U.S. patent application number 13/282773 was filed with the patent office on 2012-11-01 for solid dispersions containing an apoptosis-inducing agent.
This patent application is currently assigned to ABBOTT LABORATORIES. Invention is credited to Nathaniel Catron, David Lindley, Jonathan M. Miller, Eric A. Schmitt, Ping Tong.
Application Number | 20120277210 13/282773 |
Document ID | / |
Family ID | 44947217 |
Filed Date | 2012-11-01 |
United States Patent
Application |
20120277210 |
Kind Code |
A1 |
Catron; Nathaniel ; et
al. |
November 1, 2012 |
SOLID DISPERSIONS CONTAINING AN APOPTOSIS-INDUCING AGENT
Abstract
A pro-apoptotic solid dispersion comprises, in essentially
non-crystalline form, a Bcl-2 family protein inhibitory compound of
Formula I as defined herein, dispersed in a solid matrix that
comprises (a) a pharmaceutically acceptable water-soluble polymeric
carrier and (b) a pharmaceutically acceptable surfactant. A process
for preparing such a solid dispersion comprises dissolving the
compound, the polymeric carrier and the surfactant in a suitable
solvent, and removing the solvent to provide a solid matrix
comprising the polymeric carrier and the surfactant and having the
compound dispersed in essentially non-crystalline form therein. The
solid dispersion is suitable for oral administration to a subject
in need thereof for treatment of a disease characterized by
overexpression of one or more anti-apoptotic Bcl-2 family proteins,
for example cancer.
Inventors: |
Catron; Nathaniel; (Vernon
Hills, IL) ; Lindley; David; (Antioch, IL) ;
Miller; Jonathan M.; (Lindenhurst, IL) ; Schmitt;
Eric A.; (Libertyville, IL) ; Tong; Ping;
(Libertyville, IL) |
Assignee: |
ABBOTT LABORATORIES
Abbott Park
IL
|
Family ID: |
44947217 |
Appl. No.: |
13/282773 |
Filed: |
October 27, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61408517 |
Oct 29, 2010 |
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Current U.S.
Class: |
514/210.21 ;
514/228.2; 514/234.5; 514/235.2; 514/252.11; 514/252.17;
514/253.04; 514/254.09 |
Current CPC
Class: |
A61K 31/437 20130101;
A61P 43/00 20180101; A61K 9/145 20130101; A61K 9/4866 20130101;
A61K 31/5377 20130101; A61P 37/00 20180101; A61P 35/02 20180101;
A61K 9/1617 20130101; A61K 9/146 20130101; A61K 9/1635 20130101;
Y02A 50/30 20180101; A61P 37/06 20180101; A61P 35/00 20180101; A61P
37/02 20180101; A61K 31/496 20130101; Y02A 50/411 20180101 |
Class at
Publication: |
514/210.21 ;
514/253.04; 514/234.5; 514/252.11; 514/254.09; 514/235.2;
514/252.17; 514/228.2 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/517 20060101 A61K031/517; A61P 37/00 20060101
A61P037/00; A61P 35/00 20060101 A61P035/00; A61P 35/02 20060101
A61P035/02; A61K 31/5377 20060101 A61K031/5377; A61K 31/541
20060101 A61K031/541 |
Claims
1. A solid dispersion comprising, in essentially non-crystalline
form, a compound of Formula I ##STR00003## where: R.sup.0 is halo;
R.sup.1 and R.sup.2 are H or are independently methyl or methoxy;
R.sup.3 and R.sup.4 are independently methyl or methoxy if R.sup.1
and R.sup.2 are H, or are H if R.sup.1 and R.sup.2 are
independently methyl or methoxy; A.sup.1 and A.sup.2 are each
independently CH or N; R.sup.5 is C.sub.1-4 alkyl or haloalkyl,
C.sub.1-4 alkylsulfonyl or haloalkylsulfonyl, halo, nitro or cyano;
X is --O-- or --NH--; Y is --(CH.sub.2).sub.n-- where n is 0, 1, 2
or 3; and R.sup.6 is an unsubstituted or substituted 3- to
7-membered carbocyclic or heterocyclic ring as defined herein, or
is NR.sup.7R.sup.8; wherein, if R.sup.6 is NR.sup.7R.sup.8, R.sup.7
and R.sup.8 are each independently H or R.sup.9--(CH.sub.2).sub.m--
groups, no more than one of R.sup.7 and R.sup.8 being H, where each
R.sup.9 is independently a 3- to 7-membered carbocyclic or
heterocyclic ring, optionally substituted with no more than two
Z.sup.1 groups as defined below, and each m is independently 0 or
1; and wherein, if R.sup.6 is a substituted carbocyclic or
heterocyclic ring, substituents thereon are no more than two
Z.sup.1 groups and/or no more than one Z.sup.2 group, Z.sup.1
groups being independently selected from (a) C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4
alkylamino, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylsulfonylamino,
C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkylcarbonylamino and C.sub.1-4
alkylcarboxy, each optionally substituted with one or more
substituents independently selected from halo, hydroxy, C.sub.1-4
alkoxy, amino, C.sub.1-4 alkylamino, di-(C.sub.1-4 alkyl)amino and
cyano, (b) halo, (e) hydroxy, (f) amino and (g) oxo groups, and
Z.sup.2 being (i) a further 3- to 6-membered carbocyclic or
heterocyclic ring, optionally substituted with no more than two
Z.sup.1 groups as defined above, or (ii) NR.sup.7R.sup.8 where
R.sup.7 and R.sup.8 are as defined above; or a pharmaceutically
acceptable salt thereof; dispersed in a solid matrix that comprises
(a) at least one pharmaceutically acceptable water-soluble
polymeric carrier and (b) at least one pharmaceutically acceptable
surfactant.
2. The solid dispersion of claim 1, wherein, in the compound of
Formula I, R.sup.0 is chloro.
3. The solid disperson of claim 2, wherein, in the compound of
Formula I, R.sup.3 and R.sup.4 are each methyl.
4. The solid disperson of claim 3, wherein, in the compound of
Formula I, R.sup.1 and R.sup.2 are each hydrogen.
5. The solid disperson of claim 4, wherein, in the compound of
Formula I, A.sup.1 is N and A.sup.2 is CH.
6. The solid disperson of claim 5, wherein, in the compound of
Formula I, R.sup.5 is nitro.
7. The solid disperson of claim 6, wherein, in the compound of
Formula I, X is --NH--.
8. The solid disperson of claim 7, wherein, in the compound of
Formula I, Y is --(CH.sub.2).sub.n-- where n is 1.
9. The solid disperson of claim 8, wherein, in the compound of
Formula I, R.sup.6 is tetrahydropyran.
10. The solid dispersion of claim 9, wherein the compound is
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.
11. The solid dispersion of claim 1, wherein, in the compound of
Formula I, R.sup.1 is methyl or methoxy, R.sup.2 is methyl, and
R.sup.3 and R.sup.4 are each H.
12. The solid dispersion of claim 1, wherein, in the compound of
Formula I, if A.sup.2 is --CH-- then R.sup.5 is nitro; and if
A.sup.2 is --N-- then R.sup.5 is bromo.
13. The solid dispersion of claim 1, wherein, in the compound of
Formula I, R.sup.6 is a 3- to 7-membered carbocyclic or
heterocyclic ring, unsubstituted or substituted with no more than
two Z.sup.1 groups and/or no more than one Z.sup.2 group.
14. The solid dispersion of claim 13, wherein, in the compound of
Formula I, said carbocyclic or heterocyclic ring is a saturated
ring.
15. The solid dispersion of claim 14, wherein, in the compound of
Formula I, said saturated ring is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imazolidinyl,
pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl,
thiophanyl, thiazolidinyl, isothiazolidinyl, piperidinyl,
piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl and
tetrahydrothiopyranyl rings.
16. The solid dispersion of claim 1, wherein the compound is
selected from the group consisting of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpipe-
ridin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-
-yl)-sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]me-
thyl}-piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3--
yl}-sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}-piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}--
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl-
)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitroph-
enyl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophen-
yl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitropheny-
l]-sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]met-
hyl}-amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
pharmaceutically acceptable salts thereof.
17. The solid dispersion of claim 1, wherein the compound or salt
is present in a parent-compound-equivalent amount of about 5% to
about 40% by weight.
18. The solid dispersion of claim 1, wherein the at least one
polymeric carrier is present in an amount of about 40% to about 85%
by weight and the at least one surfactant is present in an amount
of about 5% to about 20% by weight.
19. The solid dispersion of claim 1, wherein the at least one
polymeric carrier is selected from the group consisting of
homopolymers and copolymers of N-vinyl lactams, cellulose esters,
cellulose ethers, high molecular weight polyalkylene oxides,
polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate
polymers, graft copolymers of polyethylene glycol, polyvinyl
caprolactam and polyvinyl acetate, oligo- and polysaccharides and
mixtures thereof.
20. The solid dispersion of claim 1, wherein the at least one
polymeric carrier is selected from the group consisting of
povidones, copovidones, HPMCs, polyethylene glycol/polyvinyl
caprolactam/polyvinyl acetate graft copolymers and mixtures
thereof.
21. The solid dispersion of claim 1, wherein the at least one
surfactant is non-ionic.
22. The solid dispersion of claim 1, wherein the at least one
surfactant is selected from the group consisting of polyoxyethylene
glycerides, fatty acid monoesters of sorbitan, polysorbates,
.alpha.-tocopheryl polyethylene glycol succinate (TPGS) and
mixtures thereof.
23. The solid dispersion of claim 1, wherein no more than about 5%
of the compound of Formula I is crystalline as observed by X-ray
diffraction analysis.
24. The solid dispersion of claim 1, wherein no more than about 2%
of the compound of Formula I is crystalline as observed by X-ray
diffraction analysis.
25. The solid dispersion of claim 1, wherein no more than about 1%
of the compound of Formula I is crystalline as observed by X-ray
diffraction analysis.
26. A process for preparing a solid dispersion, comprising: (a)
dissolving in a suitable solvent (i) an active pharmaceutical
ingredient (API) comprising a compound of Formula I ##STR00004##
where: R.sup.0 is halo; R.sup.1 and R.sup.2 are H or are
independently methyl or methoxy; R.sup.3 and R.sup.4 are
independently methyl or methoxy if R.sup.1 and R.sup.2 are H, or
are H if R.sup.1 and R.sup.2 are independently methyl or methoxy;
A.sup.1 and A.sup.2 are each independently CH or N; R.sup.5 is
C.sub.1-4 alkyl or haloalkyl, C.sub.1-4 alkylsulfonyl or
haloalkylsulfonyl, halo, nitro or cyano; X is --O-- or --NH--; Y is
--(CH.sub.2).sub.n-- where n is 0, 1, 2 or 3; and R.sup.6 is an
unsubstituted or substituted 3- to 7-membered carbocyclic or
heterocyclic ring as defined herein, or is NR.sup.7R.sup.8;
wherein, if R.sup.6 is NR.sup.7R.sup.8, R.sup.7 and R.sup.8 are
each independently H or R.sup.9--(CH.sub.2).sub.m-- groups, no more
than one of R.sup.7 and R.sup.8 being H, where each R.sup.9 is
independently a 3- to 7-membered carbocyclic or heterocyclic ring,
optionally substituted with no more than two Z.sup.1 groups as
defined below, and each m is independently 0 or 1; and wherein, if
R.sup.6 is a substituted carbocyclic or heterocyclic ring,
substituents thereon are no more than two Z.sup.1 groups and/or no
more than one Z.sup.2 group, Z.sup.1 groups being independently
selected from (a) C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.1-4
alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylamino, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylsulfonylamino, C.sub.1-4
alkylcarbonyl, C.sub.1-4 alkylcarbonylamino and C.sub.1-4
alkylcarboxy, each optionally substituted with one or more
substituents independently selected from halo, hydroxy, C.sub.1-4
alkoxy, amino, C.sub.1-4 alkylamino, di-(C.sub.1-4 alkyl)amino and
cyano, (b) halo, (e) hydroxy, (f) amino and (g) oxo groups, and
Z.sup.2 being (i) a further 3- to 6-membered carbocyclic or
heterocyclic ring, optionally substituted with no more than two
Z.sup.1 groups as defined above, or (ii) NR.sup.7R.sup.8 where
R.sup.7 and R.sup.8 are as defined above; or a pharmaceutically
acceptable salt thereof, (ii) at least one pharmaceutically
acceptable water-soluble polymeric carrier and (iii) at least one
pharmaceutically acceptable surfactant; and (b) removing the
solvent to provide a solid matrix comprising the at least one
polymeric carrier and the at least one surfactant and having the
compound or a salt thereof dispersed in an essentially
non-crystalline form therein.
27. The process of claim 26, wherein the API comprises a compound
of Formula I in parent-compound form; and the process further
comprises adding a pharmaceutically acceptable acid before removing
the solvent.
28. The process of claim 26, wherein the solvent is removed under
heat and/or vacuum.
29. The process of claim 26, wherein the solvent is removed by
rotary evaporation or by spray-drying.
30. The process of claim 26, wherein the solvent comprises one or
more of methanol, ethanol, acetone, tetrahydrofuran and
dichloromethane.
31. The process of claim 26, wherein the solvent comprises a
dichloromethane/methanol or THF/water mixture.
32. The process of claim 26, wherein no more than about 5% of the
compound of Formula I in the solid matrix is crystalline as
observed by X-ray diffraction analysis.
33. The process of claim 26, wherein no more than about 2% of the
compound of Formula I in the solid matrix is crystalline as
observed by X-ray diffraction analysis.
34. The process of claim 26, wherein no more than about 1% of the
compound of Formula I in the solid matrix is crystalline as
observed by X-ray diffraction analysis.
35. The process of claim 26, wherein API is
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.
36. The process of claim 35, wherein the polymeric carrier is a
copovidone.
37. The process of claim 36, wherein the surfactant is a
polysorbate.
38. An orally deliverable pharmaceutical dosage form comprising the
solid dispersion of claim 1.
39. A method for treating a neoplastic, immune or autoimmune
disease, comprising orally administering to a subject having the
disease a therapeutically effective amount of the solid dispersion
of claim 1.
40. The method of claim 39, wherein the disease is a neoplastic
disease.
41. The method of claim 40, wherein the neoplastic disease is
selected from the group consisting of cancer, mesothelioma, bladder
cancer, pancreatic cancer, skin cancer, cancer of the head or neck,
cutaneous or intraocular melanoma, ovarian cancer, breast cancer,
uterine cancer, carcinoma of the fallopian tubes, carcinoma of the
endometrium, carcinoma of the cervix, carcinoma of the vagina,
carcinoma of the vulva, bone cancer, colon cancer, rectal cancer,
cancer of the anal region, stomach cancer, gastrointestinal
(gastric, colorectal and/or duodenal) cancer, chronic lymphocytic
leukemia, acute lymphocytic leukemia, esophageal cancer, cancer of
the small intestine, cancer of the endocrine system, cancer of the
thyroid gland, cancer of the parathyroid gland, cancer of the
adrenal gland, sarcoma of soft tissue, cancer of the urethra,
cancer of the penis, testicular cancer, hepatocellular (hepatic
and/or biliary duct) cancer, primary or secondary central nervous
system tumor, primary or secondary brain tumor, Hodgkin's disease,
chronic or acute leukemia, chronic myeloid leukemia, lymphocytic
lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoid
malignancies of T-cell or B-cell origin, melanoma, multiple
myeloma, oral cancer, non-small-cell lung cancer, prostate cancer,
small-cell lung cancer, cancer of the kidney and/or ureter, renal
cell carcinoma, carcinoma of the renal pelvis, neoplasms of the
central nervous system, primary central nervous system lymphoma,
non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma,
pituitary adenoma, adrenocortical cancer, gall bladder cancer,
cancer of the spleen, cholangiocarcinoma, fibrosarcoma,
neuroblastoma, retinoblastoma and combinations thereof.
42. The method of claim 40, wherein the neoplastic disease is a
lymphoid malignancy.
43. The method of claim 42, wherein the lymphoid malignancy is
non-Hodgkin's lymphoma.
44. The method of claim 40, wherein the neoplastic disease is
chronic lymphocytic leukemia or acute lymphocytic leukemia.
45. The method of claim 39, wherein the disease is an immune or
autoimmune disease.
46. The method of claim 39, wherein the solid dispersion is
administered in a parent-compound-equivalent dose of about 50 to
about 500 mg per day of the compound of Formula I or salt thereof
at an average treatment interval of about 3 hours to about 7
days.
47. The method of claim 39, wherein the solid dispersion is
administered once daily in a parent-compound-equivalent dose of
about 50 to about 500 mg per day of the compound of Formula I or
salt thereof.
48. The method of claim 39, wherein the compound is selected from
the group consisting of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpipe-
ridin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-
-yl)-sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]me-
thyl}-piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3--
yl}-sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}-piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}--
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl-
)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitroph-
enyl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophen-
yl)-sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitropheny-
l]-sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]met-
hyl}-amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
pharmaceutically acceptable salts thereof.
49. The method of claim 48, wherein the compound is
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of provisional
application Ser. No. 61/408,517, filed Oct. 29, 2010, which is
hereby incorporated by reference as if set forth in its
entirety.
[0002] Cross-reference is also made, without claim to benefit of
priority or admission as to prior art status, to the following
pending U.S. application containing subject matter related to the
present application: Ser. No. 12/787,682 (U.S. 2010/0305122) titled
"Apoptosis-inducing agents for the treatment of cancer and immune
and autoimmune diseases," the entire disclosure of which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0003] The present invention relates to solid dispersions
comprising an apoptosis-inducing agent, to pharmaceutical dosage
forms comprising such dispersions, to processes for preparing such
dispersions and dosage forms and to methods of use thereof for
treating diseases characterized by overexpression of anti-apoptotic
Bcl-2 family proteins.
BACKGROUND OF THE INVENTION
[0004] Overexpression of Bcl-2 proteins correlates with resistance
to chemotherapy, clinical outcome, disease progression, overall
prognosis or a combination thereof in various cancers and disorders
of the immune system.
[0005] Evasion of apoptosis is a hallmark of cancer (Hanahan &
Weinberg (2000) Cell 100:57-70). Cancer cells must overcome a
continual bombardment by cellular stresses such as DNA damage,
oncogene activation, aberrant cell cycle progression and harsh
microenvironments that would cause normal cells to undergo
apoptosis. One of the primary means by which cancer cells evade
apoptosis is by up-regulation of anti-apoptotic proteins of the
Bcl-2 family.
[0006] A particular type of neoplastic disease for which improved
therapies are needed is non-Hodgkin's lymphoma (NHL). NHL is the
sixth most prevalent type of new cancer in the U.S. and occurs
primarily in patients 60-70 years of age. NHL is not a single
disease but a family of related diseases, which are classified on
the basis of several characteristics including clinical attributes
and histology.
[0007] One method of classification places different histological
subtypes into two major categories based on natural history of the
disease, i.e., whether the disease is indolent or aggressive. In
general, indolent subtypes grow slowly and are generally incurable,
whereas aggressive subtypes grow rapidly and are potentially
curable. Follicular lymphomas are the most common indolent subtype,
and diffuse large-cell lymphomas constitute the most common
aggressive subtype. The oncoprotein Bcl-2 was originally described
in non-Hodgkin's B-cell lymphoma.
[0008] Treatment of follicular lymphoma typically consists of
biologically-based or combination chemotherapy. Combination therapy
with rituximab, cyclophosphamide, doxorubicin, vincristine and
prednisone (R-CHOP) is routinely used, as is combination therapy
with rituximab, cyclophosphamide, vincristine and prednisone
(RCVP). Single-agent therapy with rituximab (targeting CD20, a
phosphoprotein uniformly expressed on the surface of B-cells) or
fludarabine is also used. Addition of rituximab to chemotherapy
regimens can provide improved response rate and increased
progression-free survival.
[0009] Radioimmunotherapy agents, high-dose chemotherapy and stem
cell transplants can be used to treat refractory or relapsed NHL.
Currently, there is not an approved treatment regimen that produces
a cure, and current guidelines recommend that patients be treated
in the context of a clinical trial, even in a first-line
setting.
[0010] First-line treatment of patients with aggressive large
B-cell lymphoma typically consists of rituximab, cyclophosphamide,
doxorubicin, vincristine and prednisone (R-CHOP), or dose-adjusted
etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin
and rituximab (DA-EPOCH-R).
[0011] Most lymphomas respond initially to any one of these
therapies, but tumors typically recur and eventually become
refractory. As the number of regimens patients receive increases,
the more chemotherapy-resistant the disease becomes. Average
response to first-line therapy is approximately 75%, 60% to
second-line, 50% to third-line, and about 35-40% to fourth-line
therapy. Response rates approaching 20% with a single agent in a
multiple relapsed setting are considered positive and warrant
further study.
[0012] Other neoplastic diseases for which improved therapies are
needed include leukemias such as chronic lymphocytic leukemia (like
NHL, a B-cell lymphoma) and acute lymphocyctic leukemia.
[0013] Chronic lymphoid leukemia (CLL) is the most common type of
leukemia. CLL is primarily a disease of adults, more than 75% of
people newly diagnosed being over the age of 50, but in rare cases
it is also found in children. Combination chemotherapies are the
prevalent treatment, for example fludarabine with cyclophosphamide
and/or rituximab, or more complex combinations such as CHOP or
R-CHOP.
[0014] Acute lymphocyctic leukemia, also known as acute
lymphoblastic leukemia (ALL), is primarily a childhood disease,
once with essentially zero survival but now with up to 75% survival
due to combination chemotherapies similar to those mentioned above.
New therapies are still needed to provide further improvement in
survival rates.
[0015] Current chemotherapeutic agents elicit their antitumor
response by inducing apoptosis through a variety of mechanisms.
However, many tumors ultimately become resistant to these agents.
Bcl-2 and Bcl-X.sub.L have been shown to confer chemotherapy
resistance in short-term survival assays in vitro and, more
recently, in vivo. This suggests that if improved therapies aimed
at suppressing the function of Bcl-2 and Bcl-X.sub.L can be
developed, such chemotherapy-resistance could be successfully
overcome.
[0016] Involvement of Bcl-2 proteins in bladder cancer, brain
cancer, breast cancer, bone marrow cancer, cervical cancer, CLL,
colorectal cancer, esophageal cancer, hepatocellular cancer,
lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies
of T-cell or B-cell origin, melanoma, myelogenous leukemia,
myeloma, oral cancer, ovarian cancer, non-small cell lung cancer,
prostate cancer, small cell lung cancer, spleen cancer and the like
is described in International Patent Publication Nos. WO
2005/024636 and WO 2005/049593.
[0017] Involvement of Bcl-2 proteins in immune and autoimmune
diseases is described, for example, by Puck & Zhu (2003)
Current Allergy and Asthma Reports 3:378-384; Shimazaki et al.
(2000) British Journal of Haematology 110(3):584-590; Rengan et al.
(2000) Blood 95(4):1283-1292; and Holzelova et al. (2004) New
England Journal of Medicine 351(14):1409-1418. Involvement of Bcl-2
proteins in bone marrow transplant rejection is disclosed in United
States Patent Application Publication No. US 2008/0182845.
[0018] Compounds that occupy a binding site on Bcl-2 proteins are
known. To be therapeutically useful by oral administration, such
compounds desirably have high binding affinity, exhibiting for
example K.sub.i<1 nM, preferably <0.1 nM, more preferably
<0.01 nM, to proteins of the Bcl-2 family, specifically Bcl-2,
Bcl-X.sub.L and Bcl-w. It is further desirable that they be
formulated in a manner that provides high systemic exposure after
oral administration. A typical measure of systemic exposure after
oral administration of a compound is the area under the curve (AUC)
resulting from graphing plasma concentration of the compound versus
time from oral administration.
[0019] Where aqueous solubility of Bcl-2 binding compounds is very
low, the formulator faces a significant challenge in assuring
acceptable oral bioavailability, which is strongly dependent on
solubility in the aqueous medium of the gastrointestinal tract.
This is true even where binding affinity is very high. The
challenge becomes even greater when considering the need to provide
an adequate drug loading in the formulation, so that a
therapeutically effective dose can be administered in an acceptably
small volume of formulated product.
[0020] Liquid dosage forms (including encapsulated liquids) can be
useful for some drugs of low aqueous solubility, provided a
suitable pharmaceutically acceptable solvent system (generally
lipid-based) can be found that provides adequate drug loading
without posing solubility or storage-stability issues. Other
approaches that have been proposed for such drugs include solid
dispersions, which bring their own challenges.
[0021] For a variety of reasons, such as patient compliance and
unpleasant taste, a solid dosage form is often preferred over a
liquid dosage form. In most instances, however, oral solid dosage
forms of a drug provide lower bioavailability than oral solutions
of the drug.
[0022] Various solutions to the challenge of low oral
bioavailability have been proposed in the art. For example, Sharma
& Joshi (2007) Asian Journal of Pharmaceutics 1(1):9-19 discuss
various solubility enhancement strategies in preparing solid
dispersions. A solvent evaporation method for preparing solid
dispersions is described therein, mentioning as an example a solid
dispersion of etoricoxib, prepared by a process that includes
dissolving polyethylene glycol (PEG), polyvinylpyrrolidone (PVP or
povidone) and the active ingredient in 2-propanol.
[0023] Apoptosis-inducing drugs that target Bcl-2 family proteins
such as Bcl-2 and Bcl-X.sub.L are best administered according to a
regimen that provides continual, for example daily, replenishment
of the plasma concentration, to maintain the concentration in a
therapeutically effective range. This can be achieved by daily
parenteral, e.g., intravenous (i.v.) or intraperitoneal (i.p.)
administration. However, daily parenteral administration is often
not practical in a clinical setting, particularly for outpatients.
To enhance clinical utility of an apoptosis-inducing agent, for
example as a chemotherapeutic in cancer patients, a solid dosage
form with acceptable oral bioavailability would be highly
desirable. Such a dosage form, and a regimen for oral
administration thereof, would represent an important advance in
treatment of many types of cancer, including NHL, CLL and ALL, and
would more readily enable combination therapies with other
chemotherapeutics.
SUMMARY OF THE INVENTION
[0024] There is now provided a solid dispersion comprising, in
essentially non-crystalline, for example amorphous, form, a
compound of Formula I:
##STR00001##
where: [0025] R.sup.0 is halo; [0026] R.sup.1 and R.sup.2 are H or
are independently methyl or methoxy; [0027] R.sup.3 and R.sup.4 are
independently methyl or methoxy if R.sup.1 and R.sup.2 are H, or
are H if R.sup.1 and R.sup.2 are independently methyl or methoxy;
[0028] A.sup.1 and A.sup.2 are each independently CH or N; [0029]
R.sup.5 is C.sub.1-4 alkyl or haloalkyl, C.sub.1-4 alkylsulfonyl or
haloalkylsulfonyl, halo, nitro or cyano; [0030] X is --O-- or
--NH--; [0031] Y is --(CH.sub.2).sub.n-- where n is 0, 1, 2 or 3;
and [0032] R.sup.6 is an unsubstituted or substituted 3- to
7-membered carbocyclic or heterocyclic ring as defined herein, or
is NR.sup.7R.sup.8; [0033] wherein, if R.sup.6 is NR.sup.7R.sup.8,
R.sup.7 and R.sup.8 are each independently H or
R.sup.9--(CH.sub.2).sub.m-- groups, no more than one of R.sup.7 and
R.sup.8 being H, where each R.sup.9 is independently a 3- to
7-membered carbocyclic or heterocyclic ring, optionally substituted
with no more than two Z.sup.1 groups as defined below, and each m
is independently 0 or 1; and [0034] wherein, if R.sup.6 is a
substituted carbocyclic or heterocyclic ring, substituents thereon
are no more than two Z.sup.1 groups and/or no more than one Z.sup.2
group, Z.sup.1 groups being independently selected from (a)
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylamino, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylsulfonylamino, C.sub.1-4 alkylcarbonyl, C.sub.1-4
alkylcarbonylamino and C.sub.1-4 alkylcarboxy, each optionally
substituted with one or more substituents independently selected
from halo, hydroxy, C.sub.1-4 alkoxy, amino, C.sub.1-4 alkylamino,
di-(C.sub.1-4 alkyl)amino and cyano, (b) halo, (e) hydroxy, (f)
amino and (g) oxo groups, and Z.sup.2 being (i) a further 3- to
6-membered carbocyclic or heterocyclic ring, optionally substituted
with no more than two Z.sup.1 groups as defined above, or (ii)
NR.sup.7R.sup.8 where R.sup.7 and R.sup.8 are as defined above; or
a pharmaceutically acceptable salt of such compound. The compound
or salt thereof is dispersed in a solid matrix that comprises (a) a
pharmaceutically acceptable water-soluble polymeric carrier and (b)
a pharmaceutically acceptable surfactant.
[0035] There is further provided a solid orally deliverable dosage
form comprising such a solid dispersion, optionally together with
one or more additional excipients.
[0036] There is still further provided a process for preparing a
solid dispersion as described above. This process comprises: [0037]
(a) dissolving (i) an active pharmaceutical ingredient (API)
comprising a compound of Formula I or a pharmaceutically acceptable
salt thereof, (ii) a pharmaceutically acceptable water-soluble
polymeric carrier and (iii) a pharmaceutically acceptable
surfactant in a suitable solvent; and [0038] (b) removing the
solvent to provide a solid matrix comprising the polymeric carrier
and the surfactant and having the compound or salt thereof
dispersed in an essentially non-crystalline form therein.
[0039] The compound present in the finished solid dispersion can be
in the same chemical form (e.g., parent compound or salt) as in the
API used to prepare it. Alternatively, in some embodiments the
process can comprise one or more additional steps wherein the API
is converted from parent compound to salt or vice versa. According
to one such embodiment, the process further comprises, prior to
removing the solvent, adding a base for conversion of the API in
salt form to its corresponding parent compound, and optionally
extracting a by-product of such conversion (e.g., a salt
by-product) from the resulting mixture. According to another such
embodiment, the process further comprises, prior to removing the
solvent, adding an acid for conversion of the API in parent
compound form to a salt, for example an acid addition salt.
[0040] There is still further provided a solid dispersion prepared
by the process described above.
[0041] There is still further provided a method for treating a
neoplastic, immune or autoimmune disease, comprising orally
administering to a subject having the disease a therapeutically
effective amount of a solid dispersion as described above, or one
or more solid dosage forms comprising such a dispersion. Examples
of neoplastic diseases include cancers. A specific illustrative
type of cancer that can be treated according to the present method
is non-Hodgkin's lymphoma (NHL). Another specific illustrative type
of cancer that can be treated according to the present method is
chronic lymphocytic leukemia (CLL). Yet another specific
illustrative type of cancer that can be treated according to the
present method is acute lymphocytic leukemia (ALL), for example in
a pediatric patient.
[0042] Additional embodiments of the invention, including more
particular aspects of those provided above, will be found in, or
will be evident from, the detailed description that follows.
DETAILED DESCRIPTION
[0043] Attempts to formulate a compound of Formula I or a salt
thereof as an orally deliverable dosage form have been frustrated
by the very limited number of pharmaceutically acceptable liquid
solvent systems providing acceptable solubility of the compound or
salt, and by a tendency with all such solvent systems tested for
precipitation of insoluble solids during storage. It has now been
found that a more successful approach is to formulate the compound
or salt as a solid dispersion. Details of that approach, by which a
combination of satisfactory drug loading, acceptable stability and
adequate bioavailability are all achievable with a very unpromising
class of active ingredient, are disclosed herein.
[0044] A solid dispersion in accordance with the present disclosure
comprises an active ingredient in an essentially non-crystalline or
amorphous form, which is usually more soluble than the crystalline
form. The term "solid dispersion" herein encompasses systems having
small solid-state particles (e.g., essentially non-crystalline or
amorphous particles) of one phase dispersed in another solid-state
phase. More particularly, the present solid dispersions comprise
particles of one or more active ingredients dispersed in an inert
carrier or matrix in solid state, and can be prepared by melting or
solvent methods or by a combination of melting and solvent methods.
According to the present invention a solvent method as described
herein is particularly favored.
[0045] An "amorphous form" refers to a particle without definite
structure, i.e., lacking crystalline structure.
[0046] The term "essentially non-crystalline" herein means that no
more than about 5%, for example no more than about 2% or no more
than about 1% crystallinity is observed by X-ray diffraction
analysis. In a particular embodiment, no detectable crystallinity
is observed by one or both of X-ray diffraction analysis or
polarization microscopy. In this regard it is to be noted that,
when no detectable crsytallinity is observed, the solid dispersion
referenced herein may additionally or alternatively be described as
a solid solution.
[0047] A. Active Compound
[0048] Compounds of Formula I, including salts thereof, useful
herein typically have very low solubility in water, being classed
as essentially insoluble, i.e., having a solubility of less than
about 10 .mu.g/ml. Examples of such active ingredients are, for
example, Biopharmaceutics Classification System (BCS) Class IV drug
substances that are characterized by low solubility and low
permeability (see "Waiver of in vivo bioavailability and
bioequivalence studies for immediate-release solid oral dosage
forms based on a biopharmaceutics classification system", U.S.
Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER),
August 2000). It will be recognized that aqueous solubility of many
compounds is pH-dependent; in the case of such compounds the
solubility of interest herein is at a physiologically relevant pH,
for example a pH of about 1 to about 8. Thus, in various
embodiments, the drug has a solubility in water, at least at one
point in a pH range from about 1 to about 8, of less than about 10
.mu.g/ml, in some cases less than about 1 .mu.g/ml or even less
than about 0.1 .mu.g/ml. Illustratively, a particular compound
useful herein has a solubility in water at pH 4 of <0.004
.mu.g/ml.
[0049] Solid dispersions of the present invention comprise as
active ingredient a compound of Formula I as defined above, or a
pharmaceutically acceptable salt of such a compound. Optionally
they may further comprise a second active ingredient, for example a
therapeutic agent useful in combination therapy with the compound
of Formula I as indicated hereinbelow.
[0050] In one embodiment, the compound has Formula I where R.sup.0
is chloro.
[0051] In a further embodiment, the compound has Formula I where
R.sup.1 is methyl or methoxy, R.sup.2 is methyl, and R.sup.3 and
R.sup.4 are each H.
[0052] In a still further embodiment, the compound has Formula I
where R.sup.5 is trifluoromethyl, trifluoromethylsulfonyl, chloro,
bromo or nitro. In a more particular embodiment, if A.sup.2 is
--CH-- then R.sup.5 is nitro; and if A.sup.2 is --N-- then R.sup.5
is bromo.
[0053] In a more particular embodiment, the compound has Formula I
where (a) R.sup.0 is chloro, (b) R.sup.1 is methyl or methoxy,
R.sup.2 is methyl, and R.sup.3 and R.sup.4 are each H, and (c)
R.sup.5 is trifluoromethyl, trifluoromethylsulfonyl, chloro, bromo
or nitro.
[0054] Compounds useful herein vary considerably in the
--X--Y--R.sup.6 substituent, more particularly the R.sup.6 group,
of Formula I. In most embodiments, R.sup.6 is a 3- to 7-membered
carbocyclic or heterocyclic ring, optionally substituted as defined
above.
[0055] The term "carbocyclic" herein embraces saturated and partly
and fully unsaturated ring structures having 3 to 7 ring carbon
atoms, including bicyclic structures. In one embodiment, R.sup.6 is
a saturated carbocyclic (i.e., cycloalkyl) ring, for example but
not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,
in each case optionally substituted as more fully described
below.
[0056] The term "heterocyclic" herein embraces saturated and partly
and fully unsaturated ring structures having 4 to 7 ring atoms, one
or more of which are heteroatoms independently selected from N, O
and S. Typically the heterocyclic ring has no more than two such
heteroatoms. In one embodiment, R.sup.6 is a saturated heterocyclic
ring, for example but not limited to azetidinyl, oxetanyl,
thietanyl, pyrrolidinyl, imazolidinyl, pyrazolidinyl,
tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, thiophanyl,
thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl,
tetrahydropyranyl, 1,4-dioxanyl, morpholinyl or
tetrahydrothiopyranyl, in each case optionally substituted as more
fully described below.
[0057] Where R.sup.6 is a carbocyclic or heterocyclic ring, for
example a saturated ring as described immediately above, it can be
unsubstituted or substituted at up to three positions on the ring.
Substituents, if present, comprise no more than two Z.sup.1 groups
and/or no more than one Z.sup.2 group.
[0058] Z.sup.1 groups are independently selected from (a) C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 alkylamino, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylsulfonylamino, C.sub.1-4 alkylcarbonyl, C.sub.1-4
alkylcarbonylamino and C.sub.1-4 alkylcarboxy, each optionally
substituted with one or more substituents independently selected
from halo, hydroxy, C.sub.1-4 alkoxy, amino, C.sub.1-4 alkylamino,
di-(C.sub.1-4 alkyl)amino and cyano, (b) halo, (e) hydroxy, (f)
amino and (g) oxo groups. Illustrative examples of such Z.sup.1
groups include without limitation methyl, cyanomethyl, methoxy,
fluoro, hydroxy, amino and methylsulfonyl.
[0059] The Z.sup.2 group, if present, is a further 3- to 7-membered
carbocyclic or heterocyclic ring, optionally substituted with no
more than two Z.sup.1 groups as described above. Ring Z.sup.2, if
present, is typically but not necessarily saturated, and in most
cases is not further substituted. In one embodiment Z.sup.2 is a
saturated carbocyclic ring, for example but not limited to
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another
embodiment Z.sup.2 is a saturated heterocyclic ring, for example
but not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,
imazolidinyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl,
isoxazolidinyl, thiophanyl, thiazolidinyl, isothiazolidinyl,
piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl,
morpholinyl or tetrahydrothiopyranyl.
[0060] In some embodiments, R.sup.6 is a group NR.sup.7R.sup.8,
where R.sup.7 and R.sup.8 are each independently H or
R.sup.9--(CH.sub.2).sub.m-- groups, no more than one of R.sup.7 and
R.sup.8 being H, where each R.sup.9 is independently a 3- to
7-membered carbocyclic or heterocyclic ring, optionally substituted
with no more than two Z.sup.1 groups as defined above, and each m
is independently 0 or 1. Each of rings R.sup.9 is typically but not
necessarily saturated, and in most cases is unsubstituted.
Illustrative carbocyclic rings at R.sup.7 and/or R.sup.8 include
without limitation cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl. Illustrative heterocyclic rings at R.sup.7 and/or
R.sup.8 include without limitation azetidinyl, oxetanyl, thietanyl,
pyrrolidinyl, imazolidinyl, pyrazolidinyl, tetrahydrofuranyl,
oxazolidinyl, isoxazolidinyl, thiophanyl, thiazolidinyl,
isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,
1,4-dioxanyl, morpholinyl or tetrahydrothiopyranyl.
[0061] In particular embodiments, R.sup.6 is selected from the
group consisting of 4-methoxycyclohexyl,
cis-4-hydroxy-4-methylcyclohexyl,
trans-4-hydroxy-4-methylcyclohexyl, 4-morpholin-4-ylcyclohexyl,
(3R)-1-(methylsulfonyl)pyrrolidin-3-yl,
(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl,
tetrahydro-2H-pyran-4-yl, (3S)-tetrahydro-2H-pyran-3-yl,
4-methoxytetrahydro-2H-pyran-4-yl,
4-fluorotetrahydro-2H-pyran-4-yl, 4-aminotetrahydro-2H-pyran-4-yl,
1-(cyanomethyl)piperidin-4-yl,
4-fluoro-1-oxetan-3-ylpiperidin-4-yl,
1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl, 4-methylpiperazin-1-yl,
1,4-dioxan-2-yl, 4-methylmorpholin-2-yl and
cyclopropyl(oxetan-3-yl)amino.
[0062] Compounds of Formula I may contain asymmetrically
substituted carbon atoms in the R- or S-configuration; such
compounds can be present as racemates or in an excess of one
configuration over the other, for example in an enantiomeric ratio
of at least about 85:15. The compound can be substantially
enantiomerically pure, for example having an enantiomeric ratio of
at least about 95:5, or in some cases at least about 98:2 or at
least about 99:1.
[0063] Compounds of Formula I may alternatively or additionally
contain carbon-carbon double bonds or carbon-nitrogen double bonds
in the Z- or E-configuration, the term "Z" denoting a configuration
wherein the larger substituents are on the same side of such a
double bond and the term "E" denoting a configuration wherein the
larger substituents are on opposite sides of the double bond. The
compound can alternatively be present as a mixture of Z- and
E-isomers.
[0064] Compounds of Formula I may alternatively or additionally
exist as tautomers or equilibrium mixtures thereof wherein a proton
shifts from one atom to another. Examples of tautomers
illustratively include keto-enol, phenol-keto, oxime-nitroso,
nitro-aci, imine-enamine and the like.
[0065] In one embodiment, the API present in the solid dispersion
is selected from compounds specifically identified in
above-referenced U.S. application Ser. No. 12/787,682 (U.S.
2010/0305122) in Examples 1-378 thereof, and pharmaceutically
acceptable salts of such compounds, independently of whether these
compounds are individually embraced by the present Formula I.
Compounds 1-378 of these Examples, and illustrative procedures for
their synthesis, are reproduced hereinbelow. In a further
embodiment, the API present in the solid dispersion is selected
from Compounds 1-378 and pharmaceutically acceptable salts thereof,
but only to the extent that such Examples are individually embraced
by the present Formula I. The entire disclosure of U.S. application
Ser. No. 12/787,682 (U.S. 2010/0305122) is expressly incorporated
herein by reference.
[0066] Description of the synthesis of representative compounds is
given below. Other compounds of Formula I can be prepared by
substantially analogous methods, as will be clear to one of skill
in the art. The exemplified compounds have been named using
ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced Chemistry
Development Inc., Toronto, Ontario), ACD/ChemSketch Version 12.01
(13 May 2009), Advanced Chemistry Development Inc., Toronto,
Ontario), or ChemDraw.RTM. Ver. 9.0.5 (CambridgeSoft, Cambridge,
Mass.). Intermediates were named using ChemDraw.RTM. Ver. 9.0.5
(CambridgeSoft, Cambridge, Mass.).
Compound 1
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({1-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b-
]pyridin-5-yloxy)benzamide
Compound 1A
tert-butyl
4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-carboxylate
[0067] 4'-Chlorobiphenyl-2-carboxaldehyde (4.1 g), tert-butyl
piperazine-1-carboxylate (4.23 g), and sodium triacetoxyborohydride
(5.61 g) in CH.sub.2Cl.sub.2 (60 ml) were stirred for 24 hours. The
reaction was quenched with methanol and poured into ether. The
solution was washed with water and brine, concentrated, and
chromatographed on silica gel with 2-25% ethyl acetate/hexanes.
Compound 1B
1-((4'-chlorobiphenyl-2-yl)methyl)piperazine
[0068] Compound 1A (3.0 g) and triethylsilane (1 ml) were stirred
in CH.sub.2Cl.sub.2 (30 ml) and trifluoroacetic acid (30 ml) for 2
hours, and the reaction was concentrated, and then taken up in
ether and concentrated again. The material was taken up in
dichloromethane (200 ml) and NaHCO.sub.3 solution (100 ml), and
partitioned. The organic layer was dried over Na.sub.2SO.sub.4, and
condensed to give the title compound.
Compound 1C
tert-butyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-fluorobe-
nzoate
[0069] Tert-butyl 4-bromo-2-fluorobenzoate (14.0 g), Compound 1B
(16.05 g), Pd.sub.2(dba).sub.3
(tris(dibenzylideneacetone)dipalladium(0)) (1.40 g),
2-(di-tert-butylphosphino)biphenyl (1.82 g), and K.sub.3PO.sub.4
(16.2 g) were stirred in 1,2-dimethoxyethane (300 ml) at 80.degree.
C. for 24 hours. The reaction was cooled and concentrated. The
crude product was chromatographed on silica gel with 10-20% ethyl
acetate/hexanes.
Compound 1D
tert-butyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4'-chlorobiphenyl-2-
-yl)methyl)piperazin-1-yl)benzoate
[0070] 1H-Pyrrolo[2,3-B]pyridine-5-ol (167 mg), Compound 1C (500
mg), and Cs.sub.2CO.sub.3 (508 mg) were stirred in
dimethylsulfoxide (5 ml) at 130.degree. C. for 24 hours. The
mixture was cooled, diluted with ethyl acetate, washed three times
with water, and brine, and dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude product was chromatographed on silica gel
with 25% ethyl acetate/hexanes.
Compound 1E
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)-
piperazin-1-yl)benzoic acid
[0071] Compound 1D (200 mg) and triethylsilane (1 ml) were stirred
in dichloromethane (15 ml) and trifluoroacetic acid (15 ml) for 1
hour. The mixture was concentrated, taken up in ethyl acetate,
washed twice with NaH.sub.2PO.sub.4, and brine, and dried
(Na.sub.2SO.sub.4), filtered and concentrated.
Compound 1F
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
[0072] 4-Fluoro-3-nitrobenzene sulfonamide (2.18 g),
1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1
g) were stirred in tetrahydrofuran (30 ml) for 24 hours. The
solution was diluted with ethyl acetate, washed with
NaH.sub.2PO.sub.4 solution and brine, and dried (Na.sub.2SO.sub.4),
filtered and concentrated. The product was triturated fromethyl
acetate.
Compound 1G
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b-
]pyridin-5-yloxy)benzamide
[0073] Compound 1E (115 mg), Compound 1F (67 mg),
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (82
mg), and 4-dimethylaminopyridine (26 mg) were stirred in
CH.sub.2Cl.sub.2 (3 ml) for 24 hours. The reaction was cooled and
chromatographed on silica gel with 0-5% methanol/ethyl acetate.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.48
(brs, 1H), 8.34 (br s, 1H), 8.31 (m, 1H), 7.90 (d, 1H), 7.68 (m,
1H), 7.58 (m, 2H), 7.46 (m, 4H), 7.35 (m, 2H), 7.21 (dd, 1H), 6.76
(m, 4H), 6.28 (m, 2H), 3.02 (m, 2H), 2.89 (m, 4H), 2.80 (m, 4H),
2.40 (m, 3H), 1.59 (m, 2H), 1.25 (m, 4H), 0.87 (m, 2H).
Compound 2
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-
-5-yloxy)benzamide
Compound 2A
4-(3-morpholinopropylamino)-3-nitrobenzenesulfonamide
[0074] This Compound was prepared by substituting
3-(N-morpholinyl)-propylamine for
1-(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 2B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-
-5-yloxy)benzamide
[0075] This Compound was prepared by substituting Compound 2A for
Compound 1F in the procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.60 (brs, 1H), 8.60 (m, 1H),
8.43 (d, 1H), 7.94 (d, 1H), 7.64 (m, 2H), 7.54 (d, 1H), 7.45 (m,
4H), 7.33 (m, 2H), 7.23 (dd, 1H), 6.96 (d, 1H), 6.85 (m, 2H), 6.32
(d, 1H), 6.26 (d, 1H), 3.60 (m, 4H), 3.10 (m, 4H), 3.05 (m, 10H),
2.40 (m, 2H), 2.33 (m, 2H), 1.77 (m, 2H).
Compound 3
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 3A
methyl 4,4-dimethyl-2-(trifluoro
methylsulfonyloxy)cyclohex-1-enecarboxylate
[0076] To a suspension of hexane washed NaH (17 g) in
dichloromethane (700 ml) was added
5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at
0.degree. C. After stirring for 30 minutes, the mixture was cooled
to -78.degree. C. and trifluoroacetic anhydride (40 ml) was added.
The reaction mixture was warmed to room temperature and stirred for
24 hours. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the
product.
Compound 3B
methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[0077] Compound 3A (62.15 g), 4-chlorophenylboronic acid (32.24 g),
CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2 g) in
2:1 dimethoxyethane/methanol (600 ml) were heated to 70.degree. C.
for 24 hours. The mixture was concentrated. Ether (4.times.200 ml)
was added and the mixture was filtered. The combined ether solution
was concentrated to give the product.
Compound 3C
2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[0078] To a mixture of LiBH.sub.4 (13 g), Compound 3B (53.8 g) and
ether (400 ml), was added methanol (25 ml) slowly by syringe. The
mixture was stirred at room temperature for 24 hours. The reaction
was quenched with 1N HCl with ice-cooling. The mixture was diluted
with water and extracted with ether (3.times.100 ml). The extracts
were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
crude product was chromatographed on silica gel with 0-30% ethyl
acetate/hexanes.
Compound 3D
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piper-
azine-1-carboxylate
[0079] Mesyl chloride (7.5 ml) was added via syringe to Compound 3C
(29.3 g) and triethylamine (30 ml) in CH.sub.2Cl.sub.2 (500 ml) at
0.degree. C., and the mixture was stirred for 1 minute.
N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was
stirred at room temperature for 24 hours. The suspension was washed
with brine, dried, (Na.sub.2SO.sub.4), filtered, and concentrated.
The crude product was chromatographed on silica gel with 10-20%
ethyl acetate/hexanes.
Compound 3E
1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
[0080] Compound 3D (1 g) was stirred in dichloromethane (10 ml),
trifluoroacetic acid (10 ml), and triethylsilane (1 ml) for 1 hour.
The mixture was concentrated, taken up in a mixture of
dichloromethane (100 ml) and saturated aqueous Na.sub.2CO.sub.3
solution (20 ml) and stirred for 10 minutes. The layers were
separated, and the organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give the product.
Compound 3F
5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
[0081] to a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g)
in tetrahydrofuran (250 ml) was added 1M lithium
hexamethyldisilazide in tetrahydrofuran (86 ml), and after 10
minutes, TIPS-Cl (triisopropylchlorosilane) (18.2 ml) was added.
The mixture was stirred at room temperature for 24 hours. The
reaction was diluted with ether, and the resulting solution was
washed twice with water. The extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was chromatographed on silica gel with 10% ethyl
acetate/hexanes.
Compound 3G
1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol
[0082] To a mixture of Compound 3F (24.3 g) in tetrahydrofuran (500
ml) at -78.degree. C. was added 2.5M BuLi (30.3 ml). After 2
minutes, trimethylborate (11.5 ml) was added, and the mixture was
allowed to warm to room temperature over 1 hour. The reaction was
poured into water, extracted three times with ethyl acetate, and
the combined extracts were washed with brine and concentrated. The
crude product was taken up in tetrahydrofuran (200 ml) at 0.degree.
C., and 1M NaOH (69 ml) was added, followed by 30% H.sub.2O.sub.2
(8.43 ml), and the solution was stirred for 1 hour.
Na.sub.2S.sub.2O.sub.3 (10 g) was added, and the pH was adjusted to
4-5 with concentrated HCl and solid NaH.sub.2PO.sub.4. The solution
was extracted twice with ethyl acetate, and the combined extracts
were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The crude product was chromatographed on silica gel
with 5-25% ethyl acetate/hexanes.
Compound 3H
methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate
[0083] A mixture of Compound 3G (8.5 g), methyl
2,4-difluorobenzoate (7.05 g), and K.sub.3PO.sub.4 (9.32 g) in
diglyme (40 ml) at 115.degree. C. was stirred for 24 hours. The
reaction was cooled, diluted with ether (600 ml), and washed twice
with water, and brine, and concentrated. The crude product was
chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Compound 3I
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0084] A mixture of Compound 3H (1.55 g), Compound 3E (2.42 g), and
HK.sub.2PO.sub.4 (1.42 g) in dimethylsulfoxide (20 ml) at
135.degree. C. was stirred for 24 hours. The reaction was cooled,
diluted with ether (400 ml), and washed with 3.times.1M NaOH, and
brine, and concentrated. The crude product was chromatographed on
silica gel with 10-50% ethyl acetate/hexanes.
Compound 3J
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0085] Compound 3I (200 mg) in dioxane (10 ml) and 1M NaOH (6 ml)
at 50.degree. C. was stirred for 24 hours. The reaction was cooled,
added to NaH.sub.2PO.sub.4 solution, and extracted three times with
ethyl acetate. The combined extracts were washed with brine, and
concentrated to give the pure product.
Compound 3K
tert-butyl 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylcarbamate
[0086] Tert-butyl piperidin-4-ylcarbamate (45.00 g, 225 mmol) and
dihydro-2H-pyran-4(3H)-one (24.74 g, 247 mmol) were added to
dichloromethane (1000 ml). Sodium triacetoxyborohydride (61.90 g,
292 mmol) was added, and the solution was stirred at room
temperature for 16 hours. The solution was extracted with 1M sodium
hydroxide and dried over anhydrous sodium sulfate. The solution was
filtered and concentrated and purified by flash column
chromatography on silica gel with 10% methanol (in dichloromethane)
increasing to 20% methanol (in dichloromethane).
Compound 3L
1-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine dihydrochloride
[0087] A solution of Compound 3K (52.57 g, 185 mmol) in
dichloromethane (900 ml) was treated with 4M aqueous HCl (462 ml),
and the solution was mixed vigorously at room temperature for 16
hours. Solvent was removed under vacuum to give crude product as
the dihydrochloride salt, which was used without further
purification.
Compound 3M
3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)benzenesulfonam-
ide
[0088] Compound 3L (22.12 g, 86 mmol) was added to 1,4-dioxane (300
ml) and water (43 ml). Triethylamine (43.6 ml, 31.6 g, 313 mmol)
was added, and the mixture was stirred at room temperature until
Compound 3L had completely dissolved.
4-Chloro-3-nitrobenzenesulfonamide was added and the mixture was
heated at 90.degree. C. for 16 hours. The mixture was cooled, and
the solvents were removed under vacuum. 10% methanol (in
dichloromethane) was added and the solution was stirred vigorously
at room temperature until a fine suspension was obtained. The solid
was isolated by vacuum filtration and washed with dichloromethane
to give pure product.
Compound 3N
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0089] This Compound was prepared by substituting Compound 3J for
Compound 1E and Compound 3M for Compound 1F in the procedure for
Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (brs, 1H), 8.53 (br s, 1H), 8.18 (m, 1H), 8.00 (br s,
1H), 7.63 (m, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.12 (m, 1H), 7.04
(d, 2H), 6.67 (dd, 1H), 6.37 (d, 1H), 6.20 (d, 1H), 3.95 (m, 2H),
3.05 (m, 10H), 2.73 (m, 4H), 2.17 (m, 10H), 1.95 (m, 2H), 1.80 (m,
2H), 1.63 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 4
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 4A
4-(1-methylpiperidin-4-ylamino)-3-nitrobenzene sulfonamide
[0090] This Compound was prepared by substituting
4-amino-N-methylpiperidine for 1-(tetrahydropyran-4-yl)methylamine
in the procedure for Compound 1F.
Compound 4B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0091] This Compound was prepared by substituting Compound 3J for
Compound 1E and Compound 4A for Compound 1F in the procedure for
Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (brs, 1H), 8.55 (br s, 1H), 8.17 (m, 1H), 8.02 (d,
1H), 7.85 (dd, 1H), 7.51 (m, 3H), 7.35 (m, 2H), 7.18 (dd, 1H), 7.05
(d, 2H), 6.68 (dd, 1H), 6.38 (d, 1H), 6.20 (d, 1H), 3.90 (m, 1H),
3.09 (m, 8H), 2.77 (m, 2H), 2.05-2.30 (m, 10H), 1.95 (s, 3H), 1.39
(t, 2H), 1.24 (m, 2H), 0.93 (s, 6H).
Compound 5
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 5A
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
[0092] A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g),
1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1
g) in tetrahydrofuran (30 ml) were stirred overnight, neutralized
with concentrated HCl and concentrated. The residue was suspended
in ethyl acetate and the precipitates were collected, washed with
water and dried to provide the title compound.
Compound 5B
methyl 4,4-dimethyl-2-(trifluoro
methylsulfonyloxy)cyclohex-1-enecarboxylate
[0093] To a suspension of hexane washed NaH (17 g) in
dichloromethane (700 ml) was added
5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at
0.degree. C. After stirring for 30 minutes, the mixture was cooled
to -78.degree. C. and trifluoroacetic anhydride (40 ml) was added.
The reaction mixture was warmed to room temperature and stirred for
24 hours. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the
product.
Compound 5C
methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[0094] Compound 5B (62.15 g), 4-chlorophenylboronic acid (32.24 g),
CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2 g) in
2:1 dimethoxyethane/methanol (600 ml) were heated to 70.degree. C.
for 24 hours. The mixture was concentrated. Ether (4.times.200 ml)
was added and the mixture was filtered. The combined ether solution
was concentrated to give the product.
Compound 5D
(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[0095] To a mixture of LiBH.sub.4 (13 g), Compound 5C (53.8 g) and
ether (400 ml), was added methanol (25 ml) slowly by syringe. The
mixture was stirred at room temperature for 24 hours. The reaction
was quenched with 1N HCl with ice-cooling. The mixture was diluted
with water and extracted with ether (3.times.100 ml). The extracts
were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
crude product was chromatographed on silica gel with 0-30% ethyl
acetate/hexanes.
Compound 5E
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piper-
azine-1-carboxylate
[0096] Mesyl chloride (7.5 ml) was added via syringe to Compound 5D
(29.3 g) and triethylamine (30 ml) in CH.sub.2Cl.sub.2 (500 ml) at
0.degree. C., and the mixture was stirred for 1 minute.
N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was
stirred at room temperature for 24 hours. The suspension was washed
with brine, dried, (Na.sub.2SO.sub.4), filtered, and concentrated.
The crude product was chromatographed on silica gel with 10-20%
ethyl acetate/hexanes.
Compound 5F
1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
[0097] Compound 5E (200 mg) and triethylsilane (1 ml) were stirred
in dichloromethane (15 ml) and trifluoroacetic acid (15 ml) for 1
hour. The mixture was concentrated, taken up in ethyl acetate,
washed twice with NaH.sub.2PO.sub.4, and brine, and dried
(Na.sub.2SO.sub.4), filtered and concentrated.
Compound 5G
5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
[0098] To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g)
in tetrahydrofuran (250 ml) was added 1M lithium
hexamethyldisilazide in tetrahydrofuran (86 ml), and after 10
minutes, TIPS-Cl (triisopropylchlorosilane) (18.2 ml) was added.
The mixture was stirred at room temperature for 24 hours. The
reaction was diluted with ether, and the resulting solution was
washed twice with water. The extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was chromatographed on silica gel with 10% ethyl
acetate/hexanes.
Compound 5H
1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol
[0099] To a mixture of Compound 5G (24.3 g) in tetrahydrofuran (500
ml) at -78.degree. C. was added 2.5M BuLi (30.3 ml). After 2
minutes, trimethylborate (11.5 ml) was added, and the mixture was
allowed to warm to room temperature over 1 hour. The reaction was
poured into water, extracted three times with ethyl acetate, and
the combined extracts were washed with brine and concentrated. The
crude product was taken up in tetrahydrofuran (200 ml) at 0.degree.
C., and 1M NaOH (69 ml) was added, followed by 30% H.sub.2O.sub.2
(8.43 ml), and the solution was stirred for 1 hour.
Na.sub.2S.sub.2O.sub.3 (10 g) was added, and the pH was adjusted to
4-5 with concentrated HCl and solid NaH.sub.2PO.sub.4. The solution
was extracted twice with ethyl acetate, and the combined extracts
were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The crude product was chromatographed on silica gel
with 5-25% ethyl acetate/hexanes.
Compound 5I
methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate
[0100] A mixture of Compound 5H (8.5 g), methyl
2,4-difluorobenzoate (7.05 g), and K.sub.3PO.sub.4 (9.32 g) in
diglyme (40 ml) at 115.degree. C. was stirred for 24 hours. The
reaction was cooled, diluted with ether (600 ml), and washed twice
with water, and brine, and concentrated. The crude product was
chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Compound 5J
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0101] A mixture of Compound 5I (1.55 g), Compound 5F (2.42 g), and
HK.sub.2PO.sub.4 (1.42 g) in dimethylsulfoxide (20 ml) at
135.degree. C. was stirred for 24 hours. The reaction was cooled,
diluted with ether (400 ml), and washed with 3.times.1M NaOH, and
brine, and concentrated. The crude product was chromatographed on
silica gel with 10-50% ethyl acetate/hexanes.
Compound 5K
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0102] Compound 5J (200 mg) in dioxane (10 ml) and 1M NaOH (6 ml)
at 50.degree. C. was stirred for 24 hours. The reaction was cooled,
added to NaH.sub.2PO.sub.4 solution, and extracted three times with
ethyl acetate. The combined extracts were washed with brine, and
concentrated to give the pure product.
Compound 5L
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0103] Compound 5K (3.39 g), Compound 5A (1.87 g),
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride
(2.39 g), and 4-dimethylaminopyridine (1.09 g) were stirred in
CH.sub.2Cl.sub.2 (40 ml) for 24 hours. The reaction was cooled and
chromatographed on silica gel with 25-100% ethyl acetate/hexanes,
then 10% methanol/ethyl acetate with 1% acetic acid, to give the
product (1.62 g, 32%) as a white solid. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.65 (brs, 1H), 8.55 (br s,
1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08
(m, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H),
3.84 (m, 1H), 3.30 (m, 4H), 3.07 (m, 4H), 2.73 (m, 2H), 2.18 (m,
6H), 1.95 (m, 2H), 1.61 (dd, 2H), 1.38 (m, 2H), 1.24 (m, 4H), 0.92
(s, 6H).
Compound 6
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 6A
4-(4-methylpiperazin-1-ylamino)-3-nitrobenzenesulfonamide
[0104] A 50 ml round-bottomed flask was charged with
4-chloro-3-nitrobenzenesulfonamide (1 g, 4.23 mmol),
4-methylpiperazin-1-amine dihydrochloride (1 g, 5.32 mmol), and
N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethylethane-1,2-diamine (3
ml, 20.01 mmol) in dioxane (10 ml). The reaction mixture was
refluxed for 12 hours. After this time, the reaction mixture was
cooled to room temperature, the salt filtered off via a Buchner
funnel, and the solvent removed in vacuo. The crude product was
added to a silica gel column (Analogix, SF65-200 g) and purified by
eluting with 0-5% methanol in dichloromethane.
Compound 6B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0105] This Compound was prepared by substituting Compound 3J for
Compound 1E and Compound 6A for Compound 1F in the procedure for
Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (brs, 1H), 9.09 (br s, 1H), 8.47 (d, 1H), 8.24 (dd,
1H), 7.99 (d, 1H), 7.50 (m, 4H), 7.34 (d, 2H), 7.04 (d, 2H), 6.64
(dd, 1H), 6.35 (d, 1H), 6.20 (d, 1H), 3.04 (m, 4H), 2.89 (m, 4H),
2.73 (m, 2H), 2.34 (s, 3H), 2.17 (m, 6H), 1.95 (br s, 2H), 1.38 (t,
2H), 1.05 (m, 4H), 0.93 (s, 6H).
Compound 7
2-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
n-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
Compound 7A
ethyl 2-(9H-carbazol-4-yloxy)-4-fluorobenzoate
[0106] This Compound was prepared by substituting ethyl
2,4-difluorobenzoate for methyl 2,4-difluorobenzoate and
4-hydroxycarbazole for Compound 3G in the procedure for Compound
3H.
Compound 7B
ethyl
2-(9H-carbazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)benzoate
[0107] This Compound was prepared by substituting Compound 7A for
Compound 3H in the procedure for Compound 3I.
Compound 7C
2-(9H-carbazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
nyl)methyl)piperazin-1-yl)benzoic acid
[0108] This Compound was prepared by substituting Compound 7B for
Compound 3I in the procedure for Compound 3J, except here upon
completion of the reaction, water and 2N HCl were added to adjust
the pH to 2, and the HCl salt of the product was extracted using
CHCl.sub.3/CH.sub.3OH.
Compound 7D
2-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
n-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
[0109] This Compound was prepared by substituting Compound 7C for
Compound 1E and Compound 4A for Compound 1F in the procedure for
Compound 1G, except here the purification was done by preparative
HPLC using a C18 column, 250.times.50 mm, 10.mu., and eluting with
a gradient of 20-100% CH.sub.3CN vs. 0.1% trifluoroacetic acid in
water, giving the product as a bistrifluoroacetate salt. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.82 (br s, 1H),
11.40 (s, 1H), 9.70, 9.40 (both v br s, total 2H), 8.40 (d, 1H),
8.10 (br d, 1H), 7.90 (br d, 1H), 7.72 (dd, 1H), 7.60 (d, 1H), 7.48
(d, 1H), 7.38 (m, 3H), 7.22 (m, 2H), 7.07 (m, 4H), 6.78 (dd, 1H),
6.43 (dd, 1H), 6.19 (s, 1H), 3.97 (m, 1H), 3.80 (m, 2H), 3.60,
3.30, 3.10, 2.80 (all br m, total 11H), 2.20, 2.10, 2.00 (all br m,
total 8H), 1.78 (m, 2H), 1.42 (m, 2H), 1.25 (m, 2H), 0.92 (s,
6H).
Compound 8
2-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
n-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amin-
o]phenyl}sulfonyl)benzamide
Compound 8A
3-nitro-4-(3-(pyrrolidin-1-yl)propylamino)benzene sulfonamide
[0110] This Compound was prepared by substituting
3-(pyrrolidin-1-yl)propan-1-amine for
1-(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 8B
2-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
n-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amin-
o]phenyl}sulfonyl)benzamide
[0111] This Compound was prepared by substituting Compound 7C for
Compound 1E and Compound 8A for Compound 1F in the procedure for
Compound 1G, except here the purification was done by preparative
HPLC using a C18 column, 250.times.50 mm, 10.mu., and eluting with
a gradient of 20-100% CH.sub.3CN vs. 0.1% trifluoroacetic acid in
water, giving the product as a bistrifluoroacetate salt. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.80 (br s, 1H),
11.42 (s, 1H), 9.50, 9.25 (both v br s, total 2H), 8.58 (br t, 1H),
8.43 (d, 1H), 7.91 (d, 1H), 7.72 (dd, 1H), 7.60 (d, 1H), 7.50 (d,
1H), 7.38 (m, 3H), 7.23 (m, 2H), 7.07 (m, 3H), 6.93 (d, 1H), 6.78
(dd, 1H), 6.44 (dd, 1H), 6.18 (s, 1H), 3.70, 3.60, 3.20. 3.00 (all
br m, total 18H), 2.18 (br m, 2H), 2.00-180 (envelope, 8H), 1.42
(m, 2H), 0.92 (s, 6H).
Compound 9
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfon-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 9A
trans-tert-butyl 4-morpholino cyclohexylcarbamate
[0112] A solution of tert-butyl-4-aminocyclohexylcarbamate (20.32
g, 95 mmol), bis(2-bromoethyl)ether (14.30 ml, 114 mmol) and
triethylamine (33.0 ml, 237 mmol) in N,N-dimethylformamide (200 ml)
was stirred for 16 hours at 70.degree. C. The reaction mixture was
cooled down to room temperature, concentrated and the product was
extracted with ethyl acetate. The organic layer was washed with
sodium carbonate solution (15% aq.), dried and concentrated. The
product was used in next step without purification.
Compound 9B
trans-4-morpholinocyclohexanamine dihydrochloride
[0113] To a solution of
trans-tert-butyl-4-morpholinocyclohexylcarbamate (19.2 g, 67.5
mmol) in dichloromethane (100 ml) was added HCl (100 ml, 400 mmol)
(4M in dioxane) and the reaction mixture was stirred for 16 hours
at room temperature. The reaction mixture was diluted with ether
and solid salt was filtered off, and dried in an oven.
Compound 9C
trans-4-(4-morpholino cyclohexylamino)-3-nitrobenzene
sulfonamide
[0114] A solution of trans-4-morpholinocyclohexanamine
dihydrochloride (5 g, 19.44 mmol),
4-fluoro-3-nitrobenzenesulfonamide (4.32 g, 19.63 mmol) and
triethylamine (20 ml, 143 mmol) in tetrahydrofuran (60 ml) was
stirred for 16 hours at room temperature. The solid product was
filtered off, washed with tetrahydrofuran, ether, dichloromethane
(3.times.) and dried under vacuum.
Compound 9D
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfon-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0115] This compound was prepared by substituting Compound 3J for
Compound 1E and Compound 9C for Compound 1F in the procedure for
Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.61 (brs, 1H), 8.49 (br s, 1H), 8.12 (m, 1H), 7.99 (br s,
1H), 7.71 (m, 1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.04 (d, 2H), 7.01
(m, 1H), 6.65 (dd, 1H), 6.36 (d, 1H), 6.21 (d, 1H), 3.60 (m, 4H),
3.04 (m, 4H), 2.73 (m, 2H), 2.57 (m, 2H), 2.42 (m, 1H), 2.18 (m,
6H), 2.05 (m, 2H), 1.95 (m, 2H), 1.90 (m, 2H), 1.38 (m, 6H), 1.15
(m, 3H), 0.92 (s, 6H).
Compound 10
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[-
2,3-b]pyridin-5-yloxy)benzamide
Compound 10A
4-(2-methoxyethylamino)-3-nitrobenzene sulfonamide
[0116] This compound was prepared by substituting
2-methoxyethylamine for 1-(tetrahydropyran-4-yl)methylamine in the
procedure for Compound 1F.
Compound 10B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[-
2,3-b]pyridin-5-yloxy)benzamide
[0117] This compound was prepared by substituting Compound 3J for
Compound 1E and Compound 10A for Compound 1F in the procedure for
Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (brs, 1H), 8.58-8.49 (m, 1H), 8.55 (d, 1H), 8.03 (d,
1H), 7.79 (m, 1H), 7.49 (m, 3H), 7.34 (m, 2H), 7.06 (m, 1H), 7.04
(d, 2H), 6.68 (dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H), 3.61-3.51 (m,
4H), 3.31 (s, 3H), 3.07 (m, 4H), 2.74 (m, 2H), 2.17 (m, 6H), 1.95
(br s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 11
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 11A
(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide
and
(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonami-
de
[0118] This racemic mixture was prepared by substituting
(tetrahydro-2H-pyran-3-yl)methanamine for
1-(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 11B
(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzene
sulfonamide
[0119] The racemic mixture of Compound 11A was resolved by chiral
SFC on an AD column (21 mm i.d.x 250 mm in length) using a gradient
of 10-30% 0.1% diethylamine methanol in CO.sub.2 over 15 minutes
(oven temperature: 40.degree. C.; flow rate: 40 ml/minute) to
provide the title compound.
Compound 11C
(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzene
sulfonamide
[0120] The racemic mixture of Compound 11A was resolved by chiral
SFC on an AD column (21 mm i.d.x 250 mm in length) using a gradient
of 10-30% 0.1% diethylamine methanol in CO.sub.2 over 15 minutes
(oven temperature: 40.degree. C.; flow rate: 40 ml/minute) to
provide the title compound.
Compound 11D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0121] To a mixture of Compound 3J (59.8 mg, 0.105 mmol), Compound
11B (33 mg, 0.105 mmol) and N,N-dimethylpyridin-4-amine (38.4 mg,
0.314 mmol) in dichloromethane (5 ml) was added
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride
(24.07 mg, 0.13 mmol). The reaction mixture was stirred at room
temperature overnight and concentrated. The residue was purified by
reverse phase HPLC on a C18 column using a gradient of 40-60%
acetonitrile/0.1% trifluoroacetic acid in water to give the title
compound as the trifluoroacetate salt. The trifluoroacetic acid
salt was dissolved in dichloromethane (6 ml) and washed with 50%
aqueous NaHCO.sub.3. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give the title compound.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s,
1H), 11.40 (s, br, 1H), 8.53-8.58 (m, 2H), 8.04 (d, 1H), 7.80 (dd,
1H), 7.47-7.54 (m, 3H), 7.34 (d, 2H), 7.02-7.09 (m, 3H), 6.67 (dd,
1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.79 (dd, 1H), 3.69-3.73 (m, 1H),
3.22-3.37 (m, 3H), 3.16-3.21 (m, 1H), 3.07 (s, 4H), 2.74 (s, 2H),
2.09-2.24 (m, 6H), 1.95 (s, 2H), 1.86-1.93 (m, 1H), 1.79-1.85 (m,
1H), 1.58-1.64 (m, 1H), 1.42-1.51 (m, 1H), 1.38 (t, 2H), 1.25-1.34
(m, 1H), 0.92 (s, 6H).
Compound 12
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo-
[2,3-b]pyridin-5-yloxy)benzamide
Compound 12A
4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzene sulfonamide
[0122] (1,4-Dioxan-2-yl)methanol (380 mg, 3.22 mmol) in
tetrahydrofuran (30 ml) was treated with sodium hydride (60%) (245
mg, 6.13 mmol) at room temperature for 30 minutes. The reaction
mixture was cooled in an ice bath and
4-fluoro-3-nitrobenzenesulfonamide (675 mg, 3.06 mmol) was added.
The resulting mixture was stirred at room temperature for 2 hours
and another portion of sodium hydride (60%) (245 mg, 6.13 mmol) was
added. The reaction mixture was stirred overnight and quenched with
ice water (3 ml). The cloudy mixture was filtered and the filtrate
was concentrated. The residue was triturated with methanol to give
the title compound.
Compound 12B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo-
[2,3-b]pyridin-5-yloxy)benzamide
[0123] The title compound was prepared as described in the
procedure for Compound 11D using Compound 12A in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67
(s, 1H), 11.42 (s, br, 1H), 8.34 (s, 1H), 8.03 (d, 2H), 7.48-7.55
(m, 3H), 7.41 (d, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H),
6.39 (dd, 1H), 6.21 (d, 1H), 4.20-4.28 (m, 2H), 3.85-3.91 (m, 1H),
3.82 (dd, 1H), 3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.41-3.51 (m,
2H), 3.05-3.17 (m, 4H), 2.83 (s, br, 2H), 2.27 (s, br, 4H), 2.15
(s, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 13
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0124] The title compound was prepared as described in the
procedure for Compound 11D using Compound 11C in place of Compound
11B. The proton NMR spectra of Compound 13 and Compound 11D are
identical. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.68 (s, 1H), 11.40 (s, br, 1H), 8.53-8.58 (m, 2H), 8.04 (d, 1H),
7.80 (dd, 1H), 7.47-7.54 (m, 3H), 7.34 (d, 2H), 7.02-7.09 (m, 3H),
6.67 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.79 (dd, 1H),
3.69-3.73 (m, 1H), 3.22-3.37 (m, 3H), 3.16-3.21 (m, 1H), 3.07 (s,
4H), 2.74 (s, 2H), 2.09-2.24 (m, 6H), 1.95 (s, 2H), 1.86-1.93 (m,
1H), 1.79-1.85 (m, 1H), 1.58-1.64 (m, 1H), 1.42-1.51 (m, 1H), 1.38
(t, 2H), 1.25-1.34 (m, 1H), 0.92 (s, 6H).
