd, J=8.6, 2.4 Hz,
1H), 7.95-7.76 (m, 2H), 7.47 (dd, J=20.3, 11.7 Hz, 2H), 7.31 (t,
J=5.9 Hz, 1H), 6.32 (d, J=2.8 Hz, 1H), 3.51 (s, 3H), 3.31 (s, 3H).
MS (ESI+) m/z 446(M+H).sup.+.
Example 173
4-[2-(2,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
[1056] Example 173 was prepared according to the procedure used for
the preparation of Example 138b, substituting 2,5-difluorophenol
for 2,4-difluorophenol, to provide the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.08-7.98 (m, 1H),
7.97-7.83 (m, 1H), 7.50-7.39 (m, 2H), 7.35 (t, J=3.3 Hz, 1H),
7.33-7.21 (m, 1H), 7.20-7.08 (m, 2H), 6.31 (d, J=2.8 Hz, 1H), 3.59
(s, 3H), 3.25 (d, J=6.7 Hz, 3H) MS (ESI+) m/z 431(M+H).sup.+.
Example 174
4-[2-(3,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
[1057] Example 174 was prepared according to the procedure used for
the preparation of Example 138b, substituting 3,4-difluorophenol
for 2,4-difluorophenol, to provide the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.99 (d, J=2.4 Hz,
1H), 7.91 (dd, J=8.6, 2.4 Hz, 1H), 7.53-7.40 (m, 2H), 7.34 (d,
J=2.8 Hz, 1H), 7.29 (ddd, J=11.4, 6.8, 2.9 Hz, 1H), 7.16 (d, J=8.7
Hz, 1H), 6.95 (dd, J=8.8, 5.0 Hz, 1H), 6.31 (d, J=2.8 Hz, 1H), 3.58
(s, 3H), 3.25 (s, 3H). MS (ESI+) m/z 431(M+H).sup.+.
Example 175
6-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]phe-
nyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1058] Example 175 was prepared according to the procedure used for
the preparation of Example 138b, substituting
4-hydroxy-2,3-dihydro-1H-inden-1-one for 2,4-difluorophenol, to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.02 (d, J=2.4 Hz, 1H), 7.92
(dd, J=8.6, 2.4 Hz, 1H), 7.50-7.41 (m, 1H), 7.36 (d, J=2.8 Hz, 1H),
7.28 (dd, J=7.3, 1.4 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 6.32 (d,
J=2.8 Hz, 1H), 3.62-3.54 (m, 2H), 3.27 (s, 1H), 2.89-2.82 (m, 1H),
2.65-2.59 (m, 1H). MS (ESI+) m/z 449(M+H).sup.+.
Example 176
4-[2-(3,5-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
[1059] Example 176 was prepared according to the procedure used for
the preparation of Example 138b, substituting 3,5-difluorophenol
for 2,4-difluorophenol, to provide the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.02 (d, J=2.4 Hz,
1H), 7.96 (dd, J=8.6, 2.4 Hz, 1H), 7.40 (s, 1H), 7.34 (dd, J=5.7,
2.8 Hz, 2H), 6.98 (tt, J=9.3, 2.3 Hz, 1H), 6.83-6.62 (m, 2H), 6.29
(d, J=2.8 Hz, 1H), 3.56 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z
431(M+H).sup.+.
Example 177
6-methyl-4-[2-(4-methylphenoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1060] Example 177 was prepared according to the procedure used for
the preparation of Example 138b, substituting 4-methylphenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.96 (d, J=2.4 Hz, 1H),
7.88-7.79 (m, 1H), 7.42 (s, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.24 (d,
J=8.4 Hz, 2H), 7.00 (dd, J=8.6, 4.3 Hz, 3H), 6.30 (d, J=2.8 Hz,
1H), 3.59 (s, 3H), 3.24 (s, 3H). MS (ESI+) m/z 409(M+H).sup.+.
Example 178
4-[2-(2-methoxyphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one
[1061] Example 178 was prepared according to the procedure used for
the preparation of Example 138b, substituting 2-methoxyphenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.94 (d, J=2.4 Hz, 1H),
7.81 (dd, J=8.7, 2.4 Hz, 1H), 7.47 (s, 1H), 7.39-7.25 (m, 2H),
7.26-7.13 (m, 2H), 7.03 (td, J=7.6, 1.5 Hz, 1H), 6.75 (d, J=8.7 Hz,
1H), 6.43 (d, J=2.8 Hz, 1H), 3.61 (s, 3H), 3.23 (s, 3H). MS (ESI+)
m/z 425(M+H).sup.+.
Example 179
6-methyl-4-{2-[(2-methylpyridin-3-yl)oxy]-5-(methylsulfonyl)phenyl}-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1062] Example 179 was prepared according to the procedure used for
the preparation of Example 138b, substituting 2-methylpyridin-3-ol
for 2,4-difluorophenol, to provide the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.38 (d, J=2.1 Hz,
1H), 8.05 (d, J=2.4 Hz, 1H), 7.98 (dd, J=8.5, 2.4 Hz, 1H), 7.73 (d,
J=8.3 Hz, 1H), 7.53 (dd, J=8.4, 4.9 Hz, 1H), 7.43 (s, 1H), 7.35 (d,
J=2.8 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 6.30 (d, J=2.8 Hz, 1H), 3.56
(s, 3H), 3.28 (s, 3H), 2.41 (s, 3H). MS (ESI+) m/z
410(M+H).sup.+.
Example 180
4-{2-[3-(dimethylamino)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1063] Example 180 was prepared according to the procedure used for
the preparation of Example 138b, substituting
3-(dimethylamino)phenol for 2,4-difluorophenol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.97 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.6, 2.4 Hz, 1H),
7.42 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 7.08
(d, J=8.6 Hz, 1H), 6.68 (dd, J=8.3, 2.4 Hz, 1H), 6.52-6.43 (m, 2H),
6.31 (d, J=2.8 Hz, 1H), 3.58 (s, 3H), 3.24 (s, 3H), 2.90 (s, 6H).
MS (ESI+) m/z 438(M+H).sup.+.
Example 181
6-methyl-4-{5-(methylsulfonyl)-2-[(1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]phe-
nyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1064] Example 181 was prepared according to the procedure used for
the preparation of Example 138b, substituting
5-hydroxy-2,3-dihydro-1H-inden-1-one for 2,4-difluorophenol, to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.04 (d, J=2.4 Hz, 1H), 7.98
(dd, J=8.6, 2.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.34
(dd, J=6.9, 5.8 Hz, 2H), 7.11 (s, 1H), 7.08-6.97 (m, 1H), 6.28 (d,
J=2.9 Hz, 1H), 3.54 (s, 3H), 3.29 (s, 3H), 3.00 (d, J=5.0 Hz, 2H),
2.62-2.58 (m, 2H). MS (ESI+) m/z 449(M+H)
Example 182
6-methyl-4-{5-(methylsulfonyl)-2-[(3-oxo-2,3-dihydro-1H-inden-5-yl)oxy]phe-
nyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1065] Example 182 was prepared according to the procedure used for
the preparation of Example 138b, substituting
6-hydroxy-2,3-dihydro-1H-inden-1-one for 2,4-difluorophenol, to
provide the title compound .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.01 (d, J=2.5 Hz, 1H), 7.92 (d,
J=8.6 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.42 (d, J=14.0 Hz, 2H),
7.34 (d, J=2.8 Hz, 1H), 7.22-7.10 (m, 2H), 6.30 (d, J=2.8 Hz, 1H),
3.56 (s, 3H), 3.26 (s, 3H), 3.06 (s, 2H), 2.69 (s, 3H). MS (ESI+)
m/z 449(M+H).sup.+.
Example 183
2-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methyls-
ulfonyl)phenoxy]benzonitrile
[1066] Example 183 was prepared according to the procedure used for
the preparation of Example 138b, substituting 2-cyanophenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.06 (d, J=2.4 Hz, 1H),
7.99 (dd, J=8.5, 2.4 Hz, 1H), 7.81 (dd, J=7.7, 1.6 Hz, 1H),
7.67-7.59 (m, 1H), 7.41 (s, 1H), 7.39-7.24 (m, 3H), 7.09 (d, J=8.4
Hz, 1H), 6.30 (d, J=2.8 Hz, 1H), 3.56 (s, 3H), 3.29 (s, 3H). MS
(ESI+) m/z 420(M+H).sup.+.
Example 184
4-[2-(3-chloro-2-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1067] Example 184 was prepared according to the procedure used for
the preparation of Example 138b, substituting
2-fluoro-3chlorophenol for 2,4-difluorophenol, to provide the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm
8.00 (d, J=2.4 Hz, 1H), 7.92 (dd, J=8.6, 2.4 Hz, 1H), 7.47-7.41 (m,
2H), 7.35 (d, J=2.8 Hz, 1H), 7.28-7.23 (m, 2H), 7.13 (d, J=8.6 Hz,
1H), 6.28 (d, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.26 (s, 3H). MS (ESI+)
m/z 447(M+H).sup.+.
Example 185
6-methyl-4-[5-(methylsulfonyl)-2-(naphthalen-1-yloxy)phenyl]-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one
[1068] Example 185 was prepared according to the procedure used for
the preparation of Example 138b, substituting naphthalen-1-ol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.02 (d, J=2.4 Hz, 1H),
7.99 (d, J=8.9 Hz, 2H), 7.96-7.87 (m, 2H), 7.86 (d, J=8.0 Hz, 1H),
7.59-7.44 (m, 4H), 7.36-7.28 (m, 2H), 7.15 (d, J=8.6 Hz, 1H), 6.37
(d, J=2.8 Hz, 1H), 3.58 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z
445(M+H).sup.+.
Example 186
4-[2-(2-fluoro-5-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1069] Example 186 was prepared according to the procedure used for
the preparation of Example 138b, substituting
2-fluoro-5methylphenol for 2,4-difluorophenol, to provide the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm
7.98 (d, J=2.4 Hz, 1H), 7.89 (dd, J=8.6, 2.4 Hz, 1H), 7.43 (s, 1H),
7.35 (d, J=2.8 Hz, 1H), 7.27 (dd, J=10.9, 8.1 Hz, 1H), 7.14-7.06
(m, 2H), 6.98 (d, J=8.6 Hz, 1H), 6.31 (d, J=2.8 Hz, 1H), 3.60 (s,
3H), 3.25 (s, 3H), 2.27 (s, 3H). MS (ESI+) m/z 427(M+H).sup.+.
Example 187
4-[2-(5-fluoro-2-methylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1070] Example 187 was prepared according to the procedure used for
the preparation of Example 138b, substituting
5-fluoro-2-methylphenol for 2,4-difluorophenol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 8.11-7.96 (m, 1H), 7.91 (dt, J=5.1, 2.8 Hz, 1H), 7.43
(s, 1H), 7.38-7.28 (m, 2H), 7.07-6.91 (m, 2H), 6.91-6.81 (m, 1H),
6.31 (t, J=3.9 Hz, 1H), 3.58 (s, 3H), 3.26 (s, 3H), 2.04 (s, 3H).
MS (ESI+) m/z 427(M+H).sup.+.
Example 188
6-methyl-4-[5-(methylsulfonyl)-2-(quinolin-7-yloxy)phenyl]-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one
[1071] Example 188 was prepared according to the procedure used for
the preparation of Example 138b, substituting quinolin-7-ol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1H), 8.67 (d,
J=8.5 Hz, 1H), 8.12 (dd, J=12.8, 5.7 Hz, 2H), 8.02 (dd, J=8.6, 2.4
Hz, 1H), 7.69 (dd, J=8.3, 4.8 Hz, 1H), 7.55-7.41 (m, 4H), 7.32 (d,
J=2.8 Hz, 1H), 6.32 (s, 1H), 3.50 (d, J=16.9 Hz, 3H), 3.30 (d,
J=9.2 Hz, 3H). MS (ESI+) m/z 446(M+H).sup.+.
Example 189
4-[2-(4-chloro-3-fluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1072] Example 189 was prepared according to the procedure used for
the preparation of Example 138b, substituting
3-fluoro-4-chlorophenol for 2,4-difluorophenol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 8.01 (t, J=3.5 Hz, 1H), 7.99-7.90 (m, 1H), 7.68-7.52
(m, 1H), 7.40 (s, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.29-7.24 (m, 1H),
7.20 (dd, J=10.3, 2.7 Hz, 1H), 7.00-6.86 (m, 1H), 6.29 (t, J=3.4
Hz, 1H), 3.57 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z
447(M+H).sup.+.
Example 190
6-methyl-4-[5-(methylsulfonyl)-2-(pyridin-3-yloxy)phenyl]-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1073] Example 190 was prepared according to the procedure used for
the preparation of Example 138b, substituting pyridin-3-ol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.03 (d, J=2.3 Hz, 1H),
8.01-7.90 (m, 1H), 7.72-7.64 (m, 1H), 7.42 (d, J=7.2 Hz, 1H),
7.37-7.30 (m, 1H), 7.30-7.15 (m, 1H), 6.36-6.24 (m, 1H), 3.56 (s,
3H), 3.27 (s, 3H). MS (ESI+) m/z 395(M+H).sup.+.
Example 191
4-[2-(2,3-dihydro-1H-inden-5-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1074] Example 191 was prepared according to the procedure used for
the preparation of Example 138b, substituting
2,3-dihydro-1H-inden-5-ol for 2,4-difluorophenol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.96 (d, J=2.4 Hz, 1H), 7.86 (dd, J=8.6, 2.4 Hz, 1H),
7.42 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.00
(d, J=8.7 Hz, 2H), 6.98 (d, J=2.2 Hz, 1H), 6.85 (dd, J=8.1, 2.3 Hz,
1H), 6.31 (d, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.23 (s, 3H), 2.88-2.79
(m, 4H), 2.03 (p, J=7.4 Hz, 2H). MS (ESI+) m/z 435(M+H).sup.+.
Example 192
6-methyl-4-{5-(methylsulfonyl)-2-[4-(propan-2-yl)phenoxy]phenyl}-1,6-dihyd-
ro-7H-pyrrolo[2,3-c]pyridin-7-one
[1075] Example 192 was prepared according to the procedure used for
the preparation of Example 138b, substituting 4-isopropylphenol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.97 (d, J=2.4 Hz, 1H),
7.88 (dd, J=8.6, 2.4 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J=2.8 Hz, 1H),
7.32-7.26 (m, 2H), 7.06-6.98 (m, 3H), 6.30 (d, J=2.8 Hz, 1H), 3.58
(s, 3H), 3.24 (s, 3H), 2.89 (p, J=6.9 Hz, 1H), 1.19 (d, J=6.9 Hz,
6H) MS (ESI+) m/z 437(M+H).sup.+.
Example 193
4-[2-(isoquinolin-8-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
[1076] Example 193 was prepared according to the procedure used for
the preparation of Example 138b, substituting isoquinolin-8-ol for
2,4-difluorophenol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.34 (bs, 1H), 8.12 (d,
J=2.3 Hz, 1H), 8.05 (dd, J=8.4, 2.4 Hz, 1H), 7.86 (t, J=7.9 Hz,
1H), 7.79 (d, J=8.2 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.48 (s, 1H),
7.32 (d, J=2.6 Hz, 1H), 7.17-7.11 (m, 1H), 6.40 (d, J=2.6 Hz, 1H),
3.44 (s, 3H), 3.32 (s, 3H). MS (ESI+) m/z 446(M+H).sup.+.
Example 194
6-methyl-4-[5-(methylsulfonyl)-2-(3,4,5-trifluorophenoxy)phenyl]-1,6-dihyd-
ro-7H-pyrrolo[2,3-c]pyridin-7-one
[1077] Example 194 was prepared according to the procedure used for
the preparation of Example 138b, substituting 3,4,5-trifluorophenol
for 2,4-difluorophenol, to provide the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.00 (d, J=2.4 Hz,
1H), 7.94 (dd, J=8.6, 2.4 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=2.8 Hz,
1H), 7.28 (d, J=8.6 Hz, 1H), 7.18-7.10 (m, 2H), 6.31 (d, J=2.8 Hz,
1H), 3.57 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 449(M+H).sup.+.
Example 195
4-(2-benzylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1078] Example 195 was prepared according to the procedure used for
the preparation of Example 95d, substituting
1-benzyl-2-bromobenzene for Example 95c, to provide the title
compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.08 (s,
1H), 7.23-7.34 (m, 5H), 7.16-7.19 (m, 2H), 7.09-7.12 (m, 1H),
6.92-6.93 (m, 3H), 5.95 (t, J=2.29 Hz, 1H), 3.89 (s, 2H), 3.47 (s,
3H). MS (ESI+) m/z 315.3 (M+H).sup.+.
Example 196
4-(biphenyl-2-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1079] Example 196 was prepared according to the procedure used for
the preparation of Example 95d, substituting biphenyl-2-ylboronic
acid for Example 6a and Example 1e for Example 95c, to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
11.88 (s, 1H), 7.44-7.49 (m, 4H), 7.18-7.24 (m, 4H), 7.13-7.16 (m,
1H), 7.08 (t, J=2.75 Hz, 1H), 6.93 (s, 1H), 5.77-5.78 (m, 1H), 3.38
(s, 3H). MS (ESI+) m/z 301.2 (M+H).sup.+.
Example 197
4-[2-(1,4-dioxaspiro[4.5]dec-8-yloxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1080] Example 197 was prepared according to the procedure used for
the preparation of Example 158, substituting Example 168c for
Example 138a, and 1,4-dioxaspiro[4.5]decan-8-ol for
cyclopropylmethanol, respectively, to provide the title compound.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.05 (s, 1H),
7.79-7.81 (m, 2H), 7.40-7.42 (m, 1H), 7.28-7.34 (m, 2H),
6.6.12-6.13 (m, 1H), 4.70-4.73 (m, 1H), 3.79-3.34 (m, 3H), 3.65 (s,
3H), 3.26-3.31 (m, 2H), 1.99-2.21 (m, 1H), 1.67-1.99 (m, 2H),
1.48-1.52 (m, 3H), 1.14 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 473.2
(M+H).sup.+.
Example 198
4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-
-pyrrolo[2,3-c]pyridin-7-one
[1081] Example 198 was prepared according to the procedure used for
the preparation of Example 158, substituting Example 168c for
Example 138a to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.04 (s, 1H), 7.79-7.82 (m, 2H), 7.37
(s, 1H), 7.29-7.33 (m, 2H), 6.13-6.14 (m, 1H), 3.99 (d, J=6.71 Hz,
2H), 3.58 (s, 3H), 3.27 (q, J=7.32 Hz, 2H), 1.11-1.14 (m, 4H),
0.45-.048 (m, 2H), 0.26-0.29 (m, 2H). MS (ESI+) m/z 387.2
(M+H).sup.+.
Example 199
4-{5-(ethylsulfonyl)-2-[(4-oxocyclohexyl)oxy]phenyl}-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
[1082] Example 197 (0.192 g, 0.406 mmol) was treated with 4.0 N
hydrogen chloride in dioxane (1.016 mL, 4.06 mmol), tetrahydrofuran
(10 mL), and water (2 mL). The reaction mixture was heated at
60.degree. C. for 2 hours. The solvent was removed, and the residue
was purified by reverse phase HPLC (C18, 10-80% CH.sub.3CN/water
(0.1% TFA)) to give the title compound (0.154 g, 0.359 mmol, 88%
yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.05 (s,
1H), 7.82-7.86 (m, 2H), 7.51 (d, J=8.85 Hz, 1H), 7.34 (s, 1H), 7.28
(t, J=2.75 Hz, 1H), 6.14 (t, J=2.29 Hz, 1H), 4.97-4.99 (m, 1H),
3.56 (s, 3H), 3.30 (q, J=7.32 Hz, 2H), 1.96-2.24 (m, 8H), 1.15 (t,
J=7.48 Hz, 3H). MS (ESI+) m/z 429.2 (M+H).sup.+.
Example 200
4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihy-
dro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 200a
2-bromo-N-(cyclopropylmethyl)-4-(ethylsulfonyl)aniline
[1083] Example 200a was prepared according to the procedure used
for the preparation of Example 147a, substituting
cyclopropylmethanamine for cyclohexanamine, and Example 168b for
2-bromo-1-fluoro-4-(methylsulfonyl)benzene to provide the title
compound.
Example 200b
4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihy-
dro-7H-pyrrolo[2,3-c]pyridin-7-one
[1084] Example 200b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 200a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.14 (s, 1H), 7.62 (dd, J=8.7, 2.29 Hz,
1H), 7.45 (d, J=2.14 Hz, 1H), 7.30 (t, J=2.75 Hz, 1H), 7.26 (s,
1H), 6.86 (J=8.85 Hz, 1H), 6.00-6.01 (m, 1H), 5.50 (br s, 1H), 3.56
(s, 3H), 3.16 (q, J=7.12 Hz, 2H), 3.04 (d, J=6.71 Hz, 2H), 1.15 (t,
J=7.48 Hz, 3H), 0.97-1.04 (m, 1H), 0.36-0.41 (m, 2H), 0.14-0.18 (m,
2H). MS (ESI+) m/z 386.2 (M+H).sup.+.
Example 201
6-methyl-4-{5-(methylsulfonyl)-2-[(tetrahydrofuran-3-ylmethyl)amino]phenyl-
}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 201a
2-bromo-4-(ethylsulfonyl)-N-((tetrahydrofuran-3-yl)methyl)aniline
[1085] Example 200a was prepared according to the procedure used
for the preparation of Example 147a, substituting
(tetrahydrofuran-3-yl)methanamine for cyclohexanamine, and Example
168b for 2-bromo-1-fluoro-4-(methylsulfonyl)benzene to provide the
title compound.
Example 201b
6-methyl-4-{5-(methylsulfonyl)-2-[(tetrahydrofuran-3-ylmethyl)amino]phenyl-
}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1086] Example 201b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 201a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.10 (s, 1H), 7.67 (dd, J=8.85, 2.44 Hz,
1H), 7.50 (d, J=2.14 Hz, 1H), 7.28 (t, J=2.9 Hz, 1H), 7.23 (s, 1H),
6.84 (J=8.85 Hz, 1H), 5.95-5.97 (m, 1H), 5.70 (br s, 1H), 3.55-3.70
(m, 7H), 3.38 (dd, J=8.54, 4.88 Hz, 2H), 3.10 (m, 5H), 1.84-1.92
(m, 1H), 1.47-1.55 (m, 1H). MS (ESI+) m/z 402.2 (M+H).sup.+.
Example 202
4-{5-(ethylsulfonyl)-2-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1087] A mixture of Example 199 (0.052 g, 0.121 mmol) and sodium
tetrahydroborate (6.89 mg, 0.182 mmol) in tetrahydrofuran (5 mL)
was heated at 60.degree. C. for 2 hours. The solvent was removed,
and the solid was treated with MeOH and a couple of drops of TFA.
The resulting solution was purified by Preparative HPLC (C18,
10-80% CH.sub.3CN/water (0.1% TFA)) to give the title compound
(second eluting peak, 0.036 g, 0.084 mmol, 68.9% yield). .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.06 (s, 1H), 7.78-7.82
(m, 2H), 7.36-7.38 (m, 2H), 7.30 (t, J=2.75 Hz, 1H), 6.14-6.16 (m,
1H), 4.62-4.63 (m, 1H), 3.51-3.58 (m, 5H), 3.25-3.31 (m, 2H),
1.75-1.81 (m, 2H), 1.50-1.64 (m, 4H), 1.32-1.40 (m, 2H), 1.14 (t,
J=7.32 Hz, 3H). MS (ESI+) m/z 431.2 (M+H).sup.+.
Example 203
4-{5-(ethylsulfonyl)-2-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one
[1088] The title compound (first eluting peak) was isolated as a
minor product during the preparation of Example 202. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.02 (s, 1H), 7.77-7.81 (m,
2H), 7.40 (d, J=8.54 Hz, 1H), 7.31 (s, 1H), 7.28 (t, J=2.75 Hz,
1H), 6.09-6.11 (m, 1H), 4.53-4.55 (m, 1H), 3.56 (s, 3H), 3.27 (q,
J=7.32 Hz, 2H), 1.95-2.00 (m, 2H), 1.68-1.71 (m, 4H), 1.27-1.38 (m,
4H), 1.13 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 431.2 (M+H).sup.+.
Example 204
4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-
-pyrrolo[2,3-d]pyridazin-7-one
Example 204a
2-bromo-1-(cyclopropylmethoxy)-4-(ethylsulfonyl)benzene
[1089] Example 204a was prepared according to the procedure used
for the preparation of Example 158, substituting Example 168b for
Example 138a, to provide the title compound.
Example 204b
2-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3-
,2-dioxaborolane
[1090] Example 204b was prepared according to the procedure used
for the preparation of Example 6a, substituting Example 204a for
Example 1e, to provide the title compound.
Example 204c
4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-
-pyrrolo[2,3-d]pyridazin-7-one
[1091] Example 204c was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 80b for
Example 95c, and Example 204b for Example 6a, respectively, to
provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.67 (s, 1H), 7.92 (dd, J=8.85, 2.44 Hz, 1H), 7.83 (d,
J=2.44 Hz, 1H), 7.43 (t, J=2.75 Hz, 1H), 7.40 (d, J=8.85 Hz, 1H),
6.29-6.30 (m, 1H), 4.02 (d, J=7.02 Hz, 2H), 3.80 (s, 3H), 3.29 (q,
J=7.12 Hz, 2H), 1.12 (t, J=7.32 Hz, 3H), 1.01-1.08 (m, 1H),
0.40-0.45 (m, 2H), 0.21-0.25 (m, 2H). MS (ESI+) m/z 388.0
(M+H).sup.+.
Example 205
6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-yloxy)phenyl]-1,6-dihy-
dro-7H-pyrrolo[2,3-c]pyridin-7-one
[1092] Example 205 was prepared according to the procedure used for
the preparation of Example 158, substituting tetrahydrofuran-3-ol
for cyclopropylmethanol, to provide the title compound. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.03 (s, 1H), 7.85-7.89 (m,
2H), 7.31-7.33 (m, 1H), 7.28 (t, J=2.75 Hz, 1H), 6.11-6.12 (m, 1H),
5.17-5.20 (m, 1H), 3.89-3.91 (m, 2H), 3.63-3.70 (m, 3H), 3.57 (s,
3H), 3.22 (s, 3H), 2.17-2.26 (m, 1H), 1.85-.1.91 (m, 1H). MS (ESI+)
m/z 389.1 (M+H).sup.+.
Example 206
4-{2-[(3-fluorooxetan-3-yl)methoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1093] Example 206 was prepared according to the procedure used for
the preparation of Example 158, substituting
(3-fluorooxetan-3-yl)methanol for cyclopropylmethanol, to provide
the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
12.06 (s, 1H), 7.90-7.93 (m, 2H), 7.42 (d, J=8.54 Hz, 1H), 7.37 (s,
1H), 7.30 (t, J=2.75 Hz, 1H), 6.16-6.17 (m, 1H), 4.52-4.64 (m, 8H),
3.56 (s, 3H), 3.23 (s, 3H). MS (ESI+) m/z 407.1 (M+H).sup.+.
Example 207
6-(cyclopropylmethoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)pyridine-3-sulfonamide
Example 207a
5-bromo-6-(cyclopropylmethoxy)pyridine-3-sulfonamide
[1094] Example 207a was prepared according to the procedure used
for the preparation of Example 29a, substituting 86a for Example
2a, and cyclopropylmethanol for tetrahydro-2H-pyran-4-ol, to
provide the title compound.
Example 207b
6-(cyclopropylmethoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)pyridine-3-sulfonamide
[1095] Example 207b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 207a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.12 (s, 1H), 8.52 (d, J=2.44 Hz, 1H),
8.12 (d, J=2.44 Hz, 1H), 7.44-7.45 (m, 3H), 7.33 (t, J=2.75 Hz,
1H), 6.22-6.24 (m, 1H), 4.23 (d, J=7.02 Hz, 2H), 3.58 (s, 3H),
1.14-1.24 (m, 1H), 0.47-0.52 (m, 2H), 0.29-0.33 (m, 2H). MS (ESI+)
m/z 374.9 (M+H).sup.+.
Example 208
6-(cyclopropylmethoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridin-4-yl)pyridine-3-sulfonamide
[1096] The title compound was isolated as a minor product during
the preparation of Example 207b. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.12 (s, 1H), 8.49 (s, 1H), 8.05 (d,
J=2.44 Hz, 1H), 7.53 (q, J=4.88 Hz, 1H), 7.46 (s, 1H), 7.33 (t,
J=2.75 Hz, 1H), 6.21-6.22 (m, 1H), 4.25 (d, J=7.32 Hz, 2H), 3.58
(s, 3H), 2.47 (d, J=4.88 Hz, 3H), 1.14-1.24 (m, 1H), 0.47-0.52 (m,
2H), 0.29-0.33 (m, 2H). MS (ESI+) m/z 389.2 (M+H).sup.+.
Example 209
6-[(cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)pyridine-3-sulfonamide
Example 209a
5-bromo-6-(cyclopropylmethylamino)pyridine-3-sulfonamide
[1097] Example 209a was prepared according to the procedure used
for the preparation of Example 96a, substituting
cyclopropylmethanamine for cyclohexanamine, to provide the title
compound.
Example 209b
6-[(cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)pyridine-3-sulfonamide
[1098] Example 209b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 209a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.17 (s, 1H), 8.38 (d, J=2.44 Hz, 1H),
7.69 (d, J=2.44 Hz, 1H), 7.32 (t, J=2.75 Hz, 1H), 7.30 (s, 1H),
7.18 (br s, 2H), 6.62 (s, 1H), 6.05-6.06 (m, 1H), 3.56 (s, 3H),
3.22 (d, J=3.97 Hz, 2H), 1.06-1.10 (m, 1H), 0.34-0.38 (m, 2H),
0.15-0.17 (m, 2H). MS (ESI+) m/z 374.2 (M+H).sup.+.
Example 210
6-[(cyclopropylmethyl)amino]-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyr-
rolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide
[1099] The title compound was isolated as a minor product during
the preparation of Example 209b. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.17 (s, 1H), 8.35 (d, J=2.44 Hz, 1H),
7.60 (d, J=2.44 Hz, 1H), 7.31-7.32 (m, 2H), 7.21 (d, J=4.58 Hz,
1H), 6.55 (s, 1H), 6.04-6.05 (m, 1H), 3.56 (s, 3H), 3.22 (d, J=5.19
Hz, 2H), 2.43 (d, J=2.75 Hz, 3H), 1.05-1.12 (m, 1H), 0.34-0.39 (m,
2H), 0.15-0.19 (m, 2H). MS (ESI+) m/z 386.7 (M+H).sup.+.
Example 211
4-{5-(ethylsulfonyl)-2-[(cis-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6-me-
thyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1100] Example 199 (0.052 g, 0.121 mmol) in tetrahydrofuran was
treated with 3.0 M methylmagnesium bromide in tetrahydrofuran
(0.485 mL, 0.485 mmol). The reaction mixture was stirred at ambient
temperature for 2 hours. The solvent was removed, and the solid was
treated with MeOH and a few drops of TFA. The resulting solution
was purified by reverse phase Preparative HPLC (C18, 10-80%
CH.sub.3CN/water (0.1% TFA)) to give the title compound (first
eluting peak, 0.018 g, 0.040 mmol, 33.4% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 12.04 (s, 1H), 7.78-7.80 (m, 2H),
7.38 (d, J=9.77 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J=2.75 Hz, 1H),
6.11-6.12 (m, 1H), 4.46-4.49 (m, 1H), 3.57 (s, 3H), 3.27 (q, J=7.32
Hz, 2H), 1.39-1.76 (m, 8H), 1.13 (t, J=7.32 Hz, 3H), 1.10 (s, 3H).
MS (ESI+) m/z 445.1 (M+H).sup.+.
Example 212
4-{5-(ethylsulfonyl)-2-[(trans-4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1101] The title compound (second eluting peak) was isolated as a
minor product in the preparation of Example 211. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 12.04 (s, 1H), 7.79-7.81 (m, 2H),
7.37 (d, J=9.46 Hz, 1H), 7.30 (s, 1H), 7.29 (t, J=2.75 Hz, 1H),
6.10-6.11 (m, 1H), 4.46-4.49 (m, 1H), 3.56 (s, 3H), 3.28 (q, J=7.32
Hz, 2H), 1.80-1.86 (m, 2H), 1.54-1.59 (m, 2H), 1.23-1.26 (m, 4H),
1.13 (t, J=7.32 Hz, 3H), 0.91 (s, 3H). MS (ESI+) m/z 445.1
(M+H).sup.+.
Example 213
4-[2-(cyclobutyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyr-
rolo[2,3-c]pyridin-7-one
[1102] A 4 mL vial was charged with a stir bar, a solution of
Example 138a (30 mg, 0.063 mmol) in tetrahydrofuran (1 mL), a
solution of cyclobutanol (32 mg, 7 equivalents, 0.46 mmol) in
tetrahydrofuran (1 mL) and neat sodium hydride (19 mg, 7
equivalents, 0.46 mmol). The reaction mixture was stirred at
60.degree. C. for 16 hours. The crude material was filtered,
concentrated, and purified by reverse phase HPLC (C18, 10-100%
CH.sub.3CN/water (0.1% TFA)) to afford the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.98-7.75 (m, 2H),
7.33 (d, J=1.4 Hz, 2H), 7.16 (d, J=8.7 Hz, 1H), 6.15 (d, J=2.8 Hz,
1H), 4.82 (p, J=7.2 Hz, 1H), 3.59 (s, 3H), 3.19 (d, J=8.5 Hz, 3H),
2.47-2.38 (m, 2H), 1.96 (p, J=9.6 Hz, 2H), 1.81-1.72 (m, 1H),
1.72-1.57 (m, 1H). MS (ESI+) m/z 373 (M+H).sup.+.
Example 214
4-[2-(cyclopentylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one
[1103] Example 214 was prepared according to the procedure used for
the preparation of Example 213, substituting cyclopentylmethanol
for cyclobutanol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.93-7.81 (m, 2H),
7.40-7.29 (m, 3H), 6.14 (d, J=2.8 Hz, 1H), 3.99 (d, J=6.6 Hz, 2H),
3.58 (s, 3H), 3.20 (s, 3H), 2.18 (dt, J=14.6, 7.2 Hz, 1H), 1.59
(dt, J=17.2, 8.5 Hz, 2H), 1.44 (dd, J=10.1, 4.8 Hz, 4H), 1.31-1.16
(m, 2H). MS (ESI+) m/z 401 (M+H).sup.+.
Example 215
4-[2-(cyclohexyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyr-
rolo[2,3-c]pyridin-7-one
[1104] Example 215 was prepared according to the procedure used for
the preparation of Example 213, substituting cyclohexanol for
cyclobutanol, to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.85 (dt, J=4.1, 2.4 Hz, 2H),
7.35 (dd, J=17.3, 5.9 Hz, 3H), 6.16 (d, J=2.8 Hz, 1H), 4.66-4.49
(m, 1H), 3.58 (s, 3H), 3.20 (s, 3H), 1.94-1.79 (m, 2H), 1.54 (d,
J=5.1 Hz, 2H), 1.50-1.28 (m, 5H), 1.21 (d, J=8.9 Hz, 1H). MS (ESI+)
m/z 401 (M+H).sup.+.
Example 216
4-[2-(cyclopentyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-py-
rrolo[2,3-c]pyridin-7-one
[1105] Example 216 was prepared according to the procedure used for
the preparation of Example 213, substituting cyclopentanol for
cyclobutanol, to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.88 (dd, J=8.7, 2.5 Hz, 1H),
7.82 (d, J=2.4 Hz, 1H), 7.32 (dd, J=10.3, 7.4 Hz, 3H), 6.10 (d,
J=2.8 Hz, 1H), 4.96 (dt, J=8.3, 2.8 Hz, 1H), 3.58 (s, 3H), 3.19 (d,
J=8.6 Hz, 3H), 2.53 (dd, J=3.5, 1.7 Hz, 2H), 1.98-1.82 (m, 2H),
1.69-1.56 (m, 2H), 1.56-1.46 (m, 4H) MS (ESI+) m/z 387
(M+H).sup.+.
Example 217
6-methyl-4-[5-(methylsulfonyl)-2-(tetrahydrofuran-3-ylmethoxy)phenyl]-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1106] Example 217 was prepared according to the procedure used for
the preparation of Example 213, substituting
(tetrahydrofuran-3-yl)methanol for cyclobutanol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.90 (dd, J=8.6, 2.5 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H),
7.37 (d, J=8.7 Hz, 1H), 7.33 (d, J=2.8 Hz, 2H), 6.14 (d, J=2.8 Hz,
1H), 4.10 (dd, J=9.4, 6.2 Hz, 1H), 4.03 (dd, J=9.4, 7.5 Hz, 1H),
3.58 (s, 5H), 3.62-3.52 (m, 6H), 3.40 (dd, J=8.6, 5.8 Hz, 1H), 3.20
(s, 3H), 1.93-1.80 (m, 1H), 1.63-1.51 (m, 1H). MS (ESI+) m/z 403
(M+H).sup.+.