Compound 14
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-(2-naphthylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0125] The title compound was prepared as described in the
procedure for Compound 11D using naphthalene-2-sulfonamide (47 mg,
0.227 mmol) in place of Compound 11B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.82 (s, 1H), 11.69 (s, 1H),
8.51 (s, 1H), 8.08 (d, 1H), 8.05 (d, 1H), 7.97 (dd, 2H), 7.82 (dd,
1H), 7.66-7.71 (m, 1H), 7.63 (t, 1H), 7.54 (d, 1H), 7.47-7.52 (m,
2H), 7.34 (d, 2H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.39 (dd, 1H), 6.18
(s, 1H), 3.04 (s, 4H), 2.72 (s, 2H), 2.10-2.20 (m, 6H), 1.95 (s,
2H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 15
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 15A
methyl 6,6-dimethyl-4-oxotetrahydro-2H-pyran-3-carboxylate
[0126] To a suspension of hexane-washed NaH (0.72 g, 60% in mineral
oil) in tetrahydrofuran (30 ml) was added a solution of
2,2-dimethyldihydro-2H-pyran-4(3H)-one (2.0 g) in tetrahydrofuran
(20 ml). The suspension was stirred at room temperature for 30
minutes. The dimethylcarbonate (6.31 ml) was added dropwise by
syringe. The mixture was heated to reflux for 4 h. LC/MS showed the
expected product as the major product. The mixture was acidified
with 5% HCl and extracted with dichloromethane (100 ml.times.3) and
washed with water, brine and dried over Na.sub.2SO.sub.4. After
evaporation, the crude product was loaded on a column and eluted
with 10% ethyl acetate in hexane to give the product.
Compound 15B
methyl
6,6-dimethyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydro-2H-pyran-3--
carboxylate
[0127] To a cooled (0.degree. C.) stirring suspension of NaH (0.983
g, 60% in mineral oil) in ether (50 ml) was added Compound 15A (3.2
g). The mixture was stirred at 0.degree. C. for 30 minutes before
the addition of Tf.sub.2O (4.2 ml). The mixture was then stirred at
room temperature overnight. The mixture was diluted with ether (200
ml) and washed with 5% HCl, water and brine. After drying over
Na.sub.2SO.sub.4, evaporation of solvent gave the crude product
which was used in the next step without further purification.
Compound 15C
methyl
4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylate
[0128] To a solution of Compound 15B (2.88 g),
4-chlorophenylboronic acid (1.88 g) and Pd(Ph.sub.3P).sub.4 (0.578
g) in toluene (40 ml) and ethanol (10 ml) was added 2N
Na.sub.2CO.sub.3 (10 ml). The mixture was stirred at reflux
overnight. The mixture was diluted ether (300 ml) and washed with
water, brine and dried over Na.sub.2SO.sub.4. After evaporation of
solvent, the residue was loaded on a column and eluted with 3%
ethyl acetate in hexane to give the product.
Compound 15D
(4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methanol
[0129] To a solution of Compound 15C (1.6 g) in ether (20 ml) was
added LiAlH.sub.4 (1.2 g). The mixture was stirred for 4 hours. The
mixture was acidified carefully with 5% HCl and extracted with
ethyl acetate (100 ml.times.3) and washed with water, brine and
dried over Na.sub.2SO.sub.4. After concentration, the crude product
was loaded on a column and eluted with 10% ethyl acetate in hexane
to give the product.
Compound 15E
4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carbaldehyde
[0130] To a solution of oxalyl chloride (1.1 g) in dichloromethane
(30 ml) at -78.degree. C. was added dimethylsulfoxide (6.12 ml).
The mixture was stirred at the temperature for 30 minutes, and then
a solution of Compound 15D (1.2 g) in dichloromethane (10 ml) was
added. The mixture was stirred at -78.degree. C. for 2 hours before
the addition of triethylamine (10 ml). The mixture was stirred
overnight and the temperature was allowed to rise to room
temperature. The mixture was diluted with ether (300 ml) and washed
with water, brine and dried over Na.sub.2SO.sub.4. Concentration of
the solvent and column purification (5% ethyl acetate in hexane)
gave the product.
Compound 15F
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(piperazin-1-yl)benzoate
[0131] A mixture of Compound 3H (20.5 g) and piperazine (37.0 g) in
dimethylsulfoxide (200 ml) was heated to 110.degree. C. for 24
hours, and the mixture was allowed to cool to room temperature. The
mixture was poured into water (1 L), extracted three times with
dichloromethane, and the combined extracts were washed with
2.times. water, and brine and filtered and concentrated to give the
pure product.
Compound 15G
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6--
dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
[0132] To a solution of Compound 15E (100 mg) and Compound 15F (177
mg) in dichloromethane (10 ml) was added sodium
triacetoxyborohydride (154 mg). The mixture was stirred overnight.
The mixture was diluted with ethyl acetate (200 ml) and washed with
2% NaOH, water and brine. After drying over Na.sub.2SO.sub.4, the
mixture was filtered and the solvent was evaporated under vacuum.
The residue was loaded on a column and eluted with 30% ethyl
acetate in hexane to give the pure product.
Compound 15H
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethy-
l-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoic acid
[0133] To a solution of Compound 15G (254 mg) in tetrahydrofuran (4
ml), methanol (2 ml) and water (2 ml) was added LiOH H.sub.2O (126
mg). The mixture was stirred overnight. The mixture was then
neutralized with 5% HCl and diluted with ethyl acetate (200 ml).
After washing with brine, it was dried over Na.sub.2SO.sub.4.
Filtration and evaporation of solvent gave the product.
Compound 15I
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0134] The title compound was prepared as described in the
procedure for Compound 1G, substituting Compound 1E with Compound
15H. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68
(br s, 1H), 11.42 (s, 1H), 8.60 (m, 1H), 8.57 (d, 1H), 8.05 (d,
1H), 7.80 (dd, 1H), 7.48-7.54 (m, 3H), 7.38 (d, 2H), 7.12 (m, 3H),
6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (s, 1H), 4.11 (s, 2H), 3.85 (m,
2H), 3.27 (m, 6H), 3.07 (m, 2H), 2.84 (m, 2H), 2.14 (m, 5H), 1.92
(m, 1H), 1.42 (m, 2H), 1.24 (m, 2H), 1.10 (s, 6H).
Compound 16
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 16A
4-(2-methoxyethylamino)-3-(trifluoromethylsulfonyl)benzene
sulfonamide
[0135] 4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide
(1.536 g, 5 mmol), 2-methoxyethanamine (0.376 g, 5 mmol), and
triethylamine (1.939 g, 15 mmol) in anhydrous tetrahydrofuran (30
ml) solution was heated at 55.degree. C. for 3 hours. The solution
was diluted with ethyl acetate, washed with water and brine, and
dried (Na.sub.2SO.sub.4), filtered and the filtrate was
concentrated. The crude material was used in the next step without
further purification.
Compound 16B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-methoxyethyl)amino]-3-[trifluoromethyl)sulfonyl]phenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0136] This Compound was prepared by substituting Compound 3J for
Compound 1E and Compound 16A for Compound 1F in the procedure for
Compound 1G. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.67 (brs, 1H), 8.14 (m 1H), 8.03 (d, 1H), 7.91 (d, 1H),
7.50 (m, 3H), 7.34 (d, 2H), 7.19 (s, 1H), 7.04 (m, 3H), 6.67 (dd,
1H), 6.39 (m, 1H), 6.19 (d, 1H), 3.51 (m, 4H), 3.28 (s, 3H), 3.06
(m, 4H), 2.75 (m, 2H), 2.17 (m, 6H), 1.95 (m, 2H), 1.39 (t, 2H),
0.93 (s, 6H).
Compound 17
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
Compound 17A
4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethylsulfonyl)benze-
nesulfonamide
[0137] This Compound was prepared by substituting
1-(tetrahydropyran-4-yl)methylamine for 2-methoxyethanamine in the
procedure for Compound 16A.
Compound 17B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
[0138] This Compound was prepared by substituting Compound 3J for
Compound 1E and Compound 17A for Compound 1F in the procedure for
Compound 1G. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.70 (brs, 1H), 8.15 (m 1H), 8.04 (d, 1H), 7.92 (d, 1H),
7.51 (m, 3H), 7.34 (d, 2H), 7.19 (s, 1H), 7.05 (m, 3H), 6.68 (dd,
1H), 6.40 (m, 1H), 6.18 (d, 1H), 3.85 (m, 2H), 3.25 (m, 4H), 3.07
(m, 4H), 2.77 (m, 2H), 2.17 (m, 6H), 1.95 (m, 2H), 1.84 (m, 1H),
1.54 (m, 2H), 1.39 (t, 2H), 1.24 (m, 2H), 0.93 (s, 6H).
Compound 18
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide
Compound 18A
methyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate
[0139] A mixture of 5-hydroxyindole (8.5 g), methyl
2,4-difluorobenzoate (7.05 g), and K.sub.3PO.sub.4 (9.32 g) in
diglyme (40 ml) at 115.degree. C. was stirred for 24 hours. The
reaction was cooled, diluted with ether (600 ml), and washed twice
with water, and brine, and concentrated. The crude product was
chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Compound 18B
methyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzoate
[0140] A mixture of Compound 18A (1.7 g), Compound 3E (1.8 g), and
HK.sub.2PO.sub.4 (1.21 g) in dimethylsulfoxide (20 ml) at
135.degree. C. was stirred for 24 hours. The reaction was cooled,
diluted with ether (400 ml), and washed with 3.times.1M NaOH, and
brine, and concentrated. The crude product was chromatographed on
silica gel with 10-50% ethyl acetate/hexanes.
Compound 18C
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
[0141] Compound 18B (200 mg) in dioxane (10 ml) and 1M NaOH (6 ml)
at 50.degree. C. was stirred for 24 hours. The reaction was cooled,
added to NaH.sub.2PO.sub.4 solution, and extracted three times with
ethyl acetate. The combined extracts were washed with brine, and
concentrated to give the pure product.
Compound 18D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide
[0142] The title compound was prepared as described in the
procedure for Compound 11D by replacing Compound 3J with Compound
18C, and Compound 1F for Compound 11B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.18 (s, 2H), 8.59-8.64 (m,
2H), 7.80 (dd, 1H), 7.52 (d, 1H), 7.39-7.42 (m, 2H), 7.33 (d, 2H),
7.16 (d, 1H), 7.10 (d, 1H), 7.03 (d, 2H), 6.8 (dd, 1H), 6.65 (dd,
1H), 6.40) s, 1H), 6.14 (d, 1H), 3.85 (dd, 2H), 3.24-3.32 (m, 4H),
3.03 (s, 3H), 2.73 (s, 2H), 2.12-2.17 (m, 5H), 1.68-1.94 (m, 3H),
1.61 (d, 2H), 1.37 (t, 2H), 1.24-1.27 (m, 2H), 0.92 (s, 6H).
Compound 19
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-
-3-nitrophenyl}sulfonyl)benzamide
[0143] The title compound was prepared as described in the
procedure for Compound 11D by replacing Compound 11B with Compound
9B and Compound 3J with Compound 18C. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 12.29 (s, 1H), 9.29 (d, J=2.1 Hz, 1H),
8.37 (d, J=7.6 Hz, 1H), 8.32 (dd, J=9.3, 2.3 Hz, 1H), 8.18 (d,
J=8.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.39-7.47 (m, 3H), 7.10 (dd,
J=8.7, 2.3 Hz, 1H), 7.05-7.08 (m, 2H), 6.90 (d, J=9.5 Hz, 1H), 6.74
(dd, J=9.0, 2.3 Hz, 1H), 6.59-6.63 (m, 1H), 6.55 (d, J=2.4 Hz, 1H),
3.72-3.78 (m, 4H), 3.33-3.43 (m, 1H), 2.99-3.09 (m, 4H), 2.76 (s,
2H), 2.46-2.54 (m, 4H), 2.16-2.29 (m, 3H), 2.09-2.14 (m, 4H), 2.05
(d, J=11.9 Hz, 2H), 1.97 (d, J=1.8 Hz, 2H), 1.87 (d, J=11.6 Hz,
2H), 1.19-1.42 (m, 6H), 0.93 (s, 6H).
Compound 20
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sul-
fonyl)benzamide
[0144] The title compound was prepared as described in the
procedure for Compound 11D by replacing Compound 11B with Compound
10A and Compound 3J with Compound 18C. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.20 (br. s, 1H) 11.15 (s, 1H)
8.59 (m, 2H) 7.81 (dd, 1H) 7.50 (d, 1H) 7.36 (m, 4H) 7.08 (m, 4H)
6.85 (dd, 1H) 6.65 (dd, 1H) 6.38 (m, 1H) 6.14 (m, 1H) 3.58 (m, 4H)
3.30 (s, 3H) 3.03 (m, 4H) 2.73 (s, 2H) 2.15 (m, 6H) 1.96 (s, 2H)
1.38 (t, 2H) 0.92 (s, 6H).
Compound 21
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylme-
thyl]amino}phenyl)sulfonyl]benzamide
[0145] The title compound was prepared as described in the
procedure for Compound 11D by replacing Compound 3J with Compound
18C. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.17
(s, 2H), 8.53-8.65 (m, 2H), 7.80 (d, 1H), 7.51 (d, 1H), 7.38-7.44
(m, 2H), 7.33 (d, 2H), 7.15 (s, 1H), 7.02-7.09 (m, 3H), 6.82-6.92
(m, 1H), 6.65 (d, 1H), 6.39 (s, 1H), 6.14 (s, 1H), 3.68-3.82 (m,
2H), 3.22-3.32 (m, 2H), 3.13-3.22 (m, 1 H), 3.03 (s, 4H), 2.72 (s,
2H), 2.09-2.23 (m, 6H), 1.78-1.98 (m, 4H), 1.56-1.66 (m, 1 H),
1.43-1.51 (m, 1H), 1.37 (t, 2H), 1.22-1.33 (m, 1H), 0.92 (s,
6H).
Compound 22
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylme-
thyl]amino}phenyl)sulfonyl]benzamide
[0146] The title compound was prepared as described in the
procedure for Compound 11D using Compound 11C in place of Compound
11B, and Compound 18C in place of Compound 3J. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 2H), 8.53-8.65
(m, 2H), 7.80 (d, 1H), 7.51 (d, 1H), 7.38-7.44 (m, 2H), 7.33 (d,
2H), 7.15 (s, 1H), 7.02-7.09 (m, 3H), 6.82-6.92 (m, 1H), 6.65 (d,
1H), 6.39 (s, 1H), 6.14 (s, 1H), 3.68-3.82 (m, 2H), 3.22-3.32 (m,
2H), 3.13-3.22 (m, 1H), 3.03 (s, 4H), 2.72 (s, 2H), 2.09-2.23 (m,
6H), 1.78-1.98 (m, 4H), 1.56-1.66 (m, 1H), 1.43-1.51 (m, 1H), 1.37
(t, 2H), 1.22-1.33 (m, 1H), 0.92 (s, 6H).
Compound 23
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide
Compound 23A
methyl 2-(1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate
[0147] The title compound was prepared as described in the
procedure for Compound 15F by replacing Compound 3H with Compound
18A.
Compound 23B
methyl
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dih-
ydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
[0148] The title compound was prepared as described in the
procedure for Compound 15G by replacing Compound 15F with Compound
23A.
Compound 23C
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl)methyl)piperazin-1-yl)benzoic acid
[0149] The title compound was prepared as described in the
procedure for Compound 15H by replacing Compound 15G with Compound
23B.
Compound 23D
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide
[0150] The title compound was prepared as described in the
procedure for Compound 11D by replacing Compound 11B with Compound
1F, and Compound 3J with Compound 23C. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.20 (br s, 1H), 11.17 (s, 1H),
8.63 (t, 1 H), 8.59 (d, 1H), 7.79 (dd, 1H), 7.51 (d, 1H), 7.36 (m,
3H), 7.13 (m, 2H), 6.86 (dd, 1H), 6.66 (dd, 1H), 6.39 (s, 1H), 6.15
(d, 1H), 4.10 (s, 2H), 3.85 (m, 3H), 3.50 (m, 2H), 3.42 (m, 2H),
3.24 (m, 4H), 3.02 (m, 4H), 2.82 (m, 2H), 2.16 (m, 2H), 1.61 (m,
3H), 1.25 (m, 4 H), 1.17 (s, 6H).
Compound 24
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 24A
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
[0151] (Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in
tetrahydrofuran (20 ml) was treated with 60% NaH (1.377 g). The
solution was stirred for 20 minutes at the room temperature. To
this solution was added 4-fluoro-3-nitrobenzenesulfonamide (2.84 g)
portion-wise. The reaction was stirred for another 2 hours. The
mixture was poured into water, neutralized with 10% HCl, and
extracted with ethyl acetate three times. The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified with flash column
chromatography on silica gel eluting with 20-60% ethyl acetate in
hexanes.
Compound 24B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0152] The title compound was prepared by substituting Compound 24A
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 8.33
(s, 1H), 8.00-8.02 (m, 2H), 7.50-7.53 (m, 3H), 7.34-7.36 (m, 3H),
7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (d, 1H), 6.21 (s, 1H), 4.06 (d,
2H), 3.88 (dd, 2H), 3.08 (s, 4H), 2.80 (s, 2H), 2.25 (s, 4H), 2.15
(s, 2H), 1.96 (s, 2H), 1.63-1.66 (m, 2H), 1.52-1.55 (m, 1H),
1.33-1.40 (m, 4H), 0.92 (s, 6H).
Compound 25
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 25A
4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide
[0153] The title compound was prepared as described in the
procedure for Compound 1F using (1,4-dioxan-2-yl)methanamine in
place of (tetrahydropyran-4-yl)methanamine.
Compound 25B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0154] The title compound was prepared as described in the
procedure for Compound 11D using Compound 25A in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66
(s, 1H), 11.38 (s, 1H), 8.53-8.59 (m, 2H), 8.03 (d, 1H), 7.81 (dd,
1H), 7.46-7.54 (m, 3H), 7.34 (d, 2H), 7.09 (d, 1H), 7.04 (d, 2H),
6.68 (dd, 1H), 6.38 (dd, 1H), 6.19 (d, 1H), 3.75-3.86 (m, 3H),
3.58-3.68 (m, 2H), 3.45-3.52 (m, 2H), 3.35-3.43 (m, 2H), 3.07 (s,
4H), 2.75 (s, 2H), 2.17 (d, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92
(s, 6H).
Compound 26
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 26A
3-nitro-4-(2,2,2-trifluoroethylamino)benzene sulfonamide
[0155] The title compound was prepared by substituting
2,2,2-trifluoroethanamine for (tetrahydropyran-4-yl)methylamine in
the procedure for Compound 1F.
Compound 26B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
[0156] The title compound was prepared by substituting Compound 26A
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.48 (s, 1H), 8.40
(m, 2H), 7.90 (d, 1H), 7.71 (dd, 1H), 7.59 (d, 1H), 7.40 (t, 1H),
7.34 (d, 2H), 7.25 (d, 1H), 7.06 (m, 3H), 6.61 (dd, 1H), 6.26 (m,
2H), 4.32 (m, 2H), 3.00 (m, 4H), 2.73 (s, 2H), 2.19 (m, 6H), 1.96
(s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 27
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 27A
3-nitro-4-(3,3,3-trifluoropropylamino)benzenesulfonamide
[0157] The title compound was prepared by substituting
3,3,3-trifluoropropan-1-amine for (tetrahydropyran-4-yl)methylamine
in the procedure for Compound 1F.
Compound 27B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0158] The title compound was prepared by substituting Compound 27A
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.47 (s, 1H), 8.37
(d, 1H), 8.29 (m, 1H), 7.89 (d, 1H), 7.61 (m, 2H), 7.39 (t, 1H),
7.35 (d, 2H), 7.22 (d, 1H), 7.05 (d, 2H), 6.75 (d, 1H), 6.62 (dd,
1H), 6.27 (m, 2H), 3.59 (q, 2H), 3.00 (m, 4H), 2.73 (s, 2H), 2.66
(m, 2H), 2.18 (m, 6H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (m,
6H).
Compound 28
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 28A
(S)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide
[0159] The racemic mixture of Compound 12A was resolved on a SFC
chiral AD column to provide the title compound.
Compound 28B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
[0160] The title compound was prepared as described in the
procedure for Compound 11D using Compound 28A in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67
(s, 2H), 8.35 (s, 1H), 8.03 (d, 2H), 7.48-7.57 (m, 3H), 7.42 (d,
1H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.21
(s, 1H), 4.19-4.30 (m, 2H), 3.85-3.92 (m, 1H), 3.73-3.85 (m, 2H),
3.58-3.70 (m, 2H), 3.40-3.52 (m, 2H), 3.10 (s, 4H), 2.85 (s, 2H),
2.18-2.39 (m, 3H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93
(s, 6H).
Compound 29
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 29A
Cis-4-((4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[0161] 4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and Compound
34A (1 g) in tetrahydrofuran (20 ml) was treated with
N,N-diisopropylethylamine (0.871 ml) overnight. The reaction
mixture was concentrated and the residue was purified by reverse
phase chromatography, eluted with 40-55% acetonitrile in 0.1%
trifluoroacetic acid in water over 25 min to give the cis isomer
Compound 29A and trans isomer Compound 34B.
Compound 29B
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0162] The title compound was prepared as described in the
procedure for Compound 11D using Compound 29A in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 1H), 11.36 (s, 1H), 8.53-8.63 (m, 2H), 8.04 (d, 1H), 7.79 (dd,
1H), 7.47-7.56 (m, 3H), 7.34 (d, 2H), 7.00-7.12 (m, 3H), 6.68 (dd,
1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.37 (s, 1H), 3.26 (t, 2H), 3.20
(s, 3H), 3.07 (s, 4H), 2.75 (s, 2H), 2.17 (d, 6H), 1.95 (s, 2H),
1.81 (dd, 2H), 1.64-1.74 (m, 1H), 1.48 (dd, 2H), 1.23-1.42 (m, 6H),
0.92 (s, 6H).
Compound 30
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 30A
(R)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide
[0163] The racemic mixture of Compound 12A was resolved on a SFC
chiral AD column to provide the title compound.
Compound 30B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
[0164] The title compound was prepared as described in the
procedure for Compound 11D using Compound 30A in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67
(s, 2H), 8.35 (s, 1H), 8.03 (d, 2H), 7.48-7.57 (m, 3H), 7.42 (d,
1H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.21
(s, 1H), 4.19-4.30 (m, 2H), 3.85-3.92 (m, 1H), 3.73-3.85 (m, 2H),
3.58-3.70 (m, 2H), 3.40-3.52 (m, 2H), 3.10 (s, 4H), 2.85 (s, 2H),
2.18-2.39 (m, 3H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93
(s, 6H).
Compound 31
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0165] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 15H and Compound 25A, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H), 11.46 (m,
1H), 8.54 (m, 2H), 8.45 (m, 1H), 8.03 (d, 1H), 7.83 (m, 2H), 7.50
(m, 3H), 7.34 (m, 3H), 7.12 (m, 2H), 6.68 (dd, 1H), 6.38 (dd, 1H),
6.20 (d, 1H), 4.11 (s, 2H), 3.79 (m, 4H), 3.51 (m, 6H), 3.05 (m,
4H), 2.17 (m, 3H), 1.17 (s, 6H).
Compound 32
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0166] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 15H and Compound 12A, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 8.37 (d,
1H), 8.03 (m, 2H), 7.50 (m, 3H), 7.37 (d, 2H), 7.13 (d, 2H), 6.68
(dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.25 (m, 2H), 4.12 (s, 2H),
3.84 (m, 3H), 3.63 (m, 2H), 3.45 (m, 2H), 3.06 (m, 4H), 2.86 (m,
2H), 2.24 (m, 6H), 1.20 (m, 6H).
Compound 33
trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]met-
hyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitropheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0167] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 15H and Compound 9C, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.63 (s, 1H), 8.51 (d,
1H), 8.15 (d, 1H), 8.01 (d, 1H), 7.76 (dd, 1H), 7.48 (m, 3H), 7.38
(d, 2H), 7.13 (d, 2H), 7.06 (d, 1H), 6.66 (dd, 1H), 6.36 (dd, 1H),
6.21 (d, 1H), 4.11 (s, 2H), 3.63 (m, 5H), 3.05 (m, 4H), 2.83 (s,
2H), 2.64 (m, 4H), 2.17 (m, 6H), 2.05 (m, 2H), 1.91 (s, 2H), 1.43
(m, 6H), 1.17 (m, 6H).
Compound 34
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 34A
(4-methoxycyclohexyl)methanamine
[0168] (4-Methoxyphenyl)methanamine (1 g, 1.29 mmol) in ethanol (10
ml) was treated with 5% Rh--Al.sub.2O.sub.3 (99.8 mg, 0.048 mmol)
under H.sub.2 atmosphere (500 psi) at 50.degree. C. for 16 hours.
Additional 5% Rh--Al.sub.2O.sub.3 (0.4 g) was added. The resulting
mixture was stirred under H.sub.2 atmosphere (500 psi) at
60.degree. C. for 2 hours. The insoluble material was filtered off
and the filtrate was concentrated to provide a mixture of cis and
trans product as an oil, which was used in the next step without
further purification.
Compound 34B
trans-4-((4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[0169] 4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and Compound
34A (1 g) in tetrahydrofuran (20 ml) was treated with
N,N-diisopropylethylamine (0.871 ml) overnight. The reaction
mixture was concentrated and the residue was purified by reverse
phase chromatography, and was eluted with 40-55% acetonitrile in
0.1% trifluoroacetic acid in water over 25 minutes.
Compound 34C
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0170] The title compound was prepared as described in the
procedure for Compound 11D using Compound 34B in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 1H), 11.37 (s, 1H), 8.52-8.62 (m, 2H), 8.04 (d, 1H), 7.79 (dd,
1H), 7.47-7.55 (m, 3H), 7.34 (d, 2H), 7.02-7.09 (m, 3H), 6.68 (dd,
1H), 6.39 (dd, 1 H), 6.19 (d, 1H), 3.21-3.27 (m, 5H), 3.02-3.12 (m,
5H), 2.75 (s, 2H), 2.20 (s, 4H), 2.14 (s, 2H), 1.93-2.04 (m, 4H),
1.79 (d, 2H), 1.55-1.65 (m, 1H), 1.38 (t, 2H), 0.97-1.12 (m, 4H),
0.92 (s, 6H).
Compound 35
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]-
sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0171] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 15H and Compound 36C, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H), 8.78 (s,
1H), 8.58 (s, 1H), 8.00 (d, 1H), 7.51 (m, 3H), 7.38 (d, 2H), 7.14
(d, 2H), 6.68 (dd, 1H), 6.37 (dd, 1H), 6.23 (d, 1H), 4.31 (d, 2H),
4.13 (s, 2H), 3.88 (dd, 2H), 3.11 (m, 5H), 2.16 (m, 6H), 1.65 (m,
2H), 1.35 (m, 2H), 1.19 (s, 6H).
Compound 36
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 36A
5-bromo-6-chloropyridine-3-sulfonamide
[0172] 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 overnight. 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 using 20-100% ethyl acetate in hexanes
to give the title compound.
Compound 36B
5-bromo-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[0173] The title compound was prepared by substituting Compound 36A
for 4-fluoro-3-nitrobenzenesulfonamide in the procedure for
Compound 24A.
Compound 36C
5-cyano-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[0174] A mixture of Compound 36B (0.702 g), dicyanozinc (0.129 g),
and tetrakis(triphenylphosphine)palladium(0) (0.231 g) in
N,N-dimethylformamide (2 ml) was degassed via vacuum/nitrogen cycle
three times. The reaction mixture was heated at 120.degree. C. for
3 hours. After cooling, it was poured into water and extracted with
ethyl acetate three times. The combined organic layers were washed
with brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified with flash column chromatography on silica gel
eluting with 20%-60% ethyl acetate in hexanes to give the title
compound.
Compound 36D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0175] The title compound was prepared by substituting Compound 36C
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.56 (s, 1H), 8.66
(s, 1H), 8.44 (s, 1H), 7.94 (d, 1H), 7.55 (d, 1H), 7.44 (t, 1H),
7.34-7.35 (m, 3H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.32 (s, 1H), 6.24
(s, 1H), 4.26 (d, 2H), 3.86 (dd, 2H), 3.10 (s, 4H), 2.75 (s, 2H),
2.31-2.35 (m, 2H), 2.01-2.05 (m, 1H), 2.15 (s, 2H), 1.96 (s, 2H),
1.63-1.66 (m, 2H), 1.33-1.40 (m, 4H), 0.92 (s, 6H).
Compound 37
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 37A
1,6-dioxaspiro[2.5]octane-2-carbonitrile
[0176] A mixture of tetrahydropyran-4-one (10 ml) and
chloroacetonitrile (6.4 ml) in tert-butanol (10 ml) was stirred for
10 minutes. To this solution was added a solution of potassium
tert-butoxide (12.11 g) in 200 ml of tert-butanol at room
temperature over 40 minutes. The reaction mixture was stirred for
16 hours, diluted with water and quenched slowly with 1 N HCl. The
solvent was partially removed by rotary evaporation. It was then
extracted with ether (5.times.200 ml). The combined extracts was
washed with brine, dried over MgSO.sub.4, filtered, and the
filtrate was concentrated and purified by flash chromatography on
silica with 3:7 to 1:1 ethyl acetate:hexanes to provide the title
compound.
Compound 37B
2-(4-fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile
[0177] Compound 37A (11.5 g) in dichloromethane (40 ml) in a
polypropylene bottle was treated with 70% hydrogen
fluoride-pyridine (10.4 ml) dropwise at 0.degree. C. The solution
was allowed to warm to room temperature over 3 hours, and stirred
for an additional 1.5 hours. The reaction mixture was diluted with
ethyl acetate (200 ml) and poured into saturated aqueous
NaHCO.sub.3. Additional solid NaHCO.sub.3 was used carefully until
bubbling ceased. The organic layer was isolated, and the aqueous
layer was extracted with additional ethyl acetate three times (150
ml each). The combined organic layers were washed with 5% HCl (50
ml each, twice), brine, dried over MgSO.sub.4, filtered and
concentrated to give the desired product which was used directly in
the next step.
Compound 37C
(4-fluorotetrahydro-2H-pyran-4-yl)methanol
[0178] Compound 37B (11.7 g, 74 mmol) in 2-propanol (150 ml) and
water (37.5 ml) was cooled to 0.degree. C. To this solution was
added NaBH.sub.4 (4.20 g, 111 mmol). The solution was stirred and
allowed to warm to room temperature over 3 hours. It was quenched
with acetone, and stirred for another 1 hour. The clear liquid was
separated from solid by decanting. Additional ethyl acetate
(2.times.100 ml) was used to wash the solid, and the mixture was
decanted. The combined organic solutions were concentrated. The
residue was purified by flash chromatography, eluting with 1:1
ethyl acetate:hexanes to provide the title compound.
Compound 37D
4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
[0179] The title compound was prepared by substituting Compound 37C
for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 24A.
Compound 37E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0180] The title compound was prepared as described in the
procedure for Compound 11D using Compound 37D in place of Compound
11B. .sup.1H NMR (dimethylsulfoxide-d.sub.6) .delta. 11.64 (s, 2H),
8.33 (s, 1H), 8.00-8.01 (m, 2H), 7.39-7.57 (m, 4H), 7.33 (d, J=8.24
Hz, 2H), 7.03 (d, J=8.54 Hz, 2H), 6.65 (dd, J=9, 1.98 Hz, 1H),
6.37-6.38 (m, 1H), 6.19 (d, J=1.53 Hz, 1H), 4.35 (d, J=20.75 Hz,
2H), 3.74-3.78 (m, 2H), 3.55-3.60 (m, 2H), 3.07 (br, 4H), 2.80 (br,
2H), 2.25 (br, 4H), 2.13 (br, 2H), 1.81-1.94 (m, 6H), 1.38 (t,
J=6.26 Hz, 2H), 0.91 (s, 6H).
Compound 38
N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 38A
3-cyano-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
[0181] The title compound was prepared by substituting
3-cyano-4-fluorobenzenesulfonamide for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 38B
5-sulfamoyl-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzamide
[0182] To a solution of Compound 38A (0.455 g) in ethanol (3 ml)
and tetrahydrofuran (1 ml) was added hydrogen peroxide (30% in
water, 2 ml) followed by 1 N aqueous NaOH (1.024 ml) and heated to
35.degree. C. for 3 hours. The reaction was poured into
dichloromethane (50 ml) and 1N aqueous HCl (25 ml). The aqueous
layer was extracted with dichloromethane (3.times.50 ml). The
precipitate contained in the combined organic layers was collected
by filtration to give the title compound.
Compound 38C
N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0183] The title compound was prepared by substituting Compound 38B
for Compound 1F and Compound 3J for Compound 1E in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.79-11.70 (m, 1H), 11.66-11.54 (m, 1H), 9.29-9.08 (m,
1H), 8.27 (d, 1H), 8.08 (d, 1H), 7.97-7.90 (m, 1H), 7.76-7.72 (m,
1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.50 (d, 1H), 7.39 (d, 1H), 7.23
(d, 1H), 7.08 (d, 1H), 6.74-6.67 (m, 1H), 6.44 (s, 1H), 6.22 (s,
1H), 4.03 (d, 6H), 3.74-3.52 (m, 4H), 3.33 (s, 4H), 3.11-2.90 (m,
2H), 2.01 (s, 4H), 1.79-1.58 (m, 2H), 1.24 (s, 5H), 0.94 (s,
6H).
Compound 39
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 39A
cis-tert-butyl-4-morpholinocyclohexylcarbamate
[0184] To a solution of morpholine (4.08 g) and tert-butyl
4-oxocyclohexylcarbamate (10 g) stirred for 24 hours at room
temperature in titanium (IV) isopropoxide (27.5 ml), methanol (10
ml) was added followed by careful addition of sodium borohydride
(3.55 g). The reaction mixture was quenched with water/NaOH
solution, extracted with ether, dried over magnesium sulfate,
filtered, and concentrated. The product was separated from the
trans isomer and purified by flash chromatography (silica gel,
50%-100% acetone in hexanes) to provide the title compound.
Compound 39B
cis-4-morpholinocyclohexanamine bis(2,2,2-trifluoroacetate)
[0185] To a solution of Compound 39A (2.43 g) in dichloromethane
(15 ml) was added trifluoroacetic acid (5 ml) and the reaction
mixture was stirred for 16 hours at room temperature. The reaction
mixture was concentrated and the crude product was used without
purification.
Compound 39C
4-(cis-4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide
[0186] A solution of Compound 39B (0.40 g),
4-fluoro-3-nitrobenzenesulfonamide (0.478 g) and triethylamine (2
ml) in tetrahydrofuran (10 ml) was stirred for 3 days at room
temperature. The reaction mixture was concentrated and purified by
flash chromatography (silica gel, 0-30% methanol/dichloromethane)
providing the product.
Compound 39D
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0187] The title compound was prepared by substituting Compound 39C
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, pyridine-d.sub.5) .delta. 13.07 (s, 1H), 9.30 (d, 1H),
8.64 (d, 1H), 8.43 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H), 7.67 (t,
2H), 7.44 (d, 2H), 7.06 (d, 2H), 6.91 (d, 1H), 6.74 (dd, 1H),
6.48-6.55 (m, 2H), 3.65-3.73 (m, 5H), 3.02-3.09 (m, 4H), 2.76 (s,
2H), 2.41-2.48 (m, 4H), 2.25 (t, 2H), 2.09-2.16 (m, 5H), 1.97 (s,
2H), 1.77-1.86 (m, 2H), 1.55-1.63 (m, 6H), 1.39 (t, 2H), 0.93 (s,
6H).
Compound 40
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 40A
5,6-dichloropyridine-3-sulfonamide
[0188] The title compound was prepared by substituting
5,6-dichloropyridine-3-sulfonyl chloride for
5-bromo-6-chloropyridine-3-sulfonyl chloride in the procedure for
Compound 36A.
Compound 40B
5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[0189] The title compound was prepared by substituting Compound 40A
for 4-fluoro-3-nitrobenzenesulfonamide in the procedure for
Compound 24A.
Compound 40C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0190] The title compound was prepared by substituting Compound 40B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 8.52
(s, 1H), 8.39 (d, 1H), 8.03 (d, 1H), 7.54 (d, 1H), 7.52 (d, 1H),
7.50 (dd, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (m,
1H), 6.21 (d, 1H), 4.25 (d, 2H), 3.87 (dd, 2H), 3.30 (m, 2H), 3.10
(v br s, 4H), 2.90 (v br s, 2H), 2.35 (v br s, 4H), 2.17 (br m,
2H), 2.05 (m, 1H), 1.96 (s, 2H), 1.64 (d, 2H), 1.40 (t, 2H), 1.35
(ddd, 2H), 0.93 (s, 6H).
Compound 41
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl-
]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0191] The title compound was prepared by substituting Compound 15H
for Compound 3J and Compound 40B for Compound 11B in the procedure
for Compound 11D. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.68 (s, 1H), 8.55 (d, 1H), 8.41 (d, 1H), 8.04 (d, 1H),
7.54 (m, 2H), 7.50 (dd, 1H), 7.38 (d, 2H), 7.14 (d, 2H), 6.68 (dd,
1H), 6.40 (m, 1H), 6.20 (d, 1H), 4.25 (d, 2H), 4.12 (s, 2H), 3.87
(dd, 2H), 3.30 (m, 2H), 3.10 (v br s, 4H), 2.90 (v br s, 2H), 2.27
(v br s, 4H), 2.17 (br m, 2H), 2.05 (m, 1H), 1.96 (s, 2H), 1.64 (d,
2H), 1.35 (ddd, 2H), 0.97 (s, 6H).
Compound 42
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide
Compound 42A
4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethyl)benzenesulfon-
amide
[0192] A mixture of 4-fluoro-3-(trifluoromethyl)benzenesulfonamide
(1.056 g), (tetrahydro-2H-pyran-4-yl)methanamine (0.5 g) and
N,N-diisopropylethylamine (1.68 g) in anhydrous dimethylsulfoxide
(15 ml) solution was heated at 90.degree. C. overnight. The
reaction mixture was cooled to room temperature and diluted with
ethyl acetate. The organic phase was washed with water, brine,
dried over anhydrous sodium sulfate, filtered and concentrated to
afford the title compound.
Compound 42B
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide
[0193] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 15H and Compound 42A, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.73 (s, 1H), 11.25 (s,
1H), 8.08 (d, 1H), 7.89 (d, 1H), 7.77 (m, 1H), 7.61 (d, 1H), 7.51
(m, 2H), 7.37 (d, 2H), 7.13 (d, 2H), 6.88 (d, 1H), 6.67 (dd, 1H),
6.53 (m, 1H), 6.43 (m, 1H), 6.15 (d, 1H), 4.11 (s, 2H), 3.82 (dd,
2H), 3.19 (m, 5H), 3.05 (m, 4H), 2.82 (s, 2H), 2.20 (m, 7H), 1.85
(m, 1H), 1.56 (m, 2H), 1.18 (s, 6H).
Compound 43
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzam-
ide
[0194] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 15H and Compound 17A, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.48 (m,
1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.92 (dd, 1H), 7.52 (m, 3H), 7.37
(d, 2H), 7.27 (m, 1H), 7.11 (m, 3H), 6.68 (dd, 1H), 6.41 (dd, 1H),
6.18 (d, 1H), 4.11 (s, 2H), 3.84 (dd, 2H), 3.25 (m, 4H), 3.07 (m,
4H), 2.84 (m, 2H), 2.23 (m, 5H), 1.84 (m, 1H), 1.55 (m, 2H), 1.25
(m, 3H), 1.18 (s, 6H).
Compound 44
trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]met-
hyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluor-
omethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benz-
amide
Compound 44A
trans-4-(4-morpholinocyclohexylamino)-3-(trifluoromethylsulfonyl)benzenesu-
lfonamide
[0195] The title compound was prepared as described in the
procedure for Compound 16A by replacing 2-methoxyethanamine with
Compound 9B.
Compound 44B
trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]met-
hyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluor-
omethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benz-
amide
[0196] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 15H and Compound 44A, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.62 (s, 1H), 8.08 (s,
1H), 8.00 (d, 1H), 7.85 (d, 1H), 7.47 (m, 3H), 7.38 (d, 2H), 7.14
(d, 2H), 6.98 (d, 1H), 6.65 (dd, 1H), 6.55 (m, 1H), 6.37 (m, 1H),
6.21 (d, 1H), 4.12 (s, 2H), 3.54 (m, 6H), 3.04 (m, 4H), 2.83 (s,
2H), 2.57 (m, 3H), 2.24 (m, 6H), 1.91 (m, 5H), 1.34 (m, 4H), 1.20
(s, 6H).
Compound 45
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)su-
lfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 45A
4-(1-methylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonam-
ide
[0197] The title compound was prepared as described in the
procedure for Compound 16A by replacing 2-methoxyethanamine with
1-methyl-4-aminopiperidine.
Compound 45B
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)su-
lfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0198] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 15H and Compound 45A, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.59 (s, 1H), 8.10 (s,
1H), 7.98 (d, 1H), 7.90 (dd, 1H), 7.49 (m, 3H), 7.39 (m, 3H), 7.14
(d, 2H), 7.02 (d, 1H), 6.65 (dd, 2H), 6.36 (dd, 1H), 6.22 (d, 1H),
4.12 (s, 2H), 3.75 (m, 1H), 3.16 (m, 4H), 2.98 (m, 5H), 2.88 (m,
5H), 2.67 (s, 2H), 2.22 (m, 6H), 1.68 (m, 1H), 1.18 (s, 6H).
Compound 46
5-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-(-
tetrahydro-2H-pyran-4-ylmethoxy)nicotinamide
Compound 46A
5-sulfamoyl-2-((tetrahydro-2H-pyran-4-yl)methoxy)nicotinamide
[0199] To Compound 36C (0.025 g) in ethanol (1 ml) and
tetrahydrofuran (1 ml) was added hydrogen peroxide (30% in water,
0.5 ml) followed by 1M aqueous sodium hydroxide (0.056 ml) then
another 1 ml of tetrahydrofuran. The reaction was heated to
45.degree. C. for 2 hours, cooled, quenched with 1N aqueous HCl (5
ml), and the product extracted into dichloromethane (10 ml). The
organic layer was dried over magnesium sulfate, filtered and
concentrated to give the title compound.
Compound 46B
5-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-(-
tetrahydro-2H-pyran-4-ylmethoxy)nicotinamide
[0200] The title compound was prepared by substituting Compound 46A
for Compound 1F and Compound 3J for Compound 1E in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
10.31-10.09 (m, 1H), 9.09 (s, 2H), 8.93-8.81 (m, 1H), 8.28-8.18 (m,
1H), 8.03-7.87 (m, 1H), 7.77-7.68 (m, 1H), 7.59-7.51 (m, 1H),
7.48-7.41 (m, 1H), 6.91 (d, 2H), 6.59-6.48 (m, 2H), 5.97 (s, 2H),
4.50 (d, 2H), 4.08-3.98 (m, 2H), 3.45 (s, 4H), 3.13-2.99 (m, 4H),
2.82-2.68 (m, 2H), 2.19 (s, 4H), 1.86 (s, 5H), 1.61-1.35 (m, 4H),
0.94 (s, 6H).
Compound 47
N-({5-bromo-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 47A
5-bromo-6-((1-methylpiperidin-4-yl)methoxy)pyridine-3-sulfonamide
[0201] To (1-methylpiperidin-4-yl)methanol (0.109 g) in
tetrahydrofuran (2 ml) was added sodium hydride (0.136 g). After 30
minutes, Compound 36A (0.230 g) was added as a solution in
tetrahydrofuran (1 ml) and the reaction was heated to 50.degree. C.
After 4 hours, the reaction was cooled, poured into water (10 ml)
and dichloromethane (50 ml), and the pH was adjusted to pH.about.8.
The aqueous layer was extracted with dichloromethane (3.times.50
ml), and the organic layers were combined, washed with brine (30
ml), dried over magnesium sulfate, filtered, and concentrated to
give the title compound.
Compound 47B
N-({5-bromo-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0202] The title compound was prepared by substituting Compound 47A
for Compound 1F and Compound 3J for Compound 1E in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.51 (s, 1H), 8.35 (d, 1H), 8.17 (d, 1H), 7.93 (d, 1H),
7.60 (d, 1H), 7.44-7.40 (m, 1H), 7.33 (dd, 3H), 7.05 (d, 2H), 6.61
(d, 1H), 6.31 (dd, 1H), 6.24 (s, 1H), 4.25 (d, 2H), 3.40 (s, 4H),
3.01 (s, 4H), 2.73 (d, J=8.2, 5H), 2.20 (s, 6H), 1.93 (d, 4H), 1.54
(s, 1H), 1.39 (s, 2H), 1.24 (s, 2H), 0.93 (s, 6H).
Compound 48
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 48A
4-((1-methylpiperidin-4-yl)methoxy)-3-nitrobenzene sulfonamide
[0203] The title compound was prepared by substituting
(1-methylpiperidin-4-yl)methanol for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 48B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0204] The title compound was prepared by substituting Compound 48A
for Compound 1F and Compound 3J for Compound 1E in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.54 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.87-7.77 (m,
1H), 7.58 (d, 1H), 7.43 (s, 1H), 7.40-7.00 (m, 7H), 6.70-6.56 (m,
1H), 6.31 (s, 1H), 6.24 (s, 1H), 4.05 (s, 2H), 3.46-3.33 (m, 2H),
3.02 (s, 6H), 2.72 (d, 5H), 2.21 (s, 6H), 1.96 (s, 5H), 1.70-1.48
(m, 2H), 1.39 (s, 2H), 0.93 (s, 6H).
Compound 49
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 49A
6-((1,4-dioxan-2-yl)methoxy)-5-bromopyridine-3-sulfonamide
[0205] The title compound was prepared by substituting
(1,4-dioxan-2-yl)methanol for (tetrahydro-2H-pyran-4-yl)methanol
and Compound 36A for 4-fluoro-3-nitrobenzenesulfonamide in the
procedure for Compound 24A.
Compound 49B
6-((1,4-dioxan-2-yl)methoxy)-5-cyanopyridine-3-sulfonamide
[0206] The title compound was prepared by substituting Compound 49A
for Compound 36B in the procedure for Compound 36C.
Compound 49C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0207] The title compound was prepared by substituting Compound 49B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (s, 1H), 8.60
(s, 1H), 8.40 (s, 1H), 7.91 (d, 1H), 7.58 (d, 1H), 7.42 (t, 1H),
7.35 (d, 2H), 7.28 (s, 1H), 7.06 (d, 2H), 6.64 (dd, 1H), 6.29 (m,
2H), 4.40 (d, 2H), 3.90 (m, 1H), 3.79 (m, 2H), 3.63 (m, 2H), 3.46
(m, 4H), 3.07 (s, 4H), 2.85 (m, 2H), 2.34 (m, 4H), 2.16 (m, 2H),
1.40 (t, 2H), 0.93 (s, 6H).
Compound 50
N-{[5-bromo-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-c-
hlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0208] The title compound was prepared by substituting Compound 49A
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.60 (s, 1H), 8.46
(s, 1H), 8.27 (s, 1H), 7.99 (d, 1H), 7.56 (d, 1H), 7.46 (m, 2H),
7.35 (d, 2H), 7.05 (d, 2H), 6.65 (dd, 1H), 6.36 (dd, 1H), 6.22 (d,
1H), 4.34 (m, 2H), 3.88 (m, 1H), 3.79 (m, 2H), 3.63 (m, 2H), 3.46
(m, 2H), 3.06 (s, 4H), 2.81 (s, 2H), 2.26 (m, 4H), 2.15 (s, 2H),
1.96 (s, 2H), 1.38 (m, 2H), 0.93 (s, 6H).
Compound 51
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 51A
4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzene
sulfonamide
[0209] The title compound was prepared as described in the
procedure for Compound 12A by replacing (1,4-dioxan-2-yl)methanol
with (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol.
Compound 51B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0210] The title compound was prepared as described in the
procedure for Compound 11D using Compound 51A in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 2H), 8.35 (s, 2H), 8.03 (d, 4H), 7.47-7.58 (m, 6H), 7.31-7.42
(m, 6H), 7.04 (d, 4H), 6.68 (dd, 2H), 6.40 (s, 2H), 6.20 (d, 2H),
3.96-4.09 (m, 2H), 3.54-3.68 (m, 2H), 3.09 (s, 4H), 2.83 (s, 2H),
2.09-2.37 (m, 7H), 1.96 (s, 2H), 1.55-1.69 (m, 2H), 1.39 (t, 2H),
1.19 (m, 8H), 0.92 (s, 6H).
Compound 52
N-({3-chloro-5-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfo-
nyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 52A
3-cyano-4-fluorobenzenesulfonamide
[0211] 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.1 g) in
1,4-dioxane (10 ml) at 0.degree. C. was treated dropwise with a 7 M
ammonia solution in methanol (3.57 ml) and stirred for 30 minutes.
A small amount of solid was removed by filtration and discarded.
The filtrate was concentrated, diluted with ethyl acetate, washed
with water and brine, dried (MgSO.sub.4), filtered, concentrated
and triturated with diethyl ether to give the product.
Compound 52B
3-cyano-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzene
sulfonamide
[0212] The title compound was prepared by substituting Compound 52A
for 4-chloro-3-nitrobenzenesulfonamide and
(tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-amine
dihydrochloride in the procedure for Compound 6A.
Compound 52C
3-chloro-5-cyano-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonami-
de
[0213] Compound 52B (0.148 g) in acetonitrile (5 ml) was treated
with N-chlorosuccinimide (0.080 g), heated at 60.degree. C. for 3
hours and filtered to remove a small amount of solid. The filtrate
was concentrated and chromatographed on silica gel with 3-15% ethyl
acetate in dichloromethane as eluent. The obtained solid was
slurried in water, filtered, rinsed with additional water and dried
under vacuum to give the product.
Compound 52D
N-({3-chloro-5-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfo-
nyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0214] The title compound was prepared by substituting Compound 52C
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta.11.70 (s, 1H), 11.41
(br s, 1H), 8.07 (d, 1H), 7.89 (s, 2H), 7.61 (m, 1H), 7.53 (m, 2H),
7.35 (d, 2H), 7.18 (m, 1H), 7.05 (d, 2H), 6.69 (m, 1H), 6.42 (dd,
1H), 6.18 (dd, 1H), 3.83 (m, 2H), 3.55 (t, 2H), 3.23 (m, 3H), 3.06
(m, 4H), 2.15 (m, 4H), 1.92 (m, 4H), 1.60 (m, 2H), 1.40 (m, 2H),
1.19 (m, 4H), 0.93 (s, 6H).
Compound 53
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 53A
N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-y-
loxy)benzamide
[0215] The title compound was prepared by substituting Compound 3J
for Compound 1E and 4-chloro-3-nitrobenzenesulfonamide for Compound
1F in the procedure for Compound 1G.
Compound 53B
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0216] A 5 ml round-bottomed flask was charged with Compound 53A
(120 mg), 1-acetylpiperidin-4-amine (28 mg), and triethylamine
(0.064 ml) in dioxane (2 ml). The reaction mixture was heated to
90.degree. C. for 24 hours. The reaction mixture was cooled to room
temperature, and added to a silica gel column and purified by
eluting with 0-5% methanol in dichloromethane. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (br s, 1H), 8.65 (d,
1H), 8.24 (d, 1H), 8.03 (d, 1H), 7.83 (dd, 1H), 7.54-7.46 (m, 3H),
7.35 (d, 2H), 7.19 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m,
1H), 6.20 (d, 1H), 4.28 (d, 1H), 3.97-3.75 (m, 2H), 3.07 (br s,
4H), 2.87-2.70 (m, 4H), 2.29-2.10 (m, 6H), 2.02 (s, 3H), 2.00-1.89
(m, 4H), 1.66-1.54 (m, 2H), 1.39 (t, 2H), 0.92 (s, 6H).
Compound 54
N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 54A
2-chloro-5-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonam-
ide
[0217] The title compound was prepared by substituting
2-chloro-4,5-difluorobenzenesulfonamide for
4-chloro-3-nitrobenzenesulfonamide and
(tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-amine
dihydrochloride in the procedure for Compound 6A.
Compound 54
N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0218] The title compound was prepared by substituting Compound 54A
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.76 (s, 1H), 11.31
(s, 1H), 8.08 (d, 1H), 7.69 (d, 1H), 7.60 (d, 1H), 7.55 (m, 2H),
7.34 (d, 2H), 7.04 (d, 2H), 6.90 (s, 1H), 6.84 (d, 1H), 6.69 (dd,
1H), 6.45 (dd, 1H), 6.13 (d, 1H), 3.82 (dd, 2H), 3.24 (t, 2H), 3.05
(m, 6H), 2.73 (s, 2H), 2.14 (m, 6H), 1.95 (s, 2H), 1.81 (m, 1H),
1.61 (m, 2H), 1.38 (t, 2H), 1.17 (m, 2H), 0.92 (s, 6H).
Compound 55
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0219] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 2A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.66 (br s, 1H), 8.75 (t, 1H), 8.54 (d, 1H), 8.03 (d, 1H),
7.79 (dd, 1H), 7.54-7.48 (m, 3H), 7.35 (d, 2H), 7.08-7.02 (m, 3H),
6.67 (dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H), 3.61 (t, 4H), 3.43 (q,
2H), 3.29 (m, 2H), 3.06 (br s, 4H), 2.73 (br s, 2H), 2.47 (br s,
4H), 2.18 (m, 6H), 1.95 (br s, 2H), 1.80 (m, 2H), 1.38 (t, 2H),
0.92 (s, 6H).
Compound 56
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 56A
5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamid-
e
[0220] The title compound was prepared by substituting Compound 37C
for tetrahydro-2H-pyran-4-yl)methanol and Compound 36A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 56B
5-cyano-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamid-
e
[0221] The title compound was prepared by substituting Compound 56A
for Compound 36B in the procedure for Compound 36C.
Compound 56C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0222] The title compound was prepared by substituting Compound 56B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.58 (s, 1H), 8.70
(s, 1H), 8.51 (s, 1H), 7.96 (d, 1H), 7.57 (d, 1H), 7.45 (t, 1H),
7.35-7.37 (m, 3H), 7.06 (d, 2H), 6.67 (dd, 1H), 6.33 (d, 1H), 6.26
(s, 1H), 4.56 (d, 2H), 3.76-3.80 (s, 2H), 3.56-3.62 (m, 2H),
3.01-3.10 (m, 4H), 2.14-2.18 (m, 2H), 1.96 (s, 2H), 1.80-1.87 (m,
4H), 1.41 (t, 2H), 0.93 (s, 6H).
Compound 57
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 57A
5-bromo-6-(2-morpholino ethoxy)pyridine-3-sulfonamide
[0223] The title compound was prepared by substituting
2-morpholinoethanol for tetrahydro-2H-pyran-4-yl)methanol and
Compound 36A for 4-fluoro-3-nitrobenzenesulfonamide in the
procedure for Compound 24A.
Compound 57B
5-cyano-6-(2-morpholino ethoxy)pyridine-3-sulfonamide
[0224] The title compound was prepared by substituting Compound 57A
for Compound 36A in the procedure for Compound 36B.
Compound 57C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0225] The title compound was prepared by substituting Compound 57B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.56 (s, 1H), 8.64
(s, 1H), 8.41 (s, 1H), 7.92 (d, 1H), 7.58 (d, 1H), 7.44 (t, 1H),
7.36 (d, 2H), 7.31 (s, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.31 (d,
1H), 6.27 (d, 1H), 4.59 (t, 2H), 3.59 (s, 4H), 3.08 (s, 4H), 2.89
(s, 2H), 2.65 (s, 4H), 2.16-2.18 (m, 2H), 1.97 (s, 2H), 1.41 (t,
2H), 0.93 (s, 6H).
Compound 58
N-[(3-chloro-4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}phenyl)sulfonyl]-4-(4-{-
[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 58A
3-chloro-4-(2-(2-methoxyethoxy)ethylthio)benzenesulfonamide
[0226] In a 25 ml microwave tube was added sodium hydride (0.6 g)
in terahydrofuran (10 ml) to give a suspension.
2-(2-Methoxyethoxy)ethanethiol (1 g) was added slowly. After
stirring for 30 minutes, 3-chloro-4-fluorobenzenesulfonamide (1.54
g) dissolved in 10 ml tetrahydrofuran was added slowly. The mixture
was heated at 110.degree. C. for 30 minutes in a Biotage Initiator
microwave reactor. Water was added, the product was extracted with
ether (20 ml.times.3), dried over Na.sub.2SO.sub.4, filtered, and
the solvent was removed under reduced pressure. The crude product
was purified by flash chromatography on silica eluting with 0-25%
ethyl acetate in hexane.
Compound 58B
3-chloro-4-(2-(2-methoxyethoxy)ethylsulfonyl)benzenesulfonamide
[0227] Compound 58A (0.15 g) was suspended in acetic acid (3 ml).
Peracetic acid (0.4 ml) was added slowly. The mixture was stirred
at room temperature overnight, then poured into
Na.sub.2S.sub.2O.sub.3 solution, and the product precipitated.
After filtration and washing with water, the product was dried
under vacuum.
Compound 58C
N-[(3-chloro-4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}phenyl)sulfonyl]-4-(4-{-
[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0228] The title compound was prepared by substituting Compound 58B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.52 (s, 1H), 7.92
(d, 1H), 7.84 (m, 2H), 7.68 (m, 1H), 7.62 (d, 1H), 7.42 (t, 1H),
7.35 (d, 2H), 7.29 (m, 1H), 7.05 (d, 2H), 6.62 (dd, 1H), 6.32 (m,
1H), 6.26 (d, 1H), 3.74 (t, 2H), 3.68 (t, 2H), 3.24 (m, 2H), 3.06
(m, 5H), 3.01 (m, 4H), 2.74 (s, 2H), 2.19 (m, 6H), 1.96 (s, 2H),
1.39 (t, 2H), 0.93 (s, 6H).
Compound 59
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-nitrophenyl)sulfonyl]-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 59A
4-(2-(2-methoxyethoxy)ethylthio)-3-nitrobenzenesulfonamide
[0229] The title compound was prepared by substituting
4-fluoro-3-nitrobenzenesulfonamide for
3-chloro-4-fluorobenzenesulfonamide in the procedure for Compound
58A.
Compound 59B
4-(2-(2-methoxyethoxy)ethylsulfonyl)-3-nitrobenzenesulfonamide
[0230] The title compound was prepared by substituting Compound 59A
for Compound 58A in the procedure for Compound 58B.
Compound 59C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-nitrophenyl)sulfonyl]-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0231] The title compound was prepared by substituting Compound 59B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.51 (s, 1H), 8.17
(m, 1H), 7.94 (m, 3H), 7.64 (d, 1H), 7.42 (m, 1H), 7.35 (d, 2H),
7.28 (d, 1H), 7.05 (d, 2H), 6.62 (m, 1H), 6.28 (m, 2H), 3.83 (m,
4H), 3.16 (m, 2H), 3.08 (s, 3H), 3.01 (m, 4H), 2.73 (s, 2H), 2.18
(m, 6H), 1.96 (m, 4H), 1.39 (t, 2H), 0.93 (s, 6H)
Compound 60
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 60A
trans-4-(4-aminocyclohexyloxy)-3-nitrobenzene sulfonamide
[0232] To a solution of tert-butyl 4-hydroxycyclohexylcarbamate
(0.250 g) in tetrahydrofuran (5 ml) was added sodium hydride (0.186
g). After stirring for 15 minutes,
4-fluoro-3-nitrobenzenesulfonamide (0.256 g) was added as a
solution in tetrahydrofuran (1 ml). The reaction was heated to
60.degree. C. for 1.5 hours, cooled, and poured into a mixture of
dichloromethane (100 ml) and water (25 ml). The aqueous layer was
adjusted to pH.about.4 with 1N aqueous HCl and the organic layer
was separated, washed with brine (50 ml), dried over magnesium
sulfate, filtered, and concentrated. The residue was loaded onto
silica gel (GraceResolv 40 g) and eluted using a gradient of 0.5%
to 7.5% methanol/dichloromethane over 30 minutes. This solid was
treated with HCl (4.0M in dioxane, 5 ml) at room temperature for 1
hour and concentrated to give the title compound.
Compound 60B
4-(trans-4-morpholino cyclohexyloxy)-3-nitrobenzene sulfonamide
[0233] To Compound 60A (0.220 g) and
1-bromo-2-(2-bromoethoxy)ethane (0.177 g) in N,N-dimethylformamide
(3 ml) was added triethylamine (0.338 ml) and the reaction heated
to 70.degree. C. for 5 hours. The reaction was cooled and the
resulting precipitate was removed by filtration. The reaction was
concentrated and loaded onto silica gel and was eluted using a
gradient of 0.5% to 7.5% methanol/dichloromethane to give the title
compound.
Compound 60C
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0234] The title compound was prepared by substituting Compound 60B
for Compound 1F and Compound 3J for Compound 1E in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.62 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.96-7.88 (m,
1H), 7.54 (d, 1H), 7.48 (s, 2H), 7.34 (d, 3H), 7.04 (d, 2H),
6.72-6.58 (m, 1H), 6.37 (s, 1H), 6.21 (s, 1H), 4.69-4.47 (m, 1H),
3.66 (s, 4H), 3.05 (s, 4H), 2.76 (s, 6H), 2.22 (s, 9H), 1.96 (s,
4H), 1.39 (s, 6H), 0.92 (s, 6H).
Compound 61
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-y-
l}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 61A
5-bromo-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)pyridine-3-sulf-
onamide
[0235] A mixture of Compound 36A (1.0 g), Compound 3L (0.95 g) and
triethylamine (3.08 ml) in anhydrous dioxane (20 ml) was heated at
110.degree. C. overnight. The organic solvent was removed under
vacuum. The residue was purified with flash column chromatography
on silica gel eluting with 2%-8% methanol/dichloromethane to give
the title compound.
Compound 61B
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-y-
l}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0236] The title compound was prepared by substituting Compound 61A
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.59 (s, 1H), 8.35
(s, 1H), 8.00 (s, 2H), 7.55 (d, 1H), 7.46 (m, 2H), 7.34 (d, 2H),
7.04 (d, 2H), 6.63 (dd, 1H), 6.49 (m, 1H), 6.36 (s, 1H), 6.20 (s,
1H), 4.05 (m, 1H), 3.94 (d, 2H), 3.28 (m, 6H), 3.01 (s, 4H), 2.72
(s, 2H), 2.16 (m, 6H), 1.93 (m, 4H), 1.80 (m, 4H), 1.57 (m, 2H),
1.38 (t, 2H), 1.17 (t, 2H), 0.90 (s, 6H).
Compound 62
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,-
3-b]pyridin-5-yloxy)benzamide
Compound 62A
4-(2-cyanoethylamino)-3-nitrobenzenesulfonamide
[0237] The title compound was prepared by substituting
3-aminopropanenitrile for Compound 39B in the procedure for
Compound 39C.
Compound 62B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-cyano
ethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-
benzamide
[0238] The title compound was prepared by substituting Compound 62A
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(501 MHz, pyridine-d.sub.5) .delta. 13.04 (s, 1H), 9.24 (d, 1H),
9.04 (t, 1H), 8.43 (d, 1H), 8.38 (dd, 1H), 8.13 (d, 1H), 7.64-7.68
(m, 2H), 7.44 (ddd, 2H), 7.07 (ddd, 2H), 7.02 (d, 1H), 6.76 (dd,
1H), 6.55 (d, 1H), 6.48 (dd, 1H), 3.83 (q, 2H), 3.07 (d, 4H), 2.98
(t, 2H), 2.77 (s, 2H), 2.26 (s, 2H), 2.11-2.17 (m, 4H), 1.97 (s,
2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 63
cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methy-
l}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0239] The title compound was prepared by substituting Compound 15H
for Compound 3J and Compound 39C for Compound 11B in the procedure
for Compound 11D. .sup.1H NMR (501 MHz, pyridine-d.sub.5) .delta.
13.09 (s, 1H), 9.30 (d, 1H), 8.64 (d, 1H), 8.43 (d, 1H), 8.38 (dd,
1H), 8.10 (d, 1H), 7.68 (dt, 2H), 7.46 (ddd, 2H), 7.12 (ddd, 2H),
6.91 (d, 1H), 6.72 (dd, 1H), 6.51 (dd, 1H), 6.49 (d, 1H), 5.69 (s,
2H), 4.40 (s, 2H), 3.69-3.73 (m, 4H), 3.68 (s, 1H), 2.95-3.02 (m,
4H), 2.84 (s, 2H), 2.40-2.46 (m, 4H), 2.21 (s, 2H), 2.08-2.15 (m,
5H), 1.76-1.84 (m, 2H), 1.55-1.63 (m, 6H), 1.29 (s, 6H).
Compound 64
trans-N-{[4-({4-[bis(cyclopropylmethyl)amino]cyclohexyl}amino)-3-nitrophen-
yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 64A
tert-butyl
(trans)-4-(bis(cyclopropylmethyl)amino)cyclohexylcarbamate
[0240] The title compound was prepared by substituting
cyclopropanecarbaldehyde for 4'-chlorobiphenyl-2-carboxaldehyde and
tert-butyl (trans)-4-aminocyclohexylcarbamate for tert-butyl
piperazine-1-carboxylate in the procedure for Compound 1A.
Compound 64B
(trans)-N.sup.1,N.sup.1-bis(cyclopropylmethyl)cyclohexane-1,4-diamine
dihydro chloride
[0241] To a solution of Compound 64A (1.4 g) in dichloromethane (10
ml) was added hydrogen chloride (10 ml, 4M in dioxane) and the
reaction was stirred for 16 hours at room temperature. The reaction
mixture was diluted with ether and pure product was filtered
off.
Compound 64C
trans-4-(4-(bis(cyclopropylmethyl)amino)cyclohexylamino)-3-nitrobenzenesul-
fonamide
[0242] The title compound was prepared by substituting Compound 64B
for Compound 39B in the procedure for Compound 39C.
Compound 64D
trans-N-{[4-({4-[bis(cyclopropylmethyl)amino]cyclohexyl}amino)-3-nitrophen-
yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0243] The title compound was prepared by substituting Compound 64C
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, pyridine-d.sub.5) .delta. 13.06 (s, 1H), 9.30 (d, 1H),
8.44 (d, 1H), 8.41 (dd, 1H), 8.37 (d, 1H), 8.12 (d, 1H), 7.67 (d,
2H), 7.44 (d, 2H), 7.07 (d, 2H), 7.00 (d, 1H), 6.75 (dd, 1H), 6.53
(d, 1H), 6.49 (dd, 1H), 3.36-3.43 (m, 1H), 3.02-3.09 (m, 4H),
2.87-2.94 (m, 1H), 2.77 (s, 2H), 2.47 (d, 4H), 2.25 (t, 2H),
2.11-2.16 (m, 4H), 2.08 (d, 2H), 1.97 (s, 2H), 1.84 (d, 2H), 1.39
(t, 2H), 1.26-1.35 (m, 4H), 0.90-0.98 (m, 8H), 0.50-0.56 (m, 4H),
0.18-0.23 (m, 4H).
Compound 65
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 65A
4-((1-methylpiperidin-4-yl)methylamino)-3-nitrobenzene
sulfonamide
[0244] The title compound was prepared by substituting
4-aminomethyl-1-methyl piperidine for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 65B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0245] The title compound was prepared by substituting Compound 65A
for Compound 130C in the procedure for Compound 130D. .sup.1H NMR
(500 MHz, dichloromethane-d.sub.2) .delta. 9.57 (bs, 1H), 8.78 (d,
1H), 8.41 (d, 1H), 8.14 (d, 1H), 7.90 (m, 2H), 7.64 (d, 1H), 7.45
(d, 1H), 7.23 (d, 2H), 6.95 (d, 2H), 6.76 (d, 1H), 6.59 (dd, 1H),
6.51 (d, 1H), 6.09 (d, 1H), 3.21 (m, 2H), 3.08 (m, 4H), 3.02 (m,
2H), 2.74 (s, 2H), 2.33 (s, 3H), 2.21-2.17 (m, 6H), 2.16-2.02 (m,
3H), 1.97 (br.s, 2H), 1.78 (m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).
Compound 66
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(morpholin-3-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 66A
tert-butyl
3-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxyl-
ate
[0246] The title compound was prepared by substituting tert-butyl
3-(aminomethyl)morpholine-4-carboxylate for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 66B
tert-butyl
3-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfam-
oyl)-2-nitrophenylamino)methyl)morpholine-4-carboxylate
[0247] The title compound was prepared by substituting Compound 66A
for Compound 1F and Compound 3J for Compound 1E in the procedure
for Compound 1F, with the exception that the product was purified
on a silica gel column eluted with 4% methanol in
dichloromethane.
Compound 66C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(morpholin-3-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
[0248] A solution of Compound 66B in 50% trifluoroacetic acid and
dichloromethane mixture was stirred at ambient temperature for 2
hours. The solvents were evaporated and the residue was purified on
a reverse phase HPLC using a gradient of 20-80% acetonitrile in
water containing 10 mM ammonium acetate. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.61 (s, 1H), 8.52 (bs, 1H),
8.49 (d, 1H), 7.98 (d, 1H), 7.78 (d, 1H), 7.54 (d, 1H), 7.46 (s,
1H), 7.42 (s, 1H), 7.34 (d, 2H), 7.04 (m, 3H), 6.65 (dd, 1H), 6.34
(s, 1H), 6.21 (d, 1H), 3.89 (d, 1H), 3.76 (d, 1H), 3.55-3.46 (m,
2H), 3.40-3.35 (m, 4H), 3.04 (m, 4H), 2.91 (t, 1H), 2.73 (s, 2H),
2.20-2.12 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 67
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0249] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 15H and Compound 6A, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.58 (s, 1H), 9.04 (s,
1H), 8.44 (d, 1H), 7.97 (d, 1H), 7.76 (dd, 1H), 7.49 (m, 4H), 7.38
(d, 2H), 7.14 (d, 2H), 6.64 (dd, 1H), 6.34 (d, 1H), 6.21 (d, 1H),
4.12 (s, 2H), 3.03 (m, 6H), 2.85 (m, 5H), 2.29 (m, 4H), 2.18 (m,
6H), 1.20 (s, 6H).
Compound 68
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 68A
4-morpholinobut-2-yn-1-ol
[0250] To a solution of morpholine (4.36 g) in toluene (15 ml) was
added 4-chlorobut-2-yn-1-ol (2.09 g) in toluene (5 ml). The
solution was stirred at 85.degree. C. for 3 hours. After cooling,
the solid was filtered off. The filtrate was subjected to vacuum
distillation to give the pure title compound.
Compound 68B
4-(4-morpholinobut-2-ynyloxy)-3-nitrobenzenesulfonamide
[0251] The title compound was prepared by substituting Compound 68A
for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 24A.
Compound 68C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0252] The title compound was prepared by substituting Compound 68B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 8.36
(s, 1H), 8.08 (d, 1H), 8.03 (d, 1H), 7.47-7.53 (m, 4H), 7.35 (d,
2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 5.15
(s, 2H), 3.52-3.55 (m, 4H), 3.09 (s, 4H), 2.84 (br s, 2H),
2.23-2.40 (m, 6H), 2.12-2.18 (m, 2H), 1.96 (s, 2H), 1.39 (t, 2H),
0.92 (s, 6H).
Compound 69
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 69A
6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-((triisopropylsilyl)ethynyl)pyridi-
ne-3-sulfonamide
[0253] Compound 36B (0.176 g), bis(triphenylphosphine)palladium(II)
chloride (0.176 g), copper(I) iodide (0.010 g),
N,N-dimethylacetamide (2.5 ml) and triethylamine (0.105 ml) were
combined, flushed with nitrogen and stirred for 2 minutes.
(Triisopropylsilyl)acetylene (0.135 ml) was added and the reaction
mixture was flushed with nitrogen again, heated at 60.degree. C.
overnight, diluted with ethyl acetate, washed with water and brine,
dried (MgSO.sub.4), filtered, concentrated and chromatographed on
silica gel with 10-30% ethyl acetate in hexanes as the eluent to
give the product.
Compound 69B
5-ethynyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[0254] Compound 69A (0.205 g) in tetrahydrofuran (3 ml) at ambient
temperature was treated with tetrabutyl ammonium fluoride (1 M in
tetrahydrofuran, 0.906 ml) and stirred at ambient temperature for 4
hours. Additional tetrabutyl ammonium fluoride (1 M in
tetrahydrofuran, 1.8 ml) was added and the mixture was heated at
40.degree. C. for 45 minutes. Solid tetrabutyl ammonium fluoride
(0.253 g) was added and heating was continued for 30 minutes. The
reaction mixture was concentrated and then chromatographed on
silica gel using 0-2% methanol in dichloromethane as the eluent to
give the product.
Compound 69C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0255] The title compound was prepared by substituting Compound 69B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.41
(s, 1H), 8.58 (d, 1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.53 (m, 3H),
7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.41 (dd, 1H), 6.18 (d,
1H), 4.56 (s, 1H), 4.24 (d, 2H), 3.87 (dd, 2H), 3.38 (m, 3H), 3.07
(m, 4H), 2.86 (m, 2H), 2.29 (m, 5H), 2.04 (m, 3H), 1.64 (dd, 2H),
1.34 (m, 4H), 0.93 (s, 6H).
Compound 70
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-oxo-3,4-dihydroquinazolin-6-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]p-
yridin-5-yloxy)benzamide
Compound 70A
4-amino-3-cyanobenzene sulfonamide
[0256] 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.1 g) was
dissolved in dioxane (4 ml). The solution was cooled to 0.degree.
C. and 7 ml of an ammonia (7N in methanol) solution was added.
After the addition was complete, the ice bath was removed and the
reaction was stirred at room temperature for 24 hours. After
concentration of the reaction mixture, the crude material was
purified by flash chromatography eluting with a gradient of 30-100%
ethyl acetate/hexanes.
Compound 70B
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-amino-3-cyanophenylsulfonyl)-4-(-
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)b-
enzamide
[0257] The title compound was prepared by substituting Compound 70A
for Compound 1F and Compound 3J for Compound 1E in the procedure
for Compound 1G.
Compound 70C
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-amino-3-carbamoylphenylsulfonyl)-
-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1--
yl)benzamide
[0258] To a solution of Compound 70B (90 mg) in ethanol (2 ml) was
added tetrahydrofuran (2 ml), hydrogen peroxide (30%, 1 ml) and 1M
sodium hydroxide solution (0.48 ml), followed by an additional 2 ml
of tetrahydrofuran. The reaction was heated to 45.degree. C. for 30
minutes, cooled, and then quenched with 5% HCl solution and
extracted twice with dichloromethane. The extracts were combined
and concentrated to obtain the product.
Compound 70D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-oxo-3,4-dihydro
quinazolin-6-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0259] Compound 70C (80 mg) was combined with trimethyl
orthoformate (2.3 ml) and trifluoroacetic acid (0.03 ml) and the
resulting solution was stirred at room temperature for 4 hours. The
mixture was purified by flash chromatography, eluting with a
gradient of 3-10% methanol/dichloromethane. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 12.61 (s, 1H), 11.71 (s, 1H),
8.65 (d, 1H), 8.24 (s, 1H), 8.17 (dd, 1H), 8.04 (m, 1H), 7.73 (d,
1H), 7.57 (d, 1H), 7.51 (m, 2H), 7.39 (d, 2H), 7.07 (d, 2H), 6.70
(dd, 1H), 6.40 (m, 1H), 6.24 (br s, 1H), 3.61 (m, 6H), 3.03 (m,
2H), 2.75 (m, 2H), 2.17 (m, 2H), 2.01 (m, 2H), 1.44 (m, 2H), 0.94
(s, 6H).
Compound 71
trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1--
yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 71A
8-chlorospiro[4.5]dec-7-ene-7-carbaldehyde
[0260] To a solution of N,N-dimethylformamide (2.81 ml) in
dichloromethane (40 ml) was added dropwise POCl.sub.3 (2.78 ml) at
0.degree. C. The reaction mixture was warmed up to room temperature
and spiro[4.5]decan-8-one (3.95 g) in dichloromethane (5 ml) was
added dropwise. The mixture was stirred overnight. The reaction was
quenched with cold aqueous sodium acetate and the resulting mixture
was extracted with ether and the organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide the title
compound.
Compound 71B
8-(4-chlorophenyl)spiro[4.5]dec-7-ene-7-carbaldehyde
[0261] To a suspension of Compound 71A (3 g) in water (50 ml) was
added 4-chlorophenylboronic acid (2.83 g), tetrabutylammonium (4.87
g), potassium carbonate (6.26 g) and palladium(II) acetate (0.169
g). The reaction mixture was stirred at 45.degree. C. for 5 hours
and extracted with dichloromethane. The organic layer was
concentrated and the residue was loaded onto a silica gel column,
and eluted with 5-20% ethyl acetate in hexane to give the title
compound.
Compound 71C
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((8-(4-chlorophenyl)spiro-
[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)benzoate
[0262] To a solution of Compound 71B (274 mg) in dichloroethane
(3.5 ml) was added Compound 15F (387 mg) and sodium
triacetoxyborohydride (317 mg). The reaction mixture was stirred
overnight. Sodium cyanoborohydride (37.6 mg) was added and the
resulting mixture stirred overnight. The reaction was quenched with
water and diluted with dichloromethane. The mixture was washed with
water extensively and the organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide the title
compound.
Compound 71D
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((8-(4-chlorophenyl)spiro[4.5]de-
c-7-en-7-yl)methyl)piperazin-1-yl)benzoic acid
[0263] The title compound was prepared as described in the
procedure for Compound 3J using Compound 71C in place of Compound
3I.
Compound 71E
trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1--
yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0264] The title compound was prepared as described in the
procedure for Compound 11D using Compound 71D and Compound 9C in
place of Compound 3J and Compound 11B, respectively. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.64 (s, 1H), 8.51
(s, 1H), 8.15 (d, 1H), 8.01 (d, 1H), 7.76 (d, 1H), 7.44-7.53 (m,
3H), 7.34 (d, 2H), 7.07 (d, 3H), 6.66 (dd, 1H), 6.37 (dd, 1H), 6.20
(d, 1H), 3.50-3.70 (m, 5H), 3.04 (s, 4H), 2.55-2.76 (m, 5H),
2.34-2.39 (m, 1H), 2.20 (d, 6H), 2.03 (s, 4H), 1.91 (s, 2H), 1.61
(q, 4H), 1.51 (t, 2H), 1.36-1.46 (m, 8H).
Compound 72
cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methy-
l}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0265] The title compound was prepared as described in the
procedure for Compound 11D using Compound 15H and 29A in place of
Compound 3J and Compound 11B, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.45 (s, 1H),
8.59 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.79 (dd, 1H), 7.54 (d,
1H), 7.47-7.52 (m, 2H), 7.37 (d, 2H), 7.13 (d, 2H), 7.08 (d, 1H),
6.68 (dd, 1H), 6.35-6.42 (m, 1H), 6.19 (d, 1H), 4.11 (s, 2H), 3.37
(s, 1H), 3.26 (t, 2H), 3.20 (s, 3H), 3.07 (s, 4H), 2.83 (s, 2H),
2.17 (d, 6H), 1.81 (dd, 2H), 1.64-1.73 (m, 1H), 1.48 (dd, 2H),
1.23-1.41 (m, 4H), 1.18 (s, 6H).
Compound 73
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N--
({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0266] The title compound was prepared as described in the
procedure for Compound 11D using Compound 71D and Compound 37D in
place of Compound 3J and Compound 11B, respectively. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 8.37
(s, 1H), 7.98-8.11 (m, 2H), 4.38 (d, 2H), 3.74-3.82 (m, 2H),
3.54-3.64 (m, 2H), 3.44 (s, 1H), 3.08 (s, 3H), 2.58-2.89 (m, 2H),
2.13-2.35 (m, 4H), 2.04 (s, 2H), 1.78-1.93 (m, 4H), 1.57-1.65 (m,
4H), 1.52 (t, 2H), 1.36-1.47 (m, 4H).
Compound 74
trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1--
yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0267] The title compound was prepared as described in the
procedure for Compound 11D using Compound 71D and Compound 34B in
place of Compound 3J and Compound 11B, respectively. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.39
(s, 1H), 8.58 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.79 (dd, 1H),
7.47-7.55 (m, 3H), 7.34 (d, 2H), 7.07 (d, 3H), 6.68 (dd, 1H), 6.39
(dd, 1H), 6.19 (d, 1H), 3.25 (t, 2H), 3.22 (s, 3H), 3.06 (s, 5H),
2.71 (s, 2H), 2.21 (s, 6H), 1.94-2.06 (m, 4H), 1.79 (d, 2H),
1.57-1.65 (m, 5H), 1.51 (t, 2H), 1.39 (t, 4H), 0.95-1.11 (m,
4H).
Compound 75
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 75A
methyl
5,5-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylat-
e
[0268] The title compound was prepared by substituting
4,4-dimethyl-2-methoxycarbonylcyclohexanone for
5,5-dimethyl-2-methoxycarbonylcyclohexanone in the procedure for
Compound 3A.
Compound 75B
methyl 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate
[0269] The title compound was prepared by substituting Compound 75A
for Compound 3A in the procedure for Compound 3B.
Compound 75C
(2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methanol
[0270] The title compound was prepared by substituting Compound 75B
for Compound 3B in the procedure for Compound 3C.
Compound 75D
2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde
[0271] To a solution of Compound 75C (2.8 g) in dichloromethane (50
ml) was added Dess-Martin Periodinane (5.68 g). The reaction
mixture was stirred at room temperature for 3 hours and diluted
with ether and washed with 5% NaOH and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by flash chromatography using 20% ethyl
acetate in hexanes to provide the title compound.
Compound 75E
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5--
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0272] The title compound was prepared by replacing
4'-chlorobiphenyl-2-carboxaldehyde with Compound 75D and tert-butyl
piperazine-1-carboxylate with Compound 15F in the procedure for
Compound 1A.
Compound 75F
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0273] The title compound was prepared as described in the
procedure for Compound 15H by replacing Compound 15G with Compound
75E.
Compound 75G
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0274] The title compound was prepared as described in the
procedure for Compound 11D using Compound 75F and Compound 1F in
place of Compound 3J and Compound 11B, respectively. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.38
(s, 1H), 8.60 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H),
7.47-7.55 (m, 3H), 7.31-7.36 (m, 2H), 7.05-7.13 (m, 3H), 6.68 (dd,
1H), 6.39 (dd, 1H), 6.18 (d, 1H), 3.85 (dd, 2H), 3.22-3.31 (m, 4H),
3.07 (s, 4H), 2.67-2.78 (m, 2H), 2.19 (s, 6H), 1.82-1.98 (m, 3H),
1.56-1.66 (m, 2H), 1.39 (t, 2H), 1.17-1.33 (m, 3H), 0.93 (s,
6H).
Compound 76
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0275] The title compound was prepared as described in the
procedure for Compound 11D using Compound 75F and Compound 36C in
place of Compound 3J and Compound 11B, respectively. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.62 (s, 1H), 8.73
(s, 1H), 8.52 (s, 1H), 7.98 (d, 1H), 7.56 (d, 1H), 7.45-7.51 (m,
1H), 7.43 (s, 1H), 7.37 (d, 2H), 7.10 (d, 2H), 6.68 (dd, 1H), 6.35
(dd, 1H), 6.25 (s, 1H), 4.29 (d, 2H), 3.88 (dd, 2H), 3.12 (d, 4H),
2.21 (s, 2H), 2.00-2.11 (m, 1H), 1.95 (s, 2H), 1.64 (dd, 2H),
1.27-1.46 (m, 4H), 0.95 (s, 6H)
Compound 77
tert-butyl
3-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}-
sulfonyl)-2-nitrophenoxy]methyl}morpholine-4-carboxylate
Compound 77A
tert-butyl
3-((2-nitro-4-sulfamoylphenoxy)methyl)morpholine-4-carboxylate
[0276] The title compound was prepared as described in the
procedure for Compound 12A by replacing (1,4-dioxan-2-yl)methanol
with tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate.
Compound 77B
tert-butyl
3-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amin-
o}sulfonyl)-2-nitrophenoxy]methyl}morpholine-4-carboxylate
[0277] The title compound was prepared as described in the
procedure for Compound 11D using Compound 77A in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67
(s, 1H), 8.36 (s, 1H), 8.01-8.11 (m, 2H), 7.47-7.61 (m, 4H), 7.35
(d, 2H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.20 (s, 1H),
4.41-4.52 (m, 2H), 4.15-4.28 (m, 1H), 3.59-3.95 (m, 3H), 3.51 (d,
1H), 3.34-3.43 (m, 1H), 3.10 (s, 5H), 2.84 (s, 2H), 2.28 (s, 4H),
2.15 (s, 2H), 1.96 (s, 2H), 1.20-1.45 (m, 12H), 0.92 (s, 6H).
Compound 78
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(morpholin-3-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[-
2,3-b]pyridin-5-yloxy)benzamide
[0278] Compound 77B (100 mg) in dichloromethane (10 ml) at
0.degree. C. was treated with trifluoroacetic acid (5 ml) for 20
minutes. The reaction mixture was concentrated. The residue was
purified by reverse phase HPLC on a C18 column using a gradient of
35-60% acetonitrile in 0.1% trifluoroacetic acid water to give the
title compound as a trifluoroacetate salt. The trifluoroacetic acid
salt was dissolved in dichloromethane (10 ml) and washed with 50%
aqueous NaHCO.sub.3. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.56 (s,
1H), 8.23 (d, 1H), 7.94 (d, 1H), 7.90 (dd, 1H), 7.57 (d, 1H),
7.42-7.46 (m, 1H), 7.31-7.37 (m, 3H), 7.25 (d, 1H), 7.01-7.09 (m,
2H), 6.64 (dd, 1H), 6.29-6.37 (m, 1H), 6.24 (d, 1H), 4.17-4.31 (m,
2H), 3.90-4.05 (m, 1H), 3.77-3.85 (m, 1H), 3.45-3.59 (m, 4H),
2.94-3.13 (m, 6H), 2.76 (s, 2H), 2.18 (d, 6H), 1.96 (s, 2H), 1.39
(t, 2H), 0.93 (s, 6H).
Compound 79
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N--
({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0279] The title compound was prepared as described in the
procedure for Compound 11D using Compound 71D and Compound 1F in
place of Compound 3J and Compound 11B, respectively. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.38
(s, 1H), 8.60 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.77-7.84 (m,
1H), 7.45-7.56 (m, 3H), 7.34 (d, 2H), 7.04-7.13 (m, 3H), 6.68 (dd,
1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.85 (dd, 2H), 3.22-3.31 (m, 4H),
3.07 (s, 4H), 2.71 (s, 2H), 2.21 (s, 6H), 2.03 (s, 2H), 1.81-1.94
(m, 1H), 1.56-1.68 (m, 6H), 1.51 (t, 2H), 1.34-1.45 (m, 4H),
1.20-1.33 (m, 2H).
Compound 80
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0280] The title compound was prepared by substituting
1-(methylsulfonyl)piperidin-4-amine for 1-acetylpiperidin-4-amine
in the procedure for Compound 53B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (br s, 1H), 8.57 (d, 1H),
8.25 (d, 1H), 8.04 (d, 1H), 7.83 (dd, 1H), 7.54-7.46 (m, 3H), 7.35
(d, 2H), 7.17 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H),
6.20 (d, 1H), 3.80 (m, 1H), 3.57 (m, 2H), 3.08 (br s, 4H), 2.95
(td, 2H), 2.92 (s, 3H), 2.85-2.72 (m, 2H), 2.30-2.10 (m, 6H),
2.07-1.93 (m, 4H), 1.70 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 81
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-nitrophenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 81A
1,1-dioxotetrahydro-2H-thiopyran-4-amine
[0281] N-Benzyl-1,1-dioxotetrahydro-2H-thiopyran-4-amine (2.00 g)
was added to ethanol (40 ml) in a pressure bottle. Palladium
hydroxide on carbon (0.587 g,) was added and the solution was
stirred under 30 psi of hydrogen at room temperature for 2 hours.
The mixture was filtered though a nylon membrane and the solvent
was removed under vacuum.
Compound 81B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-nitrophenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0282] The title compound was prepared by substituting Compound 81A
for 1-acetylpiperidin-4-amine in the procedure for Compound 53B.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (br
s, 1H), 8.55 (d, 1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.86 (dd, 1H),
7.52-7.47 (m, 3H), 7.35 (d, 2H), 7.17 (d, 1H), 7.04 (d, 2H), 6.68
(dd, 1H), 6.39 (m, 1H), 6.21 (d, 1H), 4.05 (m, 1H), 3.22-3.00 (m,
8H), 2.79 (br s, 2H), 2.31-2.11 (m, 10H), 1.96 (br s, 2H), 1.39 (t,
2H), 0.93 (s, 6H).
Compound 82
N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-y-
loxy)benzamide
[0283] The title compound was prepared by substituting Compound 3J
for Compound 1E and 4-chloro-3-nitrobenzenesulfonamide for Compound
1F in the procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.60 (br s, 1H), 8.38 (br s,
1H), 7.96 (d, 1H), 7.91 (d, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.46
(t, 1H), 7.39-7.35 (m, 3H), 7.07 (d, 2H), 6.67 (dd, 1H), 6.34 (m,
1H), 6.28 (d, 1H), 3.31 (br s, 2H), 3.17 (br s, 8H), 2.18 (m, 2H),
1.98 (br s, 2H), 1.42 (t, 2H), 0.94 (s, 6H).
Compound 83
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 83A
3-Nitro-4-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-ylamino]-benzenesulfonami-
de
[0284] The title compound was prepared by substituting
1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
6A.
Compound 83B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0285] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 82A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.66 (br s, 1H), 8.56 (d, 1H), 8.24 (d, 1H), 8.04 (d, 1H),
7.81 (dd, 1H), 7.52 (dd, 2H), 7.48 (d, 1H), 7.35 (d, 2H), 7.15 (d,
1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H), 3.68
(m, 1H), 3.22 (q, 2H), 3.07 (br s, 4H), 2.90 (m, 2H), 2.75 (br s,
2H), 2.29-2.12 (m, 8H), 1.97-1.86 (m, 4H), 1.63 (m, 2H), 1.38 (t,
2H), 0.92 (s, 6H).
Compound 84
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-
-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 84A
1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ol
[0286] Piperidin-4-ol (7.8 g) and dihydro-2H-pyran-4(3H)-one (5.0
g) were dissolved in titanium(IV) isopropoxide (30 ml) and the
reaction was stirred at room temperature overnight. Methanol (40
ml) was added and the reaction was cooled to 0.degree. C. Then
NaBH.sub.4 (3.8 g) was added in portions over one hour. After 2
hours 1N aqueous NaOH was added, followed by ethyl acetate
addition. After filtration though celite the layers were separated,
the aqueous layer extracted with ethyl acetate, and the combined
organic layers were dried over Na.sub.2SO.sub.4. The crude was
purified by column chromatography using dichloromethane having
5-10% 7N NH.sub.3 in methanol.
Compound 84B
5-bromo-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)pyridine-3-sulfon-
amide
[0287] The title compound was prepared by substituting Compound 84A
for (tetrahydro-2H-pyran-4-yl)methanol and Compound 36A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 84C
5-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)pyridine-3-sulfon-
amide
[0288] The title compound was prepared by substituting Compound 84B
for Compound 36B in the procedure for Compound 36C.
Compound 84D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-
-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0289] The title compound was prepared by substituting Compound 84C
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (s, 1H), 8.60
(d, 1H), 8.37 (d, 1H), 7.90 (d, 1H), 7.60 (d, 1H), 7.42 (dd, 1H),
7.35 (d, 2H), 7.25 (d, 1H), 7.04 (d, 2H), 6.63 (dd, 1H), 6.28 (m,
1H), 6.24 (d, 1H), 5.30 (br s, 1H), 4.50 (d, 2H), 3.95 (dd, 2H),
3.30 (m, 5H), 3.02 (br s, 4H), 2.95 (br s, 2H), 2.24 (br s, 4H),
2.17 (br m, 4H), 1.96 (s, 2H), 1.90 (br m, 4H), 1.60 (br m, 2H),
1.39 (t, 2H), 0.93 (s, 6H).
Compound 85
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-isopropyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulf-
onyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 85A
5-isopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[0290] Compound 36B (0.176 g),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.041 g), and
palladium(II) acetate (0.011 g) were combined in a 10 ml oven-dried
flask. Tetrahydrofuran (1 ml) was added and the mixture was flushed
with nitrogen and stirred at ambient temperature for 5 minutes.
2-Propylzinc bromide solution (0.5 M in tetrahydrofuran) (1.5 ml)
was added and stirring was continued under nitrogen overnight.
Additional 2-2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.041
g) and palladium(II) acetate (0.011 g) were added. The mixture was
flushed with nitrogen and stirred at ambient temperature for 5
minutes. 2-Propylzinc bromide solution (0.5 M in tetrahydrofuran)
(1.5 ml) was added and stirring was continued under nitrogen for
2.5 days. The reaction mixture was diluted with ethyl acetate,
washed with water and brine, dried (MgSO.sub.4), filtered,
concentrated, and chromatographed on silica gel with 0 to 3%
methanol in CH.sub.2Cl.sub.2 as the eluent. The obtained material
was chromatographed on silica gel a second time with 10-40% ethyl
acetate in CH.sub.2Cl.sub.2 as the eluent, triturated with diethyl
ether and dried under vacuum at 45.degree. C. to give the
product.
Compound 85B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-isopropyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulf-
onyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0291] The title compound was prepared by substituting Compound 85A
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.70 (s, 1H), 8.49
(m, 1H), 8.04 (d, 1H), 7.90 (m, 1H), 7.57 (m, 1H), 7.52 (t, 1H),
7.48 (dd, 1H), 7.34 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.41 (dd,
1H), 6.17 (s, 1H), 4.19 (m, 2H), 3.88 (m, 2H), 3.30 (m, 2H), 3.05
(m, 5H), 2.77 (s, 2H), 2.21 (s, 4H), 2.14 (s, 2H), 2.03 (m, 1H),
1.95 (s, 2H), 1.64 (m, 2H), 1.34 (m, 4H), 1.12 (d, 6H), 0.92 (s,
6H).
Compound 86
N-({3-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 86A
3-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
[0292] The title compound was prepared by substituting
3,4-difluorobenzenesulfonamide for
4-chloro-3-nitrobenzenesulfonamide and
(tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-amine
dihydrochloride in the procedure for Compound 6A.
Compound 86B
3-chloro-5-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonam-
ide
[0293] The title compound was prepared by substituting Compound 86A
for Compound 52B in the procedure for Compound 52C.
Compound 86C
N-({3-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0294] The title compound was prepared by substituting Compound 86B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.72 (s, 1H), 11.20
(s, 1H), 8.08 (d, 1H), 7.61 (m, 2H), 7.50 (m, 3H), 7.34 (d, 2H),
7.04 (d, 2H), 6.68 (dd, 1H), 6.42 (dd, 1H), 6.16 (d, 1H), 6.09 (m,
1H), 3.81 (dd, 2H), 3.25 (m, 4H), 3.07 (m, 4H), 2.76 (s, 2H), 2.18
(m, 6H), 1.95 (s, 2H), 1.72 (m, 1H), 1.53 (d, 2H), 1.38 (t, 2H),
1.16 (m, 2H), 0.92 (s, 6H).
Compound 87
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-y-
loxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
Compound 87A
methyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate
[0295] The title compound was prepared by substituting
5-hydroxyindole for Compound 3G in the procedure for Compound
3H.
Compound 87B
methyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzoate
[0296] The title compound was prepared by substituting Compound 87A
for Compound 3H in the procedure for Compound 3I.
Compound 87C
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
[0297] The title compound was prepared by substituting Compound 87B
for Compound 31 in the procedure for Compound 3J.
Compound 87D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-y-
loxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
[0298] The title compound was prepared by substituting Compound 87C
for Compound 1E in the procedure for Compound 1G, except here the
crude was purified by preparative HPLC using a 250.times.50 mm C18
column and eluting with 20-100% CH.sub.3CN vs. 0.1% trifluoroacetic
acid in water, giving the product as a trifluoroacetate salt.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.40 (br
s, 1H), 11.17 (s, 1H), 9.50 (v br s, 1H), 8.61 (t, 1H), 8.57 (d,
1H), 7.77 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 5H), 7.36 (m, 5H),
7.10 (s, 1H), 7.08 (d, 1H), 6.83 (dd, 1H), 6.69 (dd, 1H), 6.37 (m,
1H), 6.21 (d, 1H), 4.30 (br s, 1H), 3.84 (dd, 2H), 3.70 (br s, 1H),
3.30 (m, 6H), 3.20, 2.95, 2.80 (all br s, total 6H), 1.86 (m, 1H),
1.60 (m, 2H), 1.25 (m, 2H).
Compound 88
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-y-
loxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzami-
de
[0299] The title compound was prepared by substituting Compound 87C
for Compound 1E and Compound 2A for Compound 1F in the procedure
for Compound 1G, except here the crude was purified by preparative
HPLC using a 250.times.50 mm C18 column and eluting with 20-100%
CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving the
product as a trifluoroacetate salt. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.40 (br s, 1H), 11.19 (s, 1H),
9.60 (v br s, 1H), 8.69 (t, 1H), 8.60 (d, 1H), 7.83 (dd, 1H), 7.65
(br s, 1H), 7.50 (m, 5H), 7.38 (m, 5H), 7.12 (m, 2H), 6.83 (dd,
1H), 6.69 (dd, 1H), 6.39 (m, 1H), 6.20 (d, 1H), 4.38 (br s, 1H),
4.00 (m, 2H), 3.80 (br s, 1H), 3.40 (m, 4H), 3.30-2.80 (envelope,
10H), 3.20 (m, 4H), 1.96 (m, 2H).
Compound 89
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide
[0300] This Compound was prepared by substituting Compound 87C for
Compound 1E and Compound 3M for Compound 1F in the procedure for
Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.15 (s, 1H), 8.56 (d, 1H), 8.20 (d, 1H), 7.84 (dd, 1H),
7.52 (d, 1H), 7.39-7.31 (m, 4H), 7.12 (d, 2H), 7.04 (d, 2H), 6.84
(dd, 1H), 6.65 (dd, 1H), 6.38 (t, 1H), 6.14 (d, 1H), 3.94 (m, 2H),
3.84 (m, 1H), 3.02 (m, 8H), 2.79 (m, 3H), 2.72 (s, 2H), 2.20-2.02
(m, 8H), 1.85 (m, 6H), 1.60 (m, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Compound 90
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
[0301] The title compound was prepared by substituting Compound 87C
for Compound 1E and Compound 4A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.08 (s, 1H), 8.51 (d, 1H), 8.13 (d, 1H), 7.78 (dd, 1H),
7.52 (d, 1H), 7.37-7.31 (m, 4H), 7.06-7.00 (m, 4H), 6.79 (dd, 1H),
6.59 (dd, 1H), 6.35 (t, 1H), 6.14 (d, 1H), 3.73 (m, 1H), 3.05-2.95
(m, 6H), 2.71 (s, 2H), 2.60 (m, 2H), 2.48 (s, 3H), 2.16 (m, 6H),
2.01 (m, 2H), 1.95 (s, 2H), 1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Compound 91
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
[0302] The title compound was prepared by substituting Compound 6A
for Compound 11B and Compound 87C for Compound 3J in the procedure
for Compound 11D. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.14 (s, 1H), 9.18 (s, 1H), 8.53 (d, 1H), 7.84 (dd, 1H),
7.56 (d, 1H), 7.51 (d, 1H), 7.39 (m, 2H), 7.33 (d, 2H), 7.12 (d,
1H), 7.03 (d, 2H), 6.84 (dd, 1H), 6.62 (dd, 1H), 6.38 (m, 1H), 6.13
(d, 1H), 3.00 (m, 4H), 2.90 (m, 4H), 2.71 (s, 2H), 2.33 (s, 3H),
2.15 (m, 6H), 1.94 (s, 2H), 1.37 (t, 2H), 0.92 (s, 6H).
Compound 92
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-
-yloxy)benzamide
[0303] The title compound was prepared as described in the
procedure for Compound 11D using Compound 87C and Compound 12A in
place of Compound 3J and Compound 11B, respectively. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 2H), 8.39
(d, 1H), 8.06 (dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 3H), 7.34 (d,
2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39
(s, 1H), 6.15 (d, 1H), 4.20-4.28 (m, 2H), 3.85-3.91 (m, 1H), 3.82
(dd, 1H), 3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H),
3.05 (s, 4H), 2.78 (s, 2H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s,
2H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 93
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluorometh-
yl)sulfonyl]phenyl}sulfonyl)benzamide
[0304] The title compound was prepared by substituting Compound 87C
for Compound 3J and Compound 16A for Compound 11B in the procedure
for Compound 11D. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.18 (d, 1H), 7.92 (dd, 1H), 7.49 (d, 1H),
7.40 (m, 2H), 7.33 (d, 2H), 7.26 (m, 1H), 7.17 (d, 1H), 7.04 (m,
3H), 6.86 (dd, 1H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.14 (d, 1H), 3.51
(m, 4H), 3.28 (s, 3H), 3.03 (s, 4H), 2.74 (s, 2H), 2.16 (m, 6H),
1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 94
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-
-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
[0305] The title compound was prepared by substituting Compound 87C
for Compound 3J and Compound 17A for Compound 11B in the procedure
for Compound 11D. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.20 (s, 1H), 8.19 (d, 1H), 7.90 (dd, 1H), 7.53 (d, 1H),
7.40 (m, 4H), 7.33 (t, 1H), 7.17 (d, 1H), 7.07 (m, 3H), 6.86 (dd,
1H), 6.70 (dd, 1H), 6.41 (s, 1H), 6.21 (d, 1H), 3.84 (dd, 2H), 3.59
(m, 2H), 3.25 (m, 6H), 3.00 (m, 2H), 2.74 (s, 2H), 2.54 (m, 2H),
2.18 (s, 2H), 2.01 (s, 2H), 1.83 (m, 1H), 1.54 (m, 2H), 1.45 (t,
2H), 1.23 (m, 2H), 0.94 (s, 6H).
Compound 95
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}amino)-3-ni-
trophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 95A
1-(1,3-difluoropropan-2-yl)piperidin-4-amine
[0306] Tert-butyl piperidin-4-ylcarbamate (0.212 g),
1,3-difluoropropan-2-one (0.149 g) and sodium triacetoxyborohydride
(0.337 g) were stirred together in dichloroethane at room
temperature. After stirring overnight the reaction was quenched
with water (10 ml) and extracted into dichloromethane (2.times.20
ml). The organic layer was dried over magnesium sulfate, filtered,
and concentrated. The residue was treated with hydrogen chloride
(4.0M in dioxane, 1.323 ml) for 1 hour to give the title compound
as the HCl salt after concentration.
Compound 95B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}amino)-3-ni-
trophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0307] Compound 95A (0.057 g) and Compound 53A (0.162 g) were
suspended in dioxane (3 ml) and heated to 105.degree. C. overnight.
The reaction was concentrated, loaded onto silica gel (GraceResolv
12 g) and eluted with a gradient of 0.5% to 4%
methanol/dichloromethane. The product containing fractions were
concentrated and loaded onto C18 (SF25-75g analogix column) and
eluted using a gradient of 30% to 60% acetonitrile/water. The
product was partitioned between dichloromethane (20 ml) and
saturated aqueous NaHCO.sub.3 solution (20 ml). The organic layer
was dried over magnesium sulfate, filtered, and concentrated to
give the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
10.10 (s, 1H), 8.88 (d, 2H), 8.45 (d, 1H), 8.20 (s, 1H), 8.18-8.09
(m, 1H), 7.95 (d, 1H), 7.68 (d, 1H), 7.44 (s, 1H), 7.23-7.19 (m,
1H), 6.91 (d, 3H), 6.53 (d, 2H), 5.98 (d, 1H), 4.64 (dd, 4H),
3.68-3.50 (m, 1H), 3.01 (d, 6H), 2.72 (d, 4H), 2.19 (s, 11H), 1.69
(s, 2H), 1.41 (s, 2H), 0.94 (s, 6H).
Compound 96
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 96A
5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonami-
de
[0308] The title compound was prepared by substituting Compound 40A
for 4-fluoro-3-nitrobenzenesulfonamide and Compound 37C for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 96B
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0309] The title compound was prepared by substituting Compound 96A
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 8.52
(s, 1H), 8.41 (s, 1H), 8.03 (d, 1H), 7.56 (d, 1H), 7.50 (m, 2H),
7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (m, 1H), 6.22 (s,
1H), 4.50 (d, 2H), 3.78 (m, 2H), 3.60 (m, 2H), 3.12 (v br s, 4H),
2.93 (v br s, 2H), 2.38 (v br s, 4H), 2.17 (br m, 2H), 1.96 (s,
2H), 1.86 (m, 4H), 1.40 (t, 2H), 0.93 (s, 6H).
Compound 97
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(2,2-difluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 97A
tert-butyl
4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate
[0310] The title compound was prepared by substituting tert-butyl
4-aminopiperidine-1-carboxylate for 4-methylpiperazin-1-amine
dihydrochloride in the procedure for Compound 6A.
Compound 97B
3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide
[0311] Tert-butyl
4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate was
dissolved in dichloromethane (3 ml) and treated with 1N HCl in
ether (4 ml). The reaction was stirred overnight then concentrated
to give the title compound.
Compound 97C
4-(1-(2,2-difluoroethyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide
[0312] 3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide
hydrochloride (0.100 g), 1,1-difluoro-2-iodoethane (0.063 ml) and
diisopropylamine (0.156 ml) were stirred together in
N,N-dimethylformamide (3 ml) and heated to 85.degree. C. The
reaction was diluted with dichloromethane (50 ml) and washed with
water (50 ml), brine (50 ml), dried over magnesium sulfate,
filtered, and concentrated. The residue was loaded onto silica gel
(GraceResolve 12 g) and eluted using a gradient of 0.5%
methanol/dichloromethane to 3% methanol/dichloromethane over 30
minutes to give the title compound.
Compound 97D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(2,2-difluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0313] The title compound was prepared by substituting Compound 97B
for Compound 1F and Compound 3J for Compound 1E in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.67 (s, 1H), 11.54-11.27 (m, 1H), 8.55 (d, 1H), 8.24 (d,
1H), 8.03 (d, 1H), 7.81 (d, 1H), 7.50 (dd, 3H), 7.34 (d, 2H), 7.13
(d, 1H), 7.04 (d, 2H), 6.68 (d, 1H), 6.38 (dd, 1H), 6.15 (dt, 2H),
3.64 (s, 1H), 3.07 (s, 4H), 2.79 (ddd, 6H), 2.41 (t, 2H), 2.17 (d,
6H), 1.92 (d, 4H), 1.61 (d, 2H), 1.38 (s, 2H), 0.92 (s, 6H).
Compound 98
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0314] The title compound was prepared as described in the
procedure for Compound 53B by replacing 1-acetylpiperidin-4-amine
with 4-amino-1-cyclopropylpiperidine. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H), 8.54 (d, 1H),
8.22 (d, 1H), 8.02 (d, 1H), 7.80 (dd, 1H), 7.49 (m, 3H), 7.34 (d,
2H), 7.11 (d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H), 6.19
(d, 1H), 3.69 (m, 1H), 3.06 (m, 4H), 2.92 (m, 2H), 2.74 (s, 2H),
2.23 (m, 7H), 1.93 (m, 5H), 1.77 (m, 1H), 1.55 (m, 3H), 1.38 (t,
2H), 0.92 (s, 6H), 0.43 (m, 4H).
Compound 99
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0315] The title compound was prepared as described in the
procedure for Compound 53B by replacing 1-acetylpiperidin-4-amine
with 1-(4-morpholino)cyclohexanemethylamine .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.70 (s, 1H), 9.06 (s, 1H),
8.59 (d, 1H), 8.06 (d, 1H), 7.83 (dd, 1H), 7.57 (d, 1H), 7.50 (m,
2H), 7.34 (m, 3H), 7.19 (d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.41
(dd, 1H), 6.17 (d, 1H), 3.56 (m, 6H), 3.44 (m, 2H), 3.07 (m, 5H),
2.57 (m, 5H), 2.24 (m, 6H), 1.95 (s, 3H), 1.45 (m, 6H), 1.23 (m,
3H), 0.92 (s, 6H).
Compound 100
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 100A
trans-tert-butyl-4-(dicyclopropylamino)cyclohexylcarbamate
[0316] A suspension of trans-tert-butyl-4-aminocyclohexylcarbamate
(1 g), molecular sieves 3 A (1 g), acetic acid (2.67 ml),
(1-ethoxycyclopropoxy)trimethysilane (3.74 ml) and sodium
cyanoborohydride (0.880 g) in dry methanol (10 ml) was heated at
reflux for 3 hours. The insolubles were filtered off, the resulting
solution was basified with aqueous NaOH (6 M) to pH 14, and
extracted with ether. The combined extracts were washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel 80 g,
30-100% acetone/hexanes) to provide the title compound.
Compound 100B
(trans)-N.sup.1,N.sup.1-dicyclopropylcyclohexane-1,4-diamine
bis(2,2,2-trifluoro acetate)
[0317] The title compound was prepared by substituting Compound
100A for Compound 39A in the procedure for Compound 39B.
Compound 100C
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0318] A suspension of Compound 53A (0.14 g), Compound 100B (0.112
g) and N,N-diisopropylethylamine (0.310 ml) in dioxane (10 ml) was
stirred for 3 days at 100.degree. C. The product was concentrated
and purified by RP HPLC(C8, 30%-100% CH.sub.3CN/water/0.1%
trifluoroacetic acid). .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 13.07 (s, 1H), 9.28 (d, 1H), 8.41-8.45 (m, 2H), 8.37 (d,
1H), 8.12 (d, 1H), 7.67 (d, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 7.01
(d, 1H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.48-6.51 (m, 1H), 3.43 (ddd,
1H), 3.03-3.09 (m, 4H), 2.72-2.79 (m, 3H), 2.22-2.28 (m, 2H),
2.11-2.16 (m, 4H), 2.10 (s, 2H), 2.00-2.05 (m, 2H), 1.97 (s, 2H),
1.89 (s, 1H), 1.86 (s, 3H), 1.62-1.71 (m, 2H), 1.39 (t, 2H),
1.19-1.29 (m, 2H), 0.93 (s, 6H), 0.48 (d, 8H).
Compound 101
4-(4-{[2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 101A
ethyl 2-hydroxy-6,6-dimethylcyclohex-1-enecarboxylate
[0319] Into a 500 ml flame dried round-bottomed flask was added
copper(I) iodide (18 g) in ether (200 ml) to give a suspension.
After cooling to -5.degree. C., methyllithium (120 ml, 1.6M in
ether) was added dropwise. After stirring at -5.degree. C. for 1
hour, 3-methylcyclohex-2-enone (5.15 ml) in 15 ml ether was added
dropwise, and the mixture was stirred at -5.degree. C. for 1 hour.
After cooling to -78.degree. C., hexamethylphosphoramide (60 ml)
was added dropwise. Ethyl carbonocyanidate (23.74 ml) was added.
After stirring at -78.degree. C. for 20 minutes, the mixture was
warmed up to room temperature, and stirred for 1 hour. The mixture
was poured into cold water, and the layers were separated. The
aqueous layer was extracted with ether (3.times.20 ml). The
combined organic layers were washed with saturated aqueous
NH.sub.4Cl (3.times.20 ml), dried over Na.sub.2SO.sub.4, filtered,
and dried under vacuum. The crude product was added to a silica gel
column and purified by eluting with 0-10% ethyl acetate in
hexane.
Compound 101B
ethyl
6,6-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
[0320] Into a 500 ml round-bottomed flask was added hexane-washed
sodium hydride (0.5 g) in dichloromethane (100 ml) to give a
suspension. After cooling to -5.degree. C., Compound 101A (2.0 g)
was added. After stirring at -5.degree. C. for 30 minutes, the
mixture was cooled to -78.degree. C. Trifluoromethanesulfonic
anhydride (2.2 ml) was added. The mixture was warmed to room
temperature and stirred overnight. Water was added slowly to the
mixture, the aqueous layer was then extracted by dichloromethane
(2.times.20 ml). The combined organic layers were washed with
saturated NH.sub.4Cl and brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated.
Compound 101C
ethyl 2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-enecarboxylate
[0321] Into a 25 ml microwave tube was added Compound 101B (2.9 g),
4-chlorophenylboronic acid (2.2 g), and
tetrakis(triphenylphosphine)palladium (0.05 g) in
1,2-dimethoxyethane/methanol (2:1, 10 ml) to give a solution.
Cesium fluoride (4 g) was then added. The reaction mixture was
stirred at 150.degree. C. under (100 W) in a Biotage Initiator
microwave reactor for 30 minutes. After removing the solvents,
water was added, and the mixture was extracted with ethyl acetate
(2.times.). The combined organic layers were dried by MgSO.sub.4.
After filtering, the crude product was purified by reverse phase
chromatography eluting with 50-100% acetonitrile/water with 0.1%
trifluoroacetic acid.
Compound 101D
(2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-enyl)methanol
[0322] In a 100 ml round-bottomed flask was placed lithium aluminum
hydride (1 g) in ether (20 ml) to give a suspension. Compound 101C
(1 g) dissolved in ether (5 ml) was added slowly by syringe. The
mixture was stirred at room temperature overnight. After cooling to
0.degree. C., the reaction was quenched by water. Ether (2.times.10
ml) was used to extract the product. The crude product was purified
by flash chromatography on silica by eluting with 0-15% ethyl
acetate in hexane.
Compound 101E
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-6,6--
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0323] To a 0.degree. C. solution of Compound 101D (0.43 g) in
dichloromethane (5 ml) was added triethylamine (1 ml).
Methanesulfonyl chloride (0.134 ml) was then added slowly. After 5
minutes, Compound 15F (0.61 g) was added. The mixture was stirred
at room temperature overnight. The crude product was purified by
flash chromatography on silica with 0 to 25% ethyl acetate in
hexanes to provide the title compound.
Compound 101F
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-6,6-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0324] In a 5 ml microwave tube was added lithium hydroxide hydrate
(15 mg) and Compound 101E (45 mg) in dioxane/water (2:1) (2 ml) to
give a suspension. The mixture was heated to 130.degree. C. in a
Biotage Initiator microwave reactor for 20 minutes. After cooling
and neutralization by HCl, the crude product was added to a Prep
HPLC column and was eluted with 20-80% acetonitrile/water with 0.1%
trifluoroacetic acid.
Compound 101G
4-(4-{[2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0325] The title compound was prepared by substituting Compound
101F for Compound 3J and Compound 1F for Compound 11B in the
procedure for Compound 11D. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 11.47 (s, 1H),
8.58 (m, 2H), 8.03 (m, 1H), 7.79 (m, 1H), 7.51 (m, 3H), 7.31 (d,
2H), 7.10 (m, 1H), 7.02 (d, 2H), 6.65 (m, 1H), 6.39 (m, 1H), 6.15
(m, 1H), 3.85 (m, 2H), 3.27 (m, 4H), 2.97 (m, 4H), 2.76 (s, 2H),
2.14 (m, 6H), 1.70 (m, 2H), 1.61 (m, 2H), 1.44 (m, 2H), 1.26 (m,
3H), 1.16 (m, 6H)
Compound 102
N-({5-bromo-6-[(4-ethylmorpholin-3-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4--
{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 102A
(4-ethylmorpholin-3-yl)methanol
[0326] Morpholin-3-ylmethanol (500 mg) and iodoethane (666 mg) in
N,N-dimethylformamide was treated with K.sub.2CO.sub.3 (1.1 g)
overnight. The reaction mixture was diluted with water and
extracted with ethyl acetate. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide the title
compound.
Compound 102B
5-bromo-6-((4-ethylmorpholin-3-yl)methoxy)pyridine-3-sulfonamide
[0327] The title compound was prepared as described in the
procedure for Compound 12A by replacing
4-fluoro-3-nitrobenzenesulfonamide and (1,4-dioxan-2-yl)methanol
with 5-bromo-6-fluoropyridine-3-sulfonamide and Compound 102A,
respectively.
Compound 102C
N-({5-bromo-6-[(4-ethylmorpholin-3-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4--
{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0328] The title compound was prepared as described in the
procedure for Compound 11D using Compound 102B in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.62
(s, 1H), 8.51 (s, 1H), 8.30 (s, 1H), 8.00 (d, 1H), 7.55 (d, 1H),
7.45-7.50 (m, 2H), 7.35 (d, 2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.37
(s, 1H), 6.21 (d, 1H), 4.58 (dd, 1H), 4.39-4.50 (m, 1H), 3.78-3.90
(m, 1H), 3.67-3.77 (m, 1H), 3.50-3.65 (m, 2H), 3.08 (s, 4H),
2.59-3.00 (m, 4H), 2.20-2.39 (m, 2H), 2.15 (s, 2H), 1.96 (s, 2H),
1.39 (t, 2H), 0.99-1.11 (m, 3H), 0.93 (s, 6H)
Compound 103
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 103A
4-((4-ethylmorpholin-3-yl)methoxy)-3-nitrobenzenesulfonamide
[0329] The title compound was prepared as described in the
procedure for Compound 12A by replacing (1,4-dioxan-2-yl)methanol
with Compound 102A.
Compound 103B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0330] The title compound was prepared as described in the
procedure for Compound 11D using Compound 103A in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66
(s, 1H), 8.33 (s, 1H), 7.99-8.06 (m, 2H), 7.47-7.57 (m, 3H), 7.45
(d, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H),
6.20 (d, 1H), 4.42 (dd, 1H), 4.23 (dd, 1H), 3.81 (d, 1H), 3.69 (d,
1H), 3.49-3.63 (m, 2H), 3.08 (s, 4H), 2.92 (s, 1H), 2.81 (s, 4H),
2.54 (s, 1H), 2.25 (s, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t,
2H), 1.00 (t, 3H), 0.92 (s, 6H)
Compound 104
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methoxy]phe-
nyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0331] Compound 78 (20 mg) and dihydro-2H-pyran-4(3H)-one (10 mg)
in dichloroethane (2 ml) was treated with NaCNBH.sub.3 (9.74 mg)
overnight. Additional dihydro-2H-pyran-4(3H)-one (20 mg) and
titanium (IV) isoproxide (0.05 ml) were added. The resulting
mixture was stirred at room temperature overnight and concentrated.
The residue was purified by reverse phase HPLC on a C18 column
using a gradient of 35-60% acetonitrile in 0.1% trifluoroacetic
acid water to give the title compound as a trifluoroacetate salt.
The trifluoroacetic acid salt was dissolved in dichloromethane (6
ml) and washed with 50% aqueous NaHCO.sub.3. The organic layer was
dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give the
title compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.68 (s, 1H), 8.35 (s, 1H), 8.04 (s, 2H), 7.44-7.58 (m,
4H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.40 (s, 1H), 6.20
(s, 1H), 4.44 (s, 1H), 4.28 (s, 1H), 3.85 (d, 2H), 3.71 (d, 1H),
3.61 (s, 3H), 3.20-3.29 (m, 2H), 3.08 (s, 5H), 2.54-2.96 (m, 5H),
2.06-2.42 (m, 5H), 1.96 (s, 2H), 1.77 (d, 1H), 1.53-1.66 (m, 1H),
1.29-1.51 (m, 4H), 0.92 (s, 6H).
Compound 105
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}-
phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 105A
(S)-tert-butyl
1-(tetrahydro-2H-pyran-4-yl)piperidin-3-ylcarbamate
[0332] The title compound was prepared by substituting
(S)-tert-butyl piperidin-3-ylcarbamate for tert-butyl
piperazine-1-carboxylate and dihydro-2H-pyran-4(3H)-one for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 105B
(S)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-amine
[0333] The title compound was prepared by substituting Compound
105A for Compound 1A in the procedure for Compound 1B.
Compound 105C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}-
phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0334] The title compound was prepared by substituting Compound
105B for 1-acetylpiperidin-4-amine in the procedure for Compound
53B. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.68
(br s, 1H), 8.54 (br s, 1H), 8.02 (d, 1H), 7.77 (m, 1H), 7.50 (m,
3H), 7.34 (d, 2H), 7.03 (m, 3H), 6.67 (dd, 1H), 6.38 (m, 1H), 6.19
(d, 1H), 3.98 (m, 2H), 3.90 (m, 2H), 3.52 (m, 2H), 3.09 (s, 2H),
3.05 (m, 4H), 2.77 (m, 2H), 2.60 (m, 2H), 2.16 (m, 6H), 1.95 (m,
2H), 1.65 (m, 5H), 1.50 (m, 3H), 1.38 (m, 2H), 0.94 (s, 6H).
Compound 106
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 106 A
5-bromo-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide
[0335] The title compound was prepared by substituting
(tetrahydro-2H-pyran-4-yl)methanamine for Compound 3L in the
procedure for Compound 61A.
Compound 106B
5-cyano-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide
[0336] The title compound was prepared by substituting Compound
106A for Compound 36B in the procedure for Compound 36C.
Compound 106C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0337] The title compound was prepared by substituting Compound
106B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.62 (s, 1H),
8.55 (s, 1H), 8.14 (s, 1H), 8.01 (d, 1H), 7.87 (s, 1H), 7.56 (d,
1H), 7.48 (d, 2H), 7.34 (d, 2H), 7.04 (d, 2H), 6.64 (m, 1H), 6.37
(s, 1H), 6.19 (d, 1H), 3.81 (dd, 2H), 3.25 (m, 4H), 3.04 (s, 4H),
2.74 (s, 2H), 2.17 (m, 6H), 1.95 (s, 2H), 1.87 (m, 1H), 1.53 (m,
2H), 1.37 (t, 2H), 1.18 (m, 2H), 0.91 (s, 6H).
Compound 107
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 107A
3-nitro-4-(4-aminothiomorpholine-1,1-dioxide)benzene
sulfonamide
[0338] The title compound was prepared by substituting
4-aminothiomorpholine-1,1-dioxide for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 107B
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0339] The title compound was prepared by substituting Compound
107A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.64 (s, 1H),
9.58 (s, 1H), 8.50 (s, 1H), 8.02 (d, 1H), 7.78 (m, 2H), 7.50 (m,
3H), 7.34 (d, 2H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.38 (s, 1H), 6.19
(d, 1H), 3.48 (m, 4H), 3.23 (m, 4H), 3.05 (s, 4H), 2.73 (d, 2H),
2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 108
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 108A
4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide
[0340] The title compound was prepared by substituting
4-(aminomethyl)tetrahydro-2H-pyran-4-amine for
(tetrahydro-2H-pyran-4-yl)methanamine in the procedure for Compound
1F.
Compound 108B
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0341] The title compound was prepared by substituting Compound
108A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.55 (s, 1H),
8.45 (s, 2H), 7.95 (d, 1H), 7.75-7.77 (m, 1H), 7.57 (d, 2H), 7.44
(s, 1H), 7.34 (d, 2H), 7.09 (d, J=8.85 Hz, 1H), 7.05 (d, 2H), 6.69
(dd, 1H), 6.33 (d, 1H), 6.22 (d, 1H), 3.59-3.71 (m, 6H), 3.01 (s,
4H), 2.73 (s, 2H), 2.15-2.19 (m, 6H), 1.95 (s, 2H), 1.71-1.74 (m,
2H), 1.59-1.61 (m, 1H), 1.38 (t, 2H), 0.93 (s, 6H).
Compound 109
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({5-cyano-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 109A
trans-5-bromo-6-(4-morpholino
cyclohexyloxy)pyridine-3-sulfonamide
[0342] The title compound was prepared by substituting Compound 9B
for Compound 3L in the procedure for Compound 61A.
Compound 109B
trans-5-cyano-6-(4-morpholinocyclohexylamino)pyridine-3-sulfonamide
[0343] The title compound was prepared by substituting Compound
109A for Compound 36B in the procedure for Compound 36C.
Compound 109C
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({5-cyano-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0344] The title compound was prepared by substituting Compound
109B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.59 (s, 1H),
8.56 (d, 1H), 8.13 (s, 1H), 8.00 (d, 1H), 7.55 (d, 1H), 7.47 (m,
2H), 7.34 (d, 2H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.36 (d, 1H), 6.19
(d, 1H), 4.00 (m, 1H), 3.65 (m, 4H), 3.28 (m, 4H), 3.03 (m, 4H),
2.73 (m, 4H), 2.16 (m, 6H), 1.90 (m, 6H), 1.40 (m, 6H), 0.93 (s,
6H).
Compound 110
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0345] The title compound was prepared by substituting Compound 52B
for Compound 11B in the procedure for Compound 11D. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.71 (s, 1H), 11.23
(s, 1H), 8.08 (d, 1H), 7.91 (d, 1H), 7.74 (dd, 1H), 7.60 (d, 1H),
7.52 (m, 2H), 7.34 (m, 2H), 7.16 (s, 1H), 7.04 (m, 2H), 6.83 (d,
1H), 6.68 (dd, 1H), 6.43 (dd, 1H), 6.16 (d, 1H), 3.83 (dd, 2H),
3.23 (m, 2H), 3.12 (t, 2H), 3.06 (m, 4H), 2.73 (m, 2H), 2.15 (m,
6H), 1.95 (s, 2H), 1.82 (m, 1H), 1.58 (m, 2H), 1.38 (m, 2H), 1.18
(m, 2H), 0.92 (s, 6H).
Compound 111
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1S,3R)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 111A
benzyl (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentylcarbamate
[0346] (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic
acid (1.03 g), diphenylphosphoryl azide (DPPA, 1.00 ml),
triethylamine (0.929 ml), and benzyl alcohol (0.931 ml) were
combined in toluene (10 ml) and stirred at 100.degree. C. for 24
hours. The solution was cooled and chromatographed on silica gel
using 10% ethyl acetate/hexanes to give the pure product.
Compound 111B
benzyl (1S,3R)-3-aminocyclopentylcarbamate
[0347] The title compound was prepared by substituting Compound
111A for Compound 1A in the procedure for Compound 1B.
Compound 111C
benzyl (1S,3R)-3-morpholino cyclopentylcarbamate
[0348] A solution of Compound 111B (400 mg),
1-bromo-2-(2-bromoethoxy)ethane (0.246 ml), and triethylamine
(0.595 ml) in N,N-dimethylformamide (6 ml) was stirred at
70.degree. C. for 24 hours. The solution was cooled and poured into
ethyl acetate (200 ml). The solution was extracted with 3.times.
water, washed with brine, concentrated, and chromatographed on
silica gel using 10% methanol/ethyl acetate to give the pure
product.
Compound 111D
(1S,3R)-3-morpholinocyclopentanamine
[0349] Compound 111C (300 mg) and ethanol (20 ml) were added to wet
20% Pd(OH).sub.2--C (60.0 mg) in a 50 ml pressure bottle and
stirred for 8 hours at 30 psi. The mixture was filtered through a
nylon membrane and condensed to give the product.
Compound 111E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1S,3R)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0350] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 111D for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (dimethylsulfoxide-d.sub.6) .delta.
11.65 (s, 1H), 8.45 (d, 1H), 8.28 (dd, 1H), 7.97 (d, 1H), 7.68 (d,
1H), 7.52 (d, 1H), 7.44 (d, 2H), 7.35 (d, 2H), 7.05 (d, 2H), 6.92
(dd, 1H), 6.85 (dd, 1H), 6.33 (s, 1H), 6.22 (s, 1H), 4.08 (m, 1H),
3.60 (br s, 4H), 3.06 (br s, 4H), 2.73 (br s, 3H), 2.48 (m, 4H),
2.28 (m, 1H), 2.18 (m, 6H), 2.07 (m, 1H), 1.95 (s, 2H), 1.79 (m,
2H), 1.63 (m, 2H), 1.38 (t, 2H), 0.93 (s, 6H).
Compound 112
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1R,3S)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 112A
tert-butyl (1R,3S)-3-aminocyclopentylcarbamate
[0351] The title compound was prepared by substituting Compound
111A for Compound 111C in the procedure for Compound 111D.
Compound 112B
tert-butyl (1R,3S)-3-morpholinocyclopentylcarbamate
[0352] The title compound was prepared by substituting Compound
112A for Compound 111B in the procedure for Compound 111C.
Compound 112C
(1R,3S)-3-morpholinocyclopentanamine
[0353] The title compound was prepared by substituting Compound
112B for Compound 1A in the procedure for Compound 1B.
Compound 112D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1R,3S)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0354] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 112C for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (dimethylsulfoxide-d.sub.6) .delta.
11.35 (s, 1H), 8.51 (d, 1H), 8.44 (dd, 1H), 8.00 (d, 1H), 7.77 (d,
1H), 7.50 (d, 1H), 7.48 (s, 2H), 7.34 (d, 2H), 7.04 (d, 2H), 7.02
(dd, 1H), 6.67 (dd, 1H), 6.37 (dd, 1H), 6.21 (d, 1H), 4.11 (m, 1H),
3.61 (br s, 4H), 3.06 (br s, 4H), 2.73 (br s, 3H), 2.50 (m, 4H),
2.28 (m, 1H), 2.18 (m, 6H), 2.06 (m, 1H), 1.95 (s, 2H), 1.77 (m,
2H), 1.66 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 113
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(morpholin-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 113A
tert-butyl
2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxyl-
ate
[0355] The title compound was prepared by substituting tert-butyl
2-(aminomethyl)morpholine-4-carboxylate for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 113B
tert-butyl
2-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfam-
oyl)-2-nitrophenylamino)methyl)morpholine-4-carboxylate
[0356] The title compound was prepared by substituting Compound
113A for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G, with the exception that the product was
purified on a silica gel column eluted with 4% methanol in
dichloromethane.
Compound 113C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(morpholin-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
[0357] The title compound was prepared by substituting Compound
113B for Compound 66B in the procedure for Compound 66C. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.60 (s, 1H),
8.55 (br, s, 1H), 8.51 (s, 1H), 8.00 (d, 1H), 7.80 (d, 1H), 7.52
(d, 1H), 7.49-7.46 (m, 2H), 7.34 (d, 2H), 7.07 (d, 1H), 7.04 (d,
2H), 6.66 (dd, 1H), 6.36 (s, 1H), 6.20 (d, 1H), 4.00 (dd, 1H), 3.91
(m, 1H), 3.70 (t, 1H), 3.60 (m, 1H), 3.58 (m, 1H), 3.32 (m, 1H),
3.16 (d, 1H), 3.05 (m, 4H), 2.98 (td, 1H), 2.86 (t, 1H), 2.73 (s,
2H), 2.20-2.12 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Compound 114
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 114A
3-nitro-4-((tetrahydrofuran-3-yl)methylamino)benzenesulfonamide
[0358] The title compound was prepared by substituting
3-aminomethyl-tetrahydrofuran for (tetrahydropyran-4-yl)methylamine
in the procedure for Compound 1F.
Compound 114B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0359] The title compound was prepared by substituting Compound
114A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H),
11.42 (bs, 1H), 8.63 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd,
1H), 7.53-7.48 (m, 3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.04 (d, 2H),
6.68 (dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 3.82-3.79 (m, 1H), 3.71
(t, 1H), 3.62 (dd, 1H), 3.50 (dd, 1H), 3.38 (m, 1H), 3.32 (m, 1H),
3.07 (m, 4H), 2.76 (s, 2H), 2.58 (m, 1H), 2.25-2.00 (m, 6H), 1.98
(m, 1H), 1.95 (s, 2H), 1.65 (m, 1H), 1.38 (t, 2H), 0.92 (s,
6H).
Compound 115
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1{-[cis-3-fluorotetrahydro-2H-pyran-4-yl]piperidin-4-yl}amino-
)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 115A
cis-tert-butyl
1-(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-ylcarbamate
[0360] The title compound was prepared as a racemate of the cis
diastereomer by substituting tert-butyl piperidin-4-ylcarbamate for
piperidin-4-ol and 3-fluorodihydro-2H-pyran-4(3H)-one (prepared by
the method described in US 2005/0101628, incorporated herein by
reference) for dihydro-2H-pyran-4(3H)-one) in the procedure for
Compound 84A.
Compound 115B
cis-1-(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine
[0361] Compound 115A (0.29 g) was dissolved in CH.sub.2Cl.sub.2 (9
ml), then 4N HCl in dioxane (4 ml) was added and the reaction
stirred at room temperature for 16 hours. The reaction was diluted
with CH.sub.2Cl.sub.2 (30 ml), then 4N aqueous NaOH (5 ml) was
added. After shaking and separating the layers the aqueous layer
was saturated with solid NaCl and extracted with more
CH.sub.2Cl.sub.2 (10 ml). The combined organic layers were dried
over Na.sub.2SO.sub.4. After filtration and concentration the amine
was used with no further purification.
Compound 115C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({1-[cis-3-fluorotetrahydro-2H-pyran-4-yl]piperidin-4-yl}amino-
)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0362] The title compound was prepared by substituting Compound
115B for 1-acetylpiperidin-4-amine in the procedure for Compound
53B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.64
(s, 1H), 8.54 (d, 1H), 8.43 (br d, 1H), 8.03 (d, 1H), 7.80 (dd,
1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.11 (d, 1H), 7.05 (d, 2H), 6.66
(dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H), 4.92 (d, 1H), 3.95 (m, 2H),
3.70 (v br m, 1H), 3.50, 3.40, 3.30 (all m, total 5H), 3.05, 3.00
(both v br m, total 5H), 2.74 (s, 2H), 2.55 (v br m, 1H), 2.18 (br
m, 6H), 1.95 (m, 4H), 1.88 (ddd, 1H), 1.63 (v br m, 3H), 1.38 (t,
2H), 0.92 (s, 6H).
Compound 116
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)amino]phenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 116A
1-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine
[0363] Tert-butyl azetidin-3-ylcarbamate (0.46 g),
dihydro-2H-pyran-4(3H)-one (0.29 g) and sodium
triacetoxyborohydride (0.85 g) were stirred together in
dichloromethane (5 ml) overnight. The reaction was poured into
dichloromethane (50 ml) and saturated aqueous NaHCO.sub.3 solution
(25 ml). The organic layer was separated, washed with brine (25
ml), dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Silica gel chromatography (GraceResolv 12 g) eluting with a
gradient of 0.75% to 7.5% methanol/dichloromethane over 20 minutes
gave the Boc-protected intermediate. Treatment with HCl (4.0M in
dioxane, 2 ml) and methanol (1 ml) for 1 hour gave the title
compound after concentration as the di-HCl salt.
Compound 116B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)amino]phenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0364] A suspension of
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-chloro-3-nitrophenylsulfonyl)-4-
-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazinl-yl)-
benzamide (0.180 g), 1-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine
(0.078 g), and triethylamine (0.159 ml) in dioxane (2 ml) was
degassed with nitrogen for 30 seconds then sealed. The reaction was
heated to 110.degree. C. After stirring for 16 hours, more
triethylamine (10 equivalents total) and dimethylsulfoxide (1 ml)
were added and the reaction stirred for an additional 18 hours at
110.degree. C. The reaction was cooled, diluted with water (50 ml)
and extracted with dichloromethane (2.times.150 ml). The organic
layer was dried over magnesium sulfate, filtered and concentrated.
Silica gel chromatography (GraceResolv 12 g) eluting with a
gradient of 0.75% to 7.5% methanol/dichloromethane (flow=36
ml/minutes) gave the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.59 (s, 1H), 8.49 (d, 1H),
8.40 (s, 1H), 7.97 (d, 1H), 7.77 (s, 1H), 7.47 (dd, 3H), 7.34 (d,
2H), 7.04 (d, 2H), 6.90-6.78 (m, 1H), 6.65 (d, 1H), 6.35 (s, 1H),
6.21 (s, 1H), 4.47-4.23 (m, 1H), 3.83 (s, 3H), 3.05 (s, 6H), 2.73
(s, 2H), 2.18 (s, 8H), 1.95 (s, 2H), 1.68 (s, 2H), 1.38 (s, 2H),
1.24 (s, 4H), 0.92 (s, 6H).
Compound 117
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylazetidin-3-yl)amino]phenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 117A
1-(tetrahydrofuran-3-yl)azetidin-3-amine
[0365] Tert-butyl azetidin-3-ylcarbamate (0.550 g),
dihydrofuran-3(2H)-one (0.412 g) and sodium triacetoxyborohydride
(1.015 g) were stirred together in dichloromethane (5 ml). After
stirring overnight, the reaction was poured into saturated aqueous
NaHCO.sub.3 solution (25 ml) and extracted with dichloromethane (50
ml). The organic layer was washed with brine (25 ml), dried over
magnesium sulfate, filtered, and concentrated. Silica gel
chromatography (GraceResolv 12 g) eluting with a gradient of 0.5%
to 7.5% methanol/dichloromethane over 30 minutes gave tert-butyl
1-(tetrahydrofuran-3-yl)azetidin-3-ylcarbamate. The resulting
material was treated with HCl/dioxane for 1 hour, and then
concentrated to give the title compound.
Compound 117B
3-nitro-4-(1-(tetrahydro
furan-3-yl)azetidin-3-ylamino)benzenesulfonamide
[0366] 4-F luoro-3-nitrobenzene sulfonamide (0.084 g),
1-(tetrahydro furan-3-yl)azetidin-3-amine (0.090 g) and
triethylamine (0.266 ml) in tetrahydrofuran (3 ml) were heated to
60.degree. C. After stirring for 4 hours, the reaction was cooled,
the tetrahydrofuran was removed and the residue was partitioned
between dichloromethane (200 ml) and water (20 ml). The organic
layer was separated, washed with brine (25 ml), dried over
magnesium sulfate, filtered, and concentrated to give the title
compound.
Compound 117C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro
furan-3-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridi-
n-5-yloxy)benzamide
[0367] The title compound was prepared by substituting Compound
117B for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 10.39-9.79 (m, 1H), 9.17 (s, 1H), 8.87 (d, 1H), 8.51 (d,
1H), 8.15 (dd, 2H), 7.94 (d, 1H), 7.68 (d, 1H), 7.48-7.42 (m, 1H),
7.23 (d, 2H), 6.91 (d, 2H), 6.69 (d, 1H), 6.54 (dd, 2H), 5.99 (d,
1H), 4.29 (d, 1H), 4.01-3.73 (m, 4H), 3.66 (d, 2H), 3.08 (s, 6H),
2.76 (s, 2H), 2.21 (s, 6H), 2.03-1.83 (m, 3H), 1.64 (s, 2H), 1.42
(d, 2H), 0.93 (s, 6H).
Compound 118
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]meth-
yl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 118A
(R)-tert-butyl
(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methylcarbamate
[0368] The title compound was prepared by substituting
(S)-tert-butyl pyrrolidin-3-ylmethylcarbamate for tert-butyl
piperazine-1-carboxylate and dihydro-2H-pyran-4(3H)-one for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 118B
(R)-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methanamine
[0369] The title compound was prepared by substituting Compound
118A for Compound 1A in the procedure for Compound 1B.
Compound 118C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]meth-
yl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0370] The title compound was prepared by substituting Compound
118B for 1-acetylpiperidin-4-amine in the procedure for Compound
53B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.57
(s, 1H), 8.59 (br s, 1H), 8.45 (br s, 1H), 8.02 (d, 1H), 7.95 (m,
1H), 7.71 (m, 1H), 7.56 (d, 1H), 7.45 (m, 1H), 7.35 (m, 3H), 7.05
(m, 2H), 6.90 (br s, 1H), 6.64 (d, 1H), 6.33 (m, 1H), 6.22 (m, 1H),
3.90 (m, 2H), 3.44 (m, 2H), 3.27 (m, 4H), 3.02 (m, 5H), 2.73 (m,
3H), 2.59 (m, 2H), 2.19 (m, 6H), 1.95 (m, 2H), 1.85 (m, 2H), 1.64
(m, 1H), 1.50 (m, 2H), 1.39 (m, 2H), 1.23 (m, 1H), 0.94 (s,
6H).
Compound 119
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0371] The title compound was prepared as described in the
procedure for Compound 11D using Compound 75F and Compound 37D in
place of Compound 3J and Compound 11B, respectively. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 8.39
(s, 1H), 8.08 (d, 1H), 8.04 (d, 1H), 7.41-7.59 (m, 4H), 7.35 (d,
2H), 7.08 (d, 2H), 6.68 (dd, 1H), 6.37-6.43 (m, 1H), 6.20 (s, 1H),
4.38 (d, 2H), 3.73-3.82 (m, 2H), 3.54-3.63 (m, 2H), 3.09 (s, 4H),
2.81 (s, 2H), 2.16-2.39 (m, 5H), 1.94 (s, 2H), 1.79-1.93 (m, 4H),
1.40 (t, 2H), 0.94 (s, 6H).
Compound 120
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-hydroxycyclohexyl)m-
ethoxy)-3-nitrophenylsulfonyl)benzamide
Compound 120A
trans-4-(aminomethyl)cyclohexanol
[0372] Tert-butyl ((1r,4r)-4-hydroxycyclohexyl)methylcarbamate (1
g) in dichloromethane (10 ml) was treated with trifluoroacetic acid
(5 ml) at 0.degree. C. for 10 minutes and at room temperature for
30 minutes. The reaction mixture was concentrated and dried in
vacuo to provide the title compound as a trifluoroacetic acid
salt.
Compound 120B
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-hydroxycyclohexyl)m-
ethoxy)-3-nitrophenylsulfonyl)benzamide
[0373] A mixture of Compound 53A (211 mg), Compound 120A (104 mg)
and N-ethyl-N-isopropylpropan-2-amine (0.3 ml) in dimethylsulfoxide
(2 ml) was heated at 150.degree. C. in a Biotage Initiator
microwave synthesizer for 1.5 hours and concentrated. The residue
was purified by reverse phase HPLC on a C18 column using a gradient
of 40-60% acetonitrile in 0.1% trifluoroacetic acid water to give
the title compound as a trifluoroacetate salt. The trifluoroacetic
acid salt was dissolved in dichloromethane (30 ml) and washed with
50% aqueous NaHCO.sub.3. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated to give the title
compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.69 (s, 1H), 11.41 (s, 1H), 8.61 (t, 1H), 8.53-8.58 (m, 1H), 8.04
(d, 1H), 7.76-7.83 (m, 1H), 7.47-7.56 (m, 3H), 7.34 (d, 2H),
7.07-7.11 (m, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19
(d, 1H), 4.82-4.99 (m, 1H), 4.50 (d, 1H), 3.26-3.31 (m, 2H), 3.23
(t, 1H), 3.07 (s, 4H), 2.76 (s, 2H), 2.10-2.28 (m, 6H), 2.05 (dd,
1H), 1.95 (s, 2H), 1.84 (t, 2H), 1.52-1.76 (m, 2H), 1.41-1.51 (m,
1H), 1.38 (t, 2H), 0.95-1.25 (m, 4H), 0.92 (s, 6H).
Compound 121
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((cis-4-methoxycyclohexyl)met-
hoxy)-3-nitrophenylsulfonyl)benzamide
Compound 121A
(4-methoxycyclohexyl)methanol
[0374] 4-Methoxycyclohexanecarboxylic acid (7 g) in tetrahydrofuran
(20 ml) was treated with 1 M (in tetrahydrofuran)
borane-tetrahydrofuran complex (100 ml) overnight. The mixture was
concentrated and the residue was dissolved in methanol (100 ml) and
concentrated HCl (10 ml). The resulting mixture was stirred for 1
hour and concentrated. The residue was dissolved in dichloromethane
and washed with water. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give the title
compound.
Compound 121B
4-((4-methoxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide
[0375] The title compound was prepared as described in the
procedure for Compound 12A by replacing (1,4-dioxan-2-yl)methanol
with Compound 121A.
Compound 121C
4-((cis-4-methoxycyclohexyl)methoxy)-3-nitrobenzene sulfonamide
[0376] Separation of the cis and trans mixture of Compound 121B on
a reverse phase HPLC (gradient: 40-55% acetonitrile in 0.1% TFA in
water over 25 minutes) provided the title compound.
Compound 121D
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((cis-4-methoxycyclohexyl)met-
hoxy)-3-nitrophenylsulfonyl)benzamide
[0377] The title compound was prepared as described in the
procedure for Compound 11D using Compound 121C in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 1H), 11.39 (s, 1H), 8.34 (s, 1H), 7.96-8.07 (m, 2H), 7.48-7.56
(m, 3H), 7.31-7.42 (m, 3H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.40 (dd,
1H), 6.20 (d, 1H), 4.02 (d, 2H), 3.39 (s, 1H), 3.20 (s, 3H), 3.09
(s, 4H), 2.82 (s, 2H), 2.09-2.34 (m, 6H), 1.96 (s, 2H), 1.78-1.86
(m, 3H), 1.54 (dd, 2H), 1.28-1.46 (m, 6H), 0.92 (s, 6H).
Compound 122
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-N-[(4-{[4-(cyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 122A
cis-tert-butyl-4-(cyclopropylamino)cyclohexylcarbamate
[0378] The title compound was prepared by substituting tert-butyl
4-oxocyclohexylcarbamate for 4'-chlorobiphenyl-2-carboxaldehyde and
cyclopropylamine for tert-butyl piperazine-1-carboxylate in the
procedure for Compound 1A.
Compound 122B
cis-N.sup.1-cyclopropylcyclohexane-1,4-diamine bis(2,2,2-trifluoro
acetate)
[0379] The title compound was prepared by substituting Compound
122A for Compound 39A in the procedure for Compound 39B.
Compound 122C
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-N-[(4-{[4-(cyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0380] The title compound was prepared by substituting Compound
122B for Compound 100B in the procedure for Compound 100C. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.06 (s, 1H), 9.28 (d,
1H), 8.59 (d, 1H), 8.44 (d, 1H), 8.37 (dd, 1H), 8.12 (d, 1H), 7.67
(t, 2H), 7.43 (t, 2H), 7.07 (d, 2H), 6.90 (d, 1H), 6.75 (dd, 1H),
6.53 (d, 1H), 6.50 (dd, 1H), 3.56-3.63 (m, 1H), 3.02-3.08 (m, 4H),
2.77 (s, 3H), 2.26 (t, 2H), 2.10-2.16 (m, 4H), 2.06 (ddd, 1H), 1.97
(s, 2H), 1.74-1.82 (m, 2H), 1.61-1.71 (m, 5H), 1.39 (t, 2H), 0.93
(s, 6H), 0.39-0.44 (m, 4H).
Compound 123
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]am-
ino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 123A
trans-tert-butyl-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexylcarbamate
[0381] The title compound was prepared by substituting
trans-tert-butyl-4-aminocyclohexylcarbamate for tert-butyl
piperazine-1-carboxylate and dihydro-2H-pyran-4(3H)-one for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 123B
trans-N1-(tetrahydro-2H-pyran-4-yl)cyclohexane-1,4-diamine
bis(2,2,2-trifluoro acetate)
[0382] The title compound was prepared by substituting Compound
123A for Compound 39A in the procedure for Compound 39B.
Compound 123C
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]am-
ino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0383] The title compound was prepared by substituting Compound
123B for Compound 100B in the procedure for Compound 100C. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.01 (s, 1H), 9.28 (d,
1H), 8.48 (d, 1H), 8.38 (dd, 1H), 8.32 (d, 1H), 8.24 (d, 1H),
7.67-7.69 (m, 2H), 7.44 (d, 2H), 7.08 (d, 2H), 6.91 (d, 1H), 6.78
(dd, 1H), 6.59 (d, 1H), 6.48 (dd, 1H), 4.01 (d, 2H), 3.44-3.49 (m,
1H), 3.37-3.43 (m, 2H), 3.01-3.09 (m, 5H), 2.85 (t, 1H), 2.78 (s,
2H), 2.27 (t, 2H), 2.13-2.18 (m, 4H), 2.05 (t, 4H), 1.97 (s, 2H),
1.93 (d, 2H), 1.52-1.60 (m, 2H), 1.44-1.50 (m, 2H), 1.39 (t, 2H),
1.25-1.34 (m, 2H), 0.94 (s, 6H).
Compound 124
trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 124A
trans-4-morpholinocyclohexanol
[0384] Trans-4-Aminocyclohexanol (0.5 g),
1-bromo-2-(2-bromoethoxy)ethane (1.07 g) and triethylamine (2.42
ml) were dissolved in anhydrous acetonitrile (20 ml). The reaction
mixture was heated at 60.degree. C. overnight. The organic solvent
was removed under vacuum. The residue was purified with flash
column chromatography on silica gel eluting with 7%-10% methanol in
dichloromethane to give the title compound.
Compound 124B
trans-5-bromo-6-(4-morpholino
cyclohexyloxy)pyridine-3-sulfonamide
[0385] The title compound was prepared by substituting Compound
124A for (tetrahydro-2H-pyran-4-yl)methanol and Compound 36A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 124C
trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0386] The title compound was prepared by substituting Compound
124B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H),
8.56 (m, 2H), 8.03 (d, 1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.34 (d,
2H), 7.12 (m, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.19
(d, 1H), 3.99 (m, 1H), 3.67 (m, 1H), 3.37 (m, 2H), 3.24 (m, 2H),
3.07 (m, 4H), 2.89 (m, 1H), 2.71 (m, 2H), 2.16 (m, 6H), 1.96 (s,
3H), 1.80 (m, 4H), 1.38 (t, 2H), 1.27 (m, 2H), 0.92 (s, 6H).
Compound 125
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-methoxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 125A
4-(((trans)-4-methoxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide
[0387] Separation of the cis and trans mixture of Compound 121B on
a reverse phase HPLC provided the title compound.
Compound 125B
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-methoxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0388] The title compound was prepared as described in the
procedure for Compound 11D using Compound 125A in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68
(s, 1H), 8.34 (s, 1H), 7.96-8.09 (m, 2H), 7.51 (dd, 3H), 7.32-7.39
(m, 3H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H),
4.02 (d, 2H), 3.24 (s, 3H), 3.00-3.15 (m, 5H), 2.83 (s, 2H),
2.09-2.36 (m, 6H), 2.03 (d, 2H), 1.96 (s, 2H), 1.77-1.86 (m, 2H),
1.73 (s, 1H), 1.39 (t, 2H), 1.02-1.17 (m, 4H), 0.92 (s, 6H).