Example 218
6-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxoimidazolidin-1-yl)ethoxy]phenyl}-
-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1107] Example 218 was prepared according to the procedure used for
the preparation of Example 213, substituting
1-(2-hydroxyethyl)imidazolidin-2-one for cyclobutanol, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.90 (dd, J=8.6, 2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H),
7.39 (d, J=8.7 Hz, 1H), 7.34 (d, J=2.8 Hz, 2H), 6.15 (d, J=2.8 Hz,
1H), 4.20 (t, J=5.2 Hz, 2H), 3.58 (s, 3H), 3.35 (t, J=5.2 Hz, 2H),
3.21 (s, 3H), 3.07 (s, 4H). MS (ESI+) m/z 431 (M+H).sup.+.
Example 219
4-[2-(2-cyclopropylethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro--
7H-pyrrolo[2,3-c]pyridin-7-one
[1108] Example 219 was prepared according to the procedure used for
the preparation of Example 213, substituting 2-cyclopropylethanol
for cyclobutanol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.93 (dd, J=8.6, 2.4 Hz,
1H), 7.86 (d, J=2.4 Hz, 1H), 7.43-7.32 (m, 3H), 6.14 (d, J=2.8 Hz,
1H), 4.18 (t, J=6.3 Hz, 2H), 3.23 (s, 3H), 1.54 (q, J=6.5 Hz, 2H),
0.72-0.60 (m, 1H), 0.39-0.29 (m, 2H) MS (ESI+) m/z 387
(M+H).sup.+.
Example 220
4-[2-(cycloheptyloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-py-
rrolo[2,3-c]pyridin-7-one
[1109] Example 220 was prepared according to the procedure used for
the preparation of Example 213, substituting cycloheptanol for
cyclobutanol, to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.91-7.80 (m, 2H), 7.32 (d,
J=2.8 Hz, 2H), 7.34-7.27 (m, 3H), 6.14 (d, J=2.8 Hz, 1H), 4.77-4.67
(m, 1H), 3.20 (s, 3H), 1.98-1.84 (m, 2H), 1.69-1.57 (m, 2H),
1.57-1.30 (m, 8H). MS (ESI+) m/z 415 (M+H).sup.+.
Example 221
6-methyl-4-[2-(2-methylpropoxy)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1110] Example 221 was prepared according to the procedure used for
the preparation of Example 213, substituting 2-methylpropan-1-ol
for cyclobutanol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.92-7.82 (m, 2H),
7.38-7.32 (m, 3H), 7.32 (d, J=2.8 Hz, 2H), 6.13 (d, J=2.8 Hz, 1H),
3.88 (d, J=6.3 Hz, 2H), 3.20 (s, 3H), 0.83 (d, J=6.7 Hz, 6H). MS
(ESI+) m/z 375 (M+H).sup.+.
Example 222
6-methyl-4-[2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(methylsulfonyl)ph-
enyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1111] Example 222 was prepared according to the procedure used for
the preparation of Example 213, substituting
(S)-(1-methylpyrrolidin-2-yl)methanol for cyclobutanol, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.96 (dd, J=8.6, 2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H),
7.43-7.33 (m, 3H), 6.20 (d, J=2.8 Hz, 1H), 4.49 (dd, J=11.0, 3.3
Hz, 1H), 4.27 (dd, J=10.9, 8.2 Hz, 1H), 3.59 (s, 3H), 3.44-3.34 (m,
1H), 3.25-3.16 (m, 3H), 3.07-2.95 (m, 1H), 2.32-2.09 (m, 1H),
2.01-1.83 (m, 1H), 1.85-1.62 (m, 2H). MS (ESI+) m/z 416
(M+H).sup.+.
Example 223
6-methyl-4-{2-[(2-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1112] Example 223 was prepared according to the procedure used for
the preparation of Example 213, substituting
(2-methylcyclopropyl)methanol for cyclobutanol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.94-7.79 (m, 2H), 7.41-7.28 (m, 3H), 6.16 (t, J=3.0
Hz, 1H), 4.10-3.97 (m, 1H), 3.91 (dd, J=10.3, 7.3 Hz, 1H), 3.59 (d,
J=2.7 Hz, 3H), 3.19 (s, 3H), 0.91 (t, J=11.4 Hz, 3H), 0.89-0.75 (m,
1H), 0.77-0.63 (m, 1H), 0.48-0.36 (m, 1H), 0.29-0.19 (m, 1H). MS
(ESI+) m/z 387 (M+H).sup.+.
Example 224
4-[2-(cyclohexylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-
-pyrrolo[2,3-c]pyridin-7-one
[1113] Example 224 was prepared according to the procedure used for
the preparation of Example 213, substituting cyclohexylmethanol for
cyclobutanol, to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.91-7.82 (m, 2H), 7.38-7.30 (m,
3H), 6.14 (d, J=2.8 Hz, 1H), 3.91 (d, J=5.7 Hz, 2H), 3.58 (s, 3H),
3.20 (s, 3H), 1.65-1.57 (m, 5H), 1.28-0.85 (m, 5H). MS (ESI+) m/z
415 (M+H).sup.+.
Example 225
6-methyl-4-{2-[2-(1-methylpyrrolidin-2-yl)ethoxy]-5-(methylsulfonyl)phenyl-
}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1114] Example 225 was prepared according to the procedure used for
the preparation of Example 213, substituting
2-(1-methylpyrrolidin-2-yl)ethanol for cyclobutanol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.93 (dd, J=8.7, 2.4 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H),
7.36 (dd, J=10.4, 7.7 Hz, 3H), 6.15 (d, J=2.8 Hz, 1H), 4.30-4.12
(m, 2H), 3.59 (s, 3H), 3.57-3.42 (m, 1H), 3.19 (d, J=14.3 Hz, 3H),
3.04 (dt, J=9.9, 5.0 Hz, 1H), 2.93 (dt, J=11.5, 8.5 Hz, 1H), 2.53
(dt, J=3.5, 1.7 Hz, 2H), 2.34-2.19 (m, 1H), 2.06 (dtd, J=12.9, 8.1,
5.0 Hz, 1H), 1.96-1.72 (m, 3H), 1.51 (ddd, J=16.7, 13.2, 9.3 Hz,
1H). MS (ESI+) m/z 430 (M+H).sup.+.
Example 226
6-methyl-4-[5-(methylsulfonyl)-2-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}pheny-
l]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1115] Example 226 was prepared according to the procedure used for
the preparation of Example 213, substituting
(R)-5-(hydroxymethyl)pyrrolidin-2-one for cyclobutanol, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.91 (dd, J=8.7, 2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H),
7.42-7.29 (m, 3H), 6.15 (d, J=2.8 Hz, 1H), 4.08 (qd, J=9.9, 4.2 Hz,
2H), 3.81 (dt, J=28.2, 14.1 Hz, 1H), 3.58 (s, 3H), 3.19 (d, J=11.5
Hz, 3H), 2.09-1.87 (m, 2H), 1.86-1.66 (m, 2H). MS (ESI+) m/z 416
(M+H).sup.+.
Example 227
6-methyl-4-{5-(methylsulfonyl)-2-[2-(morpholin-4-yl)ethoxy]phenyl}-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1116] Example 227 was prepared according to the procedure used for
the preparation of Example 213, substituting 2-morpholinoethanol
for cyclobutanol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.97 (dd, J=8.6, 2.4 Hz,
1H), 7.87 (d, J=2.4 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.35 (d, J=2.8
Hz, 2H), 6.12 (d, J=2.8 Hz, 1H), 4.48 (t, J=4.6 Hz, 2H), 3.96 (s,
1H), 3.59 (s, 3H), 3.57-3.36 (m, 3H), 3.22 (s, 3H), 3.18 (s, 1H),
3.10-2.68 (m, 2H). MS (ESI+) m/z 432 (M+H).sup.+.
Example 228
6-methyl-4-[5-(methylsulfonyl)-2-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}pheny-
l]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1117] Example 228 was prepared according to the procedure used for
the preparation of Example 213, substituting
(S)-5-(hydroxymethyl)pyrrolidin-2-one for cyclobutanol, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.88 (tt, J=15.3, 7.7 Hz, 2H), 7.46-7.27 (m, 3H), 6.15
(d, J=2.8 Hz, 1H), 4.08 (qd, J=9.9, 4.2 Hz, 2H), 3.83 (dd, J=8.1,
4.1 Hz, 1H), 3.57 (d, J=9.0 Hz, 3H), 3.20 (s, 3H), 2.09-1.90 (m,
2H), 1.85-1.69 (m, 2H) MS (ESI+) m/z 416 (M+H).sup.+.
Example 229
4-{2-[(1-tert-butoxypropan-2-yl)oxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1118] Example 229 was prepared according to the procedure used for
the preparation of Example 213, substituting
1-tert-butoxypropan-2-ol for cyclobutanol, to provide the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm
7.92-7.80 (m, 2H), 7.45-7.24 (m, 3H), 6.19 (d, J=2.8 Hz, 1H),
4.74-4.62 (m, 1H), 3.58 (s, 3H), 3.38 (t, J=7.6 Hz, 2H), 3.19 (d,
J=8.9 Hz, 3H), 1.20 (t, J=8.9 Hz, 3H), 1.02 (s, 9H). MS (ESI+) m/z
433 (M+H).sup.+.
Example 230
4-{2-[(1S,4R)-bicyclo[2.2.1]hept-2-ylmethoxy]-5-(methylsulfonyl)phenyl}-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1119] Example 230 was prepared according to the procedure used for
the preparation of Example 213, substituting
(1S,4R)-bicyclo[2.2.1]heptan-2-ylmethanol for cyclobutanol, to
provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.92-7.81 (m, 2H), 7.43-7.28 (m,
3H), 6.14 (dd, J=8.3, 2.8 Hz, 1H), 4.15-4.07 (m, 1H), 4.01-3.78 (m,
2H), 3.20 (s, 3H), 2.18-2.00 (m, 2H), 1.50-1.34 (m, 2H), 1.32-1.15
(m, 3H), 1.14-0.95 (m, 2H). MS (ESI+) m/z 427 (M+H).sup.+.
Example 231
6-methyl-4-{2-[(1-methylcyclopropyl)methoxy]-5-(methylsulfonyl)phenyl}-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1120] Example 231 was prepared according to the procedure used for
the preparation of Example 213, substituting
(1-methylcyclopropyl)methanol for cyclobutanol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.90-7.83 (m, 2H), 7.33 (d, J=2.9 Hz, 1H), 7.30 (d,
J=8.9 Hz, 1H), 6.17 (d, J=2.8 Hz, 1H), 3.90 (s, 2H), 3.19 (s, 3H),
0.97 (s, 3H), 0.48-0.41 (m, 2H), 0.31-0.25 (m, 2H). MS (ESI+) m/z
387 (M+H).sup.+.
Example 232
6-methyl-4-{5-(methylsulfonyl)-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]phenyl}-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1121] Example 232 was prepared according to the procedure used for
the preparation of Example 213, substituting
1-(2-hydroxyethyl)pyrrolidin-2-one for cyclobutanol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.91 (dd, J=8.6, 2.4 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H),
7.41-7.30 (m, 3H), 6.10 (d, J=2.8 Hz, 1H), 4.21 (t, J=5.2 Hz, 2H),
3.58 (s, 3H), 3.45 (t, J=5.2 Hz, 2H), 3.23-3.16 (m, 3H), 3.01 (t,
J=7.0 Hz, 2H), 2.08 (t, J=8.0 Hz, 2H), 1.67 (p, J=7.5 Hz, 2H). MS
(ESI+) m/z 430 (M+H).sup.+.
Example 233
6-methyl-4-{2-[(4-methylcyclohexyl)oxy]-5-(methylsulfonyl)phenyl}-1,6-dihy-
dro-7H-pyrrolo[2,3-c]pyridin-7-one
[1122] Example 233 was prepared according to the procedure used for
the preparation of Example 213, substituting 4-methylcyclohexanol
for cyclobutanol, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.89-7.83 (m, 2H),
7.39-7.31 (m, 3H), 6.17 (d, J=2.8 Hz, 1H), 4.78-4.71 (m, 1H), 3.20
(s, 3H), 1.86-1.75 (m, 2H), 1.57-1.45 (m, 2H), 1.41-1.22 (m, 3H),
0.96-0.82 (m, 2H), 0.68 (d, J=6.2 Hz, 3H). MS (ESI+) m/z 415
(M+H).sup.+.
Example 234
4-[2-(cyclobutylmethoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-
-pyrrolo[2,3-c]pyridin-7-one
[1123] Example 234 was prepared according to the procedure used for
the preparation of Example 213, substituting cyclobutylmethanol for
cyclobutanol, to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 7.94-7.80 (m, 2H), 7.34 (dd,
J=13.2, 5.7 Hz, 3H), 6.14 (d, J=2.8 Hz, 1H), 4.07 (d, J=6.2 Hz,
2H), 3.57 (s, 3H), 3.19 (d, J=9.2 Hz, 3H), 2.61 (d, J=7.1 Hz, 1H),
1.99-1.62 (m, 6H). MS (ESI+) m/z 387 (M+H).sup.+.
Example 235
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]cyclopropanesulfonamide
[1124] Example 235 was prepared according to the procedure used for
the preparation of Example 4 (Method A), substituting Example 27c
for Example 3, and cyclopropanesulfonyl chloride for
methanesulfonyl chloride, respectively, to provide the title
compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.05 (s,
1H), 9.70 (s, 1H), 7.35-7.38 (m, 2H), 7.29-7.30 (m, 2H), 7.22 (dd,
J=8.7, 2.59 Hz, 1H), 7.06-7.10 (m, 1H), 6.98-7.01 (m, 1H), 6.92 (d,
J=8.54 Hz, 1H), 6.25-6.26 (m, 1H), 3.54 (s, 3H), 2.61-2.66 (m, 1H),
0.90-0.98 (m, 4H). MS (ESI+) m/z 472.1 (M+H).sup.+.
Example 236
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-2-methoxyethanesulfonamide
[1125] Example 236 was prepared according to the procedure used for
the preparation of Example 4, Method A, substituting Example 27b
for Example 3, and 2-methoxyethanesulfonyl chloride for
methanesulfonyl chloride, respectively, to provide the title
compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.05 (s,
1H), 9.76 (s, 1H), 7.34-7.39 (m, 2H), 7.28-7.30 (m, 2H), 7.19 (dd,
J=8.85, 2.75 Hz, 1H), 7.05-7.10 (m, 1H), 6.98-7.01 (m, 1H), 6.91
(d, J=8.54 Hz, 1H), 6.25-6.26 (m, 1H), 3.68 (t, J=6.1 Hz, 2H), 3.53
(s, 3H), 3.37 (t, J=6.1 Hz, 2H), 3.20 (s, 3H). MS (ESI+) m/z 490.1
(M+H).sup.+.
Example 237
6-methyl-4-{5-(methylsulfonyl)-2-[tricyclo[3.3.1.1.sup.37]dec-2-yloxy]phen-
yl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1126] Example 237 was prepared according to the procedure used for
the preparation of Example 158, substituting 2-adamantanol for
cyclopropylmethanol, to provide the title compound. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.04 (s, 1H), 7.88 (d, J=2.44
Hz, 1H), 7.83 (dd, J=8.85, 2.44, HZ, 1H), 7.38 (s, 1H), 7.36 (d,
J=8.85 Hz, 1H), 7.29 (t, J=2.75 Hz, 1H), 6.18-6.19 (m, 1H), 4.70
(s, 1H), 3.56 (s, 3H), 3.21 (s, 3H), 2.06 (s, 2H), 1.80 (s, 5H),
1.62-1.65 (m, 5H), 1.34 (d, J=11.29 Hz, 2H). MS (ESI+) m/z 453.2
(M+H).sup.+.
Example 238
4-[(cyclopropylmethyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)benzenesulfonamide
Example 238a
3-bromo-4-(cyclopropylmethylamino)benzenesulfonamide
[1127] Example 238a was prepared according to the procedure used
for the preparation of Example 96a, substituting
cyclopropylmethanamine for cyclohexanamine, and
3-bromo-4-fluorobenzenesulfonamide for Example 86a, respectively,
to provide the title compound.
Example 238b
4-[(cyclopropylmethyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3--
c]pyridin-4-yl)benzenesulfonamide
[1128] Example 238b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 238a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.13 (s, 1H), 7.61-7.63 (m, 1H), 7.50
(d, J=2.14 Hz, 1H), 7.30 (t, J=2.75 Hz, 1H), 7.20 (s, 1H), 6.97 (br
s, 2H), 6.80 (d, J=8.85 Hz, 1H), 6.01 (s, 1H), 3.56 (s, 3H), 3.02
(d, J=6.71 Hz, 2H), 0.97-1.03 (m, 1H), 0.35-0.39 (m, 2H), 0.13-0.16
(m, 2H). MS (ESI+) m/z 373.2 (M+H).sup.+.
Example 239
4-[(cyclopropylmethyl)amino]-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyr-
rolo[2,3-c]pyridin-4-yl)benzenesulfonamide
[1129] The title compound was isolated as a minor product in the
preparation of Example 238b. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.13 (s, 1H), 7.56 (dd, J=8.54, 2.44 Hz, 1H), 7.42 (d,
J=2.14 Hz, 1H), 7.23 (s, 1H), 7.30 (t, J=2.75 Hz, 1H), 7.02 (d,
J=4.88 Hz, 1H), 6.83 (d, J=8.54 Hz, 1H), 6.00-6.01 (m, 1H), 3.56
(s, 3H), 3.02 (d, J=6.71 Hz, 2H), 2.38 (d, J=4.58 Hz, 3H),
0.99-1.18 (m, 1H), 0.36-0.40 (m, 2H), 0.13-0.17 (m, 2H). MS (ESI+)
m/z 387.2 (M+H).sup.+.
Example 240
4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl--
1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 240a
2-bromo-1-((2,2-difluorocyclopropyl)methoxy)-4-(ethylsulfonyl)benzene
[1130] Example 240a was prepared according to the procedure used
for the preparation of Example 158, substituting Example 168b for
Example 138a, and (2,2-difluorocyclopropyl)methanol for
cyclopropylmethanol, to provide the title compound.
Example 240b
4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl--
1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1131] Example 240b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 240a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.05 (s, 1H), 7.81-7.85 (m, 2H),
7.37-7.39 (m, 2H), 7.29 (t, J=2.75 Hz, 1H), 6.14-6.15 (m, 1H),
4.25-4.29 (m, 2H), 4.16-4.20 (m, 2H), 3.57 (s, 3H), 3.29 (q, J=7.43
Hz, 2H), 2.08-2.16 (m, 1H), 1.63-1.66 (m, 1H), 1.44-1.46 (m, 1H),
1.13 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 423.1 (M+H).sup.+.
Example 241
4-(4-bromo-2-methoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin--
7-one
Example 241a
4-(4-bromo-2-methoxyphenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H-
)-one
[1132] The product from Example 6a (0.2 g, 0.467 mmol),
4-bromo-1-iodo-2-methoxybenzene (0.16 g, 0.514 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.014 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.014
g, 0.047 mmol) and potassium phosphate tribasic (0.347 g, 1.634
mmol) were combined and sparged with argon for 15 minutes.
Meanwhile a solution of 4:1 dioxane/water (7.5 mL) was sparged with
nitrogen for 15 minutes and transferred by syringe into the
reaction vessel under argon. The mixture was stirred at ambient
temperature for 20 minutes and partitioned between ethyl acetate
and water. The organic layer was washed with saturated aqueous
sodium chloride, dried (Na.sub.2SO.sub.4), treated with
3-mercaptopropyl functionalized silica gel for twenty minutes,
filtered, and concentrated. Purification by chromatography (silica
gel, 10-80% ethyl acetate in heptanes) afforded the title compound
(0.2 g, 88%)
Example 241b
4-(4-bromo-2-methoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin--
7-one
[1133] The product from Example 241a (0.2 g, 0.410 mmol), potassium
hydroxide (0.460 g, 8.21 mmol) and cetyltrimethylammonium bromide
(7.48 mg, 0.021 mmol) were combined in dioxane (8 mL) and water (4
mL) and heated at 100.degree. C. for 18 hours. The reaction mixture
was partitioned between equal volumes of ethyl acetate and water
and the pH was adjusted to pH 7 by careful addition of concentrated
HCl. The organic layer was separated and washed three times with
saturated aqueous sodium chloride, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. Purification by trituration in
dichloromethane afforded the title compound (0.1 g, 73%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 11.97 (s, 1H) 7.05-7.42 (m,
5H) 5.87-6.09 (m, 1H) 3.75 (s, 3H) 3.54 (s, 3H). MS (ESI+) m/z
333/335 (M+H).sup.+.
Example 242
6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)pyridine-3-sulfonamide
Example 242a
5-bromo-6-(2,4-difluorophenoxy)pyridine-3-sulfonamide
[1134] A mixture of Example 86a (0.543 g, 2 mmol),
2,4-difluorophenol (0.390 g, 3.00 mmol), and cesium carbonate
(1.955 g, 6.00 mmol) in DMSO (10 mL) was heated at 110.degree. C.
for 16 hours. After cooling, the reaction mixture was partitioned
between water and ethyl acetate. The aqueous layer was neutralized
with 10% HCl and extracted with additional ethyl acetate twice. The
combined organic layers were washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography (3:2
ethyl acetate/hexanes) on silica gel to give the title compound
(0.53 g, 1.451 mmol, 72.6% yield).
Example 242b
6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)pyridine-3-sulfonamide
[1135] Example 242b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 242a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.19 (s, 1H), 8.46 (d, J=2.44 Hz, 1H),
8.29 (d, J=2.14 Hz, 1H), 7.56 (s, 2H), 7.54 (s, 1H), 7.44-7.50 (m,
2H), 7.35 (t, J=2.75 Hz, 1H), 7.14-7.18 (m, 1H), 6.34 (t, J=2.44
Hz, 1H), 3.61 (s, 3H). MS (ESI+) m/z 433.2 (M+H).sup.+.
Example 243
4-{2-(cyclopropylmethoxy)-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 243a
(3-bromo-4-fluorophenyl)(trifluoromethyl)sulfane
[1136] 3-Bromo-4-fluorobenzenethiol (2.071 g, 10 mmol) in
dimethylformamide (10 mL) was treated with 60% sodium hydride
(0.480 g, 12.00 mmol). The solution was stirred for 10 minutes at
room temperature. Trifluoroiodomethane (2.74 g, 14.00 mmol) was
released into a balloon with a three-way stopcock. The balloon was
then put onto the flask and trifluoroiodomethane was released into
the reaction. After 1 hour, all the content in the balloon was
gone. And the balloon was filled with 2.74 g of
trifluoroiodomethane again. The reaction mixture was stirred for 16
hours. The reaction mixture was poured into water, and extracted
with ethyl acetate several times. The combined organic layers were
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The resulting oil
was used directly in the next reaction.
Example 243b
2-bromo-1-fluoro-4-(trifluoromethylsulfonyl)benzene
[1137] Example 243a (2.75 g, 10.00 mmol) in acetonitrile (4 mL),
carbon tetrachloride (4.00 mL), and water (16.00 mL) was treated
with sodium periodate (6.42 g, 30.0 mmol) and ruthenium(III)
chloride hydrate (0.023 g, 0.100 mmol). The reaction mixture was
stirred at ambient temperature for 16 hours. Dichloromethane (100
mL) was added to the reaction mixture, which was then filtered
through a pad of filtering agent. The filtrate was treated with
saturated sodium bicarbonate (50 mL). And the organic layer was
separated. The aqueous layer was then extracted with additional
dichloromethane three times. The combined organic layers were
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by column chromatography on silica gel eluting with 5%
ethyl acetate in hexanes to give 2.14 g of the title compound (7.85
mmol, 79% yield).
Example 243c
2-bromo-1-(cyclopropylmethoxy)-4-(trifluoromethylsulfonyl)benzene
[1138] Example 243c was prepared according to the procedure used
for the preparation of Example 158, substituting Example 243b for
Example 138a, to provide the title compound.
Example 243d
4-{2-(cyclopropylmethoxy)-5-[(trifluoromethyl)sulfonyl]phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1139] Example 243d was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 243c for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.10 (s, 1H), 8.08 (dd, J=8.85, 2.44 Hz,
1H), 7.95 (d, J=2.44 Hz, 1H), 7.50 (d, J=8.85 Hz, 1H), 7.44 (s,
1H), 7.35 (t, J=2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.09 (d, J=7.02
Hz, 2H), 3.58 (s, 3H), 1.11-1.17 (m, 1H), 0.48-0.50 (m, 2H),
0.29-0.33 (m, 2H). MS (ESI+) m/z 427.0 (M+H).sup.+.
Example 244
4-{2-[(cyclopropylmethyl)amino]-5-[(trifluoromethyl)sulfonyl]phenyl}-6-met-
hyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 244a
[1140] Example 244a was prepared according to the procedure used
for the preparation of Example 96a, substituting
cyclopropylmethanamine for cyclohexanamine, and Example 243b for
Example 86a, respectively, to provide the title compound.
Example 244b
4-{2-[(cyclopropylmethyl)amino]-5-[(trifluoromethyl)sulfonyl]phenyl}-6-met-
hyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1141] Example 244b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 244a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.16 (s, 1H), 7.80 (dd, J=8.85, 2.44 Hz,
1H), 7.53 (d, J=2.44 Hz, 1H), 7.29-7.31 (m, 2H), 7.02 (d, J=9.16
Hz, 1H), 6.41 (t, J=5.8 Hz, 1H), 5.96-5.97 (m, 1H), 3.56 (s, 3H),
3.10 (t, J=6.26 Hz, 2H), 1.01-1.06 (m, 1H), 0.39-0.43 (m, 2H),
0.16-0.20 (m, 2H). MS (ESI+) m/z 426.1 (M+H).sup.+.
Example 245
6-[(cyclopropylmethyl)amino]-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-
-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide
Example 245a
5-bromo-6-(cyclopropylmethylamino)-N,N-dimethylpyridine-3-sulfonamide
[1142] Example 245a was prepared according to the procedure used
for the preparation of Example 96a, substituting
cyclopropylmethanamine for cyclohexanamine, and Example 110a for
Example 86a, respectively, to provide the title compound.
Example 245b
6-[(cyclopropylmethyl)amino]-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-
-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide
[1143] Example 245b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 245a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.16 (s, 1H), 8.35 (d, J=2.44 Hz, 1H),
7.51 (d, J=2.44 Hz, 1H), 7.20-7.32 (m, 2H), 6.69 (t, J=5.34 Hz,
1H), 6.03-6.04 (m, 1H), 3.58 (s, 3H), 3.24 (t, J=5.95 Hz, 2H), 2.62
(s, 6H), 1.05-1.12 (m, 1H), 0.34-0.39 (m, 2H), 0.15-0.19 (m, 2H).
MS (ESI+) m/z 402.1 (M+H).sup.+.
Example 246
6-(2,4-difluorophenoxy)-N-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[-
2,3-c]pyridin-4-yl)pyridine-3-sulfonamide
[1144] The title compound was isolated as a minor product in the
preparation of Example 242b. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.19 (s, 1H), 8.45 (d, J=2.44 Hz, 1H), 8.22 (d, J=2.44
Hz, 1H), 7.60 (q, J=4.78 Hz, 1H), 7.57 (s, 1H), 7.46-7.52 (m, 3H),
7.36 (t, J=2.75 Hz, 1H), 7.14-7.19 (m, 1H), 6.34-6.35 (m, 1H), 3.61
(s, 3H), 2.50 (d, J=4.88 Hz, 3H). MS (ESI+) m/z 477.1
(M+H).sup.+.
Example 247
4-[2-(cyclopropylmethoxy)-6-methylphenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[-
2,3-c]pyridin-7-one
Example 247a
2-bromo-1-(cyclopropylmethoxy)-3-methylbenzene
[1145] A 250 mL flask with stirbar was charged with
2-bromo-3-methylphenol (2.86 g, 15.3 mmol),
(bromomethyl)cyclopropane (1.80 mL, 18.6 mmol) and cesium carbonate
(7.46 g, 22.9 mmol) in dimethylformamide (50 mL). The mixture was
stirred for 16 hours at ambient temperature and then heated at
50.degree. C. for 3 hours. The mixture was cooled to ambient
temperature and partitioned between ethyl acetate (200 mL) and
saturated aqueous sodium chloride (200 mL). The organics were
washed twice with saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate, filtered, and concentrated to provide the
title compound (3.7 g, 100%).
Example 247b
4-(2-(cyclopropylmethoxy)-6-methylphenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[1146] Example 247b was prepared according to the procedure used
for the preparation of Example 7d, substituting the product of
Example 247a for the product of Example 7c and stirring at
65.degree. C. for 2.5 hours, to provide the title compound.
Example 247c
4-(2-(cyclopropylmethoxy)-6-methylphenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridi-
n-7(6H)-one
[1147] Example 247c was prepared according to the procedure used
for the preparation of Example 4b, substituting the product of
Example 247b for the product of Example 4a to provide the title
compound. 1H NMR (400 MHz, DMSO-d.sub.6) .quadrature. ppm 11.91
(bds, 1H), 7.23-7.18 (m, 2H), 6.99 (s, 1H), 6.91 (d, J=3.1 Hz, 1H),
6.89 (m, 1H), 5.79 (m, 1H), 3.74 (dd, J=6.6, 2.3 Hz, 2H), 3.54 (s,
3H), 2.06 (s, 3H) 0.99 (m, 1H), 0.33 (m, 2H), 0.08 (m, 2H). MS
(DCI+) m/z 309.1 (M+H).sup.+.
Example 248
4-{5-(ethylsulfonyl)-2-[(cis-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 248a
2-bromo-4-(ethylsulfonyl)-1-(4-methoxycyclohexyloxy)benzene
[1148] 4-Methoxycyclohexanol (a mixture of 70% cis and 30% trans
isomers) (0.521 g, 4.00 mmol) in dioxane (20 mL) was treated with
sodium hydride (0.240 g, 6.00 mmol). The reaction mixture was
stirred for 10 minutes. To this solution was added Example 168b
(0.534 g, 2 mmol). The reaction was heated at 60.degree. C. for 16
hours. After cooling, the reaction mixture was partitioned between
water and ethyl acetate. The aqueous layer was extracted with
additional ethyl acetate two more times. The combined organic
layers were washed with saturated aqueous sodium chloride, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 70:30
ethyl acetate/hexanes) to give the title compound (0.29 g, 38.4%
yield).
Example 248b
4-{5-(ethylsulfonyl)-2-[(cis-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1149] Example 248b (second eluting peak) was prepared according to
the procedure used for the preparation of Example 95d, substituting
Example 248a for Example 95c, to provide the title compound.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.05 (s, 1H),
7.78-7.80 (m, 2H), 7.38-7.40 (m, 1H), 7.34 (s, 1H), 7.29 (t, J=2.75
Hz, 1H), 6.12-6.13 (m, 1H), 4.63-4.66 (m, 1H), 3.56 (s, 3H), 3.28
(t, J=7.32 Hz, 2H), 3.19-3.23 (m, 1H), 3.15 (s, 3H), 1.65-1.72 (m,
6H), 1.42-1.48 (m, 2H), 1.13 (t, J=7.32, 3H). MS (ESI+) m/z 445.0
(M+H).sup.+.
Example 249
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)benzenesulfonamide
Example 249a
3-bromo-4-(cyclopropylmethoxy)benzenesulfonamide
[1150] Example 249a was prepared according to the procedure used
for the preparation of Example 29a, substituting
3-bromo-4-fluorobenzenesulfonamide for Example 2a, and
cyclopropylmethanol for tetrahydro-2H-pyran-4-ol, to provide the
title compound.
Example 249b
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)benzenesulfonamide
[1151] Example 249b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 249a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.03 (s, 1H), 7.80 (d, J=2.44 Hz, 1H),
7.76 (dd, J=8.54, 2.44 Hz, 1H), 7.31 (s, 1H), 7.30 (t, J=2.9 Hz,
1H), 7.22-7.25 (m, 3H), 6.15-6.16 (m, 1H), 3.93 (d, J=6.71 Hz, 2H),
3.57 (s, 3H), 1.08-1.13 (m, 1H), 0.44-0.49 (m, 2H), 0.25-0.28 (m,
2H). MS (ESI+) m/z 374.1 (M+H).sup.+.
Example 250
4-(cyclopropylmethoxy)-N-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridin-4-yl)benzenesulfonamide
[1152] The title compound was isolated as a minor product in the
preparation of Example 249b. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.05 (s, 1H), 7.70-7.74 (m, 2H), 7.35 (s, 1H), 7.30
(t, J=2.9 Hz, 1H), 7.26-7.32 (m, 3H), 6.14 (t, J=2.44 Hz, 1H), 3.95
(d, J=6.71 Hz, 2H), 3.58 (s, 3H), 2.41 (d, J=4.88 Hz, 3H),
1.07-1.15 (m, 1H), 0.45-0.50 (m, 2H), 0.26-0.29 (m, 2H). MS (ESI+)
m/z 388.1 (M+H).sup.+.
Example 251
N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide
Example 251a
2-bromo-1-(cyclopropylmethoxy)-3-methyl-4-nitrobenzene
[1153] Example 251a was prepared according to the procedure used
for the preparation of Example 247a, substituting
2-bromo-3-methyl-4-nitrophenol for 2-bromo-3-methylphenol, to
provide the title compound.
Example 251b
4-(6-(cyclopropylmethoxy)-2-methyl-3-nitrophenyl)-6-methyl-1-tosyl-1H-pyrr-
olo[2,3-c]pyridin-7(6H)-one
[1154] Example 251b was prepared according to the procedure used
for the preparation of Example 7d, substituting the product of
Example 251a for the product of Example 7c and stirring at
65.degree. C. for 2.5 hours, to provide the title compound.
Example 251c
4-(3-amino-6-(cyclopropylmethoxy)-2-methylphenyl)-6-methyl-1-tosyl-1H-pyrr-
olo[2,3-c]pyridin-7(6H)-one
[1155] Example 251c was prepared according to the procedure used
for the preparation of Example 3, substituting the product of
Example 251b for the product of Example 2b to provide the title
compound.
Example 251d
N-(4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide
[1156] Example 251d was prepared according to the procedure used
for the preparation of Example 4 (Method A), substituting Example
251c for Example 3, and ethanesulfonyl chloride for methanesulfonyl
chloride, respectively, to provide the title compound. 1H NMR (400
MHz, DMSO-d.sub.6) .quadrature. ppm 11.93 (bds, 1H), 8.89 (bds,
1H), 7.23-7.19 (m, 2H), 6.99 (s, 1H), 6.91 (d, J=3.1 Hz, 1H), 5.75
(m, 1H), 3.74 (dd, J=6.6, 2.3 Hz, 2H), 3.54 (s, 3H), 3.07 (m, 2H),
2.06 (s, 3H), 1.27 (m, 3H), 0.99 (m, 1H), 0.33 (m, 2H), 0.08 (m,
2H). MS (ESI+) m/z 416.1 (M+H).sup.+.
Example 252
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-di-
hydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
Example 252a
1-(2,4-difluorophenoxy)-4-(methylsulfonyl)-2-nitrobenzene
[1157] A mixture of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (20
g, 91 mmol), 2,4-difluorophenol (11.87 g, 91 mmol) and potassium
carbonate (12.6 g, 91 mmol) in DMSO (90 mL) was heated at
120.degree. C. for 2 hours. The reaction mixture was quenched with
water and extracted with ethyl acetate. The combined organic layers
were washed with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 1:1 ethyl
acetate/hexanes) to provide the title compound (28 g, 89%
yield).
Example 252b
2-(2,4-difluorophenoxy)-5-(methylsulfonyl)aniline
[1158] A solution of Example 252a (10.0 g, 30.4 mmol) in
tetrahydrofuran (150 mL) was added to 10% Pd/C (1.616 g, 15.18
mmol) in a 250 mL bottle and the mixture was stirred for 24 hour
under a 30 psi hydrogen atmosphere at 40.degree. C. The mixture was
filtered through a nylon membrane and concentrated. The residue was
purified flash chromatography (silica gel, 70:30 ethyl
acetate/hexanes) to provide the title compound (8.6 g, 55%
yield).
Example 252c
1-(2,4-difluorophenoxy)-2-iodo-4-(methylsulfonyl)benzene
[1159] Example 252b (5.00 g, 16.7 mmol) in dioxane (30 mL) was
treated with concentrated HCl (150 mL) at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 10 minutes. To this
solution was added sodium nitrite (1.383 g, 20.05 mmol) in water (6
mL). The reaction mixture was stirred at 0.degree. C. for one hour.
To this solution was added potassium iodide (5.55 g, 33.4 mmol) in
water (20 mL). The reaction mixture was stirred for two hours at
10.degree. C. The reaction mixture was then partitioned between
water and ethyl acetate. The organic layer was extracted with
additional ethyl acetate twice. The combined organic layer was
washed with saturated aqueous sodium chloride, dried (anhydrous
magnesium sulfate), filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 2:3 ethyl
acetate/hexanes) to provide the title compound (8.9 g, 89%
yield)
Example 252d
ethyl
1-benzyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1160] A mixture of Example 70e (2 g, 5.14 mmol),
bis(pinacolato)diboron (2.61 g, 10.3 mmol), potassium acetate (1.11
g, 11.3 mmol tris(dibenzylideneacetone)dipalladium(0) (0.235 g,
0.257 mmol) and
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.245 g,
0.514 mmol) in dioxane (50 mL) was stirred at 90.degree. C. for 16
hour under an argon atmosphere. The mixture was filtered through
Celite, washed with ethyl acetate several times and concentrated.
The residue was purified by flash chromatography (silica gel,
50-75% ethyl acetate/petroleum ether gradient) to afford the title
compound (1.15 g, 40% yield).