Compound 126
tert-butyl
4-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amin-
o}sulfonyl)-2-nitrophenoxy]methyl}-4-fluoropiperidine-1-carboxylate
Compound 126A
tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
[0389] 1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate
(1.0 g) in tetrahydrofuran (5 ml) was treated with 1.0 N
LiAlH.sub.4 in THF (2.54 ml) at 0.degree. C. The reaction mixture
was stirred at room temperature for 2 hours. Water (0.6 ml) was
added to the reaction mixture drop-wise, followed by 2 N aqueous
NaOH (0.2 ml). The reaction was stirred for another 1 hour. The
solid was removed by filtration via a pack of Celite and washed
with ethyl acetate. The filtrate was washed with brine, dried over
MgSO.sub.4, filtered, and concentrated to give the product.
Compound 126B
tert-butyl
4-fluoro-4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-car-
boxylate
[0390] The title compound was prepared by substituting Compound
126A for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 24A.
Compound 126C
tert-butyl
4-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amin-
o}sulfonyl)-2-nitrophenoxy]methyl}-4-fluoropiperidine-1-carboxylateyl)oxy]-
benzamide
[0391] The title compound was prepared by substituting Compound
126B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H),
8.36 (s, 2H), 8.02-8.06 (m, 2H), 7.49-7.53 (m, 3H), 7.40 (d, 1H),
7.35 (d, 2H), 7.04 (d, 1H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.21 (d,
1H), 4.36 (d, 2H), 3.83-3.85 (m, 2H), 3.09 (s, 4H), 2.33 (s, 2H),
2.27-2.32 (m, 4H), 2.13-2.16 (m, 2H), 1.96 (s, 2H), 1.83-1.92 (m,
2H), 1.67-1.75 (m, 2H), 1.38-1.41 (m, 11H), 0.92 (s, 6H).
Compound 127
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0392] The title compound was prepared by substituting Compound
126C for Compound 1A in the procedure for Compound 1B. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (s, 1H), 8.14
(d, 1H), 7.90 (d, 2H), 7.80 (dd, 1H), 7.60 (d, 1H), 7.40 (t, 1H),
7.35 (d, 2H), 7.25 (t, 1H), 7.13 (d, 1H), 7.05 (d, 2H), 6.61 (dd,
1H), 6.30 (dd, 1H), 6.26 (d, 1H), 4.28 (d, 2H), 3.10-3.13 (m, 2H),
2.91-3.00 (m, 6H), 2.73 (s, 2H), 1.96-2.02 (m, 4H), 1.77-1.89 (m,
2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 128
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cy-
clohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzam-
ide
Compound 128A
tert-butyl 4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate
[0393] The title compound was prepared by substituting tert-butyl
piperazine-1-carboxylate for morpholine and
dihydro-2H-pyran-4(3H)-one for tert-butyl 4-oxocyclohexylcarbamate
in the procedure for Compound 39A.
Compound 128B
1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride
[0394] To a solution of Compound 128A (3.92 g) in ether was added
HCl (25 ml, 2M in ether) and the reaction mixture was stirred for
16 hours at room temperature. The solid product was filtered off,
dried and used in next step without further purification.
Compound 128C
trans-tert-butyl-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)cyclohexylc-
arbamate
[0395] The title compound was prepared by substituting Compound
128B for morpholine in the procedure for Compound 39A.
Compound 128D
trans-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)cyclohexanamine
tris(2,2,2-trifluoroacetate)
[0396] The title compound was prepared by substituting Compound
128C for Compound 39A in the procedure for Compound 39B.
Compound 128E
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cy-
clohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzam-
ide
[0397] The title compound was prepared by substituting Compound
128D for Compound 100B in the procedure for Compound 100C. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.07 (s, 1H), 9.28-9.32
(m, 1H), 8.44 (t, 1H), 8.34-8.39 (m, 2H), 8.10-8.14 (m, 1H),
7.66-7.69 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.92 (t, 1H),
6.73-6.77 (m, 1H), 6.52-6.55 (m, 1H), 6.49-6.52 (m, 1H), 3.99-4.06
(m, 2H), 3.29-3.36 (m, 2H), 3.03-3.09 (m, 4H), 2.77 (s, 2H), 2.62
(s, 8H), 2.24-2.29 (m, 3H), 2.10-2.16 (m, 5H), 2.05 (s, 2H), 1.97
(s, 2H), 1.92 (s, 2H), 1.70 (d, 2H), 1.57 (td, 2H), 1.34-1.43 (m,
4H), 1.20-1.30 (m, 2H), 0.93 (s, 6H).
Compound 129
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3--
nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 129A
(1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methanol
[0398] A suspension of piperidin-4-ylmethanol (0.250 g), sodium
triacetoxyborohydride (0.690 g) and 1,3-difluoropropan-2-one (0.245
g) were stirred together in dichloromethane. After stirring
overnight the reaction was poured into saturated aqueous
NaHCO.sub.3 solution (10 ml) and stirred for 15 minutes. The
reaction was extracted with dichloromethane (3.times.25 ml), dried
over magnesium sulfate, filtered, and concentrated. Silica gel
chromatography (GraceResolv 12 g) eluting with a gradient of 0.75%
to 3% methanol/dichloromethane gave the title compound.
Compound 129B
4-((1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfo-
namide
[0399] To a solution of
(1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methanol (0.068 g) in
tetrahydrofuran (1 ml) was added sodium hydride (0.056 g) and the
reaction stirred for 30 minutes at room temperature.
4-Fluoro-3-nitrobenzenesulfonamide (0.077 g) was added in one
portion and stirring was continued for 1 hour. The reaction was
poured into water (20 ml) and extracted with dichloromethane. The
pH of the aqueous layer was adjusted to pH.about.8 and it was
extracted with dichloromethane (50 ml). The organic layer was dried
over magnesium sulfate, filtered, and concentrated to give the
title compound.
Compound 129C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3--
nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0400] The title compound was prepared by substituting Compound
129B for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 11.47-10.98 (m,
1H), 8.33 (d, 1H), 8.03 (d, 2H), 7.50 (dd, 3H), 7.36 (t, 3H), 7.04
(d, 2H), 6.67 (d, 1H), 6.39 (dd, 1H), 6.20 (s, 1H), 4.62 (dd, 4H),
4.06 (d, 2H), 3.18-2.71 (m, 11H), 2.20 (d, 6H), 1.96 (s, 2H), 1.73
(d, 3H), 1.35 (d, 4H), 0.92 (s, 6H).
Compound 130
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino-
}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 130A
(R)-tert-butyl
1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcarbamate
[0401] The title compound was prepared by substituting
dihydro-2H-pyran-4(3H)-one for 4'-chlorobiphenyl-2-carboxaldehyde
and (R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl
piperazine-1-carboxylate in the procedure for Compound 1A.
Compound 130B
(R)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine
[0402] A solution of Compound 130A (550 mg) in dichloromethane (25
ml) was cooled in an ice bath under nitrogen. 2,2,2-Trifluoroacetic
acid (8.333 ml) was added and the reaction was stirred for 2 hours.
The product was obtained by concentration and high vacuum
drying.
Compound 130C
(R)-3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)benzene
sulfonamide
[0403] The title compound was prepared by substituting Compound
130B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 130D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino-
}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0404] To a solution of Compound 3J (90 mg), Compound 130C (64.2
mg), triethylamine (0.077 ml), N,N-dimethylpyridin-4-amine (38.5
mg) in a mixture of dichloromethane (5 ml) and
N,N-dimethylformamide (0.5 ml) was added
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-
-diamine, hydrochloric acid (60.4 mg) and the mixture was stirred
18 hours. This was concentrated on high vacuum and the crude was
purified by reverse phase chromatography with ammonium acetate
buffer/acetonitrile. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 13.03 (s, 1H), 9.27 (d, 1H), 8.59 (d, 1H), 8.43 (d, 1H),
8.37 (dd, 1H), 8.11 (d, 1H), 7.65-7.67 (m, 2H), 7.44 (d, 2H), 7.07
(d, 2H), 6.88 (d, 1H), 6.76 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H),
4.06 (m, 1H), 3.98 (d, 2H), 3.35 (t, 2H), 3.07 (m, 4H), 2.73-2.80
(m, 4H), 2.68-2.72 (m, 1H), 2.36 (q, 1H), 2.11-2.30 (m, 9H), 1.97
(m, 2H), 1.62-1.71 (m, 3H), 1.48-1.58 (m, 2H), 1.39 (t, 2H), 0.94
(s, 6H).
Compound 131
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl-
]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzam-
ide
Compound 131A
tert-butyl
(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcar-
bamate
[0405] The title compound was prepared by substituting
2,2-dimethyldihydro-2H-pyran-4(3H)-one for
4'-chlorobiphenyl-2-carboxaldehyde and (R)-tert-butyl
pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate in
the procedure for Compound 1A.
Compound 131B
(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine
[0406] The title compound was prepared by substituting Compound
131A for Compound 130A in the procedure for Compound 130B.
Compound 131C
4-((3R)-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)-3-n-
itrobenzenesulfonamide
[0407] The title compound was prepared by substituting Compound
131B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 131D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl-
]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzam-
ide
[0408] The title compound was prepared by substituting Compound
131C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.03 (d, 1H), 9.28 (m,
1H), 8.61 (m, 1H), 8.44 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H),
7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.89 (m, 1H), 6.76
(dd, 1H), 6.54 (m, 1H), 6.49 (m, 1H), 4.08 (m, 1H), 3.78 (m, 1H),
3.61 (m, 1H), 3.07 (m, 4H), 2.71-2.82 (m, 5H), 2.37-2.44 (m, 2H),
2.19-2.29 (m, 3H), 2.14 (m, 5H), 1.97 (s, 2H), 1.76 (m, 1H), 1.66
(m, 2H), 1.32-1.49 (m, 4H), 1.28 (d, 3H), 1.20 (s, 3H), 0.94 (s,
6H).
Compound 132
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino-
}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 132A
(S)-tert-butyl
1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcarbamate
[0409] The title compound was prepared by substituting
dihydro-2H-pyran-4(3H)-one for 4'-chlorobiphenyl-2-carboxaldehyde
and (S)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl
piperazine-1-carboxylate in the procedure for Compound 1A.
Compound 132B
(S)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine
[0410] The title compound was prepared by substituting Compound
132A for Compound 130A in the procedure for Compound 130B.
Compound 132C
(S)-3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)benzenesul-
fonamide
[0411] The title compound was prepared by substituting Compound
132B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 132D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino-
}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0412] The title compound was prepared by substituting Compound
132C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.04 (m, 1H), 9.27 (d,
1H), 8.58 (d, 1H), 8.43 (d, 1H), 8.37 (dd, 1H), 8.11 (d, 1H),
7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.88 (d, 1H), 6.75
(dd, 1H), 6.54 (m, 1H), 6.49 (m, 1H), 4.06 (m, 1H), 3.98 (d, 2H),
3.36 (t, 2H), 3.07 (m, 4H), 2.68-2.80 (m, 5H), 2.36 (m, 1H),
2.09-2.29 (m, 9H), 1.97 (s, 2H), 1.62-1.72 (m, 3H), 1.48-1.60 (m,
2H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 133
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl-
]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzam-
ide
Compound 133A
tert-butyl
(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcar-
bamate
[0413] The title compound was prepared by substituting
2,2-dimethyldihydro-2H-pyran-4(3H)-one for
4'-chlorobiphenyl-2-carboxaldehyde and (S)-tert-butyl
pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate in
the procedure for Compound 1A.
Compound 133B
(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine
[0414] The title compound was prepared by substituting Compound
133A for Compound 130A in the procedure for Compound 130B.
Compound 133C
4-(3S)-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)-3-ni-
tro benzenesulfonamide
[0415] The title compound was prepared by substituting Compound
133B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 133D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl-
]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzam-
ide
[0416] The title compound was prepared by substituting Compound
133C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.03 (d, 1H), 9.28 (m,
1H), 8.61 (m, 1H), 8.43 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H),
7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.89 (m, 1H), 6.76
(dd, 1H), 6.54 (m, 1H), 6.49 (m, 1H), 4.08 (m, 1H), 3.78 (m, 1H),
3.61 (m, 1H), 3.07 (m, 4H), 2.71-2.82 (m, 5H), 2.37-2.44 (m, 2H),
2.19-2.29 (m, 3H), 2.14 (m, 5H), 1.97 (s, 2H), 1.76 (m, 1H), 1.66
(m, 2H), 1.33-1.48 (m, 4H), 1.28 (d, 3H), 1.20 (s, 3H), 0.94 (s,
6H).
Compound 134
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 134A
4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide
[0417] A solution of Compound 113A (0.8 g) in dichloromethane (10
ml) and trifluoroacetic acid (10 ml) was stirred at room
temperature for 2 hours. The solvents were evaporated and the
residue triturated with diethyl ether. The resulting solid was
dissolved in 5% aqueous sodium carbonate solution (20 ml). The
solution was concentrated to dryness and the resulting solid was
triturated with a solution of 10% methanol in dichloromethane
several times. Evaporation of the organic solvents gave the title
compound.
Compound 134B
4-((4-methylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
[0418] To a solution of Compound 134A (158 mg) in anhydrous
N,N-dimethylformamide (4 ml) was added sodium carbonate (64 mg) and
methyl iodide (78 mg). After stirring overnight at room
temperature, the mixture was evaporated to dryness. The crude
product was then absorbed on silica gel (6 g) and purified on a
silica gel column eluting with 10% methanol in dichloromethane to
give the title compound.
Compound 134C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0419] The title compound was prepared by substituting Compound
134B for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.27 (d,
1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.65
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 3.92 (m, 1H), 3.86 (d, 1H), 3.67 (dt,
1H), 3.49-3.39 (m, 2H), 3.07 (m, 4H), 2.77 (s, 2H), 3.71 (m, 1H),
2.49 (d, 1H), 2.26 (m, 2H), 2.16 (s, 3H), 2.14 (m, 4H), 2.03 (dt,
1H), 1.97 (s, 2H), 1.90 (t, 1H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 135
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(2-methoxyethyl)morpholin-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 135A
4-((4-(2-methoxyethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[0420] The title compound was prepared by substituting
2-methoxyethyl bromide for methyl iodide in the procedure for
Compound 134B.
Compound 135B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(2-methoxyethyl)morpholin-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0421] The title compound was prepared by substituting Compound
135A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 12.98 (s, 1H), 9.26 (d,
1H), 8.88 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 3.93 (m, 1H), 3.87 (d, 1H), 3.70 (dt,
1H), 3.51 (t, 2H), 3.48-3.38 (m, 2H), 3.27 (s, 3H), 3.07 (m, 4H),
2.95 (d, 1H), 2.77 (s, 2H), 2.70 (m, 1H), 2.57 (t, 2H), 2.27-2.07
(m, 8H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 136
N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 136A
4-((4-acetylmorpholin-2-yl)methylamino)-3-nitrobenzene
sulfonamide
[0422] The title compound was prepared by substituting acetic
anhydride for methyl iodide in the procedure for Compound 134B.
Compound 136B
N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0423] The title compound was prepared by substituting Compound
136A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.26 (s,
1H), 8.85 (s, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.10 (d, 1H), 7.65
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (dd, 1H), 6.75 (dd, 1H),
6.54 (s, 1H), 6.48 (s, 1H), 4.73 (dd, 1H), 3.93-3.65 (m, 2H),
3.60-3.40 (m, 4H), 3.12 (m, 1H), 3.07 (m, 4H), 2.77 (s, 2H), 2.70
(m, 1H), 2.57 (t, 2H), 2.14 (s, 3H), 2.27-2.07 (m, 4H), 1.97 (s,
2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 137
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[trans-4-(fluoro
methyl)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 137A
ethyl 4-fluorobut-2-enoate
[0424] Ethyl 2-fluoroacetate (21.0 g) in CH.sub.2Cl.sub.2 (200 ml)
at -78.degree. C. was treated dropwise over 45 min with a 1.0 M
solution of diisobutylaluminum hydride in CH.sub.2Cl.sub.2 (200 ml)
maintaining the internal temperature below -70.degree. C. Stirring
was continued at -78.degree. C. for 30 minutes and then
(carbethoxymethylene)triphenylphosphorane (70.0 g) was added in one
portion. The reaction mixture was allowed to slowly reach room
temperature while stirring overnight. It was then quenched with
methanol, filtered and concentrated to give the product as a
mixture of isomers (E/Z=3:1).
Compound 137B
trans-ethyl 1-benzyl-4-(fluoromethyl)pyrrolidine-3-carboxylate
[0425] A mixture of
N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (4.5 g)
and Compound 137A (2.5 g) in dichloromethane (50 ml) was cooled to
0.degree. C., treated dropwise with trifluoroacetic acid (0.15 ml),
stirred for 4 hours at 0.degree. C. and neutralized with saturated
aqueous Na.sub.2CO.sub.3 solution. The mixture was poured into a
separatory funnel and the layers separated. The organic layer was
washed with water and brine, dried (MgSO.sub.4), filtered,
concentrated and chromatographed on silica gel with 0-20% ethyl
acetate in hexanes as eluent to give both the cis and trans isomers
of the product. Only the trans diastereomers were carried on in the
following steps.
Compound 137C
trans-ethyl 4-(fluoromethyl)pyrrolidine-3-carboxylate
[0426] Compound 137B (0.83 g) in ethanol (9 ml) was treated with
10% Pd/C (0.208 g) and ammonium formate (1.97 g), refluxed for 1.5
hours, concentrated, dissolved in dichloromethane, filtered though
a pad of celite rinsing with dichloromethane, and concentrated to
give the product.
Compound 137D
trans-1-benzyl 3-ethyl 4-(fluoro
methyl)pyrrolidine-1,3-dicarboxylate
[0427] Compound 137C (0.44 g) in dioxane (4 ml) and water (4 ml) at
0.degree. C. was treated sequentially with Na.sub.2CO.sub.3 (0.89
g) and benzyl chloroformate (0.48 ml). The reaction mixture was
stirred at 0.degree. C. for 3 hours and was then allowed to slowly
warm to room temperature over 1.5 hours. The reaction mixture was
diluted with ethyl acetate, washed with water and brine, dried
(MgSO.sub.4), filtered, concentrated and chromatographed on silica
gel with 10-25% ethyl acetate in hexanes as eluent to give the
product.
Compound 137E
trans-1-(benzyloxycarbonyl)-4-(fluoromethyl)pyrrolidine-3-carboxylic
acid
[0428] The title compound was prepared by substituting Compound
137D for Compound 15G in the procedure for Compound 15H.
Compound 137F
trans-benzyl
3-(fluoromethyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate
[0429] Compound 137E (0.563 g) in tetrahydrofuran (10 ml) at
0.degree. C. was treated dropwise with a 1 M solution of borane in
tetrahydrofuran (4 ml), stirred for 3 hours and then slowly
quenched with saturated aqueous NH.sub.4Cl solution. The reaction
mixture was diluted with ethyl acetate, washed with water and
brine, dried (MgSO.sub.4), filtered and concentrated to give the
product.
Compound 137G
trans-benzyl 3-(fluoro
methyl)-4-((2-nitro-4-sulfamoylphenoxy)methyl)pyrrolidine-1-carboxylate
[0430] The title compound was prepared by substituting Compound
137F for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 24A.
Compound 137H
trans-4-((4-(fluoromethyl)pyrrolidin-3-yl)methoxy)-3-nitrobenzenesulfonami-
de
[0431] Compound 137G (0.232 g) in acetic acid (2.5 ml) was treated
with hydrobromic acid (33 wt % in acetic acid) (0.875 ml) at
ambient temperature, stirred for 1 hour and concentrated. The
product was free-based using a MEGA BE-SCX column with 1:1
CH.sub.2Cl.sub.2/methanol as eluent for the hydrobromic acid and
acetic acid. The product was released from the column with 10% (7 M
ammonia in methanol) in CH.sub.2Cl.sub.2 as eluent.
Compound 137I
trans-4-((4-(fluoromethyl)-1-(oxetan-3-yl)pyrrolidin-3-yl)methoxy)-3-nitro-
benzenesulfonamide
[0432] The title compound was prepared by substituting Compound
137H for tert-butyl piperazine-1-carboxylate and 3-oxetanone for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 137J
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[trans-4-(fluoro
methyl)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0433] The title compound was prepared by substituting Compound
137I for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H),
8.35 (d, 1H), 8.03 (m, 2H), 7.51 (m, 3H), 7.37 (m, 3H), 7.04 (m,
2H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.21 (d, 1H), 4.45 (m, 6H), 4.21
(d, 2H), 3.62 (m, 1H), 3.08 (m, 4H), 2.72 (m, 5H), 2.31 (m, 9H),
1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 138
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 138A
(4-fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate
[0434] A mixture of Compound 37C (1.4 g), methanesulfonyl chloride
(1.054 ml), triethylamine (2.99 ml), and 4-dimethylaminopyridine
(0.051 g) in CH.sub.2Cl.sub.2 (20 ml) was stirred at 0.degree. C.
for 2 hours, concentrated and chromatographed on silica gel eluting
with 30% ethyl acetate in hexanes to give the product.
Compound 138B
2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione
[0435] A mixture of Compound 138A (1.8 g) and potassium phthalimide
(2.356 g) in N,N-dimethylformamide (30 ml) was heated at
150.degree. C. overnight, diluted with ethyl acetate, washed with
water and brine, dried (MgSO.sub.4), filtered, concentrated and
chromatographed on silica gel eluting with 30% ethyl acetate in
hexanes to give the product.
Compound 138C
(4-fluorotetrahydro-2H-pyran-4-yl)methanamine
[0436] A mixture of Compound 138B (1.4 g) and hydrazine (1.548 ml)
in ethanol (40 ml) was heated at 70.degree. C. overnight, cooled to
room temperature, slurried with CH.sub.2Cl.sub.2 (200 ml) and the
solid removed by filtration. The filtrate was concentrated and
chromatographed on silica gel eluting with 100:5:1 ethyl
acetate/methanol/NH.sub.4OH to give the product.
Compound 138D
4-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[0437] A mixture of 4-fluoro-3-nitrobenzenesulfonamide (0.44 g),
Compound 138C (0.266 g), and triethylamine (1.11 ml) in
tetrahydrofuran (10 ml) was heated at 70.degree. C. overnight,
diluted with ethyl acetate, washed with water and brine, dried
(MgSO.sub.4), filtered, concentrated and chromatographed on silica
gel eluting with 50% ethyl acetate in hexanes to give the
product.
Compound 138E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0438] The title compound was prepared by substituting Compound
138D for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H),
8.62 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.82 (dd, 1H), 7.48-7.54
(m, 3H), 7.34 (d, 2H), 7.24 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H),
6.39 (dd, 1H), 6.19 (d, 1H), 3.70-3.77 (m, 4H), 3.50-3.55 (m, 2H),
3.07 (s, 4H), 2.76 (s, 2H), 2.14-2.20 (m, 6H), 1.76-1.84 (m, 4H),
1.38 (t, 2H), 0.92 (s, 6H).
Compound 139
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 139A
tert-butyl
4-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamo-
yl)-2-nitrophenylamino)piperidine-1-carboxylate
[0439] The title compound was prepared as described in the
procedure for Compound 53B by replacing 1-acetylpiperidin-4-amine
with 4-amino-piperidine-1-carboxylic acid tert-butyl ester.
Compound 139B
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylamino)-
phenylsulfonyl)benzamide
[0440] To a cooled (0.degree. C.) solution of Compound 139A (960
mg) in dichloromethane (10 ml) was added dropwise trifluoroacetic
acid (5 ml). The mixture was stirred at the temperature for 3
hours. Then, the mixture was concentrated under vacuum and the
residue was dissolved in dichloromethane (200 ml) and washed with
aqueous NaHCO.sub.3 and brine. After drying over Na.sub.2SO.sub.4,
the mixture was filtered, and evaporation of the solvent from the
filtrate gave the title compound.
Compound 139C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0441] To a solution of Compound 139B (120 mg) in tetrahydrofuran
(3 ml) and acetic acid (1 ml) was added oxetan-3-one (50.8 mg) and
MP-cyanoborohydride (2.15 mmol/g, 150 mg). The mixture was stirred
at room temperature overnight. The mixture was filtered. The
filtrate was concentrated and the residue was loaded on a silica
gel cartridge and eluted with 5-10% 7N NH.sub.3 in methanol in
dichloromethane to give the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.62 (s, 1H), 8.51 (d, 1H),
8.20 (d, 1H), 7.99 (d, 1H), 7.74 (m, 1H), 7.48 (m, 3H), 7.35 (d,
2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.36 (dd, 1H), 6.20 (d, 1H), 4.54
(t, 2H), 4.43 (t, 2H), 3.66 (m, 1H), 3.44 (m, 3H), 3.04 (m, 5H),
2.73 (s, 2H), 2.61 (m, 2H), 2.12 (m, 11H), 1.61 (m, 2H), 1.38 (t,
2H), 0.93 (m, 6H).
Compound 140
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclobutylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0442] The title compound was prepared as described in the
procedure for Compound 139C by replacing oxetan-3-one with
cyclobutanone. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.58 (s, 1H), 8.47 (d, 1H), 8.12 (d, 1H), 7.97 (d, 1H),
7.74 (d, 1H), 7.53 (d, 1H), 7.45 (m, 1H), 7.36 (m, 3H), 7.02 (m,
3H), 6.64 (dd, 1H), 6.33 (m, 1H), 6.22 (d, 1H), 3.74 (m, 1H), 2.97
(m, 6H), 2.73 (s, 3H), 2.15 (m, 15H), 1.67 (m, 4H), 1.38 (t, 2H),
0.93 (s, 6H).
Compound 141
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0443] The title compound was prepared as described in the
procedure for Compound 139C by replacing oxetan-3-one with
2,2-dimethyltetrahydropyran-4-one. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.60 (s, 1H), 8.50 (d, 1H),
8.15 (m, 1H), 7.99 (d, 1H), 7.78 (m, 1H), 7.62 (m, 1H), 7.47 (m,
3H), 7.34 (m, 3H), 7.05 (m, 3H), 6.65 (m, 2H), 6.35 (dd, 1H), 6.21
(d, 1H), 4.56 (d, 3H), 3.89 (m, 3H), 3.67 (m, 6H), 3.45 (m, 2H),
3.04 (m, 3H), 2.75 (m, 3H), 2.14 (m, 3H), 1.71 (m, 5H), 1.16 (s,
9H).
Compound 142
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3S)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 142A
(S)-tert-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate
(S)-tert-butyl pyrrolidin-3-ylcarbamate (415 mg),
(1-ethoxycyclopropoxy)trimethylsilane (1.8 ml) and molecular sieves
(500 mg) were combined in methanol (4.5 ml). Acetic acid (1.3 ml)
was added, followed by sodium cyanoborohydride (420 mg). The
resulting mixture was heated to reflux for 4 hours. Insoluble
material was filtered off and reaction was made basic to pH 14 with
addition of 6M aqueous NaOH solution. The solution was extracted
three times with diethyl ether, and the combined extracts were
dried over MgSO.sub.4, filtered and concentrated to obtain an oil,
which was purified by flash chromatography, eluting first with 100%
dichloromethane, followed by 5% methanol/dichloromethane and 10%
methanol/dichloromethane.
Compound 142B
(S)-1-cyclopropylpyrrolidin-3-amine
[0444] The title compound was prepared by substituting Compound
142A for Compound 1A in the procedure for Compound 1B.
Compound 142C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3S)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0445] The title compound was prepared by substituting Compound
142B for 1-acetylpiperidin-4-amine in the procedure for Compound
53B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.64
(s, 1H), 8.51 (m, 2H), 8.30 (m, 1H), 8.00 (br s, 1H), 7.77 (m, 1H),
7.49 (m, 3H), 7.34 (d, 2H), 7.04 (d, 2H), 6.97 (br s, 1H), 6.67
(dd, 1H), 6.36 (m, 1H), 6.21 (m, 1H), 4.19 (m, 1H), 3.00 (m, 5H),
2.74 (m, 3H), 2.64 (m, 1H), 2.36 (m, 1H), 2.15 (m, 6H), 1.95 (s,
2H), 1.78 (br s, 1H), 1.68 (m, 1H), 1.38 (t, 2H), 1.23 (m, 1H),
0.92 (s, 6H), 0.39 (m, 4H).
Compound 143
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylpiperidin-4-yl)amino]phenyl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0446] The title compound was prepared as described in the
procedure for Compound 139C by replacing oxetan-3-one with
3-oxotetrahydrofuran. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H), 8.53 (d, 1H),
8.21 (m, 1H), 8.02 (m, 1H), 7.80 (dd, 1H), 7.49 (m, 3H), 7.34 (m,
3H), 7.05 (m, 3H), 6.67 (dd, 1H), 6.37 (m, 1H), 6.19 (d, 1H), 4.29
(m, 3H), 3.73 (m, 6H), 3.09 (m, 4H), 2.76 (m, 2H), 2.05 (m, 8H),
1.68 (m, 2H), 1.37 (m, 2H), 0.94 (s, 6H).
Compound 144
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 144A
(R)-tert-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate
[0447] The title compound was prepared by substituting
(R)-tert-butyl pyrrolidin-3-ylcarbamate for (S)-tert-butyl
pyrrolidin-3-ylcarbamate in the procedure for Compound 142A.
Compound 144B
(R)-1-cyclopropylpyrrolidin-3-amine
[0448] The title compound was prepared by substituting Compound
144A for Compound 1A in the procedure for Compound 1B.
Compound 144C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0449] The title compound was prepared by substituting Compound
144B for 1-acetylpiperidin-4-amine in the procedure for Compound
53B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66
(s, 1H), 8.53 (d, 2H), 8.32 (d, 1H), 8.02 (d, 1H), 7.81 (m, 1H),
7.49 (m, 3H), 7.34 (d, 2H), 7.03 (m, 3H), 6.67 (dd, 1H), 6.37 (m,
1H), 6.20 (d, 1H), 4.21 (m, 1H), 3.00 (m, 5H), 2.74 (m, 3H), 2.64
(m, 1H), 2.36 (m, 1H), 2.15 (m, 6H), 1.95 (s, 2H), 1.74 (br s, 1H),
1.66 (m, 1H), 1.38 (t, 2H), 1.23 (m, 1H), 0.92 (s, 6H), 0.39 (m,
4H).
Compound 145
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]meth-
yl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 145A
(S)-tert-butyl
(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methylcarbamate
[0450] The title compound was prepared by substituting
(R)-tert-butyl pyrrolidin-3-ylmethylcarbamate for tert-butyl
piperazine-1-carboxylate and dihydro-2H-pyran-4(3H)-one for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 145B
(S)-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methanamine
[0451] The title compound was prepared by substituting Compound
145A for Compound 1A in the procedure for Compound 1B.
Compound 145C
(S)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((1-(tetrahydro-2-
H-pyran-4-yl)pyrrolidin-3-yl)methylamino)phenylsulfonyl)benzamide
[0452] The title compound was prepared by substituting Compound
145B for 1-acetylpiperidin-4-amine in the procedure for Compound
53B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.58
(s, 1H), 8.61 (br s, 1H), 8.46 (s, 1H), 7.96 (d, 1H), 7.72 (m, 1H),
7.54 (d, 1H), 7.45 (t, 1H), 7.37 (br s, 2H), 7.34 (d, 2H), 7.04 (m,
2H), 6.94 (m, 1H), 6.64 (dd, 1H), 6.34 (m, 1H), 6.22 (d, 1H), 3.89
(m, 2H), 3.38 (m, 4H), 3.27 (m, 4H), 3.02 (m, 5H), 2.73 (s, 2H),
2.61 (m, 1H), 2.18 (m, 6H), 2.05 (m, 1H), 1.95 (m, 2H), 1.85 (m,
2H), 1.64 (m, 1H), 1.50 (m, 2H), 1.38 (m, 2H), 0.94 (s, 6H).
Compound 146
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0453] The title compound was prepared as described in the
procedure for Compound 120B using 3-amino-2,2-dimethylpropan-1-ol
in place of Compound 120A. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 11.35 (s, 1H),
8.96 (t, 1H), 8.56 (d, 1H), 8.05 (d, 1H), 7.79 (dd, 1H), 7.46-7.56
(m, 3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H),
6.39 (dd, 1H), 6.19 (d, 1H), 5.10 (t, 1H), 3.29 (d, 1H), 3.24 (d,
1H), 3.07 (s, 4H), 2.75 (s, 2H), 2.17 (d, 6H), 1.95 (s, 2H), 1.38
(t, 2H), 0.93 (d, 12H).
Compound 147
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-3-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 147A
tert-butyl (1-(methylsulfonyl)piperidin-3-yl)methylcarbamate
tert-Butyl piperidin-3-ylmethylcarbamate (500 mg) was dissolved in
anhydrous dichloromethane (10 ml), and methanesulfonyl chloride
(0.181 ml) was added followed by the addition of triethylamine (1.3
ml). The reaction mixture was stirred at room temperature
overnight. The organic solvent was removed under vacuum. The
residue was purified with flash column chromatography on silica gel
eluting with 0-70% ethyl acetate in hexane to give the title
compound.
Compound 147B
(1-(methylsulfonyl)piperidin-3-yl)methanamine
[0454] Compound 147A (400 mg) was suspended in 4N HCl in dioxane
(10 ml) followed by the addition of anhydrous methanol (1 ml). The
clear solution was stirred at room temperature for 2 hours. The
organic solvent was removed under vacuum. The solid residue was
used in the next step without further purification.
Compound 147C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-3-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0455] Compound 53A (50 mg), Compound 147B (26 mg) and
triethylamine (0.088 ml) were dissolved in anhydrous dioxane (1 ml)
and N,N-dimethylformamide (0.2 ml). The reaction vial was heated in
a Biotage Initiator microwave reactor at 130.degree. C. for 25
minutes. The solvent was removed under vacuum. The residue was
purified by reverse phase HPLC on a C18 column using a gradient of
20-80% acetonitrile/0.1% trifluoroacetic acid in water to give the
title compound as the trifluoroacetate salt. The trifluoroacetic
acid salt was dissolved in dichloromethane (6 ml) and washed with
50% aqueous NaHCO.sub.3. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (s,
1H), 8.56 (m, 2H), 8.03 (d, 1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.35
(d, 2H), 7.12 (m, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H),
6.19 (d, 1H), 3.52 (m, 1H), 3.40 (m, 2H), 3.06 (m, 4H), 2.84 (s,
3H), 2.75 (m, 2H), 2.75 (m, 4H), 2.58 (m, 1H), 2.16 (m, 6H), 1.95
(s, 3H), 1.76 (m, 2H), 1.52 (m, 1H), 1.37 (m, 2H), 0.92 (s,
6H).
Compound 148
N-[(4-{[(1-acetylpiperidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 148A
tert-butyl (1-acetylpiperidin-3-yl)methylcarbamate
[0456] The title compound was prepared by substituting acetyl
chloride for methanesulfonyl chloride in the procedure for Compound
147A.
Compound 148B
1-(3-(aminomethyl)piperidin-1-yl)ethanone
[0457] The title compound was prepared by substituting Compound
148A for Compound 147A in the procedure for Compound 147B.
Compound 148C
N-[(4-{[(1-acetylpiperidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0458] The title compound was prepared by substituting Compound
148B for Compound 147B in the procedure for Compound 147C. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H),
8.56 (m, 2H), 8.03 (d, 1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.34 (d,
2H), 7.12 (m, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.19
(d, 1H), 3.99 (m, 1H), 3.67 (m, 1H), 3.37 (m, 2H), 3.24 (m, 2H),
3.07 (m, 4H), 2.89 (m, 1H), 2.71 (m, 2H), 2.16 (m, 6H), 1.96 (s,
3H), 1.80 (m, 4H), 1.38 (t, 2H), 1.27 (m, 2H), 0.92 (s, 6H).
Compound 149
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 149A
(R)-tert-butyl 1-(methylsulfonyl)pyrrolidin-3-ylcarbamate
[0459] The title compound was prepared by substituting
(R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl
piperidin-3-ylmethylcarbamate in the procedure for Compound
147A.
Compound 149B
(R)-1-(methylsulfonyl)pyrrolidin-3-amine
[0460] The title compound was prepared by substituting Compound
149A for Compound 147A in the procedure for Compound 147B.
Compound 149C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0461] The title compound was prepared by substituting Compound
149B for Compound 147B in the procedure for Compound 147C. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H),
8.55 (d, 1H), 8.29 (d, 1H), 8.02 (d, 1H), 7.86 (dd, 1H), 7.49 (m,
3H), 7.33 (d, 2H), 7.17 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38
(dd, 1H), 6.20 (d, 1H), 4.41 (m, 1H), 3.69 (m, 1H), 3.39 (m, 3H),
3.06 (m, 4H), 2.97 (s, 3H), 2.76 (m, 2H), 2.27 (m, 8H), 1.93 (m,
2H), 1.54 (m, 1H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 150
4-(4-{[2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 150A
ethyl 2-hydroxy-3,3-dimethylcyclohex-1-enecarboxylate
[0462] Into a 500 ml round-bottomed flask was added
diisopropylamine (3.5 ml) in ether (200 ml). After cooling to
-30.degree. C., butyllithium (16 ml) (1.6M in hexane) was added
slowly. After stirring 30 minutes, the temperature was cooled to
-5.degree. C. 2,2-Dimethylcyclohexanone (3 g) was added slowly. The
mixture was warmed up to 0.degree. C. and stirred for 1 hour. After
cooling to -5.degree. C., hexamethylphosphoramide (8 ml) and ethyl
carbonocyanidate (2.5 ml) were added. After stirring at -5.degree.
C. for 20 minutes, and warming to room temperature, the reaction
was stirred for 1 hour. The mixture was poured into cold water, and
the layers were separated. The aqueous layer was extracted with
ether (3.times.20 ml). The combined the organic layers were washed
with saturated aqueous NH.sub.4Cl (3.times.20 ml). After drying
over Na.sub.2SO.sub.4, the mixture was filtered and the filtrate
was concentrated. The crude product was purified by flash
chromatography on silica with 0-10% ethyl acetate in hexanes to
provide the title compound.
Compound 150B
ethyl
3,3-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
[0463] The title compound was prepared by substituting Compound
150A for Compound 101A in the procedure for Compound 101B.
Compound 150C
ethyl 2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-enecarboxylate
[0464] The title compound was prepared by substituting Compound
150B for Compound 101B in the procedure for Compound 101C.
Compound 150D
(2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-enyl)methanol
[0465] In a 200 ml round-bottomed flask was added Compound 150C
(0.97 g) and lithium borohydride (0.47 g) in ether (20 ml) to give
a suspension. Methanol (2.2 ml) was added slowly. The mixture was
refluxed overnight. The reaction was then cooled, and methanol was
added to quench the reaction. 1N aqueous HCl was then added until
the pH<7, and ether (3.times.30 ml) was used to extract the
product. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude material
was purified by flash chromatography on silica with 0-25% ethyl
acetate in hexanes to provide the title compound.
Compound 150E
2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-enecarbaldehyde
[0466] Into a 100 ml round-bottomed flask was added Compound 150D
(0.3 g) and Dess-Martin Periodinane (0.6 g) in dichloromethane (10
ml) to give a suspension. The mixture was stirred at room
temperature overnight. After filtration, the mixture was washed
with saturated aqueous NaHCO.sub.3 (2.times.20 ml), dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was
purified by flash chromatography on silica with 0-25% ethyl acetate
in hexanes to provide the title compound.
Compound 150F
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-3,3--
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0467] The title compound was prepared by substituting Compound
150E for 4'-chlorobiphenyl-2-carboxaldehyde and Compound 15F for
tert-butyl piperazine-1-carboxylate in the procedure for Compound
1A.
Compound 150G
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-3,3-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0468] The title compound was prepared by substituting Compound
150F for Compound 101E in the procedure for Compound 101F.
Compound 150H
4-(4-{[2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0469] The title compound was prepared by substituting Compound
150G for Compound 3J and Compound 1F for Compound 11B in the
procedure for Compound 11D. .sup.1H NMR (500 MHz, dimethyl
sulfoxide-d.sub.6) .delta. 11.50 (s, 1H), 8.36 (m, 1H), 8.32 (m,
1H), 7.91 (d, 1H), 7.59 (m, 2H), 7.40 (t, 1H), 7.35 (d, 2H), 7.25
(m, 1H), 6.94 (d, 2H), 6.79 (d, 1H), 6.60 (m, 1H), 6.29 (m, 1H),
6.24 (d, 1H), 3.83 (m, 2H), 3.25 (m, 4H), 2.98 (m, 4H), 2.42 (s,
2H), 2.14 (m, 6H), 1.60 (m, 6H), 1.25 (m, 3H), 0.86 (s, 6H).
Compound 151
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}amino)-3-nit-
rophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 151A
1-(1,3-difluoropropan-2-yl)azetidin-3-amine
[0470] To a solution of tert-butyl azetidin-3-ylcarbamate (0.256 g)
and 1,3-difluoropropan-2-one (0.154 g) in dichloromethane (2 ml)
was added sodium triacetoxyborohydride (0.473 g) and the reaction
was allowed to stirred at room temperature. After 16 hours, the
reaction was quenched with saturated NaHCO.sub.3 solution (10 ml)
and extracted into dichloromethane (25 ml). The organic layer was
dried and concentrated. Silica gel chromatography (GraceResolv 12
g) eluting with a gradient of 0.5% to 3.5% methanol/dichloromethane
followed by treatment with HCl (4.0M in dioxane, 3 ml) and methanol
(0.5 ml) for 2 hours gave the title compound after
concentration.
Compound 151B
4-(1-(1,3-difluoropropan-2-yl)azetidin-3-ylamino)-3-nitrobenzenesulfonamid-
e
[0471] To a suspension of 4-chloro-3-nitrobenzenesulfonamide (0.225
g) and 1-(1,3-difluoropropan-2-yl)azetidin-3-amine (0.193 g) in
dioxane (5 ml) was added diisopropylamine (0.832 ml). The reaction
was sonicated and then heated to 100.degree. C. After stirring
overnight, the reaction was concentrated and loaded onto silica gel
(GraceResolv 12 g) and eluted with a gradient of 0.5% to 3.5%
methanol/dichloromethane to give the title compound.
Compound 151C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}amino)-3-nit-
rophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0472] The title compound was prepared by substituting Compound
151B for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H), 11.54-11.28 (m,
1H), 8.54 (d, 1H), 8.45 (s, 1H), 8.01 (d, 1H), 7.82 (d, 1H), 7.48
(d, 3H), 7.34 (d, 2H), 7.04 (d, 2H), 6.90 (d, 1H), 6.67 (d, 1H),
6.37 (s, 1H), 6.20 (s, 1H), 4.64-4.23 (m, 6H), 3.81 (s, 2H), 3.08
(s, 4H), 2.75 (s, 3H), 2.15 (s, 7H), 1.95 (s, 2H), 1.38 (s, 2H),
0.92 (s, 6H).
Compound 152
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(methylsulfonyl)pyrrolidin-3-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 152A
tert-butyl (1-(methylsulfonyl)pyrrolidin-3-yl)methylcarbamate
[0473] The title compound was prepared by substituting tert-butyl
pyrrolidin-3-ylmethylcarbamate for tert-butyl
piperidin-3-ylmethylcarbamate in the procedure for Compound
147A.
Compound 152B
(1-(methylsulfonyl)pyrrolidin-3-yl)methanamine
[0474] The title compound was prepared by substituting Compound
152A for Compound 147A in the procedure for Compound 147B.
Compound 152C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(methylsulfonyl)pyrrolidin-3-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0475] The title compound was prepared by substituting Compound
152B for Compound 147B in the procedure for Compound 147C. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.60 (s, 1H),
8.49 (m, 2H), 7.99 (s, 1H), 7.73 (m, 1H), 7.53 (d, 1H), 7.47 (s,
1H), 7.42 (m, 1H), 7.34 (d, 2H), 7.04 (m, 3H), 6.65 (m, 1H), 6.35
(s, 1H), 6.22 (s, 1H), 3.41 (m, 4H), 3.22 (m, 2H), 3.03 (m, 4H),
2.89 (s, 3H), 2.73 (m, 2H), 2.59 (m, 1H), 2.17 (m, 6H), 2.00 (m,
4H), 1.68 (m, 1H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 153
N-[(4-{[(1-acetylpyrrolidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 153A
tert-butyl (1-acetylpyrrolidin-3-yl)methylcarbamate
[0476] The title compound was prepared by substituting tert-butyl
pyrrolidin-3-ylmethylcarbamate for tert-butyl
piperidin-3-ylmethylcarbamate and acetyl chloride for
methanesulfonyl chloride in the procedure for Compound 147A.
Compound 153B
1-(3-(amino methyl)pyrrolidin-1-yl)ethanone
[0477] The title compound was prepared by substituting Compound
153A for Compound 147A in the procedure for Compound 147B.
Compound 153C
N-[(4-{[(1-acetylpyrrolidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0478] The title compound was prepared by substituting Compound
153B for Compound 147B in the procedure for Compound 147C. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H),
8.62 (m, 1H), 8.54 (s, 1H), 8.03 (m, 1H), 7.78 (d, 1H), 7.50 (m,
3H), 7.35 (t, 2H), 7.09 (s, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.37
(d, 1H), 6.20 (s, 1H), 3.56 (m, 1H), 3.42 (m, 4H), 3.43 (m, 4H),
3.23 (m, 1H), 3.07 (m, 4H), 2.74 (m, 2H), 2.16 (m, 6H), 1.93 (m,
5H), 1.38 (t, 2H), 0.93 (s, 6H).
Compound 154
N-[(4-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{-
[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 154A
(R)-tert-butyl 1-acetylpyrrolidin-3-ylcarbamate
[0479] The title compound was prepared by substituting
(R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl
piperidin-3-ylmethylcarbamate and acetyl chloride for
methanesulfonyl chloride in the procedure for Compound 147A.
Compound 154B
(R)-1-(3-aminopyrrolidin-1-yl)ethanone
[0480] The title compound was prepared by substituting Compound
154A for Compound 147A in the procedure for Compound 147B.
Compound 154C
N-[(4-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{-
[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0481] The title compound was prepared by substituting Compound
154B for Compound 147B in the procedure for Compound 147. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.61 (s, 1H),
8.50 (s, 1H), 8.17 (d, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.49 (m,
3H), 7.34 (d, 2H), 7.10 (m, 1H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.35
(s, 1H), 6.22 (s, 1H), 4.34 (m, 1H), 3.81 (m, 1H), 3.58 (m, 1H),
3.43 (m, 1H), 3.05 (m, 4H), 2.74 (s, 2H), 2.19 (m, 9H), 1.96 (m,
5H), 1.38 (t, 2H), 0.94 (s, 6H).
Compound 155
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-methoxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0482] The title compound was prepared as described in the
procedure for Compound 120B using
3-methoxy-2,2-dimethylpropan-1-amine in place of Compound 120A.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s,
1H), 11.32 (s, 1H), 8.92 (t, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.80
(dd, 1H), 7.46-7.55 (m, 3H), 7.34 (d, 2H), 7.08 (d, 1H), 7.04 (d,
2H), 6.68 (dd, 1H), 6.36-6.42 (m, 1H), 6.19 (d, 1H), 3.25-3.30 (m,
5H), 3.19 (s, 2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.17 (d, 6H), 1.95
(s, 2H), 1.38 (t, 2H), 0.96 (s, 6H), 0.92 (s, 6H).
Compound 156
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(1R,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 156A
4-(((1R,3R)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide
[0483] The title compound was prepared by substituting
(1R,3R)-3-hydroxycyclopentyl)methylamine for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 156B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(1R,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0484] The title compound was prepared by substituting Compound
156A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.05 (s, 1H), 9.29 (s,
1H), 8.62 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.10 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.85 (d, 1H), 6.74 (dd, 1H),
6.54 (s, 1H), 6.49 (m, 1H), 4.60 (m, 1H), 3.19 (dd, 2H), 3.06 (m,
4H), 2.77 (s, 2H), 2.70 (m, 1H), 2.26 (t, 2H), 2.20-2.07 (m, 6H),
2.00 (m, 1H), 1.97 (s, 2H), 1.90 (m, 1H), 1.56 (m, 1H), 1.39 (t,
2H), 1.34 (m, 1H), 0.93 (s, 6H).
Compound 157
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(1S,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 157A
4-(((1S,3S)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide
[0485] The title compound was prepared by substituting
(1S,3S)-3-hydroxycyclopentyl)methylamine for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 157B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(1S,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0486] The title compound was prepared by substituting Compound
157A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.03 (s, 1H), 9.29 (s,
1H), 8.60 (t, 1H), 8.44 (d, 1H), 8.32 (dd, 1H), 8.14 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.83 (d, 1H), 6.75 (dd, 1H),
6.55 (s, 1H), 6.49 (m, 1H), 4.60 (m, 1H), 3.19 (dd, 2H), 3.06 (m,
4H), 2.77 (s, 2H), 2.70 (m, 1H), 2.26 (t, 2H), 2.20-2.07 (m, 6H),
2.00 (m, 1H), 1.97 (s, 2H), 1.90 (m, 1H), 1.56 (m, 1H), 1.39 (t,
2H), 1.34 (m, 1H), 0.93 (s, 6H).
Compound 158
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(1S,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 158A
4-(((1S,3R)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide
[0487] The title compound was prepared by substituting
(1S,3R)-3-hydroxycyclopentyl)methylamine for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 158B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(1S,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0488] The title compound was prepared by substituting Compound
158A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 12.94 (s, 1H), 9.25 (d,
1H), 8.59 (t, 1H), 8.48 (d, 1H), 8.27 (m, 2H), 7.66 (m, 2H), 7.45
(d, 2H), 7.08 (d, 2H), 6.77 (dd, 1H), 6.72 (d, 1H), 6.60 (d, 1H),
6.47 (m, 1H), 4.53 (m, 1H), 3.30 (m, 2H), 3.06 (m, 4H), 2.78 (s,
2H), 2.27 (m, 3H), 2.19-2.10 (m, 5H), 1.98 (m, 3H), 1.85-1.66 (m,
4H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 159
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(1R,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 159A
4-(((1R,3S)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide
[0489] The title compound was prepared by substituting
(1R,3S)-3-hydroxycyclopentyl)methylamine for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 159B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(1R,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0490] The title compound was prepared by substituting Compound
158A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.02 (s, 1H), 9.28 (d,
1H), 8.59 (t, 1H), 8.44 (d, 1H), 8.29 (d, 1H), 8.13 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.08 (d, 2H), 6.82 (dd, 1H), 6.74 (d, 1H),
6.55 (d, 1H), 6.48 (m, 1H), 4.53 (m, 1H), 3.34 (m, 2H), 3.06 (m,
4H), 2.77 (s, 2H), 2.27 (m, 3H), 2.19-2.10 (m, 5H), 1.97 (m, 3H),
1.85-1.66 (m, 4H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 160
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-2-oxopiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0491] The title compound was prepared by substituting
(S)-3-aminopiperidin-2-one for 1-acetylpiperidin-4-amine in the
procedure for Compound 53B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (br s, 1H), 8.88 (d, 1H),
8.57 (d, 1H), 8.04 (d, 1H), 7.95 (br s, 1H), 7.83 (dd, 1H),
7.55-7.46 (m, 3H), 7.35 (d, 2H), 7.16 (d, 1H), 7.05 (d, 2H), 6.68
(dd, 1H), 6.38 (m, 1H), 6.21 (d, 1H), 4.41 (m, 1H), 3.22 (m, 2H),
3.09 (br s, 4H), 2.78 (br s, 2H), 2.35-2.09 (m, 8H), 1.96 (br s,
2H), 1.86 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 161
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}methyl)amin-
o]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 161A
tert-butyl
3-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfam-
oyl)-2-nitrophenylamino)methyl)azetidine-1-carboxylate
[0492] Compound 82 (305 mg). tert-butyl
3-(aminomethyl)azetidine-1-carboxylate (86 mg) and diisopropyl
amine (0.202 ml) in dioxane (3 ml) were heated to 110.degree. C.
After stirring overnight, the reaction was concentrated. Silica gel
chromatography (Reveleris, 12 g) eluting with a gradient of 0.5% to
3% methanol/dichloromethane (flow=36 ml/minute) gave the title
compound.
Compound 161B
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-(azetidin-3-ylmethylamino)-3-nit-
rophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)me-
thyl)piperazin-1-yl)benzamide
[0493] To a solution of Compound 161A (0.257 g) in dichloromethane
(5 ml) was added trifluoroacetic acid (0.211 ml). After 30 minutes
an additional 0.2 ml of trifluoroacetic acid was added. After 3
hours, the reaction was concentrated to give the title
compound.
Compound 161C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[{1-[2-fluoro-1-(fluoro
methyl)ethyl]azetidin-3-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-py-
rrolo[2,3-b]pyridin-5-yloxy)benzamide
[0494] A solution of Compound 161B (0.118 g), sodium
triacetoxyborohydride (0.035 g) and 1,3-difluoropropan-2-one (0.012
g) were stirred together in dichloromethane (1 ml) overnight. The
reaction was quenched with saturated aqueous NaHCO.sub.3 solution
(10 ml) and extracted into dichloromethane (30 ml). The organic
layer was dried and concentrated. Silica gel chromatography
(Reveleris 12 g) eluting with a gradient of 0.5% to 3.5%
methanol/dichloromethane over 30 minutes (flow=36 ml/min) gave the
title compound. 1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.67 (s, 1H), 11.47-11.21 (m, 1H), 8.85 (s, 1H), 8.55 (d, 1H),
8.03 (d, 1H), 7.80 (dd, 1H), 7.54-7.45 (m, 3H), 7.33 (s, 2H), 7.04
(d, 3H), 6.67 (d, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.43 (dt, 4H),
3.56 (t, 2H), 3.46 (s, 2H), 3.12 (m, 6H), 2.74 (m, 3H), 2.17 (m,
7H), 1.95 (s, 2H), 1.39 (d, 2H), 0.92 (s, 6H).
Compound 162
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylazetidin-3-yl)methyl]amino}phenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0495] The title compound was prepared by substituting oxetan-3-one
for 1,3-difluoropropan-2-one in the procedure for Compound 161C.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (s,
1H), 11.51-11.03 (m, 1H), 8.81 (s, 1H), 8.54 (d, 1H), 8.02 (d, 1H),
7.79 (dd, 1H), 7.50 (dd, 3H), 7.34 (d, 2H), 7.04 (d, 3H), 6.67 (d,
1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.57 (s, 2H), 4.43-4.35 (m, 2H),
3.82 (s, 1H), 3.59 (t, 2H), 3.44 (t, 2H), 3.20 (s, 2H), 3.06 (s,
4H), 2.73 (s, 3H), 2.18 (s, 6H), 1.95 (s, 2H), 1.39 (d, 2H), 0.92
(s, 6H).
Compound 163
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylpiperidin-4-yl)methyl]amino}phenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 163A
tert-butyl
4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfam-
oyl)-2-nitrophenylamino)methyl)piperidine-1-carboxylate
[0496] The title compound was prepared by substituting tert-butyl
4-(aminomethyl)piperidine-1-carboxylate for
1-acetylpiperidin-4-amine in the procedure for Compound 53B.
Compound 163B
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylmethyl-
amino)phenylsulfonyl)benzamide
[0497] The title compound was prepared by substituting Compound
163A for Compound 1A in the procedure for Compound 1B.
Compound 163C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylpiperidin-4-yl)methyl]amino}phenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0498] The title compound was prepared by substituting Compound
163B for Compound 161B and oxetan-3-one for
1,3-difluoropropan-2-one in the procedure for Compound 161C.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s,
1H), 8.60 (t, 1H), 8.54 (d, 1H), 8.03 (d, 1H), 7.79 (dd, 1H), 7.50
(m, 3H), 7.34 (d, 2H), 7.09 (d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H),
6.39 (m, 1H), 6.19 (d, 1H), 4.55 (t, 2H), 4.46 (t, 2H), 3.52 (br s,
1H), 3.28 (m, 2H), 3.17 (d, 1H), 3.06 (m, 4H), 2.82 (m, 2H), 2.74
(m, 2H), 2.17 (m, 6H), 1.95 (m, 3H), 1.72 (m, 3H), 1.38 (t, 2H),
1.28 (m, 2H), 0.92 (s, 6H).
Compound 164
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1-cyclopropylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0499] The title compound was prepared by substituting Compound
163B for (S)-tert-butyl pyrrolidin-3-ylcarbamate in the procedure
for Compound 142A. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.96 (br s, 1H), 11.62 (br s, 1H), 8.50 (m, 2H), 7.98 (d,
1H), 7.72 (m, 1H), 7.52 (d, 1H), 7.45 (m, 2H), 7.34 (d, 2H), 7.04
(m, 2H), 6.94 (m, 1H), 6.64 (dd, 1H), 6.34 (m, 1H), 6.22 (d, 1H),
3.28 (m, 3H), 3.04 (m, 5H), 2.72 (s, 2H), 2.64 (m, 1H), 2.64 (m,
1H), 2.36 (m, 1H), 2.16 (m, 7H), 1.95 (s, 2H), 1.68 (m, 3H), 1.38
(t, 2H), 1.18 (m, 3H), 0.94 (s, 6H), 0.35 (m, 3H).
Compound 165
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl-
]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 165A
4-((4-(2-fluoroethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
[0500] The title compound was prepared by substituting
2-fluoro-ethyl bromide for methyl iodide in the procedure for
Compound 134B.
Compound 165B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl-
]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0501] The title compound was prepared by substituting Compound
165A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.26 (d,
1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.92 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (dd, 1H), 3.93 (m, 1H), 4.63, 4.51 (dt, 2H),
3.95-3.85 (m, 2H), 3.68 (dt, 1H), 3.43-3.37 (m, 2H), 3.07 (m, 4H),
2.92 (d, 1H), 2.77 (s, 2H), 2.65 (m, 2H), 2.59 (m, 1H), 2.26 (m,
2H), 2.17-2.08 (m, 5H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s,
6H).
Compound 166
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitroph-
enyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 166A
4-((4-(2,2-difluoroethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfona-
mide
[0502] The title compound was prepared by substituting
2,2-difluoro-ethyl bromide for methyl iodide in the procedure for
Compound 134B.
Compound 166B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitroph-
enyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0503] The title compound was prepared by substituting Compound
166A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.01 (s, 1H), 9.26 (d,
1H), 8.86 (t, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.11 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.93 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 6.31, 6.20, 6.09 (tt, 1H), 3.90 (m,
1H), 3.85 (d, 1H), 3.67 (dt, 1H), 3.49-3.30 (m, 2H), 3.07 (m, 4H),
2.84 (d, 1H), 2.82-2.75 (m, 4H), 2.69 (d, 1H), 2.33 (dt, 1H),
2.27-2.20 (m, 3H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93
(s, 6H).
Compound 167
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluoro-1-oxetan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 167A
4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonam-
ide
[0504] The title compound was prepared by substituting Compound
173A for tert-butyl piperazine-1-carboxylate and 3-oxetanone for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 167B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluoro-1-oxetan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0505] The title compound was prepared by substituting Compound
167A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) 11.69 (s, 1H), 8.39 (s,
1H), 8.09 (d, 1H), 8.04 (d, 1H), 7.52 (m, 4H), 7.35 (d, 2H), 7.05
(m, 2H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (s, 1H), 4.57 (t, 2H),
4.48 (m, 2H), 4.38 (d, 2H), 4.02 (m, 1H), 3.63 (m, 2H), 3.08 (m,
4H), 2.74 (m, 4H), 2.17 (m, 6H), 1.88 (m, 6H), 1.40 (t, 2H), 0.93
(s, 6H).
Compound 168
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(2S)-4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yl]methoxy}-3-ni-
trophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 168A
(S)-methyl 4,4-difluoropyrrolidine-2-carboxylate
[0506] (S)-1-tert-butyl 2-methyl
4,4-difluoropyrrolidine-1,2-dicarboxylate (0.472 g) in
CH.sub.2Cl.sub.2 (1 ml) was treated with trifluoroacetic acid (1.4
ml), stirred at ambient temperature for 4 hours, and concentrated.
The product was free-based using a MEGA BE-SCX column with 1:1
CH.sub.2Cl.sub.2/methanol as eluent for the trifluoroacetic acid.
The product was released from the column with 5% (7 M ammonia in
methanol) in CH.sub.2Cl.sub.2 as eluent.
Compound 168B
(S)-methyl
4,4-difluoro-1-(oxetan-3-yl)pyrrolidine-2-carboxylate
[0507] The title compound was prepared by substituting Compound
168A for tert-butyl piperazine-1-carboxylate and 3-oxetanone for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 168C
(S)-(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-2-yl)methanol
[0508] Compound 168B (0.180 g) in tetrahydrofuran (3 ml) was
treated sequentially with a solution of calcium chloride (0.245 g)
in ethanol (3 ml) and NaBH.sub.4 (0.167 g) and then stirred at
ambient temperature for 7 hours. The reaction was quenched with
saturated aqueous NH.sub.4Cl solution and extracted with ethyl
acetate. The combined extracts were washed with brine, dried
(MgSO.sub.4), filtered, concentrated and chromatographed on silica
gel with 50% ethyl acetate in hexanes as eluent to give the
product.
Compound 168D
(S)-4-((4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-2-yl)methoxy)-3-nitrobenzen-
esulfonamide
[0509] The title compound was prepared by substituting Compound
168C for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 24A.
Compound 168E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(2S)-4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yl]methoxy}-3-ni-
trophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0510] The title compound was prepared by substituting Compound
168D for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H),
8.38 (s, 1H), 8.06 (m, 2H), 7.49 (m, 4H), 7.35 (d, 2H), 7.05 (d,
2H), 6.68 (dd, 1H), 6.40 (m, 1H), 6.21 (s, 1H), 4.54 (m, 3H), 4.43
(t, 1H), 4.23 (m, 1H), 4.12 (m, 2H), 3.44 (m, 2H), 3.12 (m, 7H),
2.58 (m, 1H), 2.29 (m, 7H), 1.97 (s, 2H), 1.40 (t, 2H), 0.93 (s,
6H).
Compound 169
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyl]ami-
no}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 169A
tert-butyl
3-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfam-
oyl)-2-nitrophenylamino)methyl)morpholine-4-carboxylate
[0511] The title compound was prepared as described in the
procedure for Compound 53B by replacing 1-acetylpiperidin-4-amine
with tert-butyl 3-(aminomethyl)morpholine-4-carboxylate.
Compound 169B
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(morpholin-3-ylmethylamino)-3-
-nitrophenylsulfonyl)benzamide
[0512] The title compound was prepared as described in the
procedure for Compound 139B by replacing Compound 139A with
Compound 169A.
Compound 169C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyl]ami-
no}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0513] The title compound was prepared as described in the
procedure for Compound 139C by replacing Compound 139B and
oxetan-3-one with Compound 169B and tetrahydropyran-4-one,
respectively. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.69 (s, 1H), 8.77 (m, 1H), 8.57 (d, 1H), 8.05 (d, 1H),
7.84 (dd, 1H), 7.52 (m, 3H), 7.34 (m, 2H), 7.03 (m, 3H), 6.68 (dd,
1H), 6.40 (dd, 1H), 6.18 (d, 1H), 3.86 (m, 2H), 3.72 (m, 2H), 3.11
(m, 6H), 2.74 (m, 4H), 2.20 (m, 6H), 1.95 (m, 3H), 1.51 (m, 7H),
0.92 (s, 6H).
Compound 170
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-cyclobutylmorpholin-3-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0514] The title compound was prepared as described in the
procedure for Compound 139C by replacing Compound 139B and
oxetan-3-one with Compound 169B and cyclobutanone. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 8.72 (s,
1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.84 (dd, 1H), 7.52 (m, 3H), 7.34
(m, 3H), 7.03 (m, 4H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.18 (d, 1H),
3.47 (m, 3H), 3.10 (m, 6H), 2.72 (m, 6H), 2.25 (m, 8H), 1.95 (m,
4H), 1.56 (m, 3H), 1.38 (m, 2H), 0.92 (s, 6H).
Compound 171
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(4-tetrahydrofuran-3-ylmorpholin-3-yl)methyl]amino}p-
henyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0515] The title compound was prepared as described in the
procedure for Compound 139C by replacing Compound 139B and
oxetan-3-one with Compound 169B and 3-oxotetrahydrofuran,
respectively. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.64 (s, 1H), 8.66 (s, 1H), 8.53 (d, 1H), 8.01 (d, 1H),
7.80 (d, 1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.98 (d,
1H), 6.66 (dd, 1H), 6.37 (d, 1H), 6.19 (d, 1H), 3.68 (m, 8H), 3.05
(m, 6H), 2.85 (m, 3H), 2.73 (s, 2H), 2.25 (m, 6H), 1.91 (m, 3H),
1.37 (m, 3H), 0.95 (m, 6H).
Compound 172
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methyl)ami-
no]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0516] The title compound was prepared by substituting Compound
163B for tert-butyl piperazine-1-carboxylate and
1,3-difluoropropan-2-one for 4'-chlorobiphenyl-2-carboxaldehyde in
the procedure for Compound 1A. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 11.40 (br s, 1H),
8.57 (m, 2H), 8.03 (d, 1H), 7.78 (d, 1H), 7.50 (m, 3H), 7.34 (d,
2H), 7.07 (d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (m 1H), 6.19
(d, 1H), 4.63 (d, 2H), 4.53 (d, 2H), 3.28 (m, 2H), 3.07 (m, 4H),
2.89 (m, 2H), 2.74 (m, 2H), 2.40 (m, 2H), 2.16 (m, 6H), 1.95 (s,
2H), 1.67 (m, 3H), 1.38 (t, 2H), 1.23 (m, 3H), 0.94 (s, 6H).
Compound 173
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 173A
4-((4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide
[0517] The title compound was prepared by substituting Compound
126B for Compound 1A in the procedure for Compound 1B.
Compound 173B
4-((1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzene
sulfonamide
[0518] To Compound 173A (0.24 g) in methanol (3 ml) was added 3
.ANG. molecular sieves (0.1 g), followed sequentially by acetic
acid (0.31 ml), (1-ethoxycyclopropoxy)trimethylsilane (0.64 ml),
and sodium cyanoborohydride (0.148 g). The reaction was heated
under reflux overnight. After cooling, the reaction mixture was
loaded onto a silica gel column. After drying, the column was
eluted with 100:2:0.2 ethyl acetate/methanol/NH.sub.4OH to give the
title compound.
Compound 173C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0519] The title compound was prepared by substituting Compound
173B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H),
8.33 (s, 1H), 8.01 (m, 2H), 7.53 (d, 1H), 7.48-7.49 (m, 2H),
7.34-7.38 (m, 3H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.38 (dd, 1H), 6.21
(d, 1H), 4.32 (d, 2H), 3.70-3.77 (m, 2H), 3.07 (s, 4H), 2.92 (s,
2H), 2.80 (s, 2H), 2.58 (s, 2H), 2.25 (s, 4H), 2.13-2.16 (m 2H),
1.38 (t, 2H), 0.92 (s, 6H), 0.40-0.49 (m, 4H).
Compound 174
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo-
[2,3-b]pyridin-5-yloxy)benzamide
[0520] A suspension of Compound 53A (120 mg),
(4-methoxyphenyl)methanamine (31 mg) and Hunig's Base (0.159 ml) in
dimethylsulfoxide (2 ml) was heated for 2 hours at 150.degree. C.
in a Biotage Initiator microwave reactor. The reaction mixture was
diluted with methanol (2 ml) and purified by reverse phase HPLC
(C8, 30%-100% CH.sub.3CN/water/0.1% trifluoroacetic acid). .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.07 (s, 1H), 9.32 (d,
1H), 9.17 (t, 1H), 8.43 (d, 1H), 8.28 (dd, 1H), 8.08 (d, 1H),
7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.38 (d, 2H), 7.07 (d, 2H),
6.97-7.02 (m, 2H), 6.90 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49
(dd, 1H), 4.55 (d, 2H), 3.68 (s, 3H), 3.03-3.09 (m, 4H), 2.77 (s,
2H), 2.26 (t, 2H), 2.10-2.17 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H),
0.93 (s, 6H).
Compound 175
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[3-(trifluoromethoxy)benzyl]amino}phenyl)sulfonyl]-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0521] The title compound was prepared by substituting
(3-trifluoromethoxyphenyl)methanamine for
(4-methoxyphenyl)methanamine in the procedure for Compound 174.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 13.06 (s, 1H), 9.38
(t, 1H), 9.31 (d, 1H), 8.42 (d, 1H), 8.28 (dd, 1H), 8.08 (d, 1H),
7.65 (ddd, 2H), 7.41-7.46 (m, 3H), 7.36-7.40 (m, 2H), 7.07 (d, 2H),
6.88 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (d, 1H), 4.73 (d,
2H), 3.02-3.08 (m, 4H), 2.77 (s, 2H), 2.22-2.28 (m, 2H), 2.09-2.16
(m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 176
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo-
[2,3-b]pyridin-5-yloxy)benzamide
[0522] The title compound was prepared by substituting
(3-methoxyphenyl)methanamine for (4-methoxyphenyl)methanamine in
the procedure for Compound 174. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 13.06 (s, 1H), 9.27-9.32 (m, 2H), 8.42
(d, 1H), 8.26 (dd, 1H), 8.08 (d, 1H), 7.64-7.67 (m, 2H), 7.44 (d,
2H), 7.32 (t, 1H), 7.14 (s, 1H), 7.04-7.09 (m, 3H), 6.88-6.94 (m,
2H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.48-6.50 (m, 1H), 4.64 (d, 2H),
3.68 (s, 3H), 3.03-3.09 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H),
2.10-2.18 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 177
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0523] The title compound was prepared by substituting
(4-difluoromethoxyphenyl)methanamine for
(4-methoxyphenyl)methanamine in the procedure for Compound 174.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 13.06 (s, 1H), 9.32
(d, 1H), 9.28 (t, 1H), 8.42 (d, 1H), 8.28 (dd, 1H), 8.07 (d, 1H),
7.66 (t, 1H), 7.64 (d, 1H), 7.58 (s, 1H), 7.44 (s, 2H), 7.26 (s,
1H), 7.25 (d, 1H), 7.07 (d, 2H), 6.87 (d, 1H), 6.74 (dd, 1H), 6.52
(d, 1H), 6.49 (dd, 1H), 4.64 (d, 2H), 3.03-3.10 (m, 4H), 2.77 (s,
2H), 2.26 (t, 2H), 2.11-2.17 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H),
0.93 (s, 6H).
Compound 178
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxaspiro[4.5]dec-8-ylamino)-3-nitrophenyl]sulfonyl}-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0524] The title compound was prepared by substituting
1,4-dioxa-spiro[4.5]dec-8-ylamine for 1-acetylpiperidin-4-amine in
the procedure for Compound 53B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (br s, 1H), 8.55 (d, 1H),
8.26 (d, 1H), 8.04 (d, 1H), 7.81 (dd, 1H), 7.54-7.46 (m, 3H), 7.35
(d, 2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (m, 1H),
6.19 (d, 1H), 3.89 (s, 4H), 3.78 (m, 1H), 3.07 (br s, 4H), 2.78 (br
s, 2H), 2.28-2.11 (m, 6H), 2.00-1.88 (m, 4H), 1.75-1.57 (m, 4H),
1.54-1.35 (m, 4H), 0.92 (s, 6H).
Compound 179
trans-N-[(4-{[4-(acetylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 179A
tert-butyl trans-4-acetamidocyclohexylcarbamate
[0525] Tert-butyl (trans)-4-aminocyclohexylcarbamate (1.500 g) and
triethylamine (2.93 ml, 2.125 g) were added to dichloromethane and
stirred until the tert-butyl (trans)-4-aminocyclohexylcarbamate had
dissolved completely. Acetyl chloride (0.577 g) was added slowly,
and the solution was stirred at room temperature for 16 hours. The
solvent was removed, and the residue taken up in ethyl acetate,
washed with pH 4 buffer, washed with brine, dried with anhydrous
sodium sulfate, and filtered. The filtrate was concentrated under
vacuum.
Compound 179B
N-(trans-4-aminocyclohexyl)acetamide
[0526] The title compound was prepared by substituting Compound
179A for Compound 1A in the procedure for Compound 1B.
Compound 179C
trans-N-[(4-{[4-(acetylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0527] The title compound was prepared by substituting Compound
179B for 1-acetylpiperidin-4-amine in the procedure for Compound
53B. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67
(br s, 1H), 8.55 (d, 1H), 8.20 (d, 1H), 8.04 (d, 1H), 7.82-7.76 (m,
2H), 7.53-7.46 (m, 3H), 7.35 (d, 2H), 7.16 (d, 1H), 7.04 (d, 2H),
6.68 (dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 3.57 (m, 2H), 3.07 (br
s, 4H), 2.75 (br s, 2H), 2.28-2.10 (m, 6H), 2.03-1.94 (m, 4H), 1.83
(d, 2H), 1.80 (s, 3H), 1.55-1.24 (m, 6H), 0.92 (s, 6H).
Compound 180
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 180A
(R)-tert-butyl 1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate
[0528] To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate
(500 mg) and 1,1-difluoro-2-iodoethane (618 mg) in
N,N-dimethylformamide (6 ml) was added
N-ethyl-N-isopropylpropan-2-amine (1.403 ml) and the mixture was
stirred at 70.degree. C. for 72 hours. The reaction mixture was
concentrated and the crude product was purified on silica gel with
methanol/dichloromethane.
Compound 180B
(R)-1-(2,2-difluoroethyl)pyrrolidin-3-amine
[0529] To a solution of Compound 180A (525 mg) in a mixture of
dichloromethane (3 ml) and methanol (4.0 ml) was added hydrogen
chloride, 4M in dioxane (5.24 ml) and the reaction was stirred for
1.5 hours. The reaction was concentrated and the crude material was
taken up in dichloromethane and the solvent evaporated, then taken
up in ether and the solvent evaporated, and then dried on high
vacuum.
Compound 180C
(R)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzene
sulfonamide
[0530] The title compound was prepared by substituting Compound
180B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 180D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0531] The title compound was prepared by substituting Compound
180C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.02 (m, 1H), 9.27 (d,
1H), 8.55 (d, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.10 (d, 1H),
7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.83 (d, 1H), 6.75
(dd, 1H), 6.54 (m, 1H), 6.48 (m, 1H), 6.04-6.29 (m, 1H), 4.06 (m,
1H), 3.07 (m, 4H), 2.83-2.95 (m, 4H), 2.74-2.82 (m, 3H), 2.47 (m,
1H), 2.09-2.30 (m, 8H), 1.97 (s, 2H), 1.67 (m, 1H), 1.39 (t, 2H),
0.93 (s, 6H).
Compound 181
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3S)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)s-
ulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 181A
(S)-tert-butyl 1-(2-fluoroethyl)pyrrolidin-3-ylcarbamate
[0532] The title compound was prepared by substituting
1-fluoro-2-iodoethane for 1,1-difluoro-2-iodoethane and
(S)-tert-butyl pyrrolidin-3-ylcarbamate for (R)-tert-butyl
pyrrolidin-3-ylcarbamate in the procedure for Compound 180A.
Compound 181B
(S)-1-(2-fluoroethyl)pyrrolidin-3-amine
[0533] The title compound was prepared by substituting Compound
181A for Compound 180A in the procedure for Compound 180B.
Compound 181C
(S)-4-(1-(2-fluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide
[0534] The title compound was prepared by substituting Compound
181B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 181D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3S)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)s-
ulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0535] The title compound was prepared by substituting Compound
181C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (m, 1H), 9.26 (d,
1H), 8.56 (d, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (d, 1H),
7.63-7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.82 (d, 1H), 6.75
(dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 4.60 (t, 1H), 4.51 (t, 1H),
4.05 (m, 1H), 3.07 (m, 4H), 2.84 (m, 1H), 2.66-2.79 (m, 6H), 2.39
(q, 1H), 2.20-2.29 (m, 3H), 2.15 (m, 5H), 1.97 (s, 2H), 1.66 (m,
1H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 182
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 182A
(S)-tert-butyl 1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate
[0536] The title compound was prepared by substituting
(S)-tert-butyl pyrrolidin-3-ylcarbamate for (R)-tert-butyl
pyrrolidin-3-ylcarbamate in the procedure for Compound 180A.
Compound 182B
(S)-1-(2,2-difluoroethyl)pyrrolidin-3-amine
[0537] The title compound was prepared by substituting Compound
182A for Compound 180A in the procedure for Compound 180B.
Compound 182C
(S)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamid-
e
[0538] The title compound was prepared by substituting Compound
182B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 182D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0539] The title compound was prepared by substituting Compound
182C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.02 (m, 1H), 9.27 (d,
1H), 8.54 (d, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H),
7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.82 (d, 1H), 6.75
(dd, 1H), 6.54 (m, 1H), 6.48 (m, 1H), 6.04-6.29 (m, 1H), 4.06 (m,
1H), 3.07 (m, 4H), 2.83-2.95 (m, 4H), 2.74-2.82 (m, 3H), 2.47 (m,
1H), 2.09-2.30 (m, 8H), 1.97 (s, 2H), 1.67 (m, 1H), 1.39 (t, 2H),
0.93 (s, 6H).
Compound 183
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)s-
ulfonyl]-2-(1H-pyrrolo[2,b]pyridin-5-yloxy)benzamide
Compound 183A
(R)-tert-butyl 1-(2-fluoroethyl)pyrrolidin-3-ylcarbamate
[0540] The title compound was prepared by substituting
1-fluoro-2-iodoethane for 1,1-difluoro-2-iodoethane in the
procedure for Compound 180A.
Compound 183B
(R)-1-(2-fluoroethyl)pyrrolidin-3-amine
[0541] The title compound was prepared by substituting Compound
183A for Compound 180A in the procedure for Compound 180B.
Compound 183C
(R)-4-(1-(2-fluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzene
sulfonamide
[0542] The title compound was prepared by substituting Compound
183B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 183D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)s-
ulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0543] The title compound was prepared by substituting Compound
183C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (m, 1H), 9.26 (d,
1H), 8.56 (d, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (d, 1H),
7.63-7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.83 (d, 1H), 6.75
(dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 4.60 (t, 1H), 4.50 (t, 1H),
4.04 (m, 1H), 3.07 (m, 4H), 2.84 (m, 1H), 2.66-2.79 (m, 6H), 2.39
(q, 1H), 2.19-2.28 (m, 3H), 2.14 (m, 5H), 1.97 (s, 2H), 1.66 (m,
1H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 184
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}phenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 184A
(S)-tert-butyl
3-((2-nitro-4-sulfamoylphenoxy)methyl)pyrrolidine-1-carboxylate
[0544] To a solution of (S)-tert-butyl
3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.300 g) in
tetrahydrofuran (5 ml) was added sodium hydride (0.238 g). After
stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.295
g) was added and reaction stirred at room temperature. After 1
hour, the reaction was partitioned between water (25 ml) and
dichloromethane (50 ml) and the reaction quenched with 1N aqueous
HCl (5.96 ml). The organic layer was separated, dried over
magnesium sulfate, filtered, and concentrated. Silica gel
chromatography (Reveleris 12 g) eluting with a gradient of 0.2% to
2% methanol/dichloromethane over 30 minutes (flow=36 m/minute) gave
the title compound.
Compound 184B
(S)-3-nitro-4-((1-(oxetan-3-yl)pyrrolidin-3-yl)methoxy)benzene
sulfonamide
[0545] To (S)-tert-butyl
3-((2-nitro-4-sulfamoylphenoxy)methyl)pyrrolidine-1-carboxylate
(0.433 g) was added hydrogen chloride (4.0M in dioxane, 1.0 ml).
After stirring for 1 hour, the reaction was concentrated and
partitioned between dichloromethane (50 ml) and saturated aqueous
NaHCO.sub.3 solution (50 ml). The aqueous layer was separated and
concentrated. The residue was triturated with methanol (100 ml),
filtered and concentrated and treated with sodium cyanoborohyde
(0.068 g) and cyclobutanone (0.078 g) and stirred overnight. The
reaction was partitioned between dichloromethane (50 ml) and water
(25 ml) and saturated aqueous NaHCO.sub.3 (10 ml). The organic
layer was dried over magnesium sulfate, filtered, and concentrated
to give the title compound.
Compound 184C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}phenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0546] The title compound was prepared by substituting Compound
184B for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.64 (s, 1H), 11.45-11.01 (m,
1H), 8.30 (d, 1H), 7.98 (dd, 2H), 7.60-7.43 (m, 3H), 7.33 (t, 3H),
7.04 (d, 2H), 6.74-6.59 (m, 1H), 6.37 (dd, 1H), 6.21 (d, 1H), 4.49
(td, 2H), 4.33 (s, 1H), 4.13 (dd, 2H), 3.79 (s, 2H), 3.44 (dd, 2H),
3.07 (s, 4H), 2.74 (d, 6H), 2.19 (d, 6H), 1.98 (d, 2H), 1.74-1.52
(m, 1H), 1.39 (t, 2H), 0.92 (s, 6H).
Compound 185
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo-
[2,3-b]pyridin-5-yloxy)benzamide
[0547] The title compound was prepared by substituting
(4-hydroxyphenyl)methanamine for (4-methoxyphenyl)methanamine in
the procedure for Compound 174. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 13.06 (s, 1H), 11.67 (bs, 1H), 9.32 (d,
1H), 9.14 (s, 1H), 8.44 (d, 1H), 8.28 (dd, 1H), 8.09 (d, 1H),
7.65-7.68 (m, 2H), 7.44 (d, 2H), 7.37-7.41 (m, 2H), 7.19 (s, 2H),
7.07 (d, 2H), 6.93 (d, 1H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.49 (dd,
1H), 4.54 (d, 2H), 3.02-3.09 (m, 4H), 2.77 (s, 2H), 2.22-2.29 (m,
2H), 2.10-2.17 (m, 4H), 1.97 (d, 2H), 1.39 (t, 2H), 0.94 (s,
6H).
Compound 186
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-hydroxybenzyl)a min
o]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0548] The title compound was prepared by substituting
(3-hydroxyphenyl)methanamine for (4-methoxyphenyl)methanamine in
the procedure for Compound 174. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 13.06 (s, 1H), 11.67 (bs, 1H), 9.27-9.32
(m, 2H), 8.43 (d, 1H), 8.20 (dd, 1H), 8.08 (d, 1H), 7.66 (t, 2H),
7.44 (d, 2H), 7.33 (t, 1H), 7.25 (s, 1H), 7.13 (dd, 1H), 7.07 (d,
2H), 6.98 (d, 1H), 6.88 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49
(dd, 1H), 4.64 (d, 2H), 3.02-3.09 (m, 4H), 2.77 (s, 2H), 2.22-2.28
(m, 2H), 2.09-2.16 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s,
6H).
Compound 187
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0549] The title compound was prepared by substituting
(3-difluoromethoxyphenyl)methanamine for
(4-methoxyphenyl)methanamine in the procedure for Compound 174.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 13.06 (s, 1H), 9.34
(t, 1H), 9.30 (d, 1H), 8.42 (d, 1H), 8.26 (dd, 1H), 8.08 (d, 1H),
7.66 (ddd, 2H), 7.40-7.45 (m, 3H), 7.36 (t, 1H), 7.27-7.30 (m, 2H),
7.19 (d, 1H), 7.07 (d, 2H), 6.87 (d, 1H), 6.74 (dd, 1H), 6.52 (d,
1H), 6.49 (dd, 1H), 4.69 (d, 2H), 3.02-3.08 (m, 4H), 2.77 (s, 2H),
2.26 (t, 2H), 2.09-2.16 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93
(s, 6H).
Compound 188
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-{[cis-3-morpholin-4-ylcyclopentyl]methyl}amino)-3-nitrophenyl]-
sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 188A
cis-methyl 3-morpholinocyclopentanecarboxylate
[0550] The title compound was prepared by substituting methyl
3-oxocyclopentanecarboxylate for 4'-chlorobiphenyl-2-carboxaldehyde
and morpholine for tert-butyl piperazine-1-carboxylate in the
procedure for Compound 1A.
Compound 188B
cis-3-morpholino cyclopentyl)methanol
[0551] The title compound was prepared by substituting Compound
188A for Compound 101C in the procedure for Compound 101D.
Compound 188C
4-((cis-3-morpholino
cyclopentyl)methoxy)-3-nitrobenzenesulfonamide
[0552] The title compound was prepared by substituting Compound
188B for (1,4-dioxan-2-yl)methanol in the procedure for Compound
12A.
Compound 188D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[cis-3-morpholin-4-ylcyclopentyl]methyl}amino)-3-nitrophenyl-
]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0553] The title compound was prepared by substituting Compound
188C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.57 (s, 1H),
8.17 (m, 1H), 7.94 (m, 1H), 7.82 (m, 1H), 7.56 (d, 1H), 7.44 (t,
1H), 7.34 (m, 3H), 7.16 (m, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.33
(m, 1H), 6.24 (d, 1H), 4.06 (m, 2H), 3.62 (m, 4H), 3.03 (m, 4H),
2.75 (s, 2H), 2.35 (m, 2H), 2.19 (m, 6H), 2.03 (m, 2H), 1.96 (s,
2H), 1.78 (m, 2H), 1.51 (m, 4H), 1.39 (t, 2H), 0.93 (s, 6H)
Compound 189
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-{[4-({4-[(methylsulfonyl)amino]cyclohexyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 189A
trans-(4-methanesulfonylamino-cyclohexyl)-carbamic acid tert-butyl
ester
[0554] The title compound was prepared by substituting
methanesulfonyl chloride for acetyl chloride in the procedure for
Compound 179A.
Compound 189B
trans-N-(4-aminocyclohexyl)-methanesulfonamide
[0555] The title compound was prepared by substituting Compound
189A for Compound 1A in the procedure for Compound 1B.
Compound 189C
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-{[4-({4-[(methylsulfonyl)amino]cyclohexyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0556] The title compound was prepared by substituting Compound
189B for 1-acetylpiperidin-4-amine in the procedure for Compound
53B. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68
(br s, 1H), 8.55 (d, 1H), 8.18 (d, 1H), 8.04 (d, 1H), 7.84 (d, 1H),
7.79 (dd, 1H), 7.56-7.47 (m, 3H), 7.34 (d, 2H), 7.16 (d, 1H), 7.04
(d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 3.56 (m, 1H),
3.17 (m, 1H), 3.07 (br s, 4H), 2.93 (s, 3H), 2.75 (br s, 2H),
2.28-2.10 (m, 6H), 2.05-1.90 (m, 6H), 1.55-1.32 (m, 6H), 0.92 (s,
6H).
Compound 190
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfo-
nyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 190A
4-(1-cyclopropylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzene
sulfonamide
[0557] The title compound was prepared as described in the
procedure for Compound 17A by replacing
(tetrahydropyran-4-yl)methylamine with
4-amino-1-cyclopropylpiperidine.
Compound 190B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({-4-[(1-cyclopropylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulf-
onyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0558] The title compound was prepared as described in the
procedure for Compound 1G by replacing Compound 1E and Compound 1F
with Compound 3J and Compound 190A, respectively. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H), 8.13 (d,
1H), 8.02 (d, 1H), 7.91 (m, 1H), 7.48 (m, 3H), 7.34 (d, 2H), 7.04
(d, 2H), 6.67 (m, 2H), 6.38 (dd, 1H), 6.19 (d, 1H), 3.64 (m, 1H),
3.13 (m, 5H), 2.73 (m, 5H), 2.22 (m, 6H), 1.92 (m, 5H), 1.70 (m,
1H), 1.41 (m, 5H), 0.94 (s, 6H), 0.41 (m, 4H).
Compound 191
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 191A
3-nitro-4-(piperidin-4-ylmethoxy)benzenesulfonamide
[0559] To a solution of tert-butyl
4-(hydroxymethyl)piperidine-1-carboxylate (0.300 g) in
tetrahydrofuran (5 ml) was added sodium hydride (0.223 g). After
stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.276
g) was added and reaction stirred at room temperature. After 1 hour
the reaction was partitioned between water (25 ml) and
dichloromethane (50 ml) and the reaction quenched with 1N aqueous
HCl (5.57 ml). The organic layer was separated, dried over
magnesium sulfate, filtered, and concentrated. Treatment with HCl
(4.0M in dioxane, 2 ml) and methanol (2 ml) for 1 hour, followed by
concentration, trituration with dichloromethane and filtration gave
the title compound.
Compound 191B
3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)methoxy)benzenesulfonamide
[0560] To a suspension of
3-nitro-4-(piperidin-4-ylmethoxy)benzenesulfonamide (0.100 g) and
cyclobutanone (0.030 g) in methanol (1 ml) was added sodium
cyanoborohydride (0.027 g). After stirring overnight, the reaction
was quenched with saturated NaHCO.sub.3 (5 ml) and extracted into
dichloromethane (2.times.10 ml). The organic layer was dried over
magnesium sulfate, filtered, and concentrated to give the title
compound.
Compound 191C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0561] The title compound was prepared by substituting Compound
191B for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.64 (s, 1H), 11.46-10.46 (m,
1H), 8.29 (s, 1H), 8.00 (d, 2H), 7.61-7.41 (m, 3H), 7.35 (d, 3H),
7.04 (d, 2H), 6.66 (d, 1H), 6.37 (s, 1H), 6.21 (s, 1H), 4.67-4.40
(m, 4H), 4.08 (d, 2H), 3.06 (s, 4H), 2.78 (s, 4H), 2.19 (m, 6H),
1.96 (s, 4H), 1.79 (m, 4H), 1.39 (s, 4H), 0.93 (s, 6H).
Compound 192
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxy]-3-
-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 192A
4-((4-fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-3-nitrobe-
nzenesulfonamide
[0562] A mixture of Compound 173A (0.4 g),
dihydro-2H-pyran-4(3H)-one (0.179 g), sodium cyanoborohydride
(0.112 g), and acetic acid (0.5 ml) in tetrahydrofuran (3 ml) was
stirred overnight. The solvents were removed under reduced
pressure. The residue was purified with flash column chromatography
on silica gel eluting with 100:5:0.5 ethyl
acetate/methanol/NH.sub.4OH to give the desired product.
Compound 192B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxy]-3-
-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0563] The title compound was prepared by substituting Compound
192A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.58 (s, 1H),
8.25 (s, 1H), 7.96 (d, 1H), 7.93 (d, 1H), 7.57 (d, 1H), 7.45 (t,
1H), 7.34-7.37 (m, 3H), 7.26 (d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H),
6.34 (dd, 1H), 6.23 (d, 1H), 4.34 (d, 2H), 3.93 (dd, 2H), 3.03 (s,
6H), 2.76 (s, 4H), 2.09-2.22 (m, 6H), 1.96 (s, 2H), 1.52-1.27 (m,
2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 193
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluoro-1-tetrahydrofuran-3-ylpiperidin-4-yl)methoxy]-3-nit-
rophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 193A
4-((4-fluoro-1-(tetrahydro
furan-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide
[0564] The title compound was prepared by substituting
dihydrofuran-3(2H)-one for dihydro-2H-pyran-4(3H)-one in the
procedure for Compound 192A.
Compound 193B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluoro-1-tetrahydro
furan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2-
,3-b]pyridin-5-yloxy)benzamide
[0565] The title compound was prepared by substituting Compound
193A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.63 (s, 1H),
8.31 (s, 1H), 7.99-8.00 (m, 2H), 7.54 (d, 1H), 7.46-7.48 (m, 2H),
7.34-7.35 (m, 3H), 7.05 (d2H), 6.66 (dd, 1H), 6.37 (dd, 1H), 6.21
(d, 1H), 4.34 (d, 2H), 3.76-3.83 (m, 3H), 3.62-3.65 (m, 2H), 3.03
(s, 4H), 2.79 (s, 4H), 2.24 (s, 2H), 2.15 (s, 2H), 1.84-1.99 (m,
8H), 1.52-1.27 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 194
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-fluoro-1-(methylsulfonyl)piperidin-4-yl]methoxy}-3-nitroph-
enyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 194A
4-((4-fluoro-1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-nitrobenzene
sulfonamide
[0566] A mixture of Compound 173A (0.4 g), methanesulfonyl chloride
(0.113 g), and triethylamine (0.64 ml) in dichloromethane (5 ml)
was stirred overnight. The reaction mixture was loaded onto a
silica gel column and eluted with 100:1 ethyl acetate:methanol to
give the clean product.
Compound 194B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-fluoro-1-(methylsulfonyl)piperidin-4-yl]methoxy}-3-nitroph-
enyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0567] The title compound was prepared by substituting Compound
194A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H),
8.37 (s, 1H), 8.06 (d, 1H), 8.02 (d, 1H), 7.49-7.53 (m, 3H), 7.42
(d, 1H), 7.35 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.38-6.39 (m,
1H), 6.21 (d, 1H), 4.40 (d, 2H), 3.51-3.54 (m, 2H), 3.09 (s, 4H),
2.96-3.01 (m, 4H), 2.92 (s, 3H), 2.82 (s, 2H), 2.25-2.34 (m, 4H),
2.13-2.16 (m, 6H), 2.01-2.07 (m, 2H0, 1.99 (s, 2H), 1.39 (t, 2H),
0.93 (s, 6H).
Compound 195
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[(3R)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 195A
(R)-tert-butyl
3-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)--
4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nit-
rophenylamino)methyl)pyrrolidine-1-carboxylate
[0568] The title compound was prepared by substituting
(R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate for
1-acetylpiperidin-4-amine in the procedure for Compound 53B.
Compound 195B
(S)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(pyrrolidin-3-ylm-
ethylamino)phenylsulfonyl)benzamide
[0569] The title compound was prepared by substituting Compound
195A for Compound 1A in the procedure for Compound 1B.
Compound 195C
(R)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((1-(oxetan-3-yl)-
pyrrolidin-3-yl)methylamino)phenylsulfonyl)benzamide
[0570] The title compound was prepared by substituting Compound
195B for tert-butyl piperazine-1-carboxylate and oxetan-3-one for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67
(s, 1H), 8.81 (t, 1H), 8.55 (d, 1H), 8.02 (d, 1H), 7.79 (dd, 1H),
7.50 (m, 3H), 7.35 (m, 2H), 7.04 (m, 3H), 6.67 (dd, 1H), 6.39 (m,
1H), 6.19 (d, 1H), 4.57 (m, 2H), 4.48 (m, 2H), 3.68 (m, 2H), 3.30
(m, 2H), 3.06 (m, 4H), 2.74 (m, 3H), 2.56 (m, 3H), 2.44 (m, 1H),
2.18 (m, 5H), 1.95 (m, 3H), 1.58 (m, 1H), 1.36 (m, 2H), 0.94 (s,
6H).
Compound 196
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-hydroxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 196A
trans-4-(4-(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-3-nitrobenzenes-
ulfonamide
[0571] The title compound was prepared as described in the
procedure for Compound 12A by replacing (1,4-dioxan-2-yl)methanol
with trans-(4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol (made
according to the procedures in WO 2008/124878, incorporated herein
by reference).
Compound 196B
trans-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-(((1r,4r)-4-(tert-butyldim-
ethylsilyloxy)cyclohexyl)methoxy)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide
[0572] The title compound was prepared as described in the
procedure for Compound 1G using Compound 196A in place of Compound
1F and Compound 3J in place of Compound 1E.
Compound 196C
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-hydroxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0573] Compound 196B (150 mg) in dichloromethane (5 ml) and
methanol (2 ml) was treated with 10% aqueous HCl (3 ml) for 1 hour
and concentrated. The residue was purified by reverse phase HPLC on
a C18 column using a gradient of 40-60% acetonitrile in 0.1%
trifluoroacetic acid water to give the title compound as a
trifluoroacetate salt. The trifluoroacetic acid salt was dissolved
in dichloromethane (30 ml) and washed with 50% aqueous NaHCO.sub.3.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated to give the title compound. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.27
(s, 1H), 8.34 (d, 1H), 7.95-8.08 (m, 2H), 7.47-7.55 (m, 3H),
7.32-7.40 (m, 3H), 7.01-7.07 (m, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H),
6.20 (d, 1H), 4.54 (d, 1H), 3.96-4.06 (m, 2H), 3.10 (s, 4H), 2.84
(s, 2H), 2.05-2.39 (m, 6H), 1.96 (s, 2H), 1.46-1.93 (m, 5H), 1.39
(t, 2H), 0.98-1.29 (m, 4H), 0.92 (s, 6H).
Compound 197
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({4-[3-(dimethylamino)propoxy]benzyl}amino)-3-nitrophenyl]sulf-
onyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 197A
3-(4-(aminomethyl)phenoxy)-N,N-dimethylpropan-1-amine
[0574] 4-(3-(Dimethylamino)propoxy)benzonitrile (300 mg) in
methanol (20 ml) was treated with Raney nickel (wet, 1.5 g) under
H.sub.2 (30 psi) for 4 hour. The insoluble material was filtered
off and the filtrate was concentrated to provide the title
compound.
Compound 197B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({4-[3-(dimethylamino)propoxy]benzyl}amino)-3-nitrophenyl]sulf-
onyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0575] The title compound was prepared as described in the
procedure for Compound 120B using Compound 197A in place of
Compound 120A. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.56 (s, 1H), 8.80 (t, 1H), 8.42 (d, 1H), 7.93 (d, 1H),
7.52-7.61 (m, 2H), 7.41-7.47 (m, 1H), 7.26-7.36 (m, 5H), 7.03-7.08
(m, 2H), 6.89 (d, 2H), 6.73 (d, 1H), 6.61 (dd, 1H), 6.31 (dd, 1H),
6.22 (d, 1H), 4.52 (d, 2H), 3.99 (t, 2H), 2.90-3.05 (m, 7H), 2.72
(s, 2H), 2.61 (s, 6H), 2.09-2.24 (m, 6H), 1.89-2.04 (m, 5H), 1.38
(t, 2H), 0.92 (s, 6H).
Compound 198
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(2-morpholin-4-ylethoxy)benzyl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 198A
(4-(2-morpholinoethoxy)phenyl)methanamine
[0576] The title compound was prepared as described in the
procedure for Compound 197A using
4-(2-morpholinoethoxy)benzonitrile in place of
4-(3-(dimethylamino)propoxy)benzonitrile.
Compound 198B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(2-morpholin-4-ylethoxy)benzyl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0577] The title compound was prepared as described in the
procedure for Compound 120B using Compound 198A in place of
Compound 120A. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.69 (s, 1H), 9.00 (t, 1H), 8.56 (d, 1H), 8.02 (d, 1H),
7.72 (dd, 1H), 7.46-7.54 (m, 3H), 7.27-7.36 (m, 4H), 7.01-7.07 (m,
2H), 6.89-6.95 (m, 3H), 6.66 (dd, 1H), 6.38 (dd, 1H), 6.18 (d, 1H),
4.56 (d, 2H), 4.07 (t, 2H), 3.54-3.61 (m, 4H), 3.06 (s, 4H),
2.71-2.78 (m, 4H), 2.07-2.24 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H),
0.92 (s, 6H).
Compound 199
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(E)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfo-
nyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 199A
4-[((E)-4-hydroxy-adamantan-1-ylmethyl)-amino]-3-nitro-benzene
sulfonamide
[0578] 4-Fluoro-3-nitrobenzenesulfonamide (0.5 g) and
5-(aminomethyl)adamantan-2-ol (0.6 g) in tetrahydrofuran (10 ml)
were treated with triethylamine (1 ml) overnight. The reaction
mixture was concentrated and the residue was purified by reverse
phase HPLC, eluting 40-60% acetonitrile in 0.1 trifluoroacetic acid
water to give two isomers, which were temporarily assigned as
Compound 199A and Compound 199B, respectively.
Compound 199B
4-[((Z)-4-hydroxy-adamantan-1-ylmethyl)-amino]-3-nitro-benzenesulfonamide
[0579] 4-Fluoro-3-nitrobenzenesulfonamide (0.5 g) and
5-(aminomethyl)adamantan-2-ol (0.6 g) in tetrahydrofuran (10 ml)
were treated with triethylamine (1 ml) overnight. The reaction
mixture was concentrated and the residue was purified by reverse
phase HPLC, eluting 40-60% acetonitrile in 0.1 trifluoroacetic acid
water to give two isomers, which were temporarily assigned as
Compound 199A and Compound 199B, respectively.
Compound 199C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(E)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfo-
nyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0580] The title compound was prepared as described in the
procedure for Compound 11D using Compound 199A in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68
(s, 1H), 11.40 (s, 1H), 8.55 (d, 1H), 8.50 (t, 1H), 8.03 (d, 1H),
7.77 (dd, 1H), 7.46-7.54 (m, 3H), 7.31-7.38 (m, 2H), 7.14 (d, 1H),
7.01-7.06 (m, 2H), 6.68 (dd, 1H), 6.38 (dd, 1H), 6.19 (d, 1H), 4.61
(d, 1H), 3.63 (d, 1H), 3.02-3.16 (m, 6H), 2.75 (s, 2H), 2.17 (d,
6H), 2.04 (d, 2H), 1.95 (s, 2H), 1.76-1.88 (m, 3H), 1.49-1.61 (m,
6H), 1.38 (t, 2H), 1.29 (d, 2H), 0.92 (s, 6H).
Compound 200
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(Z)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfo-
nyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0581] The title compound was prepared as described in the
procedure for Compound 11D using Compound 199B in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68
(s, 1H), 11.39 (s, 1H), 8.55 (d, 1H), 8.51 (t, 1H), 8.04 (d, 1H),
7.77 (dd, 1H), 7.46-7.55 (m, 3H), 7.31-7.37 (m, 2H), 7.14 (d, 1H),
7.01-7.06 (m, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 4.61
(d, 1H), 3.61 (d, 1H), 3.08 (d, 6H), 2.75 (s, 2H), 2.17 (d, 6H),
1.79-1.99 (m, 7H), 1.55-1.69 (m, 4H), 1.49 (s, 2H), 1.38 (t, 2H),
1.22 (d, 2H), 0.92 (s, 6H).
Compound 201
N-({4-[(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy]-3-nitrophenyl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 201A
4-((1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy)-3-nitrobenzene
sulfonamide
[0582] The title compound was prepared as described in the
procedure for Compound 12A by replacing (1,4-dioxan-2-yl)methanol
with (1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethanol.
Compound 201B
N-({4-[(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy]-3-nitrophenyl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0583] The title compound was prepared as described in the
procedure for Compound 11D using Compound 201A in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 1H), 8.35 (d, 1H), 7.95-8.10 (m, 2H), 7.47-7.58 (m, 3H),
7.30-7.45 (m, 3H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.40 (d, 1H),
5.92-6.23 (m, 3H), 3.65-4.39 (m, 3H), 3.00-3.22 (m, 4H), 2.76-2.98
(m, 4H), 2.28 (s, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.71-1.91 (m,
1H), 1.33-1.47 (m, 3H), 1.20-1.32 (m, 2H), 0.92 (s, 6H), 0.50-0.66
(m, 1H).
Compound 202
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0584] Compound 82 (140 mg) was dissolved in dioxane (3.0 ml), and
4-amino-1-methylpyrrolidin-2-one hydrochloride (30 mg) and
triethylamine (0.100 ml) were added. The reaction mixture was
heated at 110.degree. C. for 40 hours. The reaction was
concentrated and the crude material was purified by preparative
HPLC using a C18 column, 250.times.50 mm, 10.mu., and eluting with
a gradient of 20-100% CH.sub.3CN vs. 0.1% trifluoroacetic acid in
water, giving the product as a trifluoroacetate salt. The salt was
dissolved in dichloromethane (6 ml) and washed with 50% aqueous
NaHCO.sub.3. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (s,
1H), 8.74 (d, 1H), 8.37 (br d, 1H), 8.02 (d, 1H), 7.83 (dd, 1H),
7.49 (m, 3H), 7.34 (d, 2H), 7.07 (d, 1H), 7.04 (d, 2H), 6.68 (dd,
1H), 6.38 (m, 1H), 6.21 (d, 1H), 4.46 (m, 1H), 3.81 (dd, 1H), 3.38
(dd, 1H), 3.08 (br m, 4H), 2.82 (dd, 1H), 2.75 (s, 5H), 2.43 (dd,
1H), 2.21 (br m, 4H), 2.16 (br t, 2H), 1.95 (s, 2H), 1.39 (t, 2H),
0.94 (s, 6H).
Compound 203
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}--
3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 203A
4-(((1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]heptan-2-yl)methoxy)-3-nitrob-
enzenesulfonamide
[0585] To a solution of Compound 201A (340 mg) in tetrahydrofuran
(10 ml) and water (1 ml) was added N-methylmorpholine N-oxide (184
mg) and OsO.sub.4 (2.5% in 2-methyl-2-propanol) (1.05 ml). The
reaction mixture was stirred overnight and purified by reverse
phase HPLC to provide two isomers, which were temporarily assigned
as Compound 203A and Compound 203B, respectively.
Compound 203B
4-(((1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.1]heptan-2-yl)methoxy)-3-nitrob-
enzenesulfonamide
[0586] To a solution of Compound 201A (340 mg) in tetrahydrofuran
(10 ml) and water (1 ml) was added N-methylmorpholine N-oxide (184
mg) and OsO.sub.4 (2.5% in 2-methyl-2-propanol) (1.05 ml). The
reaction mixture was stirred overnight and purified by reverse
phase HPLC to provide two isomers, which were temporarily assigned
as Compound 203A and Compound 203B, respectively.
Compound 203C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}--
3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0587] The title compound was prepared as described in the
procedure for Compound 11D using Compound 203A in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68
(s, 1H), 8.33 (s, 1H), 7.97-8.07 (m, 2H), 7.48-7.55 (m, 3H), 7.41
(d, 1H), 7.32-7.37 (m, 2H), 7.02-7.07 (m, 2H), 6.67 (dd, 1H), 6.40
(dd, 1H), 6.20 (d, 1H), 4.58 (dd, 2H), 4.07-4.19 (m, 2H), 3.82 (t,
1H), 3.51 (t, 1H), 3.09 (s, 4H), 2.81 (s, 2H), 2.09-2.34 (m, 8H),
2.04-2.09 (m, 2H), 1.93-2.01 (m, 3H), 1.62-1.77 (m, 2H), 1.39 (t,
2H), 1.11 (d, 1H), 0.92 (s, 6H), 0.67-0.76 (m, 1H).
Compound 204
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}--
3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0588] The title compound was prepared as described in the
procedure for Compound 11D using Compound 203B in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68
(s, 1H), 8.33 (s, 1H), 7.98-8.07 (m, 2H), 7.49-7.54 (m, 3H), 7.41
(d, 1H), 7.32-7.36 (m, 2H), 7.02-7.07 (m, 2H), 6.67 (dd, 1H), 6.40
(dd, 1H), 6.20 (d, 1H), 4.58 (dd, 2H), 4.13 (dd, 2H), 3.82 (t, 1H),
3.51 (t, 1H), 3.09 (s, 4H), 2.81 (s, 2H), 2.09-2.35 (m, 8H), 2.07
(s, 2H), 1.93-2.02 (m, 3H), 1.61-1.80 (m, 2H), 1.39 (t, 2H), 1.11
(d, 1H), 0.92 (s, 6H), 0.66-0.78 (m, 1H).
Compound 205
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(3-oxocyclohexyl)methoxy]phenyl}sulfonyl)-2-(1H-pyrro-
lo[2,3-b]pyridin-5-yloxy)benzamide
Compound 205A
methyl 1,4-dioxaspiro[4.5]decane-7-carboxylate
[0589] To a solution of trimethylsilyltrifluoromethanesulfonate
(0.034 ml) in dry dichloromethane (5 ml) was added
1,2-bis(trimethylsiloxy)ethane (4.55 ml) followed by methyl
3-oxocyclohexanecarboxylate (2.9 g). The reaction mixture was
stirred for 3 hours at -78.degree. C. The reaction mixture was
quenched with dry pyridine (0.5 ml), poured into saturated aqueous
NaHCO.sub.3, and extracted with ether. The ether layer was dried
over Na.sub.2CO.sub.3/Na.sub.2SO.sub.4. The reaction mixture was
concentrated and purified by flash chromatography on silica with 5
to 30% ethyl acetate in hexanes to provide the title compound.
Compound 205B
1,4-dioxaspiro[4.5]decan-7-ylmethanol
[0590] The title compound was prepared by substituting Compound
205A for Compound 101C in the procedure for Compound 101D.
Compound 205C
3-nitro-4-((3-oxocyclohexyl)methoxy)benzene sulfonamide
[0591] Into a 250 ml round-bottomed flask was added sodium hydride
(0.5 g) in tetrahydrofuran (10 ml) and then
1,4-dioxaspiro[4.5]decan-7-ylmethanol (0.5 g) was added. After the
mixture stirred at room temperature for 20 minutes,
4-fluoro-3-nitrobenzenesulfonamide (0.65 g) was added. The mixture
was stirred at room temperature for overnight. Water (20 ml) was
added slowly. The aqueous layer was extracted by dichloromethane
(3.times.20 ml). The combined organic layers were dried over
Na.sub.2SO.sub.4. After filtration, and concentration of the
filtrate, the residue was purified by reverse phase chromatography,
eluting with 30-60% acetonitrile in water with 0.1% trifluoroacetic
acid.
Compound 205D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(3-oxocyclohexyl)methoxy]phenyl}sulfonyl)-2-(1H-pyrro-
lo[2,3-b]pyridin-5-yloxy)benzamide
[0592] The title compound was prepared by substituting Compound
205C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.59 (s, 1H),
8.22 (s, 1H), 7.96 (d, 1H), 7.87 (m, 1H), 7.55 (d, 1H), 7.45 (t,
1H), 7.35 (m, 3H), 7.20 (m, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.34
(m, 1H), 6.23 (d, 1H), 4.07 (d, 2H), 3.04 (m, 4H), 2.76 (s, 2H),
2.35 (m, 2H), 2.20 (m, 8H), 1.96 (m, 4H), 1.58 (m, 2H), 1.39 (t,
2H), 0.93 (s, 6H).
Compound 206
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dien-1-yl]methyl}piper-
azin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 206A
2-chloro-5,5-dimethylcyclohexa-1,3-dienecarbaldehyde
[0593] In a 250 ml round-bottomed flask was added
N,N-dimethylformamide (3.5 ml) in dichloromethane (30 ml), and the
mixture was cooled to -10.degree. C. Phosphoryl trichloride (4 ml)
was added dropwise, and the solution was warmed up to room
temperature. 4,4-Dimethylcyclohex-2-enone (5.5 ml) was then added
slowly, and the mixture was heated to reflux overnight. The
reaction mixture was cooled and quenched with a 0.degree. C.
solution of sodium acetate (25 g in 50 ml water). The aqueous layer
was extracted with diethyl ether (200 ml.times.3). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give the product.
Compound 206B
2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dienecarbaldehyde
[0594] Into a 1 L round-bottomed flask was added Compound 206A (6.8
g), 4-chlorophenylboronic acid (6.5 g), and palladium (II) acetate
(0.2 g) in water (100 ml) to give a suspension. Potassium carbonate
(15 g) and tetrabutylammonium bromide (10 g) were added. After
degassing, the mixture was stirred at 45.degree. C. for 4 hours.
After cooling and filtering though silica gel in a funnel, diethyl
ether (4.times.200 ml) was used to extract the product. The
combined organic layers were dried over Na.sub.2SO.sub.4, and
filtered. The filtrate was concentrated and purified by flash
chromatography on silica with 0-10% ethyl acetate in hexanes to
provide the title compound.
Compound 206C
[0595] Methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimeth-
ylcyclohexa-1,3-dienyl)methyl)piperazin-1-yl)benzoate
[0596] The title compound was prepared by substituting Compound
206B for 4'-chlorobiphenyl-2-carboxaldehyde and Compound 15F for
tert-butyl piperazine-1-carboxylate in the procedure for Compound
1A.
Compound 206D
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethy-
lcyclohexa-1,3-dienyl)methyl)piperazin-1-yl)benzoic acid
[0597] The title compound was prepared by substituting Compound
206C for Compound 101E in the procedure for Compound 101F.
Compound 206E
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dien-1-yl]methyl}piper-
azin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0598] The title compound was prepared by substituting Compound
206D for Compound 3J and Compound 1F for Compound 11B in the
procedure for Compound 11D. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.61 (s, 1H), 8.49 (m, 2H),
7.99 (m, 1H), 7.72 (m, 1H), 7.53 (d, 1H), 7.41 (m, 4H), 7.12 (d,
2H), 6.99 (m, 1H), 6.66 (dd, 1H), 6.35 (m, 1H), 6.23 (d, 1H), 5.74
(d, 1H), 5.58 (d, 1H), 3.84 (m, 2H), 3.26 (m, 4H), 3.06 (m, 4H),
2.88 (s, 2H), 2.24 (m, 6H), 1.61 (m, 2H), 1.26 (m, 3H), 1.00 (s,
6H).
Compound 207
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-
)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 207A
(R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-amine
[0599] The title compound was prepared by substituting
(R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl
azetidin-3-ylcarbamate in the procedure for Compound 151A.
Compound 207B
(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-nitrobenzenesulf-
onamide
[0600] The title compound was prepared by substituting Compound
207A for Compound 151A in the procedure for Compound 151B.
Compound 207C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-
)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0601] The title compound was prepared by substituting Compound
207B for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 11.52-11.24 (m,
1H), 8.55 (d, 1H), 8.37 (d, 1H), 8.03 (d, 1H), 7.83 (dd, 1H),
7.57-7.45 (m, 3H), 7.34 (d, 2H), 7.06 (t, 3H), 6.67 (d, 1H), 6.38
(dd, 1H), 6.20 (d, 1H), 4.70 (d, 2H), 4.54 (d, 2H), 4.23 (s, 1H),
3.11-2.87 (m, 7H), 2.74 (dd, 4H), 2.35-2.13 (m, 7H), 1.95 (s, 2H),
1.70 (s, 1H), 1.39 (d, 2H), 0.92 (s, 6H).
Compound 208
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl-
)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 208A
2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-5-iodo-3-(trifluoromethyl)py-
ridine
[0602] A mixture of Compound 37C (0.537 g),
5-iodo-3-(trifluoromethyl)pyridin-2-ol (1.156 g), and
triphenylphosphine (1.574 g) in tetrahydrofuran (20 ml) was cooled
to 0.degree. C. To this solution was added (E)-di-tert-butyl
diazene-1,2-dicarboxylate (0.921 g). The reaction mixture was
stirred overnight. The solvent was removed, and the residue was
purified with column flash chromatography on silica gel eluting
with 4:1 hexanes/ethyl acetate to give the desired product.
Compound 208B
6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)pyridine--
3-sulfonamide
[0603] Compound 207A (1.3 g) in tetrahydrofuran (10 ml) was cooled
to -42.degree. C. with a cold bath of CH.sub.3CN/dry ice. To this
solution was added 2.0 M isopropylmagnesium chloride (1.6 ml)
dropwise over 5 minutes. The reaction mixture was stirred for 30
minutes at -42.degree. C., then allowed to warm to 0.degree. C.
over 10 minutes. The reaction mixture was cooled again to
-42.degree. C., and SO.sub.2 was bubbled though it for 10 minutes.
The reaction mixture was stirred for another 30 minutes. To this
solution was sulfuryl dichloride (0.433 g). On warming to room
temperature, concentrated NH.sub.4OH (10 ml) was added and the
reaction mixture was stirred for another 2 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 brine, dried
over MgSO.sub.4, filtered, and concentrated. The residue was
purified by flash column chromatography on silica gel eluting with
3:1 hexanes/ethyl acetate to give the title compound.
Compound 208C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl-
)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0604] The title compound was prepared by substituting Compound
208B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.61 (s, 1H),
8.72 (s, 1H), 8.36 (s, 1H), 7.98 (d, 1H), 7.55 (d, 1H), 7.42-7.47
(m, 2H), 7.36 (d, 2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.35 (s, 1H),
6.23 (s, 1H), 4.56 (d, 2H), 3.75-3.79 (m, 2H), 3.56-3.61 (m, 2H),
3.09 (s, 4H), 2.32-2.37 (m, 2H), 2.16 (s, 2H), 1.97-1.99 (m, 2H),
1.79-1.86 (m, 4H), 1.40 (t, 2H), 0.93 (s, 6H).
Compound 209
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 209A
(S)-tert-butyl (1-(oxetan-3-yl)pyrrolidin-3-yl)methylcarbamate
[0605] The title compound was prepared by substituting
(R)-tert-butyl pyrrolidin-3-ylmethylcarbamate for tert-butyl
piperazine-1-carboxylate and 3-oxetanone for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 209B
(S)-(1-(oxetan-3-yl)pyrrolidin-3-yl)methanamine
[0606] The title compound was prepared by substituting Compound
209A for (S)-1-tert-butyl 2-methyl
4,4-difluoropyrrolidine-1,2-dicarboxylate in the procedure for
Compound 168A.
Compound 209C
(S)-3-nitro-4-((1-(oxetan-3-yl)pyrrolidin-3-yl)methylamino)benzene
sulfonamide
[0607] The title compound was prepared by substituting
4-fluoro-3-nitrobenzenesulfonamide for
4-chloro-3-nitrobenzenesulfonamide and Compound 209B for
4-methylpiperazin-1-amine dihydrochloride in the procedure for
Compound 6A.
Compound 209D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0608] The title compound was prepared by substituting Compound
209C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.05 (s, 1H), 9.30 (d,
1H), 9.02 (t, 1H), 8.42 (d, 1H), 8.34 (dd, 1H), 8.10 (d, 1H), 7.67
(dd, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.82 (d, 1H), 6.75 (m, 1H),
6.52 (m, 2H), 4.82 (t, 1H), 4.75 (t, 1H), 4.67 (t, 2H), 3.57 (m,
1H), 3.24 (t, 2H), 3.07 (m, 4H), 2.75 (m, 3H), 2.57 (dd, 1H), 2.45
(s, 1H), 2.36 (t, 1H), 2.26 (s, 2H), 2.18 (m, 5H), 1.93 (m, 3H),
1.56 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 210
trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 210A
(4-methoxycyclohexyl)methanol
[0609] The title compound was prepared by substituting
4-methoxycyclohexanecarboxylic acid for 1-tert-butyl 4-ethyl
4-fluoropiperidine-1,4-dicarboxylate in the procedure for Compound
126A.
Compound 210B
trans-5-chloro-6-((4-methoxycyclohexyl)methoxy)pyridine-3-sulfonamide
[0610] The title compound was prepared by substituting Compound
210A for tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 210C
trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0611] The title compound was prepared by substituting Compound
210C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H),
8.50 (s, 1H), 8.17 (s, 1H), 8.02 (d, 1H), 7.49-7.54 (m, 3H), 7.35
(d, 2H), 7.05 (d, 2H), 6.67 (dd, J 1H), 6.39 (s, 1H), 6.21 (s, 1H),
4.20 (d, 2H), 3.23 (s, 3H), 3.06-3.09 (m, 4H), 2.15-2.37 (m, 4H),
1.96-2.03 (m, 4H), 1.74-1.84 (m, 2H), 1.40 (t, 2H), 1.04-1.13 (m,
4H), 0.93 (s, 6H).
Compound 211
cis-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4--
(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 211A
cis-5-chloro-6-((4-methoxycyclohexyl)methoxy)pyridine-3-sulfonamide
[0612] The title compound was isolated as a by-product in the
synthesis of Compound 210B.
Compound 211B
cis-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4--
(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0613] The title compound was prepared by substituting Compound
211A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H),
8.51 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H), 7.49-7.54 (m, 3H), 7.35
(d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.39 (s, 1H), 6.21 (s, 1H),
4.21 (d, 2H), 3.20 (s, 3H), 3.06 (s, 4H), 2.15-2.37 (m, 4H), 1.96
(s, 2H), 1.80-1.84 (m, 2H), 1.50-1.54 (m, 2H), 1.34-1.44 (m, 6H),
0.93 (s, 6H).
Compound 212
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]amino}phenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 212A
(S)-tert-butyl 1-(oxetan-3-yl)pyrrolidin-3-ylcarbamate
[0614] The title compound was prepared by substituting
(S)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl
piperazine-1-carboxylate and 3-oxetanone for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 212B
(S)-1-(oxetan-3-yl)pyrrolidin-3-amine
[0615] The title compound was prepared by substituting Compound
212A for (S)-1-tert-butyl 2-methyl
4,4-difluoropyrrolidine-1,2-dicarboxylate in the procedure for
Compound 168A.
Compound 212C
(S)-3-nitro-4-(1-(oxetan-3-yl)pyrrolidin-3-ylamino)benzenesulfonamide
[0616] The title compound was prepared by substituting
4-fluoro-3-nitrobenzenesulfonamide for
4-chloro-3-nitrobenzenesulfonamide and Compound 212B for
4-methylpiperazin-1-amine dihydrochloride in the procedure for
Compound 6A.
Compound 212D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]amino}phenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0617] The title compound was prepared by substituting Compound
212C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.03 (s, 1H), 9.27 (d,
1H), 8.58 (d, 1H), 8.42 (d, 1H), 8.37 (dd, 1H), 8.09 (d, 1H), 7.67
(t, 1H), 7.64 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.86 (d, 1H),
6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (dd, 1H), 4.67 (m, 4H), 4.09 (m,
1H), 3.59 (m, 1H), 3.07 (m, 4H), 2.77 (s, 2H), 2.69 (m, 2H), 2.62
(dd, 1H), 2.28 (m, 4H), 2.14 (m, 4H), 1.97 (s, 2H), 1.68 (m, 1H),
1.39 (t, 2H), 0.93 (s, 6H).
Compound 213
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[({4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3--
nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 213A
4-((4-(2-(2-methoxyethoxy)ethyl)morpholin-2-yl)methylamino)-3-nitrobenzene-
sulfonamide
[0618] The title compound was prepared by substituting
2-(2'-methoxyethoxy)ethyl bromide for methyl iodide in the
procedure for Compound 134B.
Compound 213B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-R
{4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}s-
ulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0619] The title compound was prepared by substituting Compound
213A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 12.98 (s, 1H), 9.26 (d,
1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 3.96-3.86 (m, 2H), 3.72 (dd, 1H),
3.67-3.61 (m, 4H), 3.51 (t, 2H), 3.48-3.38 (m, 2H), 3.28 (s, 3H),
3.07 (m, 4H), 2.95 (d, 1H), 2.77 (s, 2H), 2.70 (m, 1H), 2.60 (t,
2H), 2.30-2.05 (m, 8H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s,
6H).
Compound 214
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]s-
ulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 214A
4-((4-(cyanomethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
[0620] The title compound was prepared by substituting
2-bromoacetonitrile for methyl iodide in the procedure for Compound
134B.
Compound 214B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]s-
ulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0621] The title compound was prepared by substituting Compound
214A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.01 (s, 1H), 9.26 (d,
1H), 8.86 (t, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 3.93 (m, 1H), 3.87 (d, 1H), 3.77 (s,
2H), 3.65 (dt, 1H), 3.51-3.40 (m, 2H), 3.07 (m, 4H), 2.87 (d, 1H),
2.77 (s, 2H), 2.60 (d, 1H), 2.50 (m, 1H), 2.38 (t, 1H), 2.26 (m,
2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 215
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrop-
henyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 215A
4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenzene
sulfonamide
[0622] The title compound was prepared by substituting
2-dimethylaminoacetyl chloride hydrochloride for methyl iodide in
the procedure for Compound 134B.
Compound 215B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrop-
henyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0623] The title compound was prepared by substituting Compound
215A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.27 (d,
1H), 8.87 (bs, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (dd, 1H),
7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (dd, 1H), 6.75 (d,
1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.55 (dd, 1H), 4.20 (dd, 1H),
3.95-3.76 (m, 2H), 3.60-3.40 (m, 3H), 3.32 (dd, 1H), 3.25-3.12 (m,
2H), 3.07 (m, 4H), 2.80 (m, 1H), 2.77 (s, 2H), 2.26 (s, 6H), 2.23
(s, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s,
6H).
Compound 216
(2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-
piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-n-
itrophenyl)amino]methyl}morpholin-4-yl)acetic acid
Compound 216A
tert-butyl
2-(2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholino)acetate
[0624] The title compound was prepared by substituting tert-butyl
2-bromoacetate for methyl iodide in the procedure for Compound
134B.
Compound 216B
tert-butyl
2-(2-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-c-
hlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sul-
famoyl)-2-nitrophenylamino)methyl)morpholino)acetate
[0625] The title compound was prepared by substituting Compound
216A for Compound 130C in the procedure for Compound 130D.
Compound 216C
(2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-
piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-n-
itrophenyl)amino]methyl}morpholin-4-yl)acetic acid
[0626] The title compound was prepared by treating Compound 216B
with 50% trifluoroacetic acid in dichloromethane. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 12.97 (s, 1H), 9.26 (d, 1H), 8.87
(t, 1H), 8.43 (d, 1H), 8.30 (dd, 1H), 8.12 (d, 1H), 7.69 (t, 1H),
7.64 (d, 1H), 7.43 (d, 2H), 7.08 (d, 2H), 6.88 (d, 1H), 6.76 (dd,
1H), 6.55 (d, 1H), 6.47 (m, 1H), 4.05-4.00 (m, 1H), 3.91 (d, 1H),
3.79 (dt, 1H), 3.50 (s, 2H), 3.45 (m, 2H), 3.13 (d, 1H), 3.07 (m,
4H), 2.88 (d, 1H), 2.78 (s, 2H), 2.57 (dt, 1H), 2.43 (t, 1H), 2.26
(m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s,
6H).
Compound 217
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]s-
ulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 217A
3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)benzenesulfonamide
[0627] The title compound was prepared by substituting Compound
134A for tert-butyl piperazine-1-carboxylate and 3-oxetanone for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 217B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]s-
ulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0628] The title compound was prepared by substituting Compound
217A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.26 (d,
1H), 8.87 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 4.64 (m, 4H), 3.93 (m, 1H), 3.89 (d,
1H), 3.68 (dt, 1H), 3.53-3.35 (m, 3H), 3.07 (m, 4H), 2.77 (s, 2H),
2.72 (d, 1H), 2.44 (d, 1H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s,
2H), 1.85 (t, 1H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 218
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 218A
4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
[0629] The title compound was prepared by substituting Compound
134A for Compound 173A in the procedure for Compound 173B.
Compound 218B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0630] The title compound was prepared by substituting Compound
218A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.26 (d,
1H), 8.88 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 3.88 (d, 1H), 3.84-3.81 (m, 1H), 3.59
(dt, 1H), 3.50-3.40 (m, 2H), 3.07 (m, 4H), 2.93 (d, 1H), 2.77 (s,
2H), 2.69 (d, 1H), 2.34 (dt, 1H), 2.26 (m, 2H), 2.21 (t, 1H), 2.14
(m, 4H), 1.97 (s, 2H), 1.58 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H),
0.45-0.39 (m, 4H).
Compound 219
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{5-(methylsulfonyl)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-y-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 219A
5-(methylthio)-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[0631] A mixture of Compound 36B (0.1 g) and sodium methanethiolate
(0.04 g) in N,N-dimethylformamide (2 ml) was heated at 80.degree.
C. overnight. After cooling, the reaction mixture was partitioned
between water and ethyl acetate. The organic layer was separated,
and 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 column chromatography on silica gel using 10-50%
ethyl acetate in hexanes to provide the title compound.
Compound 219B
5-(methylsulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfona-
mide
[0632] A mixture of Compound 219A (0.15 g) and 75%
meta-chloroperoxybenzoic acid (0.217 g) in chloroform (4 ml) was
stirred at room temperature. The reaction mixture was stirred
overnight. The reaction mixture was then partitioned between ethyl
acetate and water. The organic layer was separated, and 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 column chromatography on silica gel using 10-50% ethyl
acetate in hexanes to provide the title compound.
Compound 219C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-(methylsulfonyl)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3--
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0633] The title compound was prepared by substituting Compound
219B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H),
8.81 (s, 1H), 8.55 (d, 1H), 8.01 (d, 1H), 7.55 (d, 1H), 7.49-7.50
(m, 2H), 7.37 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H),
6.21 (d, 1H), 4.36 (d, 2H), 3.88 (dd, 2H), 3.13 (s, 4H), 2.95 (s,
2H), 2.36-2.38 (m, 2H), 2.03-2.16 (m, 4H), 1.97 (s, 3H), 1.66-1.69
(m, 2H), 1.38-1.402 (m, 4H), 0.93 (s, 6H).
Compound 220
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethy-
l)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 220A
4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-(trifluoromethylsulfonyl)b-
enzenesulfonamide
[0634] To a solution of Compound 37C (0.500 g) in tetrahydrofuran
(5 ml) was added sodium hydride (0.596 g). Additional
tetrahydrofuran (25 ml) was added and the mixture stirred for 30
minutes, then
4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.145 g)
was added as a solution in tetrahydrofuran (5 ml). After stirring
for 2 hours, the reaction mixture was partioned between 1N aqueous
HCl (50 ml) and dichloromethane (200 ml). The organic layer was
dried over magnesium sulfate, filtered, and concentrated. The
resulting solid was chromatographed over silica gel (Reveleris 80
g) eluting with a gradient of 0.5% to 7.5% methanol/dichloromethane
over 30 minutes (flow=40 ml/min) to provide the title compound.
Compound 220B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethy-
l)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0635] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 220A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.66 (s, 1H), 8.42 (s, 1H), 8.35-8.22 (m, 1H), 8.01 (s,
1H), 7.49 (d, 4H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (s, 1H), 6.38
(s, 1H), 6.21 (s, 1H), 4.42 (d, 2H), 3.76 (s, 2H), 3.59 (s, 2H),
3.10 (s, 6H), 2.15 (s, 6H), 2.02-1.74 (m, 6H), 1.40 (s, 2H), 0.93
(s, 6H).
Compound 221
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-methyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 221A
4-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
[0636] The title compound was prepared by substituting
(4-methyltetrahydro-2H-pyran-4-yl)methanol for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 221B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-methyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0637] The title compound was prepared by substituting Compound
221A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H),
8.36 (s, 1H), 8.04-8.06 (m, 2H), 7.50-7.53 (m, 3H), 7.41 (d, 1H),
7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d,
1H), 4.00 (s, 2H), 3.63-3.67 (m, 2H), 3.53-3.58 (m, 2H), 3.09 (s,
4H), 2.82 (s, 2H), 2.27 (s, 2H), 2.15 (s, 2H), 1.58-1.63 (m, 2H),
1.39 (t, 2H), 1.30-1.34 (m, 2H), 1.09 (s, 3H), 0.92 (s, 6H).
Compound 222
ethyl
4-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}--
2-nitrophenyl)piperazine-1-carboxylate
Compound 222A
ethyl 4-(2-nitro-4-sulfamoylphenyl)piperazine-1-carboxylate
[0638] The title compound was prepared by substituting ethyl
piperazine-1-carboxylate for 1-(tetrahydropyran-4-yl)methylamine in
the procedure for Compound 1F.
Compound 222B
ethyl
4-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}--
2-nitrophenyl)piperazine-1-carboxylate
[0639] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 222A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.52 (br. s, 1H), 8.08 (d, 1H), 7.89 (d, 1H), 7.59 (m,
2H), 7.43 (t, 1H), 7.35 (d, 2H), 7.23 (d, 1H), 7.05 (d, 2H), 6.94
(d, 1H), 6.63 (dd, 1H), 6.29 (m, 2H), 4.07 (q, 2H), 3.47 (m, 4H),
3.17 (d, 2H), 3.00 (m, 8H), 2.73 (s, 2H), 2.18 (m, 6H), 1.96 (s,
2H), 1.39 (t, 2H), 1.20 (t, 3H), 0.93 (s, 6H).
Compound 223
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl}sulfonyl)-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 223A
4-(4-morpholinopiperidin-1-yl)-3-nitrobenzene sulfonamide
[0640] The title compound was prepared by substituting
4-(piperidin-4-yl)morpholine for
1-(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 223B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl}sulfonyl)-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0641] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 223A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.53 (br. s, 1H), 8.05 (d, 1H), 7.91 (d, 1H), 7.58 (m,
2H), 7.43 (t, 1H), 7.35 (d, 2H), 7.26 (d, 1H), 7.05 (d, 2H), 6.91
(d, 1H), 6.62 (dd, 1H), 6.29 (m, 2H), 5.76 (s, 1H), 3.57 (m, 4H),
3.20 (m, 2H), 3.01 (m, 4H), 2.80 (t, 2H), 2.73 (s, 2H), 2.47 (m,
4H), 2.32 (m, 1H), 2.18 (m, 6H), 1.96 (m, 3H), 1.82 (m, 2H), 1.44
(m, 4H), 0.93 (s, 6H).
Compound 224
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]amino}phenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 224A
(R)-tert-butyl 1-(oxetan-3-yl)pyrrolidin-3-ylcarbamate
[0642] The title compound was prepared by substituting
(R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl
piperazine-1-carboxylate and 3-oxetanone for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 224B
(R)-1-(oxetan-3-yl)pyrrolidin-3-amine
[0643] The title compound was prepared by substituting Compound
224A for (S)-1-tert-butyl 2-methyl
4,4-difluoropyrrolidine-1,2-dicarboxylate in the procedure for
Compound 168A.
Compound 224C
(R)-3-nitro-4-(1-(oxetan-3-yl)pyrrolidin-3-ylamino)benzene
sulfonamide
[0644] The title compound was prepared by substituting
4-fluoro-3-nitrobenzenesulfonamide for
4-chloro-3-nitrobenzenesulfonamide and Compound 224B for
4-methylpiperazin-1-amine dihydrochloride in the procedure for
Compound 6A.
Compound 224D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]amino}phenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0645] The title compound was prepared by substituting Compound
224C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, pyridine-d.sub.5) .delta. 13.03 (s, 1H), 9.26 (d,
1H), 8.57 (d, 1H), 8.42 (d, 1H), 8.36 (dd, 1H), 8.09 (d, 1H), 7.66
(m, 1H), 7.64 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.86 (d, 1H),
6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (dd, 1H), 4.67 (m, 4H), 3.58 (m,
1H), 3.07 (m, 4H), 2.77 (m, 2H), 2.68 (m, 2H), 2.61 (m, 1H), 2.28
(m, 4H), 2.14 (m, 4H), 1.97 (m, 2H), 1.67 (m, 1H), 1.39 (t, 2H),
0.93 (s, 6H).
Compound 225
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}-3-[(t-
rifluoromethyl)sulfonyl]phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-ylo-
xy)benzamide
Compound 225A
(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-(trifluoromethyl-
sulfonyl)benzenesulfonamide
[0646] To Compound 207A (0.217 g) and
4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (0.281 g) in
tetrahydrofuran (5 ml) was added diisopropylethylamine (0.559 ml)
and the reaction was allowed to stir at room temperature for 1 hour
and was then heated to 50.degree. C. for 1 hour. The reaction was
concentrated, the residue was loaded onto silica gel (Reveleris 40
g) and eluted with a gradient of 0.75% methanol/dichloromethane to
7.5% methanol/dichloromethane to provide the title compound.
Compound 225B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}-3-[(t-
rifluoro
methyl)sulfonyl]phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl-
oxy)benzamide
[0647] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 225A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.69 (s, 1H), 11.52-11.23 (m, 1H), 8.17 (d, 1H), 8.04 (d,
1H), 7.95 (d, 1H), 7.54 (d, 1H), 7.53-7.50 (m, 1H), 7.48 (d, 1H),
7.34 (d, 2H), 7.10-6.97 (m, 4H), 6.67 (d, 1H), 6.40 (dd, 1H), 6.18
(d, 1H), 4.60 (dd, 4H), 4.20 (s, 1H), 3.11-2.63 (m, 12H), 2.19 (d,
6H), 1.95 (s, 2H), 1.58 (s, 1H), 1.40 (d, 2H), 0.92 (s, 6H).
Compound 226
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 226A
tert-butyl
4-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamo-
yl)-2-nitrophenylamino)piperidine-1-carboxylate
[0648] To a solution of Compound 82 (800 mg) and tert-butyl
4-aminopiperidine-1-carboxylate (203 mg) in dioxane (10 ml) was
added Hunig's Base (1 ml). The mixture was stirred at 120.degree.
C. overnight. The mixture was diluted with ethyl acetate (200 ml)
and washed with water, brine and dried over Na.sub.2SO.sub.4. After
filtration and evaporation of solvent, the residue was loaded on a
silica gel cartridge and eluted with 3% methanol in dichloromethane
to give the title compound.
Compound 226B
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylamino)-
phenylsulfonyl)benzamide
[0649] To a solution of Compound 226A (902 mg) in dichloromethane
(10 ml) was added trifluoroacetic acid (5 ml). The mixture was
stirred at room temperature for 3 hours. The mixture was
concentrated under vacuum and co-concentrated with dichloromethane
twice to afford the crude product which was used in the next step
without further purification.
Compound 226C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0650] To a solution of Compound 226B (79 mg) in tetrahydrofuran (3
ml) and acetic acid (1 ml) was added acetone (54 mg) and
MP-cyanoborohydride (150 mg, 2.25 mmol/g). The mixture was stirred
overnight. The mixture was filtered. The filtrate was concentrated
and the residue was loaded on a silica gel cartridge and eluted
with 5 to 10% 7N NH.sub.3 in methanol in dichloromethane to provide
the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 12.09 (s, 1H), 8.34 (m, 1H),
7.93 (m, 2H), 7.66 (m, 4H), 7.35 (d, 2H), 7.06 (d, 2H), 6.89 (m,
1H), 6.74 (dd, 1H), 6.59 (dd, 1H), 6.50 (d, 1H), 3.11 (m, 6H), 2.73
(m, 4H), 2.26 (m, 9H), 1.97 (s, 3H), 1.40 (t, 2H), 1.23 (s, 8H),
0.94 (s, 6H).
Compound 227
N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-
-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 227A
1-tert-butylpiperidin-4-amine
[0651] To a solution of 1-tert-butylpiperidin-4-one (5.0 g) in
methanol (100 ml) and water (10 ml) was added ammonium formate
(20.3 g) and 0.5 g of Pd/C (10%). The mixture was stirred
overnight. The mixture was filtered and the filtrate was
concentrated under vacuum and the residue was diluted with ethyl
acetate (500 ml) and washed with water and brine. After drying over
Na.sub.2SO.sub.4 and filtration, the solvent was evaporated under
vacuum to provide the title compound.
Compound 227B
4-(1-tert-butylpiperidin-4-ylamino)-3-nitrobenzene sulfonamide
[0652] To a mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.2 g)
and Compound 227A (1.56 g) in tetrahydrofuran (20 ml) was added
Hunig's Base (6 ml). The mixture was stirred for 3 days. The
mixture was diluted with ethyl acetate (300 ml) and water (100 ml)
and stirred until the solid disappeared into the solution. The
layers were separated and the organic phase was washed with water
and brine, dried over Na.sub.2SO.sub.4, and filtered. The combined
aqueous layers were extracted again with ethyl acetate and the
combined organic phases were dried over Na.sub.2SO.sub.4. After
filtration, the solvent was evaporated to provide the title
compound.
Compound 227C
N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-
-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0653] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 227B for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.51 (s, 1H), 8.43 (d, 1H), 8.04 (m, 1H), 7.93 (d, 1H),
7.72 (m, 1H), 7.56 (dd, 1H), 7.42 (m, 1H), 7.34 (m, 3H), 7.05 (d,
2H), 6.93 (dd, 1H), 6.62 (dd, 1H), 6.28 (m, 1H), 3.04 (m, 6H), 2.73
(s, 3H), 2.25 (m, 9H), 1.95 (s, 2H), 1.68 (m, 2H), 1.32 (m, 9H),
0.93 (s, 6H).
Compound 228
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(2-methoxyethyl)piperidin-3-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 228A
tert-butyl
3-((2-nitro-4-sulfamoylphenylamino)methyl)piperidine-1-carboxyl-
ate
[0654] The title compound was prepared by substituting tert-butyl
3-(aminomethyl)piperidine-1-carboxylate for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 228B
3-nitro-4-(piperidin-3-ylmethylamino)benzenesulfonamide
[0655] The title compound was prepared by substituting Compound
228A for Compound 113A in the procedure for Compound 134A.
Compound 228C
4-((1-(2-methoxyethyl)piperidin-3-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[0656] The title compound was prepared by substituting Compound
228B for Compound 134A and 2-methoxyethyl bromide for methyl iodide
in the procedure for Compound 134B.
Compound 228D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(2-methoxyethyl)piperidin-3-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0657] The title compound was prepared by substituting Compound
228C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5, 90.degree. C.) .delta. 12.40 (s,
1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.20 (m, 2H), 7.95 (bs, 1H), 7.80
(s, 1H), 7.46 (d, 1H), 7.36 (d, 2H), 7.07 (d, 2H), 7.05 (s, 1H),
6.75 (d, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 3.65-3.50 (m, 5H), 3.20
(s, 3H), 3.04 (m, 5H), 2.81 (s, 3H), 2.74 (m, 1H), 2.24 (m, 7H),
2.06 (s, 2H), 2.00 (s, 2H), 1.75 (m, 1H), 1.57 (m, 2H), 1.42 (t,
2H), 1.15 (m, 1H), 0.95 (s, 6H).
Compound 229
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(cyanomethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]s-
ulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 229A
4-((1-(cyanomethyl)piperidin-3-yl)methylamino)-3-nitrobenzenesulfonamide
[0658] The title compound was prepared by substituting Compound
228B for Compound 134A and 2-bromoacetonitrile for methyl iodide in
the procedure for Compound 134B.
Compound 229B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(cyanomethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]s-
ulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0659] The title compound was prepared by substituting Compound
229A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.06 (s, 1H), 9.03 (s,
1H), 8.42 (s, 1H), 8.30 (d, 1H), 8.10 (d, 1H), 7.68 (m, 2H), 7.44
(d, 2H), 7.08 (m, 3H), 6.99 (d, 1H), 6.75 (d, 1H), 6.51 (m, 2H),
3.78 (m, 2H), 3.43 (d, 1H), 3.13 (m, 1H), 3.04 (m, 4H), 2.76 (s,
2H), 2.71-2.65 (m, 3H), 2.52 (m, 1H), 2.25 (m, 2H), 2.14 (m, 4H),
1.97 (s, 2H), 1.84 (m, 1H), 1.68 (m, 1H), 1.50 (m, 2H), 1.39 (t,
2H), 1.07-0.99 (m, 1H), 0.93 (s, 6H).
Compound 230
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]-3-[(trifluoromethyl-
)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 230A
4-((4-fluoro-1-methylpiperidin-4-yl)methoxy)-3-(trifluoromethylsulfonyl)be-
nzenesulfonamide
[0660] To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol
(0.315 g) in tetrahydrofuran (5 ml) was added sodium hydride (0.342
g). After stirring for 15 minutes,
4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (0.658 g)
was added as a solution in tetrahydrofuran (2 ml) followed by
additional tetrahydrofuran (5 ml). After stirring for 1 hour, the
reaction was poured in dichloromethane (50 ml) and water (25 ml)
and the pH of the water layer was adjusted to 8. The organic layer
was dried over magnesium sulfate, filtered, and concentrated. The
resulting oil was chromatographed over silica gel (Reveleris 40 g)
eluting with a gradient of 1.0% to 10% 7N NH.sub.3 in
methanol/dichloromethane over 20 minutes then maintaining 10% 7N
NH.sub.3 in methanol/dichloromethane for 5 minutes (flow=30 ml/min)
to provide the title compound.
Compound 230B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]-3-[(trifluoromethyl-
)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0661] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 230A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.63-11.57 (m, 1H), 8.40-8.36 (m, 1H), 8.28-8.17 (m, 1H),
7.97 (s, 1H), 7.53 (d, 1H), 7.50-7.32 (m, 5H), 7.05 (d, 1H), 7.05
(d, 1H), 6.68-6.61 (m, 1H), 6.35 (s, 1H), 6.22 (s, 1H), 4.55-4.40
(m, 2H), 3.06 (s, 8H), 2.79 (s, 4H), 2.06 (d, 13H), 1.39 (s, 2H),
0.93 (s, 6H).
Compound 231
N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}pyr-
idin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 231A
(R)-5-chloro-6-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)pyridine-3-
-sulfonamide
[0662] To Compound 207A (0.051 g) and Compound 40A (0.049 g) in
dioxane (5 ml) was added diisopropylethylamine (0.131 ml) and the
reaction was heated to 75.degree. C. for 1 hour then 85.degree. C.
for 2 days. The reaction was concentrated, loaded onto silica gel
(Reveleris 12 g) and eluted with a gradient of 0.75%
methanol/dichloromethane to 7.5% methanol/dichloromethane to
provide the title compound.
Compound 231B
N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}pyr-
idin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0663] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 231A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.71 (s, 1H), 11.44-11.11 (m, 1H), 8.44 (d, 1H), 8.07 (d,
1H), 7.90 (d, 1H), 7.61 (d, 1H), 7.52 (dd, 2H), 7.34 (d, 2H), 7.19
(s, 1H), 7.04 (d, 2H), 6.67 (d, 1H), 6.42 (dd, 1H), 6.16 (s, 1H),
4.77-4.39 (m, 5H), 3.19-2.63 (m, 11H), 2.19 (s, 7H), 1.91 (d, 3H),
1.38 (s, 2H), 0.92 (s, 6H).
Compound 232
tert-butyl
4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfa-
moyl}-2-nitrophenyl)amino]piperazine-1-carboxylate
Compound 232A
tert-butyl 4-nitrosopiperazine-1-carboxylate
[0664] In a 500 ml round-bottomed flask, 6N aqueous HCl (30 ml) was
cooled to -10.degree. C., and tert-butyl piperazine-1-carboxylate
(10 g) was added. Sodium nitrite (4.5 g) dissolved in 35 ml water
was added slowly. NaOH (10 g in 20 ml water) was used to neutralize
the solution. Dichloromethane (3.times.50 ml) was used to extract
the product. After drying over Na.sub.2SO.sub.4 and filtration, the
solution was concentrated. The crude product was added to a silica
gel column (Analogix, SF65-400 g,) and purified by eluting with
0-30% ethyl acetate in hexane.
Compound 232B
tert-butyl 4-aminopiperazine-1-carboxylate
[0665] In a 100 ml round-bottomed flask was added Compound 232A
(0.15 g) and zinc (1 g) in water/methanol (1:1, 10 ml) to give a
suspension. The mixture was cooled to 0.degree. C. 12N Aqueous HCl
(2 ml) was added slowly, and the mixture was stirred at 0.degree.
C. for 30 minutes. 2N Aqueous NaOH solution was used to adjust the
mixture to basic pH. The mixture was filtered, and extracted with
ether (3.times.30 ml). After drying over Na.sub.2SO.sub.4,
filtration, and concentration, the crude product was added to a
silica gel column (Analogix, SF15-12 g,) and purified by eluting
with 0-25% ethyl acetate in hexane.
Compound 232C
tert-butyl
4-(2-nitro-4-sulfamoylphenylamino)piperazine-1-carboxylate
[0666] The title compound was prepared by substituting Compound
232B for 1-(tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 232D
tert-butyl
4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfa-
moyl}-2-nitrophenyl)amino]piperazine-1-carboxylate
[0667] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 232C for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.47 (br. s, 1H), 8.86 (s, 1H), 8.34 (d, 1H), 7.90 (d,
1H), 7.59 (m, 2H), 7.36 (m, 4H), 7.23 (m, 1H), 7.05 (d, 2H), 6.61
(dd, 1H), 6.27 (m, 2H), 2.99 (m, 5H), 2.76 (m, 6H), 2.19 (m, 6H),
1.96 (s, 2H), 1.41 (m, 11H), 1.24 (m, 4H), 0.93 (s, 6H).
Compound 233
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-(pentafluoro-lambda-6-sulfanyl)-4-[(tetrahydro-2H-pyran-4-ylme-
thyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 233A
2-(5-bromo-2-nitrophenyl)sulfur pentafluoride
[0668] To a solution of 3-bromophenylsulfur pentafluoride (2.18 g)
in concentrated H.sub.2SO.sub.4 (5 ml) was added KNO.sub.3 (780
mg). The mixture was stirred overnight. The mixture was diluted
with diethyl ether (100 ml) and washed with water and brine. After
drying over Na.sub.2SO.sub.4 and filtration, the solvent was
evaporated under vacuum to provide the title compound.
Compound 233B
2-(5-bromo-2-aminophenyl)sulfur pentafluoride
[0669] Compound 233A (6.4 g) and tetrahydrofuran (300 ml) were
added to Ra--Ni, (12.80 g) in a 50 ml pressure bottle and the
mixture stirred for 2 hours at 30 psi and room temperature. The
mixture was filtered though a nylon membrane and the filtrate was
concentrated under vacuum to provide the title compound.
Compound 233C
4-bromo-2-pentafluoro
sulfanyl-N-(tetrahydro-2H-pyran-4-ylmethyl)aniline
[0670] To a solution of Compound 233B (4.4 g) in methanol (50 ml)
was added tetrahydro-2H-pyran-4-carbaldehyde (1.68 g) and
decaborane (1.1 g). The mixture was stirred and monitored by thin
layer chromatography. More tetrahydro-2H-pyran-4-carbaldehyde (500
mg) was added to the stirring mixture to drive the reaction to
completion. The reaction mixture was concentrated under vacuum and
ethyl acetate (500 ml) and brine (200 ml) were added. The organic
phase was dried over Na.sub.2SO.sub.4. Filtration and evaporation
of the solvent and flash chromatography (20% ethyl acetate in
hexane) gave the title compound.
Compound 233D
4-thioacetoxy-2-pentafluorosulfanyl-N-(tetrahydro-2H-pyran-4-ylmethyl)anil-
ine
[0671] To a solution of Compound 233C (456 mg) and potassium
ethanethioate (197 mg) in dioxane (4 ml) was added
tris(dibenzylideneacetone)dipalladium(0) (27 mg) and xantphos (33
mg) followed by N,N-diisopropylethylamine (0.5 ml). The mixture was
purged with argon, sealed and stirred under microwave irradiation
for 60 minutes at 120.degree. C. The mixture was dissolved in ethyl
acetate (300 ml) and water (100 ml). The organic phase was washed
with brine and dried over Na.sub.2SO.sub.4. Filtration and
evaporation of the solvent followed by flash chromatography (20%
ethyl acetate in hexane) provided the title compound.