Example 252e
ethyl
1-benzyl-4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-meth-
yl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1161] Example 252d (2.3 g, 5.27 mmol), Example 252c (2.270 g, 5.54
mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.154 g, 0.527 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.121 g, 0.132 mmol) and potassium phosphate (1.119 g, 5.27 mmol)
were combined and sparged with argon for 30 minutes. A mixture of
degassed dioxane (30 mL) and water (7.5 mL) was added and the
reaction mixture was stirred at 60.degree. C. for 16 hours. The
reaction mixture was cooled to ambient temperature and partitioned
between ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, dried (anhydrous sodium
sulfate), filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 20-100% ethyl acetate in
petroleum ether) to afford the title compound (1.77 g, 33.4%
yield).
Example 252f
ethyl
4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo--
6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1162] A mixture of Example 252e, anisole (1.585 mL, 14.51 mmol)
and concentrated sulfuric acid (4.3 mL, 81 mmol) in trifluoroacetic
acid (20 mL, 260 mmol) was heated at 90.degree. C. for 4 hours.
Excess trifluoroacetic acid was removed under reduced pressure, and
the residue was partitioned between water (100 mL) and ethyl
acetate (200 mL). The organic layer was separated, and the aqueous
layer was extracted with additional ethyl acetate (2.times.200 mL).
The combined organic layers were washed with saturated aqueous
sodium bicarbonate (100 mL), followed by saturated aqueous sodium
chloride (100 mL), dried over anhydrous magnesium sulfate,
filtered, and concentrated. The crude material was taken into
methanol (50 mL) and the resulting solid was filtered, rinsed with
methanol, and dried to provide the title compound (3.1 g, 63%
yield).
Example 252g
4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-di-
hydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1163] Example 252f (1.1 g, 2.2 mmol) in dioxane (60 mL) was
treated with 2.0 M aqueous lithium hydroxide (4.38 mL, 8.76 mmol).
The reaction mixture was heated at 65.degree. C. for two hours. The
reaction mixture was cooled to ambient temperature and the solvent
was removed under reduced pressure. The residue was dissolved in
water (50 mL) and the pH adjusted to 5 with HCl (3M). The resulting
solid was filtered and dissolved in ethyl acetate (200 mL). The
solution was dried over anhydrous sodium sulfate, filtered, and
concentrated to provide the title compound (0.85 g, 77% yield).
Example 252h
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-di-
hydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[1164] To a solution of Example 252g (0.10 g, 0.21 mmol) in
anhydrous dichloromethane (5 mL) was added oxalyl chloride (0.037
mL, 0.42 mmol) and dimethylformamide (0.816 .mu.l, 10.5 .mu.mol)
The reaction mixture was stirred at ambient temperature for 2
hours. The reaction mixture was concentrated. The residue was
redissolved in dichloromethane (5 mL) and treated with ammonium
hydroxide (2 mL, 92 mmol) and the reaction mixture was stirred at
ambient temperature for 16 hours. The reaction mixture was
partitioned between water (15 mL) and ethyl acetate (25 mL). The
aqueous layer was extracted with additional ethyl acetate
(2.times.15 mL). The combined organic layers were dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue
was triturated with ethyl acetate and the resulting solid was
filtered, washed with dichloromethane and dried under vacuo to
provide the title compound (48 mg, 47% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.33 (s, 1H), 7.98 (s, 1H),
7.98-7.88 (m, 1H), 7.82 (s, 1H), 7.56-7.40 (m, 4H), 7.19 (m, 1H),
7.00 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 3.59 (s, 3H), 3.27 (s, 3H).
MS (ESI+) m/z 474.1 (M+H).sup.+
Example 253
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N-ethyl-6-methyl-7-ox-
o-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[1165] Example 253 was prepared according to the procedure used for
the preparation of Example 252h, substituting ethanamine for
ammonium hydroxide, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.32 (s, 1H), 8.35-8.32 (m, 1H),
7.98 (s, 1H), 7.89 (dd, J=2.4, 6.4 Hz, 1H), 7.56-7.21 (m, 3H),
7.20-7.16 (m, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.85 (s, 1H), 3.59 (s,
3H), 3.30-3.23 (m, 5H), 1.11 (t, J=7.2 Hz, 3H). MS (ESI+) m/z 502.1
(M+H).sup.+.
Example 254
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-N-(2,2-
,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[1166] Example 254 was prepared according to the procedure used for
the preparation of Example 252h, substituting
2,2,2-trifluoroethanamine for ammonium hydroxide, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
12.56 (s, 1H), 8.94 (t, J=6 Hz, 1H), 7.99 (s, 1H), 7.98-7.89 (m,
1H), 7.52-7.50 (m, 2H), 7.42-7.40 (m, 1H), 7.17 (m, 1H), 7.03-7.00
(m, 2H), 4.13-4.08 (m, 2H), 3.59 (s, 3H), 3.26 (s, 3H). MS (ESI+)
m/z 556.1 (M+H).sup.+.
Example 255
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(morpholin-
-4-ylcarbonyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1167] Example 255 was prepared according to the procedure used for
the preparation of Example 252h, substituting morpholine for
ammonium hydroxide, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.99 (s, 1H), 7.88 (dd, J=2.4, 6 Hz,
1H), 7.59-7.42 (m, 3H), 7.22-7.17 (m, 1H), 6.98 (d, J=8.4 Hz, 1H),
6.50 (s, 1H), 3.59 (s, 3H), 3.55 (m, 8H), 3.27 (s, 3H). MS (ESI+)
m/z 544.2 (M+H).sup.+.
Example 256
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methyl-
piperazin-1-yl)carbonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1168] Example 256 was prepared according to the procedure used for
the preparation of Example 252h, substituting 1-methylpiperazine
for ammonium hydroxide, to provide the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.97 (d, J=2 Hz, 1H), 7.84 (dd,
J=2.4, 6 Hz, 1H), 7.32 (s, 1H), 7.13-7.10 (m, 2H), 6.94-6.91 (m,
2H), 6.51 (s, 1H), 3.68-3.65 (m, 4H), 3.60 (s, 3H), 3.08 (s, 3H),
2.38 (m, 4H), 2.24 (s, 3H). MS (ESI+) m/z 557.2 (M+H).sup.+.
Example 257
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-N-(1,3-
-thiazol-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[1169] Example 257 was prepared according to the procedure used for
the preparation of Example 252h, substituting thiazol-2-amine for
ammonium hydroxide, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H), 12.49 (s, 1H), 8.01
(s, 1H), 7.92 (dd, J=2.4, 6.4 Hz, 1H), 7.56-7.45 (m, 4H), 7.34-7.29
(m, 2H), 7.22-7.18 (m, 1H), 7.03 (d, J=8.4 Hz, 1H), 3.61 (s, 3H),
3.28 (s, 3H). MS (ESI+) m/z 557.1 (M+H).sup.+.
Example 258
ethyl
4-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(m-
ethylsulfonyl)phenoxy]piperidine-1-carboxylate
[1170] Example 258 was prepared according to the procedure used for
the preparation of Example 158, substituting ethyl
4-hydroxypiperidine-1-carboxylate for cyclopropylmethanol, to
provide the title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.01 (s, 1H), 7.84-7.87 (m, 2H), 7.41 (d, J=9.46 Hz,
1H), 7.31 (s, 1H), 7.27 (t, J=2.59 Hz, 1H), 6.12 (s, 1H), 4.75-4.79
(m, 1H), 3.98 (q, J=7.02 Hz, 2H), 3.56 (s, 3H), 3.22-3.26 (m, 2H),
3.20 (s, 3H), 2.10 (s, 1H), 1.83-1.88 (m, 2H), 1.43-1.55 (M, 2H),
1.13 (t, J=7.02 Hz, 3H). MS (ESI+) m/z 474.1 (M+H).sup.+.
Example 259
4-[2-ethoxy-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3--
c]pyridin-7-one
[1171] The title compound was isolated as a minor product in the
preparation of Example 258. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.02 (s, 1H), 7.88 (dd, J=8.54, 2.44 Hz, 1H), 7.82 (d,
J=2.44 Hz, 1H), 7.32-7.34 (m, 2H), 7.28 (t, J=2.75 Hz, 1H),
6.10-6.11 (m, 1H), 4.17 (q, J=6.92 Hz, 2H), 3.57 (s, 3H), 3.21 (s,
3H), 3.20 (s, 3H), 1.22 (t, J=7.02 Hz, 3H). MS (ESI+) m/z 347.1
(M+H).sup.+.
Example 260
4-{5-(ethylsulfonyl)-2-[(trans-4-methoxycyclohexyl)oxy]phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1172] The title compound (first eluting peak) was isolated as a
second product in the preparation of Example 248b. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 12.03 (s, 1H), 7.78-7.81 (m, 2H),
7.40 (d, J=8.54 Hz, 1H), 7.31 (s, 1H), 7.28 (t, J=2.75 Hz, 1H),
6.10-6.11 (m, 1H), 4.57-4.61 (m, 1H), 3.56 (s, 3H), 3.28 (t, J=7.32
Hz, 2H), 3.19 (s, 3H), 3.14-3.18 (m, 1H), 1.93-1.97 (m, 2H),
1.73-1.77 (m, 2H), 1.31-1.42 (m, 4H), 1.13 (t, J=7.32, 3H). MS
(ESI+) m/z 445.0 (M+H).sup.+.
Example 261
4-{2-[(cyclopropylmethyl)amino]-5-(propan-2-ylsulfonyl)phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 261a
(3-bromo-4-fluorophenyl)(isopropyl)sulfane
[1173] Example 261a was prepared according to the procedure used
for the preparation of Example 168a, substituting 2-iodopropane for
iodoethane, to provide the title compound.
Example 261b
2-bromo-1-fluoro-4-(isopropylsulfonyl)benzene
[1174] Example 261b was prepared according to the procedure used
for the preparation of Example 168b, substituting Example 261a for
Example 168a, to provide the title compound.
Example 261c
2-bromo-N-(cyclopropylmethyl)-4-(isopropylsulfonyl)aniline
[1175] Example 261c was prepared according to the procedure used
for the preparation of Example 147a, substituting
cyclopropylmethanamine for cyclohexanamine, and Example 261b for
2-bromo-1-fluoro-4-(methylsulfonyl)benzene to provide the title
compound.
Example 261d
4-{2-[(cyclopropylmethyl)amino]-5-(propan-2-ylsulfonyl)phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1176] Example 261d was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 261c for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.12 (s, 1H), 7.59 (dd, J=8.7, 2.29 Hz,
1H), 7.40 (d, J=2.44 Hz, 1H), 7.30 (t, J=2.9 Hz, 1H), 7.25 (s, 1H),
6.88 (d, J=8.85 Hz, 1H), 5.98-5.99 (m, 1H), 5.61 (br s, 1H), 3.56
(s, 3H), 3.22-3.30 (m, 2H), 3.03 (d, J=6.71 Hz, 2H), 1.16 (d,
J=7.02 Hz, 6H), 0.98-1.14 (m, 1H), 0.36-0.41 (m, 2H), 0.14-0.18 (m,
2H). MS (ESI+) m/z 400.1 (M+H).sup.+.
Example 262
N-[4-(cyclopropylmethoxy)-2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide
[1177] Example 262 was prepared according to the procedure used for
the preparation of Example 4 (Method A), substituting Example 251c
for Example 3, to provide the title compound. .sup.1H NMR (500 MHz,
CD.sub.3OD) .quadrature. ppm 7.34 (d, J=8.9 Hz, 1H), 7.28 (d, J=2.8
Hz, 1H), 6.98 (s, 1H), 6.93 (d, J=8.9 Hz, 1H), 5.93 (d, J=2.8 Hz,
1H), 3.78 (m, 2H), 3.69 (s, 3H), 2.98 (s, 3H), 2.13 (m, 3H), 0.99
(m, 1H), 0.35 (m, 2H), 0.08 (m, 2H). MS (ESI+) m/z 402.1
(M+H).sup.+.
Example 263
N-[4-(cyclopropylmethoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide
Example 263a
1-bromo-2-(cyclopropylmethoxy)-4-methyl-5-nitrobenzene
[1178] Example 263a was prepared according to the procedure used
for the preparation of Example 247a, substituting
2-bromo-5-methyl-4-nitrophenol for 2-bromo-3-methylphenol to
provide the title compound.
Example 263b
4-(2-(cyclopropylmethoxy)-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1H-pyrr-
olo[2,3-c]pyridin-7(6H)-one
[1179] Example 263b was prepared according to the procedure used
for the preparation of Example 7d, substituting the product of
Example 263a for the product of Example 7c and stirring at
65.degree. C. for 2.5 hours, to provide the title compound.
Example 263c
4-(5-amino-2-(cyclopropylmethoxy)-4-methylphenyl)-6-methyl-1-tosyl-1H-pyrr-
olo[2,3-c]pyridin-7(6H)-one
[1180] Example 263c was prepared according to the procedure used
for the preparation of Example 3, substituting the product of
Example 263b for the product of Example 2b to provide the title
compound.
Example 263d
N-(4-(cyclopropylmethoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl)methanesulfonamide
[1181] Example 263d was prepared according to the procedure used
for the preparation of Example 4 (Method A), substituting Example
263c for Example 3, to provide the title compound. 1H NMR (500 MHz,
CD.sub.3OD) .quadrature. ppm 7.36 (s, 1H), 7.31 (d, J=2.8 Hz, 1H),
7.28 (s, 1H), 6.96 (s, 1H), 6.35 (d, J=2.8 Hz, 1H), 3.84 (d, J=6.7
Hz, 2H), 3.69 (s, 3H), 3.11 (s, 3H), 2.41 (s, 3H), 1.11 (m, 1H),
0.47 (m, 2H), 0.24 (m, 2H). MS (ESI+) m/z 402.1 (M+H).sup.+.
Example 264
4-[5-(ethylsulfonyl)-2-(tetrahydro-2H-thiopyran-4-yloxy)phenyl]-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 264a
4-(2-bromo-4-(ethylsulfonyl)phenoxy)tetrahydro-2H-thiopyran
[1182] Example 264a was prepared according to the procedure used
for the preparation of Example 158, substituting Example 168b for
Example 138a, and tetrahydro-2H-thiopyran-4-ol for
cyclopropylmethanol, respectively, to provide the title
compound.
Example 264b
4-[5-(ethylsulfonyl)-2-(tetrahydro-2H-thiopyran-4-yloxy)phenyl]-6-methyl-1-
,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1183] Example 264b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 264a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.05 (s, 1H), 7.79-7.82 (m, 2H), 7.40
(d, J=9.77 Hz, 1H), 7.34 (s, 1H), 7.30 (t, J=2.75 Hz, 1H),
6.12-6.13 (m, 1H), 4.69-4.72 (m, 1H), 3.58 (s, 3H), 3.28 (d, J=7.32
Hz, 2H), 2.50-2.62 (m, 4H), 2.06-2.12 (m, 2H), 1.74-1.81 (m, 2H),
1.13 (d, J=7.32 Hz, 6H). MS (ESI+) m/z 433.1 (M+H).sup.+.
Example 265
4-{2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-5-(ethylsulfonyl)pheny-
l}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1184] Example 265 was prepared according to the procedure used for
the preparation of Example 168b, substituting 264b for Example
168a, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.09 (s, 1H), 7.83-7.87 (m, 2H), 7.48
(d, J=8.85 Hz, 1H), 7.35 (s, 1H), 7.29 (t, J=2.75 Hz, 1H),
6.14-6.15 (m, 1H), 4.90-4.93 (m, 1H), 3.58 (s, 3H), 3.30 (q, J=7.43
Hz, 2H), 3.01-3.04 (m, 2H), 2.76-2.82 (m, 2H), 2.12-2.18 (m, 4H),
1.14 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 465.1 (M+H).sup.+.
Example 266
6-(2,4-difluorophenoxy)-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrr-
olo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide
Example 266a
5-bromo-6-(2,4-difluorophenoxy)-N,N-dimethylpyridine-3-sulfonamide
[1185] Example 242a (0.365 g, 1 mmol) in dimethylformamide (5 mL)
was treated with 60% sodium hydride (0.120 g, 3.00 mmol). The
solution was stirred for 10 minutes. To this solution was added
iodomethane (0.355 g, 2.500 mmol). The reaction mixture was stirred
at ambient temperature for 2 hours. The reaction mixture was
partitioned between water and ethyl acetate. The aqueous layer was
extracted with additional ethyl acetate two more times. The
combined organic layers were washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel to give the title compound (0.365 g, 0.928 mmol, 93%
yield).
Example 266b
6-(2,4-difluorophenoxy)-N,N-dimethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrr-
olo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide
[1186] Example 266b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 266a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.17 (s, 1H), 8.50 (d, J=2.44 Hz, 1H),
8.18 (d, J=2.44 Hz, 1H), 7.57 (s, 1H), 7.46-7.51 (m, 2H), 7.35 (t,
J=2.75 Hz, 1H), 7.15-7.18 (m, 1H), 6.33-6.34 (m, 1H), 3.61 (s, 3H),
2.71 (s, 6H). MS (ESI+) m/z 461.1 (M+H).sup.+.
Example 267
4-[2-(cyclopropylamino)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
Example 267a
2-bromo-N-cyclopropyl-4-(ethylsulfonyl)aniline
[1187] Example 267a was prepared according to the procedure used
for the preparation of Example 147a, substituting cyclopropylamine
for cyclohexanamine, and Example 168b for
2-bromo-1-fluoro-4-(methylsulfonyl)benzene to provide the title
compound.
Example 267b
4-[2-(cyclopropylamino)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-p-
yrrolo[2,3-c]pyridin-7-one
[1188] Example 267b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 267a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.32 (s, 1H), 7.92 (dd, J=8.7, 2.29 Hz,
1H), 7.68 (d, J=2.44 Hz, 1H), 7.51 (t, J=2.75 Hz, 1H), 7.45 (s,
1H), 7.40 (d, J=8.54 Hz, 1H), 6.14-6.15 (m, 1H), 6.11 (s, 1H), 3.77
(s, 3H), 3.40 (q, J=7.32 Hz, 2H), 2.63-2.67 (m, 1H), 1.35 (t,
J=7.32 Hz, 3H), 0.95-0.97 (m, 2H), 0.62-0.68 (m 2H). MS (ESI+) m/z
372.1 (M+H).sup.+.
Example 268
4-(5-(ethylsulfonyl)-2-(cis-4-methoxy-4-methylcyclohexyloxy)phenyl)-6-meth-
yl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
Example 268a
8-(2-bromo-4-(ethylsulfonyl)phenoxy)-1,4-dioxaspiro[4.5]decane
[1189] Example 268a was prepared according to the procedure used
for the preparation of Example 158, substituting Example 168b for
Example 138a, and 1,4-dioxaspiro[4.5]decan-8-ol for
cyclopropylmethanol, respectively, to provide the title
compound.
Example 268b
4-(2-bromo-4-(ethylsulfonyl)phenoxy)cyclohexanone
[1190] Example 268b was prepared according to the procedure used
for the preparation of Example 199, substituting Example 268a for
Example 197, to provide the title compound.
Example 268c
(cis)-4-(2-bromo-4-(ethylsulfonyl)phenoxy)-1-methylcyclohexanol
[1191] Example 268b (0.95 g, 2.63 mmol) in THF (15 mL) was cooled
to 0.degree. C. This solution was treated with 3.0 M
methylmagnesium bromide (2.63 ml, 7.89 mmol) and stirred at room
temperature overnight. The reaction mixture was quenched with
saturated NH.sub.4Cl solution and partitioned between water and
ethyl acetate. The aqueous layer was extracted with additional
ethyl acetate twice. The combined organic layers were washed with
brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel
eluting with 1:1 ethyl acetate/hexanes to give two fractions.
Example 268c was the first fraction to elute from the column.
Example 268d
2-bromo-4-(ethylsulfonyl)-1-((cis)-4-methoxy-4-methylcyclohexyloxy)benzene
[1192] Example 268c (0.43 g, 1.140 mmol) in tetrahydrofuran (5 mL)
was treated with 60% sodium hydride (0.182 g, 4.5 mmol). The
reaction was stirred at ambient temperature for 10 minutes. To this
solution was added iodomethane (2) (0.65 g, 4.5 mmol). The reaction
mixture was heated at 40.degree. C. for 16 ours. The reaction
mixture was partitioned between water and ethyl acetate. The
aqueous layer was extracted with additional ethyl acetate two more
times. The combined organic layers were washed with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel to give the title compound (0.356 g,
0.910 mmol, 80% yield).
Example 268e
4-(5-(ethylsulfonyl)-2-(cis-4-methoxy-4-methylcyclohexyloxy)phenyl)-6-meth-
yl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1193] Example 268e was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 268d for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.04 (s, 1H), 7.77-7.81 (m, 2H), 7.39
(d, J=8.85 Hz, 1H), 7.31 (s, 1H), 7.29 (t, J=2.75 Hz, 1H),
6.10-6.11 (m, 1H), 4.50-4.55 (m, 1H), 3.57 (s, 3H), 3.28 (q, J=7.32
Hz, 2H), 1.69-1.78 (m, 4H), 1.46-1.53 (m, 2H), 1.33-1.38 (m, 2H),
1.13 (t, J=7.32 Hz, 3H), 1.05 (s, 3H). MS (ESI+) m/z 459.1
(M+H).sup.+.
Example 269
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N,N,6-trimethyl-7-oxo-
-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[1194] Example 269 was prepared according to the procedure used for
the preparation of Example 252h, substituting dimethylamine for
ammonium hydroxide, to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.08 (s, 1H), 7.95 (dd, J=2.4, 6 Hz,
1H), 7.43 (s, 1H), 7.26-7.15 (m, 2H), 7.05-6.99 (m, 2H), 6.69 (s,
1H), 3.72 (s, 3H), 3.25 (s, 3H), 3.19 (s, 3H), 3.12 (s, 1H). MS
(ESI+) m/z 502.0 (M+H).sup.+.
Example 270
6-methyl-4-{5-(methylsulfonyl)-2-[4-(methylsulfonyl)phenoxy]phenyl}-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1195] Example 270 was prepared according to the procedure used for
the preparation of Example 138b, substituting
4-(methylsulfonyl)phenol for 2,4-difluorophenol, to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
12.08 (s, 1H), 8.06 (d, J=2.44 Hz, 1H), 7.97 (dd, J=8.7, 2.29 Hz,
1H), 7.85-7.88 (m, 2H), 7.40 (s, 1H), 7.35 (d, J-=8.54 Hz, 1H),
7.29 (t, J=2.75 Hz, 1H), 7.20-7.23 (m, 2H), 6.24-6.25 (m, 1H), 3.54
(s, 3H), 3.30 (s, 3H), 3.17 (s, 3H). MS (ESI+) m/z 471.2
(M+H).sup.+.
Example 271
4-[2-(2,4-difluorophenoxy)-5-(propan-2-ylsulfonyl)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 271a
2-bromo-1-(2,4-difluorophenoxy)-4-(isopropylsulfonyl)benzene
[1196] Example 271a was prepared according to the procedure used
for the preparation of Example 138b, substituting Example 261b for
Example 138a, to provide the title compound.
Example 271b
4-[2-(2,4-difluorophenoxy)-5-(propan-2-ylsulfonyl)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1197] Example 271b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 271a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.11 (s, 1H), 7.88 (d, J=2.44 Hz, 1H),
7.80 (dd, J=8.85, 2.44 Hz, 1H), 7.50-7.54 (m, 1H), 7.42-7.49 (m,
2H), 7.31 (t, J=2.75 Hz, 1H), 7.15-7.19 (m, 1H), 7.00 (d, J=8.54,
Hz, 1H), 6.25-6.26 (m, 1H), 3.59 (s, 3H), 3.44-3.48 (m, 1H), 1.20
(d, J=7.02 Hz, 6H). MS (ESI+) m/z 459.0 (M+H).sup.+.
Example 272
6-(cyclopropylmethoxy)-N,N-diethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide
Example 272a
5-bromo-6-(cyclopropylmethoxy)-N,N-diethylpyridine-3-sulfonamide
[1198] Example 272a was prepared according to the procedure used
for the preparation of Example 266a, substituting Example 207a for
Example 242a, and ethyl iodide for iodomethane, respectively, to
provide the title compound.
Example 272b
6-(cyclopropylmethoxy)-N,N-diethyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide
[1199] Example 272b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 272a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.10 (s, 1H), 8.54 (d, J=2.44 Hz, 1H),
8.01 (d, J=2.44 Hz, 1H), 7.44 (s, 1H), 7.32 (t, J=2.75 Hz, 1H),
6.15-6.16 (m, 1H), 4.24 (d, J=7.02 Hz, 2H), 3.58 (s, 3H), 3.21 (q,
J=7.02 Hz, 4H), 1.17-1.20 (m, 4H), 1.08 (t, J=7.02 Hz, 6H),
0.47-0.51 (m, 2H), 0.29-0.32 (m, 2H). MS (ESI+) m/z 431.1
(M+H).sup.+.
Example 273
4-(cyclopropylmethoxy)-N,N-dimethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)benzenesulfonamide
Example 273a
3-bromo-4-(cyclopropylmethoxy)-N,N-dimethylbenzenesulfonamide
[1200] Example 273a was prepared according to the procedure used
for the preparation of Example 266a, substituting Example 249a for
Example 242a, to provide the title compound.
Example 273b
4-(cyclopropylmethoxy)-N,N-dimethyl-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)benzenesulfonamide
[1201] Example 273b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 273a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.05 (s, 1H), 7.70 (dd, J=8.54, 2.44 Hz,
1H), 7.66 (d, J=2.44 Hz, 1H), 7.37 (s, 1H), 7.29-7.32 (m, 2H),
6.12-6.13 (m, 1H), 3.98 (d, J=6.71 Hz, 2H), 3.57 (s, 3H), 2.62 (s,
6H), 3.21 (q, J=7.02 Hz, 4H), 1.11-1.15 (m, 1H), 0.46-0.49 (m, 2H),
0.27-0.30 (m, 2H). MS (ESI+) m/z 402.1 (M+H).sup.+.
Example 274
4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[-
2,3-c]pyridin-7-one
Example 274a
2-bromo-1-(cyclopropylmethoxy)-4-fluorobenzene
[1202] To a solution of 2-bromo-4-fluorophenol (0.50 g, 2.6 mmol)
in tetrahydrofuran (13 mL) were added cyclopropanemethanol (0.209
mL, 2.62 mmol), triphenylphosphine (0.687 g, 2.62 mmol), and DIAD
(0.509 mL, 2.62 mmol). The reaction mixture was stirred for 16
hours at ambient temperature. The solvent was removed under reduced
pressure. The residue was triturated with hexanes. The mixture was
filtered, and the filtrate containing the product was concentrated
by under reduced pressure. The residue was purified by flash
chromatography (silica gel, hexanes) to provide the title compound
(400 mg, 62% yield).
Example 274b
(2-(cyclopropylmethoxy)-5-fluorophenyl)boronic acid
[1203] To a solution of Example 274a (0.1 g, 0.408 mmol) in
tetrahydrofuran (2 mL) at -20.degree. C. was added nBuLi (0.180 mL
of a 2.5 M solution in hexanes, 0.449 mmol). The reaction mixture
was stirred for 2 hours, then cooled to -40.degree. C.
2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.092 mL,
0.449 mmol) was added dropwise. The reaction mixture was stirred
for 30 minutes. The reaction mixture was quenched with 1M citric
acid at 0.degree. C. The mixture was stirred at ambient temperature
for 1 hour and then extracted with ethyl acetate. The layers were
separated, and the organic layer was dried over anhydrous sodium
sulfate, filtered, and concentrated. The crude material was
purified by flash chromatography (silica gel, 10-33% ethyl
acetate/hexanes gradient) to provide the title compound (23 mg, 20%
yield).
Example 274c
4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[-
2,3-c]pyridin-7-one
[1204] Nitrogen was bubbled through a 4:1 dimethoxyethane/ethanol
solution for 20 minutes. A microwave vial was charged with Example
1e (0.05 g, 0.131 mmol), Example 274b (0.046 g, 0.144 mmol),
Pd(Ph.sub.3P).sub.4 (7.58 mg, 6.56 .mu.mol), and cesium fluoride
(0.060 g, 0.393 mmol). The vial was sealed and flushed with
nitrogen. The 4:1 dimethoxyethane/ethanol mixture (0.5 mL) was
added. The reaction mixture was heated in a microwave reactor at
120.degree. C. for 40 minutes. The reaction mixture was partitioned
between water and ethyl acetate. The layers were separated. The
aqueous layer was extracted with ethyl acetate. The combined
organics were dried over anhydrous sodium sulfate, filtered, and
concentrated. The crude material was purified by flash
chromatography (silica gel, 20-80% ethyl acetate/hexanes gradient)
to provide the title compound (5 mg, 23% yield). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .quadrature. ppm 11.98 (s, 1H), 7.29 (s, 1H),
7.26 (t, J=2.71 Hz, 1H), 7.05-7.18 (m, 3H), 6.14 (dd, J=2.71, 2.03
Hz, 1H), 3.80 (d, J=6.78 Hz, 2H), 3.55 (s, 3H), 0.98-1.09 (m, 1H),
0.39-0.46 (m, 2H), 0.17-0.22 (m, 2H). MS (ESI+) m/z 313.1
(M+H).sup.+.
Example 275
4-[2-(2,4-difluorophenoxy)-5-(trifluoromethyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one
Example 275a
2-bromo-1-(2,4-difluorophenoxy)-4-(trifluoromethyl)benzene
[1205] A mixture of 3-bromo-4-fluorobenzotrifluoride (0.5 mL, 3.52
mmol), 2,4-difluorophenol (0.337 mL, 3.52 mmol), and potassium
carbonate (0.486 g, 3.52 mmol) in dimethylformamide (7 mL) was
heated at 80.degree. C. for 16 hours. The reaction mixture was
cooled to ambient temperature and partitioned between ethyl acetate
and water. The layers were separated, and the aqueous layer was
extracted with ethyl acetate. The combined organics were washed
with water and saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate, filtered, and concentrated. The crude
material was purified by flash chromatography (silica gel, 0-10%
ethyl acetate/hexanes gradient) to provide the title compound (1.0
g, 80% yield).
Example 275b
(2-(2,4-difluorophenoxy)-5-(trifluoromethyl)phenyl)boronic acid
[1206] To a suspension of magnesium (0.083 g, 3.42 mmol) in
tetrahydrofuran (1.00 mL) was added 0.5 mL of a solution of Example
275a (1.099 g, 3.11 mmol) in tetrahydrofuran (1.5 mL). The reaction
mixture was warmed (about 40-50.degree. C.) until reaction
commenced. The remaining solution of starting bromide was added
dropwise. The reaction mixture was stirred at ambient temperature
for 1 hour. The resulting solution was added dropwise to a solution
of trimethyl borate (0.696 mL, 6.23 mmol) in tetrahydrofuran (1.5
mL) at 0.degree. C. The reaction mixture was stirred at ambient
temperature for 1 hour, quenched with ice water and then
neutralized with 2 M HCl. The mixture was extracted with ethyl
acetate. The combined organics were washed with saturated aqueous
sodium chloride, dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 10-33% ethyl acetate/hexanes gradient) to provide the
title compound (650 mg, 66% yield).
Example 275c
4-[2-(2,4-difluorophenoxy)-5-(trifluoromethyl)phenyl]-6-methyl-1,6-dihydro-
-7H-pyrrolo[2,3-c]pyridin-7-one
[1207] Example 275c was prepared according to the procedure used
for the preparation of Example 274c, substituting example 275b for
example 274b, to provide the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. ppm 12.06 (s, 1H), 7.78 (d, J=2.37 Hz,
1H), 7.70 (dd, J=8.48, 1.70 Hz, 1H), 7.49 (td, J=11.36, 8.65, 3.05
Hz, 1H), 7.40 (s, 1H), 7.34-7.43 (m, 1H), 7.28 (t, J=2.71 Hz, 1H),
7.10-7.17 (m, 1H), 6.95 (d, J=8.48 Hz, 1H), 6.24 (dd, J=2.71, 2.03
Hz, 1H), 3.57 (s, 3H). MS (ESI+) m/z 421.1 (M+H).sup.+.
Example 276
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(hydroxymethyl)-6-m-
ethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1208] To a suspension of Example 252f (0.20 g, 0.40 mmol) in
tetrahydrofuran (5 mL) stirring at 0.degree. C. was added lithium
aluminum hydride (1M in tetrahydrofuran, 0.398 mL, 0.398 mmol) and
the mixture was stirred at 0.degree. C. for two hours. The solvent
was evaporated under reduced pressure and the residue was
partitioned between ethyl acetate (30 mL) and water (20 mL). The
mixture was filtered to remove the undissolved materials. The
aqueous layer was extracted with ethyl acetate (2.times.30 mL). The
combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was triturated with
dichloromethane and the resulting solid was filtered and dried to
provide the title compound (0.10 g, 55% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 11.91 (s, 1H), 7.97 (d, J=2.4 Hz,
1H), 7.86 (dd, J=2.4, 6.4 Hz, 1H), 7.56-7.38 (m, 3H), 7.20-7.15 (m,
1H), 6.97 (d, J=8.4 Hz, 1H), 6.18 (s, 1H), 5.11 (t, J=5.6 Hz, 1H),
4.50 (d, J=5.6 Hz, 2H), 3.57 (s, 3H), 3.16 (s, 3H). MS (ESI+) m/z
461.2 (M+H).sup.+.
Example 277
4-[2-(2,3-dihydro-1H-inden-2-yloxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1209] Example 277 was prepared according to the procedure used for
the preparation of Example 158, substituting
2,3-dihydro-1H-inden-2-ol for cyclopropylmethanol, to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
11.97 (s, 1H), 7.91 (dd, J=8.54, 2.44 Hz, 1H), 7.85 (d, J=2.44 Hz,
1H), 7.47 (d, J=8.85 Hz, 1H), 7.20-7.23 (m, 2H), 7.12-7.17 (m, 3H),
7.07 (s, 1H), 6.00-6.01 (m, 1H), 5.41-5.44 (m, 1H), 3.36-3.42 (m,
2H), 3.56 (s, 3H), 3.23 (s, 3H), 3.20 (s, 3H), 2.97 (dd, J=16.94,
1.98 Hz, 2H). MS (ESI+) m/z 435.1 (M+H).sup.+.
Example 278
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(1-hydroxyethyl)-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 278a
4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-di-
hydro-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde
[1210] To the solution of Example 276 (1.0 g, 2.2 mmol) in
dichloromethane (50 mL) at 0.degree. C. was added
Dess-MartinPeriodinane (1.84 g, 4.34 mmol) and the reaction mixture
was stirred at 0.degree. C. for 30 minutes. The reaction mixture
was then stirred at ambient temperature for three hours. A solution
of sodium bisulfite (0.9 g, 9 mmol) in saturated aqueous sodium
bicarbonate (5 mL) was added, and the reaction mixture was stirred
for 15 minutes and extracted with ethyl acetate. The organic layer
was dried (anhydrous sodium sulfate), filtered, and concentrated to
provide the title compound (0.80 g, 70% yield).
Example 278b
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(1-hydroxyethyl)-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1211] To a solution of Example 278a (0.20 g, 0.44 mmol) in
tetrahydrofuran (6 mL) at 0.degree. C. was added methylmagnesium
bromide (1.0 M in tetrahydrofuran, 0.873 mL, 0.873 mmol). The
reaction mixture was stirred at 0.degree. C. for one hour, and then
1M aqueous HCl (2 mL) was added. The reaction mixture was
concentrated and partitioned between saturated aqueous sodium
chloride (10 mL) and ethyl acetate (2.times.30 mL). The combined
organic phase was washed with saturated aqueous sodium chloride (30
mL), dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was purified by preparative thin layer
chromatography (silica gel, dichloromethane/methanol, 15/1) to
provide the title compound (51 mg, 24% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 11.83 (s, 1H), 7.96 (d, J=2.4 Hz,
1H), 7.86 (dd, J=2.4, 6.4 Hz, 1H), 7.55-7.50 (m, 1H), 7.42-7.36 (m,
2H), 7.20-7.15 (m, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.15 (d, J=2 Hz,
1H), 5.13 (d, J=5.2 Hz, 1H), 4.80-4.77 (m, 1H), 3.57 (s, 3H), 3.25
(s, 3H), 1.38 (d, J=6.4 Hz, 3H). MS (ESI+) m/z 475.1
(M+1).sup.+.
Example 279
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-[(dimethylamino)met-
hyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1212] To a solution of Example 278a (0.20 g, 0.44 mmol) and
dimethylamine hydrochloride (0.071 g, 0.873 mmol) in methanol (6
mL) was added zinc chloride (0.059 g, 0.436 mmol) at ambient
temperature. The reaction mixture was stirred at ambient
temperature for one hour, and then sodium cyanoborohydride (0.055
g, 0.873 mmol) was added and the reaction mixture was stirred at
ambient temperature for three days. The resulting solid was
filtered and washed with methanol (10 mL), and the eluant was
concentrated. The residue was purified by preparative thin layer
chromatography (silica gel, dichloromethane/methanol, 15/1) to
provide the title compound (75 mg, 34% yield). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. ppm 8.07 (d, J=2.4 Hz, 1H), 7.94 (dd,
J=2.4, 6.4 Hz, 1H), 7.38 (s, 1H), 7.25-7.06 (m, 2H), 7.04-6.98 (m,
2H), 6.31 (s, 1H), 3.71 (s, 3H), 3.67 (s, 2H), 3.19 (s, 3H), 2.28
(s, 6H). MS (ESI+) m/z 488.1 (M+H).sup.+.
Example 280
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(morpholin-
-4-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1213] Example 280 was prepared according to the procedure used for
the preparation of Example 279, substituting morpholine for
dimethylamine hydrochloride, to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.98 (s, 1H), 7.98 (d,
J=2.4 Hz, 1H), 7.87 (dd, J=2.4, 6.4 Hz, 1H), 7.56-7.50 (m, 1H),
7.44-7.38 (m, 2H), 7.19-7.16 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.15
(s, 1H), 3.58 (s, 3H), 3.55 (s, 2H), 3.49-3.47 (m, 4H), 3.26 (s,
3H), 2.31 (m, 4H). MS (ESI+) m/z 530.2 (M+H).sup.+.
Example 281
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(4-methyl-
piperazin-1-yl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1214] Example 281 was prepared according to the procedure used for
the preparation of Example 279, substituting 1-methylpiperazine for
dimethylamine hydrochloride, to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.94 (s, 1H), 7.98 (d,
J=2.4 Hz, 1H), 7.87 (dd, J=2.4, 6.4 Hz, 1H), 7.55-7.49 (m, 1H),
7.43-7.37 (m, 2H), 7.18-7.13 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.12
(s, 1H), 3.57 (s, 3H), 3.52 (s, 2H), 3.26 (s, 3H), 2.32-2.21 (m,
8H), 2.09 (s, 3H). MS (ESI+) m/z 543.2 (M+H).sup.+.
Example 282
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(phenylam-
ino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1215] Example 282 was prepared according to the procedure used for
the preparation of Example 279, substituting aniline for
dimethylamine hydrochloride, to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.95 (s, 1H), 7.93 (d,
J=2.4 Hz, 1H), 7.84 (dd, J=2.4, 6.8 Hz, 1H), 7.48 (m, 1H), 7.40 (s,
1H), 7.29-7.28 (m, 1H), 7.12 (m, 1H), 6.99-6.91 (m, 3H), 6.58 (d,
J=7.6 Hz, 2H), 6.49 (t, J=7.2 Hz, 1H), 6.19 (d, J=2.0 Hz, 1H), 5.94
(m, 1H), 4.31 (d, J=6.4 Hz, 2H), 3.56 (s, 3H), 3.23 (s, 3H). MS
(ESI+) m/z 536.2 (M+H).sup.+.
Example 283
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(1,3-thia-
zol-2-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1216] Example 283 was prepared according to the procedure used for
the preparation of Example 279, substituting thiazol-2-amine for
dimethylamine hydrochloride, to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.99 (s, 1H), 7.94 (d,
J=2.4 Hz, 1H), 7.86-7.83 (m, 2H), 7.51-7.45 (m, 1H), 7.42 (s, 1H),
7.30-7.26 (m, 1H), 7.14-7.13 (m, 1H), 6.99-6.92 (m, 2H), 6.62 (d,
J=3.6 Hz, 1H), 6.18 (s, 1H), 5.94 (m, 1H), 4.49 (d, J=5.6 Hz, 2H),
3.58 (s, 3H), 3.24 (s, 3H). MS (ESI+) m/z 543.2 (M+H).sup.+.
Example 284
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(tetrahyd-
rofuran-3-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1217] Example 284 was prepared according to the procedure used for
the preparation of Example 279, substituting
tetrahydrofuran-3-amine for dimethylamine hydrochloride, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
11.86 (s, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.87-7.85 (m, 2H), 7.54-7.39
(m, 3H), 7.18-7.16 (m, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.17 (s, 1H),
3.72-3.66 (m, 3H), 3.57-3.53 (m, 5H), 3.25 (s, 3H), 3.14-3.13 (m,
1H), 2.27-2.26 (m, 1H), 1.82-1.77 (m, 1H), 1.58-1.57 (m, 1H). MS
(ESI+) m/z 530.2 (M+H).sup.+.
Example 285
4-[2-(cyclopropylmethoxy)-5-(phenylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one
Example 285a
1-(cyclopropylmethoxy)-4-(phenylsulfonyl)benzene
[1218] Example 285a was prepared according to the procedure used
for the preparation of Example 158, substituting
1-fluoro-4-(phenylsulfonyl)benzene for Example 138a, to provide the
title compound.
Example 285b
2-bromo-1-(cyclopropylmethoxy)-4-(phenylsulfonyl)benzene
[1219] Example 285a (0.087 g, 0.3 mmol) in acetic acid (5 mL) was
cooled to 0.degree. C. To this solution was added
1-bromopyrrolidine-2,5-dione (2) (0.059 g, 0.330 mmol). The
reaction mixture was heated at 80.degree. C. for 16 hours. After
cooling, the reaction mixture was partitioned between water and
ethyl acetate. The aqueous layer was extracted with additional
ethyl acetate two more times. The combined organic layers were
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel to give the title
compound (0.032 g, 0.087 mmol, 29% yield).
Example 285c
4-[2-(cyclopropylmethoxy)-5-(phenylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrrolo[2,3-c]pyridin-7-one
[1220] Example 285c was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 285b for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 11.80 (s, 1H), 7.63-7.74 (m, 4H),
7.36-7.46 (m, 3H), 7.12 (s, 1H), 7.04-7.06 (m, 2H), 5.80-5.81 (m,
1H), 3.72 (d, J=6.71 Hz, 2H), 3.34 (s, 3H), 0.82-0.89 (m, 1H),
0.29-0.24 (m, 2H), 0.00-0.04 (m, 2H). MS (ESI+) m/z 434.9
(M-H).sup.+.
Example 286
4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 286a
4-(3-bromo-4-fluorophenylsulfonyl)morpholine
[1221] 3-Bromo-4-fluorobenzene-1-sulfonyl chloride (0.44 g, 1.609
mmol) in tetrahydrofuran (10 mL) was treated with morpholine (0.294
g, 3.38 mmol). The reaction mixture was stirred for 16 hours at
ambient temperature. The solvent was removed, and the residue was
loaded onto a silica gel column and eluted with 20% ethyl acetate
in hexanes to give the title compound (0.45 g, 1.388 mmol, 86%
yield).
Example 286b
4-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonyl)morpholine
[1222] Example 286b was prepared according to the procedure used
for the preparation of Example 158, substituting Example 286a for
Example 138a, to provide the title compound.
Example 286c
4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1223] Example 286c was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 286b for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.03 (s, 1H), 7.69 (dd, J=8.85, 2.44 Hz,
1H), 7.64 (d, J=2.44 Hz, 1H), 7.37 (s, 1H), 7.33 (d, J=8.85 Hz,
1H), 7.29 (t, J=2.75 Hz, 1H), 6.11-6.13 (m, 1H), 3.97 (d, J=6.71
Hz, 2H), 3.62-3.65 (m, 4H), 3.57 (s, 3H), 2.86-2.88 (m, 4H),
0.45-0.48 (m, 2H), 0.27-0.29 (m, 2H). MS (ESI+) m/z 444.1
(M+H).sup.+.
Example 287
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 287a
3-bromo-4-(2,4-difluorophenoxy)benzaldehyde
[1224] A mixture of 3-bromo-4-fluorobenzaldehyde (4.06 g, 20 mmol),
2,4-difluorophenol (2.60 g, 20 mmol) and cesium carbonate (7.17 g,
22 mmol) in dimethyl sulfoxide (20 mL) was heated at 100.degree. C.
for 1 hour. The reaction mixture was partitioned with ethyl acetate
and water. The organic layer was washed with saturated aqueous
sodium chloride twice, dried with anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 20% ethyl acetate in heptanes) to
provide the title compound (5.94 g, 95%).
Example 287b
(3-bromo-4-(2,4-difluorophenoxy)phenyl)methanol
[1225] To a solution of Example 287a (3.76 g, 12 mmol) in the
mixture of ethanol (10 mL) and tetrahydrofuran (10 mL) was added
sodium borohydride (0.136 g, 3.60 mmol). The reaction mixture was
stirred at ambient temperature for 1 hour. The solvent was
evaporated and the residue was partitioned with ethyl acetate and
water. The organic layer was washed with saturated aqueous sodium
chloride, dried with anhydrous sodium sulfate, filtered, and
concentrated to provide the title compound (3.72 g, 98%).
Example 287c
2-bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene
[1226] To a solution of Example 287b (3.70 g, 11.74 mmol) in
dichloromethane (20 mL) was added phosphorus tribromide (1.11 mL,
11.7 mmol) dropwise. The reaction mixture was stirred at ambient
temperature for 3 hours, and poured into ice water. The pH was
adjusted to basic by the careful addition of saturated aqueous
sodium bicarbonate and the mixture was extracted with
dichloromethane. The organic layer was washed with saturated
aqueous sodium chloride, dried with anhydrous sodium sulfate,
filtered, and concentrated to provide the title compound (4.15 g,
93%).
Example 287d
(3-bromo-4-(2,4-difluorophenoxy)benzyl)(methyl)sulfane
[1227] A mixture of Example 287c (1.512 g, 4.00 mmol) and sodium
thiomethoxide (0.280 g, 4.00 mmol) in dimethylformamide (8 mL) was
stirred at ambient temperature for 6 hours. The reaction mixture
was partitioned with ethyl acetate and water. The organic layer was
washed with saturated aqueous sodium chloride twice, dried with
anhydrous sodium sulfate, filtered, and concentrated to provide the
title compound (1.38 g, 100%).
Example 287e
2-bromo-1-(2,4-difluorophenoxy)-4-(methylsulfonylmethyl)benzene
[1228] To a solution of Example 287d (1.38 g, 4.00 mmol) in
methanol (15 mL) was added oxone (5.16 g, 8.40 mmol) in water (15
mL) at 0.degree. C. The reaction mixture was stirred at ambient
temperature for 1 hour. The reaction mixture was partitioned with
ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 20 to 40% ethyl acetate in
heptanes) to provide the title compound (1.49 g, 98%).
Example 287f
4-(2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl)-6-methyl-1-tosy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1229] Example 287e (94 mg, 0.25 mmol), Example 6a (107 mg, 0.250
mmol), potassium phosphate (186 mg, 0.875 mmol),
tris(dibenzylideneacetone)dipalladium (6.9 mg, 7.5 .mu.mol) and
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (6.6
mg, 0.023 mmol) were combined in a microwave tube and purged with
nitrogen for 15 minutes. A mixture of dioxane (2 mL) and water (0.5
mL) was purged with nitrogen for 15 minutes and transferred to the
microwave tube. The reaction mixture was heated at 60.degree. C.
for 1 hour. The reaction mixture was partitioned with ethyl acetate
and water. The organic layer was washed with saturated aqueous
sodium chloride, dried with anhydrous sodium sulfate, treated with
3-mercaptopropyl functionalized silica gel, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 1 to 2% methanol in dichloromethane) to provide the
title compound (62 mg, 41%).
Example 287g
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1230] Example 287f (59.9 mg, 0.100 mmol), potassium hydroxide (84
mg, 1.5 mmol) and cetyltrimethylammonium bromide (1.8 mg, 5.0
.mu.mol) were combined in a mixture of tetrahydrofuran (4 mL) and
water (2 mL). The reaction mixture was heated at 100.degree. C. for
44 hours and then cooled to ambient temperature. To this mixture
was added water, and the pH was adjusted to pH 7 by the addition of
1M HCl. The mixture was extracted with ethyl acetate and the
organic layer was washed with saturated aqueous sodium chloride
twice, dried with anhydrous sodium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 2 to 4% methanol in dichloromethane) to provide the
title compound (31 mg, 70%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.04 (s, 1H) 7.57 (d, J=2.37 Hz, 1H) 7.26-7.48 (m, 4H)
7.16-7.26 (m, 1H) 7.00-7.11 (m, 1H) 6.88 (d, J=8.48 Hz, 1H)
6.23-6.33 (m, 1H) 4.51 (s, 2H) 3.55 (s, 3H) 2.94 (s, 3H). MS (ESI+)
m/z 445 (M+H).sup.+.
Example 288
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridin-3-yl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 288a
2-fluoro-5-(methylthio)pyridine
[1231] A mixture of 5-bromo-2-fluoropyridine (2.05 g, 11.7 mmol)
and N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethylethane-1,2-diamine
(2.27 mL, 15.1 mmol) was purged with nitrogen for 45 minutes.
Toluene (116 mL) was added and the reaction mixture was cooled to
-78.degree. C. N-butyllithium (2.5 M in hexanes, 5.59 mL, 14.0
mmol) was added dropwise over 6 minutes. The reaction mixture was
stirred at -78.degree. C. for 1 hour. Dimethyl disulfide (1.26 mL,
14.0 mmol) was added. The reaction mixture was stirred at
-78.degree. C. for 1 hour. The reaction mixture was warmed to
0.degree. C., then immediately quenched with saturated aqueous
ammonium chloride. The layers were separated, and the organic layer
was washed with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (10% ethyl
acetate/heptane) to provide the title compound (1.00 g, 60%).
Example 288b
2-fluoro-5-(methylsulfonyl)pyridine
[1232] To a solution of Example 288a (2.17 g, 15.2 mmol) in
dichloromethane (50.5 mL) was added 3-chlorobenzoperoxoic acid
(7.15 g, 31.1 mmol) portionwise over 10 minutes. The reaction
mixture was stirred at ambient temperature for 4 hours. Additional
3-chlorobenzoperoxoic acid (2.62 g, 15.16 mmol) was added and the
reaction mixture was stirred at ambient temperature for 1 hour. The
reaction mixture was quenched with saturated aqueous sodium
carbonate, and the layers were separated. The aqueous layer was
extracted with dichloromethane. The combined organic layers were
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 0-10%
methanol/dichloromethane) to provide the title compound (1.81 g,
68%).
Example 288c
5-(methylsulfonyl)pyridin-2(1H)-one
[1233] Example 288b (0.679 g, 3.88 mmol) was treated with acetic
acid (35.2 mL) and water (3.52 mL) at 110.degree. C. for 16 hours.
The reaction mixture was cooled to ambient temperature and the
solvent was removed to provide the title compound (0.700 g,
100%).
Example 288d
[1234] 3-bromo-5-(methylsulfonyl)pyridin-2(1H)-one To a solution of
Example 288c (0.671 g, 3.87 mmol) and sodium acetate (0.318 g, 3.87
mmol) in acetic acid (8.50 mL) was added bromine (0.201 mL, 3.91
mmol) dropwise as a solution in acetic acid (1.7 mL). The reaction
mixture was stirred at 40.degree. C. for 3 hours. Bromine (0.05 mL)
was added, and the reaction mixture was stirred at 40.degree. C.
for 2 hours. The reaction mixture was cooled to ambient temperature
and quenched with 100 mL of 10% aqueous sodium thiosulfate. The
resulting suspension was filtered, and the solid collected and
dried for 16 hours to provide the title compound (0.64 g, 66%).
Example 288e
3-bromo-2-chloro-5-(methylsulfonyl)pyridine
[1235] Example 288d (0.6395 g, 2.54 mmol) was treated with
phosphorus oxychloride (12.7 mL) at 110.degree. C. for 4 hours. The
reaction mixture was cooled to ambient temperature and poured onto
ice. The resulting suspension was filtered and rinsed with water,
and the off white solid was collected and dried in a 60.degree. C.
vacuum oven for 16 hours to provide the title compound (0.244 g,
35%).
Example 288f
3-bromo-2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridine
[1236] Example 288f was prepared according to the procedure used
for the preparation of Example 2b, substituting 2,4-difluorophenol
for phenol, and Example 288e for Example 2a, respectively, to
provide the title compound.
Example 288g
4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridin-3-yl)-6-methyl-1-tosy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1237] Example 288g was prepared according to the procedure used
for the preparation of Example 4a, substituting Example 288f for
Example 7c to provide the title compound.
Example 288h
4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)pyridin-3-yl)-6-methyl-1H-pyr-
rolo[2,3-c]pyridin-7(6H)-one
[1238] Example 288h was prepared according to the procedure used
for the preparation of Example 4b, substituting Example 288g for
Example 4a to provide the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. ppm 12.16 (s, 1H) 8.59 (d, J=2.37 Hz,
1H) 8.37 (d, J=2.37 Hz, 1H) 7.58 (s, 1H) 7.48 (m, 2H) 7.34 (t,
J=2.71 Hz, 1H) 7.16 (m, 1H) 6.36 (dd, J=2.71, 2.03 Hz, 1H) 3.61 (s,
3H) 3.35 (s, 3H). MS (ESI+) m/z 432.4 (M+H).sup.+.
Example 289
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(pyridin--
3-yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 289a
2-(chloromethyl)-4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-me-
thyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1239] A mixture of Example 276 (0.50 g, 1.09 mmol) and thionyl
chloride (5.0 mL, 69 mmol) was heated under reflux for 2 hours. The
solvent was removed under reduced pressure and the residue was
dried under vacuo for 1 hour to provide the title compound.
Example 289b
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[(pyridin--
3-yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1240] To a solution of pyridin-3-ol (0.039 g, 0.407 mmol) in
tetrahydrofuran (5 mL) was added sodium hydride (16 mg, 0.407 mmol)
at 0.degree. C., and the mixture was stirred for 30 minutes. To
this solution was added Example 289a (0.25 g, 0.204 mmol) and the
reaction mixture was heated under reflux for 16 hours. The reaction
mixture was poured into a mixture of ethyl acetate (30 mL) and
saturated aqueous sodium chloride (20 mL). The aqueous layer was
extracted with ethyl acetate (20 mL). The combined organic layers
were dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by reverse phase HPLC (C18,
water (10 mM NH.sub.4HCO.sub.3):acetonitrile, 25-50% gradient) to
provide the title compound (18 mg, 16% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.52 (s, 1H), 7.95 (d, J=2.4 Hz,
1H), 7.87 (dd, J=2.4, 6.4 Hz, 1H), 7.56-7.38 (m, 5H), 7.22-7.18 (m,
2H), 6.97 (d, J=8.4 Hz, 1H), 6.84-6.82 (m, 1H), 6.48 (s, 1H), 5.38
(s, 2H), 3.58 (s, 3H), 3.25 (s, 3H). MS (ESI+) m/z 538.1
(M+1).sup.+.
Example 290
4-[5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 290a
(3-bromo-4-fluorophenyl)(cyclopropyl)sulfane
[1241] Example 290a was prepared according to the procedure used
for the preparation of Example 168a, substituting bromocyclopropane
for iodoethane, to provide the title compound
Example 290b
2-bromo-4-(cyclopropylsulfonyl)-1-fluorobenzene
[1242] Example 290b was prepared according to the procedure used
for the preparation of Example 168b, substituting Example 290a for
Example 168a, to provide the title compound.
Example 290c
2-bromo-4-(cyclopropylsulfonyl)-1-(2,4-difluorophenoxy)benzene
[1243] Example 290c was prepared according to the procedure used
for the preparation of Example 138b, substituting Example 290b for
Example 138a, to provide the title compound.
Example 290d
4-[5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1244] Example 290d was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 290c for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.11 (s, 1H), 7.94 (d, J=2.44 Hz, 1H),
7.83 (dd, J=8.54, 2.44 Hz, 1H), 7.42-7.55 (m, 3H), 7.32 (t, J=2.75
Hz, 1H), 7.15-7.20 (m, 1H), 6.97 (d, J=8.54 Hz, 1H), 6.28-6.29 (m,
1H), 3.59 (s, 3H), 2.90-2.96 (m, 1H), 1.12-1.15 (m, 2H), 1.03-1.09
(m, 2H). MS (ESI+) m/z 457.1 (M+H).sup.+.
Example 291
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(prop-1-en-
-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1245] To a solution of Example 252f (0.10 g, 0.20 mmol) in
tetrahydrofuran (6 mL) stirring at 0.degree. C. was added
methylmagnesium bromide (0.498 mL, 0.498 mmol). The reaction
mixture was stirred at 0.degree. C. for 1 hour, and then aqueous
HCl (1 M, 2 mL) was added. The reaction mixture was concentrated
and partitioned between saturated aqueous sodium chloride (10 mL)
and ethyl acetate. The organic phase was washed with saturated
aqueous sodium chloride (30 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by
reverse phase-HPLC (C18 40-90% gradient acetonitrile:water (0.1%
TFA)) to provide the title compound (25 mg, 25% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 12.05 (s, 1H), 7.98 (d, J=2.4
Hz, 1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.61-7.36 (m, 3H), 7.18 (t,
J=8.6 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.34 (d, J=2.2 Hz, 1H), 5.85
(s, 1H), 5.07 (s, 1H), 3.60 (s, 3H), 3.26 (s, 3H), 2.02 (s, 3H). MS
(ESI+) m/z 471.1 (M+1).sup.+.
Example 292
4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(phenoxyme-
thyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1246] Example 292 was prepared according to the procedure used for
the preparation of Example 289b, substituting phenol for
pyridin-3-ol, to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.32 (s, 1H), 7.96 (d, J=2.4 Hz, 1H),
7.86 (dd, J=2.4, 6.4 Hz, 1H), 7.55-7.50 (m, 1H), 7.49 (s, 1H),
7.45-7.36 (m, 1H), 7.26-7.16 (m, 3H), 6.98-6.89 (m, 4H), 6.37 (s,
1H), 5.11 (s, 2H), 3.59 (s, 3H), 3.23 (s, 3H). MS (ESI+) m/z 537.2
(M+1).sup.+
Example 293
4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 293a
4-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)morpholine
[1247] Example 293a was prepared according to the procedure used
for the preparation of Example 138b, substituting Example 286a for
Example 138a, to provide the title compound.
Example 293b
4-[2-(2,4-difluorophenoxy)-5-(morpholin-4-ylsulfonyl)phenyl]-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1248] Example 293b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 293a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.10 (s, 1H), 7.76 (d, J=2.44 Hz, 1H),
7.83 (dd, J=8.7, 2.44 Hz, 1H), 7.42-7.54 (m, 3H), 7.30 (t, J=2.75
Hz, 1H), 7.14-7.16 (m, 1H), 7.01 (d, J=8.54 Hz, 1H), 6.25-6.27 (m,
1H), 3.64-3.66 (m, 4H), 3.59 (s, 3H), 2.88-2.92 (m, 4H). MS (ESI+)
m/z 502.2 (M+H).sup.+.
Example 294
4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)pyridin-3-yl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 294a
3-bromo-2-chloro-5-(ethylsulfonyl)pyridine
[1249] Sodium sulfite (1.755 g, 13.92 mmol) and sodium bicarbonate
(1.231 g, 14.65 mmol) were dissolved in water (37 mL) to give a
colorless solution. The mixture was heated at 75.degree. C.
3-Bromo-2-chloropyridine-5-sulfonyl chloride (2.132 g, 7.33 mmol)
was added portionwise over 1 hour. The reaction mixture was stirred
at 75.degree. C. for 1 hour. The mixture was concentrated and
N,N-dimethylformamide (13.88 mL) was added. Sodium bicarbonate
(1.231 g, 14.65 mmol) and iodoethane (0.589 mL, 7.33 mmol) were
added. The resulting mixture was heated to 75.degree. C. for 2
hours and then cooled to ambient temperature. The mixture was
partitioned between ethyl acetate and water. The organic layer was
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 0-100% ethyl
acetate/heptane) to provide the title compound.
Example 294b
4-(2-chloro-5-(ethylsulfonyl)pyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-
-c]pyridin-7(6H)-one
[1250] Example 294b was prepared according to the procedure used
for the preparation of Example 4a, substituting Example 294a for
Example 7c to provide the title compound.
Example 294c
4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)pyridin-3-yl)-6-methyl-1H-pyrr-
olo[2,3-c]pyridin-7(6H)-one
[1251] Example 294c was prepared according to the procedure used
for the preparation of Example 2b, substituting 2,4-difluorophenol
for phenol, and Example 294b for Example 2a, respectively, to
provide the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 12.17 (bs, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4
Hz, 1H), 7.58 (s, 1H), 7.54-7.43 (m, 2H), 7.34 (t, J=2.7 Hz, 1H),
7.21-7.12 (m, 1H), 6.35 (t, J=2.1 Hz, 1H), 3.61 (s, 3H), 3.44 (q,
J=7.3 Hz, 2H), 1.18 (t, J=7.3 Hz, 1H). MS (ESI+) m/z 446.2
(M+H).sup.+.
Example 295
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-2-(morpholin-4-yl)ethanesulfonamide
Example 295a
4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[1252] Example 295a was prepared according to the procedure used
for the preparation of Example 138a, substituting Example 1e for
2-bromo-1-fluoro-4-(methylsulfonyl)benzene, and Example 148c for
Example 6a, respectively, to provide the title compound.
Example 295b
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-2-(morpholin-4-yl)ethanesulfonamide
[1253] A mixture of Example 295a, 2-chloroethanesulfonyl chloride
(0.098 g, 0.600 mmol), and triethylamine (0.081 g, 0.800 mmol) in
dichloromethane (3 mL) was stirred at ambient temperature for 2
hours. The solvent was removed, and the residue was redissolved in
MeOH (5 mL). To this solution was added morpholine (0.697 g, 8.00
mmol). The reaction mixture was heated at 50.degree. C. for 2
hours. To this solution was added 2.0 N sodium hydroxide (2.00 mL,
4.00 mmol). The reaction mixture was heated at 85.degree. C. for 2
hours. After cooling, the reaction mixture was partitioned between
ethyl acetate and 1.0 N HCl. The aqueous layer was extracted with
additional ethyl acetate several times. The combined organic layers
were washed with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by preparative HPLC (10-80% acetonitrile in
0.1% TFA water) to give the TFA salt of the title compound (0.077
g, 0.117 mmol, 58.5% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.08 (s, 1H), 10.18 (s, 1H), 7.37-7.43 (m, 2H),
7.30-7.31 (m, 2H), 7.22 (dd, J=8.85, 2.75 Hz, 1H), 7.08-7.14 (m,
1H), 7.00-7.04 (m, 1H), 6.91 (d, J=8.54 Hz, 1H), 6.28-6.29 (m, 1H),
3.51-3.62 (m, 11H), 3.24 (br s, 4H). MS (ESI+) m/z 545.1
(M+H).sup.+.
Example 296
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-N-[2-(dimethylamino)ethyl]ethanesulfonamide
[1254] A mixture of Example 36e (0.15 g, 0.326 mmol),
2-(dimethylamino)ethanol (0.029 g, 0.326 mmol), and
triphenylphosphine (0.128 g, 0.490 mmol) in tetrahydrofuran (3 mL)
was stirred at ambient temperature for 10 minutes. To this solution
was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (0.113 g,
0.490 mmol). The solution was stirred for three hours at ambient
temperature. The solvent was removed, and the residue was purified
by preparative HPLC (10-80% acetonitrile in 0.1% TFA water) to give
the title compound (0.055 g, 0.104 mmol, 31.8% yield). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.06 (s, 1H), 7.51 (d, J=2.44
Hz, 1H), 7.41-7.47 (m, 1H), 7.35-7.37 (m, 2H), 7.23-7.31 (m, 2H),
7.06-7.11 (m, 1H), 6.85 (d, J=8.85 Hz, 1H), 3.57 (t, J=6.71 Hz,
2H), 3.56 (s, 3H), 3.17 (q, J=7.32 Hz, 1H), 2.25 (m, 2H), 2.13 (s,
6H), 1.25 (q, J=7.48 Hz, 3H). MS (ESI+) m/z 531.2 (M+H).sup.+.
Example 297
4-{2-(2,4-difluorophenoxy)-5-[(ethylsulfonyl)methyl]phenyl}-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 297a
(3-bromo-4-(2,4-difluorophenoxy)benzyl)(ethyl)sulfane
[1255] Example 297a was prepared according to the procedure used
for the preparation of Example 287d, substituting sodium
ethanethiolate for sodium thiomethoxide, to provide the title
compound (1.04 g, 99%).
Example 297b
2-bromo-1-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene
[1256] Example 297b was prepared according to the procedure used
for the preparation of Example 287e, substituting Example 297a for
Example 287d, to provide the title compound (1.01 g, 89%).
Example 297c
4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl)-6-methyl-1-tosyl-
-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1257] Example 297c was prepared according to the procedure used
for the preparation of Example 287f, substituting Example 297b for
Example 287e. Purification by flash chromatography (silica gel, 0
to 2% methanol in dichloromethane) afforded the title compound (63
mg, 51%).
Example 297d
4-{2-(2,4-difluorophenoxy)-5-[(ethylsulfonyl)methyl]phenyl}-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1258] Example 297d was prepared according to the procedure used
for the preparation of Example 287g, substituting Example 297c for
Example 287f, to provide the title compound (34 mg, 75%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .quadrature. ppm 12.04 (s, 1H) 7.56 (d,
J=2.37 Hz, 1H) 7.15-7.48 (m, 5H) 6.99-7.11 (m, 1H) 6.87 (d, J=8.14
Hz, 1H) 6.25-6.35 (m, 1H) 4.49 (s, 2H) 3.55 (s, 3H) 3.07 (q, J=7.23
Hz, 2H) 1.23 (t, J=7.46 Hz, 3H). MS (ESI+) m/z 459 (M+H).sup.+.
Example 298
4-{2-(2,4-difluorophenoxy)-5-[2-(ethylsulfonyl)propan-2-yl]phenyl}-6-methy-
l-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 298a
2-bromo-1-(2,4-difluorophenoxy)-4-(2-(ethylsulfonyl)propan-2-yl)benzene
[1259] To a solution of Example 297b (469 mg, 1.20 mmol) in
tetrahydrofuran (10 mL) was added 60% sodium hydride in mineral oil
(240 mg, 6.00 mmol) at 0.degree. C. The reaction mixture was
stirred at ambient temperature under nitrogen for 10 minutes.
Iodomethane (0.750 mL, 12.0 mmol) was added. The reaction mixture
was stirred at ambient temperature for 20 hours. The reaction
mixture was partitioned with ethyl acetate and water. The organic
layer was washed with saturated aqueous sodium chloride, dried with
anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by flash chromatography (silica gel, 20 to 40% ethyl
acetate in heptanes) to provide the title compound (442 mg,
88%).
Example 298b
4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methy-
l-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1260] Example 298b was prepared according to the procedure used
for the preparation of Example 287f, substituting Example 298a for
Example 287e. Purification by flash chromatography (silica gel, 0
to 2% methanol in dichloromethane) afforded the title compound (80
mg, 62%).
Example 298c
4-{2-(2,4-difluorophenoxy)-5-[2-(ethylsulfonyl)propan-2-yl]phenyl}-6-methy-
l-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1261] Example 298c was prepared according to the procedure used
for the preparation of Example 287g, substituting Example 298b for
Example 287f and the reaction time was 16 hours instead of 44
hours, to provide the title compound (52 mg, 88%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .quadrature..quadrature. ppm 12.06 (s, 1H) 7.71
(d, J=2.44 Hz, 1H) 7.55 (dd, J=8.70, 2.59 Hz, 1H) 7.38-7.48 (m, 1H)
7.33 (s, 1H) 7.19-7.31 (m, 2H) 7.02-7.12 (m, 1H) 6.85 (d, J=8.24
Hz, 1H) 6.29 (d, J=2.14 Hz, 1H) 3.56 (s, 3H) 2.90 (q, J=7.43 Hz,
2H) 1.77 (s, 6H) 1.06 (t, J=7.48 Hz, 3H). MS (ESI+) m/z 487
(M+H).sup.+.
Example 299
4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 299a
1-((3-bromo-4-fluorophenyl)sulfonyl)pyrrolidine
[1262] To a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride
(1.0 g, 3.66 mmol) in 20 mL dichloromethane at 0.degree. C. was
added pyrrolidine (0.635 mL, 7.68 mmol). The mixture was stirred at
0.degree. C. for 30 minutes and then at room temperature overnight.
The reaction mixture was diluted with dichloromethane, washed with
1% HCl solution and water, dried over anhydrous magnesium sulfate,
filtered, and concentrated to give the title compound (0.86 g, 76%
yield)
Example 299b
1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)pyrrolidine
[1263] A mixture of Example 299a (250 mg, 0.811 mmol),
2,4-difluorophenol (106 mg, 0.811 mmol) and cesium carbonate (317
mg, 0.973 mmol) in 5 mL dimethylsulfoxide was heated at 110.degree.
C. for 2 hours. Water was added and the mixture was extracted with
ethyl acetate. The organic phase was washed with water (2.times.),
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, and filtered. The filtrate was concentrated to give the
title compound (278 mg, 82% yield), which was used without further
purification.
Example 299c
4-[2-(2,4-difluorophenoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1264] A mixture of Example 299b (100 mg, 0.239 mmol), Example 6a
(102 mg, 0.239 mmol), tetrakis(triphenylphosphine)palladium(0)
(13.81 mg, 0.012 mmol) and cesium fluoride (109 mg, 0.717 mmol) in
2 mL dimethxoyethane and 1 mL methanol was heated at 120.degree. C.
in a microwave oven (Biotage Initiator) for 40 minutes. The mixture
was then treated with 4 N NaOH (1 mL) and stirred at ambient
temperature for 2 hours. Water was added and the mixture was
extracted with ethyl acetate (2.times.). The organic phase was
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, and filtered. The filtrate was concentrated and
the residue was purified by flash chromatography (silica gel,
60-100% ethyl acetate/heptanes gradient) to give the title compound
(75 mg, 64.6% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 12.06 (s, 1H), 12.06 (s, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.81 (d,
J=2.4 Hz, 1H), 7.77-7.72 (m, 1H), 7.79-7.72 (m, 1H), 7.47 (ddd,
J=11.5, 8.8, 3.0 Hz, 1H), 7.47 (ddd, J=17.8, 10.4, 6.0 Hz, 1H),
7.42-7.39 (m, 1H), 7.43-7.35 (m, 2H), 7.30 (t, J=2.8 Hz, 1H), 7.30
(t, J=2.8 Hz, 1H), 7.28-7.09 (m, 1H), 7.17-7.09 (m, 1H), 6.98-6.93
(m, 1H), 6.99-6.93 (m, 1H), 6.24 (ddd, J=23.2, 2.6, 2.2 Hz, 1H),
6.22 (dd, J=2.6, 2.2 Hz, 1H), 3.57 (s, 3H), 3.57 (s, 3H), 3.22-3.09
(m, 4H), 3.19-3.11 (m, 4H), 1.72-1.64 (m, 4H), 1.75-1.61 (m, 4H),
1.17 (dd, J=18.8, 11.7 Hz, 1H), 0.87-0.74 (m, 1H). MS (ESI+) m/z
464.2 (M+H).sup.+.
Example 300
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-2-(dimethylamino)ethanesulfonamide
[1265] Example 300 was prepared according to the procedure used for
the preparation of Example 295b, substituting N, N-dimethylamine
for morpholine, to provide the TFA salt of the title compound.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.07 (s, 1H),
10.18 (s, 1H), 9.86 (br s, 1H), 7.37-7.42 (m, 2H), 7.29-7.31 (m,
2H), 7.22 (dd, J=8.54, 2.75 Hz, 1H), 7.09-7.14 (m, 1H), 7.01-7.07
(m, 1H), 6.91 (d, J=8.85 Hz, 1H), 6.28 (t, J=2.29 Hz, 1H),
3.62-3.65 (m, 2H), 3.54 (s, 3H), 3.48-3.51 (m, 2H), 2.83 (s, 6H).
MS (ESI+) m/z 503.1 (M+H).sup.+.
Example 301
ethyl
4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenoxy]piperidine-1-carboxylate
Example 301a
ethyl
4-(2-bromo-4-(ethylsulfonyl)phenoxy)piperidine-1-carboxylate
[1266] Example 301a was prepared according to the procedure used
for the preparation of Example 158, substituting Example 138a for
Example 168b, and ethyl 4-hydroxypiperidine-1-carboxylate for
cyclopropylmethanol, respectively, to provide the title
compound.
Example 301b
ethyl
4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenoxy]piperidine-1-carboxylate
[1267] Example 301b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 301a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.04 (s, 1H), 7.80-7.83 (m, 2H), 7.44
(d, J=8.54 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J=2.75 Hz, 1H),
6.12-6.13 (m, 1H), 4.76-4.81 (m, 1H), 3.99 (q, J=7.02 Hz, 2H), 3.57
(s, 3H), 3.24-3.39 (m, 6H), 1.86-1.90 (m, 2H), 1.49-1.53 (m, 2H),
1.12-1.16 (M, 6H). MS (ESI+) m/z 488.1 (M+H).sup.+.
Example 302
4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 302a
1-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfonyl)pyrrolidine
[1268] To a solution of cyclopropylmethanol (115 .mu.L, 1.460 mmol)
in dioxane (8 mL) at room temperature was added sodium hydride (78
mg, 1.947 mmol). After stirring at ambient temperature for 10
minutes, Example 299a (300 mg, 0.973 mmol) was added as a solid.