Compound 233E
3-pentafluoro
sulfanyl-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenylsulfonamide
[0672] N-chlorosuccinimide (527 mg) was added to a mixture of 2N
aqueous HCl (1.5 ml) and acetonitrile (12 ml) and then cooled to
0.degree. C. A solution of Compound 233D (386 mg) in acetonitrile
(3 ml) was added to the mixture which was then stirred at 0.degree.
C. for 2 hours, and then diluted with ethyl acetate (300 ml) and
washed with brine and dried over Na.sub.2SO.sub.4. After filtration
and evaporation of solvent, the residue was dissolved in isopropyl
alcohol (20 ml) and cooled to 0.degree. C. with stirring. Then,
ammonium hydroxide (conc. 10 ml) was added to mixture. After
stirring for 2 hours, the mixture was concentrated under vacuum and
the residue was added to ethyl acetate (400 ml) and water (150 ml).
The organic layer was washed with brine and dried over
Na.sub.2SO.sub.4. After filtration and evaporation of solvent, the
residue was purified by flash column (20% ethyl acetate in
dichloromethane) to provide the title compound.
Compound 233F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-(pentafluoro-lambda-6-sulfanyl)-4-[(tetrahydro-2H-pyran-4-ylme-
thyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0673] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 233E for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.71 (s, 1H), 11.33 (m, 1H), 8.12 (m, 2H), 7.72 (d, 1H),
7.54 (m, 3H), 7.33 (m, 2H), 7.02 (m, 3H), 6.67 (m, 2H), 6.42 (m,
1H), 6.16 (d, 1H), 3.82 (m, 2H), 3.21 (m, 4H), 3.05 (m, 4H), 2.73
(s, 2H), 2.21 (m, 8H), 1.97 (m, 3H), 1.29 (m, 4 H), 0.92 (s,
6H).
Compound 234
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 234A
4-vinyltetrahydro-2H-pyran-4-ol
[0674] Dihydro-2H-pyran-4(3H)-one (8.01 g) in anhydrous ethyl ether
(50 ml) was treated with 1.0 M vinylmagnesium bromide (104 ml) over
20 minutes at 0.degree. C. The reaction mixture was stirred at room
temperature overnight. The reaction was quenched with saturated
NH.sub.4Cl, and the organic layer was separated. The aqueous layer
was extracted with additional ethyl ether three times. The combined
organic layers were washed with brine, dried, filtered, and
concentrated. The residue was purified by flash column
chromatography on silica gel using 20% ethyl acetate in hexanes to
provide the title compound.
Compound 234B
4-methoxy-4-vinyltetrahydro-2H-pyran
[0675] To a solution of Compound 234A (9.4 g) in tetrahydrofuran
(150 ml) was added 60% sodium hydride (5.28 g) at 0.degree. C.
portionwise. After the addition was complete, the solution was
heated under reflux for three hours. After cooling, to this
suspension was added dimethyl sulfate (8.41 ml) slowly. The
solution was heated under reflux overnight, cooled to room
temperature, and hydrolyzed with cool saturated aqueous NH.sub.4Cl.
After extraction with diethyl ether several times, the combined
organic layers were washed with brine, dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by flash
column chromatograph on silica gel using 1-10% ethyl acetate in
hexanes to provide the title compound.
Compound 234C
4-methoxytetrahydro-2H-pyran-4-carbaldehyde
[0676] Compound 234B (4.3 g) in tetrahydrofuran (200 ml) and water
(67 ml) was treated with 4% osmium tetroxide in water (9.24 ml). To
this solution was added potassium periodate (13.91 g) portionwise
over 2 hours. The solution was stirred overnight at room
temperature. Water was added to the mixture followed by repeat
extractions with diethyl ether. The combined organic layers were
dried over MgSO.sub.4, filtered, and concentrated. The residue was
purified by flash column chromatography on silica gel using 5-20%
ethyl acetate in hexanes to provide the title compound.
Compound 234D
(4-methoxytetrahydro-2H-pyran-4-yl)methanol
[0677] Compound 234C (1.8 g) in 2-propanol (28 ml) and water (7 ml)
was cooled to 0.degree. C. To this solution was added sodium
borohydride (0.709 g). The solution was stirred and allowed to warm
to room temperature over 3 hours. The reaction was quenched with
acetone, and stirred for another 1 hour. The clear liquid was
separated from solid by decanting. Additional ethyl acetate was
used to wash the solid, and was the mixture was decanted. The
combined organic solutions were concentrated. The residue was
purified by flash chromatography on silica gel eluting 1:1 ethyl
acetate:hexane to provide the title compound.
Compound 234E
4-((4-methoxytetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
[0678] The title compound was prepared by substituting Compound
234D for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 24A.
Compound 234F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0679] The title compound was prepared by substituting Compound
234E for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H),
8.36 (s, 1H), 8.04-8.07 (m, 2H), 7.50-7.53 (m, 3H), 7.45 (d, 1H),
7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (d,
1H), 4.21 (s, 2H), 3.65-3.67 (m, 2H), 3.53-3.56 (m, 2H), 3.19 (s,
3H), 3.10 (s, 4H), 2.86 (s, 2H), 2.30 (s, 4H), 2.15 (s, 2H), 1.96
(s, 2H), 1.61-1.74 (m, 4H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 235
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}-3-nitro-
phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 235A
(R)-tert-butyl
3-(2-nitro-4-sulfamoylphenoxy)pyrrolidine-1-carboxylate
[0680] The title compound was prepared by substituting
(R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 235B
(R)-tert-butyl
3-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4-
,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitr-
ophenoxy)pyrrolidine-1-carboxylate
[0681] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 235A for Compound 1F in the procedure
for Compound 1G.
Compound 235C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}-3-nitro-
phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0682] To a solution of Compound 235B (0.230 g) in dichloromethane
(3 ml) was added trifluoroacetic acid (0.377 ml). After stirring
for 4 hours, the reaction was concentrated then dissolved in
dichloromethane (3 ml) and treated with 1,3-difluoropropan-2-one
(0.028 g) followed by sodium triacetoxyborohydride (0.078 g). After
stirring for 4 hours, the reaction was quenched by the addition of
saturated aqueous NaHCO.sub.3 and dichloromethane (5 ml). The
reaction was diluted with dichloromethane (250 ml) and saturated
aqueous NaHCO.sub.3 (100 ml) was added. The organic layer was
separated, washed with brine (100 ml), dried over magnesium
sulfate, filtered and concentrated. Trituration with acetonitrile
gave the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 8.34 (s, 1H),
8.03 (s, 2H), 7.52 (d, 3H), 7.35 (d, 3H), 7.04 (d, 2H), 6.75-6.60
(m, 1H), 6.40 (s, 1H), 6.20 (s, 1H), 5.17-5.06 (m, 1H), 4.60 (d,
4H), 2.98 (d, 12H), 2.37-2.02 (m, 6H), 1.96 (s, 3H), 1.39 (s, 2H),
0.93 (s, 6H).
Compound 236
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[4-(oxetan-3-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 236A
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperazin-1-ylamino)-
phenylsulfonyl)benzamide
[0683] The title compound was prepared by substituting Compound
232D for Compound 1A in the procedure for Compound 1B.
Compound 236B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[4-(oxetan-3-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0684] The title compound was prepared by substituting Compound
236A for tert-butyl piperazine-1-carboxylate and oxetan-3-one for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67
(br. s, 1H), 9.20 (s, 1H), 8.53 (d, 1H), 8.04 (d, 1H), 7.83 (dd,
1H), 7.53 (m, 4H), 7.34 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39
(m, 1H), 6.18 (d, 1H), 4.55 (t, 2H), 4.44 (t, 2H), 3.47 (m, 1H),
3.06 (m, 4H), 2.88 (m, 4H), 2.74 (m, 4H), 2.09 (m, 11H), 1.38 (t,
2H), 0.91 (s, 6H).
Compound 237
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]amino}phe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0685] The title compound was prepared by substituting Compound
236A for tert-butyl piperazine-1-carboxylate and
dihydro-2H-pyran-4(3H)-one for 4'-chlorobiphenyl-2-carboxaldehyde
in the procedure for Compound 1A. .sup.1H NMR (400 MHz,
pyridine-d.sub.5) .delta. 13.05 (br. s, 1H), 9.27 (d, 1H), 9.23 (s,
1H), 8.44 (m, 2H), 8.12 (d, 1H), 7.68 (m, 3H), 7.44 (m, 2H), 7.06
(m, 2H), 6.75 (dd, 1H), 6.51 (m, 2H), 4.02 (m, 2H), 3.31 (m, 2H),
3.06 (m, 4H), 2.91 (m, 5H), 2.76 (s, 2H), 2.38 (m, 2H), 2.26 (m,
2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.65 (m, 2H), 1.39 (m, 7H), 0.93
(s, 6H).
Compound 238
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(3R)-tetrahydrofuran-3-ylamino]phenyl}sulfonyl)-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 238A
(R)-3-nitro-4-(tetrahydro furan-3-ylamino)benzenesulfonamide
[0686] The title compound was prepared by substituting
(R)-tetrahydrofuran-3-amine for 4-methylpiperazin-1-amine
dihydrochloride in the procedure for Compound 6A.
Compound 238B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(3R)-tetrahydro
furan-3-ylamino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benz-
amide
[0687] The title compound was prepared by substituting Compound
238A for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.59 (s, 1H), 8.47 (d, 1H),
8.19 (m, 2H), 7.97 (d, 1H), 7.74 (m, 1H), 7.52 (d, 1H), 7.46 (t,
1H), 7.34 (m, 2H), 7.05 (m, 2H), 6.96 (d, 1H), 6.89 (d, 1H), 6.65
(dd, 1H), 6.33 (m, 1H), 6.22 (d, 1H), 4.31 (m, 1H), 3.92 (m, 1H),
3.87 (m, 1H), 3.76 (m, 1H), 3.69 (m, 1H), 3.04 (m, 4H), 2.73 (m,
2H), 2.33 (m, 1H), 2.18 (m, 6H), 1.95 (m, 2H), 1.88 (m, 1H), 1.39
(t, 2H), 0.92 (s, 6H).
Compound 239
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 239A
tert-butyl (4,4-difluorocyclohexyl)methylcarbamate
[0688] Tert-butyl (4-oxocyclohexyl)methylcarbamate (5 g) and
diethylaminosulfur trifluoride (7.45 g) were stirred in
dichloromethane (100 ml) for 24 hours. The mixture was quenched
with pH 7 buffer (100 ml), and poured into ether (400 ml). The
resulting solution was separated, and the organic layer was washed
twice with water, and once with brine, and then concentrated to
give the crude product and fluoroolefin by-product in a 3:2 ratio.
The crude material was taken up in tetrahydrofuran (70 ml) and
water (30 ml), and N-methylmorpholine-N-oxide (1.75 g), and
OsO.sub.4 (2.5 wt % solution in t-butanol) were added, and the
mixture was stirred for 24 hours. Na.sub.2S.sub.2O.sub.3 (10 g) was
then added, and the mixture was stirred for 30 minutes. The mixture
was then diluted with ether (300 ml), and the resulting solution
was separated, and rinsed twice with water, and once with brine,
and concentrated. The crude product was chromatographed on silica
gel using 5-10% ethyl acetate in hexanes to provide the title
compound.
Compound 239B
(4,4-difluorocyclohexyl)methanamine
[0689] A solution of Compound 239A (3 g) in dichloromethane (35
ml), trifluoroacetic acid (15 ml), and triethylsilane (1 ml) was
stirred for 2 hours. The solution was concentrated, then
concentrated from toluene, and left on high vacuum for 24 hours.
The semi-solid was taken up in ether/hexane and filtered to provide
the title compound as its trifluoroacetic acid salt.
Compound 239C
4-((4,4-difluorocyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[0690] The title compound was prepared by substituting Compound
239B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 239D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0691] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 239C for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 12.40 (s, 1H), 11.61 (br s, 1H), 8.53 (m, 1H), 8.50 (d,
1H), 7.99 (d, 1H), 7.73 (d, 1H), 7.49 (m, 2H), 7.32 (d, 2H), 7.04
(d, 2H), 7.00 (d, 1H), 6.65 (d, 1H), 6.32 (s, 1H), 6.21 (s, 1H),
3.37 (m, 4H), 3.06 (m, 4H), 2.73 (m, 2H), 2.18 (m, 4H), 1.97 (m,
4H), 1.81 (m, 4H), 1.38 (m, 2H), 1.20 (m, 4H), 0.92 (s, 6H).
Compound 240
N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phe-
nyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 240A
4-(1-tert-butylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulf-
onamide
[0692] To a mixture of
4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (307 mg) and
Compound 227A (156 mg) in tetrahydrofuran (4 ml) was added Hunig's
Base (1 ml). The mixture was stirred for 3 days. The mixture was
diluted with ethyl acetate (300 ml) and water (100 ml) and stirred
until the solid disappeared into the solution. The layers were
separated and the organic phase was washed with water, brine and
dried over Na.sub.2SO.sub.4. After filtration, the combined aqueous
layers were extracted again with ethyl acetate and the combined
organic phase was dried over Na.sub.2SO.sub.4. After filtration,
the solvent was evaporated to provide the title compound.
Compound 240B
N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phe-
nyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0693] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 240A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.53 (s, 1H), 8.04 (s, 1H), 7.94 (d, 1H), 7.86 (m, 1H),
7.55 (d, 2H), 7.44 (d, 1H), 7.33 (m, 3H), 7.05 (d, 2H), 6.92 (m,
1H), 6.62 (dd, 1H), 6.43 (m, 1 H), 6.29 (d, 2H), 3.79 (m, 1H), 3.05
(m, 6H), 2.73 (s, 3H), 2.19 (m, 8H), 1.96 (s, 3H), 1.27 (m, 12H),
0.92 (s, 6H).
Compound 241
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)-3-[(trifluorome-
thyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzami-
de
Compound 241A
tert-butyl
2-((4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)methyl)m-
orpholine-4-carboxylate
[0694] The title compound was prepared by substituting tert-butyl
2-(aminomethyl)morpholine-4-carboxylate for
(tetrahydropyran-4-yl)methylamine and
4-fluoro-3-(trifluoromethylsulfonyl)benzene sulfonamide for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
1F.
Compound 241B
tert-butyl
2-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfam-
oyl)-2-(trifluoromethylsulfonyl)phenylamino)methyl)morpholine-4-carboxylat-
e
[0695] The title compound was prepared by substituting Compound
241A for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G.
Compound 241C
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(morpholin-2-ylmethylamino)-3-
-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide
[0696] The title compound was prepared by substituting Compound
241B for Compound 1A in the procedure for Compound 1B.
Compound 241D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)-3-[(trifluorome-
thyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzami-
de
[0697] The title compound was prepared by substituting Compound
241C for tert-butyl piperazine-1-carboxylate and oxetan-3-one for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 1H), 8.15 (d, 1H), 8.04 (d, 1H), 7.92 (dd, 1H), 7.54 (d, 1H),
7.51 (t, 1H), 7.48 (d, 1H), 7.34 (d, 2H), 7.25 (m, 1H), 7.04 (m,
3H), 6.68 (dd, 1H), 6.41 (m, 1H), 6.19 (d, 1H), 4.54 (t, 2H), 4.43
(m, 2H), 3.85 (m, 1H), 3.69 (m, 1H), 3.52 (m, 1H), 3.48 (m, 1H),
3.39 (m, 2H), 3.07 (m, 4H), 2.77 (br s, 2H), 2.69 (d, 1H), 2.56 (d,
1H), 2.21 (br s, 4H), 2.15 (t, 2H), 1.94 (m, 3H), 1.76 (t, 1H),
1.38 (t, 2H), 0.92 (s, 6H).
Compound 242
N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 242A
5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfo-
namide
[0698] The title compound was prepared by substituting Compound 40A
for 4-fluoro-3-nitrobenzenesulfonamide in the procedure for
Compound 138D.
Compound 242B
N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0699] The title compound was prepared by substituting Compound
242A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.71 (s, 1H),
8.41 (d, 1H), 8.07 (d, 1H), 7.93 (d, 1H), 7.60 (d, 1H), 7.51-7.53
(m, 2H), 7.40 (s, 1H), 7.33-7.35 (m, 2H), 7.03-7.05 (m, 2H), 6.68
(dd, 1H), 6.42 (dd, 1H), 6.16 (d, 1H), 3.77 (d, 1H), 3.69-3.71 (m,
3H), 3.48-3.53 (m, 2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.14-2.20 (m,
6H), 1.96 (s, 2H), 1.65-1.76 (m, 4H), 1.38 (t, 2H), 0.93 (s,
6H).
Compound 243
N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 243A
5-chloro-6-(1-cyclopropylpiperidin-4-ylamino)pyridine-3-sulfonamide
[0700] The title compound was prepared by substituting Compound 40A
for 4-chloro-3-nitrobenzenesulfonamide,
1-cyclopropylpiperidin-4-amine for 4-methylpiperazin-1-amine
dihydrochloride and Hunig's base for
N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethylethane-1,2-diamine in
the procedure for Compound 6A.
Compound 243B
N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0701] The title compound was prepared by substituting Compound
243A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H),
8.40 (d, 1H), 8.05 (d, 1H), 7.88 (d, 1H), 7.56 (d, 1H), 7.50 (m,
2H), 7.34 (d, 2H), 7.03 (d, 2H), 6.97 (br d, 1H), 6.66 (dd, 1H),
6.40 (m, 1H), 6.16 (d, 1H), 4.04 (m, 1H), 3.03 (br m, 6H), 2.73 (s,
2H), 2.42 (br m, 2H), 2.18 (br m, 6H), 1.95 (s, 2H), 1.80 (m, 3H),
1.62 (m, 2H), 1.38 (t, 2H), 0.91 (s, 6H), 0.47 (m, 2H), 0.40 (br m,
2H).
Compound 244
N-[(5-chloro-6-{[(2S)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)s-
ulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 244A
(S)-tert-butyl
2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-carboxylate
[0702] The title compound was prepared by substituting
(S)-tert-butyl 2-(hydroxymethyl)-morpholine-4-carboxylate for
tetrahydro-2H-pyran-4-yl-methanol and Compound 40A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 244B
(S)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide
[0703] The title compound was prepared by substituting Compound
244A for Compound 113A in the procedure for Compound 134A.
Compound 244C
(S)-5-chloro-6-((4-(cyano
methyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide
[0704] The title compound was prepared by substituting Compound
244B for Compound 134A and 2-bromoacetonitrile for methyl iodide in
the procedure for Compound 134B.
Compound 244D
N-[(5-chloro-6-{[(2S)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)s-
ulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0705] The title compound was prepared by substituting Compound
244C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 12.99 (s, 1H), 9.09 (d,
1H), 8.70 (d, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d, 2H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.48 (m, 1H),
4.55 (dd, 1H), 4.43 (dd, 1H), 4.05 (m, 1H), 3.85 (d, 1H), 3.76 (s,
2H), 3.63 (dt, 1H), 3.06 (m, 4H), 2.91 (d, 1H), 2.77 (s, 2H), 2.58
(d, 1H), 2.51-2.44 (m, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s,
2H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 245
N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-
-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 245A
(S)-5-chloro-6-(4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridine-
-3-sulfonamide
[0706] The title compound was prepared by substituting Compound
244B for Compound 134A and 2-(dimethylamino)acetyl chloride
hydrochloride for methyl iodide in the procedure for Compound
134B.
Compound 245B
N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-
-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0707] The title compound was prepared by substituting Compound
245A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.09 (d,
1H), 8.69 (s, 1H), 8.42 (s, 1H), 8.11 (t, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d, 2H), 6.76 (s, 1H), 6.54 (s, 1H), 6.49 (s, 1H),
4.85-4.46 (m, 3H), 4.45-3.87 (m, 3H), 3.50 (m, 1H), 3.37 (dd, 1H),
3.21 (m, 2H), 3.07 (m, 4H), 2.86 (t, 1H), 2.77 (s, 2H), 2.27 (m,
8H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 246
N-[(5-chloro-6-{[(2R)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)s-
ulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 246A
(R)-tert-butyl
2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-carboxylate
[0708] The title compound was prepared by substituting
(R)-tert-butyl 2-(hydroxymethyl)-morpholine-4-carboxylate for
tetrahydro-2H-pyran-4-yl-methanol and Compound 40A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 246B
(R)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide
[0709] The title compound was prepared by substituting Compound
246A for Compound 113A in the procedure for Compound 134A.
Compound 246C
(R)-5-chloro-6-((4-(cyano
methyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide
[0710] The title compound was prepared by substituting Compound
246B for Compound 134A and 2-bromoacetonitrile for methyl iodide in
the procedure for Compound 134B.
Compound 246D
N-[(5-chloro-6-{[(2R)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)s-
ulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0711] The title compound was prepared by substituting Compound
246C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 12.99 (s, 1H), 9.09 (d,
1H), 8.70 (d, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d, 2H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.48 (m, 1H),
4.55 (dd, 1H), 4.43 (dd, 1H), 4.05 (m, 1H), 3.85 (d, 1H), 3.76 (s,
2H), 3.63 (dt, 1H), 3.06 (m, 4H), 2.91 (d, 1H), 2.77 (s, 2H), 2.58
(d, 1H), 2.51-2.44 (m, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s,
2H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 247
N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-
-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 247A
(R)-5-chloro-6-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridin-
e-3-sulfonamide
[0712] The title compound was prepared by substituting Compound
246B for Compound 134A and 2-(dimethylamino)acetyl chloride
hydrochloride for methyl iodide in the procedure for Compound
134B.
Compound 247B
N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-
-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0713] The title compound was prepared by substituting Compound
247A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.09 (d,
1H), 8.69 (s, 1H), 8.42 (s, 1H), 8.11 (t, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d, 2H), 6.76 (s, 1H), 6.54 (s, 1H), 6.49 (s, 1H),
4.85-4.46 (m, 3H), 4.45-3.87 (m, 3H), 3.50 (m, 1H), 3.37 (dd, 1H),
3.21 (m, 2H), 3.07 (m, 4H), 2.86 (t, 1H), 2.77 (s, 2H), 2.27 (m,
8H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 248
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 248A
5-bromo-3-fluoro-2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine
[0714] The title compound was prepared by substituting
5-bromo-2,3-difluoropyridine for 4-fluoro-3-nitrobenzenesulfonamide
and Compound 37C for (tetrahydro-2H-pyran-4-yl)methanol in the
procedure for Compound 24A.
Compound 248B
tert-butyl
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-
-ylcarbamate
Compound 248A (0.308 g), tert-butyl carbamate (0.141 g),
palladium(II) acetate (0.011 g), Xantphos (0.043 g) and cesium
carbonate (0.489 g) were combined with dioxane (5.0 ml) in a 20-ml
vial equipped with a magnetic stir bar. The vial was flushed with
nitrogen, capped and stirred at 100.degree. C. overnight.
Additional palladium(II) acetate (0.011 g), Xantphos (0.043 g) and
tert-butyl carbamate (0.141 g) were added and heating was continued
at 100.degree. C. for 8 hours. The cooled reaction mixture was
diluted with ethyl acetate, washed with water and brine, dried
(MgSO.sub.4), filtered and concentrated. The concentrate was
chromatographed on silica gel with 7-25% ethyl acetate in hexanes
as the eluent.
Compound 248C
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonyl
chloride
[0715] Under ice-cooling, thionyl chloride (1.563 ml) was added
dropwise over 20 minutes to water (9 ml). The mixture was stirred
for 12 hours to give a SO.sub.2-containing solution. Separately,
Compound 248B (0.295 g) was added to a mixture of 1,4-dioxane (3.2
ml) and concentrated HCl (8 ml) at 0.degree. C. After stirring for
15 minutes, a solution of sodium nitrite (0.065 g) in water (2 ml)
was added dropwise and stirring was continued at 0.degree. C. for 3
hours. Copper(I) chloride (0.042 g) and then the freshly prepared
solution of diazotized material were added sequentially to the
previously prepared SO.sub.2-containing solution. The resulting
solution was stirred for 30 minutes and then extracted with ethyl
acetate (2.times.125 ml). The combined extracts were dried
(MgSO.sub.4), filtered and concentrated. The concentrate was
chromatographed on silica gel with 5% ethyl acetate in hexanes as
the eluent.
Compound 248D
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonami-
de
Compound 248C (0.08 g) in isopropanol (2 ml) at 0.degree. C. was
treated with ammonium hydroxide (1.697 ml), stirred overnight and
then concentrated to dryness. The obtained solid was slurried in
water, filtered, rinsed with water and dried under high vacuum to
provide the title compound.
Compound 248E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0716] The title compound was prepared by substituting Compound
248D for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.05 (s, 1H), 9.03 (d,
1H), 8.44 (dd, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.67 (m, 1H), 7.65
(d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.77 (dd, 1H), 6.53 (d, 1H),
6.49 (dd, 1H), 4.55 (d, 2H), 3.80 (m, 4H), 3.08 (m, 4H), 2.77 (s,
2H), 2.26 (t, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.88 (m, 4H), 1.39
(t, 2H), 0.94 (s, 6H).
Compound 250
N-({5-chloro-6-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyridin-3-yl}s-
ulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 250A
5-chloro-6-((3-methyloxetan-3-yl)methoxy)pyridine-3-sulfonamide
[0717] The title compound was prepared by substituting
(3-methyloxetan-3-yl)methanol for
(tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 250B
N-({5-chloro-6-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyridin-3-yl}s-
ulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0718] The title compound was prepared by substituting Compound
250A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.05 (s, 1H), 9.22 (d,
1H), 8.51 (d, 1H), 8.42 (d, 1H), 8.09 (d, 1H), 7.66 (t, 2H),
7.43-7.46 (m, 2H), 7.04-7.09 (m, 2H), 6.75 (dd, 1H), 6.45-6.54 (m,
2H), 4.47 (s, 2H), 3.81-3.84 (m, 2H), 3.74 (d, 2H), 3.03-3.11 (m,
4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.10-2.17 (m, 4H), 1.97 (s, 2H),
1.39 (t, 2H), 1.16 (s, 3H), 0.94 (s, 6H).
Compound 251
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfon-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 251A
5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamid-
e
[0719] The title compound was prepared by substituting
(4-fluorotetrahydro-2H-pyran-4-yl)methanol for
(tetrahydro-2H-pyran-4-yl)methanol and
5-bromo-6-chloropyridine-3-sulfonamide for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 251B
6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[0720] To a suspension of
5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonami-
de (200 mg) and cyclohexene (0.549 ml) in ethyl acetate (10 ml) was
added 10% palladium on carbon (57.6 mg). The suspension was stirred
for 60 minutes at 120.degree. C. The reaction mixture was filtered
and concentrated. The product was purified by reverse-phase flash
chromatography (C18, 150 g, 10%-100%
acetonitrile/H.sub.2O/trifluoroacetic acid 0.1%).
Compound 251C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfon-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0721] The title compound was prepared by substituting Compound
251B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.06 (s, 1H), 9.29 (d,
1H), 8.50 (dd, 1H), 8.41 (d, 1H), 8.07 (d, 1H), 7.66-7.70 (m, 1H),
7.64 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.84 (d, 1H), 6.75 (dd,
1H), 6.52 (d, 1H), 6.49 (dd, 1H), 4.50 (d, 2H), 3.81-3.89 (m, 2H),
3.70-3.81 (m, 2H), 3.02-3.12 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H),
2.10-2.18 (m, 4H), 1.97 (s, 2H), 1.77-1.94 (m, 4H), 1.39 (t, 2H),
0.94 (s, 6H).
Compound 252
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(1,3-difluoropropan-2-yl)morpholin-2-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 252A
tert-butyl
(4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate
[0722] The title compound was prepared by substituting
1,3-difluoropropan-2-one for 4'-chlorobiphenyl-2-carboxaldehyde and
tert-butyl morpholin-2-ylmethylcarbamate for tert-butyl
piperazine-1-carboxylate in the procedure for Compound 1A.
Compound 252B
(4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methanamine
[0723] A solution of Compound 252A (538 mg) in dioxane (4 ml) was
treated with 4.0M HCl in dioxane solution (1.8 ml). The reaction
was stirred at room temperature overnight. The reaction mixture was
concentrated under vacuum and used without further
purification.
Compound 252C
4-((4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylamino)-3-nitrobenzenes-
ulfonamide
[0724] The title compound was prepared by substituting Compound
252B for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 252D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(1,3-difluoropropan-2-yl)morpholin-2-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0725] The title compound was prepared by substituting Compound
252C for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.64 (s, 1H), 8.59 (t, 1H),
8.57 (d, 1H), 8.04 (d, 1H), 7.83 (dd, 1H), 7.51 (m, 3H), 7.33 (d,
2H), 7.07 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.39 (m, 1H), 6.19
(d, 1H), 4.69 (t, 2H), 4.57 (t, 2H), 3.85 (m, 1H), 3.70 (m, 1H),
3.52 (m, 2H), 3.41 (m, 2H), 3.07 (br s, 4H), 2.91 (d, 1H), 2.74 (m,
3H), 2.59 (m, 1H), 2.43 (m, 1H), 2.20 (m, 4H), 2.15 (m, 2H), 1.95
(br s, 2H), 1.39 (t, 2H), 0.92 (s, 6H).
Compound 253
N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfon-
yl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 253A
tert-butyl
4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)piperidine-1-car-
boxylate
[0726] The title compound was prepared by substituting tert-butyl
4-(hydroxymethyl)piperidine-1-carboxylate for
tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 253B
5-chloro-6-(piperidin-4-ylmethoxy)pyridine-3-sulfonamide
ditrifluoroacetic acid
[0727] The title compound was prepared by substituting Compound
253A for Compound 39A in the procedure for Compound 39B.
Compound 253C
5-chloro-6-((1-(cyanomethyl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide
[0728] Compound 253B (0.061 g), 2-chloroacetonitrile (0.017 g),
sodium carbonate (0.025 g) and N,N-dimethylformamide (1 ml) were
combined in a 4-ml vial and heated at 60.degree. C. overnight. The
cooled reaction mixture was diluted with ethyl acetate, washed with
water and brine, dried (MgSO.sub.4), filtered and concentrated. The
concentrate was chromatographed on silica gel with 2-10% methanol
in CH.sub.2Cl.sub.2 as the eluent.
Compound 253D
N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfon-
yl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0729] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 253C for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (400 MHz, pyridine-d.sub.5) .delta.
13.04 (s, 1H), 9.14 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.66 (t,
2H), 7.44 (m, 2H), 7.07 (m, 2H), 6.74 (dd, 1H), 6.50 (m, 2H), 4.18
(d, 2H), 3.64 (s, 2H), 3.05 (s, 4H), 2.77 (m, 4H), 2.24 (m, 4H),
2.13 (m, 4H), 1.97 (s, 2H), 1.69 (m, 3H), 1.41 (m, 4H), 0.93 (s,
6H).
Compound 254
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-ni-
trophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 254A
(R)-tert-butyl
3-(2-nitro-4-sulfamoylphenylamino)pyrrolidine-1-carboxylate
[0730] The title compound was prepared by substituting
(R)-tert-butyl 3-aminopyrrolidine-1-carboxylate for
1-(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 254B
(R)-3-nitro-4-(pyrrolidin-3-ylamino)benzenesufonamide
[0731] The title compound was prepared by substituting Compound
254A for Compound 113A in the procedure for Compound 134A.
Compound 254C
(R)-4-(1-(2-(2-methoxyethoxy)ethyl)pyrrolidin-3-ylamino)-3-nitrobenzene
sulfonamide
[0732] To a solution of
(R)-3-nitro-4-(pyrrolidin-3-ylamino)benzenesulfonamide (440 mg) in
N,N-dimethylformamide (10 ml) was added sodium carbonate (132 mg)
and 1-bromo-2-(2-methoxyethoxy)ethane (0.155 ml). The reaction
mixture was heated at 60.degree. C. for 18 hours and after an
aqueous workup, the crude product was purified on silica gel with a
2.5-10% methanol in methylene chloride gradient to provide the
title compound.
Compound 254D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-ni-
trophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yl-oxy)benzamide
[0733] The title compound was prepared by substituting Compound
254C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 12.96 (m, 1H), 9.25 (m,
1H), 8.57 (d, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.11 (d, 1H), 7.66
(t, 1H) 7.64 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.82 (d, 1H),
6.76 (dd, 1H), 6.55 (m, 1H), 6.47 (m, 1H), 5.26 (br s, 1H), 4.02
(m, 1H), 3.63 (m, 4H), 3.53 (m, 2H), 3.28 (s, 3H), 3.07 (m, 4H),
2.89-2.81 (m, 2H), 2.78 (s, 2H), 2.75-2.66 (m, 3H), 2.37 (m, 1H),
2.26 (m, 2H), 2.24-2.18 (m, 1H), 2.15 (m, 4H), 1.97 (s, 2H), 1.65
(m, 1H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 255
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 255A
(R)-4-(1-(2-(dimethylamino)acetyl)pyrrolidin-3-ylamino)-3-nitrobenzenesufo-
namide
[0734] The title compound was prepared by substituting
2-(dimethylamino)acetyl chloride, hydrochloric acid for
1-bromo-2-(2-methoxyethoxy)ethane in the procedure for Compound
254C except the reaction was stirred at ambient temperature for 18
hours.
Compound 255B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0735] The title compound was prepared by substituting Compound
255A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.01 (d, 1H), 9.26 (m,
1H), 8.46-8.33 (m, 3H), 8.14 (d, 1H), 7.66 (m, 2H), 7.44 (d, 2H),
7.07 (d, 2H), 7.01-6.89 (m, 1H), 6.76 (dd, 1H), 6.55 (m, 1H), 6.48
(m, 1H), 5.32 (br s, 1H), 4.27-4.14 (m, 1H), 4.05-3.95 (m, 1H),
3.82-3.62 (m, 3H), 3.27-3.15 (m, 2H), 3.07 (m, 4H), 2.77 (s, 2H),
2.34 (2, 3H), 2.32 (s, 3H), 2.30-2.20 (m, 3H), 2.15 (m, 4H), 1.97
(s, 2H), 1.87-1.81 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 256
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[1-(oxetan-3-yl)azetidin-3-yl]amino}phenyl)sulfonyl]--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 256A
tert-butyl
3-(2-nitro-4-sulfamoylphenylamino)azetidine-1-carboxylate
[0736] The title compound was prepared by substituting tert-butyl
3-aminoazetidine-1-carboxylate for 4-methylpiperazin-1-amine
dihydrochloride in the procedure for Compound 6A.
Compound 256B
4-(azetidin-3-ylamino)-3-nitrobenzenesulfonamide
[0737] The title compound was prepared by substituting Compound
256A for (S)-1-tert-butyl 2-methyl
4,4-difluoropyrrolidine-1,2-dicarboxylate in the procedure for
Compound 168A.
Compound 256C
3-nitro-4-(1-(oxetan-3-yl)azetidin-3-ylamino)benzenesulfonamide
[0738] The title compound was prepared by substituting Compound
256B for tert-butyl piperazine-1-carboxylate and 3-oxetanone for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 256D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[1-(oxetan-3-yl)azetidin-3-yl]amino}phenyl)sulfonyl]--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0739] The title compound was prepared by substituting Compound
256C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.04 (s, 1H), 9.27 (d,
1H), 8.62 (d, 1H), 8.42 (d, 1H), 8.35 (dd, 1H), 8.09 (d, 1H), 7.67
(m, 1H), 7.63 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H),
6.67 (d, 1H), 6.55 (d, 1H), 6.48 (dd, 1H), 4.66 (t, 2H), 4.58 (m,
2H), 4.23 (m, 1H), 3.71 (m, 3H), 3.12 (dd, 2H), 3.07 (m, 4H), 2.77
(s, 2H), 2.26 (t, 2H), 2.14 (t, 4H), 1.97 (s, 2H), 1.39 (t, 2H),
0.94 (s, 6H).
Compound 257
N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 257A
tert-butyl
4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperid-
ine-1-carboxylate
[0740] The title compound was prepared by substituting Compound
126A for (tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 257B
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide
ditrifluoroacetic acid
[0741] The title compound was prepared by substituting Compound
257A for Compound 39A in the procedure for Compound 39B.
Compound 257C
5-chloro-6-((1-(cyanomethyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-sul-
fonamide
[0742] Compound 257B (0.166 g) in acetonitrile (3 ml) was treated
with 2-chloroacetonitrile (0.027 g) and sodium carbonate (0.064 g),
heated at 60.degree. C. overnight, cooled to room temperature and
chromatographed on silica gel with 0 to 3% methanol in
CH.sub.2Cl.sub.2 as the eluent. The obtained solid was slurried in
water, filtered, rinsed with water and diethyl ether, and dried in
a vacuum oven at 80.degree. C.
Compound 257D
N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0743] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 257C for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (400 MHz, pyridine-d.sub.5) .delta.
13.05 (s, 1H), 9.12 (d, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d,
1H), 7.66 (m, 2H), 7.44 (m, 2H), 7.07 (m, 2H), 6.75 (dd, 1H), 6.50
(m, 2H), 4.49 (d, 2H), 3.72 (s, 2H), 3.06 (m, 4H), 2.77 (s, 2H),
2.73 (m, 4H), 2.26 (t, 2H), 2.13 (m, 4H), 2.07 (m, 2H), 1.90 (m,
4H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 258
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 258A
(S)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate
[0744] To a solution of (S)-tert-butyl
2-(hydroxymethyl)morpholine-4-carboxylate (1 g) in dichloromethane
(50 ml) was added triethylamine (1.604 ml) and
4-methylbenzene-1-sulfonyl chloride (1.097 g). The mixture was
stirred at ambient temperature under nitrogen for 72 hours. The
reaction was diluted with methylene chloride (50 ml) and brine (100
ml). The brine layer was extracted with methylene chloride (75 ml).
The combined organics were dried over sodium sulfate, filtered and
concentrated. The crude material was purified on a silica gel
column eluting with a 15-65% ethyl acetate in hexane gradient to
provide the title compound.
Compound 258B
(S)-tert-butyl 2-(azidomethyl)morpholine-4-carboxylate
[0745] A solution of Compound 258A (1.66 g) and sodium azide (0.581
g) in anhydrous N,N-dimethylformamide (10 ml) was stirred at
90.degree. C. for 4 hours. The mixture was cooled and concentrated
to dryness. The residue was taken up in 5% aqueous sodium carbonate
solution and extracted with methylene chloride. The organic
solution was dried (MgSO.sub.4), filtered and concentrated to give
a solid.
Compound 258C
(R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate
[0746] This compound was obtained by hydrogenation of Compound 258B
under 60 psi of hydrogen over 10% palladium on carbon in methanol
for 24 hours, followed by filtration and evaporation of the
solvent.
Compound 258D
(R)-tert-butyl
2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate
[0747] The title compound was prepared by substituting Compound
258C for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 258E
(S)-4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide
[0748] The title compound was prepared by substituting Compound
258D for Compound 113A in the procedure for Compound 134A.
Compound 258F
(R)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenz-
enesulfonamide
[0749] The title compound was prepared by substituting Compound
258E for Compound 134A and 2-(dimethylamino)acetyl chloride
hydrochloride for methyl iodide in the procedure for Compound
134B.
Compound 258G
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0750] The title compound was prepared by substituting Compound
258F for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.27 (d,
1H), 8.87 (bs, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (dd, 1H),
7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (dd, 1H), 6.75 (d,
1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.55 (dd, 1H), 4.20 (dd, 1H),
3.95-3.76 (m, 2H), 3.60-3.40 (m, 3H), 3.32 (dd, 1H), 3.25-3.12 (m,
2H), 3.07 (m, 4H), 2.80 (m, 1H), 2.77 (s, 2H), 2.26 (s, 6H), 2.23
(s, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s,
6H).
Compound 259
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 259A
(R)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate
[0751] The title compound was prepared by substituting
(R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate for
(S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate in the
procedure for Compound 258A.
Compound 259B
(R)-tert-butyl 2-(azidomethyl)morpholine-4-carboxylate
[0752] The title compound was prepared by substituting Compound
259A for Compound 258A in the procedure for Compound 258B.
Compound 259C
(S)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate
[0753] The title compound was prepared by substituting Compound
259B for Compound 258B in the procedure for Compound 258C.
Compound 259D
(S)-tert-butyl
2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate
[0754] The title compound was prepared by substituting Compound
259C for (tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 259E
(R)-4-(morpholin-2-ylmethylamino)-3-nitrobenzene sulfonamide
[0755] The title compound was prepared by substituting Compound
259D for Compound 113A in the procedure for Compound 134A.
Compound 259F
(S)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenz-
enesulfonamide
[0756] The title compound was prepared by substituting Compound
259E for Compound 134A and 2-(dimethylamino)acetyl chloride
hydrochloride for methyl iodide in the procedure for Compound
134B.
Compound 259G
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0757] The title compound was prepared by substituting Compound
259F for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.27 (d,
1H), 8.87 (bs, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (dd, 1H),
7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (dd, 1H), 6.75 (d,
1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.55 (dd, 1H), 4.20 (dd, 1H),
3.95-3.76 (m, 2H), 3.60-3.40 (m, 3H), 3.32 (dd, 1H), 3.25-3.12 (m,
2H), 3.07 (m, 4H), 2.80 (m, 1H), 2.77 (s, 2H), 2.26 (s, 6H), 2.23
(s, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s,
6H).
Compound 260
N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}pyridin-3-yl-
)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 260A
5-chloro-6-((1-(2-(dimethylamino)acetyl)piperidin-4-yl)methoxy)pyridine-3--
sulfonamide
[0758] Compound 253B (0.061 g), 2-(dimethylamino)acetyl chloride,
hydrochloric acid (0.061 g), and sodium carbonate (0.032 g) were
combined in a 4-ml vial with N,N-dimethylformamide (2 ml). The
mixture was stirred at ambient temperature for 3 days. Additional
2-(dimethylamino)acetyl chloride, hydrochloric acid (0.037 g),
sodium carbonate (0.032 g) and N,N-dimethylformamide (1 ml) were
added and stirring was continued for 24 hours. The reaction mixture
was diluted with ethyl acetate, washed with water and brine, dried
(MgSO.sub.4), filtered, concentrated and chromatographed on silica
gel with 0 to 20% methanol in CH.sub.2Cl.sub.2 as the eluent.
Compound 260B
N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}pyridin-3-yl-
)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0759] The title compound was prepared by substituting Compound
260A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, pyridine-d.sub.5) .delta. 12.91 (s, 1H), 9.16 (d,
1H), 8.75 (d, 1H), 8.51 (d, 1H), 8.33 (d, 1H), 7.70 (d, 1H), 7.62
(d, 1H), 7.45 (m, 2H), 7.09 (m, 2H), 6.77 (dd, 1H), 6.60 (d, 1H),
6.45 (d, 1H), 4.81 (d, 1H), 4.15 (m, 3H), 3.24 (m, 2H), 3.04 (m,
4H), 2.89 (m, 1H), 2.79 (s, 2H), 2.53 (m, 1H), 2.29 (m, 6H), 2.26
(m, 2H), 2.18 (m, 4H), 1.98 (m, 2H), 1.91 (m, 1H), 1.71 (m, 2H),
1.39 (t, 2H), 1.25 (m, 2H), 0.94 (s, 6H).
Compound 261
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-y-
l)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 261A
(R)-tert-Butyl
3-(3-chloro-5-sulfamoylpyridin-2-yloxy)pyrrolidine-1-carboxylate
[0760] The title compound was prepared by substituting Compound 40A
for 4-fluoro-3-nitrobenzenesulfonamide and (R)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 261B
(R)-5-Chloro-6-(pyrrolidin-3-yloxy)pyridine-3-sulfonamide
[0761] The title compound was prepared by substituting Compound
261A for tert-butyl
(4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate in the
procedure for Compound 252B.
Compound 261C
(R)-5-chloro-6-(1-(2,2-difluoroethyl)pyrrolidin-3-yloxy)pyridine-3-sulfona-
mide
[0762] A mixture of Compound 261B (353 mg),
1,1-difluoro-2-iodoethane (268 mg), sodium carbonate (283 mg) in
N,N-dimethylformamide (10 ml) was heated at 80.degree. C.
overnight. The reaction mixture was cooled to room temperature and
diluted with ethyl acetate. The organic phase was washed with
water, brine, dried over magnesium sulfate, filtered, and
concentrated. The residue was loaded onto silica gel column and
eluted using a gradient of 0.5 to 3% methanol in dichloromethane to
provide the title compound.
Compound 261D
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-y-
l)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0763] The title compound was prepared by substituting Compound
261C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.55 (s, 1H),
8.04 (s, 1H), 7.95 (d, 1H), 7.58 (d, 1H), 7.44 (t, 1H), 7.35 (m,
3H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.33 (m, 1H), 6.24 (d, 1H),
6.25-5.97 (m, 1H), 5.39 (m, 1H), 2.98 (m, 6H), 2.86 (m, 6H), 2.55
(m, 2H), 2.24 (m, 7H), 1.96 (s, 2H), 1.83 (m, 1H), 1.39 (t, 2H),
0.93 (s, 6H)
Compound 262
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 262A
(R)-4-(1-(cyanomethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide
[0764] The title compound was prepared by substituting
2-bromoacetonitrile for 1-bromo-2-(2-methoxyethoxy)ethane in the
procedure for Compound 254C.
Compound 262B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0765] The title compound was prepared by substituting Compound
262A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (400 MHz, pyridine-d.sub.5) .delta. 13.03 (s, 1H), 9.27 (d,
1H), 8.53 (d, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.10 (d, 1H),
7.67-7.64 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.81 (d, 1H), 6.76
(dd, 1H), 6.54 (m, 1H), 6.48 (m, 1H), 5.15 (br s, 1H), 4.10 (m,
1H), 3.89 (s, 2H), 3.07 (m, 4H), 2.93-2.86 (m, 2H), 2.80-2.77 (m,
3H), 2.61-2.53 (m, 1H), 2.31-2.21 (m, 3H), 2.14 (m, 4H), 1.97 (s,
2H), 1.75-1.68 (m, 1H), 1.39 (t, 2H), 0.94 (m, 6H).
Compound 263
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({5-chlor-
o-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 263A
tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate
[0766] Sodium hydride (6.63 g, 60% in mineral oil) was added to
trimethylsulfoxonium iodide (36.5 g) in dimethyl sulfoxide (150 ml)
and tetrahydrofuran (150 ml), was and stirred for 30 minutes.
tert-Butyl 4-oxopiperidine-1-carboxylate (25.4 g) was added and the
reaction was stirred for 3 hours. The reaction was poured into
water (800 ml) and extracted three times with ether. The combined
extracts were washed three times with water, and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to yield the crude
product which was used without further purification.
Compound 263B
tert-butyl
4-(2-(benzyloxy)benzyl)-4-hydroxypiperidine-1-carboxylate
[0767] (2-(Benzyloxy)phenyl)magnesium bromide (33.8 ml, 1M) was
added to a solution of Compound 263A (6.0 g) and CuI (1.07 g) in
tetrahydrofuran (220 ml) at 0.degree. C. over 10 minutes. The
reaction was quenched with pH 7 buffer (20 ml), extracted twice
with ether, and the combined extracts were washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The crude
product was chromatographed on silica gel using 2-20% ethyl acetate
in hexanes to provide the title compound.
Compound 263C
tert-butyl
4-hydroxy-4-(2-hydroxybenzyl)piperidine-1-carboxylate
[0768] Compound 263B (11.5 g) and methanol (120 ml) were added to
Raney Nickel (1.150 g) in a 250 ml SS pressure bottle and stirred
for 1 hour at 30 psi under hydrogen. The mixture was filtered
through a nylon membrane and the solution was concentrated to yield
the title compound.
Compound 263D
tert-butyl
4-hydroxy-4-(2-(trifluoromethylsulfonyloxy)benzyl)piperidine-1--
carboxylate
[0769] A mixture of Compound 263C (4.6 g),
N-phenylbis(trifluoromethanesulfonimide) (5.88 g), and Hunig's base
(2.88 ml) in dichloromethane (100 ml) was stirred for 24 hours. The
mixture was concentrated and chromatographed on silica gel using
5-50% ethyl acetate in hexanes to provide the title compound.
Compound 263E
tert-butyl
4-((4'-chlorobiphenyl-2-yl)methyl)-4-hydroxypiperidine-1-carbox-
ylate
[0770] A mixture of Compound 263D (4.3 g), 4-chlorophenylboronic
acid (1.84 g), K.sub.3PO.sub.4 (2.91 g), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.36
g) in 2-methyltetrahydrofuran (50 ml) was stirred at 70.degree. C.
for 24 hours. The reaction was cooled and quenched with water (50
ml), extracted twice with ether, and the combined extracts were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude product was chromatographed on silica gel
using 5-30% ethyl acetate in hexanes to provide the title
compound.
Compound 263F
tert-butyl
4-((4'-chlorobiphenyl-2-yl)methyl)-4-methoxypiperidine-1-carbox-
ylate
[0771] Sodium hydride (0.36 g, 60% in mineral oil) was added to
Compound 263E (4.3 g), in tetrahydrofuran (40 ml) and the reaction
was stirred for 10 minutes. Hexamethylphosphoramide (5 ml) and
CH.sub.3I (2.34 ml) were added and the reaction was stirred at
50.degree. C. for 18 hours. The reaction was cooled and quenched
with water (50 ml), extracted twice with ether, and the combined
extracts were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude product was chromatographed
on silica gel using 5-25% ethyl acetate in hexanes to provide the
title compound.
Compound 263G
4-((4'-chlorobiphenyl-2-yl)methyl)-4-methoxypiperidine
[0772] The title compound was prepared by substituting Compound
263F for Compound 1A in the procedure for Compound 1B.
Compound 263H
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)-
methyl)-4-methoxypiperidin-1-yl)benzoate
[0773] A solution of Compound 263G (1.4 g), Compound 3H (1.06 g)
and Hunig's base (0.75 ml) in dimethylsulfoxide (20 ml) was stirred
at 120.degree. C. for 18 hours. The reaction was cooled and
quenched with water (200 ml), extracted three times with ether, and
the combined extracts were washed three times with water, and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
crude product was chromatographed on silica gel using 5-50% ethyl
acetate in hexanes to provide the title compound.
Compound 263I
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)-
-4-methoxypiperidin-1-yl)benzoic acid
[0774] The title compound was prepared by substituting Compound
263H for Compound 31 in the procedure for Compound 3J.
Compound 263J
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({5-chlor-
o-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0775] The title compound was prepared by substituting Compound
263I for Compound 1E and Compound 96A for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.71 (s, 1H), 11.58 (br s, 1H),
8.58 (d, 1H), 8.28 (d, 1H), 8.05 (d, 1H), 7.56 (d, 1H), 7.52 (m,
1H), 7.46 (d, 1H), 7.44 (d, 2H), 7.28 (m, 5H), 7.11 (dd, 1H), 6.62
(dd, 1H), 6.41 (dd, 1H), 6.11 (d, 1H), 4.54 (d, 2H), 3.75 (m, 2H),
3.59 (m, 2H), 3.20 (m, 2H), 2.97 (s, 3H), 2.81 (m, 2H), 2.74 (m,
2H), 1.89 (m, 2H), 1.83 (m, 2H), 1.36 (m, 2H), 1.09 (m, 2H).
Compound 264
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({3-nitro-
-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2-
,3-b]pyridin-5-yloxy)benzamide
[0776] The title compound was prepared by substituting Compound
263I for Compound 1E in the procedure for Compound 1G. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.71 (s, 1H), 11.40
(br s, 1H), 8.62 (t, 1H), 8.58 (d, 1H), 8.03 (d, 1H), 7.81 (dd,
1H), 7.54 (m, 2H), 7.44 (m, 3H), 7.28 (m, 5H), 7.13 (dd, 1H), 6.62
(dd, 1H), 6.41 (dd, 1H), 6.11 (d, 1H), 3.85 (dd, 2H), 3.31 (m, 4H),
3.20 (m, 2H), 2.97 (s, 3H), 2.81 (m, 2H), 2.73 (m, 2H), 1.89 (m,
1H), 1.62 (m, 2H), 1.38 (m, 2H), 1.25 (m, 2H), 1.09 (m, 2H).
Compound 265
4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-
-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamid-
e
Compound 265A
benzyl 4-(piperidin-1-ylmethylene)piperidine-1-carboxylate
[0777] To a solution of benzyl 4-formylpiperidine-1-carboxylate
(12.5 g) in toluene (120 ml) was added piperidine (6.46 g). The
mixture was stirred at reflux under a Dean-Stark trap overnight.
The mixture was then concentrated under vacuum and the residue was
used directly in the next step.
Compound 265B
benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate
[0778] To a solution of Compound 265A (15.88 g) in ethanol (300 ml)
was added but-3-enone (3.89 g). The mixture was stirred at reflux
overnight. Then acetic acid (30 ml) was added to the mixture which
was stirred at reflux again overnight. The mixture was then
concentrated under vacuum and the residue was diluted with ethyl
acetate (400 ml) and washed with water and brine and dried over
Na.sub.2SO.sub.4. After filtration and evaporation of the solvent,
column purification gave the title compound.
Compound 265C
benzyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate
[0779] Compound 265B (21 g) and tetrahydrofuran (160 ml) were added
to 5% Pt--C wet (3.15 g) in a 250 ml pressure bottle and stirred
for 1 hour at 30 psi and room temperature. The mixture was filtered
though a nylon membrane and the filtrate was concentrated under
vacuum to provide the title compound.
Compound 265D
benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate
[0780] To a solution of Compound 265C (8.0 g) in dichloromethane
(200 ml) was added Dess-Martin Periodinane (11.2 g). The mixture
was stirred overnight. The mixture was diluted with ethyl acetate
(400 ml) and washed with 2N aqueous NaOH, water, and brine. After
drying over Na.sub.2SO.sub.4 and filtration, concentration of the
solvent gave the crude product which was used directly in the next
reaction without further purification.
Compound 265E
benzyl
9-chloro-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate
[0781] Phosphorus oxychloride (2.33 ml) was added dropwise to a
cooled (0.degree. C.) solution of Compound 265D (7.5 g) in
N,N-dimethylformamide (10 ml) and dichloromethane (30 ml). The
mixture was then stirred overnight before it was diluted with ethyl
acetate (300 ml) and washed with aqueous sodium acetate, water
(3.times.), and brine and dried over Na.sub.2SO.sub.4. After
filtration and concentration, the crude product was used directly
in the next reaction without further purification.
Compound 265F
benzyl
9-(4-chlorophenyl)-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylat-
e
[0782] To a mixture of 4-chlorophenylboronic acid (5.94 g),
Compound 265E (11.01 g), palladium(II) acetate (142 mg),
K.sub.2CO.sub.3 (13.2 g) and tetrabutylammonium bromide (10.2 g)
was added water (120 ml). The mixture was stirred at 50.degree. C.
overnight. The mixture was diluted with ethyl acetate (400 ml) and
washed with water (3.times.) and brine and dried over
Na.sub.2SO.sub.4. After filtration and concentration, the residue
was loaded on a column and eluted with 5 to 20% ethyl acetate in
hexane to provide the title compound.
Compound 265G
benzyl
8-((4-(3-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(methoxycarbonyl)phen-
yl)piperazin-1-yl)methyl)-9-(4-chlorophenyl)-3-azaspiro[5.5]undec-8-ene-3--
carboxylate
[0783] To a solution of Compound 15F (1.37 g) and Compound 265F
(1.65 g) in dichloromethane (20 ml) was added sodium
triacetoxyborohydride (1.24 g). The mixture was stirred overnight.
The mixture was diluted with ethyl acetate (200 ml) and washed with
2N aqueous NaOH, water and brine. After drying over
Na.sub.2SO.sub.4, the mixture was filtered and the solvent was
evaporated under vacuum to provide the title compound.
Compound 265H
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-az-
aspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate
[0784] Compound 265G (2 g) and tetrahydrofuran (10 ml) were added
to 20% Pd(OH).sub.2--C, wet (0.400 g) in a 50 ml pressure bottle
and stirred for 16 hours at 30 psi and room temperature. The
mixture was filtered though a nylon membrane and evaporation of the
solvent gave the title compound.
Compound 265I
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(1-
,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1--
yl)benzoate
[0785] To a solution of Compound 265H (320 mg) in dichloromethane
(5 ml) was added 1,3-difluoroacetone (139 mg) and sodium
triacetoxyborohydride (157 mg). The mixture was stirred overnight.
The mixture was diluted with ethyl acetate (200 ml) and washed with
2N aqueous NaOH, water and brine. After drying over
Na.sub.2SO.sub.4, the mixture was filtered and the solvent was
evaporated under vacuum to provide the title compound.
Compound 265J
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(1,3-difl-
uoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benz-
oic acid
[0786] To a solution of Compound 2651 (320 mg) in tetrahydrofuran
(4 ml) and methanol (2 ml) was added LiOH H.sub.2O (120 mg) and the
solution was stirred overnight. The reaction was cooled, carefully
neutralized with 1N aqueous HCl and extracted with dichloromethane
(3.times.50 ml). The combined organic layers were washed with brine
(25 ml), dried over sodium sulfate, filtered and concentrated under
vacuum to provide the title compound.
Compound 265K
4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-
-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamid-
e
[0787] The title compound was prepared by substituting Compound
265J for Compound 1E in the procedure for Compound 1G. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.61 (s, 1H), 8.49
(d, 2H), 7.72 (m, 1H), 7.49 (m, 2H), 7.32 (d, 2H), 7.07 (m, 3H),
6.65 (dd, 1H), 6.35 (d, 1H), 6.20 (m, 1H), 4.66 (m, 2H), 4.50 (m,
2H), 3.84 (m, 2H), 3.04 (m, 5H), 2.70 (m, 6H), 2.23 (m, 6H), 2.00
(m, 4H), 1.35 (m, 12H).
Compound 266
4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methy-
l}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phe-
nyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 266A
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-is-
opropyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate
[0788] To a solution of Compound 265H (320 mg) in dichloromethane
(5 ml) was added acetone (143 mg) and sodium triacetoxyborohydride
(157 mg). The mixture was stirred overnight. The mixture was
diluted with ethyl acetate (200 ml) and washed with 2N aqueous
NaOH, water and brine. After drying over Na.sub.2SO.sub.4, the
mixture was filtered and the solvent was evaporated under vacuum to
provide the title compound.
Compound 266B
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-isopropyl-
-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoic
acid
[0789] The title compound was prepared by substituting Compound
266A for Compound 2651 in the procedure for Compound 265J.
Compound 266C
4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methy-
l}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phe-
nyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0790] The title compound was prepared by substituting Compound
266B for Compound 1E in the procedure for Compound 1G. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.54 (s, 1H), 8.38
(m, 2H), 7.93 (d, 1H), 7.60 (m, 3H), 7.39 (m, 4H), 7.09 (d, 2H),
6.85 (d, 1H), 6.63 (dd, 1H), 6.27 (dd, 2H), 3.84 (m, 3H), 3.08 (m,
8H), 2.71 (s, 3H), 2.15 (m, 8H), 1.71 (m, 9H), 1.24 (m, 11H).
Compound 267
4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-
-8-en-8-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-yl-
methoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzami-
de
[0791] The title compound was prepared by substituting Compound
265J for Compound 1E and Compound 40B for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.56 (s, 1H), 8.38 (s, 1H),
8.06 (m, 1H), 7.57 (d, 1H), 7.38 (m, 5H), 7.07 (m, 3H), 6.64 (dd,
1H), 6.33 (d, 1H), 6.23 (m, 1H), 4.68 (d, 2H), 4.52 (d, 2H), 4.21
(d, 2H), 3.86 (dd, 2H), 3.08 (m, 8H), 2.71 (m, 6H), 2.10 (m, 12H),
1.42 (m, 7H).
Compound 268
4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methy-
l}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin--
3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0792] The title compound was prepared by substituting Compound
266B for Compound 1E and Compound 40B for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.49 (s, 1H), 8.28 (d, 1H),
7.94 (dd, 2H), 7.60 (d, 1H), 7.35 (m, 4H), 7.08 (m, 2H), 6.61 (dd,
1H), 6.28 (dd, 2H), 4.18 (d, 2H), 3.85 (m, 2H), 3.05 (m, 7 H), 2.71
(s, 3H), 2.25 (m, 6H), 2.02 (m, 2H), 1.63 (m, 8H), 1.30 (m,
9H).
Compound 269
N-({5-chloro-6-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulf-
onyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 269A
5-chloro-6-((4-fluoro-1-methylpiperidin-4-yl)methoxy)pyridine-3-sulfonamid-
e
[0793] Compound 257B (0.131 g) in N,N-dimethylformamide (3.0 ml)
was treated with iodomethane (0.043 g) and sodium carbonate (0.079
g) and stirred at ambient temperature for 3 days. The
N,N-dimethylformamide was removed on high vacuum and the
concentrate was chromatographed on amine functionalized silica gel
with 0 to 2% methanol in CH.sub.2Cl.sub.2 as the eluent.
Compound 269B
N-({5-chloro-6-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulf-
onyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0794] The title compound was prepared by substituting Compound
269A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, pyridine-d.sub.5) .delta. 13.01 (s, 1H), 9.11 (d,
1H), 8.71 (d, 1H), 8.44 (d, 1H), 8.16 (d, 1H), 7.66 (m, 2H), 7.44
(m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.54 (d, 1H), 6.49 (dd, 1H),
4.49 (d, 2H), 3.06 (m, 4H), 2.77 (s, 2H), 2.68 (m, 2H), 2.38 (m,
2H), 2.26 (m, 5H), 2.14 (t, 4H), 1.97 (m, 6H), 1.39 (t, 2H), 0.94
(s, 6H).
Compound 270
N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyr-
idin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 270A
5-chloro-6-((1-(2-(dimethylamino)acetyl)-4-fluoropiperidin-4-yl)methoxy)py-
ridine-3-sulfonamide
[0795] Compound 257B (0.131 g), 2-(dimethylamino)acetyl chloride,
hydrochloric acid (0.139 g), and sodium carbonate (0.048 g) were
combined in a 5-ml vial with N,N-dimethylformamide (3.0 ml) and
stirred overnight at ambient temperature. Additional sodium
carbonate (0.048 g) was added followed by 2-(dimethylamino)acetyl
chloride, hydrochloric acid (0.139 g) and stirring was continued
over a second night. The reaction mixture was concentrated under
high vacuum, slurried in CH.sub.2Cl.sub.2, filtered, concentrated
and chromatographed on amine functionalized silica gel with 0 to 4%
methanol in CH.sub.2Cl.sub.2 as the eluent.
Compound 270B
N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyr-
idin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0796] The title compound was prepared by substituting Compound
270A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.04 (s, 1H), 9.12 (d,
1H), 8.73 (d, 1H), 8.42 (d, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.44
(m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.52 (d, 1H), 6.49 (dd, 1H),
4.66 (d, 1H), 4.52 (dd, 2H), 4.07 (d, 1H), 3.46 (m, 1H), 3.40 (m,
1H), 3.30 (m, 1H), 3.11 (m, 1H), 3.06 (m, 4H), 2.77 (s, 2H), 2.35
(s, 6H), 2.26 (t, 2H), 2.14 (m, 4H), 2.05 (m, 2H), 1.97 (s, 2H),
1.81 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 271
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({3-nitro--
4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,-
3-b]pyridin-5-yloxy)benzamide
Compound 271A
tert-butyl
4-((4'-chlorobiphenyl-2-yl)methyl)-4-fluoropiperidine-1-carboxy-
late
[0797] A solution of Compound 263E (2.0 g) and diethylaminosulfur
trifluoride (1.39 ml) in dichloromethane (40 ml) was stirred for 24
hours. The reaction was quenched with water (30 ml), extracted
twice with ether, and the combined extracts were washed with water,
and brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The crude product was chromatographed on silica gel using 5% ethyl
acetate in hexanes to provide the title compound.
Compound 271B
4-((4'-chlorobiphenyl-2-yl)methyl)-4-fluoropiperidine
[0798] The title compound was prepared by substituting Compound
271A for Compound 1A in the procedure for Compound 1B.
Compound 271C
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)-
methyl)-4-fluoropiperidin-1-yl)benzoate
[0799] The title compound was prepared by substituting Compound
271B for Compound 263G in the procedure for Compound 263H.
Compound 271D
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)-
-4-fluoropiperidin-1-yl)benzoic acid
[0800] The title compound was prepared by substituting Compound
271C for Compound 31 in the procedure for Compound 3J.
Compound 271E
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({3-nitro--
4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,-
3-b]pyridin-5-yloxy)benzamide
[0801] The title compound was prepared by substituting Compound
271D for Compound 1E Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H), 11.46 (br s, 1H),
8.62 (t, 1H), 8.56 (d, 1H), 8.03 (d, 1H), 7.81 (dd, 1H), 7.52 (m,
3H), 7.44 (d, 2H), 7.28 (m, 5H), 7.14 (m, 1H), 6.68 (dd, 1H), 6.40
(dd, 1H), 6.19 (d, 1H), 3.84 (dd, 2H), 3.31 (m, 9H), 2.95 (d, 2H),
2.81 (m, 2H), 1.91 (m, 1H), 1.62 (m, 2H), 1.45 (m, 2H), 1.29 (m,
2H).
Compound 272
4-{4-[(4'-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({5-chloro-
-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0802] The title compound was prepared by substituting Compound
271D for Compound 1E and Compound 96A for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 11.64 (br s, 1H),
8.58 (m, 1H), 8.25 (m, 1H), 8.03 (d, 1H), 7.70 (dd, 1H), 7.50 (m,
4H), 7.43 (m, 3H), 7.28 (m, 4H), 7.15 (m, 1H), 6.68 (dd, 1H), 6.40
(dd, 1H), 6.19 (d, 1H), 4.54 (d, 2H), 4.04 (m, 1H), 3.75 (m, 2H),
3.58 (m, 2H), 2.95 (d, 2H), 2.80 (m, 2H), 1.88 (m, 2H), 1.82 (m,
2H), 1.48 (m, 2H), 1.28 (m, 2H), 0.85 (m, 2H).
Compound 273
4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methy-
l}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl}sulfonyl)benzamide
[0803] The title compound was prepared by substituting Compound
266B for Compound 1E and Compound 42A for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.57 (s, 1H), 7.97 (d, 1H),
7.77 (s, 1H), 7.55 (m, 2H), 7.45 (m, 1H), 7.36 (m, 3H), 7.08 (d,
2H), 6.62 (dd, 2H), 6.35 (dd, 1H), 6.21 (d, 1H), 3.82 (m, 3 H),
3.06 (m, 9H), 2.72 (m, 3H), 2.25 (m, 8H), 2.09 (m, 2H), 1.56 (m,
9H), 1.20 (m, 10H).
Compound 274
N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}pyrid-
in-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 274A
(R)-5-chloro-6-(1-(3-fluoro-2-(fluoromethyl)propyl)pyrrolidin-3-yloxy)pyri-
dine-3-sulfonamide
[0804] The title compound was prepared by substituting
1,3-difluoropropan-2-one for 4'-chlorobiphenyl-2-carboxaldehyde and
Compound 261B for tert-butyl piperazine-1-carboxylate in the
procedure for Compound 1A.
Compound 274B
N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}pyrid-
in-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0805] The title compound was prepared by substituting Compound
274A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.52 (s, 1H),
8.32 (d, 1H), 8.01 (d, 1H), 7.93 (d, 1H), 7.59 (d, 1H), 7.42 (m,
1H), 7.33 (m, 3H), 7.05 (d, 2H), 6.63 (dd, 1H), 6.31 (dd, 1H), 6.25
(d, 1H), 5.38 (m, 1H), 4.65 (t, 2H), 4.53 (t, 2H), 3.02 (s, 4H),
2.94 (m, 5H), 2.75 (s, 2H), 2.66 (m, 1H), 2.23 (m, 7H), 1.96 (s,
2H), 1.82 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 275
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenyl}sulfonyl)-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 275A
3-(2-(benzyloxy)ethoxy)tetrahydrofuran
[0806] Tetrahydrofuran-3-ol (0.881 g) in tetrahydrofuran (15 ml)
was treated with 60% sodium hydride (0.8 g). After 10 minutes,
((2-bromoethoxy)methyl)benzene (3.23 g) was added. The solution was
stirred for 16 hours. The reaction mixture was partitioned between
water and ethyl acetate. The aqueous layer was separated, and 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 1:1 ethyl acetate:hexane to provide the
title compound.
Compound 275B
2-(tetrahydrofuran-3-yloxy)ethanol
[0807] Compound 275A (0.85 g) and 5% palladium on carbon (0.1 g) in
ethanol (10 ml) was treated with a balloon of hydrogen. The
reaction was stirred overnight. The solid was filtered off, and the
filtrate was concentrated to give the title compound.
Compound 275C
3-nitro-4-(2-(tetrahydro furan-3-yloxy)ethoxy)benzene
sulfonamide
[0808] The title compound was prepared by substituting Compound
275B for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 24A.
Compound 275D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[2-(tetrahydro
furan-3-yloxy)ethoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy-
)benzamide
[0809] The title compound was prepared by substituting Compound
275C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H),
8.32 (s, 1H), 8.00-8.02 (m, 2H), 7.49-7.52 (m, 2H), 7.39-7.41 (m,
1H), 7.38 (d, 2H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.21
(d, 1H), 4.33-4.35 (m, 2H), 4.18-4.21 (m, 1H), 3.62-3.67 (m, 4H),
3.09 (s, 4H), 2.83 (s, 2H), 2.26 (s, 2H), 2.15 (s, 2H), 1.96 (s,
2H), 1.85-1.94 (m, 2H), 1.39 (t, 2H), 0.92 (s, 6H).
Compound 276
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 276A
trans-4-(aminomethyl)cyclohexanecarbonitrile
[0810] To a solution of tert-butyl
(trans-4-(cyanomethyl)cyclohexyl)methylcarbamate (500 mg) in
dichloromethane (10 ml) was slowly added trifluoroacetic acid (2
ml) at 0.degree. C. The reaction mixture was warmed to room
temperature, stirred for 1 hour and concentrated to provide the
title compound.
Compound 276B
4-((trans-4-cyanocyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[0811] A mixture of 4-fluoro-3-nitrobenzenesulfonamide (347 mg) and
Compound 276A (300 mg) in tetrahydrofuran (20 ml) was treated with
triethylamine (1.4 ml) overnight and concentrated. The residue was
triturated with ethyl acetate to provide the title compound.
Compound 276C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-4-cyano
cyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyri-
din-5-yloxy)benzamide
[0812] The title compound was prepared as described in the
procedure for Compound 11D using Compound 276B in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 1H), 11.36 (s, 1H), 8.60 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1 H),
7.79 (dd, 1H), 7.47-7.54 (m, 3H), 7.34 (d, 2H), 7.01-7.09 (m, 3H),
6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.25 (t, 2H), 3.07 (s,
4H), 2.76 (s, 2H), 2.57-2.68 (m, 1H), 2.17 (d, 6H), 1.92-2.06 (m,
4H), 1.78 (d, 2H), 1.66 (s, 1H), 1.35-1.53 (m, 4H), 0.96-1.10 (m,
2H), 0.92 (s, 6H).
Compound 277
N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 277A
methyl 4,4-dimethyl-2-(trifluoro
methylsulfonyloxy)cyclohex-1-enecarboxylate
[0813] To a suspension of hexane washed NaH (17 g) in
dichloromethane (700 ml) was added
5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at
0.degree. C. After stirring for 30 minutes, the mixture was cooled
to -78.degree. C. and trifluoroacetic anhydride (40 ml) was added.
The reaction mixture was warmed to room temperature and stirred for
24 hours. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the
product.
Compound 277B
methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[0814] Compound 277A (62.15 g), 4-chlorophenylboronic acid (32.24
g), CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2 g)
in 2:1 dimethoxyethane/methanol (600 ml) were heated to 70.degree.
C. for 24 hours. The mixture was concentrated. Ether (4.times.200
ml) was added and the mixture was filtered. The combined ether
solution was concentrated to give the product.
Compound 277C
(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[0815] To a mixture of LiBH.sub.4 (13 g), Compound 277B (53.8 g)
and ether (400 ml), was added methanol (25 ml) slowly by syringe.
The mixture was stirred at room temperature for 24 hours. The
reaction was quenched with 1N HCl with ice-cooling. The mixture was
diluted with water and extracted with ether (3.times.100 ml). The
extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated.
The crude product was chromatographed on silica gel with 0-30%
ethyl acetate/hexanes.
Compound 277D
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piper-
azine-1-carboxylate
[0816] Mesyl Chloride (7.5 ml) was added via syringe to Compound
277C (29.3 g) and triethylamine (30 ml) in CH.sub.2Cl.sub.2 (500
ml) at 0.degree. C., and the mixture was stirred for 1 minute.
N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was
stirred at room temperature for 24 hours. The suspension was washed
with brine, dried, (Na.sub.2SO.sub.4), filtered, and concentrated.
The crude product was chromatographed on silica gel with 10-20%
ethyl acetate/hexanes.
Compound 277E
1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
[0817] Compound 277D (1 g) was stirred in dichloromethane (10 ml),
trifluoroacetic acid (10 ml), and triethylsilane (1 ml) for 1 hour.
The mixture was concentrated, taken up in a mixture of
dichloromethane (100 ml) and saturated aqueous Na.sub.2CO.sub.3
solution (20 ml) and stirred for 10 minutes. The layers were
separated, and the organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give the product.
Compound 277F
5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
[0818] To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g)
in tetrahydrofuran (250 ml) was added 1M lithium
hexamethyldisilazide in tetrahydrofuran (86 ml), and after 10
minutes, TIPS-Cl (triisopropylchlorosilane) (18.2 ml) was added.
The mixture was stirred at room temperature for 24 hours. The
reaction was diluted with ether, and the resulting solution was
washed twice with water. The extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was chromatographed on silica gel with 10% ethyl
acetate/hexanes.
Compound 277G
1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol
[0819] To a mixture of Compound 277F (24.3 g) in tetrahydrofuran
(500 ml) at -78.degree. C. was added 2.5M BuLi (30.3 ml). After 2
minutes, trimethylborate (11.5 ml) was added, and the mixture was
allowed to warm to room temperature over 1 hour. The reaction was
poured into water, extracted three times with ethyl acetate, and
the combined extracts were washed with brine and concentrated. The
crude product was taken up in tetrahydrofuran (200 ml) at 0.degree.
C., and 1M NaOH (69 ml) was added, followed by 30% H.sub.2O.sub.2
(8.43 ml), and the solution was stirred for 1 hour.
Na.sub.2S.sub.2O.sub.3 (10 g) was added, and the pH was adjusted to
4-5 with concentrated HCl and solid NaH.sub.2PO.sub.4. The solution
was extracted twice with ethyl acetate, and the combined extracts
were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The crude product was chromatographed on silica gel
with 5-25% ethyl acetate/hexanes.