The mixture was then heated at 65.degree. C. overnight. Water was
added. The mixture was extracted with ethyl acetate, washed with
water (2.times.), saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 0-50%
ethyl acetate/heptanes gradient) to give the title compound (156
mg, 44.5% yield)
Example 302b
4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylsulfonyl)phenyl]-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1269] A mixture of Example 302a (84 mg, 0.233 mmol), Example 6a
(100 mg, 0.233 mmol), tetrakis(triphenylphosphine)palladium(0)
(13.49 mg, 0.012 mmol) and cesium fluoride (106 mg, 0.700 mmol) in
2 mL dimethoxyethane and 1 mL methanol was purged with nitrogen gas
and heated at 130.degree. C. under microwave conditions (Biotage
Initiator) for 40 minutes. The mixture was then treated with 4 N
NaOH (1 mL) and stirred at room temperature for 2 hours. Water was
added and the mixture was extracted with ethyl acetate, washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was absorbed on
silica gel and purified by flash chromatography (silica gel, 0-10%
methanol/dichloromethane gradient) to give the title compound (64
mg, 64.1% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
12.10-11.92 (m, 1H), 7.77-7.70 (m, 2H), 7.37 (s, 1H), 7.30 (dd,
J=6.9, 4.1 Hz, 2H), 6.17-6.03 (m, 1H), 3.97 (d, J=6.8 Hz, 2H), 3.58
(s, 3H), 3.14 (t, J=6.7 Hz, 4H), 1.71-1.64 (m, 4H), 1.15-1.08 (m,
1H), 0.50-0.44 (m, 2H), 0.30-0.24 (m, 2H). MS (ESI+) m/z 482.2
(M+H).sup.+.
Example 303
4-{2-[(1-acetylpiperidin-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 303a
1-(4-(2-bromo-4-(ethylsulfonyl)phenoxy)piperidin-1-yl)ethanone
[1270] Example 303a was prepared according to the procedure used
for the preparation of Example 158, substituting Example 168b for
Example 138a, and substituting 1-(4-hydroxypiperidin-1-yl)ethanone
for cyclopropylmethanol, respectively, to provide the title
compound.
Example 303b
4-{2-[(1-acetylpiperidin-4-yl)oxy]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-d-
ihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1271] Example 303b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 303a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.04 (s, 1H), 7.80-7.84 (m, 2H), 7.45
(d, J=8.54 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J=2.75 Hz, 1H),
6.12-6.13 (m, 1H), 4.81-4.84 (m, 1H), 3.57 (s, 3H), 3.24-3.39 (m,
6H), 2.09 (s, 3H), 1.49-1.53 (m, 2H), 1.12-1.16 (m, 3H). MS (ESI+)
m/z 458.2 (M+H).sup.+.
Example 304
4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridi-
n-4-yl)phenoxy]benzonitrile
[1272] Example 304 was prepared according to the procedure used for
the preparation of Example 138b, substituting Example 168c for
Example 138a, and 4-cyanophenol for 2,4-difluorophenol,
respectively, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.09 (s, 1H), 8.00 (d, J=2.44 Hz, 1H),
7.92 (dd, J=8.54, 2.54 Hz, 1H), 7.79-7.82 (m, 2H), 7.39 (s, 1H),
7.35 (d, J=8.54 Hz, 1H), 7.29 (t, J=2.75 Hz, 1H), 7.14-7.17 (m,
2H), 6.22-6.23 (m, 1H), 3.54 (s, 3H), 3.38 (q, J=7.32 Hz, 2H), 1.17
(t, J=7.32 Hz, 3H). MS (ESI+) m/z 434.2 (M+H).sup.+.
Example 305
4-[2-(cyclopropylmethoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6-m-
ethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 305a
1-(3-bromo-4-fluorophenylsulfonyl)indoline
[1273] A solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride
(Aldrich) (2.53 g, 8.33 mmol), indoline (0.99 g, 8.33 mmol),
N,N-diisopropylethylamine (1.60 mL, 9.16 mmol) and tetrahydrofuran
(20 mL) was stirred at ambient temperature for 16 hours. The
reaction mixture was partitioned between water and ethyl acetate.
The aqueous layer was extracted twice with additional ethyl
acetate. The combined organic layers were washed with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered, and concentrated to afford a brown oil which solidified
upon standing. The crude product was recrystallized from
ether/heptane to afford the title compound (1.99 g, 5.59 mmol, 67%
yield).
Example 305b
1-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonyl)indoline
[1274] Example 305b was prepared according to the procedure used
for the preparation of Example 29a, substituting
cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and substituting
Example 305a for Example 2a to afford the title compound.
Example 305c
4-(2-(cyclopropylmethoxy)-5-(indolin-1-ylsulfonyl)phenyl)-6-methyl-1-tosyl-
-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1275] Example 305c was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 305b for
Example 6b to afford the title compound.
Example 305d
4-(2-(cyclopropylmethoxy)-5-(indolin-1-ylsulfonyl)phenyl)-6-methyl-1H-pyrr-
olo[2,3-c]pyridin-7(6H)-one
[1276] Example 305d was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 305c for
Example 6c to afford the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. 0.24 (tt, J=13.4, 6.6 Hz, 2H) 0.35-0.50
(m, 2H) 1.01-1.18 (m, 1H) 2.90 (t, J=8.3 Hz, 2H) 3.54 (s, 3H) 3.90
(t, J=8.4 Hz, 2H) 3.92 (d, J=6.8 Hz, 2H) 5.80-5.86 (m, 1H) 7.04
(td, J=7.4, 1.0 Hz, 1H) 7.14-7.36 (m, 5H) 7.50 (d, J=8.0 Hz, 1H)
7.66 (d, J=2.4 Hz, 1H) 7.77 (dd, J=8.7, 2.5 Hz, 1H) 12.02 (bs, 1H).
MS (ESI+) m/z 476 [M+H].sup.+.
Example 306
4-{2-(2,4-difluorophenoxy)-5-[(phenylsulfonyl)methyl]phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 306a
(3-bromo-4-(2,4-difluorophenoxy)benzyl)(phenyl)sulfane
[1277] Example 306a was prepared according to the procedure used
for the preparation of Example 287d, substituting sodium
thiophenoxide for sodium thiomethoxide, to provide the title
compound (815 mg, 100%).
Example 306b
2-bromo-1-(2,4-difluorophenoxy)-4-(phenylsulfonylmethyl)benzene
[1278] Example 306b was prepared according to the procedure used
for the preparation of Example 287e, substituting Example 306a for
Example 287d, to provide the title compound (867 mg, 99%).
Example 306c
4-(2-(2,4-difluorophenoxy)-5-(phenylsulfonylmethyl)phenyl)-6-methyl-1-tosy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1279] Example 306c was prepared according to the procedure used
for the preparation of Example 287f, substituting Example 306b for
Example 287e. Purification by flash chromatography (silica gel, 0
to 2% methanol in dichloromethane) afforded the title compound (51
mg, 52%).
Example 306d
4-{2-(2,4-difluorophenoxy)-5-[(phenylsulfonyl)methyl]phenyl}-6-methyl-1,6--
dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1280] Example 306d was prepared according to the procedure used
for the preparation of Example 287g, substituting Example 306c for
Example 287f, to provide the title compound (30 mg, 80%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .quadrature..quadrature. ppm 12.02 (s,
1H) 7.69-7.81 (m, 3H) 7.55-7.67 (m, 2H) 7.34-7.46 (m, 1H) 7.20-7.29
(m, 2H) 6.98-7.18 (m, 4H) 6.80 (d, J=8.48 Hz, 1H) 6.09 (dd, J=2.37,
1.70 Hz, 1H) 4.71 (s, 2H) 3.52 (s, 3H). MS (ESI+) m/z 507
(M+H).sup.+.
Example 307
4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(pyrrolidin-1-ylsulfonyl)phenyl}-
-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 307a
1-((3-bromo-4-((2,2-difluorocyclopropyl)methoxy)phenyl)sulfonyl)pyrrolidin-
e
[1281] Example 307a was prepared according to the procedure used
for the preparation of Example 302a, substituting
(2,2-difluorocyclopropyl)methanol for cyclopropylmethanol, to
provide the title compound.
Example 307b
4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(pyrrolidin-1-ylsulfonyl)phenyl}-
-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1282] Example 307b was prepared according to the procedure used
for the preparation of Example 302b, substituting 307a for 302a, to
provide the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.05 (s, 1H), 12.05 (s, 1H), 7.76 (tt, J=6.9, 3.5 Hz,
2H), 7.81-7.71 (m, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.38-7.27 (m, 3H),
7.30 (t, J=2.6 Hz, 1H), 6.12 (dd, J=2.5, 1.6 Hz, 1H), 6.12 (dd,
J=2.5, 1.6 Hz, 1H), 4.21 (dt, J=18.8, 9.6 Hz, 2H), 3.57 (s, 3H),
3.57 (s, 3H), 3.15 (t, J=6.7 Hz, 4H), 3.15 (t, J=6.7 Hz, 4H),
2.21-2.04 (m, 1H), 2.19-1.98 (m, 1H), 1.74-1.57 (m, 5H), 1.77-1.57
(m, 5H), 1.52-1.36 (m, 1H), 1.53-1.38 (m, 1H). MS (ESI+) m/z 464.2
(M+H).sup.+.
Example 308
4-{2-(cyclopropylmethoxy)-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]phenyl}-6-
-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 308a
1-((3-bromo-4-fluorophenyl)sulfonyl)-3,3-difluoroazetidine
[1283] To a suspension of 3,3-difluoroazetidine hydrochloric acid
(0.947 g, 7.31 mmol) in 20 mL dichloromethane at 0.degree. C. was
added N-ethyl-N-isopropylpropan-2-amine (2.80 mL, 16.1 mmol)
followed by the addition of a solution of
3-bromo-4-fluorobenzene-1-sulfonyl chloride (2.0 g, 7.3 mmol) in 4
mL dichloromethane. The mixture was stirred at room temperature
overnight and then heated at 55.degree. C. for 5 hours, diluted
with dichloromethane, washed with water, dried over anhydrous
magnesium sulfate, and filtered. The filtrate was concentrated and
the residue was purified by flash chromatography (silica gel,
10-50% ethyl acetate/heptanes gradient) to give the title compound
(1.5 g, 62.1% yield)
Example 308b
1-((3-bromo-4-(cyclopropylmethoxy)phenyl)sulfonyl)-3,3-difluoroazetidine
[1284] Example 308b was prepared according to the procedure used
for the preparation of Example 302a, substituting Example 308a for
Example 299a to provide the title compound.
Example 308c
4-{2-(cyclopropylmethoxy)-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]phenyl}-6-
-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1285] Example 308c was prepared according to the procedure used
for the preparation of Example 302b, substituting Example 308b for
Example 302a to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.04 (s, 1H), 7.87 (dd, J=8.7, 2.4 Hz,
1H), 7.78 (d, J=2.4 Hz, 1H), 7.40 (s, 1H), 7.36 (d, J=8.8 Hz, 1H),
7.29 (t, J=2.7 Hz, 1H), 6.12-6.08 (m, 1H), 4.26 (t, J=12.7 Hz, 4H),
4.01 (d, J=6.8 Hz, 2H), 3.58 (s, 3H), 1.14-1.08 (m, 1H), 0.50-0.43
(m, 2H), 0.30-0.25 (m, 2H). MS (DCI+) m/z 491.4
(M+CH3CN).sup.+.
Example 309
4-{2-[2-(2-hydroxyethyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1286] Example 304 was prepared according to the procedure used for
the preparation of Example 138b, substituting
2-(2-hydroxyethyl)phenol for 2,4-difluorophenol, to provide the
title compound. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
12.11 (s, 1H), 8.00 (d, J=2.44 Hz, 1H), 7.85 (dd, J=8.85, 2.44 Hz,
1H), 7.45 (s, 1H), 7.36 (dd, J=7.63, 1.53 Hz, 1H), 7.32 (t, J=2.9
Hz, 1H), 7.24-7.28 (m, 1H), 7.14-7.18 (m, 1H), 6.98-7.01 (m, 1H),
6.89 (d, J=8.54 Hz, 1H), 6.29-6.31 (m, 1H), 3.57 (s, 3H), 3.46 (t,
J=7.02 Hz, 2H), 3.25 (s, 3H), 2.63 (t, J=7.02 Hz, 2H). MS (ESI+)
m/z 439.1 (M+H).sup.+.
Example 310
4-[2-(cyclopropylmethoxy)-5-{[3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}ph-
enyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 310a
1-(3-bromo-4-fluorophenylsulfonyl)-N,N-dimethylpyrrolidin-3-amine
[1287] A solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride
(Combi-blocks) (250 mg, 0.91 mmol), N,N-dimethylpyrrolidin-3-amine
(218 mg, 1.9 mmol) in tetrahydrofuran (5.7 mL) was stirred at
ambient temperature for 16 hours. The solvent was evaporated and
residue was purified by flash chromatography (silica gel,
dichloromethane/gradient with MeOH) to afford the title compound
(220 mg, 69% yield).
Example 310b
1-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonyl-N,N-dimethyl-3-amine
[1288] Example 310b was prepared according to the procedure used
for the preparation of Example 29a, substituting
cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and substituting
Example 310a for Example 2a to afford the title compound.
Example 310c
4-(2-(cyclopropylmethoxy)-5-(3-(dimethylamino)pyrrolidin-1-ylsulfonyl)phen-
yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1289] Example 310c was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 310b for
Example 6b, to afford the title compound.
Example 310d
4-(2-(cyclopropylmethoxy)-5-(3-(dimethylamino)pyrrolidin-1-ylsulfonyl)phen-
yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1290] Example 310d was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 310c for
Example 6c, to afford the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. ppm 0.25-0.31 (m, 2H) 0.44-0.51 (m, 2H)
1.06-1.17 (m, 1H) 1.45-1.59 (m, 1H) 1.86-1.97 (m, 1H) 2.04 (s, 6H)
2.52-2.57 (m, 1H) 2.82-2.90 (m, 1H) 3.07-3.18 (m, 1H) 3.25-3.28 (m,
1H) 3.34-3.42 (m, 1H) 3.57 (s, 3H) 3.98 (d, J=6.78 Hz, 2H) 6.12 (t,
J=2.71, 2.03 Hz, 1H) 7.28-7.33 (m, 2H) 7.35 (s, 1H) 7.71-7.79 (m,
2H) 12.04 (s, 1H). MS (ESI+) m/z 471 [M+H].sup.+.
Example 311
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]pyridin-3-yl}-6-methy-
l-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 311a
5-bromo-6-(2,4-difluorophenoxy)nicotinic acid
[1291] 5-bromo-6-chloronicotinic acid (3 g, 12.69 mmol),
2,4-difluorophenol (3.30 g, 25.4 mmol) and cesium carbonate (16.54
g, 50.8 mmol) were combined in DMSO (25.4 mL), heated at
100.degree. C. for 6 hours, cooled, diluted with 150 mL of iced
water and the pH was adjusted to pH 3 with 12M HCl. The resulting
solid was collected by filtration, washed with cold water and dried
to constant mass to afford the title compound (2.84 g, 64%).
Example 311b
(5-bromo-6-(2,4-difluorophenoxy)pyridin-3-yl)methanol
[1292] The product from Example 311a (1.0 g, 3.03 mmol) and borane
tetrahydrofuran complex (6.06 mL, 6.06 mmol) were combined in
tetrahydrofuran (15.15 mL) and heated at 50.degree. C. for 2 hours,
cooled, treated with 10 mL of methanol, heated at 50.degree. C. for
1 hour, cooled and concentrated. The residue was partitioned
between ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. Purification by chromatography (silica
gel, 0-50% ethyl acetate in heptanes) afforded the title compound
(0.73 g, 76%).
Example 311c
3-bromo-5-(bromomethyl)-2-(2,4-difluorophenoxy)pyridine
[1293] A solution of the product from Example 311b (0.73 g, 2.309
mmol) in dichloromethane (11.55 mL) under nitrogen was treated
dropwise with tribromophosphine (0.218 mL, 2.309 mmol), stirred for
one hour at ambient temperature and poured into ice water and the
pH was adjusted to pH 9 by addition of solid sodium bicarbonate
added portionwise. An emulsion formed that was partially removed by
filtration. The aqueous layer was extracted with dichloromethane
and the organics were combined, washed with saturated aqueous
sodium chloride, dried (Na.sub.2SO.sub.4) filtered, and
concentrated to afford the title compound (0.75 g, 86%).
Example 311d
3-bromo-2-(2,4-difluorophenoxy)-5-(methylthiomethyl)pyridine
[1294] The product from Example 311c (0.75 g, 1.979 mmol) and
sodium thiomethoxide (0.139 g, 1.979 mmol) were combined in
dimethylformamide (3.96 mL), stirred for 4 hours at ambient
temperature, and partitioned into ethyl acetate and cold water. The
organic layer was washed with saturated aqueous sodium chloride,
dried (Na.sub.2SO.sub.4), filtered, and concentrated to afford the
title compound (0.66 g, 96%).
Example 311e
3-bromo-2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)pyridine
[1295] A solution of the product from Example 311d (0.66 g, 1.906
mmol) at 0.degree. C. in methanol (7.33 mL) was treated with a
solution of Oxone (2.461 g, 4.00 mmol) in water (7.33 mL), stirred
at ambient temperature for two hours and partitioned between ethyl
acetate and water. The organic layer was washed with saturated
aqueous sodium chloride, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. Purification by chromatography (silica gel, 0-5%
methanol in dichloromethane) afforded the title compound (0.433 g,
60%).
Example 311f
4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)pyridin-3-yl)-6-methy-
l-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1296] The product from Example 311e (0.075 g, 0.198 mmol), the
product from Example 6a (0.085 g, 0.198 mmol),
tris(dibenzylideneacetone)dipalladium(0) (5.45 mg, 5.95 .mu.mol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (5.80
mg, 0.020 mmol) and potassium phosphate (0.126 g, 0.595 mmol) were
combined and sparged with argon for 15 minutes. Meanwhile a
solution of 4:1 dioxane/water (2 mL) was sparged with nitrogen for
15 minutes and transferred by syringe into the reaction vessel
under argon. The mixture was stirred for 2 hours at 60.degree. C.
and partitioned between ethyl acetate and water. The organic layer
was washed with saturated aqueous sodium chloride, dried
(Na.sub.2SO.sub.4), treated with 3-mercaptopropyl functionalized
silica gel, filtered, and concentrated. Purification by trituration
in dichloromethane afforded the title compound (0.083 g, 70%).
Example 311g
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]pyridin-3-yl}-6-methy-
l-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1297] The product from Example 311f (0.083 g, 0.138 mmol),
potassium hydroxide (0.194 g, 3.46 mmol) and
N,N,N-trimethylhexadecan-1-aminium bromide (2.52 mg, 6.92 .mu.mol)
were combined in dioxane (1.8 mL)/water (0.9 mL) and heated at
100.degree. C. for 4 hours, cooled, and partitioned into ethyl
acetate adjusting the pH to 7 with 1 M HCl. The organic layer was
washed with saturated aqueous sodium chloride, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. Purification by
chromatography (silica gel, 0-4% methanol in dichloromethane)
afforded the title compound (0.035 g, 57%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.14 (s, 1H) 8.03 (dd, J=22.74, 2.29 Hz,
2H) 7.30-7.51 (m, 4H) 7.03-7.17 (m, 1H) 6.39 (d, J=2.14 Hz, 1H)
4.57 (s, 2H) 3.60 (s, 3H) 3.00 (s, 3H). MS (ESI+) m/z 446
[M+H].sup.+.
Example 312
tert-butyl
4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylate
Example 312a
tert-butyl
4-(2-bromo-4-(ethylsulfonyl)phenoxy)piperidine-1-carboxylate
[1298] Example 312a was prepared according to the procedure used
for the preparation of Example 158, substituting Example 168b for
Example 138a, and tert-butyl 4-hydroxypiperidine-1-carboxylate for
cyclopropylmethanol, respectively, to provide the title
compound.
Example 312b
tert-butyl
4-[4-(ethylsulfonyl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2-
,3-c]pyridin-4-yl)phenoxy]piperidine-1-carboxylate
[1299] Example 312b was prepared according to the procedure used
for the preparation of Example 95d, substituting Example 312a for
Example 95c, to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.02 (s, 1H), 7.79-7.842 (m, 2H), 7.42
(d, J=8.54 Hz, 1H), 7.31 (s, 1H), 7.27 (t, J=2.75 Hz, 1H),
6.10-6.11 (m, 1H), 4.74-4.78 (m, 1H), 3.55 (s, 3H), 3.14-3.32 (m,
6H), 1.82-1.87 (m, 2H), 1.43-1.51 (m, 2H), 1.35 (s, 9H), 1.12 (t,
J=7.32 Hz, 3H). MS (ESI+) m/z 515.9 (M+H).sup.+.
Example 313
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)-N-phenylbenzenesulfonamide
Example 313a
3-bromo-4-fluoro-N-phenylbenzenesulfonamide
[1300] Example 313a was prepared according to the procedure used
for the preparation of Example 305a, substituting aniline for
indoline. The crude product was purified by flash chromatography
(silica gel, eluted with 10% ethyl acetate in heptane) to afford
title compound
Example 313b
3-bromo-4-(cyclopropylmethoxy)-N-phenylbenzenesulfonamide
[1301] Example 313b was prepared according to the procedure used
for the preparation of Example 29a, substituting
cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and substituting
Example 313a for Example 2a to afford the title compound.
Example 313c
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,-
3-c]pyridin-4-yl)-N-phenylbenzenesulfonamide
[1302] Example 313c was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 313b for
Example 6b to afford the title compound.
Example 313d
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)-N-phenylbenzenesulfonamide
[1303] Example 313d was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 313c for
Example 6c to afford the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. 0.25 (tt, J=15.6, 7.6 Hz, 2H) 0.39-0.50
(m, 2H) 1.01-1.18 (m, 1H) 3.55 (s, 3H) 3.91 (d, J=6.8 Hz, 2H) 5.91
(dd, J=2.8, 2.0 Hz, 1H) 7.01-7.15 (m, 3H) 7.15-7.34 (m, 5H)
7.65-7.72 (m, 2H) 10.12 (s, 1H) 12.02 (bs, 1H). MS (ESI+) m/z 450
[M+H].sup.+.
Example 314
4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylmethyl)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 314a
4-bromo-1-(cyclopropylmethoxy)-2-iodobenzene
[1304] A mixture of 4-bromo-2-iodophenol (5.00 g, 16.7 mmol),
bromomethylcyclopropane (2.26 g, 16.7 mmol) and cesium carbonate
(6.54 g, 20.1 mmol) in 15 mL dimethylformamide was stirred at
50.degree. C. overnight. Water was added and the mixture was
extracted with ethyl acetate. The organic phase was washed with
water, saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, and filtered. The filtrate was concentrated to
the provide title compound (5.84 g, 99% yield).
Example 314b
4-(5-bromo-2-(cyclopropylmethoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c-
]pyridin-7(6H)-one
[1305] A mixture of Example 6a (1.1 g, 2.57 mmol), Example 314a
(0.907 g, 2.57 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane
(0.060 g, 0.21 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.094 g, 0.103 mmol), and potassium phosphate (1.635 g, 7.70 mmol)
in 15 mL dioxane and 5 mL water was purged with nitrogen gas and
then heated at 55.degree. C. for 3 hours. Saturated aqueous sodium
chloride was added and the mixture was extracted with ethyl acetate
(2.times.). The combined organic phases were dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 0-80% ethyl
acetate/heptanes gradient) to give the title compound (1.24 g, 92%
yield).
Example 314c
4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylmethyl)phenyl]-6-methyl-1,6-di-
hydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1306] A mixture of Example 314b (100 mg, 0.190 mmol), potassium
trifluoro(pyrrolidin-1-ylmethyl)borate (36.2 mg, 0.190 mmol),
palladium(II)acetate (2.55 mg, 0.011 mmol),
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (10.85
mg, 0.023 mmol), and cesium carbonate (185 mg, 0.569 mmol) in 4 mL
dioxane/water (9:1) was purged with nitrogen gas and then heated
under microwave conditions (Biotage Initiator) at 140.degree. C.
for 40 minutes. The reaction mixture was then treated with 2 mL of
4 N NaOH and heated in a microwave oven (Biotage Initiator) at
100.degree. C. for 30 minutes. Water was added. The mixture was
extracted with ethyl acetate, washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, and filtered. The
filtrate was concentrated and the residue was purified by flash
chromatography (silica gel, 2-14% methanol/dichloromethane
gradient) to give the title compound (8.0 mg, 11% yield). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 11.93 (s, 1H), 7.29-7.17
(m, 4H), 7.00 (d, J=8.4 Hz, 1H), 6.11 (dd, J=2.6, 2.2 Hz, 1H), 3.81
(d, J=6.7 Hz, 2H), 3.56 (s, 3H), 3.53 (s, 2H), 2.43 (s, 4H), 1.68
(s, 4H), 1.13-0.98 (m, 1H), 0.48-0.36 (m, 2H), 0.26-0.16 (m, 2H).
MS (ESI+) m/z 378.0 (M+H).sup.+.
Example 315
4-[2-(cyclopropylmethoxy)-5-(pyridin-3-yl)phenyl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one
[1307] A suspension of Example 314b (100 mg, 0.190 mmol),
pyridin-3-ylboronic acid (23.31 mg, 0.190 mmol), sodium carbonate
(60.3 mg, 0.569 mmol), and
tris(dibenzylideneacetone)-dipalladium(0) (15.48 mg, 0.019 mmol) in
4 mL dioxane-water (3:1) was heated under nitrogen under microwave
conditions (Biotage Initiator) at 120.degree. C. for 30 minutes.
The reaction mixture was the treated with 1 mL aqueous 4 N NaOH and
heated at 120.degree. C. under microwave conditions again for 30
minutes. The mixture was diluted with water and extracted with
ethyl acetate (2.times.), washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, and filtered. The
filtrate was concentrated and the residue was purified by flash
chromatography (silica gel, 0-10% methanol/dichloromethane
gradient) to give the title compound (53 mg, 75% yield). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 11.95 (s, 1H), 8.90 (dd,
J=2.4, 0.7 Hz, 1H), 8.56-8.49 (m, 1H), 8.07 (ddd, J=8.0, 2.4, 1.7
Hz, 1H), 7.71-7.64 (m, 2H), 7.45 (ddd, J=7.9, 4.8, 0.8 Hz, 1H),
7.34 (s, 1H), 7.26 (t, J=2.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 6.18
(dd, J=2.6, 2.2 Hz, 1H), 3.91 (d, J=6.7 Hz, 2H), 3.58 (s, 3H),
1.15-1.04 (m, 1H), 0.49-0.42 (m, 2H), 0.28-0.21 (m, 2H). MS (ESI+)
m/z 372.2 (M+H).sup.+.
Example 316
4-[2-(cyclopropylmethoxy)-5-(morpholin-4-ylmethyl)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1308] Example 316 was prepared according to the procedure used for
the preparation of Example 314c, substituting potassium
trifluoro(morpholinomethyl)borate for potassium
trifluoro(pyrrolidin-1-ylmethyl)borate to afford the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.01 (s,
1H), 7.50 (d, J=1.9 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.28 (dd,
J=4.9, 2.0 Hz, 2H), 7.18 (d, J=8.5 Hz, 1H), 6.21-6.14 (m, 1H), 4.32
(s, 2H), 3.97 (d, J=12.4 Hz, 2H), 3.89 (d, J=6.7 Hz, 2H), 3.63 (d,
J=11.7 Hz, 2H), 3.57 (s, 3H), 3.29 (d, J=12.8 Hz, 2H), 3.10 (d,
J=10.4 Hz, 2H), 1.17-1.02 (m, 1H), 0.51-0.42 (m, 2H), 0.28-0.21 (m,
2H). MS (ESI+) m/z 394.0 (M+H).sup.+.
Example 317
4-{5-(ethylsulfonyl)-2-[3-(hydroxymethyl)phenoxy]phenyl}-6-methyl-1,6-dihy-
dro-7H-pyrrolo[2,3-c]pyridin-7-one
[1309] Example 317 was prepared according to the procedure used for
the preparation of Example 138b, substituting
3-(hydroxymethyl)phenol for 2,4-difluorophenol, and Example 168c
for Example 138a, respectively, to provide the title compound.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.07 (s, 1H), 7.93 (d,
J=2.44 Hz, 1H), 7.83 (dd, J=8.7, 2.29 Hz, 1H), 7.42 (s, 1H), 7.35
(t, J=7.93 Hz, 1H), 7.30 (t, J=2.75 Hz, 1H), 7.15 (d, J=7.63 Hz,
1H), 7.02-7.05 (m, 2H), 6.97 (dd, J=7.93, 2.14 Hz, 1H), 6.26 (t,
J=2.44 Hz, 1H), 4.48 (s, 2H), 3.57 (s, 3H), 3.34 (q, J=7.32 Hz,
2H), 1.15 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 439.0 (M+H).sup.+.
Example 318
4-[2-(cyclopropylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-methyl-1,6-
-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1310] Example 318 was prepared according to the procedure used for
the preparation of Example 315, substituting
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
for pyridin-3-ylboronic acid to afford the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.93 (s, 1H), 8.05 (d,
J=7.4 Hz, 1H), 7.77 (dd, J=6.3, 0.6 Hz, 1H), 7.48 (q, J=2.2 Hz,
2H), 7.28-7.24 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.21-6.05 (m, 1H),
3.83 (d, J=4.9 Hz, 5H), 3.56 (d, J=5.7 Hz, 3H), 1.06-1.02 (m, 1H),
0.46-0.40 (m, 2H), 0.24-0.19 (m, 2H). MS (ESI+) m/z 375.2
(M+H).sup.+.
Example 319
4-[2-(2,4-difluorophenoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 319a
1-(3-bromo-4-(2,4-difluorophenoxy)phenylsulfonyl)indoline
[1311] Example 319a was prepared according to the procedure used
for the preparation of Example 2b, substituting 2,4-difluorophenol
for phenol and substituting Example 305a for Example 2a, to provide
the title compound.
Example 319b
4-(2-(2,4-difluorophenoxy)-5-(indolin-1-ylsulfonyl)phenyl)-6-methyl-1-tosy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1312] Example 319b was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 319a for
Example 6b, to afford the title compound.
Example 319c
4-[2-(2,4-difluorophenoxy)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]-6--
methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1313] Example 319c was prepared according to the procedure used
for the preparation of Example 6d, and substituting Example 319b
for Example 6c to afford the title compound. .sup.1H NMR (300 MHz,
DMSO-d6) .quadrature. 2.92 (t, J=8.3 Hz, 2H) 3.55 (s, 3H) 3.93 (t,
J=8.3 Hz, 2H) 5.98 (dd, J=2.8, 1.9 Hz, 1H) 6.91 (dd, J=9.3, 1.0 Hz,
1H) 6.98-7.29 (m, 6H) 7.34-7.58 (m, 3H) 7.74-7.91 (m, 2H) 12.08
(bs, 1H). MS (ESI+) m/z 534 [M+H].sup.+. Example 320
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c-
]pyridin-4-yl)phenyl]ethanesulfonamide
Example 320a
5-bromo-1,4-dimethyl-3-nitropyridin-2(1H)-one
[1314] Example 320a was prepared according to the procedure used
for the preparation of Example 1e, substituting Example 1d for
5-bromo-4-methyl-3-nitropyridin-2-ol, to provide the title
compound.
Example 320b
3-amino-5-bromo-1,4-dimethylpyridin-2(1H)-one
[1315] Example 320b was prepared according to the procedure used
for the preparation of Example 7b, substituting Example 320a for
Example 7a, to provide the title compound.
Example 320c
4-bromo-6-methyl-1H-pyrazolo[3,4-c]pyridin-7(6H)-one
[1316] Example 320b (1 g, 4.61 mmol), acetic anhydride (1.304 mL,
13.82 mmol), and potassium acetate (0.543 g, 5.53 mmol) were
stirred in toluene (25 mL) for 18 hours. Isoamyl nitrite (0.930 mL,
6.91 mmol) was added dropwise and the solution heated at 80.degree.
C. for 24 hours. The solution was cooled, water added, and the
aqueous extracted with ethyl acetate. The combined organics were
washed with saturated aqueous sodium chloride, dried (anhydrous
magnesium sulfate), filtered, and concentrated. The residue was
triturated with 30% ethyl acetate in hexanes to afford 0.415 g of
the title compound.
Example 320d
4-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]py-
ridin-7(6H)-one
[1317] Example 320c (0.228 g, 1.000 mmol) in dimethylformamide (5
mL) was treated with sodium hydride (0.060 g, 1.500 mmol). The
reaction mixture was stirred at ambient temperature for 10 minutes.
To this solution was added (2-(chloromethoxy)ethyl)trimethylsilane
(0.200 g, 1.200 mmol). The reaction mixture was stirred at ambient
temperature for 2 hours. The reaction mixture was partitioned
between ethyl acetate and water, and the organic phase separated,
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, ethyl acetate/heptane
gradient) to afford the title compound (0.301 g, 0.840 mmol, 84%
yield).
Example 320e
4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one
[1318] Example 320e was prepared according to the procedure used
for the preparation of Example 138a, substituting Example 320d for
2-bromo-1-fluoro-4-(methylsulfonyl)benzene, and Example 148c for
Example 6a, respectively, to provide the title compound.
Example 320f
N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)-
methyl)-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl)-N-(ethylsulfony-
l)ethanesulfonamide
[1319] A mixture of Example 320e (0.1 g, 0.201 mmol),
ethanesulfonyl chloride (0.077 g, 0.602 mmol), and triethylamine
(0.081 g, 0.802 mmol) in dichloromethane was stirred for 2 hours at
room temperature. The solvent was removed, and the residue was
purified by flash chromatography on silica gel (4:1 ethyl
acetate/hexanes) to give the title compound (0.11 g, 0.161 mmol,
80% yield).
Example 320g
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c-
]pyridin-4-yl)phenyl]ethanesulfonamide
[1320] Example 320f in dichloromethane (3 mL) was treated with
2,2,2-trifluoroacetic acid (1.837 g, 16.11 mmol). The reaction
mixture was stirred for 16 hours at ambient temperature. The
solvent was removed, and the residue was put on high vacuum for 1
hour. It was then treated with dioxane (5 mL) and 2.0 N sodium
hydroxide (1.611 mL, 3.22 mmol). The reaction mixture was heated at
85.degree. C. for 2 hours. After cooling, the reaction mixture was
partitioned between 0.1% HCl and ethyl acetate. The aqueous layer
was extracted with additional ethyl acetate twice. The combined
organic layers were washed with saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The residue was then purified by reverse phase preparative HPLC
(10-80% acetonitrile in 0.1% TFA water) to afford the TFA salt of
the title compound (0.055 g, 0.119 mmol, 74.1% yield). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 9.80 (s, 1H), 7.86 (s, 1H),
7.36-7.42 (m, 3H), 7.22 (dd, J=8.85, 2.75 Hz, 1H), 7.13-7.15 (m,
1H), 6.99-7.04 (m, 1H), 6.92 (d, J=8.85 Hz, 1H), 3.56 (s, 3H), 3.13
(t, J=7.32 Hz, 2H), 1.23 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 461.0
(M+H).sup.+.
Example 321
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6--
dihydro-7H-pyrazolo[3,4-c]pyridin-7-one
Example 321a
2-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane
[1321] Example 287e (1.13 g, 3 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.52
g, 6 mmol), potassium acetate (1.18 g, 12 mmol), and
bis(triphenylphosphine)palladium(II) chloride (0.126 g, 0.18 mmol)
were combined in a 20-mL microwave vial and sparged with nitrogen
for 30 minutes. To this mixture was added nitrogen-sparged dioxane
(15 mL). The reaction mixture was heated at 90.degree. C. for 8
hours. The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate, treated with
3-mercaptopropyl-functionalized silica gel, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 0 to 10% ethyl acetate in dichloromethane) and then
triturated with heptane to provide the title compound (0.64 g,
50%).
Example 321b
4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-((-
2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one
[1322] Example 320d (0.04 g, 0.112 mmol), Example 321a (0.052 g,
0.123 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0031 g,
3.35 mol),
(1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamanta-
ne (0.0033 g, 0.011 mmol) and sodium carbonate (0.051 g, 0.48 mmol)
were combined in a 5-mL microwave vial and sparged with nitrogen
for 30 minutes. To this mixture was added nitrogen-sparged dioxane
(0.8 mL) and water (0.2 mL). The reaction mixture was stirred at
60.degree. C. for 4.5 hours. The reaction mixture was cooled to
ambient temperature and then partitioned between ethyl acetate and
water. The organic layer was washed with saturated aqueous sodium
chloride, treated with 3-mercaptopropyl-functionalized silica gel,
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The residue was purified by flash chromatography (silica gel, 0 to
10% methanol in dichloromethane) to provide the title compound
(0.06 g, 93%).
Example 321c
4-{2-(2,4-difluorophenoxy)-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6--
dihydro-7H-pyrazolo[3,4-c]pyridin-7-one
[1323] Example 321b (0.06 g, 0.104 mmol) was treated with
2,2,2-trifluoroacetic acid (2 mL, 26.1 mmol), stirred at ambient
temperature for 30 minutes and then concentrated to dryness. The
residue was purified by reverse phase HPLC (C18, CH.sub.3CN/water
(0.1% TFA), 20-80%) to provide the title compound (0.03 g, 65%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .quadrature. ppm 7.91 (s, 1H),
7.60 (d, J=2.14 Hz, 1H), 7.42 (m, 3H), 7.29 (m, J=9.23, 9.23, 5.65
Hz, 1H), 7.09 (m, 1H), 6.89 (d, J=8.54 Hz, 1H), 4.53 (s, 2H), 3.58
(s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 446.1 (M+H).sup.+.
Example 322
4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7-
H-pyrazolo[3,4-c]pyridin-7-one
Example 322a
ethyl(4-fluorophenyl)sulfane
[1324] Triethylamine (5.44 mL, 39 mmol) was added to a solution of
4-fluorobenzenethiol (5 g, 39 mmol) and iodoethane (3.78 mL, 46.8
mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred
at ambient temperature for 2 hours and then filtered. The filtrate
was concentrated, triturated with hexane, and dried under vacuum to
afford the title compound (4.8 g, 76%).
Example 322b
1-(ethylsulfonyl)-4-fluorobenzene
[1325] Example 322a (5 g, 32 mmol) in dichloromethane (200 mL) was
treated with 3-chloroperoxybenzoic acid (14.3 g, 70.4 mmol) and
stirred at ambient temperature for 6 hours.
[1326] The solid formed during the reaction mixture was removed by
filtration and washed with additional dichloromethane. The combined
filtrate was washed with 10% aqueous sodium hydroxide solution (50
mL, twice) and saturated aqueous sodium bicarbonate solution, dried
over anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, 15% ethyl
acetate in petroleum ether) to afford the title compound (4.6 g,
76%).
Example 322c
2-bromo-4-(ethylsulfonyl)-1-fluorobenzene
[1327] Example 322b (1 g, 5.31 mmol) in sulfuric acid (6 mL, 113
mmol) was treated with N-bromosuccinimide (1.04 g, 5.84 mmol),
stirred at ambient temperature for 6 hours and then at 50.degree.
C. for 16 hours. The reaction mixture was then poured into ice
water and the resulting solid was collected by filtration, washed
with cold water three times, and dried in a vacuum oven for 16
hours. The solid was then purified by flash chromatography (silica
gel, 9-20% ethyl acetate in petroleum ether) to afford the title
compound (1.1 g, 78%).
Example 322d
2-(5-(ethylsulfonyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborola-
ne
[1328] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(0.665 g, 2.62 mmol), Example 322c (0.5 g, 1.9 mmol), potassium
acetate (0.367 g, 3.74 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.041
g, 0.056 mmol) were combined in an argon-sparged mixture of dioxane
(10 mL)/dimethyl sulfoxide (0.3 mL) and heated at 90.degree. C.
under argon for 24 hours. The reaction mixture was partitioned
between ethyl acetate and water and filtered through a plug of
Celite to remove elemental palladium. The layers were separated and
the organic layer was washed with saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate, treated with
3-mercaptopropyl-functionalized silica gel for 15 minutes,
filtered, and concentrated. The residue was triturated in a minimal
amount of heptane/diethyl ether (20:1) and filtered to give crude
product. This material was then dissolved in ethyl acetate, treated
again with 3-mercaptopropyl-functionalized silica gel, filtered,
and concentrated. The residue was recrystallized from heptane/ethyl
acetate (9:1) to afford the title compound (0.3 g, 77%).
Example 322e
4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy-
)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one
[1329] Example 322e was prepared according to the procedure used
for the preparation of Example 321b, substituting Example 322d for
Example 321a, to provide the title compound (0.0635 g, 55%).
Example 322f
4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1-((2-(trimet-
hylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one
[1330] Example 322e (0.0635 g, 0.136 mmol), 2,4-difluorophenol
(0.021 g, 0.164 mmol) and cesium carbonate (0.089 g, 0.273 mmol)
were combined in a 4-mL vial with dimethyl sulfoxide (1.5 mL),
stirred at 60.degree. C. for 8 hours and then at ambient
temperature for 16 hours. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, 0 to 8% methanol in
dichloromethane) to provide the title compound (0.0574 g, 73%).
Example 322g
4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrazolo[3-
,4-c]pyridin-7(6H)-one
[1331] Example 322g was prepared according to the procedure used
for the preparation of Example 321c, substituting Example 322f for
Example 321b, to provide the title compound (0.0299 g, 67%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .quadrature. ppm 7.96 (d,
J=2.14 Hz, 1H), 7.91 (s, 1H), 7.85 (dd, J=8.70, 2.29 Hz, 1H), 7.54
(m, 3H), 7.20 (m, 1H), 7.00 (d, J=8.85 Hz, 1H), 3.61 (s, 3H), 3.35
(q, J=7.32 Hz, 2H), 1.15 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 446.2
(M+H).sup.+.
Example 323
4-[2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-
-pyrazolo[3,4-c]pyridin-7-one
Example 323a
4-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1-((2-(trimeth-
ylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one
[1332] Cyclopropylmethanol (0.018 g, 0.25 mmol) in dioxane (0.75
mL) was treated with sodium hydride (60% oil dispersion) (0.023 g,
0.587 mmol) and stirred at ambient temperature for 10 minutes. A
solution of Example 322e (0.0683 g, 0.147 mmol) in dioxane (0.75
mL) was added and the mixture was stirred at 60.degree. C. for 8
hours and then at ambient temperature for 16 hours. Additional
cyclopropylmethanol (0.018 g, 0.249 mmol) and sodium hydride (60%
oil dispersion) (0.023 g, 0.587 mmol) were added and the mixture
was heated at 70.degree. C. for 9 hours. The reaction mixture was
cooled to ambient temperature and then partitioned between ethyl
acetate and water. The organic layer was washed with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 0 to 30% ethyl acetate in
dichloromethane) to provide the title compound (0.0685 g, 90%).
Example 323b
4-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrazolo[3,-
4-c]pyridin-7(6H)-one
[1333] Example 323b was prepared according to the procedure used
for the preparation of Example 321c, substituting Example 323a for
Example 321b, to provide the title compound (0.0302 g, 59%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .quadrature. ppm 14.07 (s, 1H),
7.85 (dd, J=8.70, 2.29 Hz, 1H), 7.80 (d, J=2.14 Hz, 1H), 7.78 (m,
1H), 7.41 (s, 1H), 7.34 (d, J=8.54 Hz, 1H), 4.01 (d, J=7.02 Hz,
2H), 3.60 (s, 3H), 3.29 (q, J=7.32 Hz, 2H), 1.13 (t, J=7.32 Hz,
3H), 1.06 (m, 1H), 0.45 (m, 2H), 0.27 (m, 2H). MS (ESI+) m/z 388.2
(M+H).sup.+.
Example 324
N-[2-cyano-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide
Example 324a
4-bromo-5-(2,4-difluorophenoxy)-2-nitrobenzoic acid
[1334] Example 324a was prepared according to the procedure used
for the preparation of Example 7a, substituting
4-bromo-5-fluoro-2-nitrobenzoic acid for
2-bromo-1-fluoro-4-nitrobenzene (Combi Blocks) and substituting
2,4-difluorophenol for phenol to afford the title compound.
Example 324b
methyl 4-bromo-5-(2,4-difluorophenoxy)-2-nitrobenzoate
[1335] Oxalyl chloride (1.4 mL, 16.6 mmol) was added dropwise to a
0.degree. C. suspension of Example 324a (5.47 g, 14.6 mmol) and
dichloromethane (65 mL). 3 drops dimethylformamide was added and
the reaction mixture was stirred at ambient temperature for 2
hours. After cooling to 0.degree. C., methanol (12 mL, 296 mmol)
was added dropwise. The solution was stirred for 15 minutes at
0.degree. C. and for 2.5 hours at ambient temperature. The solution
was diluted with dichloromethane and was washed with water,
saturated aqueous sodium bicarbonate, saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate, filtered and
concentrated to afford the title compound (5.42 g, 96% yield).
Example 324c
methyl 2-amino-4-bromo-5-(2,4-difluorophenoxy)benzoate
[1336] Example 324c was prepared according to the procedure used
for the preparation of Example 7b, substituting Example 324b for
Example 7a to afford the title compound.
Example 324d
4-bromo-5-(2,4-difluorophenoxy)-2-(ethylsulfonamido)benzoic
acid
[1337] Example 324d was prepared according to the procedure used
for the preparation of Example 7c, substituting Example 324c for
Example 7b to afford the title compound.
Example 324e
4-bromo-5-(2,4-difluorophenoxy)-2-(ethylsulfonamido)benzamide
[1338] Oxalyl chloride (0.046 mL, 0.54 mmol) was added dropwise to
a suspension of Example 324d (214 mg, 0.49 mmol) and
dichloromethane (2.2 mL). 1 Drop dimethylformamide was added and
the reaction mixture was stirred at ambient temperature for 2
hours. The solvent was evaporated and the residue was dried
(in-vacuo). The resulting acid chloride was suspended in
tetrahydrofuran (1.0 mL) and was cooled to 0.degree. C. as ammonium
hydroxide (0.65 mL, 4.7 mmol) was added dropwise. The reaction
mixture was stirred at ambient temperature for 2 hours. Ethyl
acetate was added and the solution was washed with water, saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 1-8% methanol/dichloromethane gradient)
to afford the title compound (176 mg, 82% yield).
Example 324f
N-(5-bromo-2-cyano-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide
[1339] To a suspension of Example 324e (230 mg, 0.53 mmol) and
dioxane (1.5 mL) was added pyridine (0.14 mL, 1.7 mmol) followed by
2,2,2-trifluoroacetic anhydride (0.14 mL, 0.99 mmol). The reaction
mixture was stirred at ambient temperature for 1 hour. Water was
added and the solution was extracted with ethyl acetate. The
organic layer was washed with water, saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography
(silica gel, 5-40% ethyl acetate/heptane gradient) to afford the
title compound (135 mg, 61% yield).
Example 324g
N-(2-cyano-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1-
H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide
[1340] Example 324g was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 324f for
Example 6b to afford the title compound.
Example 324h
N-(2-cyano-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrol-
o[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide
[1341] Example 324h was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 324g for
Example 6c to afford the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. ppm 1.32 (t, J=7.12 Hz, 3H) 3.20 (q,
J=7.46, 5.76 Hz, 2H) 3.54-3.57 (m, 3H) 6.32 (t, J=2.71, 2.03 Hz,
1H) 7.03-7.11 (m, 1H) 7.24-7.32 (m, 1H) 7.32 (t, J=2.71 Hz, 1H)
7.37 (s, 1H) 7.38-7.48 (m, 1H) 7.46 (s, 1H) 7.59 (s, 1H) 10.07 (s,
1H) 12.13 (brs, 1H). MS (ESI+) m/z 485 [M+H].sup.+.
Example 325
tert-butyl
4-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrr-
olo[2,3-c]pyridin-4-yl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate
[1342] Example 325 was prepared according to the procedure used for
the preparation of Example 315, substituting tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate for pyridin-3-ylboronic acid to afford the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.93 (s,
1H), 7.40-7.34 (m, 2H), 7.27-7.22 (m, 2H), 7.04 (d, J=9.0 Hz, 1H),
6.13-6.09 (m, 1H), 6.07 (s, 1H), 3.97 (s, 2H), 3.83 (d, J=6.7 Hz,
2H), 3.56 (s, 3H), 3.52 (dd, J=9.1, 3.4 Hz, 2H), 2.45 (s, 2H), 1.42
(d, J=5.3 Hz, 9H), 1.06-0.97 (m, 1H), 0.46-0.38 (m, 2H), 0.26-0.17
(m, 2H). MS (ESI+) m/z 476.2 (M+H).sup.+.
Example 326
4-[5-(6-aminopyridin-3-yl)-2-(cyclopropylmethoxy)phenyl]-6-methyl-1,6-dihy-
dro-7H-pyrrolo[2,3-c]pyridin-7-one
[1343] Example 326 was prepared according to the procedure used for
the preparation of Example 315, substituting
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine for
pyridin-3-ylboronic acid to afford the title compound. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 11.93 (s, 1H), 8.21 (d, J=2.4
Hz, 1H), 7.67 (dd, J=8.6, 2.5 Hz, 1H), 7.49 (dd, J=6.3, 2.4 Hz,
2H), 7.30 (s, 1H), 7.25 (t, J=2.7 Hz, 1H), 7.14-7.07 (m, 1H), 6.49
(t, J=7.5 Hz, 1H), 6.16 (t, J=2.4 Hz, 1H), 5.94 (s, 2H), 3.86 (d,
J=6.7 Hz, 2H), 3.57 (s, 3H), 1.14-1.00 (m, 1H), 0.51-0.38 (m, 2H),
0.27-0.14 (m, 2H). MS (ESI+) m/z 387.2 (M+H).sup.+.
Example 327
4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl--
7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-car-
boxamide
Example 327a
ethyl
1-benzyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1344] Example 327a was prepared according to the procedure used
for the preparation of Example 6a, substituting Example 70e for
Example 1e, to provide the title compound.
Example 327b
ethyl
1-benzyl-4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-6,7-dih-
ydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1345] Example 327b was prepared according to the procedure used
for the preparation of Example 138a, substituting Example 327a for
Example 6a, and Example 168b for
2-bromo-1-fluoro-4-(methylsulfonyl)benzene, respectively, to
provide the title compound.
Example 327c
ethyl
4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-p-
yrrolo[2,3-c]pyridine-2-carboxylate
[1346] Example 327c was prepared according to the procedure used
for the preparation of Example 70j, substituting Example 327b for
Example 70i, to provide the title compound.
Example 327d
4-(2-((2,2-difluorocyclopropyl)methoxy)-5-(ethylsulfonyl)phenyl)-6-methyl--
7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1347] To the solution of Example 327c (1 g, 2.460 mmol) and
(2,2-difluorocyclopropyl)methanol (0.532 g, 4.92 mmol) in
dimethylsulfoxide (10 mL) was added cesium carbonate (1.203 g, 3.69
mmol). The reaction mixture was sealed in a microwave tube and
heated at 110.degree. C. for 5 days. During the 5 days, three
additional batches of (2,2-difluorocyclopropyl)methanol (0.532 g,
4.92 mmol) were added into the reaction mixture. The reaction
mixture was poured into ethyl acetate (150 mL) and water (150 mL).
The aqueous layer was extracted with ethyl acetate (100
mL.times.2). The combined organic layers were dried over anhydrous
sodium sulfate, filtered, and concentrated to give the
corresponding ethyl ester (1.2 g, 1.869 mmol, 76% yield). The
aqueous layer was adjusted pH to about 3 with 1N HCl and the
resulting solid was filtered and dried to give the title compound
(0.30 g, 0.64 mmol).
Example 327e
4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl--
7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-car-
boxamide
[1348] To a solution of Example 327d (0.070 g, 0.15 mmol) in
anhydrous dichloromethane (5 mL) were added oxalyl chloride (0.026
mL, 0.300 mmol) and dimethylformamide (0.581 .mu.l, 7.50 .mu.mol).
The reaction mixture was stirred at ambient temperature for 2 hours
and then evaporated. The residue was dissolved in dichloromethane
(5 mL) and treated with 2,2,2-trifluoroethylamine (0.048 mL, 0.600
mmol) and the mixture was stirred at ambient temperature overnight.
The reaction mixture was partitioned between water (15 mL) and
ethyl acetate (25 mL). The aqueous layer was extracted with
additional ethyl acetate (15 mL) twice. The combined organic layers
were dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was purified by reverse phase HPLC (C18,
mobile phase A:water (10 mM NH.sub.4HCO.sub.3); B: acetonitrile,
Gradient 25-60% B in A) to give the title compound (70 mg, 85%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 7.96-7.90 (m, 2H),
7.66-7.25 (m, 2H), 6.92 (s, 1H), 4.29 (t, J=7.5 Hz, 1H), 4.16 (t,
J=9.2 Hz, 1H), 4.05 (tt, J=9.2, 4.5 Hz, 2H), 3.72 (s, 3H), 3.22 (q,
J=7.4 Hz, 2H), 2.00 (td, J=12.0, 7.3 Hz, 1H), 1.58-1.46 (m, 1H),
1.32-1.25 (m, 4H). MS (ESI+) m/z 548.1 (M+H).sup.+.
Example 328
4-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-
-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 328a
1-((methylsulfonyl)methyl)-4-nitrobenzene
[1349] To a solution of 4-nitrobenzyl bromide (10.02 g, 46.4 mmol)
in N,N-dimethylformamide (25 mL) was added sodium methanesulfinate
(7.10 g, 69.6 mmol). The reaction mixture was stirred at 65.degree.
C. for 1 hour. The reaction mixture was cooled to ambient
temperature and diluted with water. The resulting suspension was
stirred for 10 minutes and filtered through a medium frit to
provide the title compound.
Example 328b
4-((methylsulfonyl)methyl)aniline
[1350] Example 328a (8.2 g, 38.1 mmol) and tetrahydrofuran (200 mL)
were added to 5% Pd/C, wet (1.6 g, 0.376 mmol) in a 50 mL pressure
bottle and stirred for 2 hours at 30 psi and 50.degree. C. The
mixture was filtered through a nylon membrane and washed with a
small amount of tetrahydrofuran and methanol. The solvent was
evaporated to provide the title compound.
Example 328c
2-iodo-4-((methylsulfonyl)methyl)aniline
[1351] To a solution of Example 328b (3.80 g, 20.5 mmol) in
N,N-dimethylformamide (103 mL) was added N-iodosuccinimide (5.08 g,
22.56 mmol). The reaction mixture was stirred at ambient
temperature for 1 hour. The reaction mixture was quenched with 150
mL 10% aqueous sodium thiosulfate and 100 mL saturated aqueous
sodium bicarbonate. The reaction mixture was extracted with ethyl
acetate. The combined organic layers were washed with saturated
aqueous sodium chloride and concentrated. Water was added, and the
resulting suspension was stirred at ambient temperature 10 minutes.
The suspension was filtered, and the solids collected was rinsed
with water, and dried overnight to provide the title compound.
Example 328d
N-(cyclopropylmethyl)-2-iodo-4-((methylsulfonyl)methyl)aniline
[1352] Example 328c (0.200 g, 0.643 mmol) and
cyclopropanecarbaldehyde (0.062 mL, 0.836 mmol) were suspended in
dichloromethane (3.21 mL) and methanol (3.21 mL). Acetic acid
(0.368 mL, 6.43 mmol) was added. The reaction mixture was heated at
50.degree. C. for 30 minutes and then cooled to ambient
temperature. Polymer supported cyanoborohydride (0.817 g, 1.928
mmol) was added. The reaction mixture was stirred at ambient
temperature overnight. Cyclopropanecarbaldehyde (0.062 mL, 0.836
mmol) was added, and the reaction mixture was stirred at ambient
temperature for 2 hours. The reaction mixture was filtered,
thoroughly rinsed with dichloromethane, and concentrated. The
residue was purified by flash chromatography (silica gel, 20-100%
ethyl acetate/heptane gradient) to provide the title compound.
Example 328e
4-(2-((cyclopropylmethyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-
-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1353] Example 328e was prepared according to the procedure used
for the preparation of Example 4a, substituting Example 328d for
Example 7c to provide the title compound.
Example 328f
4-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-
-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1354] Example 328f was prepared according to the procedure used
for the preparation of Example 4b, substituting Example 328e for
Example 4a to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.08 (bs, 1H), 7.29 (t, J=2.3 Hz, 1H),
7.21 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J=2.1 Hz, 1H),
6.73 (d, J=8.3 Hz, 1H), 6.05 (d, J=2.7 Hz, 1H), 4.67 (t, J=5.7 Hz,
1H), 4.30 (bs, 2H), 3.55 (s, 3H), 2.96 (t, J=6.1 Hz, 2H), 2.86 (s,
3H), 1.05-0.92 (m, 1H), 0.41-0.29 (m, 2H), 0.19-0.10 (m, 2H). MS
(ESI+) m/z 386.0 (M+H).sup.+
Example 329
4-{2-[(cyclopropylmethyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 329a
2-bromo-N-(cyclopropylmethyl)-4-(methylsulfonyl)aniline
[1355] Example 329a was prepared according to the procedure used
for the preparation of Example 147a, substituting
cyclopropylmethanamine for cyclohexanamine to provide the title
compound.
Example 329b
4-(2-((cyclopropylmethyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-
-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1356] Example 329b was prepared according to the procedure used
for the preparation of Example 7d, substituting the product of
Example 329a for the product of Example 7c and stirring at
100.degree. C. for 30 minutes, to provide the title compound.
Example 329c
4-{2-[(cyclopropylmethyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1357] Example 329c was prepared according to the procedure used
for the preparation of Example 4 (Method B), substituting the
product of Example 329b for the product of Example 7d, and purified
by Preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water)
to provide the TFA salt of the title compound. 1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. ppm 12.12 (bds, 1H), 7.67 (dd, J=2.4,
8.8 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.29 (t, J=3.1 Hz, 1H), 7.26
(s, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.02 (t, J=2.2 Hz, 1H), 5.45 (m,
1H), 3.56 (s, 3H), 3.10 (m, 2H), 3.04 (m, 2H), 1.01 (m, 1H), 0.37
(m, 2H), 0.16 (m, 2H). MS (ESI+) m/z 372.1 (M+H).sup.+.
Example 330
4-[5-(ethylsulfonyl)-2-(pyrrolidin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-py-
rrolo[2,3-c]pyridin-7-one
Example 330a
4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6-
H)-one
[1358] A mixture of Example 168b (0.935 g, 3.50 mmol), Example 6a
(1.5 g, 3.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.202
g, 0.175 mmol) and cesium fluoride (1.596 g, 10.51 mmol) in 12 mL
dimethoxyethane and 4 mL methanol was heated at 120.degree. C.
under microwave conditions for 40 minutes. The mixture was
concentrated and the residue was absorbed on silica gel and
purified by flash chromatography (SiO.sub.2, 0-10%
methanol/dichloromethane gradient) to give the title compound (1.01
g, 86% yield).
Example 330b
4-[5-(ethylsulfonyl)-2-(pyrrolidin-1-yl)phenyl]-6-methyl-1,6-dihydro-7H-py-
rrolo[2,3-c]pyridin-7-one
[1359] A mixture of Example 330a (90 mg, 0.27 mmol) and pyrrolidine
(668 .mu.L, 8.08 mmol) in 1 mL DMSO was heated at 160.degree. C.
under microwave conditions for 30 minutes. The product was purified
by preparative HPLC (C18, 10-80% CH.sub.3CN/water (0.1% TFA)) to
give the title compound (37 mg, 35.7% yield). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 12.07 (s, 1H), 7.61 (dd, J=8.8, 2.4 Hz,
1H), 7.48 (d, J=2.4 Hz, 1H), 7.26 (t, J=2.8 Hz, 1H), 7.20 (s, 1H),
6.95 (d, J=8.9 Hz, 1H), 5.99-5.94 (m, 1H), 3.56 (s, 3H), 3.16 (q,
J=7.3 Hz, 2H), 3.06 (s, 4H), 1.69 (t, J=6.3 Hz, 4H), 1.10 (t, J=7.4
Hz, 3H). MS (ESI+) m/z 386.1 (M+H).sup.+.
Example 331
4-[5-(ethylsulfonyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-methyl-1,6-dihydr-
o-7H-pyrrolo[2,3-c]pyridin-7-one
[1360] Example 331 was prepared according to the procedure used for
the preparation of Example 330b, substituting N-methylpiperazine
for pyrrolidine, to afford the TFA salt of the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.12 (s, 1H), 9.57
(s, 1H), 7.80 (dd, J=8.5, 2.3 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.45
(s, 1H), 7.32 (dd, J=8.6, 5.7 Hz, 2H), 6.17 (t, J=2.3 Hz, 1H), 3.60
(s, 3H), 3.49 (t, J=6.7 Hz, 2H), 3.28 (q, J=7.4 Hz, 4H), 2.94 (t,
J=11.8 Hz, 2H), 2.71 (s, 3H), 2.68-2.53 (m, 2H), 1.13 (t, J=7.3 Hz,
3H). MS (ESI+) m/z 415.2 (M+H).sup.+.
Example 332
4-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydr-
o-7H-pyrrolo[2,3-c]pyridin-7-one
Example 332a
4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[1361] Example 6a (1.71 g, 4.00 mmol),
2-bromo-4-(methylsulfonyl)aniline (1.00 g, 4.00 mmol),
tris(dibenzylideneacetone)dipalladium (0.110 g, 0.120 mmol),
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.117
g, 0.400 mmol) and sodium carbonate (1.48 g, 14.0 mmol) were
combined and purged with argon for 15 minutes. A mixture of dioxane
(21.3 mL) and water (5.3 mL) was purged with nitrogen for 15
minutes and transferred to the reaction vessel. The reaction
mixture was heated at 60.degree. C. for 3 hours, cooled to ambient
temperature and diluted with water. The resulting solid was
filtered, washed with water and dried to afford the title compound
(2.06 g, quantitative yield).
Example 332b
4-(2-((4-fluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-
-pyrrolo[2,3-c]pyridin-7(6H)-one
[1362] Example 332a (47.2 mg, 0.100 mmol), 1-bromo-4-fluorobenzene
(17.5 mg, 0.100 mmol), diacetoxypalladium (0.9 mg, 4 .mu.mol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(3.8 mg, 8.0 .mu.mol) and cesium carbonate (45.6 mg, 0.140 mmol)
were combined in a mixture of toluene (1.6 mL) and tert-butanol
(0.4 mL). The reaction mixture was heated in a microwave reactor at
150.degree. C. for 15 minutes. The reaction mixture was partitioned
with ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride, dried with anhydrous sodium
sulfate, treated with 3-mercaptopropyl functionalized silica gel,
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 2 to 4% methanol in dichloromethane) to
provide the title compound (30 mg, 53%).
Example 332c
4-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydr-
o-7H-pyrrolo[2,3-c]pyridin-7-one
[1363] Example 332b (28 mg, 0.050 mmol), potassium hydroxide (41.7
mg, 0.743 mmol) and cetyltrimethylammonium bromide (0.90 mg, 2.5
mol) were combined in a mixture of tetrahydrofuran (2 mL) and water
(1 mL). The reaction mixture was heated at 100.degree. C. for 20
hours and then cooled to ambient temperature. To this mixture was
added water, and the pH was adjusted to pH 7 by the addition of 1M
HCl. The mixture was extracted with ethyl acetate and the organic
layer was washed with saturated aqueous sodium chloride twice,
dried with anhydrous sodium sulfate, filtered, and concentrated.
The residue was purified by flash chromatography (silica gel, 2 to
4% methanol in dichloromethane) to provide the title compound (13
mg, 64%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.04 (s,
1H) 7.57-7.71 (m, 3H) 7.34 (s, 1H) 7.08-7.27 (m, 6H) 6.06 (t,
J=2.20 Hz, 1H) 3.57 (s, 3H) 3.15 (s, 3H). MS (ESI+) m/z 412
(M+H).sup.+.
Example 333
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide
Example 333a
3-bromo-4-fluoro-N-(pyridin-3-ylmethyl)benzenesulfonamide
[1364] Example 333a was prepared according to the procedure used
for the preparation of Example 305a, substituting
pyridin-3-ylmethanamine for indoline. The crude product was
purified by crystallization from ethyl acetate/ethyl ether to
afford title compound
Example 333b
3-bromo-4-(cyclopropylmethoxy)-N-(pyridin-3-ylmethyl)benzenesulfonamide
[1365] Example 333b was prepared according to the procedure used
for the preparation of Example 29a, substituting
cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and substituting
Example 333a for Example 2a to afford the title compound.
Example 333c
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,-
3-c]pyridin-4-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide
[1366] Example 333c was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 333b for
Example 6b to afford the title compound.
Example 333d
4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)-N-(pyridin-3-ylmethyl)benzenesulfonamide
[1367] Example 333d was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 333c for
Example 6c, and purified by Preparative HPLC (C18, 10-100%
acetonitrile in 0.1% TFA/water) to provide the TFA salt of the
title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .quadrature.
ppm 12.03 (s, 1H) 8.55 (s, 2H) 8.17 (t, J=6.44 Hz, 1H) 7.88 (d,
J=7.80 Hz, 1H) 7.70-7.76 (m, 2H) 7.50 (dd, J=7.12, 4.75 Hz, 1H)
7.27-7.32 (m, 2H) 7.20-7.26 (m, 1H) 6.10-6.16 (m, 1H) 4.11 (d,
J=6.44 Hz, 2H) 3.95 (d, J=6.78 Hz, 2H) 3.58 (s, 3H) 1.03-1.19 (m,
1H) 0.44-0.52 (m, 2H) 0.24-0.31 (m, 2H). MS (ESI+) m/z 465.0
[M+H].sup.+.
Example 334
4-[4-(cyclopropylmethoxy)-3'-fluorobiphenyl-3-yl]-6-methyl-1,6-dihydro-7H--
pyrrolo[2,3-c]pyridin-7-one
Example 334a
4-(5-bromo-2-(cyclopropylmethoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c-
]pyridin-7(6H)-one
[1368] Example 334a was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 314a for
Example 6b to afford the title compound.
Example 334b
4-(4-(cyclopropylmethoxy)-3'-fluorobiphenyl-3-yl)-6-methyl-1-tosyl-1H-pyrr-
olo[2,3-c]pyridin-7(6H)-one
[1369] Example 334b was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 334a for
Example 6b and substituting (3-fluorophenyl)boronic acid for
Example 6a to afford the title compound.
Example 334c
4-(4-(cyclopropylmethoxy)-3'-fluorobiphenyl-3-yl)-6-methyl-1H-pyrrolo[2,3--
c]pyridin-7(6H)-one
[1370] Example 334c was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 334b for
Example 6c to afford the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. ppm 0.22-0.28 (m, 2H) 0.42-0.49 (m, 2H)
1.03-1.14 (m, 1H) 3.58 (s, 3H) 3.90 (d, J=6.78 Hz, 2H) 6.17 (t,
J=2.71, 2.03 Hz, 1H) 7.09-7.20 (m, 2H) 7.27 (t, J=3.05 Hz, 1H) 7.34
(s, 1H) 7.42-7.55 (m, 3H) 7.62-7.69 (m, 2H) 11.98 (brs, 1H). MS
(ESI+) m/z 389 [M+H].sup.+.
Example 335
4-{2-[(4-fluorophenyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 335a
4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2-
,3-c]pyridin-7(6H)-one
[1371] Example 335a was prepared according to the procedure used
for the preparation of Example 4a, substituting Example 328c for
Example 7c to provide the title compound.
Example 335b
4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1--
tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1372] 4-Bromofluorobenzene (0.027 mL, 0.25 mmol), Example 335a
(0.100 g, 0.206 mmol), palladium(II)acetate (1.849 mg, 8.24
.mu.mol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(7.85 mg, 0.016 mmol), and cesium carbonate (0.094 g, 0.29 mmol)
were suspended in toluene (1.37 mL) and t-butanol (0.69 mL). The
reaction mixture was heated at 150.degree. C. for 30 minutes under
microwave conditions. The reaction mixture was filtered through a
2.5 g Celite column and rinsed thoroughly with ethyl acetate. The
filtrate was washed with saturated aqueous sodium chloride, dried
over anhydrous magnesium sulfate and mercaptopropyl silica gel,
filtered, and concentrated. The residue was purified by flash
chromatography (silica gel, 0-4% methanol/dichloromethane gradient)
to provide the title compound.
Example 335c
4-{2-[(4-fluorophenyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,-
6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1373] Example 335c was prepared according to the procedure used
for the preparation of Example 4b, substituting Example 335b for
Example 4a to provide the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 11.99 (bs, 1H), 7.32 (d, J=2.1 Hz, 1H),
7.25 (dd, J=8.3, 2.0 Hz, 1H), 7.18-7.23 (m, 4H), 6.97-7.07 (m, 4H),
6.06 (t, J=2.0 Hz, 1H), 4.40 (bs, 2H), 3.53 (s, 3H), 2.91 (s, 3H).
MS (ESI+) m/z 426.2 (M+H).sup.+
Example 336
[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)phenyl]acetonitrile
[1374] A mixture of Example 314b (100 mg, 0.190 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (44.4 mg,
0.228 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium (II),
complex with dichloromethane (1:1) (15.5 mg, 0.019 mmol), and
potassium fluoride (44.1 mg, 0.758 mmol) in dimethylsulfoxide (1.9
mL) and water (0.75 mL) was purged with nitrogen gas and heated
under microwave conditions at 130.degree. C. at for 1.5 hours. The
mixture was then treated with 1 mL 4N NaOH and stirred at ambient
temperature for 2 hours. The reaction mixture was partitioned
between water and ethyl acetate, and the aqueous layers was
extracted with ethyl acetate. The combined organic phases were
washed with water (2.times.), saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, and filtered. The filtrate
was concentrated and the residue was purified by flash
chromatography (silica gel, 0-8% methanol/dichloromethane gradient)
to give the title compound (30 mg, 48% yield). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 12.00 (s, 1H), 12.00 (s, 1H), 7.32
(d, J=2.4 Hz, 1H), 7.34-7.25 (m, 4H), 7.30-7.25 (m, 3H), 7.10 (d,
J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.14 (dd, J=2.6, 2.2 Hz,
1H), 6.14 (dd, J=2.6, 2.2 Hz, 1H), 3.99 (s, 2H), 3.99 (s, 2H), 3.84
(d, J=6.7 Hz, 2H), 3.84 (d, J=6.7 Hz, 2H), 3.56 (s, 3H), 3.56 (s,
3H), 1.11-1.02 (m, 1H), 1.12-1.02 (m, 1H), 0.48-0.39 (m, 2H),
0.49-0.35 (m, 2H), 0.31-0.18 (m, 2H), 0.26-0.19 (m, 2H). MS (ESI+)
m/z 334.1 (M+H).sup.+.
Example 337
N-{4-(2,4-difluorophenoxy)-3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-
-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide
Example 337a
ethyl
4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-1-benzyl-6-methyl-7-oxo-6,-
7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1375] Example 337a was prepared according to the procedure used
for the preparation of Example 138a, substituting Example 70e for
2-bromo-1-fluoro-4-(methylsulfonyl)benzene, and Example 148c for
Example 6a, respectively, to provide the title compound.
Example 337b
ethyl
1-benzyl-4-(2-(2,4-difluorophenoxy)-5-(N-(ethylsulfonyl)ethylsulfona-
mido)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbox-
ylate
[1376] Example 337b was prepared according to the procedure used
for the preparation of Example 320f, substituting Example 337a for
Example 320e, to provide the title compound.
Example 337c
ethyl
4-(2-(2,4-difluorophenoxy)-5-(N-(ethylsulfonyl)ethylsulfonamido)phen-
yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
[1377] Example 337c was prepared according to the procedure used
for the preparation of Example 70j, substituting Example 337b for
Example 70i, to provide the title compound.
Example 337d
4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-6-methyl-7-oxo-6,7--
dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
[1378] Example 337d was prepared according to the procedure used
for the preparation of Example 70k, substituting Example 337c for
Example 70j, to provide the title compound.
Example 337e
N-{4-(2,4-difluorophenoxy)-3-[2-(hydroxymethyl)-6-methyl-7-oxo-6,7-dihydro-
-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide
[1379] Example 337d (0.060 g, 0.12 mmol) in tetrahydrofuran (5 mL)
was treated with 1.0 N borane (0.119 mL, 0.119 mmol). The reaction
mixture was heated at 60.degree. C. for 2 hours. The reaction
mixture was partitioned between water and ethyl acetate. The
organic layer was extracted with additional ethyl acetate twice.
The combined organic layer were washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered,
and concentrated. The residue was purified by reverse phase HPLC
(C18, 10-100% acetonitrile in 0.1% TFA/water) to give the title
product. (0.035 g, 60% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 11.81 (s, 1H), 9.78 (s, 1H), 7.33-7.39 (m, 2H), 7.28
(s, 1H), 7.20 (dd, J=8.7, 2.59 Hz, 1H), 6.97-7.08 (m, 2H), 6.91 (d,
J=8.85 Hz, 1H), 6.15 (d, J=2.14 Hz, 1H), 4.50 (s, 2H), 3.52 (s,
3H), 3.10 (q, J=7.32 Hz, 2H), 1.23 (t, J=7.32 Hz, 3H). MS (ESI+)
m/z 490.2 (M+H).sup.+.
Example 338
N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)carbonyl-
]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide
Example 338a
4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-6-methyl-7-oxo-6,7--
dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl chloride
[1380] Example 338a was prepared according to the procedure used
for the preparation of Example 13a, substituting Example 337d for
Example 10, to provide the title compound.
Example 338b
N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)carbonyl-
]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide
[1381] Example 338b was prepared according to the procedure used
for the preparation of Example 13b, substituting Example 338a for
Example 13a, and 1-methylpiperazine for ethylamine, respectively,
to provide the TFA salt of the title compound. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 12.53 (s, 1H), 10.14 (br s, 1H),
9.81 (s, 1H), 7.34-7.40 (m, 3H), 7.20 (dd, J=8.85, 2.75 Hz, 1H),
7.06-7.12 (m, 1H), 6.98-7.04 (m, 1H), 6.93 (d, J=8.54 Hz, 1H), 6.53
(d, J=2.14 Hz, 1H), 3.55 (s, 3H), 3.02-3.43 (m, 6H), 2.84 (s, 3H),
1.24 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 586.2 (M+H).sup.+.