Compound 277H
methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate
[0820] A mixture of Compound 277G (8.5 g), methyl
2,4-difluorobenzoate (7.05 g), and K.sub.3PO.sub.4 (9.32 g) in
diglyme (40 ml) at 115.degree. C. was stirred for 24 hours. The
reaction was cooled, diluted with ether (600 ml), and washed twice
with water, and brine, and concentrated. The crude product was
chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Compound 277I
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0821] A mixture of Compound 277H (1.55 g), Compound 277E (2.42 g),
and HK.sub.2PO.sub.4 (1.42 g) in dimethylsulfoxide (20 ml) at
135.degree. C. was stirred for 24 hours. The reaction was cooled,
diluted with ether (400 ml), and washed three times with 1M NaOH,
and brine, and concentrated. The crude product was chromatographed
on silica gel with 10-50% ethyl acetate/hexanes.
Compound 277J
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0822] Compound 277I (200 mg) in dioxane (10 ml) and 1M NaOH (6 ml)
at 50.degree. C. was stirred for 24 hours. The reaction was cooled,
added to NaH.sub.2PO.sub.4 solution, and extracted three times with
ethyl acetate. The combined extracts were washed with brine, and
concentrated to give the pure product.
Compound 277K
5,6-dichloropyridine-3-sulfonamide
[0823] To a solution of 5,6-dichloropyridine-3-sulfonyl chloride
(32.16 g) in isopropyl alcohol (300 ml) at 0.degree. C. was added a
30% aqueous solution of NH.sub.4OH (50.8 ml). After stirring
overnight, the solvent was reduced to 1/3 of the original volume.
It was then partitioned between water and ethyl acetate. The
aqueous layer was extracted with additional ethyl acetate. The
combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was
chromatographed on silica gel. The material was then slurried in
1:9 ethyl acetate/hexanes, filtered and dried under vacuum to give
the title compound.
Compound 277L
tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
[0824] 1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate
(1.0 g) in tetrahydrofuran (5 ml) was treated with 1.0 N
LiAlH.sub.4 in tetrahydrofuran (2.54 ml) at 0.degree. C. The
reaction mixture was stirred at room temperature for 2 hours. Water
(0.6 ml) was added to the reaction mixture drop-wise, followed by 2
N aqueous NaOH (0.2 ml). The reaction was stirred for another 1
hour. The solid was removed by filtration via a pack of
diatomaceous earth and washed with ethyl acetate. The filtrate was
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated to give the product.
Compound 277M
tert-butyl
4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperid-
ine-1-carboxylate
[0825] To a solution of Compound 277L (1 g) in tetrahydrofuran (15
ml) was added NaH (60% dispersion in mineral oil, 685 mg), and the
solution was stirred for 10 minutes. Compound 227K (1 g) was added
and the reaction stirred for 24 hours. The mixture was poured into
water, neutralized with 10% HCl, and extracted with ethyl acetate
three times. The combined organic layers were washed with brine,
dried over MgSO.sub.4, filtered, and concentrated. The residue was
purified with flash column chromatography on silica gel eluting
with 30% ethyl acetate in hexanes.
Compound 277N
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide
ditrifluoroacetic acid
[0826] Compound 277M (13 ml) was treated with trifluoroacetic acid
(2.363 ml), stirred at ambient temperature for 2 hours,
concentrated and dried to give the title compound.
Compound 277O
5-chloro-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridine-3-sul-
fonamide
[0827] Compound 277N (0.088 g) and oxetan-3-one (0.014 g) were
combined in dichloromethane (2.0 ml) and dimethylformamide (1.0 ml)
and stirred at ambient temperature for 45 minutes. Sodium
triacetoxyborohydride (0.064 g) was added in portions. Stirring was
continued overnight at ambient temperature. Additional oxetan-3-one
(0.014 g) was added and stirring was continued for 30 minutes at
ambient temperature before more sodium triacetoxyborohydride (0.064
g) was added. The reaction mixture was stirred for 72 hours at
ambient temperature, concentrated, chromatographed on silica gel
with 0 to 5% methanol in dichloromethane as the eluent, and dried
in a vacuum oven at 80.degree. C. to give the title compound.
Compound 277P
N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0828] Compound 277J (0.063 g), Compound 2770 (0.042 g),
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride
(0.032 g), and 4-dimethylaminopyridine (0.027 g) were combined in a
4-ml vial with dichloromethane (1.0 ml) and stirred overnight at
ambient temperature. The reaction mixture was chromatographed
directly without aqueous workup on silica gel with 0-4% methanol in
dichloromethane as the eluent. Fractions containing the desired
product were concentrated, slurried in acetonitrile, concentrated
and dried overnight in a vacuum oven at 80.degree. C. to give the
title compound. .sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta.
13.05 (s, 1H), 9.13 (d, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d,
1H), 7.67 (m, 1H), 7.66 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.76
(dd, 1H), 6.51 (m, 2H), 4.63 (m, 4H), 4.53 (d, 2H), 3.39 (m, 1H),
3.07 (m, 4H), 2.77 (s, 2H), 2.51 (m, 2H), 2.25 (m, 2H), 2.18 (m,
2H), 2.13 (m, 4H), 2.06 (t, 2H), 1.97 (s, 2H), 1.89 (m, 2H), 1.39
(t, 2H), 0.93 (s, 6H).
Compound 278
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-3-yl}sulfo-
nyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 278A
5-bromo-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide
[0829] The title compound was prepared by substituting
2-(tetrahydro-2H-pyran-4-yl)ethanol for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
36B.
Compound 278B
5-cyano-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide
[0830] The title compound was prepared by substituting Compound
278A for Compound 36B in the procedure for Compound 36C.
Compound 278C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-3-yl}sulfo-
nyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0831] The title compound was prepared by substituting Compound
278B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.60 (s, 1H),
8.70 (s, 1H), 8.48 (s, 1H), 7.96 (d, 1H), 7.56 (d, 1H), 7.45-7.47
(m, 1H), 7.40 (s, 1H), 7.36 (d, 2H), 7.06 (d, 2H), 6.67 (dd, 1H),
6.34 (dd, 1H), 6.25 (d, 1H), 4.47 (d, 2H), 3.80-3.84 (m, 2H),
3.24-3.28 (m, 2H), 3.12 (s, 2H), 2.16 (s, 2H), 1.97 (s, 2H),
1.61-1.71 (m, 4H), 1.40 (t, 2H), 1.21-1.25 (m, 2H), 0.93 (s,
6H).
Compound 279
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(3-furylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]p-
yridin-5-yloxy)benzamide
Compound 279A
4-(furan-3-ylmethoxy)-3-nitrobenzenesulfonamide
[0832] The title compound was prepared by substituting
furan-3-ylmethanol for (tetrahydro-2H-pyran-4-yl)methanol in the
procedure for Compound 24A.
Compound 279B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(3-furylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]p-
yridin-5-yloxy)benzamide
[0833] The title compound was prepared by substituting Compound
279A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H),
8.34 (s, 1H), 8.03-8.06 (m, 2H), 7.83 (s, 1H), 7.69 (t, 1H),
7.51-7.53 (m, 4H), 7.34-7.36 (m, 2H), 7.04-7.06 (m, 2H), 6.68 (dd,
1H), 6.57 (s, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 5.23 (s, 2H), 3.10
(s, 4H), 2.83 (s, 2H), 2.15-2.32 (m, 6H), 1.39 (t, 2H), 0.92 (s,
6H).
Compound 280
N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]methoxy}p-
yridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en--
1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 280A
(R)-tert-butyl
3-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)pyrrolidine-1-carboxylate
[0834] The title compound was prepared by substituting Compound 40A
for 4-fluoro-3-nitrobenzenesulfonamide and (R)-tert-butyl
3-(hydroxymethyl)pyrrolidine-1-carboxylate for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 280B
(R)-5-chloro-6-(pyrrolidin-3-ylmethoxy)pyridine-3-sulfonamide
[0835] The title compound was prepared by substituting Compound
280A for tert-butyl
(4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate in the
procedure for Compound 252B.
Compound 280C
(R)-5-chloro-6-((1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl)methoxy)pyridi-
ne-3-sulfonamide
[0836] The title compound was prepared by substituting
1,3-difluoropropan-2-one for 4'-chlorobiphenyl-2-carboxaldehyde and
Compound 280B for tert-butyl piperazine-1-carboxylate in the
procedure for Compound 1A.
Compound 280D
N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]methoxy}p-
yridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en--
1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0837] The title compound was prepared by substituting Compound
280C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.57 (s, 1H),
8.38 (d, 1H), 8.07 (d, 1H), 7.96 (d, 1H), 7.57 (d, 1H), 7.44 (m,
1H), 7.35 (m, 3H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.33 (dd, 1H), 6.23
(d, 1H), 4.65 (d, 2H), 4.53 (dd, 2H), 2.92 (m, 8H), 2.75 (m, 4H),
2.58 (m, 2H), 2.20 (m, 6H), 1.96 (m, 4H), 1.53 (m, 1H), 1.39 (t,
2H), 0.89 (s, 6H).
Compound 281
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-
-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 281A
(R)-5-chloro-6-((1-(2,2-difluoroethyl)pyrrolidin-3-yl)methoxy)pyridine-3-s-
ulfonamide
[0838] The title compound was prepared by substituting Compound
280B for Compound 261B in the procedure for Compound 261C.
Compound 281B
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-
-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0839] The title compound was prepared by substituting Compound
281A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.59 (s, 1H),
8.41 (d, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.56 (d, 1H), 7.46 (m,
1H), 7.41 (d, 1H), 7.34 (d, 2H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.35
(dd, 1H), 6.23 (m, 1H), 6.03 (m, 1H), 3.06 (s, 4H), 2.84 (m, 6H),
2.63 (m, 4H), 2.20 (m, 6H), 1.94 (m, 3H), 1.53 (m, 1H), 1.39 (t,
2H), 0.91 (s, 6H).
Compound 282
N-[(5-chloro-6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methox-
y}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzami-
de
Compound 282A
5-chloro-6-((1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl)methoxy)py-
ridine-3-sulfonamide
[0840] Compound 257B (0.088 g) and 1,3-difluoropropan-2-one (0.028
g) were combined in dichloromethane (2 ml) and
N,N-dimethylformamide (0.500 ml) and stirred at ambient temperature
for 45 minutes. Sodium triacetoxyborohydride (0.064 g) was added in
portions and then the reaction mixture was stirred overnight at
ambient temperature. Additional 1,3-difluoropropan-2-one (0.028 g)
was added, followed 30 minutes later by the addition of more sodium
triacetoxyborohydride (0.064 g). The reaction mixture was stirred
at ambient temperature for 72 hours. Additional
1,3-difluoropropan-2-one (0.028 g) was again added, followed 30
minutes later by the addition of more sodium triacetoxyborohydride
(0.064 g). The reaction mixture was stirred overnight at ambient
temperature. Additional 1,3-difluoropropan-2-one (0.028 g) was
again added, followed 30 minutes later by the addition of more
sodium triacetoxyborohydride (0.064 g). The reaction mixture was
stirred overnight at ambient temperature. The reaction mixture was
concentrated under high vacuum to remove N,N-dimethylformamide and
then chromatographed on silica gel with 0 to 4% methanol in
CH.sub.2Cl.sub.2 as the eluent.
Compound 282B
N-[(5-chloro-6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methox-
y}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzami-
de
[0841] The title compound was prepared by substituting Compound
282A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, pyridine-d.sub.5) .delta. 13.05 (s, 1H), 9.12 (t,
1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.66 (m, 2H), 7.44
(m, 2H), 7.07 (m, 2H), 6.75 (dd, 1H), 6.50 (m, 2H), 4.77 (dd, 1H),
4.65 (dd, 1H), 4.52 (dd, 2H), 3.06 (m, 4H), 2.93 (t, 1H), 2.80 (m,
5H), 2.52 (m, 1H), 2.26 (t, 2H), 2.13 (m, 4H), 2.04 (m, 2H), 1.97
(s, 2H), 1.85 (m, 2H), 1.39 (t, 2H), 1.28 (m, 2H), 0.93 (s,
6H).
Compound 283
N-({3-chloro-4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]phenyl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 283A
3-chloro-4-((4-fluoro-1-methylpiperidin-4-yl)methoxy)benzene
sulfonamide
[0842] To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol
(0.265 g) in tetrahydrofuran (2 ml) was added sodium hydride (0.288
g). After 15 minutes, 3-chloro-4-fluorobenzenesulfonamide (0.377 g)
was added as a solution in tetrahydrofuran (1 ml). The reaction was
stirred for 2 hours, quenched with water (5 ml), adjusted to
pH.about.7 with 1N aqueous HCl, and extracted with dichloromethane
(2.times.25 ml). The organic layer was washed with brine (25 ml),
dried over magnesium sulfate, filtered and concentrated. Silica gel
chromatography (Reveleris 40 g) eluting with a gradient of 0.1% to
10% methanol containing 2N NH.sub.3/dichloromethane over 30 minutes
gave the title compound.
Compound 283B
N-({3-chloro-4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]phenyl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0843] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 283A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.60 (s, 1H), 10.68-9.84 (m, 1H), 7.99 (d, 1H), 7.79 (d,
1H), 7.63 (t, 1H), 7.54 (d, 1H), 7.50-7.38 (m, 2H), 7.34 (d, 2H),
7.04 (d, 3H), 6.64 (dd, 1H), 6.36 (dd, 1H), 6.22 (s, 1H), 4.23 (d,
2H), 3.03 (s, 6H), 2.71 (m, 4H), 2.07 (m, 12H), 1.38 (s, 3H), 1.24
(s, 2H), 0.92 (s, 6H).
Compound 284
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 284A
3-cyano-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzene
sulfonamide
[0844] To a solution of (tetrahydro-2H-pyran-4-yl)methanol (0.258
g) in tetrahydrofuran (5 ml) was added sodium hydride (0.355 g) and
the reaction stirred at room temperature for 15 minutes. Compound
52A (0.400 g) was added and the reaction stirred for an additional
1 hour. The reaction was poured into ethyl acetate (50 ml) and 1N
aqueous HCl (35 ml). The organic layer was washed with brine (35
ml) dried over magnesium sulfate, filtered, and concentrated.
Silica gel chromatography (Reveleris 40 g) eluting with a gradient
of 10% to 100% ethyl acetate/hexanes over 30 minutes gave the title
compound.
Compound 284B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0845] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 284A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.69 (s, 1H), 11.60-11.16 (m, 1H), 8.15 (s, 1H), 8.08-8.01
(m, 2H), 7.58-7.46 (m, 3H), 7.35 (d, J=8.4, 2H), 7.29 (d, 1H), 7.04
(d, 2H), 6.68 (d, 1H), 6.40 (dd, 1H), 6.20 (s, 1H), 4.05 (d, 2H),
3.89 (d, 2H), 3.37 (d, 4H), 3.09 (s, 4H), 2.81 (s, 2H), 2.21 (d,
7H), 1.96 (s, 2H), 1.67 (d, 2H), 1.39 (s, 2H), 0.92 (s, 6H).
Compound 285
N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyri-
din-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 285A
5-chloro-6-((1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-
-3-sulfonamide
[0846] Compound 257B (0.263 g), 1,1-difluoro-2-iodoethane (0.23 g),
and sodium carbonate (0.254 g) were combined in a 20-ml vial with
N,N-dimethylformamide (6 ml) and stirred at 70.degree. C.
overnight. The reaction mixture was concentrated under high vacuum
and then chromatographed on silica gel with 0 to 5% methanol in
CH.sub.2Cl.sub.2 as the eluent.
Compound 285B
N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyri-
din-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0847] The title compound was prepared by substituting Compound
285A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, pyridine-d.sub.5) .delta. 13.05 (s, 1H), 9.12 (d,
1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.66 (m, 2H), 7.43
(m, 2H), 7.06 (m, 2H), 6.75 (dd, 1H), 6.50 (m, 2H), 6.18 (tt, 2H),
4.51 (d, 2H), 3.07 (m, 4H), 2.80 (m, 6H), 2.60 (td, 2H), 2.25 (t,
2H), 2.13 (m, 4H), 2.03 (t, 2H), 1.97 (s, 2H), 1.93 (m, 1H), 1.85
(m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 286
N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 286A
3-chloro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
[0848] The title compound was prepared by substituting Compound 37C
for (4-fluoro-1-methylpiperidin-4-yl)methanol in the procedure for
Compound 283A.
Compound 286B
N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0849] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 286A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.71 (s, 1H), 11.56-11.16 (m, 1H), 8.06 (d, 1H), 7.90 (d,
1H), 7.81 (d, 1H), 7.64-7.45 (m, 3H), 7.34 (d, 2H), 7.26 (d, 1H),
7.04 (d, 2H), 6.68 (d, 1H), 6.42 (dd, 1H), 6.18 (s, 1H), 4.28 (d,
2H), 3.78 (d, 2H), 3.61 (dd, 2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.17
(d, 6H), 1.87 (dd, 6H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 287
N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 287A
(4,4-difluoro cyclohexyl)methanol
[0850] Ethyl 4,4-difluorocyclohexanecarboxylate (1.0 g, 5.20 mmol)
in diethyl ether (2 ml) was added dropwise to lithium aluminium
hydride (0.24 g) in diethyl ether (15 ml), and heated under reflux
for 4 hours. The reaction was then cooled to 0.degree. C., and
water was added (0.24 ml), followed by 5N aqueous NaOH (0.24 ml)
and water (0.72 ml). Then Na.sub.2SO.sub.4 and more diethyl ether
(40 ml) were added, and the mixture was stirred for 30 minutes,
then filtered through celite. After concentration, the residue was
diluted with CH.sub.2Cl.sub.2 and Na.sub.2SO.sub.4 was added, and
the mixture was filtered and concentrated to provide the title
compound.
Compound 287B
5-chloro-6-((4,4-difluorocyclohexyl)methoxy)pyridine-3-sulfonamide
[0851] The title compound was prepared by substituting Compound 40A
for 4-fluoro-3-nitrobenzenesulfonamide and Compound 287A for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 287C
[0852]
N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfon-
yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0853] The title compound was prepared by substituting Compound
287B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.63 (s, 1H),
8.46 (d, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.56 (d, 1H), 7.47 (m,
2H), 7.35 (d, 2H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.37 (m, 1H), 6.21
(d, 1H), 4.25 (d, 2H), 3.07 (br m, 4H), 2.82 (br s, 2H), 2.30 (br
m, 4H), 2.16 (br m, 2H), 2.00, 1.95, 1.85 (all m, total 9H), 1.40
(t, 2H), 1.37 (m, 2H), 0.92 (s, 6H).
Compound 288
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}--
5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yl-
oxy)benzamide
Compound 288A
5-nitro-3-(trifluoromethyl)pyridin-2-ol
[0854] 3-(Trifluoromethyl)pyridin-2-ol (2.3 g) was added to
concentrated sulfuric acid (15 ml) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 5 minutes. To this solution was added
fuming nitric acid (6 ml) dropwise over 5 minutes. The reaction
mixture was stirred at room temperature for 2 hours, and then
heated at 50.degree. C. for 3 hours. After cooling, the reaction
mixture was poured onto ice (200 g), and the mixture was extracted
with ethyl acetate three times. The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure to provide the title
compound.
Compound 288B
2-chloro-5-nitro-3-(trifluoromethyl)pyridine
[0855] A mixture of Compound 288A (1.69 g), phosphorus
pentachloride (2.03 g), and phosphoryl trichloride (0.97 ml) was
heated at 90.degree. C. for 3 hours. After cooling, the reaction
mixture was poured into ice, and extracted with ethyl acetate three
times. The extract was washed with brine, dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel eluting with
10% ethyl acetate in hexanes to provide the title compound.
Compound 288C
6-chloro-5-(trifluoromethyl)pyridin-3-amine
[0856] A mixture of iron (1.5 g) and ammonium chloride (2.38 g) in
water (40 ml) was stirred at room temperature for 5 minutes. To
this suspension was added Compound 288B in methanol (40 ml). The
reaction mixture was stirred at room temperature for 1 hour. More
iron (1.8 g) was added to the reaction mixture, and it was stirred
for another 3 hours. The solid from the reaction mixture was
filtered off, and the filtrate was partitioned between water and
ethyl acetate. The combined organic layers were washed with brine,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel eluting with 20% ethyl acetate in hexanes to provide
the title compound.
Compound 288D
6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride
[0857] Under ice-cooling, thionyl chloride (4 ml) was added
dropwise over 20 minutes to water (27 ml). The mixture was stirred
overnight for 12 hours to give a SO.sub.2 containing solution.
Separately, Compound 288C (1.14 g) in dioxane (5 ml) was added to
concentrated HCl (20 ml) at 0.degree. C. The solution was stirred
for 5 minutes. To this suspension/solution was added sodium nitrite
(0.44 g) in water (6 ml) dropwise at 0.degree. C. The solution was
stirred at 0.degree. C. for 3 hours. During this time, any solid
formed was crushed with a glass rod to make sure that Compound 288C
was completely reacted. To the SO.sub.2 containing solution was
added copper(I) chloride (0.115 g). Then, to this solution was
added the diazotized Compound 288C at 0.degree. C. The solution was
stirred for 30 minutes. The reaction mixture was extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel eluting with 5% ethyl acetate in hexanes to provide
the title compound.
Compound 288E
6-chloro-5-(trifluoromethyl)pyridine-3-sulfonamide
[0858] Compound 288D (2.03 g) in dioxane (20 ml) solution was
cooled to 0.degree. C. Ammonium hydroxide solution was added
dropwise. The reaction mixture was stirred at 0.degree. C. for 2
hours followed by room temperature over night. The solvent was
partially removed, and the residue was partitioned between water
and ethyl acetate. The organic phase was washed with brine, dried
over MgSO.sub.4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel eluting with 0-3% methanol in dichloromethane to afford the
title compound.
Compound 288F
tert-butyl
4-fluoro-4-((5-sulfamoyl-3-(trifluoromethyl)pyridin-2-yloxy)met-
hyl)piperidine-1-carboxylate
[0859] The title compound was prepared by substituting Compound
288E for 4-fluoro-3-nitrobenzenesulfonamide and Compound 322A for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 288G
6-(((4-fluoropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfona-
mide
[0860] The title compound was prepared by substituting Compound
288F for tert-butyl
(4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate in the
procedure for Compound 252B
Compound 288H
6-((1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl)methoxy)-5-(trifluo-
romethyl)pyridine-3-sulfonamide
[0861] The title compound was prepared by substituting
1,3-difluoropropan-2-one for 4'-chlorobiphenyl-2-carboxaldehyde and
Compound 288G for tert-butyl piperazine-1-carboxylate in the
procedure for Compound 1A.
Compound 288I
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}--
5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yl-
oxy)benzamide
[0862] The title compound was prepared by substituting Compound
288H for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (s, 1H),
8.57 (s, 1H), 8.27 (d, 1H), 7.91 (d, 1H), 7.58 (d, 1H), 7.40 (m,
1H), 7.35 (d, 2H), 7.28 (d, 1H), 7.05 (d, 2H), 6.61 (dd, 1H), 6.29
(dd, 1H), 6.24 (d, 1H), 4.67 (d, 2H), 4.55 (d, 2H), 4.50 (s, 1H),
4.44 (s, 1H), 3.06 (m, 5H), 2.73 (m, 6H), 2.19 (d, 6H), 1.90 (m, 7
H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 289
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-chloro-6-[2-(tetrahydrofuran-2-yl)ethoxy]pyridin-3-yl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 289A
5-chloro-6-(2-(tetrahydro
furan-2-yl)ethoxy)pyridine-3-sulfonamide
[0863] The title compound was prepared by substituting
2-(tetrahydro-2H-pyran-4-yl)ethanol for
(tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for Compound
36A in the procedure for Compound 36B.
Compound 289B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-chloro-6-[2-(tetrahydro
furan-2-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl-
oxy)benzamide
[0864] The title compound was prepared by substituting Compound
289A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H),
8.52 (d, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.50-7.55 (m, 3H), 7.35
(d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.38 (dd, 1H), 6.21 (d, 1H),
4.39-4.51 (m, 4H), 3.87-3.94 (m, 1H), 3.73-3.78 (m, 1H), 3.57-3.62
(m, 1H), 3.11 (s, 4H), 2.89 (s, 2H), 2.33 (s, 4H), 2.15 (s, 2H),
1.77-2.01 (m, 7H), 1.45-1.54 (m, 1H), 1.40 (t, 2H), 0.93 (s,
6H).
Compound 290
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-methylp-
iperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 290A
2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde
[0865] Into a 250 ml round-bottomed flask was added
N,N-dimethylformamide (3.5 ml) in dichloromethane (30 ml). The
mixture was cooled to -10.degree. C., and phosphoryl trichloride (4
ml) was added dropwise. The solution was warmed up to room
temperature and 3,3-dimethylcyclohexanone (5.5 ml) was added
slowly. The mixture was heated to reflux overnight. The reaction
mixture was quenched by 0.degree. C. solution of sodium acetate (25
g in 50 ml water). The aqueous layer was extracted with ether
(3.times.200 ml). The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered, and dried under vacuum.
Compound 290B
2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde
[0866] Into a 1 L round-bottomed flask was added Compound 290A (6.8
g), 4-chlorophenylboronic acid (6.5 g) and palladium(II) acetate
(0.2 g) in water (100 ml) to give a suspension. Potassium carbonate
(15 g) and tetrabutylammonium bromide (10 g) were added. After
degassing after subjecting to vacuum and nitrogen, the mixture was
stirred at 45.degree. C. for 4 hours. After filtering through
silica gel, diethyl ether (4.times.200 ml) was used to extract the
product. The combined organic layers were dried over
Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated and
purified by flash chromatography on silica with 0-10% ethyl acetate
in hexanes to provide the title compound.
Compound 290C
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-3-me-
thylpiperazine-1-carboxylate
[0867] To a solution of tert-butyl 3-methylpiperazine-1-carboxylate
(0.256 g) and Compound 290B (0.350 g) in dichloromethane (2 ml) was
added sodium triacetoxyborohydride (0.406 g) and the reaction was
stirred at room temperature overnight. The reaction was quenched
with NaHCO.sub.3 solution (50 ml) and extracted with
dichloromethane (50 ml). The organic layer was dried over magnesium
sulfate, filtered and concentrated. Silica gel chromatography
(Reveleris 40 g) eluting with a gradient of 0.5% to 2.5%
methanol/dichloromethane gave the title compound.
Compound 290D
1-((2-chiorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-2-methylpiperazine
[0868] A solution of Compound 290C (0.298 g) and HCl (4.0M in
dioxane, 2 ml) were stirred for 1 hour. The reaction was
concentrated and partioned between dichloromethane (100 ml) and
NaHCO.sub.3 (100 ml). The organic layer was washed with brine (50
ml), dried over magnesium sulfate, filtered and concentrated to
provide the title compound.
Compound 290E
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-enyl)methyl)-3-methylpiperazin-1-yl)benzoate
[0869] The title compound was prepared by substituting Compound
290D for Compound 3E in the procedure for Compound 31.
Compound 290F
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)-3-methylpiperazin-1-yl)benzoic acid
[0870] The title compound was prepared by substituting Compound
290E for Compound 15G in the procedure for Compound 15H.
Compound 290G
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-methylp-
iperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0871] The title compound was prepared by substituting Compound
290F for Compound 1E in the procedure for Compound 1G. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H),
11.54-11.30 (m, 1H), 8.62-8.53 (m, 2H), 8.03 (d, 1H), 7.78 (d, 1H),
7.48 (d, 3H), 7.34 (d, 2H), 7.06 (t, 3H), 6.68 (d, 1H), 6.38 (dd,
1H), 6.21 (s, 1H), 3.84 (d, 2H), 3.23 (s, 4H), 2.75 (s, 4H), 1.64
(s, 8H), 1.62 (d, 2H), 1.42-1.17 (m, 6H), 0.92 (s, 6H), 0.87 (s,
3H).
Compound 291
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(cyclopropylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 291A
tert-butyl 2-cyanoethyl(cyclopropyl)carbamate
[0872] To a solution of 3-(cyclopropylamino)propanenitrile (5.0 g)
in tetrahydrofuran (30 ml) was added di-tert-butyl dicarbonate
(9.91 g) and a catalytic amount of 4-dimethylaminopyridine. The
mixture was stirred overnight. The mixture was diluted with ethyl
acetate (400 ml) and washed with 5% aqueous HCl, water and brine.
After drying over Na.sub.2SO.sub.4, the mixture was filtered, and
the solvent was evaporated under vacuum to provide the title
compound.
Compound 291B
tert-butyl 3-aminopropyl(cyclopropyl)carbamate
[0873] Compound 291A (9.75 g) and 7M NH.sub.3-methanol (25 ml) were
added to a Ra--Ni 2800, water slurry (19.50 g, 332 mmol) in a 250
ml pressure bottle and stirred for 2 hours at 30 psi and room
temperature. The mixture was filtered though a nylon membrane and
evaporation of the solvent gave the title compound.
Compound 291C
tert-butyl
cyclopropyl(3-(2-nitro-4-sulfamoylphenylamino)propyl)carbamate
[0874] To a solution of 4-chloro-3-nitrobenzenesulfonamide (2.5 g),
and Compound 291B (2.26 g) in dioxane (20 ml) was added
N,N-diisopropylethylamine (5 ml). The mixture was stirred at reflux
overnight. The mixture was diluted with ethyl acetate (400 ml) and
washed with water and brine. After drying over Na.sub.2SO.sub.4,
the mixture was filtered, and the solvent was evaporated under
vacuum to provide the title compound.
Compound 291D
tert-butyl
3-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamo-
yl)-2-nitrophenylamino)propyl(cyclopropyl)carbamate
[0875] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 291C for Compound 1F in the procedure
for Compound 1G.
Compound 291E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(cyclopropylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0876] To a solution of Compound 291D (2.56 g) in dichloromethane
(10 ml) was added trifluoroacetic acid (10 ml). The mixture was
stirred for 2 hours. The mixture was concentrated under vacuum and
the residue was dissolved in dichloromethane (300 ml) and washed
with aqueous NaHCO.sub.3, water, and brine and dried over
Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave
the crude product. The title compound was obtained by dissolving
200 mg of the crude material in dimethylsulfoxide/methanol (1:1, 10
ml) and loaded on Gilson, C18(100 A) 250.times.121.2 mm (10
micron), eluting with 30% acetonitrile to 65% acetonitrile over 40
minutes. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.54 (s, 1H), 8.43 (m, 2H), 7.94 (d, 1H), 7.71 (dd, 1H), 7.57 (d,
1H), 7.43 (m, 1H), 7.34 (m, 3H), 7.05 (d, 2H), 6.90 (d, 1H), 6.63
(dd, 1 H), 6.29 (d, 2H), 3.43 (m, 2H), 2.96 (m, 6H), 2.73 (m, 2H),
2.22 (m, 7H), 1.87 (m, 4H), 1.38 (m, 3H), 0.94 (m, 6H), 0.62 (m,
4H).
Compound 292
N-{[5-chloro-6-(2-methoxyethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorop-
henyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo-
[2,3-b]pyridin-5-yloxy)benzamide
Compound 292A
5-chloro-6-(2-methoxyethoxy)pyridine-3-sulfonamide
[0877] The title compound was prepared by substituting Compound 40A
for 4-fluoro-3-nitrobenzenesulfonamide and 2-methoxyethanol for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 292B
N-{[5-chloro-6-(2-methoxyethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorop-
henyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo-
[2,3-b]pyridin-5-yloxy)benzamide
[0878] The title compound was prepared by substituting Compound
292A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.63 (s, 1H),
8.48 (d, 1H), 8.17 (d, 1H), 8.01 (d, 1H), 7.56 (d, 1H), 7.49 (m,
2H), 7.35 (d, 2H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.37 (m, 1H), 6.21
(d, 1H), 4.52 (m, 2H), 3.70 (m, 2H), 3.28 (s, 3H), 3.13 (br m, 4H),
2.88 (br s, 2H), 2.34 (br m, 4H), 2.16 (br m, 2H), 1.97 (s, 2H),
1.40 (t, 2H), 0.92 (s, 6H).
Compound 293
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 293A
5-bromo-3-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine
[0879] The title compound was prepared by substituting
5-bromo-2,3-difluoropyridine for 4-fluoro-3-nitrobenzenesulfonamide
in the procedure for Compound 24A.
Compound 293B
tert-butyl
5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-ylcarba-
mate
[0880] The title compound was prepared by substituting Compound
293A for Compound 248A in the procedure for Compound 248B.
Compound 293C
5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonyl
chloride
[0881] The title compound was prepared by substituting Compound
293B for Compound 248B in the procedure for Compound 248C.
Compound 293D
5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[0882] The title compound was prepared by substituting Compound
293C for Compound 248C in the procedure for Compound 248D.
Compound 293E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0883] The title compound was prepared by substituting Compound
293D for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, pyridine-d.sub.5) .delta. 13.07 (s, 1H), 9.05 (d,
1H), 8.44 (dd, 1H), 8.41 (d, 1H), 8.09 (d, 1H), 7.67 (t, 1H), 7.65
(d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.53 (d, 1H),
6.49 (dd, 1H), 4.21 (d, 2H), 3.96 (dd, 2H), 3.31 (td, 2H), 3.07 (m,
4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.14 (m, 4H), 1.97 (m, 3H), 1.58
(dd, 2H), 1.38 (m, 4H), 0.94 (s, 6H).
Compound 294
N-[(3-chloro-4-{[1-(methoxyacetyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 294A
tert-butyl
4-((2-chloro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate
[0884] The title compound was prepared by substituting
tert-butyl-4-(hydroxymethyl)piperidine-1-carboxylate for
(4-fluoro-1-methylpiperidin-4-yl)methanol in the procedure for
Compound 283A.
Compound 294B
tert-butyl
4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfam-
oyl)-2-chlorophenoxy)methyl)piperidine-1-carboxylate
[0885] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 294A for Compound 1F in the procedure
for Compound 1G.
Compound 294C
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(3-chloro-4-(piperidin-4-ylmethoxy)-
phenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)meth-
yl)piperazin-1-yl)benzamide
[0886] To Compound 294B (0.286 g) in dichloromethane (3 ml) was
added trifluoroacetic acid (1 ml) and the reaction stirred at room
temperature. After 3 hours the reaction was concentrated to provide
the title compound.
Compound 294D
N-[(3-chloro-4-{[1-(methoxyacetyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0887] To Compound 294C (0.75 g) as a solution in dichloromethane
(1 ml) was added N,N-diisopropylethylamine (0.055 ml) followed by
2-methoxyacetyl chloride (6 .mu.l). After stirring for 10 minutes
the reaction was loaded onto silica gel (Reveleris 40 g) and eluted
using a gradient of 0.5% to 3.5% methanol/dichloromethane over 30
minutes (flow=40 ml/minutes) to provide the title compound. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.71 (s, 1H),
11.55-11.24 (m, 1H), 8.06 (d, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.57
(s, 1H), 7.51 (s, 1H), 7.48 (d, 1H), 7.34 (d, 2H), 7.21 (d, 1H),
7.04 (d, 2H), 6.67 (d, 1H), 6.42 (dd, 1H), 6.18 (s, 1H), 4.42-4.32
(m, 1H), 4.03 (dd, 4H), 3.86-3.74 (m, 1H), 3.28 (s, 3H), 3.07 (s,
5H), 2.77 (s, 3H), 2.30-1.92 (m, 9H), 1.77 (s, 2H), 1.31 (d, 4H),
0.92 (s, 6H).
Compound 295
N-[(3-chloro-4-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}phenyl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0888] The title compound was prepared by substituting
2-(dimethylamino)acetyl chloride for 2-methoxyacetyl chloride in
the procedure for Compound 294D. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.58 (s, 1H), 10.35-9.94 (m,
1H), 7.96 (d, 1H), 7.74 (d, 1H), 7.55 (d, 2H), 7.45 (s, 1H),
7.41-7.29 (m, 3H), 7.05 (d, 3H), 6.63 (d, 1H), 6.37-6.32 (m, 1H),
6.22 (d, 1H), 4.39 (d, 1H), 3.94 (s, 6H), 3.01 (s, 6H), 2.73 (m,
4H), 2.55 (m, 5H), 2.19 (s, 6H), 1.95 (m, 2H), 1.82 (m, 2H), 1.38
(s, 4H), 0.93 (s, 6H).
Compound 296
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl]methyl}piperidin-1-yl)-N--
({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 296A
tert-butyl
4-((4,4-dimethyl-2-oxocyclohexyl)methyl)piperidine-1-carboxylat-
e
[0889] 3,3-Dimethylcyclohexanone (5.60 ml) was added to sodium
bis(trimethylsilyl)amide (45.3 ml, 1M in tetrahydrofuran), and the
reaction was stirred for 1 hour. tert-Butyl
4-(bromomethyl)piperidine-1-carboxylate (11.1 g) in
dimethylsulfoxide (30 ml) was added, and the reaction was stirred
at 50.degree. C. for 24 hours. The reaction was cooled, poured into
water (300 ml), extracted three times with ether, and the combined
extracts were washed three times with water, and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was
chromatographed on silica gel using 5-20% ethyl acetate in hexanes
to provide the title compound.
Compound 296B
tert-butyl
4-((2-(4-chlorophenyl)-2-hydroxy-4,4-dimethylcyclohexyl)methyl)-
piperidine-1-carboxylate
[0890] (4-Chlorophenyl)magnesium bromide (14.1 ml, 1M in ether) was
added to Compound 296A (3.25 g) in tetrahydrofuran (40 ml) at
-78.degree. C., and the reaction was stirred for 20 minutes, and
then allowed to warm to room temperature overnight. The reaction
was quenched with pH 7 buffer (20 ml), extracted with
2.times.ether, and the combined extracts were washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude
product was chromatographed on silica gel using 1-20% ethyl acetate
in hexanes to provide the title compound.
Compound 296C
trans-4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl)methyl)piperidine
[0891] The title compound was prepared by substituting Compound
296B for Compound 1A in the procedure for Compound 1B.
Compound 296D
trans-methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohexyl)methyl)piperidin-1-yl)benzoate
[0892] The title compound was prepared by substituting Compound
296C for Compound 263G in the procedure for Compound 263H.
Compound 296E
trans-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-d-
imethylcyclohexyl)methyl)piperidin-1-yl)benzoic acid
[0893] The title compound was prepared by substituting Compound
296D for Compound 31 in the procedure for Compound 3J.
Compound 296F
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl]methyl}piperidin-1--
yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0894] The title compound was prepared by substituting Compound
296E for Compound 1E in the procedure for Compound 1G. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.36
(br s, 1H), 8.60 (t, 1H), 8.55 (d, 1H), 8.03 (d, 1H), 7.78 (dd,
1H), 7.52 (m, 3H), 7.27 (d, 2H), 7.16 (d, 2H), 7.09 (m, 1H), 6.63
(dd, 1H), 6.38 (dd, 1H), 6.11 (d, 1H), 3.83 (dd, 2H), 3.52 (m, 2H),
3.26 (m, 4H), 2.61 (m, 2H), 2.35 (m, 1H), 1.89 (m, 2H), 1.76 (m,
1H), 1.62 (m, 2H), 1.38 (m, 4H), 1.25 (m, 6H), 1.12 (m, 2H), 0.95
(m, 2H), 0.94 (s, 3H), 0.88 (s, 3H).
Compound 297
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-yl-
methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide
Compound 297A
6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfon-
amide
[0895] The title compound was prepared by substituting Compound
288E for 4-fluoro-3-nitrobenzenesulfonamide in the procedure for
Compound 24A.
Compound 297B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-yl-
methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide
[0896] The title compound was prepared by substituting Compound
297A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.49 (s, 1H),
8.56 (d, 1H), 8.23 (d, 1H), 7.90 (d, 1H), 7.58 (d, 1H), 7.40 (m,
1H), 7.34 (m, 2H), 7.26 (d, 1H), 7.05 (d, 2H), 6.61 (dd, 1H), 6.28
(dd, 1H), 6.24 (d, 1H), 4.24 (d, 2H), 3.86 (dd, 2H), 3.30 (m, 4H),
3.00 (s, 4H), 2.73 (s, 2H), 2.16 (m, 6H), 1.97 (m, 2H), 1.61 (dd,
2H), 1.33 (m, 4H), 0.93 (s, 6H).
Compound 298
N-({5-chloro-6-[(trans-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 298A
6-((trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-5-chloropyridi-
ne-3-sulfonamide
[0897] The title compound was prepared by substituting
(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol for
(tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for Compound
36A in the procedure for Compound 36B.
Compound 298B
N-({5-chloro-6-[(trans-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0898] The title compound was prepared by substituting Compound
298A for Compound 11B in the procedure for Compound 11D. After the
reaction was over, the solvent was removed, and the residue was
treated with 1:1 trifluoroacetic acid/dichloromethane for two
hours. The solvents were removed, and the residue was purified by
reverse phase Gilson Prep HPLC system with a Phenomenex prep column
(Luna, 5.mu., C18(2), 250.times.21.20 mm, 5 .ANG.) eluting with
20-80% acetonitrle in water with 0.1% trifluoroacetic acid to
provide the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H), 8.47 (s, 1H),
8.15 (s, 1H), 8.01 (d, 1H), 7.54 (d, 1H), 7.48-7.49 (m, 1H), 7.35
(d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.37 (d, 1H), 6.21 (s, 1H),
4.53 (t, 1H), 4.18 (d, 2H), 3.08 (s, 4H), 2.84 (s, 2H), 2.29 (s,
4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.79-1.83 (m, 5H), 1.39 (t, 2H),
1.08-1.13 (m, 5H), 0.93 (s, 6H).
Compound 299
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-cyano-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy].sub.p
henyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 299A
3-cyano-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
[0899] The title compound was prepared by substituting Compound 37C
for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 284A.
Compound 299B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-cyano-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0900] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 299A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.72 (s, 1H), 10.24-9.27 (m, 1H), 8.21 (d, 1H), 8.12 (dd,
1H), 8.05 (d, 1H), 7.63-7.46 (m, 3H), 7.45-7.31 (m, 3H), 7.07 (d,
2H), 6.70 (dd, 1H), 6.42 (s, 1H), 6.23 (s, 1H), 4.38 (d, 2H),
3.91-3.73 (m, 2H), 3.68-3.51 (m, 2H), 3.22-2.96 (m, 10H), 2.31-2.12
(m, 2H), 1.99 (s, 6H), 1.43 (t, 2H), 0.93 (s, 6H).
Compound 300
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({6-[(trans-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridi-
n-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 300A
6-((trans-4-methoxycyclohexyl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfo-
namide
[0901] The title compound was prepared by substituting Compound
288E for 4-fluoro-3-nitrobenzenesulfonamide and Compound 121A for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 300B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({6-[(trans-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridi-
n-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0902] The title compound was prepared by substituting Compound
300A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (s, 1H),
8.56 (d, 1H), 8.23 (d, 1H), 7.90 (d, 1H), 7.58 (d, 1H), 7.40 (m,
1H), 7.35 (d, 2H), 7.27 (d, 1H), 7.05 (d, 2H), 6.61 (dd, 1H), 6.28
(dd, 1H), 6.24 (d, 1H), 4.20 (d, 2H), 3.23 (s, 3H), 3.03 (m, 5H),
2.73 (s, 2H), 2.18 (m, 6H), 1.98 (m, 5H), 1.80 (m, 3H), 1.39 (t,
2H), 1.09 (m, 4H), 0.93 (s, 6H).
Compound 301
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({6-[(cis-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin--
3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 301A
6-((cis-4-methoxycyclohexyl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfona-
mide
[0903] The title compound was prepared by substituting Compound
288E for 4-fluoro-3-nitrobenzenesulfonamide and Compound 121A for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 301B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({6-[(cis-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin--
3-yl}sulfonyl)-2-(1H-pyrrolo[2,3b]pyridin-5-yloxy)benzamide
[0904] The title compound was prepared by substituting Compound
301A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.49 (m, 1H),
8.54 (m, 1H), 8.23 (d, 1H), 7.91 (d, 1H), 7.59 (d, 1H), 7.40 (m,
1H), 7.34 (m, 2H), 7.27 (d, 1H), 7.04 (d, 2H), 6.61 (dd, 1H), 6.29
(dd, 1H), 6.24 (d, 1H), 4.20 (d, 2H), 3.37 (m, 2H), 3.19 (s, 3H),
3.00 (s, 4H), 2.73 (s, 2H), 2.18 (m, 6H), 1.96 (s, 2H), 1.80 (m,
3H), 1.50 (dd, 2H), 1.37 (m, 6H), 0.93 (s, 6H).
Compound 302
N-({5-chloro-6-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
eridin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 302A
4-((2-((4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperidine
[0905] Compound 296B (1.0 g) was stirred in dichloromethane (15 ml)
and trifluoroacetic acid (15 ml) at 35.degree. C. for 48 hours. The
mixture was concentrated, taken up in dichloromethane (100 ml), and
stirred, and saturated Na.sub.2CO.sub.3 solution (20 ml) was added
slowly. The solution was separated and the organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated to provide the
title compound.
Compound 302B
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-enyl)methyl)piperidin-1-yl)benzoate
[0906] The title compound was prepared by substituting Compound
302A for Compound 263G in the procedure for Compound 263H.
Compound 302C
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperidin-1-yl)benzoic acid
[0907] The title compound was prepared by substituting Compound
302B for Compound 31 in the procedure for Compound 3J.
Compound 302D
1,1-difluoro4-methylenecyclohexane
[0908] Butyllithium (12.32 ml, 2.5 M solution in hexanes) was added
to a solution of methyltriphenylphosphonium chloride (9.63 g) in
tetrahydrofuran (50 ml) at 0.degree. C., and the reaction was
stirred for 5 minutes. 4,4-Difluorocycleohexanone (3.76 g) in
dioxane (150 ml) was then added, and the reaction was stirred for
30 minutes. Water (3 ml) was added, and then hexane (150 ml) was
slowly added, the reaction was filtered, and the solution carried
on.
Compound 302E
4,4-difluoro-1-(hydroxymethyl)cyclohexanol
[0909] To the solution from Compound 302D was added water (75 ml),
then N-methylmorpholine-N-oxide (6.4 ml, 50% solution in water) and
OsO.sub.4 (14.2 g, 2.5 wt % solution in tert-butanol) were added,
and the reaction was stirred for 96 hours at 50.degree. C. The
solution was cooled to room temperature, treated with saturated
aqueous Na.sub.2S.sub.2O.sub.3 solution (100 ml) for 30 minutes,
and then acidified with concentrated aqueous HCl. The solution was
then extracted three times with ethyl acetate, and the organic
layers were combined, washed with 1M HCl, and brine, and
concentrated. The crude mixture was chromatographed on silica gel
using 10-100% ethyl acetate in hexanes, and then 5% methanol in
ethyl acetate to give the product.
Compound 302F
5-chloro-6-((4,4-difluoro-1-hydroxycyclohexyl)methoxy)pyridine-3-sulfonami-
de
[0910] This compound was prepared by substituting Compound 302E for
tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 302G
N-({5-chloro-6-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
eridin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0911] The title compound was prepared by substituting Compound
302C for Compound 1E and Compound 302F for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.65 (br s, 2H), 8.51 (s, 1H),
8.18 (s, 1H), 8.02 (d, 1H), 7.53 (m, 3H), 7.35 (d, 2H), 7.04 (d,
2H), 6.69 (dd, 1H), 6.39 (dd, 1H), 6.21 (d, 1H), 4.88 (s, 1H), 4.27
(s, 2H), 3.10 (m, 4H), 2.88 (m, 1H), 2.33 (m, 2H), 2.15 (m, 4H),
1.97 (s, 2H), 1.91 (m, 2H), 1.73 (m, 4H), 1.52 (m, 1H), 1.40 (m,
2H), 1.31 (m, 1H), 0.93 (s, 3H), 0.91 (m, 2H).
Compound 303
N-[(3-chloro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]methoxy}phenyl)sulfony-
l]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 303A
trans-4-morpholino cyclohexyl)methanol
[0912] To tert-butyl trans-4-(hydroxymethyl)cyclohexylcarbamate
(0.500 g) was added hydrogen chloride (4.0M in dioxane, 2.2 ml) and
the reaction was stirred for 1 hour and concentrated. The resulting
solid was dissolved in acetonitrile (4 ml) and treated with
N,N-diisopropylethylamine (1.523 ml) followed by
1-bromo-2-(2-bromoethoxy)ethane (0.556 g) and heated to 60.degree.
C. After stirring overnight the reaction was concentrated, loaded
onto silica gel (Reveleris 40 g) and eluted using a gradient of 1%
to 10% methanol/dichloromethane over 30 minutes (flow=40 ml/min) to
provide the title compound.
Compound 303B
3-chloro-4-(((1r,4r)-4-morpholino
cyclohexyl)methoxy)benzenesulfonamide
[0913] The title compound was prepared by substituting Compound
303A for (4-fluoro-1-methylpiperidin-4-yl)methanol in the procedure
for Compound 283A.
Compound 303C
N-[(3-chloro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]methoxy}phenyl)sulfony-
l]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0914] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 303B for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (s, 1H), 10.96-10.59 (m, 1H), 8.02 (d, 1H), 7.82 (d,
1H), 7.69 (s, 1H), 7.50 (dd, 3H), 7.38-7.30 (m, 2H), 7.15-6.99 (m,
3H), 6.65 (dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 3.91 (d, 2H), 3.64
(s, 4H), 3.04 (s, 4H), 2.73 (s, 7H), 2.18 (s, 6H), 1.93 (m, 6H),
1.80-1.65 (m, 1H), 1.32 (m, 6H), 0.92 (s, 6H).
Compound 304
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({3-[cyclopropyl(1,3-thiazol-5-ylmethyl)amino]propyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0915] To a solution of Compound 291E (95 mg) in dichloromethane (2
ml) and acetic acid (0.5 ml) was added thiazole-5-carbaldehyde (13
mg) followed by sodium triacetoxyborohydride (35 mg). The mixture
was stirred overnight. The mixture was diluted with dichloromethane
(300 ml) and washed with aqueous NaHCO.sub.3, water, and brine and
dried over Na.sub.2SO.sub.4. Filtration and evaporation of the
solvent gave crude product which was dissolved in
dimethylsulfoxide/methanol (6 ml, 1:1) and loaded on Gilson,
C18(100 A) 250.times.121.2 mm (10 micron), with 30% acetonitrile to
65% acetonitrile over 40 minutes. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 8.95 (s, 1H),
8.57 (m, 2H), 8.03 (d, 1H), 7.78 (m, 2H), 7.49 (m, 3H), 7.35 (m,
2H), 7.02 (m, 3H), 6.67 (dd, 1H), 6.38 (dd, 1 H), 6.19 (d, 1H),
4.00 (s, 2H), 3.05 (d, 4H), 2.73 (m, 2H), 2.60 (m, 2H), 2.18 (m,
7H), 1.95 (s, 2H), 1.79 (m, 3H), 1.37 (m, 3H), 0.92 (s, 6H), 0.45
(m, 4H).
Compound 305
N-({3-chloro-4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{-
[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 305A
3-chloro-4-((trans-4-hydroxycyclohexyl)methoxy)benzenesulfonamide
[0916] (Trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol
(275 mg, prepared according to a procedures in WO 2008/124878) and
3-chloro-4-fluorobenzenesulfonamide (259 mg) in tetrahydrofuran (15
ml) were treated with sodium hydride (180 mg, 60%) overnight. The
reaction was quenched with water (1 ml) and trifluoroacetic acid (4
ml) was added. The resulting mixture was stirred for 1 hour and
concentrated. The residue was triturated with water and methanol to
provide the title compound.
Compound 305B
N-({3-chloro-4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{-
[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0917] The title compound was prepared as described in the
procedure for Compound 11D using Compound 305A in place of Compound
11B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.71
(s, 1H), 11.38 (s, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 7.76 (dd, 1 H),
7.57 (d, 1H), 7.51-7.55 (m, 1H), 7.49 (d, 1H), 7.34 (d, 2H), 7.18
(d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.42 (dd, 1H), 6.18 (d, 1H),
4.54 (d, 1H), 3.91 (d, 2H), 3.07 (s, 4H), 2.75 (s, 2H), 2.17 (d,
6H), 1.95 (s, 2H), 1.78-1.90 (m, 4H), 1.63-1.75 (m, 1H), 1.38 (t,
2H), 1.00-1.25 (m, 4H), 0.92 (s, 6H).
Compound 306
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-chloro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 306A
3-chloro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
[0918] The title compound was prepared by substituting
4-fluoro-3-chlorobenzenesulfonamide for
4-chloro-3-nitrobenzenesulfonamide,
(tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-amine
dihydrochloride and Hunig's base for
N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethylethane-1,2-diamine in
the procedure for Compound 6A.
Compound 306B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-chloro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0919] The title compound was prepared by substituting Compound
306A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.80 (s, 1H),
11.17 (br s, 1H), 8.09 (d, 1H), 7.71 (d, 1H), 7.63 (d, 1H), 7.58
(dd, 1H), 7.53 (dd, 1H), 7.50 (d, 1H), 7.34 (d, 2H), 7.03 (d, 2H),
6.74 (d, 1H), 6.66 (dd, 1H), 6.42 (m, 1H), 6.40 (t, 1H), 6.16 (d,
1H), 3.83 (m, 2H), 3.24 (m, 2H), 3.10 (m, 2H), 3.06 (br m, 4H),
2.72 (s, 2H), 2.17 (br m, 6H), 1.95 (s, 2H), 1.83 (m, 1H), 1.59 (br
m, 2H), 1.38 (t, 2H), 1.20 (ddd, 2H), 0.92 (s, 6H).
Compound 307
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl-
)phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 307A
4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-(trifluoromethyl)benzene
sulfonamide
[0920] The title compound was prepared by substituting
4-fluoro-3-(trifluoromethyl)benzenesulfonamide for
4-fluoro-3-nitrobenzenesulfonamide and Compound 37C for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 307B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl-
)phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0921] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 307A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (400 MHz, pyridine-d.sub.5) .delta.
13.07 (s, 1H), 8.78 (d, 1H), 8.58 (dd, 1H), 8.42 (d, 1H), 8.09 (d,
1H), 7.67 (t, 1H), 7.65 (d, 1H), 7.43 (m, 2H), 7.16 (d, 1H), 7.06
(m, 2H), 6.74 (dd, 1H), 6.51 (m, 2H), 4.21 (d, 2H), 3.87 (m, 2H),
3.78 (td, 2H), 3.06 (m, 4H), 2.76 (s, 2H), 2.25 (t, 2H), 2.13 (m,
4H), 1.95 (m, 6H), 1.39 (t, 2H), 0.93 (s, 6H).
Compound 308
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({3-[cyclopropyl(2,2,2-trifluoroethyl)amino]propyl}amino)-3-ni-
trophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 308A
4-(3-(cyclopropylamino)propylamino)-3-nitrobenzenesulfonamide
[0922] To a solution of Compound 291C (4.14 g) in dichloromethane
(10 ml) was added trifluoroacetic acid (10 ml). The mixture was
stirred for 2 hours. The mixture was concentrated under vacuum and
the residue was dissolved in dichloromethane (300 ml) and washed
with aqueous NaHCO.sub.3, water, and brine and dried over
Na.sub.2SO.sub.4. Filtration and evaporation of solvent gave the
title compound.
Compound 308B
4-(3-(cyclopropyl(2,2,2-trifluoroethyl)amino)propylamino)-3-nitrobenzenesu-
lfonamide
[0923] To a solution of Compound 308A (314 mg) in dichloromethane
(6 ml) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate
(255 mg) and N,N-diisopropylethylamine (258 mg). The mixture was
stirred overnight. The mixture was diluted with dichloromethane
(300 ml) and washed with aqueous NaHCO.sub.3, water, brine and
dried over Na.sub.2SO.sub.4. Filtration and evaporation of solvent
gave the title compound.
Compound 308C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({3-[cyclopropyl(2,2,2-trifluoroethyl)amino]propyl}amino)-3-ni-
trophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0924] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 308B for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.67 (s, 1H), 11.38 (m, 1H), 8.55 (d, 2H), 8.03 (d, 1H),
7.81 (dd, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.05 (m, 3H), 6.67 (dd,
1H), 6.38 (dd, 1H), 6.19 (d, 1 H), 3.07 (m, 4H), 2.82 (m, 4H), 2.18
(m, 7H), 1.38 (m, 2H), 0.92 (s, 6H), 0.44 (m, 4H).
Compound 309
N-[(3-chloro-4-{[1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4--
(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0925] To a solution of Compound 294B (0.150 g) in dichloromethane
(2 ml) was added trifluoroacetic acid (1 ml). After stirring for 1
hour the reaction was concentrated and dried under high vacuum. The
residue was dissolved in dichloromethane (2 ml) and treated with
sodium triacetoxyborohydride (0.050 g) and oxetan-3-one (0.017 g)
and stirred overnight at room temperature. The reaction was
quenched with saturated aqueous NaHCO.sub.3 (20 ml) and extracted
into dichloromethane (50 ml). The organic layer was separated,
washed with brine (25 ml), dried over Na.sub.2SO.sub.4, filtered,
and concentrated. Silica gel chromatography (Reveleris 40 g)
eluting with a gradient of 0.5% to 5% methanol/dichloromethane over
30 minutes (flow=40 ml/min) provided the title compound. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.70 (s, 1H),
11.21 (s, 1H), 8.05 (d, 1H), 7.87 (d1H), 7.75 (dd, 1H), 7.61-7.42
(m, 3H), 7.42-7.26 (m, 2H), 7.18 (d, 1H), 7.14-6.97 (m, 2H), 6.67
(dd, 1H), 6.41 (dd, 1H), 6.18 (d, 1H), 4.51 (dt, 4H), 3.99 (d, 2H),
3.56-3.32 (m, 1H), 3.06 (s, 4H), 2.89-2.68 (m, 4H), 2.16 (d, 6H),
2.01-1.69 (m, 7H), 1.50-1.07 (m, 4H), 0.92 (s, 6H).
Compound 310
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3,5-difluoro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 310A
3,5-difluoro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonami-
de
[0926] Compound 37C (0.423 g) in tetrahydrofuran (30 ml) was
treated with NaH (60% oil dispersion) (0.480 g), stirred 20 minutes
at ambient temperature, treated with
3,4,5-trifluorobenzenesulfonamide (0.633 g) and stirred 30 minutes.
N,N-Dimethylacetamide (15 ml) was added to increase solubility of
the reactants and stirring was continued overnight at ambient
temperature. Additional NaH (60% oil dispersion) (0.480 g) and
N,N-dimethylacetamide (15 ml) were added and the mixture was heated
overnight at 50.degree. C. The reaction was quenched with saturated
aqueous NH.sub.4Cl solution and then partitioned between saturated
aqueous NH.sub.4Cl solution and ethyl acetate. The organic layer
was washed with water and brine, dried (MgSO.sub.4), filtered and
concentrated. The concentrate was chromatographed on amine
functionalized silica gel with 0 to 2% methanol in CH.sub.2Cl.sub.2
as the eluent. The residue was further purified by reverse phase
HPLC on a C18 column using a gradient of 10-70% acetonitrile/0.1%
trifluoroacetic acid in water to provide the title compound.
Compound 310B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3,5-difluoro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0927] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 310A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta.
13.06 (s, 1H), 8.41 (d, 1H), 8.11 (m, 2H), 8.08 (d, 1H), 7.66 (m,
2H), 7.44 (m, 2H), 7.07 (m, 2H), 6.75 (dd, 1H), 6.52 (d, 1H), 6.50
(dd, 1H), 4.26 (d, 2H), 3.85 (dd, 1H), 3.83 (dd, 1H), 3.74 (m, 2H),
3.07 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.14 (m, 4H), 1.97 (s,
2H), 1.87 (m, 4H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 311
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl-
]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 311A
4-(3-(cyclopropyl(oxetan-3-yl)amino)propylamino)-3-nitrobenzene
sulfonamide
[0928] To a solution of Compound 308A (314 mg) in dichloromethane
(5 ml) was added oxetan-3-one (72 mg) followed by sodium
triacetoxyborohydride (318 mg). The mixture was stirred overnight.
The mixture was diluted with dichloromethane (300 ml) and washed
with aqueous NaHCO.sub.3, water and brine and dried over
Na.sub.2SO.sub.4. After filtration, evaporation of the solvent gave
the crude title compound.
Compound 311B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl-
]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0929] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 311A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (s, 1H), 11.37 (s, 1H), 8.68 (s, 1H), 8.54 (d, 1H),
8.02 (d, 1H), 7.79 (d, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.03 (m,
3H), 6.67 (dd, 1H), 6.38 (dd, 1 H), 6.19 (d, 1H), 4.62 (m, 2H),
4.48 (t, 2H), 3.98 (m, 1H), 3.37 (m, 2H), 3.06 (m, 4H), 2.73 (d,
2H), 2.59 (m, 2H), 2.23 (m, 6H), 1.95 (s, 2H), 1.74 (m, 3H), 1.38
(t, 2H), 0.92 (s, 6H), 0.41 (m, 4H).
Compound 312
N-[(3-chloro-4-{[1-(1-methyl-L-prolyl)piperidin-4-yl]methoxy}phenyl)sulfon-
yl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0930] To Compound 294B (0.065 g) was added hydrogen chloride (4.0M
in dioxane, 0.339 ml) and a few drops of methanol. After 30
minutes, the reaction was concentrated, and
(S)-1-methylpyrrolidine-2-carboxylic acid (0.013 g),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (0.026 g), suspended in dichloromethane (0.5 ml)
were added followed by diisopropylethylamine (0.036 ml). The
mixture stirred at room temperature. After stirring overnight, the
reaction mixture was loaded onto silica gel (Reveleris 40 g) and
eluted using a gradient of 1% to 10% methanol (containing 1N
NH.sub.3)/dichloromethane over 30 minutes (flow=40 ml/minutes) to
provide the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.51 (s, 1H), 10.00-9.22 (m,
1H), 7.92 (d, 1H), 7.68 (d, 1H), 7.57 (d, 1H), 7.47 (dd, 1H),
7.44-7.38 (m, 1H), 7.38-7.31 (m, 2H), 7.29 (d, 1H), 7.12-7.01 (m,
2H), 6.90 (d, 1H), 6.61 (dd, 1H), 6.31 (dd, 1H), 6.25 (d, 1H), 5.85
(d, 1H), 4.40 (s, 1H), 3.92 (s, 4H), 3.17-2.89 (m, 8H), 2.73 (s,
4H), 2.38 (s, 3H), 2.18 (m, 6H), 1.96 (s, 2H), 1.80 (m, 2H), 1.57
(s, 2H), 1.39 (s, 2H), 1.22 (m, 2H), 0.96 (m, 6H).
Compound 313
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3,4-difluoro-5-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 313A
3,4-difluoro-5-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonami-
de
[0931] The title compound was obtained as a side product in the
procedure for Compound 310A.
Compound 313B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3,4-difluoro-5-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0932] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 313A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (400 MHz, pyridine-d.sub.5) .delta.
13.05 (s, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.98 (m, 2H), 7.66 (m,
1H), 7.63 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.77 (dd, 1H), 6.54
(d, 1H), 6.48 (dd, 1H), 4.12 (d, 2H), 3.83 (m, 2H), 3.75 (m, 2H),
3.08 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.15 (m, 4H), 1.97 (s,
2H), 1.82 (m, 4H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 314
N-[(5-chloro-6-{[(2S)-4-cyclopropylmorpholin-2-yl]methoxy}pyridin-3-yl)sul-
fonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 314A
(S)-5-chloro-6-((4-cyclopropylmorpholin-2-yl)methoxy)pyridine-3-sulfonamid-
e
[0933] A solution of Compound 244B (250 mg), anhydrous methanol (6
ml), (1-ethoxycyclopropoxy)trimethylsilane (0.474 ml), and acetic
acid (0.509 ml) was heated at 70.degree. C. for 30 minutes. After
cooling to ambient temperature, sodium cyanoborohydride (112 mg)
was added and the mixture was stirred for 18 hours. Additional
sodium cyanoborohydride (75 mg) was added and stirring was
continued 18 hours. The reaction was concentrated and the residue
was partitioned between methylene chloride and saturated sodium
bicarbonate solution. The crude product was isolated from the dried
methylene chloride layer and was purified on silica gel and was
eluted with a 1, 2.5, 5, 10% methanol in methylene chloride step
gradient to provide the title compound.
Compound 314B
N-[(5-chloro-6-{[(2S)-4-cyclopropylmorpholin-2-yl]methoxy}pyridin-3-yl)sul-
fonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0934] The title compound was prepared by substituting Compound
314A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (400 MHz, pyridine-d.sub.5) .delta. 12.98 (s, 1H), 9.09 (d,
1H), 8.69 (d, 1H), 8.41 (d, 1H), 8.11 (d, 1H), 7.66-7.64 (m, 2H),
7.44 (d, 2H), 7.07 (d, 2H), 6.75 (dd, 1H), 6.53 (m, 1H), 6.48 (m,
1H), 5.72 (br s, 1H), 4.62-4.57 (m, 1H), 4.51-4.47 (m, 1H), 3.99
(m, 1H), 3.85 (m, 1H), 3.57 (m, 1H), 3.08-3.01 (m, 5H), 2.77 (s,
2H), 2.69 (m, 1H), 2.39-2.24 (m, 4H), 2.14 (m, 4H), 1.97 (s, 2H),
1.57 (m, 1H), 1.39 (t, 2H), 0.94 (m, 6H), 0.48-0.3 (m, 4H).
Compound 315
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0935] The title compound was prepared by substituting Compound
302C for Compound 1E and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.70 (s, 1H), 11.35 (br s, 1H),
8.61 (m, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.82 (dd, 1H), 7.45-7.57
(m, 3H), 7.33 (d, 2H), 7.15 (d, 1H), 7.01 (d, 2H), 6.65 (dd, 1H),
6.40 (dd, 1H), 6.11 (d, 1H), 3.85 (dd, 2H), 3.53 (m, 2H), 3.27 (m,
4H), 2.63 (m, 2H), 2.04 (m, 2H), 1.91 (s, 2H), 1.77 (m, 2H), 1.62
(m, 4H), 1.45 (m, 2H), 1.38 (m, 2H), 1.27 (m, 1H), 1.23 (m, 4H),
0.92 (s, 6H).
Compound 316
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin--
1-yl)-N-{[3-chloro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 316A
3-chloro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
[0936] The title compound was prepared by substituting
(tetrahydro-2H-pyran-4-yl)methanol for
(4-fluoro-1-methylpiperidin-4-yl)methanol in the procedure for
Compound 283A.
Compound 316B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin--
1-yl)-N-{[3-chloro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(-
1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0937] The title compound was prepared by substituting Compound
302C for Compound 1E and Compound 316A for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.77 (s, 1H), 11.35 (br s, 1H),
8.06 (m, 1H), 7.88 (d, 1H), 7.79 (dd, 1H), 7.58 (s, 1H), 7.53 (t,
1H), 7.46 (d, 1H), 7.34 (d, 2H), 7.22 (d, 1H), 7.01 (d, 2H), 6.66
(dd, 1H), 6.42 (dd, 1H), 6.11 (d, 1H), 3.99 (d, 2H), 3.88 (dd, 2H),
3.52 (m, 2H), 3.34 (m, 4H), 2.62 (m, 2H), 2.04 (m, 4H), 1.76 (m,
2H), 1.68 (m, 2H), 1.46 (m, 2H), 1.38 (m, 4H), 0.92 (s, 6H), 0.75
(m, 2H).
Compound 317
methyl
2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoy-
l}-2-nitrophenyl)amino]methyl}morpholine-4-carboxylate
Compound 317A
methyl
2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate
[0938] The title compound was prepared by substituting methyl
chloroformate for methyl iodide in the procedure for Compound
134B.
Compound 317B
methyl
2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoy-
l}-2-nitrophenyl)amino]methyl}morpholine-4-carboxylate
[0939] The title compound was prepared by substituting Compound
317A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.26 (d,
1H), 8.84 (t, 1H), 8.43 (d, 1H), 8.35 (d, 1H), 8.12 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (bs, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 4.29-4.03 (m, 1H), 3.89-3.70 (m, 3H),
3.71 (s, 3H), 3.55-3.38 (m, 3H), 3.07 (m, 4H), 2.96 (dt, 1H), 2.86
(dd, 1H), 2.77 (s, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H),
1.39 (t, 2H), 0.94 (s, 6H).
Compound 318
2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-ni-
trophenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide
Compound 318A
N-ethyl-N-methyl-2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-ca-
rboxamide
[0940] The title compound was prepared by substituting
N-methyl-N-ethyl carbamyl chloride for methyl iodide in the
procedure for Compound 134B.
Compound 318B
2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-ni-
trophenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide
[0941] The title compound was prepared by substituting Compound
318A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.26 (d,
1H), 8.86 (t, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.12 (d, 1H), 7.67
(t, 1H), 7.64 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (d, 1H),
6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 3.92-3.85 (m, 2H), 3.75
(d, 1H), 3.62 (dt, 1H), 3.55-3.48 (m, 1H), 3.45-3.39 (m, 2H), 3.21
(q, 2H), 3.07 (m, 4H), 2.99 (dt, 1H), 2.90 (dd, 1H), 2.77 (s, 2H),
2.76 (s, 3H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t,
2H), 1.06 (t, 3H), 0.93 (s, 6H).
Compound 319
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 319A
4-((4-(methylsulfonyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[0942] The title compound was prepared by substituting
methanesulfonyl chloride for methyl iodide in the procedure for
Compound 134B.
Compound 319B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0943] The title compound was prepared by substituting Compound
319A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.25 (d,
1H), 8.84 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.13 (d, 1H), 7.67
(t, 1H), 7.65 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.92 (d, 1H),
6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 3.99 (m, 1H), 3.92-3.88
(m, 2H), 3.64 (m, 2H), 3.56 (m, 1H), 3.50 (m, 1H), 3.07 (m, 4H),
3.04 (s, 3H), 2.95-2.88 (m, 2H), 2.77 (s, 2H), 2.26 (m, 2H), 2.14
(m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 320
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({3-[cyclobutyl(cyclopropyl)amino]propyl}amino)-3-nitrophenyl]-
sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 320A
4-(3-(cyclobutyl(cyclopropyl)amino)propylamino)-3-nitrobenzene
sulfonamide
[0944] To a solution of Compound 308A (314 mg) in dichloromethane
(5 ml) was added cyclobutanone (70 mg) followed by sodium
triacetoxyborohydride (318 mg). The mixture was stirred overnight.
The mixture was diluted with dichloromethane (300 ml) and washed
with aqueous NaHCO.sub.3, water and brine and dried over
Na.sub.2SO.sub.4. After filtration, evaporation of solvent gave the
title compound.
Compound 320B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({3-[cyclobutyl(cyclopropyl)amino]propyl}amino)-3-nitrophenyl]-
sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0945] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 320A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (s, 1H), 8.70 (m, 1H), 8.54 (d, 1H), 8.02 (d, 1H),
7.79 (dd, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.03 (m, 3H), 6.66 (dd,
1H), 6.38 (dd, 1H), 6.19 (d, 1 H), 3.37 (q, 2H), 3.06 (m, 4H), 2.73
(s, 2H), 2.63 (m, 2H), 2.21 (m, 8H), 1.82 (m, 3H), 1.53 (m, 2H),
1.38 (t, 2H), 0.94 (m, 6H), 0.41 (m, 4H).
Compound 321
4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 321A
ethyl 5,5-difluoro-2-oxocyclohexanecarboxylate
[0946] To a solution of diethyl 4,4-difluoroheptanedioate (4.3 g)
in toluene (50 ml) was added potassium 2-methylpropan-2-olate (2.87
g) and the reaction stirred overnight at room temperature. The
reaction was quenched with 1N aqueous HCl (100 ml) and extracted
with diethyl ether (150 ml). The ether layer was washed with brine
(50 ml), dried over magnesium sulfate, filtered, and concentrated.
Silica gel chromatography (Reveleris 40 g) eluting with a gradient
of 1% to 5% ethyl acetate/hexanes gave the title compound.
Compound 321B
ethyl
5,5-difluoro-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
[0947] To a solution of Compound 321A (2.37 g) in dichloromethane
(40 ml) at 0.degree. C. was added N,N-diisopropylethylamine (5.02
ml) followed by trifluoromethanesulfonic anhydride (2.33 ml) and
the reaction was allowed to slowly warm to room temperature. After
stirring overnight the reaction was quenched with 10 ml of water
then 1N aqueous HCl (100 ml). The reaction was extracted with
dichloromethane (3.times.75 ml), and the combined organics were
washed with brine (50 ml) and concentrated. Silica gel
chromatography (Reveleris 40 g) eluting with a gradient of 1% to
25% ethyl acetate/hexanes gave the title compound.
Compound 321C
ethyl 2-(4-chlorophenyl)-5,5-difluorocyclohex-1-enecarboxylate
[0948] A solution of Compound 321B (3.47 g), 4-chlorophenylboronic
acid (1.925 g) and cesium fluoride (3.43 g) in 30 ml of
1,2-dimethoxyethane and 15 ml of ethanol was degassed with nitrogen
for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.237 g)
was added and the reaction was heated to 70.degree. C. The reaction
was diluted with ether (200 ml) and washed with 1N aqueous HCl (100
ml) and brine (100 ml), dried over magnesium sulfate, filtered, and
concentrated. Silica gel chromatography (Reveleris 40 g) eluting
with a gradient of 1% to 8% ethyl acetate/hexanes over 40 minutes
gave the title compound.
Compound 321D
(2-(4-chlorophenyl)-5,5-difluoro cyclohex-1-enyl)methanol
[0949] To a solution of Compound 321C (1.84 g) in diethyl ether (25
ml) at 0.degree. C. was added lithium aluminum hydride (1.0M, 4.28
ml). The reaction was quenched with the dropwise addition of water,
then 1N aqueous HCl (50 ml) was added and the reaction diluted with
diethyl ether (100 ml). The organic layer was separated, washed
with brine (50 ml) dried over magnesium sulfate, filtered and
concentrated to provide the title compound.
Compound 321E
2-(4-chlorophenyl)-5,5-difluoro cyclohex-1-enecarbaldehyde
[0950] To a solution of Compound 321D (1.38 g) in dichloromethane
(25 ml) was added Dess-Martin periodinane (2.489 g) and the
reaction stirred for 1 hour at room temperature. The reaction was
quenched with 1N aqueous NaOH solution (75 ml) and the product was
extracted into dichloromethane (2.times.100 ml). The combined
organics were washed with brine (75 ml), dried over magnesium
sulfate, filtered, and concentrated. Silica gel chromatography
(Reveris 80 g) eluting with a gradient of 1% to 10% ethyl
acetate/hexanes over 40 minutes gave the title compound.
Compound 321F
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5--
difluorocyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0951] The title compound was prepared by substituting Compound
321E for Compound 15E in the procedure for Compound 15G.
Compound 321G
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-difluor-
o cyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0952] The title compound was prepared by substituting Compound
321F for Compound 15G in the procedure for Compound 15H.