Example 339
N-[4-(2,4-difluorophenoxy)-3-{6-methyl-2-[(4-methylpiperazin-1-yl)methyl]--
7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide
[1382] Example 339 was prepared according to the procedure used for
the preparation of Example 337e, substituting Example 338b for
Example 337d, to provide the TFA salt of the title compound.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.01 (s, 1H), 9.80
(s, 1H), 7.34-7.39 (m, 2H), 7.31 (s, 1H), 7.19 (dd, J=8.85, 2.75
Hz, 1H), 7.05-7.11 (m, 1H), 6.98-7.04 (m, 1H), 6.91 (d, J=8.85 Hz,
1H), 6.19 (d, J=2.14 Hz, 1H), 3.75 (s, 2H), 3.11 (q, J=7.32 Hz,
2H), 2.95 (br s, 2H), 2.76 (s, 3H), 2.35 (br s, 2H), 1.24 (t,
J=7.32 Hz, 3H). MS (ESI+) m/z 572.0 (M+H).sup.+.
Example 340
4-[2-(cyclopropylmethoxy)-5-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-6-meth-
yl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
[1383] Example 325 (100 mg, 0.210 mmol) in 2 mL dichloromethane was
treated with 1 mL trifluoroacetic acid. The mixture was stirred at
ambient temperature for 2 hours. The solvent was evaporated. The
residue was treated with saturated aqueous sodium carbonate
solution and then extracted with ethyl acetate (4.times.). The
organic phase was dried over anhydrous magnesium sulfate, filtered,
and concentrated to give the title compound (26 mg, 32.9% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 11.94 (s, 1H),
7.37-7.31 (m, 1H), 7.25 (dd, J=5.3, 3.0 Hz, 2H), 7.18 (d, J=2.2 Hz,
1H), 7.13 (dd, J=8.4, 2.3 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.12 (m,
2H), 3.80 (d, J=6.7 Hz, 2H), 3.56 (s, 3H), 3.09 (d, J=12.1 Hz, 2H),
2.73-2.53 (m, 2H), 1.76 (d, J=11.0 Hz, 1H), 1.55 (qd, J=12.4, 3.8
Hz, 2H), 1.12-1.01 (m, 1H), 0.49-0.38 (m, 2H), 0.25-0.17 (m, 2H).
MS ((DCI+) m/z 376.5 (M+H).sup.+.
Example 341
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-N-(2-methoxyethyl)ethanesulfonamide
[1384] To a 4 mL vial was added (azidocarbonyl) dipiperidine (ADDP)
(25.9 mg, 0.102 mmol) in anhydrous toluene. The vial was introduced
into a dry box and tributylphosphine (41.5 mg, 3 eq, 0.205 mmol)
was added to the vial. This mixture was shaken until the solution
turned clear. To this solution was added a solution of
2-methoxyethanol in anhydrous tetrahydrofuran (1.2 equivalents,
0.082 mmol, 6.24 mg). This mixture was stirred for 10 minutes at
ambient temperature. To this mixture was added a solution of
Example 36e (0.068 mmol, 31.4 mg) in anhydrous toluene/anhydrous
tetrahydrofuran (1:1 v/v) (1 mL). The reaction mixture was stirred
at room temperature overnight in the dry box. The reaction mixture
was concentrated to dryness and the residue purified by reverse
phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to provide
the title compound (4.24%, 1.5 mg). .sup.1H NMR (400 MHz, DMSO
d.sub.6/D.sub.2O) 8 ppm 7.49 (d, J=2.75 Hz, 1H), 7.38-7.43 (m, 1H),
7.37 (d, J=2.75 Hz, 1H), 7.35-7.36 (m, 1H), 7.34 (d, J=2.75 Hz,
1H), 7.22-7.27 (m, 1H), 7.05-7.11 (m, 1H), 6.87 (d, J=8.54 Hz, 1H),
6.30 (d, J=2.75 Hz, 1H), 3.78-3.81 (m, 2H), 3.57 (s, 3H), 3.37 (t,
J=5.65 Hz, 2H), 3.20 (s, 3H), 3.16 (t, J=7.32 Hz, 2H), 1.26 (t,
J=7.48 Hz, 3H). ESI.sup.+ m/z=518.0 (M+H).sup.+.
Example 342
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-N-(pyridin-2-ylmethyl)ethanesulfonamide
[1385] Example 342 was prepared according to the procedure used for
the preparation of Example 341, substituting pyridin-2-ylmethanol
for 2-methoxyethanol, to provide the TFA salt of the title
compound. .sup.1H NMR (400 MHz, DMSO d.sub.6/D.sub.2O) 8 ppm 8.60
(d, J=4.58 Hz, 1H), 8.07 (t, J=7.78 Hz, 1H), 7.70 (d, J=7.93 Hz,
1H), 7.56 (d, J=2.44 Hz, 1H), 7.53 (dd, J=7.02, 5.80 Hz, 1H), 7.45
(dd, J=8.85, 2.75 Hz, 1H), 7.35-7.41 (m, 1H), 7.33 (d, J=2.75 Hz,
1H), 7.29 (s, 1H), 7.17-7.23 (m, 1H), 7.03-7.09 (m, 1H), 6.81 (d,
J=8.85 Hz, 1H), 6.17 (d, J=2.75 Hz, 1H), 5.10 (s, 2H), 3.56 (s,
3H), 3.33 (q, J=7.43 Hz, 2H), 1.31 (t, J=7.32 Hz, 3H). ESI.sup.+
m/z=551.0 (M+H).sup.+.
Example 343
N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dih-
ydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide
[1386] Example 343 was prepared according to the procedure used for
the preparation of Example 341, substituting cyclopropylmethanol
for 2-methoxyethanol, to provide the title compound. .sup.1H NMR
(400 MHz, DMSO d.sub.6/D.sub.2O) 8 ppm 7.51 (d, J=2.44 Hz, 1H),
7.36-7.42 (m, 2H), 7.35 (s, 1H), 7.34 (d, J=2.75 Hz, 1H), 7.20-7.27
(m, 1H), 7.04-7.10 (m, 1H), 6.88 (d, J=8.85 Hz, 1H), 6.29 (d,
J=2.75 Hz, 1H), 3.57 (s, 3H), 3.52 (d, J=7.02 Hz, 2H), 3.12-3.18
(m, 2H), 1.26 (t, J=7.32 Hz, 3H), 0.83-0.93 (m, 1H), 0.40-0.45 (m,
2H), 0.08-0.13 (m, 2H). ESI.sup.+ m/z=514.0 (M+H).sup.+.
Example 344
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]ethanesulfonamide
[1387] Example 344 was prepared according to the procedure used for
the preparation of Example 341, substituting
1-(2-hydroxyethyl)pyrrolidin-2-one for 2-methoxyethanol, to provide
the title compound. .sup.1H NMR (400 MHz, DMSO d.sub.6/D.sub.2O) 8
ppm 7.50 (d, J=2.44 Hz, 1H), 7.38-7.43 (m, 2H), 7.37 (s, 1H), 7.33
(d, J=2.75 Hz, 1H), 7.22-7.28 (m, 1H), 7.05-7.11 (m, 1H), 6.84 (d,
J=8.54 Hz, 1H), 6.34 (d, J=2.75 Hz, 1H), 3.83 (t, J=5.65 Hz, 2H),
3.58 (s, 3H), 3.27-3.32 (m, 4H), 3.14 (q, J=7.32 Hz, 2H), 2.11 (t,
J=8.09 Hz, 2H), 1.74-1.82 (m, 2H), 1.25 (t, J=7.32 Hz, 3H).
ESI+m/z=571.1 (M+H).sup.+.
Example 345
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-N-(tetrahydrofuran-2-ylmethyl)ethanesulfonamide
[1388] Example 345 was prepared according to the procedure used for
the preparation of Example 341, substituting
(tetrahydrofuran-2-yl)methanol for 2-methoxyethanol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO d.sub.6/D.sub.2O) 8 ppm
7.51 (d, J=2.75 Hz, 1H), 7.37-7.43 (m, 2H), 7.36 (s, 1H), 7.34 (d,
J=2.75 Hz, 1H), 7.21-7.27 (m, 1H), 7.04-7.11 (m, 1H), 6.86 (d,
J=8.85 Hz, 1H), 6.31 (d, J=2.75 Hz, 1H), 3.78-3.84 (m, 1H),
3.58-3.70 (m, 4H), 3.57 (s, 3H), 3.13-3.19 (m, 2H), 1.73-1.93 (m,
3H), 1.51-1.59 (m, 1H), 1.25 (t, J=7.32 Hz, 3H). ESI.sup.+
m/z=544.0 (M+H).sup.+.
Example 346
N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]-
pyridin-4-yl)phenyl]-N-(3,3,3-trifluoropropyl)ethanesulfonamide
[1389] Example 346 was prepared according to the procedure used for
the preparation of Example 341, substituting
3,3,3-trifluoropropan-1-ol for 2-methoxyethanol, to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 7.54 (d, J=2.75 Hz, 1H), 7.31-7.44 (m, 4H), 7.23-7.30
(m, 1H), 7.05-7.11 (m, 1H), 6.89 (d, J=8.54 Hz, 1H), 6.31 (d,
J=2.75 Hz, 1H), 3.93-3.98 (m, 2H), 3.57 (s, 3H), 3.18 (q, J=7.32
Hz, 2H), 2.41-2.51 (m, 2H), 1.25 (t, J=7.32 Hz, 3H). ESI.sup.+
m/z=556.0 (M+H).sup.+.
Example 347
4-(cyclopropylmethoxy)-N-(4-fluorophenyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-
-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide
Example 347a
3-bromo-4-fluoro-N-(4-fluorophenyl)benzenesulfonamide
[1390] Example 347a was prepared according to the procedure used
for the preparation of Example 305a, substituting 4-fluoroaniline
for indoline. The crude product was purified by flash
chromatography (silica gel, 10% ethyl acetate in heptane) to afford
title compound
Example 347b
3-bromo-4-(cyclopropylmethoxy)-N-(4-fluorophenyl)benzenesulfonamide
[1391] Example 347b was prepared according to the procedure used
for the preparation of Example 29a, substituting
cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and substituting
Example 347a for Example 2a to afford the title compound.
Example 347c
4-(cyclopropylmethoxy)-N-(4-fluorophenyl)-3-(6-methyl-7-oxo-1-tosyl-6,7-di-
hydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide
[1392] Example 347c was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 347b for
Example 6b to afford the title compound.
Example 347d
4-(cyclopropylmethoxy)-N-(4-fluorophenyl)-3-(6-methyl-7-oxo-6,7-dihydro-1H-
-pyrrolo[2,3-c]pyridin-4-yl)benzenesulfonamide
[1393] Example 347d was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 347c for
Example 6c to afford the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. ppm 12.04 (s, 1H) 10.07 (s, 1H)
7.60-7.68 (m, 2H) 7.23-7.31 (m, 2H) 7.20 (d, J=9.16 Hz, 1H) 7.12
(d, J=6.78 Hz, 4H) 5.88-5.95 (m, 1H) 3.92 (d, J=6.78 Hz, 2H) 3.55
(s, 3H) 1.02-1.17 (m, 1H) 0.43-0.50 (m, 2H) 0.22-0.30 (m, 2H). MS
(ESI+) m/z 468.1 [M+H].sup.+.
Example 348
4-[2-(cyclopropylmethoxy)-5-(6-fluoropyridin-3-yl)phenyl]-6-methyl-1,6-dih-
ydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 348a
4-(2-(cyclopropylmethoxy)-5-(6-fluoropyridin-3-yl)phenyl)-6-methyl-1-tosyl-
-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1394] Example 348a was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 334a for
Example 6b and substituting (6-fluoropyridin-3-yl)boronic acid for
Example 6a to afford the title compound.
Example 348b
4-(2-(cyclopropylmethoxy)-5-(6-fluoropyridin-3-yl)phenyl)-6-methyl-1H-pyrr-
olo[2,3-c]pyridin-7(6H)-one
[1395] Example 348b was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 348a for
Example 6c to afford the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. ppm 0.21-0.28 (m, 2H) 0.41-0.49 (m, 2H)
1.03-1.15 (m, 1H) 3.57 (s, 3H) 3.91 (d, J=6.78 Hz, 2H) 6.17 (t,
J=2.71, 2.03 Hz, 1H) 7.17-7.28 (m, 3H) 733 (s, 1H) 7.63-7.69 (m,
2H) 8.23-8.32 (m, 1H) 8.54 (d, J=2.37 Hz, 1H) 11.95 (brs, 1H). MS
(ESI+) m/z 390 [M+H].sup.+.
Example 349
N-[4-(2,4-difluorophenoxy)-3-(3-formyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide
Example 349a
4-bromo-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1396] A mixture of Example 1e (7 g, 18.36 mmol) and lithium
hydroxide monohydrate (3.08 g, 73.4 mmol) in tetrahydrofuran (50
mL) and water (20 mL) was heated at 80.degree. C. overnight. After
cooling to ambient temperature, the reaction mixture was poured
into 300 mL of water. The resulting solid was collected by vacuum
filtration to give the title compound (3.92 g, 17.26 mmol, 94%
yield).
Example 349b
4-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyr-
idin-7(6H)-one
[1397] Example 349a (3.92 g, 17.26 mmol) in tetrahydrofuran (100
mL) was treated with 60% sodium hydride (1.036 g, 25.9 mmol). The
reaction was stirred at ambient temperature for 10 minutes. To this
solution was added (2-(chloromethoxy)ethyl)trimethylsilane (4.58
mL, 25.9 mmol). The reaction mixture was stirred overnight. The
resulting solid was filtered off, and the filtrate was
concentrated. The residue was purified by flash chromatography
(silica gel, 20% ethyl acetate in heptanes) to give the title
compound (5.84 g, 95% yield).
Example 349c
4-bromo-6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-
-pyrrolo[2,3-c]pyridine-3-carbaldehyde
[1398] Example 349b (3.92 g, 17.3 mmol) in dimethylformamide (15
mL) was treated with phosphorus oxychloride (9.66 mL, 104 mmol)
dropwise at 0.degree. C. After the addition was complete, the
solution was heated at 80.degree. C. for 6 hours. After cooling to
ambient temperature, the reaction mixture was partitioned between
water and ethyl acetate. The organic layer was extracted with
additional ethyl acetate twice. The combined organic layers were
washed with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 50-100% ethyl
acetate/heptanes) to give the title compound (1.35 g, 20.3%
yield).
Example 349d
4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-1-((2-(trimethyls-
ilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde
[1399] Example 349d was prepared according to the procedure used
for the preparation of Example 138a, substituting Example 349c for
2-bromo-1-fluoro-4-(methylsulfonyl)benzene, and Example 148c for
Example 6a, respectively, to provide the title compound. After
aqueous workup, the crude product was used for the next reaction
without purification.
Example 349e
N-[4-(2,4-difluorophenoxy)-3-(3-formyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrro-
lo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide
[1400] A mixture of Example 349d (0.5 g, 0.951 mmol),
ethanesulfonyl chloride (0.226 mL, 2.38 mmol) and triethylamine
(0.817 mL, 5.71 mmol) in dichloromethane (10 mL) was stirred at
ambient temperature for 2 hours. The solvent was evaporated under
reduced pressure, and the residue was treated with dichloromethane
(3 mL) and trifluoroacetic acid (3 mL). The reaction mixture was
stirred at ambient temperature for 3 hours. The solvent was removed
under reduced pressure, and the residue was treated with dioxane
(10 mL) and 2.0 N NaOH (5 mL). The reaction mixture was heated at
90.degree. C. for 2 hours. After cooling to ambient temperature,
the reaction mixture was partitioned between water and ethyl
acetate. The organic layer was extracted with additional ethyl
acetate twice. The combined organic layers were washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, ethyl acetate) to give the title
compound (0.42 g, 0.862 mmol, 91% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 13.07 (s, 1H), 9.78 (s, 1H), 9.40, (s,
1H), 7.99 (d, J=3.36 Hz, 1H), 7.38 (s, 1H), 7.23-7.31 (m, 3H),
6.89-6.97 (m, 3H), 3.55 (s, 3H), 3.10 (q, J=7.32 Hz, 2H),1.21 (t,
J=7.32 Hz, 3H). MS (ESI+) m/z 488.0 (M+H).sup.+.
Example 350
N-{4-(2,4-difluorophenoxy)-3-[6-methyl-3-(morpholin-4-ylmethyl)-7-oxo-6,7--
dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide
[1401] A mixture of Example 349e (0.04 g, 0.082 mmol), morpholine
(0.014 g, 0.164 mmol), and sodium triacetoxyhydroborate (0.035 g,
0.164 mmol) in 1,2-dichloroethane (2 mL) was stirred at ambient
temperature overnight. The solvent was evaporated under reduced
pressure, and the residue was purified by reverse phase HPLC (C18,
10-100% acetonitrile in 0.1% TFA/water) to give the TFA salt of the
title compound (0.035 g, 0.052 mmol, 63.4% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 12.59 (s, 1H), 9.86 (s, 1H), 9.58,
(s, 1H), 7.56 (s, 1H), 7.26-7.38 (m, 4H), 7.00-7.09 (m, 2H), 6.93
(d, J=8.85 Hz, 1H), 4.23-4.29 (m, 1H), 3.75-3.81 (m, 3H), 3.52 (s,
3H), 3.16 (q, J=7.32 Hz, 2H), 2.37-2.71 (m 4H), 1.24 (t, J=7.32 Hz,
3H). MS (ESI+) m/z 558.9 (M+H).sup.+.
Example 351
N-[4-(2,4-difluorophenoxy)-3-{6-methyl-3-[(4-methylpiperazin-1-yl)methyl]--
7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}phenyl]ethanesulfonamide
[1402] Example 351 was prepared according to the procedure used for
the preparation of Example 350, substituting 1-methylpiperazine for
morpholine, to provide the TFA salt of the title compound. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.11 (s, 1H), 9.86 (s,
1H), 9.58, (s, 1H), 7.29-7.35 (m, 2H), 7.20-7.22 (m, 2H), 7.11 (s,
1H), 6.97-7.06 (m, 2H), 6.91 (d, J=9.46 Hz, 1H), 3.85 (br s, 4H),
3.48 (s, 3H), 3.12-3.40 (m, 4H), 2.69 (s, 3H), 1.25 (t, J=7.32 Hz,
3H). MS (ESI+) m/z 571.9 (M+H).sup.+.
Example 352
4-{2-[(cyclopropylmethyl)amino]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-
-c]pyridin-7-one
Example 352a
2-bromo-N-(cyclopropylmethyl)aniline
[1403] A solution of 2-bromoaniline (1.720 g, 10.00 mmol),
cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), and acetic acid
(2.86 mL, 50.0 mmol) in dichloromethane (50 mL) was heated at
50.degree. C. for 1 hour. The solution was cooled in an ice bath
and sodium triacetoxyborohydride (2.119 g, 10.00 mmol) was added.
This mixture was stirred for 2 hours while warming to ambient
temperature and then partitioned between saturated sodium
bicarbonate solution (100 mL) and ethyl acetate (100 mL). The
organic layer was dried over anhydrous sodium sulfate, filtered,
and concentrated. The residue was purified by flash column
chromatography (silica gel, 0-10% ethyl acetate in heptane) to
provide the title compound (1.05 g, 93% yield).
Example 352b
4-(2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]p-
yridin-7(6H)-one
[1404] Example 352b was prepared according to the procedure used
for the preparation of Example 4a, substituting Example 352a for
Example 7c with the exception that the reaction mixture was heated
at 90.degree. C. for 2.5 hours and the material was purified by
flash column chromatography (silica gel, 0-5% methanol in
dichloromethane) to provide the title compound.
Example 352c
4-{2-[(cyclopropylmethyl)amino]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-
-c]pyridin-7-one
[1405] Example 352c was prepared according to the procedure used
for the preparation of Example 4b, substituting Example 352b for
Example 4a with the exception that the reaction was heated at
90.degree. C. for 2.5 hours and the material was purified by flash
column chromatography (silica gel, 0-5% methanol in
dichloromethane) to provide the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 10.99 (s, 1H) 7.24-7.31 (m, 2H) 7.15
(dd, J=7.32, 1.53 Hz, 1H) 6.97 (s, 1H) 6.70-6.78 (m, 2H) 6.20-6.25
(m, 1H) 3.99 (s, 1H) 3.73 (s, 3H) 2.97 (d, J=6.41 Hz, 2H) 0.90-1.02
(m, 1H) 0.38-0.45 (m, 2H) 0.09-0.15 (m, 2H). MS (ESI+) m/z 294.0
(M+H).sup.+.
Example 353
4'-(cyclopropylmethoxy)-3'-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)biphenyl-3-carbonitrile
Example 353a
4'-(cyclopropylmethoxy)-3'-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[-
2,3-c]pyridin-4-yl)biphenyl-3-carbonitrile
[1406] Example 353a was prepared according to the procedure used
for the preparation of Example 6c, substituting Example 334a for
Example 6b and substituting (3-cyanophenyl)boronic acid for Example
6a to afford the title compound.
Example 353b
4'-(cyclopropylmethoxy)-3'-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)biphenyl-3-carbonitrile
[1407] Example 353b was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 353a for
Example 6c to afford the title compound. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .quadrature. ppm 0.21-0.28 (m, 2H) 0.41-0.49 (m, 2H)
1.00-1.15 (m, 1H) 3.58 (s, 3H) 3.91 (d, J=6.78 Hz, 2H) 6.17 (t,
J=2.03 Hz, 1H) 7.20 (d, J=8.48 Hz, 1H) 7.26 (t, J=2.71 Hz, 1H) 7.33
(s, 1H) 7.63 (t, J=7.80 Hz, 1H) 7.67-7.79 (m, 3H) 8.03 (d, J=8.14
Hz, 1H) 8.16 (t, J=1.70 Hz, 1H) 11.94 (brs, 1H). MS (ESI+) m/z 396
[M+H].sup.+.
Example 354
4-{2-(cyclopropylmethoxy)-5-[(4-hydroxypiperidin-1-yl)sulfonyl]phenyl}-6-m-
ethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
Example 354a
1-(3-bromo-4-fluorophenylsulfonyl)piperidin-4-ol
[1408] Example 354a was prepared according to the procedure
described for the preparation of Example 310a, substituting
piperidin-4-ol for N,N-dimethylpyrrolidin-3-amine to afford the
title compound.
Example 354b
1-(3-bromo-4-fluorophenylsulfonyl)-4-(tetrahydro-2H-pyran-2-yloxy)piperidi-
ne
[1409] 3,4-Dihydro-2H-pyran (0.28 mL, 3.1 mmol) was added dropwise
to a 0.degree. C. solution of Example 354a (0.51 g, 1.5 mmol),
4-methylbenzenesulfonic acid hydrate (0.59 g, 3.1 mmol), and
dichloromethane (28 mL). The reaction mixture was stirred at
ambient temperature for 5 hours. Water was added and the mixture
was extracted with dichloromethane. The organic layer was washed
with water, saturated aqueous sodium chloride, dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was purified
by flash chromatography (silica gel, dichloromethane/gradient with
methanol) to afford the title compound (420 mg, 65.9% yield).
Example 354c
1-(3-bromo-4-(cyclopropylmethoxy)phenylsulfonyl)-4-(tetrahydro-2H-pyran-2--
yloxy)piperidine
[1410] Example 354c was prepared according to the procedure used
for the preparation of Example 29a, substituting
cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and substituting
Example 354b for Example 2a to afford the title compound.
Example 354d
4-(2-(cyclopropylmethoxy)-5-(4-(tetrahydro-2H-pyran-2-yloxy)piperidin-1-yl-
sulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1411] Example 354d was prepared according the to the procedure
used for the preparation of Example 6c, substituting Example 354c
for Example 6b to afford the title compound.
Example 354e
4-(2-(cyclopropylmethoxy)-5-(4-(tetrahydro-2H-pyran-2-yloxy)piperidin-1-yl-
sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1412] Example 354e was prepared according to the procedure used
for the preparation of Example 6d, substituting Example 354d for
Example 6c to afford the title compound.
Example 354f
4-(2-(cyclopropylmethoxy)-5-(4-hydroxypiperidin-1-ylsulfonyl)phenyl)-6-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
[1413] A solution of Example 354e (54 mg, 0.10 mmol), acetic acid
(4 mL, 69.9 mmol), tetrahydrofuran (2 mL) and water (1 mL) was
stirred at 45.degree. C. for 2.5 hours. The reaction mixture was
concentrated to dryness and the residue was dried overnight
(in-vacuo). The crude product was triturated with diethyl ether,
filtered and dried (in-vacuo) to afford the title compound (30 mg,
66% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .quadrature. ppm
0.25-0.31 (m, 2H) 0.44-0.51 (m, 2H) 1.08-1.17 (m, 1H) 1.38-1.51 (m,
2H) 1.70-1.80 (m, 2H) 2.70-2.80 (m, 2H) 3.10-3.18 (m, 2H) 3.51-3.56
(m, 1H) 3.57 (s, 3H) 3.97 (d, J=6.78 Hz, 2H) 4.66 (d, J=4.07 Hz,
1H) 6.12 (t, J=2.71, 2.03 Hz, 1H) 7.27-7.32 (m, 2H) 7.36 (s, 1H)
7.64-7.70 (m, 2H) 12.04 (brs, 1H). MS (ESI+) m/z 458
[M+H].sup.+.
Biological Examples
Bromodomain Domain Binding Assay
[1414] A time-resolved fluorescence resonance energy transfer
(TR-FRET) assay was used to determine the affinities of compounds
of the Examples listed in Table 1 for each bromodomain of human
BRD4. His-tagged first (BD1: amino acids K57-E168) and second (BD2:
amino acids E352-E168) bromodomains of human BRD4 were expressed
and purified. An Alexa647-labeled BET-inhibitor was used as the
fluorescent probe in the assay.
Synthesis of Alexa647-labeled bromodomain inhibitor compound
2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triaz-
olo[4,3-a][1,4]diazepin-6-yl)acetic acid
[1415] Methyl
2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triaz-
olo[4,3-a][1,4]diazepin-6-yl)acetate (see e.g., WO
2006129623)(100.95 mg, 0.243 mmol was suspended in 1 mL methanol to
which was added a freshly prepared solution of lithium hydroxide
monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken at ambient
temperature for 3 hours. The methanol was evaporated and the pH
adjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) and
extracted four times with ethyl acetate. The combined ethyl acetate
layers were dried over magnesium sulfate and concentrated to afford
2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triaz-
olo[4,3-a][1,4]diazepin-6-yl)acetic acid (85.3 mg, 87.0%); ESI-MS
m/z=401.1 [(M+H).sup.+]which was used directly in the next
reaction.
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-tr-
imethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide
bis(2,2,2-trifluoroacetate)
[1416]
2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4-
]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (85.3 mg, 0.213
mmol) was combined with 2,2'-(ethane-1,2-diylbis(oxy))diethanamine
(Sigma-Aldrich, 0.315 mg, 2.13 mmol) were combined in 5 mL
anhydrous dimethylformamide.
(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium
hexafluorophosphate(V) (PyBOB, CSBio, Menlo Park Calif.; 332 mg,
0.638 mmol) was added and the reaction shaken at ambient
temperature for 16 hours. The reaction mixture was diluted to 6 mL
with dimethylsulfoxide:water (9:1, v:v) and purified in two
injections with time collection Waters Deltapak C18 200.times.25 mm
column eluted with a gradient of 0.1% trifluoroacetic acid (v/v) in
water and acetonitrile. The fractions containing the two purified
products were lyophilized to afford
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)--
2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)a-
cetamide bis(2,2,2-trifluoroacetate) (134.4 mg, 82.3%); ESI-MS
m/z=531.1 [(M+H)+]; 529.1 [(M-H)-] and
(S,Z)-N,N'-(2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(2-((6S-
,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-
-a][1,4]diazepin-6-yl)acetamide)bis(2,2,2-trifluoroacetate) (3.0
mg, 1.5%); ESI-MS m/z=913.2 [(M+H)+]; 911.0 [(M-H)-].
N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophen-
yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6--
yl)acetamide(2,2,2-trifluoroacetate)
[1417]
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2-
,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)ac-
etamide bis(2,2,2-trifluoroacetate) (5.4 mg, 0.0071 mmol) was
combined with Alexa Fluor.RTM. 647 carboxylic Acid, succinimidyl
ester (Life Technologies, Grand Island, N.Y.; 3 mg, 0.0024 mmol)
were combined in 1 mL anhydrous dimethylsulfoxide containing
diisopropylethylamine (1% v/v) and shaken at ambient temperature
for 16 hours. The reaction was diluted to 3 mL with
dimethylsulfoxide:water (9:1, v:v) and purified in one injection
with time collection Waters Deltapak C18 200.times.25 mm column
eluted with a gradient of 0.1% trifluoroacetic acid (v/v) in water
and acetonitrile. The fractions containing the purified product
were lyophilized to afford
N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophe-
nyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-
-yl)acetamide(2,2,2-trifluoroacetate) (1.8 mg); MALDI-MS
m/z=1371.1, 1373.1 [(M+H).sup.+] as a dark blue powder.
[1418] Assay
[1419] Compound dilution series were prepared in DMSO via a 3-fold
serial dilution from 2.5 mM to 42 nM. Compounds were then diluted
6:100 in assay buffer (20 mM Sodium Phosphate, pH 6.0, 50 mM NaCl,
1 mM Ethylenediaminetetraacetic acid disodium salt dihydrate, 0.01%
Triton X-100, 1 mM .quadrature.L-Dithiothreitol) to yield 3.times.
working solutions. Six microliters (.quadrature.L) of the working
solution was then transferred to white, low-volume assay plates
(Costar #3673). A 1.5.times. assay mixture containing His-tagged
bromodomain, Europium-conjugated anti-His antibody (Invitrogen
PV5596) and the Alexa-647-conjugated probe molecule was also
prepared. Twelve .quadrature.L of this solution were added to the
assay plate to reach a final volume of 18 .quadrature.L. The final
concentration of 1.times. assay buffer contains 2% DMSO, 50
.quadrature.M-0.85 nM compound, 8 nM His-tagged bromodomain, 1 nM
Europium-conjugated anti-His-tag antibody and 100 nM or 30 nM probe
(for BDI or BDII, respectively). After a one-hour incubation at
room temperature, TR-FRET ratios were determined using an Envision
multilabel plate reader (Ex 340, Em 495/520).
[1420] TR-FRET data were normalized to the means of 24 no-compound
controls ("high") and 8 controls containing 1 .mu.M un-labeled
probe ("low"). Percent inhibition was plotted as a function of
compound concentration and the data were fit with the 4 parameter
logistic equation to obtain IC.sub.50s. Inhibition constants
(K.sub.i) were calculated from the IC.sub.50s, probe K.sub.d and
probe concentration. Typical Z' values were between 0.65 and 0.75.
The minimum significant ratio was determined to evaluate assay
reproducibility (Eastwood et al., (2006) J Biomol Screen, 11:
253-261). The MSR was determined to be 2.03 for BDI and 1.93 for
BDII, and a moving MSR (last six run MSR overtime) for both BDI and
BDII was typically <3. The K.sub.i values are reported in Table
1.
MX-1 Cell Line Proliferation Assay
[1421] The impact of compounds of the Examples on cancer cell
proliferation was determined using the breast cancer cell line MX-1
(ATCC) in a 3-day proliferation assay. MX-1 cells were maintained
in RPMI 1640 medium (Sigma) supplemented with 10% FBS (Fetal Bovine
Serum) at 37 C..degree. and an atmosphere of 5% CO.sub.2. For
compound testing, MX-1 cells were plated in 96-well black bottom
plates at a density of 5000 cells/well in 90 .mu.L of culture media
and incubated at 37.degree. overnight to allow cell adhesion and
spreading. Compound dilution series were prepared in DMSO via a
3-fold serial dilution from 3 mM to 0.1 .quadrature.M. The DMSO
dilution series were then diluted 1:100 in phosphate buffered
saline, and 10 .quadrature.L of the resulted solution were added to
the appropriate wells of the MX-1 cell plate. The final compound
concentrations in the wells were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003,
0.001, 0.0003 and 0.0001 .quadrature.M. After the addition of
compounds, the cells were incubated for 72 more hours and the
amounts of viable cells were determined using the Cell Titer Glo
assay kit (Promega) according to manufacturer suggested protocol.
Luminescence readings from the Cell Titer Glo assay were normalized
to the DMSO treated cells and analyzed using the GraphPad Prism
software with sigmoidal curve fitting to obtain EC.sub.50s. The
minimum significant ratio (MSR) was determined to evaluate assay
reproducibility (Eastwood et al., (2006) J Biomol Screen, 11:
253-261). The overall MSR was determined to be 2.1 and a moving MSR
(last six run MSR overtime) has been <2.
Proliferation Panel Assay
[1422] The compounds of Examples 4 and 78 were tested for their
impact on proliferation of a panel of cancer cell lines types (with
specific cell line tested) as set out in (Table 2). Cells were
plated in 96-well plates at 1500 cells/well in the appropriate
culture media without test compound and incubated overnight at
37.degree. C. and an atmosphere of 5% CO.sub.2. Series dilution of
compounds were prepared and added to the wells as in the MX-1
proliferation assay. After the addition of compounds, cells were
incubated for another 3 days at 37.degree. C. and an atmosphere of
5% CO.sub.2. The amounts of viable cells were determined using the
Cell Titer Glo assay kit (Promega) according to manufacturer
suggested protocol. Cell proliferation data were analyzed as
described above in the MX-1 proliferation assay to obtain the
EC.sub.50 for the compounds of Examples 4 and 78 and reported in
Table 2.
TABLE-US-00001 TABLE 1 TR-FRET Binding TR-FRET Binding Cellular Ki:
BRD4 Ki: BRD4 proliferation: Compound (BDI_K57-E168)
(BDII_E352-M457) EC.sub.50 of Ex. No. (.mu.M) (.mu.M) (.mu.M) 1
0.136* 0.0410* 0.137 2 0.529* 0.178* 0.860 3 0.0646 0.0736 0.185 4
0.0014* 0.0020* 0.0164 5 0.0150 0.0064 0.0310 6 0.0053 0.0058
0.0460 7 0.119 0.0773 >3.0 8 0.0026 0.0039 0.0244* 9 0.0180
0.0101 0.113* 10 0.0154 0.0086 >3.0 11 0.0018 0.0024 0.0342 12
1.8 4.33 >3.0 13 0.0037 0.0034 0.128 14 0.0055 0.0123 0.170 15
0.0042 0.0075 0.140 16 0.0043 0.0053 0.0946 17 0.0171* 0.0322*
0.283 18 0.0102* 0.0103* 0.209 19 0.0074 0.0042 0.123 20 0.0109
0.00068 0.190 21 0.00039 0.00025 0.0139* 22 0.0022 0.0010 0.0652 23
0.0012 0.00075 0.0459 24 0.0025 0.0021 0.0126 25 0.0030 0.0036
0.0562 26 0.0021 0.0033 0.0171 27 0.0025* 0.0022* 0.0317 28 0.0017
0.0020 0.0239 29 0.0011 0.0067 0.0718 30 0.0177 0.0104 0.562 31
0.0018 0.0134 0.0398 32 0.0160 0.0075 0.0833 33 0.0026 0.0048
0.0417 34 0.0035 0.0021 0.0268 35 0.661 1.14 NA 36 0.0035* 0.0014*
0.0174* 37 0.0113 0.0108 0.0593 38 0.148 0.257 NA 39 0.112 0.124 NA
40 0.0145 0.0439 0.167 41 0.0028 0.00051 0.0298 42 0.0546 0.0934
>3.0 43 0.0017 0.0012 0.0169 44 0.286 0.236 0.828 45 0.0128
0.0190 0.233 46 0.0516 0.0169 0.588 47 0.235 0.205 1.1 48 0.0023
0.0033 0.0235 49 0.0017* 0.0015* 0.0196* 50 0.0215 0.0081 0.206* 51
0.0097 0.0161 0.101 52 0.0241 0.0260 0.309 53 0.0622 0.0054 0.0765
54 0.0951 0.0375 0.266 55 0.0555 0.0336 0.200 56 0.0122 0.0024
0.251 57 0.00088 0.0020 0.0138* 58 0.0021 0.0081 0.0451 59 0.00084
0.0016 0.0187* 60 0.00075 0.0066 0.0142* 61 >13.0 >22.2 NA 62
0.0030* 0.0019* 0.0079* 63 0.0180 0.0427 0.105 64 0.0531* 0.0633*
0.773 65 0.0116* 0.0049* 0.0255 66 0.00074 0.0034 0.0332 67 0.0561*
0.0938* 0.341 68 1.7 2.55 5.9 69 0.0390 0.0123 0.140 70 0.0118
0.0468 >3.0 71 0.00081* 0.0012* 0.0175* 72 0.0015* 0.0011*
0.0457* 73 0.00098 0.00050 0.0207 74 0.0961 0.101 0.275 75 0.137
0.0594 0.478 76 0.0658 0.0297 0.290 77 0.0124 0.0157 >3.0 78
0.0025 0.0018 0.400 79 0.0062 0.0018 0.887 80 0.0091 0.0061 0.0620
81 0.0095 0.00099 0.103 82 0.519 0.183 0.767 83 0.0209 0.0422 0.424
84 0.00167 0.00065 0.231 85 0.0064 0.0017 0.0520 86 0.0043 0.0024
0.182 87 0.0056 0.0067 0.0534 88 0.635 0.236 >3.0 89 0.0016
0.0021 0.0252* 90 0.0040 0.0068 0.0168 91 0.0122 0.0874 0.240 92
0.0025 0.0253 0.0840 93 0.0076 0.0322 0.120 94 0.0162 0.0100 0.110
95 0.0087 0.0011 0.0560 96 0.00063 0.0011 0.0160 97 0.0023 0.0028
0.0140 98 0.0065 0.0027 0.0529 99 0.0035 0.0247 0.0977 100 0.0014
0.0027 0.107 101 0.0012 0.0043 0.0112 102 0.0034 0.0242 0.0615 103
0.0019 0.0038 0.0338 104 0.0044 0.0179 0.0653 105 0.00052 0.0015
0.0160 106 0.0013 0.0109 0.0468 107 0.00050 0.00087 0.0310 108
0.0014 0.0053 0.0380 109 0.00072 0.0034 0.0320 110 0.0031 0.0051
0.0324 111 0.0087 0.0103 0.199 112 0.0169 0.0206 0.240 113 0.0474
0.381 >3.0 114 0.136 0.121 >3.0 115 0.0671 0.0269 0.0550 116
0.105 0.0891 NA 117 2.3 0.486 NA 118 NA NA NA 119 0.0444 0.0225 NA
120 0.190 0.304 NA 121 0.0155 0.0334 0.251 122 NA NA NA 123 0.0271
0.0361 0.118 124 0.320 0.169 NA 125 0.215 0.274 NA 126 2.0 0.768 NA
127 NA NA NA 128 0.0725 0.112 NA 129 0.0379 0.0456 0.118 130 0.183
0.174 NA 131 0.0986 0.0600 NA 132 0.238 0.344 NA 133 NA NA NA 134
0.0435 0.0073 0.137* 135 0.274 0.0774 NA 136 0.234 0.295 NA 137
0.0687 0.0089 0.303* 138 0.0167 0.0095 0.0851 139 7.1 3.89 NA 140
3.6 1.58 NA 141 0.0054 0.0152 0.125 142 0.0065 0.0794 0.138 143
0.0223 0.107 0.370 144 0.0136 0.0178 0.0769 145 0.0027 0.0056
0.0264 146 0.0075 0.0019 0.0609 147 0.0021 0.0011 0.0148 148 0.205
0.152 0.740 149 0.0115 0.0030 0.0297 150 0.0097 0.0042 0.0665 151
0.0107 0.0081 0.0549 152 0.0246 0.0048 0.105 153 0.0228 0.0082
0.0933 154 0.0208 0.0131 0.0655 155 0.0193 0.0148 0.117 156 0.0113
0.0209 0.114 157 0.0308 0.0218 0.150 158 0.0041* 0.0097* 0.0243*
159 0.0370 0.0207 0.0624 160 0.0416 0.0065 0.119 161 0.0204 0.0055
0.104 162 0.0111 0.0046 0.127 163 0.0857 0.0235 0.295 164 NA NA NA
165 0.0050 0.0022 0.104 166 0.0109 0.0036 0.0482 167 0.0065 0.0122
0.0430 168 0.0054 0.0013 0.0277 169 0.00088* 0.00086* 0.0053 170
0.0228 0.0940 0.332 171 0.0138 0.0103 NA 172 0.0133 0.0059 NA 173
0.0157 0.0066 NA 174 0.0192 0.0143 NA 175 0.0258 0.0178 NA 176
0.0213 0.0060 NA 177 0.0113 0.0044 0.0535 178 0.0105 0.0032 0.0362
179 0.0225 0.0165 NA 180 0.0179 0.0071 0.115 181 0.0305 0.0224 NA
182 0.0190 0.0097 NA 183 0.0412 0.0198 NA 184 0.0166 0.0045 0.0788
185 0.0345 0.0122 NA 186 0.0101 0.0033 0.0484 187 0.0248 0.0082 NA
188 0.0294 0.0180 NA 189 0.0304 0.0230 NA 190 0.0346 0.0181 NA 191
0.0178 0.0088 NA 192 0.0513 0.0096 NA 193 0.0704 0.0136 NA 194
0.0289 0.0191 NA 195 5.5 1.02 NA 196 9.5 0.479 NA 197 0.0015
0.00079 0.0117 198 0.0013 0.0016 0.0093* 199 0.0019 0.0035 NA 200
0.00086 0.0011 0.0113 201 0.0102 0.0407 0.135 202 0.0017 0.0014
0.0228* 203 0.00069 0.00075 0.0047 204 0.0205 0.0102 0.0829 205
0.0062 0.0102 0.0391* 206 0.0116 0.0228 0.0777 207 0.0031 0.0018
0.0251* 208 0.0056 0.0060 0.0235 209 0.0046 0.0036 0.0368 210
0.0045 0.0053 0.0367 211 0.0014 0.0021 0.0119 212 0.0018 0.0013
0.0073 213 0.0032 0.0048 0.0287 214 0.0024 0.0017 0.0105 215
0.00083 0.00046 0.0019 216 0.0018 0.0018 0.0066 217 0.0033 0.0081
0.0342 218 0.0693 0.0689 NA 219 0.0036 0.0029 0.0177 220 0.0028
0.0012 0.0213 221 0.0066 0.0050 0.0061 222 0.225 0.969 NA 223
0.0024 0.0050 0.0133 224 0.0069 0.0070 0.0076 225 0.264 0.845 NA
226 0.141 0.438 >3.0 227 0.0739 0.211 0.658 228 0.0390 0.108
>3.0 229 0.0343 0.0613 0.288 230 0.0026 0.0015 0.0236 231 0.0037
0.0067 0.0063 232 0.213 0.443 NA 233 0.0022* 0.0015* 0.0069* 234
0.0030 0.0034 0.0159 235 0.0174 0.0070 0.0665 236 0.0145 0.0051
0.0250 237 0.0030 0.0035 0.0350 238 0.0011 0.00078 0.0033 239
0.0028 0.0024 0.0101 240 0.0020 0.0028 0.0115 241 0.332 0.603 NA
242 0.0365 0.0058 0.289
243 0.0115 0.0382 0.249 244 0.0232 0.0737 0.254 245 0.0025 0.0037
0.0269 246 0.0180 0.0046 0.0975 247 1.1 3.00 NA 248 0.0019 0.0013
0.0264* 249 0.0015 0.00083 0.0144* 250 0.0015* 0.0015* 0.0180* 251
0.0631 0.171 0.573 252 0.0101 0.0017 0.246 253 0.0204 0.0012 0.145
254 0.0796 0.0087 0.0751 255 0.0105 0.154 0.265 256 0.0061 0.0840
0.405 257 0.0588 0.0030 0.360 258 0.0059 0.0124 0.0765 259 0.0242
0.0203 0.123 260 0.0010 0.0012 0.0063 261 0.0015 0.0016 0.0072 262
0.125 0.489 NA 263 0.0088 0.0163 0.0769 264 0.0012 0.0012 0.0178
265 0.0090 0.0356 >3.0 266 0.0215 0.0078 0.0564 267 0.0044
0.0042 0.0436 268 0.00076 0.00057 0.0062 269 0.0124 0.0569 0.329
270 0.0487 0.0226 0.421 271 0.0029 0.0019 0.0213 272 0.0102 0.0116
0.112 273 0.0012 0.0013 0.0090 274 0.0933 0.310 NA 275 0.526 1.13
NA 276 0.0114 0.0171 0.149 277 0.0063 0.0143 0.0211 278 0.0121
0.0112 0.135 279 0.0314 0.131 0.364 280 0.0192 0.0920 0.292 281
0.0018 0.108 0.191 282 0.0173 0.0723 0.204 283 0.0189 0.0346 0.138
284 0.0183 0.130 0.131 285 0.0108 0.0075 0.111 286 0.0121 0.0054
0.0746 287 0.0089 0.0095 0.0195* 288 0.0719 0.0539 0.173 289 0.0124
0.310 >3.0 290 0.0050 0.0019 0.0362 291 0.0329 0.0237 NA 292
0.0532 0.0558 0.366 293 0.180 0.0193 0.381 294 0.0479 0.0217 0.332
295 0.0279 0.0307 0.223 296 0.705 0.101 0.535 297 0.0142 0.0052
0.0186 298 0.0029 0.0031 0.0061 299 0.0801 0.0050 0.0360 300 0.389
0.190 0.176 301 0.0179 0.0155 0.0421 302 0.0058 0.0035 0.0169 303
0.0039 0.0071 0.335* 304 0.0090 0.0218 0.0323 305 0.327 0.0257
0.110 306 0.0822 0.0639 0.0516 307 0.0024 0.0029 0.122 308 0.0499
0.0065 0.0293 309 0.0306 0.0169 0.0859 310 0.0409 0.0711 0.103 311
0.0148 0.0045 0.0224 312 0.0141 0.0190 0.0675 313 0.0158 0.0061
0.0509 314 1.6 1.29 NA 315 0.0376 0.231 0.160 316 >2.4 3.07 NA
317 0.0067 0.0036 0.0168 318 0.346 0.625 >3.0 319 0.372 0.0099
0.435 320 0.0030 0.0037 0.0187 321 0.0334 0.0321 0.0344 322 0.181
0.0456 0.0668 323 0.0231 0.0255 0.0377 324 0.0032 0.0012 NA 325
0.155 0.199 0.703 326 0.145 0.272 0.286 327 0.0085 0.0042 0.0354
328 0.0245 0.0797 0.0426 329 0.0089 0.0126 0.0171 330 0.0509 0.0046
0.0306 331 0.561 0.311 0.481 332 0.0304 0.0306 0.0531 333 0.0369
0.0327 0.0740 334 0.661 1.17 0.515 335 0.0111 0.0536 0.0224 336
0.0762 0.152 0.115 337 0.0043 0.0042 0.0158 338 0.00086 0.0127
0.0779 339 0.00080 0.0316 0.0774 340 0.942 1.25 NA 341 0.295 0.0817
0.622 342 0.0719 0.0115 0.510 343 0.0427 0.0048 0.224 344 0.430
0.136 0.636 345 0.129 0.0326 0.479 346 0.0962 0.0160 0.213 347
0.0156 0.0040 0.0839 348 0.157 0.422 1.0 349 0.0066 0.0031 0.0321
350 1.4 0.505 NA 351 0.223 0.153 1.1 352 0.404 0.625 NA 353 0.158
0.256 0.786 354 0.066 0.0129 0.0954 *indicates average value of
multiple experiments NA means not determined
TABLE-US-00002 TABLE 2 Compound Compound of Example 4 of Example 78
Cellular Cellular Proliferation Proliferation Cell line Type Cell
Line EC.sub.50 (.mu.M) EC.sub.50 (.mu.M) AML SKM1 0.005 0.058 AML
Raji 0.006 0.084 Bladder EJ-1 0.202 2.090 Breast MDAMB231 0.22 1.22
Breast MDAMB453 0.02 0.24 Colon GEO 0.08 1.29 Colon DLD-1 0.20 4.97
Glioblastoma D54MG 0.038 2.299 Head & Neck FaDu 0.02 0.39
Hepatocellular HepG2 0.074565 0.8851 Melanoma A-375 0.020 3.606
Multiple OPM2 0.001 0.039 Myeloma Multiple RPMI-8226 0.011 1.402
Myeloma Multiple NCI-H929 0.003 0.154 Myeloma NHL Ramos 0.02 0.32
NHL Ly18 0.02 0.42 NSCLC H1299 0.06 2.57 NSCLC H1975 0.02 1.37
NSCLC H460 3.77 >10 Pancreas HPAC 0.05 1.19 Pancreas BxPC3FP5
0.01 0.74 Prostate PC3M 0.07 8.11 RCC 786-0 0.011 0.884 Sarcoma
SK-LMS-1 0.025 0.934
Human, Rat, and Mouse Microsome Stability Assay
[1423] Microsome stability assays were carried out on compounds of
the Examples listed in Table 3 ("test compounds"). Human, rat, and
mouse liver microsomal incubations were carried out at 37.degree.
C. with a final incubation volume of 135 L. Human liver microsomes
(mixed gender, Catalog No. H2610) were obtained from XenoTech. Rat
liver microsomes (male Sprague-Dawley, Catalog No. 42501) were
obtained from BD Gentest. Mouse liver microsomes (male CD1, Catalog
No. 452701) were obtained from BD Gentest. Incubations were
conducted using a test compound (initially dissolved in DMSO at 5
.mu.M concentration) concentration of 0.5 .mu.M and 0.25 mg/mL
microsomal protein in 50 mM phosphate buffer at pH 7.4. Time zero
samples were prepared by transferring 13.5 .mu.L of
compound-microsomal mix to the quench plates containing 45 .mu.L of
quench solution made of 10 nM Buspirone (Sigma) or 50 nM
Carbutamide (Princeton Bio) as internal standard in 1:1
methanol:acetonitrile. An aliquot of 1.5 .mu.L
.quadrature..quadrature.Nicotinamide adenine dinucleotide phosphate
reduced tetrasodium salt (NADPH) was also added to the time zero
plates. The reaction was then initiated by the addition of 13.5
.mu.L NADPH to the compound-microsomal mix. At each of the
remaining time points (5, 10, 15, 20 and 30 min) 15 .mu.L of
incubation mixture was added to 45 .mu.L of quench solution.
Samples were centrifuged for 15-30 minutes at 3800 rpm. Samples
were then pooled for 6 per group. An aliquot of 60 .mu.L of
supernatant was transferred to 384-well plate, and a 5 .mu.L
aliquot was injected and analyzed by LC-MS/MS (Applied Biosystems
API 5500 QTrap). The intrinsic clearance of a compound was
calculated by converting the peak area ratios (analyte peak area/IS
peak area) to % parent remaining using the area ratio at time 0 as
100%. The slope (k) was determined from the plot of the % parent
remaining versus incubation time, from which the half life
(t.sub.1/2; minutes), intrinsic clearance (CL.sub.int; .mu.L/min/mg
protein for liver microsomes and .mu.L/min/million cells for
hepatocytes) and scaled intrinsic clearance (scaled CL.sub.int;
L/h/kg) were then derived. The t.sub.1/2 values are reported in
Table 3. The term "N/A" means not determined.
TABLE-US-00003 TABLE 3 Stability in human Stability in rat
Stability in mouse Compound liver microsomes liver microsomes liver
microsomes of Ex. No. (t.sub.1/2 in minutes) (t.sub.1/2 in minutes)
(t.sub.1/2 in minutes) 1 9 1 1 4 59 4 57 5 100 6 24 6 30 7 3 7 12 2
4 8 19 1 9 9 NA 1 1 10 78 >120 >120 11 48 19 27 12 51 10 33
13 66 2 22 14 37 6 8 15 10 4 7 16 >120 4 22 17 31 18 16 18 31 11
15 19 92 13 33 20 18 1 7 21 >120 3 22 22 32 3 10.7 23 64 11
>120 24 29 5 55 27 32 >120 59 28 21 9 NA 29 >120 26
>120 31 56 >120 19 32 24 82 32 33 >120 >120 46 34 37 42
35 35 37 >120 42 36 >120 >120 41 37 88.9 54 3 38 16.8 25
NA 39 09.7 8 NA 40 13.1 1 6 41 13.6 1 10 42 >120 >120 >120
43 34.9 2 5 44 33.7 6 27 45 NA 2 3 46 10 4 13 47 8 3 5 48 37 32 35
49 71 51 46 50 35 88 46 51 6 63 >120 54 3 30 2 55 25 9 13 56 39
30 36 57 13 6 5 58 >120 1 4 59 >120 40 23 60 68 64 34 61
>120 >120 >120 62 64 45 25 63 39 13 18 64 NA 3 4 65 88
>120 11 66 >120 >120 NA 67 6 5 6 69 6 2 3 70 41 9 68 71 2
1 6 72 34 1 70 73 36 2 31 74 17 3 5 75 9 3 4 80 62 2 31 82 19 2 2
83 NA 3 43 84 112 92 >120 85 43 6 34 86 >120 >120 43 87
>120 23 NA 88 23 12 NA 91 17 7 7 92 97 20 11 93 54 102 25 94 47
28 25 95 >120 7 36 96 24 13 33 97 26 9 28 98 26 33 10 99 >120
22 35 100 77 71 60 101 92 12 20 102 36 3 8 103 47 16 37 104 27 8 7
105 >120 13 7 106 39 8 4 107 71 16 8 108 37 33 13 109 71 61
>120 111 >120 42 63 112 49 28 51 114 13 5 8 115 41 38 55 117
34 36 1 118 81 34 18 119 14 24 2 >120 19 12 10 121 21 25 24 122
8 16 2 123 >120 >120 45 124 2 4 NA 125 45 23 12 126 100 21 25
127 44 71 20 128 11 21 4 129 54 38 12 131 >120 71 83 133 4 5 3
134 15 21 2 135 8 24 5 137 38 31 10 138 52 51 45 139 13 8 7 140 19
13 18 141 >120 110 49 142 112 35 32 144 18 19 17 145 >120 12
16 146 >120 52 55 147 11 8 32 148 58 2 6 152 51 10 22 153 33 8
11 154 42 66 18 155 >120 >120 25 156 >120 >120 33 157
27 53 12 158 >120 >120 >120 159 89 107 59 160 67 119 21
161 5 10 4 162 96 41 11 165 >120 111 27 166 85 23 22 168 66 82
25 169 86 34 38 170 >120 113 27 171 15 13 9 172 9 15 7 173 38 5
16 174 40 46 14 176 48 8 29 177 16 6 18 178 27 7 10 179 80 55 34
180 12 7 5 186 9 3 8 187 9 4 5 188 26 22 6 189 34 55 NA 190 27 66 8
191 7 6 2 192 9 5 3 193 11 7 2 194 41 38 49 195 13 1 1 196 59 5 3
197 16 15 10 198 NA NA 55 199 94 1 3 200 >120 31 >120 201 56
117 >120 202 NA >120 NA 203 NA >120 NA 204 >120 81 68
205 >120 81 118 206 >120 118 95 207 102 78 100 208 88 23 37
209 >120 105 116 210 104 >120 >120 211 65 48 63 212 69 67
53 213 79 38 89 214 27 9 8 215 12 6 11 217 70 101 68 218 >120
>120 >120 220 5 5 4 221 63 24 43 222 65 80 98 223 54 24 48
224 6 8 5 225 52 59 >120 226 105 >120 >120 227 50 70
>120 228 >120 107 >120 229 25 33 9 230 6 8 7 231 33
>120 72 232 57 >120 >120 235 81 49 22 236 33 32 15 237 3 7
2 238 103 >120 63 240 >120 >120 47 241 39 9 4 242 >120
86 >120 243 >120 20 109 244 53 6 87 245 32 24 12 246 52 53 56
248 13 16 5 249 >120 >120 >120 250 56 36 37 251 118 23 44
252 68 >120 >120 253 72 110 90 254 74 >120 91 255 70
>120 >120 256 58 58 71 257 18 56 20.3 258 42 91 69.8 259 117
87 NA 260 34 58 29 261 25 5 16 262 >120 25 NA 263 70 72 NA 264
14 6 NA 265 >120 >120 NA 266 8 20 NA 267 95 18 >120 268 10
26 NA 269 79 83 58 270 >120 >120 >120 271 23 12 11 272 2 4
1 273 9 12 8 276 >120 82 71 277 4 5 1 278 >120 >120
>120 279 NA 41 91 280 17 84 36 281 25 119 116 282 9 21 7 283 7
22 12 284 12 108 >120
285 19 10 12 286 10 19 11 287 >120 116 29 288 85 >120 >120
290 73 48 52 291 16 8 16 292 8 22 12 293 4 9 3 294 >120 >120
>120 295 7 15 3 296 7 13 6 297 83 43 NA 298 9 47 3 299 1 2 1 300
30 21 17 301 20 82 13 302 5 4 3 303 42 69 >120 304 >120 65 72
305 1 2 2 306 11 9 3 307 3 3 2 308 20 10 16 309 >120 >120
>120 310 8 5 9 311 >120 83 >120 312 56 32 9 313 5 4 3 314
81 4 6 315 34 4 11 316 47 3 12 317 88 115 83 318 35 24 13 319 2 2 2
320 >120 57 116 321 >120 103 >120 322 >120 57 >120
323 >120 >120 >120 324 >120 >120 >120 325 21 10 8
326 112 5 27 327 >120 >120 >120 328 >120 36 >120 329
>120 >120 >120 330 29.9 12 28 331 >120 >120 >120
332 65 70 >120 333 0.8 3 1 334 34 NA 21 335 35 34 54 336 44 5 17
337 >120 >120 >120 338 39 29 20 339 100 76 67 340 >120
4 9 342 2 5 1 343 2 7 1 344 NA NA 1 345 2 4 2 346 4 5 2 347 4 6 NA
348 >120 2 25 349 >120 39 36 350 59 32 23 351 76 66 30 353 40
8 10 354 23 41 24
LPS (Lipopolysaccharide) Induced IL-6 Production Mouse Assay
[1424] Compounds of the Examples listed in Table 4 were assayed for
their ability to inhibit LPS (lipopolysaccharide) induced IL-6
production in mice. Fox Chase SCID.RTM. female mice (Charles Rivers
Labs, 8 per group) received an intraperitoneal challenge of
lipopolysaccharide (2.5 mg/kg, L2630 E. coli 0111:B4) one hour
after oral administration of compounds. Mice were euthanized 2
hours after lipopolysaccharide injection, blood was removed by
cardiac puncture, and then the serum harvested from the blood
samples was frozen at -80.degree. C. On the day of the assay the
serum samples were brought to room temperature and then diluted
1:20 in phosphate-buffered saline containing 2% bovine serum
albumin. Interleukin-6 measurements were performed using a cytokine
assay from Meso Scale Discovery (Gaithersburg, Md.) for mouse serum
analysis according to the manufacturer's protocol and read on a
SECTOR Imager 6000 (Meso Scale Discovery, Gaithersburg, Md.)
instrument. Statistical analysis was performed using Prism software
(version 5.0) incorporating Dunnett's one way ANOVA. The IL-6 mean
and standard deviation of the group of vehicle treated animals were
compared with the IL-6 mean and standard deviation of the group
treated with test compound. A p value <0.05 means that there is
less than a 5% probability that the mean values in the two groups
are equal. The % inhibition values in Table 4 all exhibited a p
value less than 0.05.
TABLE-US-00004 TABLE 4 Inhibition of LPS induced IL-6 production in
Mice Example # % inhibition at 3 mg/kg 4 69* 5 74% at 50 mg/kg 11
34 24 58 26 60 27 89 28 52 32 69 34 78 36 78* 48 62 49 57 56 28 59
54 62 67 65 63 80 69% at 30 mg/kg 84 69 85 80 86 55 87 57 138 72
144 48 146 80 147 61 149 69 150 54 151 66 154 73 159 58 160 51 162
41 166 44 167 64 168 70 169 67 197 59 198 66 200 75 202 68 203 78
204 35 205 48 207 62 210 78 212 47 231 51 238 69 240 62 242 46 245
71 246 71 248 82 249 59 260 66 267 74 273 47 276 25 278 51 286 57
287 73 288 60 290 64 294 79 304 67 308 48 311 74 321 63 328 40 329
63 330 45 *indicates average value of multiple experiments
Xenograft Tumor Growth Inhibition Assay
[1425] The effect of the compound of Example 36 to inhibit the
growth of OPM-2 and MX-1 xenograft tumors implanted in mice was
evaluated. Briefly, 5.times.10.sup.6 human cancer cells (OPM-2) or
1:10 tumor brie (MX-1) (in S-MEM (MEM, Suspension, no Calcium, no
Glutamine))(Life Technologies Corporation) was inoculated
subcutaneously into the right hind flank of female SCID-beige or
female Fox Chase SCID.RTM. (Charles River Labs) mice respectively
on study day 0. Administration of compound (in (2% EtOH, 5%
Tween-80, 20% PEG-400, 73% HPMC))(PO, QDx14) was initiated at the
time of size match on day 17 (OPM-2) or day 12 (MX-1). The tumors
were measured by a pair of calipers twice a week starting at the
time of size match and tumor volumes were calculated according to
the formula V=L.times.W.sup.2/2 (V: volume, mm.sup.3; L: length,
mm. W: width, mm). Tumor volume was measured for the duration of
the experiment until the mean tumor volume in each group reached an
endpoint of >1000 mm.sup.3 for OPM-2 or until day 27 post
inoculation for MX-1. Results are shown in Tables 5 and 6.
TABLE-US-00005 TABLE 5 OPM-2 human multiple myeloma cancer
xenograft model. Group Treatment Dose route, regimen % TGI .sup.a %
TGD .sup.b 1 Vehicle 0 mg/kg/day IP, QDx14.sup. -- -- 2 Compound of
3 mg/kg/day PO, QDx14 90*** 78*** Example 36 .sup.a Tumor growth
inhibition, % TGI = 100 - mean tumor volume of treatment group/mean
tumor volume of control group .times. 100. Number of mice per
treatment group = 10. The p values (as indicated by asterisks) are
derived from Student's T test comparison of treatment group vs.
control group. Based on day 31. *p < 0.05, **p < 0.01, ***p
< 0.001. .sup.b Tumor growth delay, % TGD = (T - C)/C .times.
100, where T = median time to endpoint of treatment group and C =
median time to endpoint of control group. The p values (as
indicated by asterisks) derived from Kaplan Meier log-rank
comparison of treatment group vs. treatment control group. Based on
an endpoint of 1000 mm.sup.3. *p < 0.05, **p < 0.01, ***p
< 0.001.
TABLE-US-00006 TABLE 6 Efficacy of BET inhibitor in the MX-1 human
breast cancer xenograft model. Group Treatment Dose route, regimen
% TGI.sup.a 1 Vehicle 0 mg/kg/day PO, QDx14 -- 2 Compound of 0.3
mg/kg/day PO, QDx14 43** Example 36 3 Compound of 1 mg/kg/day PO,
QDx14 60*** Example 36 4 Compound of 3 mg/kg/day PO, QDx14 76***
Example 36 .sup.aTumor growth inhibition, % TGI = 100 - mean tumor
volume of treatment group/tumor volume of control group .times.
100. p values (as indicated by asterisks) are derived from
Student's T test comparison of treatment group vs. control group.
Based on day 27. *p < 0.05, **p < 0.01, ***p < 0.001.
[1426] Xenograft efficacy studies were conducted with additional
example compounds using OPM-2, MX-1, HT1080, MV4-11, SKM1 and Ramos
human cancer cells. Cancer cells were prepared from culture or from
tumor brie (MX-1) as described above and inoculated subcutaneously
into the right hind flank of female SCID-beige mice (OPM-2, HT1080,
MV4-11) or female Fox Chase SCID (Charles River Labs) mice (MX-1,
SKM1, Ramos). Administration of compound was initiated at the time
of size match. Tumors were measured by a pair of calipers twice a
week starting at the time of size match and tumor volumes were
calculated according to the formula V=L.times.W.sup.2/2 (V: volume,
mm.sup.3; L: length, mm. W: width, mm). Tumor volume was measured
for the duration of the experiment until the mean tumor volume in
each group reached a model-dependent endpoint of 500-2000 mm.sup.3.
Results are shown in Table 7.
TABLE-US-00007 TABLE 7 Efficacy of BET inhibitors in human
xenograft models. % removed Compound dose route, from of Ex. No.
model mg/kg/day regimen vehicle.sup.a % TGI.sup.b % TGD.sup.c study
4 MX-1 12.5 PO, BID F 73*** 70*** 10 (5 on, 3 off) .times. 2 4 MX-1
25 PO, F 77*** 81*** 30 BID (5 on, 3 off) .times. 2 4 Ramos 3.125
PO, F 19 27* 0 BID (5 d on, 3 d off) .times. 2 4 Ramos 6.25 PO, F
24* 28* 0 BID (5 d on, 3 d off) .times. 2 27 MX-1 0.3 PO, QD F 38**
35 0 27 MX-1 1 PO, QD F 57*** 13 0 27 MX-1 3 PO, QD F 69*** ND 0 (5
on, 3 off, 5 on) 27 OPM-2 1 PO, A 59 -2 0 QD .times. 14 27 OPM-2 3
PO, QD A 67 7* 0 (5 on, 3 off, 5 on) 36 HT1080 0.3 PO, H 26 -1 30
QD .times. 14 36 HT1080 1 PO, H 41* 3 10 QD .times. 14 36 HT1080 3
PO, H 47** 46*** 10 QD .times. 14 36 MV4- 0.2 PO, D 22* 16*** 0 11
QD .times. 21 36 MV4- 0.67 PO, D 57*** 59*** 0 11 QD .times. 21 36
MV4- 2 PO, D 81*** 94* 0 11 QD .times. 21 cytarabine MV4- 250 IP,
BID C 47*** 37*** 0 11 Q7D .times. 3 36/ MV4- 0.67/250 PO/IP, E
64*** 53*** 0 cytarabine 11 QD .times. 21/ BID Q7D .times. 3 36/
MV4- 2/250 PO/IP, E 90*** 102*** 0 cytarabine 11 QD .times. 21/ BID
Q7D .times. 3 36 MX-1 0.3 PO, QD F 43** 40 0 36 MX-1 1 PO, QD F
60*** ND 0 36 MX-1 3 PO, QD F 76*** ND 0 36 OPM-2 0.25 PO, A 19 29
0 QD .times. 21 36 OPM-2 0.25 IP, F 45 55* 0 QD .times. 21 36 OPM-2
0.5 PO, A 75*** 101*** 0 QD .times. 21 36 OPM-2 0.5 IP, F 49* 52**
0 QD .times. 21 36 OPM-2 1 PO, A 75*** 107*** 10 QD .times. 21 36
OPM-2 1 PO, A 72** 64* 10 QD .times. 21 36 OPM-2 1 PO, A 79***
140*** 0 QD .times. 21 36 OPM-2 1 PO, A 74*** 140*** 10 BID .times.
21 36 OPM-2 1 PO, A 70** 85** 0 QD .times. 21 36 OPM-2 1 IV, C 69**
66** 0 Q4D .times. 3 36 OPM-2 1 IP, F 61* 80*** 0 Q4D .times. 3 36
OPM-2 1 IV, C 80** 112*** 0 Q4D .times. 3 36 OPM-2 2 PO, A 60 QD
.times. 21 36 OPM-2 3 PO, A 90*** 21*** 10 QD .times. 14 36 OPM-2 3
PO, A 88*** 131*** 30 QD .times. 21 36 OPM-2 3 PO, A 70 BID .times.
21d 36 OPM-2 3 IP, F 40 QD .times. 21 36 OPM-2 3 IP, F 70 QD
.times. 21 36 OPM-2 4.2 PO, A 50 QD(5 on 2 off) .times. 3 36 OPM-2
5.25 PO, A 40 QD(4 on 3 off) .times. 3 36 OPM-2 6 PO, A 82* 84** 20
Q2D .times. 21d 36 OPM-2 6 IP, F 100 QD .times. 21 36 OPM-2 7 PO, A
81*** 97*** 0 QD(3 on 4 off) .times. 3 36 OPM-2 7 PO, A 90 BID (3
on 4 off) .times. 3 36 OPM-2 10.5 PO, A 75*** 94*** 0 QD(2 on 5
off) .times. 3 Bortezomib OPM-2 1 IV, B 80** 93*** 10 Q4D .times. 3
36/ OPM-2 0.25/1 IP/IV, B 94** 195*** 20 Bortezomib QD .times. 21/
Q4D .times. 3 36/ OPM-2 0.5/1 IP/IV, B 40 Bortezomib QD .times. 21/
Q4D .times. 3 36/ OPM-2 1/1 PO/IV, B 100 Bortezomib QD .times. 21/
Q4D .times. 3 36/ OPM-2 1/1 IP/IV, G 40 Bortezomib QD .times. 21/
Q4D .times. 3 36 SKM1 0.2 PO, A 41* 93 0 QD .times. 21 36 SKM1 0.67
PO, A 58* 444*** 0 QD .times. 21 36 SKM1 2 PO, A 86** 721*** 0 QD
.times. 21 azacitidine SKM1 6 IV, C 54** 98* 0 Q7D .times. 3 36/
SKM1 0.67/6 PO/IV, B 86** 649*** 10 azacitidine QD .times. 21/ Q7D
.times. 3 36/ SKM1 2/6 PO/IV, B 91** 958*** 10 azacitidine QD
.times. 21/ Q7D .times. 3 cytarabine SKM1 250 IP, BID C 20 30 0 Q7D
.times. 3 36/ SKM1 0.67/250 PO/IP, B 69** 514*** 0 cytarabine QD
.times. 21/ BID Q7D .times. 3 36/ SKM1 2/250 PO/IP, B 87** 739*** 0
cytarabine QD .times. 21/ BID Q7D .times. 3 146 OPM-2 1 PO, A 39 35
10 QD .times. 21 146 OPM-2 3 PO, A 76* 78** 0 QD .times. 21 158
OPM-2 6 PO, A 53 34 10 QD .times. 21 158 OPM-2 20 PO, A 78* 72** 30
QD .times. 21 169 OPM-2 3 PO, A 69* 77* 10 QD .times. 21 169 OPM-2
10 PO, A 100 QD .times. 21 200 OPM-2 1 PO, A 50 44 10 QD .times. 21
200 OPM-2 3 PO, A 80** 82** 20 QD .times. 21 250 OPM-2 3 PO, A 42**
29 0 QD .times. 21 250 OPM-2 10 PO, A 40 QD .times. 21 287 OPM-2 10
PO, A 50 QD .times. 21 287 OPM-2 20 PO, A 70 QD .times. 21 311
OPM-2 1.25 PO, A 60* 90* 0 QD .times. 21 311 OPM-2 2.5 PO, A 56 QD
.times. 21 .sup.aCompounds were formulated in the following
vehicles: A: 10% EtOH, 30% PEG 400, 60% Phosol 53 MCT (Lipoid AG)
B: 10% EtOH, 30% PEG 400, 60% Phosol 53 MCT (Lipoid AG)/0.9% Saline
C: 0.9% Saline D: 10% EtOH, 27.5% PEG 400, 60% Phosol 53 MCT
(Lipoid AG) E: 10% EtOH, 27.5% PEG 400, 60% Phosol 53 MCT (Lipoid
AG)/0.9% Saline F: 2% EtOH, 5% Tween-80, 20% PEG400, 73% 0.2% HPMC
G: 2% EtOH, 5% Tween-80, 20% PEG400, 73% 0.2% HPMC/0.9% Saline and
H: 5% EtOH, 30% PEG 400, 60% Phosol 53 MCT (Lipoid AG) .sup.bTumor
growth inhibition, % TGI = 100 - mean tumor volume of treatment
group/mean tumor volume of control group .times. 100. Number of
mice per treatment group = 8 (MX-1, MV4-11, SKM1) or 10 (OPM-2).
The p values (as indicated by asterisks) are derived from Student's
T test comparison of treatment group vs. control group. Based on
day 31. *p < 0.05, **p < 0.01, ***p < 0.001. % TGI values
are not presented if mortality .quadrature.40%. .sup.cTumor growth
delay, % TGD = (T - C)/C .times. 100, where T = median time to
endpoint of treatment group and C = median time to endpoint of
control group. The p values (as indicated by asterisks) derived
from Kaplan Meier log-rank comparison of treatment group vs.
treatment control group. *p < 0.05, **p < 0.01, ***p <
0.001. % TGD values are not presented if mortality .quadrature.40%.
ND = Not determined
In Vivo Rat Collagen Induced Arthritis Model
[1427] Compound of Example 36 inhibits paw swelling in a rat
collagen induced arthritis (rCIA) model of inflammation. On day 0
of the rCIA model female Lewis rats (n=9/group) were immunized
intradermally (id) with 600 .mu.g of bovine type II collagen in an
emulsion with incomplete Freund's adjuvant (IFA). Immunization was
given over three sites receiving a 100 .mu.L intradermal injection
at each site. On day 6 rats were boosted with 600 .mu.g of bovine
type II collagen in a manner identical to the initial immunization
protocol. A control group of rats received the same volume of IFA
alone, also on day 0 and day 6. Using a plethysmograph water
displacement system paw volume was measured on day 7 (baseline
measurement) and on days 10, 12, 14 and 17. Dose groups included
IFA immunized non-arthritic rats, PBS vehicle treated, prednisolone
treated (3 mg/kg positive control), compound vehicle treated (10%
EtOH/30% PEG400/60% Phosal 53) and Example 36 dosed orally at 1.0,
0.3, 0.1, and 0.03 mg/kg. Dosing began on day 10 and animals were
treated once daily through day 17 via oral dosing with a 1.0 mL
volume. Paw swelling is reported as change in paw volume from
baseline and area under the curve (AUC) was calculated for the paw
swelling in each dose group. Example 36 inhibited inflammation in
the arthritic paw in a dose dependent manner with an ED.sub.50 of
0.21 mg/kg and an ED.sub.80 of 0.69 mg/kg corresponding to maximum
plasma concentrations of 6.8 ng/mL and 22.3 ng/mL at the ED.sub.50
and ED.sub.80, respectively.
TABLE-US-00008 TABLE 8 AUC of Paw Swelling (ml-day) Treatment group
MEAN SEM IFA immunized (non- 0.13** 0.06 arthritic) PBS Vehicle
4.33 0.49 Compound vehicle 4.90 0.32 Example 36 dosed at 0.70**
0.16 1.0 mg/kg Example 36 dosed at 1.84** 0.23 0.3 mg/kg Example 36
dosed at 3.66* 0.21 0.1 mg/kg Example 36 dosed at 4.19 0.34 0.03
mg/kg Prednisolone dosed at 0.67** 0.20 3 mg/kg One way Anova (vs.
compound vehicle) *p < 0.05 **p < 0.001
It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of use of the invention, may
be made without departing from the spirit and scope thereof. All
publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
* * * * *