Compound 321H
4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0953] The title compound was prepared by substituting Compound
321G for Compound 1E and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.74-11.63 (m, 1H), 11.53-11.29
(m, 1H), 8.57 (d, 2H), 8.05 (d, 1H), 7.85-7.77 (m, 1H), 7.49 (d,
3H), 7.38 (d, 2H), 7.16-7.06 (m, 3H), 6.73-6.64 (m, 1H), 6.43-6.36
(m, 1H), 6.21-6.14 (m, 1H), 3.93-3.77 (m, 2H), 3.29 (d, 4H), 3.07
(s, 4H), 2.79-2.57 (m, 4H), 2.45 (dd, 2H), 2.19 (s, 6H), 1.99-1.80
(m, 1H), 1.70-1.54 (m, 2H), 1.38-1.13 (m, 2H).
Compound 322
N-[(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sul-
fonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 322A
tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
[0954] 1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (2
g) was taken up in tetrahydrofuran (20 ml) and cooled in an ice
bath. Lithium aluminum hydride (1.0M in dioxane, 5.09 ml) was added
dropwise. The reaction was stirred at room temperature for 2 hours.
The reaction was quenched with water and with 1M aqueous NaOH
solution and then stirred another 1 hour at room temperature. The
mixture was extracted with ethyl acetate, and the extracts were
combined and washed with water and with brine, dried over
MgSO.sub.4, filtered and concentrated under vacuum. The crude
product was used without further purification.
Compound 322B
tert-butyl
4-((2-chloro-4-sulfamoylphenoxy)methyl)-4-fluoropiperidine-1-ca-
rboxylate
[0955] The title compound was prepared by substituting Compound
322A for (tetrahydro-2H-pyran-4-yl)methanol and
3-chloro-4-fluorobenzenesulfonamide for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 322C
3-chloro-4-((4-fluoropiperidin-4-yl)methoxy)benzene sulfonamide
[0956] The title compound was prepared by substituting Compound
322B for Compound 1A in the procedure for Compound 1B.
Compound 322D
3-chloro-4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)benzenesulfona-
mide
[0957] To a solution of Compound 322C (830 mg) in tetrahydrofuran
(15 ml) and acetic acid (5 ml) was added oxetan-3-one (163 mg) and
MP-cyanoborohydride (2.38 mmol/g, 1.9 g). The mixture was stirred
at room temperature overnight. The reaction was then filtered and
the filtrate was concentrated under vacuum. The residue was
slurried in ether and the solid product was collected by
filtration.
Compound 322E
N-[(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sul-
fonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0958] The title compound was prepared by substituting Compound
322D for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.71 (s, 1H), 8.06 (d, 1H),
7.89 (d, 1H), 7.79 (m, 1H), 7.58 (d, 1H), 7.52 (t, 1H), 7.49 (d,
1H), 7.34 (d, 2H), 7.25 (d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.42
(m, 1H), 6.18 (d, 1H), 4.55 (t, 2H), 4.44 (t, 2H), 4.24 (d, 2H),
3.44 (m, 2H), 3.07 (br s, 4H), 2.74 (m, 2H), 2.59 (m, 2H), 2.14 (m,
7H), 1.95 (m, 4H), 1.78 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Compound 323
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]sulfonyl}-2-(1H-p-
yrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 323A
3-chloro-4-((tetrahydrofuran-3-yl)methoxy)benzenesulfonamide
[0959] The title compound was prepared by substituting
4-fluoro-3-chlorobenzenesulfonamide for
4-fluoro-3-nitrobenzenesulfonamide and
(tetrahydrofuran-3-yl)methanol for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A, except here, dimethylformamide was used in place of
tetrahydrofuran and the reaction was heated at 70.degree. C. for
two days.
Compound 323B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-chloro-4-(tetrahydro
furan-3-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)be-
nzamide
[0960] The title compound was prepared by substituting Compound
323A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.73 (s, 1H),
8.07 (d, 1H), 7.89 (d, 1H), 7.80 (dd, 1H), 7.59 (d, 1H), 7.51 (dd,
1H), 7.49 (d, 1H), 7.34 (d, 2H), 7.23 (d, 1H), 7.03 (d, 2H), 6.66
(dd, 1H), 6.42 (m, 1H), 6.19 (d, 1H), 4.07 (m, 2H), 3.80 (m, 2H),
3.68 (m, 1H) 3.56 (m, 1H), 3.10 (br m, 4H), 2.85 (br s, 2H), 2.69
(m, 1H), 2.32 (br m, 4H), 2.17 (br m, 2H), 2.02 (m, 1H), 1.96 (s,
2H), 1.69 (m, 1H), 1.40 (t, 2H), 0.92 (s, 6H).
Compound 324
4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 324A
4-((trans-4-hydroxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[0961] The title compound was prepared by substituting Compound
120A for Compound 39B in the procedure for Compound 39C.
Compound 324B
4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-pyrrolo[2,3-b.]pyridin-5-yloxy)benzamide
[0962] The title compound was prepared by substituting Compound
321G for Compound 1E and Compound 324A for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.41 (s, 1H),
8.65-8.50 (m, 2H), 8.05 (d, 1H), 7.80 (dd, 1H), 7.60-7.44 (m, 3H),
7.41-7.34 (m, 2H), 7.14-7.02 (m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H),
6.17 (d, 1H), 4.50 (d, 1H), 3.23 (t, 2H), 3.06 (s, 4H), 2.70 (d4H),
2.44 (s, 2H), 2.33-1.94 (m, 6H), 1.78 (dd, 4H), 1.51 (d, 2H), 1.23
(s, 2H), 1.16-0.92 (m, 2H).
Compound 325
N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-
-4-(4-{[9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl]-
methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 325A
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(o-
xetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate
[0963] The title compound was prepared by substituting oxetan-3-one
for 1,3-difluoropropan-2-one in the procedure for Compound
265G.
Compound 325B
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(oxetan-3-
-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoic
acid
[0964] The title compound was prepared by substituting Compound
325A for Compound 15G in the procedure for Compound 15H.
Compound 325C
N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-
-4-(4-{[9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl]-
methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0965] The title compound was prepared by substituting Compound
325B for Compound 1E and Compound 286A for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 11.13 (s, 1H),
8.05 (d, 1H), 7.87 (d, 1H), 7.80-7.70 (m, 1H), 7.59-7.46 (m, 3H),
7.34 (d, 2H), 7.21 (d, 1H), 7.11-7.03 (m, 2H), 6.66 (d, 1H), 6.41
(dd, 1H), 6.18 (d, 1H), 4.50 (dd, 4H), 4.26 (d, 2H), 3.85-3.69 (m,
2H), 3.61 (d, 3H), 3.05 (s, 4H), 2.69 (s, 2H), 2.37 (s, 4H), 2.17
(s, 6H), 2.04 (s, 2H), 1.87 (d, 4H), 1.49 (d, 6H).
Compound 326
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2R)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 326A
(R)-4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzene
sulfonamide
[0966] The title compound was prepared by substituting Compound
258E for Compound 173A in the procedure for Compound 173B.
Compound 326B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2R)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0967] The title compound was prepared by substituting Compound
326A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.26 (d,
1H), 8.88 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 3.88 (d, 1H), 3.84-3.81 (m, 1H), 3.59
(dt, 1H), 3.50-3.40 (m, 2H), 3.07 (m, 4H), 2.93 (d, 1H), 2.77 (s,
2H), 2.69 (d, 1H), 2.34 (dt, 1H), 2.26 (m, 2H), 2.21 (t, 1H), 2.14
(m, 4H), 1.97 (s, 2H), 1.58 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H),
0.45-0.39 (m, 4H).
Compound 327
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 327A
(S)-4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
[0968] The title compound was prepared by substituting Compound
259E for Compound 173A in the procedure for Compound 173B.
Compound 327B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0969] The title compound was prepared by substituting Compound
327A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.26 (d,
1H), 8.88 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 3.88 (d, 1H), 3.84-3.81 (m, 1H), 3.59
(dt, 1H), 3.50-3.40 (m, 2H), 3.07 (m, 4H), 2.93 (d, 1H), 2.77 (s,
2H), 2.69 (d, 1H), 2.34 (dt, 1H), 2.26 (m, 2H), 2.21 (t, 1H), 2.14
(m, 4H), 1.97 (s, 2H), 1.58 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H),
0.45-0.39 (m, 4H).
Compound 328
4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N--
({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 328A
spiro[2.5]octan-5-one
[0970] To a solution of 3-ethoxycyclohex-2-enone (48.1 ml) in ether
(1000 ml) was added titanium(IV) isopropoxide (110 ml) followed by
addition of ethylmagnesium bromide (357 ml) at ambient temperature.
The reaction mixture was stirred for 2 hours at ambient temperature
and was then quenched with water (500 ml). The organic layer was
separated (decanted) and the water layer was extracted with ether
(3.times.300 ml). The combined extracts were partially concentrated
to approximately 300 ml. p-Toluenesulfonic acid monohydrate (3.0 g)
was added and the reaction mixture was stirred overnight at ambient
temperature. The reaction mixture was then washed with saturated
aqueous NaHCO.sub.3 solution., dried (MgSO.sub.4), filtered and
concentrated. The concentrate was purified by fractional
distillation (1st fraction b.p. 27.degree. C. at 23 torr (not
product), 2nd fraction (product) b.p. 75.degree. C. at 8 torr).
Compound 328B
5-chlorospiro[2.5]oct-5-ene-6-carbaldehyde
[0971] N,N-dimethylformamide (2.1 ml) in dichloromethane (3.2 ml)
at -5.degree. C. was treated slowly with POCl.sub.3 (2.33 ml)
keeping the bath temperature less than 0.degree. C. The cooling
bath was removed and the mixture was stirred at ambient temperature
for 30 minutes. The reaction mixture was returned to the cooling
bath and Compound 328A (2.484 g) in dichloromethane (4 ml) was
added slowly to the reaction mixture. The reaction mixture was
heated at 45.degree. C. for 15 hours, cooled to room temperature
and then poured into a mixture of ice and saturated aqueous sodium
acetate solution. After the ice melted, the mixture was extracted
with diethyl ether. The combined extracts were washed with
saturated aqueous NaHCO.sub.3 solution and brine, dried
(MgSO.sub.4), filtered and concentrated. The concentrate was
chromatographed with 0 to 10% CH.sub.2Cl.sub.2 in hexanes, then 25%
CH.sub.2Cl.sub.2 in hexanes and then 100% CH.sub.2Cl.sub.2 as the
eluents.
Compound 328C
5-(4-chlorophenyl)spiro[2.5]oct-5-ene-6-carbaldehyde
[0972] Compound 328B (2.9 g), 4-chlorophenylboronic acid (2.87 g),
palladium(II) acetate (0.103 g), K.sub.2CO.sub.3 (5.28 g) and
tetrabutylammonium bromide (4.93 g) were combined in a 100-ml round
bottomed flask with water (17.0 ml). The flask was flushed with
nitrogen and stirred at 45.degree. C. for 14 hours. The reaction
mixture was partitioned between brine and diethyl ether. The
organic layer was washed with brine, dried (MgSO.sub.4), filtered
through a plug of celite, concentrated and chromatographed on
silica gel with 0 to 2% ethyl acetate in hexanes as the eluent.
Compound 328D
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((5-(4-chlorophenyl)spiro-
[2.5]oct-5-en-6-yl)methyl)piperazin-1-yl)benzoate
[0973] The title compound was prepared by substituting Compound 15F
for tert-butyl piperazine carboxylate and Compound 328C for
4-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 328E
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((5-(4-chlorophenyl)spiro[2.5]oc-
t-5-en-6-yl)methyl)piperazin-1-yl)benzoic acid hydrochloride
[0974] Compound 328D (0.85 g) in a mixture of tetrahydrofuran (4.8
ml), methanol (2.4 ml) and water (2.4 ml) was treated with
LiOH.H.sub.2O (0.184 g) and heated overnight at 50.degree. C. The
reaction mixture was cooled to room temperature, concentrated to
remove tetrahydrofuran and methanol and acidified with 1 N aqueous
HCl causing precipitation of the product. The solid was collected
by filtration, rinsed with water and dried overnight in a vacuum
oven at 80.degree. C. to provide the title compound.
Compound 328F
4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N--
({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0975] The title compound was prepared by substituting Compound
328E for Compound 1E in the procedure for Compound 1G. .sup.1H NMR
(500 MHz, pyridine-d.sub.5) 13.07 (s, 1H), 9.32 (d, 1H), 8.68 (t,
1H), 8.44 (d, 1H), 8.38 (dd, 1H), 8.10 (d, 1H), 7.68 (m, 1H), 7.66
(d, 1H), 7.43 (m, 2H), 7.10 (m, 2H), 6.91 (d, 1H), 6.75 (dd, 1H),
6.51 (m, 2H), 3.97 (dd, 2H), 3.30 (td, 2H), 3.16 (t, 2H), 3.06 (m,
4H), 2.81 (s, 2H), 2.37 (t, 2H), 2.16 (m, 4H), 2.11 (s, 2H), 1.81
(m, 1H), 1.58 (dd, 2H), 1.45 (t, 2H), 1.32 (qd, 2H), 0.38 (s,
4H).
Compound 329
N-{[5-chloro-6-({4-[cyclopropyl(oxetan-3-yl)amino]cyclohexyl}methoxy)pyrid-
in-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 329A
ethyl 4-(cyclopropylamino)cyclohexanecarboxylate
[0976] To a solution of ethyl 4-oxocyclohexanecarboxylate (3.4 g)
in dichloromethane (30 ml) was added cyclopropanamine (1.14 g)
followed by sodium triacetoxyborohydride (4.24 g). The mixture was
stirred overnight. The mixture was diluted with dichloromethane
(300 ml) and washed with 2N NaOH, water, brine and dried over
Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave
the title compound.
Compound 329B
ethyl 4-(cyclopropyl(oxetan-3-yl)amino)cyclohexanecarboxylate
[0977] To a solution of Compound 329A (1.05 g) in dichloromethane
(10 ml) was added oxetan-3-one (0.358 g) followed by sodium
triacetoxyborohydride (1.05 g). The mixture was stirred overnight.
The mixture was diluted with dichloromethane (300 ml) and washed
with 2N aqueous NaOH, water, brine and dried over Na.sub.2SO.sub.4.
Filtration and evaporation of the solvent gave the title
compound.
Compound 329C
(4-(cyclopropyl(oxetan-3-yl)amino)cyclohexyl)methanol
[0978] To a solution of Compound 329B (1.2 g) in tetrahydrofuran
(20 ml) was added lithium aluminum hydride (0.681 g). The mixture
was stirred overnight. 2N aqueous NaOH solution was added dropwise
to the reaction mixture. The mixture was then diluted with ethyl
acetate (300 ml) and washed with water, brine and dried over
Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave
the title compound.
Compound 329D
5-chloro-6-((4-(cyclopropyl(oxetan-3-yl)amino)cyclohexyl)methoxy)pyridine--
3-sulfonamide
[0979] To a solution of Compound 329C (706 mg) in
N,N-dimethylformamide (6 ml) was added NaH (60% in mineral oil, 300
mg). The mixture was stirred for 30 minutes, and then
5,6-dichloropyridine-3-sulfonamide (706 mg) was added. The mixture
was stirred overnight. The mixture was poured over aqueous
NH.sub.4Cl and extracted with ethyl acetate (3.times.200 ml). The
combined organic layers were washed with water, brine and dried
over Na.sub.2SO.sub.4. After filtration and evaporation of the
solvent the residue was loaded on a silica gel cartridge and eluted
with 5 to 10% 7N NH.sub.3 in methanol in dichloromethane to provide
the title compound.
Compound 329E
N-{[5-chloro-6-({4-[cyclopropyl(oxetan-3-yl)amino]cyclohexyl}methoxy)pyrid-
in-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0980] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 329D for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.64 (s, 1H), 8.50 (m, 1H), 8.16 (s, 1H), 8.02 (d, 1H),
7.51 (m, 3H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (m,
1H), 6.21 (s, 1H), 4.70 (m, 2H), 4.43 (t, 3H), 4.19 (m, 2H), 3.12
(m, 4H), 2.84 (m, 2H), 2.19 (m, 6H), 1.96 (s, 3H), 1.77 (m, 3H),
1.38 (m, 7H), 0.93 (s, 6H), 0.44 (m, 4H).
Compound 330
4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N--
[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0981] The title compound was prepared by substituting Compound
328E for Compound 3J and Compound 218A for Compound 11B in the
procedure for Compound 11D. .sup.1H NMR (400 MHz, pyridine-d.sub.5)
.delta. 13.01 (s, 1H), 9.26 (d, 1H), 8.88 (t, 1H), 8.43 (d, 1H),
8.34 (dd, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.42 (m, 2H), 7.09 (m,
2H), 6.95 (d, 1H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.49 (dd, 1H), 3.84
(m, 2H), 3.58 (td, 1H), 3.45 (m, 2H), 3.06 (m, 4H), 2.93 (d, 1H),
2.81 (s, 2H), 2.69 (d, 1H), 2.35 (m, 3H), 2.19 (m, 5H), 2.11 (s,
2H), 1.58 (m, 1H), 1.45 (t, 2H), 0.42 (m, 8H).
Compound 331
N-({3-chloro-4-[(4-cyclopropylmorpholin-2-yl)methoxy]phenyl}sulfonyl)-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 331A
tert-butyl
2-((2-chloro-4-sulfamoylphenoxy)methyl)morpholine-4-carboxylate
[0982] To a solution of tert-butyl
2-(hydroxymethyl)morpholine-4-carboxylate (0.478 g) in anhydrous
N,N-dimethylformamide (5 ml) was added sodium hydride (0.280 g).
The mixture was stirred at room temperature for 30 minutes,
followed by addition of 3-chloro-4-fluorobenzenesulfonamide (0.419
g). The mixture was stirred at 40.degree. C. overnight. The
reaction was quenched with water (10 ml), and the mixture was
adjusted to .about.pH 7 and extracted with ethyl acetate. The crude
product was purified on a silica gel column eluting with 60% ethyl
acetate in hexane to provide the title compound.
Compound 331B
3-chloro-4-(morpholin-2-ylmethoxy)benzenesulfonamide
[0983] The title compound was prepared by substituting Compound
331A for Compound 113A in the procedure for Compound 134A.
Compound 331C
3-chloro-4-((4-cyclopropylmorpholin-2-yl)methoxy)benzene
sulfonamide
[0984] The title compound was prepared by substituting Compound
331B for Compound 173A in the procedure for Compound 173B.
Compound 331D
N-({3-chloro-4-[(4-cyclopropylmorpholin-2-yl)methoxy]phenyl}sulfonyl)-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0985] The title compound was prepared by substituting Compound
331C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.04 (s, 1H), 8.54 (d,
1H), 8.43 (d, 1H), 8.27 (dd, 1H), 8.09 (d, 1H), 7.66 (m, 2H), 7.44
(d, 2H), 7.07 (d, 2H), 7.05 (d, 1H), 6.75 (dd, 1H), 6.52 (d, 1H),
6.50 (m, 1H), 4.20 (dd, 1H), 4.10 (dd, 1H), 3.94 (m, 1H), 3.86 (d,
1H), 3.58 (dt, 1H), 3.06 (m, 5H), 2.77 (s, 2H), 2.69 (d, 1H),
2.40-2.20 (m, 4H), 2.14 (m, 4H), 1.97 (s, 2H), 1.60 (m, 1H), 1.39
(t, 2H), 0.94 (s, 6H), 0.41 (m, 4H).
Compound 332
N-[(3-chloro-4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl-
]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 332A
tert-butyl
2-((2-chloro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxy-
late
[0986] A solution of 3-chloro-4-fluorobenzenesulfonamide (1.0 g),
tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.135 g) and
N-ethyl-N-isopropylpropan-2-amine (1.246 ml) in dimethylsulfoxide
(15 ml) was stirred at 115.degree. C. for 72 hours. The mixture was
concentrated, and the residue was purified on a silica gel column
eluting with 60% ethyl acetate to provide the title compound.
Compound 332B
3-chloro-4-(morpholin-2-ylmethylamino)benzenesulfonamide
[0987] The title compound was prepared by substituting Compound
332A for Compound 113A in the procedure for Compound 134A.
Compound 332C
3-chloro-4-(((4-cyclopropylmorpholin-2-yl)methyl)amino)benzene
sulfonamide
[0988] The title compound was prepared by substituting Compound
332B for Compound 173A in the procedure for Compound 173B.
Compound 332D
N-[(3-chloro-4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl-
]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0989] The title compound was prepared by substituting Compound
332C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.05 (s, 1H), 8.45 (m,
2H), 8.21 (dd, 1H), 8.12 (d, 1H), 7.69 (d, 1H), 7.67 (t, 1H), 7.44
(d, 2H), 7.07 (d, 2H), 6.78 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H),
6.50 (m, 1H), 6.37 (m, 1H), 3.84 (d, 1H), 3.77 (m, 1H), 3.54 (dt,
1H), 3.35 (m, 2H), 3.05 (m, 4H), 2.94 (d, 1H), 2.77 (s, 2H), 2.68
(d, 1H), 2.32 (dt, 1H), 2.26 (m, 2H), 2.18-2.12 (m, 5H), 1.97 (s,
2H), 1.55 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H), 0.41 (m, 4H).
Compound 333
2-{[(2-chloro-4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfam-
oyl}phenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide
Compound 333A
2-((2-chloro-4-sulfamoylphenylamino)methyl)-N-ethyl-N-methylmorpholine-4-c-
arboxamide
[0990] The title compound was prepared by substituting Compound
332B for Compound 134A and N-methyl-N-ethyl carbamyl chloride for
methyl iodide in the procedure for Compound 134B.
Compound 333B
2-{[(2-chloro-4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfam-
oyl}phenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide
[0991] The title compound was prepared by substituting Compound
333A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.05 (s, 1H), 8.46 (s,
1H), 8.45 (s, 1H), 8.20 (dd, 1H), 8.10 (d, 1H), 7.69 (d, 1H), 7.67
(t, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.79 (d, 1H), 6.73 (dd, 1H),
6.52 (dd, 1H), 6.49 (d, 1H), 6.43 (m, 1H), 3.83 (d, 2H), 3.73 (d,
1H), 3.59 (dt, 1H), 3.41-3.35 (m, 3H), 3.20 (q, 2H), 3.05 (m, 4H),
2.95 (t, 1H), 2.84 (dd, 1H), 2.76 (s, 2H), 2.73 (s, 3H), 2.25 (m,
2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 1.04 (t, 3H), 0.94
(s, 6H).
Compound 334
(2S)-2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-
-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]s-
ulfamoyl}pyridin-2-yl)oxy]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide
Compound 334A
(S)-2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-N-ethyl-N-methylmorpho-
line-4-carboxamide
[0992] The title compound was prepared by substituting Compound
244B for Compound 134A and N-methyl-N-ethyl carbamyl chloride for
methyl iodide in the procedure for Compound 134B.
Compound 334B
(2S)-2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-
-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]s-
ulfamoyl}pyridin-2-yl)oxy]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide
[0993] The title compound was prepared by substituting Compound
334A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 12.98 (s, 1H), 9.08 (d,
1H), 8.70 (d, 1H), 8.42 (d, 1H), 8.11 (d, 1H), 7.67 (t, 1H), 7.64
(d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.75 (dd, 1H), 6.53 (d, 1H),
6.48 (m, 1H), 4.58 (dd, 1H), 4.47 (dd, 1H), 4.03 (m, 1H), 3.84 (m,
2H), 3.63 (dt, 1H), 3.45 (d, 1H), 3.22 (q, 2H), 3.07 (m, 4H),
3.05-2.95 (m, 2H), 2.78 (s, 3H), 2.77 (s, 2H), 2.26 (m, 2H), 2.14
(m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 1.07 (t, 3H), 0.94 (s,
6H).
Compound 335
N-[(5-chloro-6-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}pyridin-3-yl)su-
lfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 335A
tert-butyl
2-((3-chloro-5-sulfamoylpyridin-2-ylamino)methyl)morpholine-4-c-
arboxylate
[0994] The title compound was prepared by substituting Compound 40A
for 4-fluoro-3-nitrobenzenesulfonamide and tert-butyl
2-(aminomethyl)morpholine-4-carboxylate for
(tetrahydropyran-4-yl)methylamine in the procedure for Compound
1F.
Compound 335B
5-chloro-6-(morpholin-2-ylmethylamino)pyridine-3-sulfonamide
[0995] The title compound was prepared by substituting Compound
335A for Compound 113A in the procedure for Compound 134A.
Compound 335C
5-chloro-6-((4-cyclopropylmorpholin-2-yl)methylamino)pyridine-3-sulfonamid-
e
[0996] The title compound was prepared by substituting Compound
335B for Compound 173A in the procedure for Compound 173B.
Compound 335D
N-[(5-chloro-6-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}pyridin-3-yl)su-
lfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0997] The title compound was prepared by substituting Compound
335C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.02 (s, 1H), 9.15 (d,
1H), 8.49 (d, 1H), 8.43 (d, 1H), 8.11 (d, 1H), 7.80 (t, 1H), 7.69
(d, 1H), 7.65 (t, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.73 (dd, 1H),
6.52 (m, 1H), 6.49 (d, 1H), 3.92 (m, 1H), 3.84 (m, 2H), 3.70 (m,
1H), 3.54 (dt, 1H), 3.05 (m, 4H), 2.99 (d, 1H), 2.76 (s, 2H), 2.68
(d, 1H), 2.32 (dt, 1H), 2.25 (m, 2H), 2.12 (m, 5H), 1.97 (s, 2H),
1.53 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H), 0.40 (m, 4H).
Compound 336
2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfam-
oyl}pyridin-2-yl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide
Compound 336A
2-((3-chloro-5-sulfamoylpyridin-2-ylamino)methyl)-N-ethyl-N-methylmorpholi-
ne-4-carboxamide
[0998] The title compound was prepared by substituting Compound
335B for Compound 134A and N-methyl-N-ethyl carbamyl chloride for
methyl iodide in the procedure for Compound 134B.
Compound 336B
2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfam-
oyl}pyridin-2-yl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide
[0999] The title compound was prepared by substituting Compound
336A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.03 (s, 1H), 9.14 (d,
1H), 8.51 (d, 1H), 8.43 (d, 1H), 8.11 (d, 1H), 7.89 (m, 1H), 7.69
(d, 1H), 7.66 (t, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.74 (dd, 1H),
6.51 (m, 1H), 6.48 (d, 1H), 3.96 (m, 1H), 3.90-3.70 (m, 4H), 3.59
(dt, 1H), 3.43 (d, 1H), 3.17 (q, 2H), 3.05 (m, 4H), 2.95 (dt, 1H),
2.81 (dd, 1H), 2.76 (s, 2H), 2.72 (s, 3H), 2.25 (m, 2H), 2.13 (m,
4H), 1.97 (s, 2H), 1.39 (t, 2H), 1.03 (t, 3H), 0.93 (s, 6H).
Compound 337
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 337A
methyl 4,4-dimethyl-2-(trifluoro
methylsulfonyloxy)cyclohex-1-enecarboxylate
[1000] To a suspension of hexane washed NaH (17 g) in
dichloromethane (700 ml) was added
5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at
0.degree. C. After stirring for 30 minutes, the mixture was cooled
to -78.degree. C. and trifluoroacetic anhydride (40 ml) was added.
The reaction mixture was warmed to room temperature and stirred for
24 hours. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the
product.
Compound 337B
methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[1001] Compound 337A (62.15 g), 4-chlorophenylboronic acid (32.24
g), CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2 g)
in 2:1 dimethoxyethane/methanol (600 ml) were heated to 70.degree.
C. for 24 hours. The mixture was concentrated. Ether (4.times.200
ml) was added and the mixture was filtered. The combined ether
solution was concentrated to give the product.
Compound 337C
(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[1002] To a mixture of LiBH.sub.4 (13 g), Compound 337B (53.8 g)
and ether (400 ml), was added methanol (25 ml) slowly by syringe.
The mixture was stirred at room temperature for 24 hours. The
reaction was quenched with 1N HCl with ice-cooling. The mixture was
diluted with water and extracted with ether (3.times.100 ml). The
extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated.
The crude product was chromatographed on silica gel with 0-30%
ethyl acetate/hexanes.
Compound 337D
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piper-
azine-1-carboxylate
[1003] Mesyl Chloride (7.5 ml) was added via syringe to Compound
337C (29.3 g) and triethylamine (30 ml) in CH.sub.2Cl.sub.2 (500
ml) at 0.degree. C., and the mixture was stirred for 1 minute.
N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was
stirred at room temperature for 24 hours. The suspension was washed
with brine, dried, (Na.sub.2SO.sub.4), filtered, and concentrated.
The crude product was chromatographed on silica gel with 10-20%
ethyl acetate/hexanes.
Compound 337E
1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
[1004] Compound 337D (1 g) was stirred in dichloromethane (10 ml),
trifluoroacetic acid (10 ml), and triethylsilane (1 ml) for 1 hour.
The mixture was concentrated, taken up in a mixture of
dichloromethane (100 ml) and saturated aqueous Na.sub.2CO.sub.3
solution (20 ml) and stirred for 10 minutes. The layers were
separated, and the organic layer was dried over Na.sub.2SO.sub.4,
and concentrated to give the product.
Compound 337F
5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
[1005] To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g)
in tetrahydrofuran (250 ml) was added 1M lithium
hexamethyldisilazide in tetrahydrofuran (86 ml), and after 10
minutes, TIPS-Cl (triisopropylchlorosilane) (18.2 ml) was added.
The mixture was stirred at room temperature for 24 hours. The
reaction was diluted with ether, and the resulting solution was
washed twice with water. The extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was chromatographed on silica gel with 10% ethyl
acetate/hexanes.
Compound 337G
1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol
[1006] To a mixture of Compound 337F (24.3 g) in tetrahydrofuran
(500 ml) at -78.degree. C. was added 2.5M BuLi (30.3 ml). After 2
minutes, trimethylborate (11.5 ml) was added, and the mixture was
allowed to warm to room temperature over 1 hour. The reaction was
poured into water, extracted three times with ethyl acetate, and
the combined extracts were washed with brine and concentrated. The
crude product was taken up in tetrahydrofuran (200 ml) at 0.degree.
C., and 1M aqueous NaOH (69 ml) was added, followed by 30% aqueous
H.sub.2O.sub.2 (8.43 ml), and the solution was stirred for 1 hour.
Na.sub.2S.sub.2O.sub.3 (10 g) was added, and the pH was adjusted to
4-5 with concentrated HCl and solid NaH.sub.2PO.sub.4. The solution
was extracted twice with ethyl acetate, and the combined extracts
were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The crude product was chromatographed on silica gel
with 5-25% ethyl acetate/hexanes.
Compound 337H
methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate
[1007] A mixture of Compound 337G (8.5 g), methyl
2,4-difluorobenzoate (7.05 g), and K.sub.3PO.sub.4 (9.32 g) in
diglyme (40 ml) at 115.degree. C. was stirred for 24 hours. The
reaction was cooled, diluted with ether (600 ml), and washed twice
with water, and brine, and concentrated. The crude product was
chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Compound 337I
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[1008] A mixture of Compound 337H (1.55 g), Compound 337E (2.42 g),
and HK.sub.2PO.sub.4 (1.42 g) in dimethylsulfoxide (20 ml) at
135.degree. C. was stirred for 24 hours. The reaction was cooled,
diluted with ether (400 ml), and washed three times with 1M aqueous
NaOH, and brine, and concentrated. The crude product was
chromatographed on silica gel with 10-50% ethyl
acetate/hexanes.
Compound 337J
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[1009] Compound 337I (200 mg) in dioxane (10 ml) and 1M aqueous
NaOH (6 ml) at 50.degree. C. was stirred for 24 hours. The reaction
was cooled, added to NaH.sub.2PO.sub.4 solution, and extracted
three times with ethyl acetate. The combined extracts were washed
with brine, and concentrated to give the pure product.
Compound 337K
tert-butyl (4-hydroxy-4-methylcyclohexyl)methylcarbamate
[1010] To a vigorous stirring solution of tert-butyl
(4-oxocyclohexyl)methylcarbamate (1.7 g) in tetrahydrofuran (40 ml)
at -78.degree. C. was dropwise added 1.6 M methyllithium (14.02 ml)
in ether. After completion of the addition, the mixture was stirred
at -78.degree. C. for 1.2 hours and poured into a cold NH.sub.4Cl
aqueous solution. The resulting mixture was extracted with
dichloromethane (100 ml, three times) and the organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was dissolved in dichloromethane and loaded onto an
Analogix purification system, and it was eluted with 0-50% ethyl
acetate in dichloromethane to provide the title compound.
Compound 337L
4-(aminomethyl)-1-methylcyclohexanol
[1011] Compound 337K (1.3 g) in dichloromethane (5 ml) at 0.degree.
C. was treated with trifluoroacetic acid (2.1 ml) and a few drops
of water for 1 hour. The reaction mixture was concentrated and the
residue was directly used for next step.
Compound 337M
4-((trans-4-hydroxy-4-methylcyclohexyl)methylamino)-3-nitrobenzenesulfonam-
ide
[1012] Compound 337L (732 mg) and
4-fluoro-3-nitrobenzenesulfonamide (1.1 g) in tetrahydrofuran (15
ml) was treated with triethylamine overnight. The reaction mixture,
was concentrated and the residue was purified by a reverse phase
chromatography, eluting with 30%-50% acetonitrile in 0.1%
trifluoroacetic acid water solution to isolate the title
compound.
Compound 337N
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1013] A mixture of Compound 337J (3.0 g), Compound 337M (1.98 g),
N,N-dimethylpyridin-4-amine (1.93 g) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (1.31 g) in dichloromethane (50 ml) was stirred
overnight and concentrated. The residue was purified by reverse
chromatography, eluted with 40%-70% acetonitrile in 0.1% TFA water.
The desired fractions were concentrated to remove acetonitrile,
neutralized with NaHCO.sub.3 and extracted with dichloromethane.
The organic layer was dried over Na.sub.2SO.sub.4, concentrated and
dried to provide the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 8.52-8.58 (m,
2H), 8.04 (d, 1H), 7.79 (dd, 1 H), 7.53 (d, 1H), 7.47-7.52 (m, 2H),
7.30-7.37 (m, 2H), 7.07 (d, 1H), 7.01-7.06 (m, 2H), 6.68 (dd, 1H),
6.39 (dd, 1H), 6.19 (d, 1H), 4.25 (s, 1H), 3.25-3.32 (m, 4H), 3.07
(s, 4H), 2.75 (s, 2H), 2.09-2.24 (m, 6H), 1.95 (s, 2H), 1.50-1.73
(m, 5H), 1.28-1.43 (m, 4 H), 1.06-1.18 (m, 5H), 0.92 (s, 6H).
Compound 338
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 338A
methyl 4,4-dimethyl-2-(trifluoro
methylsulfonyloxy)cyclohex-1-enecarboxylate
[1014] To a suspension of hexane washed NaH (17 g) in
dichloromethane (700 ml) was added
5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at
0.degree. C. After stirring for 30 minutes, the mixture was cooled
to -78.degree. C. and trifluoroacetic anhydride (40 ml) was added.
The reaction mixture was warmed to room temperature and stirred for
24 hours. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the
product.
Compound 338B
methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[1015] Compound 338A (62.15 g), 4-chlorophenylboronic acid (32.24
g), CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2 g)
in 2:1 dimethoxyethane/methanol (600 ml) were heated to 70.degree.
C. for 24 hours. The mixture was concentrated. Ether (4.times.200
ml) was added and the mixture was filtered. The combined ether
solution was concentrated to give the product.
Compound 338C
(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[1016] To a mixture of LiBH.sub.4 (13 g), Compound 338B (53.8 g)
and ether (400 ml), was added methanol (25 ml) slowly by syringe.
The mixture was stirred at room temperature for 24 hours. The
reaction was quenched with 1N aqueous HCl with ice-cooling. The
mixture was diluted with water and extracted with ether
(3.times.100 ml). The extracts were dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The crude product was chromatographed
on silica gel with 0-30% ethyl acetate/hexanes.
Compound 338D
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piper-
azine-1-carboxylate
[1017] Mesyl Chloride (7.5 ml) was added via syringe to Compound
338C (29.3 g) and triethylamine (30 ml) in CH.sub.2Cl.sub.2 (500
ml) at 0.degree. C., and the mixture was stirred for 1 minute.
N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was
stirred at room temperature for 24 hours. The suspension was washed
with brine, dried, (Na.sub.2SO.sub.4), filtered, and concentrated.
The crude product was chromatographed on silica gel with 10-20%
ethyl acetate/hexanes.
Compound 338E
1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
[1018] Compound 338D (1 g) was stirred in dichloromethane (10 ml),
trifluoroacetic acid (10 ml), and triethylsilane (1 ml) for 1 hour.
The mixture was concentrated, taken up in a mixture of
dichloromethane (100 ml) and saturated aqueous Na.sub.2CO.sub.3
solution (20 ml) and stirred for 10 minutes. The layers were
separated, and the organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give the product.
Compound 338F
5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
[1019] To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g)
in tetrahydrofuran (250 ml) was added 1M lithium
hexamethyldisilazide in tetrahydrofuran (86 ml), and after 10
minutes, TIPS-Cl (triisopropylchlorosilane) (18.2 ml) was added.
The mixture was stirred at room temperature for 24 hours. The
reaction was diluted with ether, and the resulting solution was
washed twice with water. The extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was chromatographed on silica gel with 10% ethyl
acetate/hexanes.
Compound 338G
1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol
[1020] To a mixture of Compound 338F (24.3 g) in tetrahydrofuran
(500 ml) at -78.degree. C. was added 2.5M BuLi (30.3 ml). After 2
minutes, trimethylborate (11.5 ml) was added, and the mixture was
allowed to warm to room temperature over 1 hour. The reaction was
poured into water, extracted three times with ethyl acetate, and
the combined extracts were washed with brine and concentrated. The
crude product was taken up in tetrahydrofuran (200 ml) at 0.degree.
C., and 1M aqueous NaOH (69 ml) was added, followed by 30% aqueous
H.sub.2O.sub.2 (8.43 ml), and the solution was stirred for 1 hour.
Na.sub.2S.sub.2O.sub.3 (10 g) was added, and the pH was adjusted to
4-5 with concentrated HCl and solid NaH.sub.2PO.sub.4. The solution
was extracted twice with ethyl acetate, and the combined extracts
were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The crude product was chromatographed on silica gel
with 5-25% ethyl acetate/hexanes.
Compound 338H
methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate
[1021] A mixture of Compound 338G (8.5 g), methyl
2,4-difluorobenzoate (7.05 g), and K.sub.3PO.sub.4 (9.32 g) in
diglyme (40 ml) at 115.degree. C. was stirred for 24 hours. The
reaction was cooled, diluted with ether (600 ml), and washed twice
with water, and brine, and concentrated. The crude product was
chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Compound 338I
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[1022] A mixture of Compound 338H (1.55 g), Compound 338E (2.42 g),
and HK.sub.2PO.sub.4 (1.42 g) in dimethylsulfoxide (20 ml) at
135.degree. C. was stirred for 24 hours. The reaction was cooled,
diluted with ether (400 ml), and washed three times with 1M aqueous
NaOH, and brine, and concentrated. The crude product was
chromatographed on silica gel with 10-50% ethyl
acetate/hexanes.
Compound 338J
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[1023] Compound 3381 (200 mg) in dioxane (10 ml) and 1M NaOH (6 ml)
at 50.degree. C. was stirred for 24 hours. The reaction was cooled,
added to NaH.sub.2PO.sub.4 solution, and extracted three times with
ethyl acetate. The combined extracts were washed with brine, and
concentrated to give the pure product.
Compound 338K
tert-butyl (4-hydroxy-4-methylcyclohexyl)methylcarbamate
[1024] To a vigorous stirring solution of tert-butyl
(4-oxocyclohexyl)methylcarbamate (1.7 g) in tetrahydrofuran (40 ml)
at -78.degree. C. was dropwise added 1.6 M methyllithium (14.02 ml)
in ether. After completion of the addition, the mixture was stirred
at -78.degree. C. for 1.2 hours and poured into a cold NH.sub.4Cl
aqueous solution. The resulting mixture was extracted with
dichloromethane (100 ml, three times) and the organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was dissolved in dichloromethane and loaded onto an
Analogix purification system, and it was eluted with 0-50% ethyl
acetate in dichloromethane to provide the title compound.
Compound 338L
4-(aminomethyl)-1-methylcyclohexanol
[1025] Compound 338K (1.3 g) in dichloromethane (5 ml) at 0.degree.
C. was treated with trifluoroacetic acid (2.1 ml) and a few drops
of water for 1 hour. The reaction mixture was concentrated and the
residue was directly used for next step.
Compound 338M
4-((cis-4-hydroxy-4-methylcyclohexyl)methylamino)-3-nitrobenzene
sulfonamide
[1026] Compound 338L (732 mg) and
4-fluoro-3-nitrobenzenesulfonamide (1.1 g) in tetrahydrofuran (15
ml) was treated with triethylamine overnight. The reaction mixture,
was concentrated and the residue was purified by a reverse phase
chromatography, eluting with 30%-50% acetonitrile in 0.1%
trifluoroacetic acid water solution to isolate the title
compound.
Compound 338N
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1027] A mixture of Compound 338J (144 mg), Compound 338M (95 mg),
N,N-dimethylpyridin-4-amine (123 mg) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (62.7 mg) in dichloromethane (7 ml) was stirred
overnight and concentrated. The residue was purified by reverse
chromatography, eluted with 40%-70% acetonitrile in 0.1% TFA water.
The desired fractions were concentrated, neutralized with
NaHCO.sub.3 and extracted with dichloromethane. The organic layer
was dried over Na.sub.2SO.sub.4, filtered, concentrated and dried
to provide the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.38 (s, 1H),
8.59 (t, 1H), 8.55 (d, 1H), 8.04 (d, 1 H), 7.79 (dd, 1H), 7.54 (d,
1H), 7.46-7.52 (m, 2H), 7.30-7.38 (m, 2H), 7.00-7.10 (m, 3 H), 6.68
(dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.95 (s, 1H), 3.25 (t, 4H),
3.07 (s, 4H), 2.75 (s, 2H), 2.10-2.26 (m, 6H), 1.95 (s, 2H),
1.29-1.62 (m, 8H), 1.16-1.30 (m, 2H), 1.08 (s, 3H), 0.92 (s,
6H).
Compound 339
N-[(5-chloro-6-{[(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]m-
ethoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)be-
nzamide
[1028] Compound 339A
(1R,4S)-methyl
spiro[bicyclo[2.2.1]heptane-2,2'-[1,3]dioxolane]-5-carboxylate
[1029] A reaction mixture of 1,4-dioxaspiro[4.4]non-6-ene (5 g),
methyl acrylate (10.24 g), and hydroquinone (0.13 g) was heated at
100.degree. C. in acetonitrile (12 ml) for three days. After
cooling, the solvent was removed, and residue was purified by flash
chromatography on silica gel eluting with 4:1 hexane/ethyl acetate
to provide the title compound as a mixture of two isomers.
Compound 339B
(1R,4S)-spiro[bicyclo[2.2.1]heptane-2,2'-[1,3]dioxolane]-5-ylmethanol
[1030] Compound 339A (1.0 g) in tetrahydrofuran was cooled to
0.degree. C. To this solution was added 1.0 N lithium aluminum
hydride (2.8 ml) dropwise. The reaction mixture was stirred for 2
hours. Water (0.4 ml) was added followed by 2 N aqueous NaOH (0.2
ml). The solid was filtered off, and the filtrate was concentrated.
Toluene was added, and it was then distilled to remove any trace
amount of water. The title compound was used for the next reaction
without further purification.
Compound 339C
5-chloro-6-(((1S,2R,4R)-5-oxob
icyclo[2.2.1]heptan-2-yl)methoxy)pyridine-3-sulfonamide
[1031] The title compound was prepared by substituting Compound
339B for (tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for
Compound 36A in the procedure for Compound 36B. The two
stereoisomers at the 5 position were isolated by reverse phase
Gilson Prep HPLC system with a Phenomenex prep column (Luna, 5.mu.,
C18(2), 250.times.21.20 mm, 5 .ANG.) eluting with 20-80%
acetonitrle in water with 0.1% trifluoroacetic acid. The desired
fractions were collected, and the solvents were removed under
reduced vacuum at 60.degree. C. During this process, a lot of solid
formed. It was then partitioned between water and ethyl acetate.
The organic layer was separated, and the aqueous layer was
extracted with additional ethyl acetate. The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered and
concentrated to give the title compound.
Compound 339D
5-chloro-6-(((1S,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]heptan-2-yl)met-
hoxy)pyridine-3-sulfonamide
[1032] Compound 339C (0.44 g) in tetrahydrofuran (15 ml) was
treated with 3.0 M methylmagnesium bromide (5.3 ml) at 0.degree. C.
The solution was stirred for 16 hours. The reaction mixture was
then partitioned between ethyl acetate and 0.05 N aqueous HCl (20
ml). The organic layer was separated, and 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
column chromatography on silica gel using 10-50% ethyl acetate in
hexanes to provide the title compound.
Compound 339E
N-[(5-chloro-6-{[(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]m-
ethoxyl}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)b-
enzamide
[1033] The title compound was prepared by substituting Compound
339D for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H),
8.50 (s, 1H), 8.16 (s, 1H), 8.02 (d, 1H), 7.49-7.55 (m, 3H), 7.35
(d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H), 6.20 (s, 1H),
4.40-4.48 (m, 2H), 4.31 (s, 1H), 3.09 (s, 4H), 2.83 (s, 2H),
2.15-2.33 (m, 7H), 1.96 (s, 2H), 1.87 (d, 1H), 1.65-1.69 (m, 1H),
1.54-1.56 (m, 2H), 1.36-1.47 (m, 6H), 1.26-1.30 (m, 1H), 1.19 (s,
3H), 0.93 (s, 6H).
Compound 340
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]cyclohexyl}amino)-3-nitr-
ophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1034] Compound 340A
4-(1,4-dioxaspiro[4.5]decan-8-ylamino)-3-nitrobenzene
sulfonamide
[1035] To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.4 g)
in tetrahydrofuran (30 ml) was added
1,4-dioxaspiro[4.5]decan-8-amine (1.0 g) and diisopropylethylamine
(5 ml). The mixture was stirred overnight. The mixture was diluted
with ethyl acetate (300 ml) and washed with water, brine and dried
over Na.sub.2SO.sub.4. Filtration and evaporation of the solvent
gave the title compound.
Compound 340B
N-(4-(1,4-dioxaspiro[4.5]decan-8-ylamino)-3-nitrophenylsulfonyl)-2-(1H-pyr-
rolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzamide
[1036] To a solution of Compound 3J (617 mg) and Compound 340A (386
mg) in dichloromethane (10 ml) was added
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (288
mg) and 4-(dimethylamino)pyridine (183 mg). The mixture was stirred
overnight. The mixture was diluted with dichloromethane (300 ml)
and washed with aqueous NaHCO.sub.3, water, brine and dried over
Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave
the title compound.
Compound 340C
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(4-oxocyclohexylamino-
)phenylsulfonyl)benzamide
[1037] To a solution of Compound 340B (386 mg) in acetone (10 ml)
and water (5 ml) was added para-toluenesulfonic acid monohydrate
(50 mg). The mixture was stirred at 120.degree. C. in a Biotage
Initiator microwave reactor for 30 minutes. The mixture was diluted
with dichloromethane (300 ml) and washed with aqueous NaHCO.sub.3,
water, brine and dried over Na.sub.2SO.sub.4. Filtration and
evaporation of the solvent gave the title compound.
Compound 340D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({4-[(2-cyano
ethyl)(cyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1038] To a solution of Compound 340C (240 mg) and
3-(cyclopropylamino)propanenitrile (62 mg) in tetrahydrofuran (10
ml) was added acetic acid (2 ml) and MP-cyanoborohydride (300 mg,
2.15 mmol/g). The mixture was stirred overnight. The mixture was
filtered and concentrated under vacuum and the residue was
dissolved in dimethylsulfoxide/methanol (1:1, 10 ml) and loaded on
Gilson, C18(100 A) 250.times.121.2 mm (10 micron), with 30%
acetonitrile to 65% acetonitrile over 40 minutes. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H), 8.55 (dd,
1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1 H), 7.49 (m, 3H), 7.34
(d, 2H), 7.11 (m, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (d, 1H),
6.19 (d, 1H), 4.01 (m, 1H), 3.56 (m, 1H), 3.06 (m, 4H), 2.88 (t,
2H), 2.65 (m, 6H), 2.19 (m, 6H), 2.00 (m, 7H), 1.51 (m, 6H), 0.92
(s, 6H), 0.42 (m, 4H).
Compound 341
N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}s-
ulfonyl)-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-
-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 341A
ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate
[1039] To a solution of ethyl 4-oxocyclohexanecarboxylate (31.8 g)
in toluene (100 ml) was added ethylene glycol (36.5 ml) and
p-toluenesulfonic acid monohydrate (0.426 g). The two phase mixture
was stirred rapidly at ambient temperature for 72 hours. The
reaction was diluted with water (900 ml) and extracted with ether
(900 ml). The organic layer was washed with saturated sodium
bicarbonate solution and brine, and then dried over anhydrous
sodium sulfate. After filtration, the title compound was obtained
by concentration under high vacuum.
Compound 341B
1,4-dioxaspiro[4.5]decan-8-ylmethanol
[1040] To a suspension of lithium aluminum hydride (8.19 g) in
tetrahydrofuran (400 ml) was added dropwise a solution of Compound
341A (37.8 g) in tetrahydrofuran (75 ml). The mixture was then
heated at reflux for 2 hours. The reaction mixture was cooled in an
ice bath and quenched very slowly with water (8 ml). Then added
sequentially were 4N sodium hydroxide (8 ml), ether (200 ml), water
(24 ml), ether (500 ml) and anhydrous sodium sulfate (250 g). The
resulting mixture was stirred rapidly for 2 hours and was filtered.
The title compound was isolated by concentration of the
filtrate.
Compound 341C
8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane
[1041] To a suspension of sodium hydride (60% oil dispersion, 8.86
g) in tetrahydrofuran (170 ml) was added a solution of Compound
341B (30.52 g) in tetrahydrofuran (100 ml). This mixture was
stirred for 30 minutes and benzyl bromide (24 ml) was added. After
stirring for 72 hours, the reaction was quenched with saturated
ammonium chloride solution (400 ml) and diluted with ether (500
ml). The layers were separated and the aqueous layer was extracted
with ether (2.times.150 ml). The combined organics were dried over
sodium sulfate, filtered and concentrated. The crude product was
purified on silica gel eluting with a 0, 10, 15, 75% ethyl acetate
in hexanes step gradient to provide the title compound.
Compound 341D
4-(benzyloxymethyl)cyclohexanone
[1042] To a solution of Compound 341C (43.02 g) in dioxane (500 ml)
was added water (125 ml) and 2M hydrochloric acid (90 ml). The
mixture was heated at 85.degree. C. for 18 hours. Upon cooling, the
reaction mixture was diluted with brine (1500 ml), saturated sodium
bicarbonate solution (300 ml) and ether (1000 ml). The organic
layer was dried over sodium sulfate, filtered and concentrated. The
crude product was purified on silica gel eluting with a 5-50% ethyl
acetate in hexanes step gradient to provide the title compound.
Compound 341E
trans-4-(benzyloxymethyl)-1-methylcyclohexanol
[1043] To 2,6-di-t-butyl-4-methylphenol (83.4 g) in toluene (1100
ml) was added 2.0M (in hexanes) trimethylaluminum (95 ml) somewhat
carefully to control methane evolution and a small exotherm. The
reaction mixture was stirred at ambient temperature under N.sub.2
for 75 minutes and was then cooled to -77.degree. C. A solution of
Compound 341D (14 g) in toluene (15 ml) was added dropwise, keeping
the temperature below -74.degree. C. Methyllithium (1.6M in diethyl
ether, 120 ml) was then added dropwise, keeping the temperature
below -65.degree. C. The resulting mixture was stirred at
-77.degree. C. under N.sub.2 for 2 hours. The reaction mixture was
then poured into 1N aqueous HCl (1600 ml), rinsing the flask with
toluene. The organic layer was washed with brine and the combined
aqueous layers were extracted with diethyl ether. The combined
organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated. The concentrate was chromatographed on 650 g of
spherical silica gel using 2.5 L of 80/20 hexanes/ethyl acetate,
then 3.0 L of 75/25 hexanes/ethyl acetate, and finally 4.0 L of
70/30 hexanes/ethyl acetate as the eluents to provide the title
compound.
Compound 341F
trans-4-(hydroxymethyl)-1-methylcyclohexanol
[1044] Compound 341E (12.6 g) and ethanol (120 ml) were added to
20% Pd(OH).sub.2/C, wet (1.260 g) in a 500 ml SS pressure bottle.
The reaction mixture was stirred at ambient temperature under 30
psi hydrogen gas. Hydrogen uptake ceased at 5 minutes. The mixture
was filtered through a nylon membrane rinsing with ethanol. The
filtrate was concentrated and then azeotroped with toluene (100 ml)
to remove any remaining ethanol. The concentrate was dried under
high vacuum for 40 minutes to provide the title compound.
Compound 341G
5-chloro-6-((trans-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine-3-sulfona-
mide
[1045] The title compound was prepared by substituting Compound 40A
for 4-fluoro-3-nitrobenzenesulfonamide and Compound 341F for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 341H
N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}s-
ulfonyl)-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-
-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1046] The title compound was prepared by substituting Compound
328E for Compound 3J and Compound 341G for Compound 11B in the
procedure for Compound 11D. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 13.09 (s, 1H), 9.18 (d, 1H), 8.74 (d, 1H), 8.41 (d, 1H),
8.09 (d, 1H), 7.67 (m, 2H), 7.42 (m, 2H), 7.09 (m, 2H), 6.74 (dd,
1H), 6.52 (dd, 1H), 6.49 (d, 1H), 4.29 (d, 2H), 3.05 (m, 4H), 2.80
(s, 2H), 2.37 (t, 2H), 2.15 (m, 4H), 2.11 (s, 2H), 1.89 (m, 6H),
1.75 (m, 2H), 1.45 (t, 2H), 1.41 (s, 3H), 1.32 (m, 2H), 0.37 (m,
4H).
Compound 342
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethoxy)-
pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 342A
methyl 5,6,7,8-tetrahydro imidazo[1,2-a]pyridine-6-carboxylate
[1047] To a 50 ml pressure bottle were placed methyl
imidazo[1,2-a]pyridine-6-carboxylate (0.26 g), acetic acid (10 ml),
and wet 5% palladium on carbon (0.052 g). The reaction mixture was
stirred for 16 hours at 30 psi and 50.degree. C. The solid was
filtered off, and the filtrate was concentrated. The residue was
taken up in ethyl acetate. It was then washed with saturated sodium
bicarbonate, brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash column
chromatography on silica gel using 10-100% ethyl acetate in hexanes
to provide the title compound.
Compound 342B
(5,6,7,8-tetrahydro imidazo[1,2-a]pyridin-6-yl)methanol
[1048] The title compound was prepared by substituting Compound
342A for Compound 339A in the procedure for Compound 339B.
Compound 342C
5-chloro-6-((5,6,7,8-tetrahydro
imidazo[1,2-a]pyridin-6-yl)methoxy)pyridine-3-sulfonamide
[1049] The title compound was prepared by substituting Compound
342B for (tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for
Compound 36A in the procedure for Compound 36B.
Compound 342D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethoxy)-
pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1050] The title compound was prepared by substituting Compound
342C for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.54 (s, 1H),
8.36 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.58 (d, 1H), 7.41-7.44
(m, 2H), 7.2-7.36 (m, 4H), 7.05 (d, 2H), 6.63 (dd, 1H), 6.32 (dd,
1H), 6.24 (d, 1H), 4.42-4.51 (m, 1H), 4.37-4.40 (m, 1H), 4.29 (dd,
1H), 3.91 (dd, 1H), 3.03 (s, 4H), 2.90-2.95 (m, 2H), 2.77 (s, 2H),
2.51-2.52 (m, 1H), 2.07-2.23 (m, 7H), 1.96 (s, 2H), 1.76-1.82 (m,
1H), 1.65-1.69 (m, 2H), 1.54-1.56 (m, 2H), 1.39 (t, 2H), 0.93 (s,
6H).
Compound 343
N-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]m-
ethoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)be-
nzamide
Compound 343A
5-chloro-6-(((1S,2S,4R)-5-oxobicyclo[2.2.1]heptan-2-yl)methoxy)pyridine-3--
sulfonamide
[1051] The title compound was isolated as another isomer in the
procedure for Compound 339C.
Compound 343B
5-chloro-6-(((1S,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]heptan-2-yl)met-
hoxy)pyridine-3-sulfonamide
[1052] The title compound was prepared by substituting Compound
343A for Compound 339B in the procedure for Compound 339C.
Compound 343C
N-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]m-
ethoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)be-
nzamide
[1053] The title compound was prepared by substituting Compound
343B for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H),
8.51 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.49-7.55 (m, 3H), 7.35
(d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H),
4.27 (s, 1H), 4.11-4.19 (m, 2H), 3.11 (s, 4H), 2.87 (s, 2H),
1.96-2.23 (m, 10H), 1.88 (d, 1H), 1.50 (dd, 1H), 1.33-1.44 (m, 2H),
1.13-1.19 (m, 4H), 0.88-0.93 (m, 8H).
Compound 344
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 344A
4-((cis-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrobenzenesulfonamide
[1054] Compound 347A (732 mg) and
4-fluoro-3-nitrobenzenesulfonamide (1.2 g) in tetrahydrofuran (40
ml) were treated with 60% sodium hydride (1.6 g) for 3 days. The
reaction was quenched with water. The resulting mixture was
neutralized with diluted aqueous HCl, and extracted with ethyl
acetate. The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by a reverse
phase chromatography, eluting with 30-50% CH.sub.3CN in 0.1%
trifluoroacetic acid water to provide the title compound as a
single enantiomer.
Compound 344B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1055] The title compound was prepared by substituting Compound
344A for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 8.34 (d, 1H),
8.04 (m, 2H), 7.52 (m, 3H), 7.40 (d, 1H), 7.35 (d, 2H), 7.04 (d,
2H), 6.68 (dd, 1H), 6.40 (m, 1H), 6.20 (d, 1H), 4.02 (d, 2H), 3.96
(s, 1H), 3.10 (br s, 4H), 2.85 (m, 2H), 2.29 (m, 3H), 2.15 (t, 2H),
1.96 (br s, 2H), 1.68 (m, 1H), 1.55 (m, 4H), 1.42 (m, 4H), 1.27 (m,
2H), 1.10 (s, 3H), 0.92 (s, 6H).
Compound 345
N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3--
yl)sulfonyl]-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1056] The title compound was prepared by substituting Compound
328E for Compound 3J and Compound 277O for Compound 11B in the
procedure for Compound 11D. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 13.07 (s, 1H), 9.13 (d, 1H), 8.41 (d, 1H), 8.09 (d, 1H),
7.68 (t, 1H), 7.66 (d, 1H), 7.42 (m, 2H), 7.09 (m, 2H), 6.75 (dd,
1H), 6.51 (m, 2H), 4.64 (d, 4H), 4.53 (d, 2H), 3.39 (m, 1H), 3.06
(m, 4H), 2.81 (s, 2H), 2.51 (m, 2H), 2.37 (m, 2H), 2.12 (m, 10H),
1.90 (m, 2H), 1.45 (t, 2H), 0.38 (s, 4H).
Compound 346
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1057] The title compound was prepared by substituting
3,3-difluoropyrrolidine hydrochloride for
3-(cyclopropylamino)propanenitrile in the procedure for Compound
340D. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.68 (s, 1H), 11.38 (m, 1H), 8.55 (m, 1H), 8.36 (d, 1H), 8.03 (d,
1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.13 (d, 1H), 7.04
(d, 2H), 6.83 (m, 1H), 6.68 (m, 1H), 6.38 (d, 1H), 6.19 (s, 1H),
4.02 (s, 1H), 3.83 (m, 1H), 3.06 (m, 4H), 2.96 (m, 2H), 2.73 (m,
4H), 2.26 (m, 8H), 1.97 (m, 4H), 1.68 (m, 4H), 1.37 (m, 2H), 0.92
(s, 6H).
Compound 347
N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}s-
ulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 347A
4-(hydroxymethyl)-1-methylcyclohexanol
[1058] 4-(Hydroxymethyl)cyclohexanone (800 mg) in tetrahydrofuran
(15 ml) was treated with 3 M methylmagnesium chloride in
tetrahydrofuran (6.24 ml) at 0.degree. C. The reaction was warmed
to room temperature over 2 hours and quenched with methanol and
water. The resulting mixture was concentrated and the residue was
suspended in ethyl acetate. The precipitates were filtered off and
the filtrate was concentrated. The residue was purified by
chromatography, eluting with 0-100% ethyl acetate in hexane to
provide the title compound.
Compound 347B
5-chloro-6-((trans-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine-3-sulfona-
mide
[1059] Compound 347A (970 mg) and Compound 40A (1.6 g) in
N,N-dimethylformamide (8 ml) were treated with sodium hydride (1.8
g, 60%) at room temperature for 2 days. The reaction was quenched
with water. The resulting mixture was neutralized with diluted
aqueous HCl, and extracted with ethyl acetate. The organic layer
was dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by a reverse phase chromatography, eluting
with 30-45% acetonitrile in 0.1% trifluoroacetic acid water to
isolate the title compound.
Compound 347C
5-chloro-6-((cis-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine-3-sulfonami-
de
[1060] The title compound was prepared and isolated as described in
the procedure for Compound 347B.
Compound 347D
N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}s-
ulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1061] The title compound was prepared as described in the
procedure for Compound 11D using Compound 347B in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67
(s, 1H), 8.51 (d, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.48-7.56 (m,
3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.21
(d, 1H), 4.17-4.34 (m, 3H), 3.11 (s, 4H), 2.89 (s, 2H), 2.24-2.42
(m, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.66-1.82 (m, 3H), 1.55 (d,
2H), 1.31-1.44 (m, 4H), 1.12-1.27 (m, 2H), 1.10 (s, 3H), 0.93 (s,
6H).
Compound 348
N-({5-chloro-6-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1062] The title compound was prepared as described in the
procedure for Compound 11D using Compound 347C in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67
(s, 1H), 8.51 (d, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.47-7.58 (m,
3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.21
(d, 1H), 4.21 (d, 2H), 3.95 (s, 1H), 3.11 (s, 4H), 2.89 (s, 2H),
2.33 (d, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.63-1.77 (m, 1H),
1.48-1.60 (m, 4H), 1.35-1.48 (m, 4H), 1.20-1.33 (m, 2H), 1.09 (s,
3H), 0.93 (s, 6H).
Compound 349
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({4-[(2,2-difluorocyclopropyl)amino]cyclohexyl}amino)-3-nitrop-
henyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1063] The title compound was prepared by substituting
2,2-difluorocyclopropanamine hydrochloride for
3-(cyclopropylamino)propanenitrile in the procedure for Compound
340D. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.60 (s, 1H), 8.47 (m, 2H), 8.12 (m, 1H), 7.98 (m, 1H), 7.72 (m,
2H), 7.47 (m, 3H), 7.34 (m, 3H), 7.05 (m, 3H), 6.65 (dd, 1H), 6.35
(m, 1H), 6.22 (d, 1H), 3.54 (m, 2H), 3.08 (m, 4H), 2.74 (m, 4H),
2.25 (m, 4H), 2.01 (m, 4 H), 1.38 (m, 4H), 0.92 (s, 6H).
Compound 350
N-({5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 350A
ethyl
spiro[benzo[d][1,3]dioxole-2,1'-cyclohexane]-4'-carboxylate
[1064] To a solution of ethyl 4-oxocyclohexanecarboxylate (22.75 g)
and pyrocatechol (14.75 g) in toluene (200 ml) was added catalytic
amount of para-toluenesulfonic acid monohydrate and the mixture was
stirred under reflux and a Dean-Stark trap overnight. The mixture
was diluted with diethyl ether (600 ml) and washed with aqueous
NaHCO.sub.3, water and brine. After drying over Na.sub.2SO.sub.4,
the mixture was filtered and the solvent was evaporated under
vacuum to provide the title compound.
Compound 350B
ethyl
4'-fluorospiro[benzo[d][1,3]dioxole-2,1'-cyclohexane]-4'-carboxylate
[1065] A solution of Compound 350A (5.25 g) in tetrahydrofuran (40
ml) was added dropwise to a solution of lithium diisopropylamide
(12 ml, 2.0M in tetrahydrofuran/heptane/ethylbenzene) at 0.degree.
C. The solution was stirred at 0.degree. C. for 30 minutes, and
then was transferred by cannula to a pre-cooled (0.degree. C.)
stirring solution of N-fluorobenzenesulformimide (7.89 g) in dry
tetrahydrofuran (20 ml). The reaction mixture was stirred at
0.degree. C. for 30 minutes, and then at 20.degree. C. for 18
hours. The reaction mixture was poured over aqueous NH.sub.4Cl and
extracted with diethyl ether (3.times.200 ml). The combined organic
layers were washed with water, brine and dried over
Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave
the crude product.
Compound 350C
(4'-fluorospiro[benzo[d][1,3]dioxole-2,1'-cyclohexane]-4'-yl)methanol
[1066] To a solution of Compound 350B (23 g) in tetrahydrofuran
(150 ml) was added lithium aluminum hydride (3.11 g). The mixture
was stirred overnight. Aqueous 2N NaOH solution was added dropwise
to the reaction mixture. The mixture was then diluted with ethyl
acetate (600 ml) and washed with water, brine and dried over
Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave
the crude product which was loaded on a 600 g analogics column and
eluted with 10% to 20% ethyl acetate in hexane to provide the title
compound.
Compound 350D
5-chloro-6-((4'-fluorospiro[benzo[d][1,3]dioxole-2,1'-cyclohexane]-4'-yl)m-
ethoxy)pyridine-3-sulfonamide
[1067] To a solution of Compound 350C (89 mg) in
N,N-dimethylformamide (3 ml) was added NaH (65% in mineral oil, 36
mg). The mixture was stirred for 30 minutes, and then
5,6-dichloropyridine-3-sulfonamide (85 mg) was added. The mixture
was stirred overnight. The mixture was poured over aqueous
NH.sub.4Cl and extracted with ethyl acetate (100 ml). The combined
organic layers were washed with water, brine and dried over
Na.sub.2SO.sub.4. After filtration and evaporation of the solvent,
the residue was loaded on a silica gel cartridge and eluted with
30% ethyl acetate in hexane to provide the title compound.
Compound 350E
5-chloro-6-((1-fluoro-4-oxocyclohexyl)methoxy)pyridine-3-sulfonamide
[1068] To a solution of Compound 350D (1.6 g) and pyridinium
p-toluenesulfonate (1.2 g) in acetone (10 ml) was added water (2
ml) and the mixture was stirred under microwave irradiation at
100.degree. C. for 10 minutes. The mixture was diluted with
dichloromethane (300 ml) and washed with aqueous NaHCO.sub.3,
water, brine and dried over Na.sub.2SO.sub.4. Filtration and
evaporation of the solvent gave the title compound.
Compound 350F
5-chloro-6-((cis-1-fluoro-4-hydroxycyclohexyl)methoxy)pyridine-3-sulfonami-
de
[1069] To a solution of Compound 350E (336 mg) in tetrahydrofuran
(10 ml) was added NaBH.sub.4 (75 mg). The mixture was stirred for
45 minutes. The mixture was diluted with ethyl acetate (300 ml) and
washed with 2N aqueous NaOH, water, and brine. After drying over
Na.sub.2SO.sub.4, the mixture was filtered and the solvent was
evaporated to give the crude product.
Compound 350G
N-({5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1070] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 350F for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.63 (s, 1H), 8.48 (s, 1H), 8.18 (s, 1H), 8.01 (d, 1H),
7.50 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.37 (dd,
1H), 6.21 (d, 1H), 4.62 (d, 1 H), 4.47 (s, 1H), 4.40 (s, 1H), 3.46
(m, 1H), 3.06 (m, 4H), 2.88 (m, 1H), 2.25 (m, 6H), 1.99 (m, 4H),
1.58 (m, 8H), 0.93 (s, 6H).
Compound 351
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-(2-oxaspiro[3.5]non-7-ylmethoxy)phenyl]sulfonyl}-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 351A
diethyl 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylate
[1071] A 500 ml round-bottomed flask was charged with
diisopropylamine (16 ml) and tetrahydrofuran (311 ml). The solution
was cooled to -78.degree. C. under N.sub.2 and n-BuLi (2.5 M in
hexanes, 44.8 ml)) was added. The reaction was stirred for 30
minutes at -78.degree. C. and ethyl
1,4-dioxaspiro[4.5]decane-8-carboxylate (20 g) was added as a
tetrahydrofuran solution (ca. 10 ml). The solution was stirred at
-78.degree. C. for 1 hour and ethyl chloroformate (9 ml) was added
neat. After stirring at -78.degree. C. for 10 minutes, the reaction
was warmed to room temperature over 2 hours. The reaction was
quenched with saturated aqueous NH.sub.4Cl and was diluted with
diethyl ether. The layers were separated, the aqueous layer was
extracted with diethyl ether and the combined organics were dried
(Na.sub.2SO.sub.4), filtered and concentrated by rotary
evaporation. The residue was purified by regular phase flash column
chromatography (Analogix, 0-65% hexanes/ethyl acetate).
Compound 351B
1,4-dioxaspiro[4.5]decane-8,8-diyldimethanol
[1072] To a 1 L round-bottomed flask was added Compound 351A (26.6
g) and tetrahydrofuran (310 ml) to give a colorless solution. The
solution was cooled to 0.degree. C. and lithium aluminum hydride
(2M in tetrahydrofuran, 62 ml) was added via syringe. The reaction
was allowed to warm to room temperature and stirred overnight. The
mixture was cooled back down to 0.degree. C. and quenched slowly
with 4.7 ml water, 4.7 ml 10% aqueous NaOH and 14 ml water. The
mixture was allowed to stir until salts were formed and was then
filtered through a Supelco 90 mm silica gel Buchner funnel. The
filtrate was concentrated by rotary evaporation and the residue was
purified by regular phase flash column chromatography (Analogix,
0-80% hexanes/ethyl acetate).
Compound 351C
2,8,11-trioxa-dispiro[3.2.4]tridecane
[1073] To a 1 L round-bottomed flask was added Compound 351B (13 g)
in tetrahydrofuran (321 ml). The solution was cooled to -78.degree.
C. under N.sub.2 and n-BuLi (25.7 ml) was added dropwise via
syringe. After addition was complete, the mixture stirred for 30
minutes and a tetrahydrofuran solution of 4-toluenesulfonyl
chloride (12.25 g) was added via addition funnel. The reaction was
allowed to stir overnight, and gradually warm to room temperature.
The reaction mixture was cooled to -78.degree. C. and n-BuLi (25.7
ml) was added. The mixture was warmed to room temperature and
stirred for 3 hours. The reaction was quenched with sat aqueous
NH.sub.4Cl and diluted with diethyl ether. The layers were
separated, the aqueous layers extracted with diethyl ether and the
combined organics were dried (Na.sub.2SO.sub.4), filtered and
concentrated by rotary evaporation. The residue was purified by
regular phase flash column chromatography (Analogix, 0-20%
acetone/hexanes).
Compound 351D
2-oxaspiro[3.5]nonan-7-one
[1074] To a 500 ml round-bottomed flask was added Compound 351C (11
g) in 80% aqueous acetic acid (200 ml). The reaction was heated to
65.degree. C. and stirred for about 4 hours. Most of the acetic
acid and water were removed by rotary evaporation and the residue
was purified by regular phase flash column chromatography
(Analogix, 0-65% hexanes/ethyl acetate).
Compound 351E
7-methylene-2-oxaspiro[3.5]nonane
[1075] To a 250 ml round-bottomed flask was added
methyltriphenylphosphonium iodide (4.33 g) in tetrahydrofuran (35.7
ml) to give a suspension. The suspension was cooled to -15.degree.
C. n-BuLi (2.5 M in hexanes, 4.28 ml) was added dropwise and the
mixture was stirred at -15.degree. C. for 40 minutes and Compound
351D (1 g) was added as a tetrahydrofuran (ca. 5 ml) solution. The
mixture was stirred at -15.degree. C. for about 15 minutes and
warmed to room temperature. After 1.5 hours, the reaction was
complete and was quenched with saturated aqueous NH.sub.4Cl and
diluted with diethyl ether. The layers were separated and the
aqueous layer was extracted (2.times.) with diethyl ether. The
combined organics were washed with brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated by rotary evaporation. The residue was
purified by regular phase chromatography (Analogix, 80 g Grace
silica gel column, 0-50% hexanes/ethyl acetate).
Compound 351F
2-oxaspiro[3.5]nonan-7-ylmethanol
[1076] To a 25 ml round-bottomed flask was added Compound 351E (568
mg) and Compound 351F tetrahydrofuran (4.11 ml) to give a colorless
solution. 9-Borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran,
24.7 ml) was added and the reaction was allowed to stir for 2 hours
at room temperature. Ethanol (11 ml) was added followed by aqueous
NaOH (5M, 4.11 ml) and then hydrogen peroxide (2.1 ml) was added.
The reaction was heated at 50.degree. C. for 2 hours. The mixture
was concentrated by rotary evaporation, and diluted with water and
ethyl acetate. The aqueous layer was extracted with ethyl acetate
(3.times.) and the combined organics were dried (Na.sub.2SO.sub.4),
filtered and concentrated by rotary evaporation. The residue was
purified by regular phase flash column chromatography (Analogix, 80
g Grace, 0-70% hexanes/ethyl acetate).
Compound 351G
4-(2-oxaspiro[3.5]nonan-7-ylmethoxy)-3-nitrobenzene sulfonamide
[1077] Compound 351G was prepared substituting Compound 351F for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 351H
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-(2-oxaspiro[3.5]nonan-7-ylmethox-
y)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-enyl)methyl)piperazin-1-yl)benzamide
[1078] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 351G for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.67 (s, 1H) 8.34 (s, 1H) 8.03 (d, 2H) 7.45-7.57 (m, 3H)
7.30-7.40 (m, 3H) 7.04 (d, 2H) 6.67 (dd, 1H) 6.39 (dd, 1H)
6.17-6.23 (m, 1H) 4.29 (s, 2H) 4.20 (s, 2H) 4.00 (d, 2H) 3.08 (s,
4H) 2.73-2.90 (m, 2H) 2.72 (s, 1H) 2.01-2.32 (m, 6 H) 1.96 (s, 2H)
1.64-1.78 (m, 4H) 1.33-1.50 (m, 6H) 0.96-1.15 (m, 2H) 0.92 (s,
6H).
Compound 352
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1079] Compound 352A
4-((trans-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrobenzene
sulfonamide
[1080] The title compound was prepared by substituting Compound
341F for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 24A.
Compound 352B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1081] The title compound was prepared by substituting Compound
352A for Compound 1F and Compound 3J for Compound 1E in the
procedure for Compound 1G. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H), 8.31 (br s, 1H),
8.01 (m, 2H), 7.49 (m, 3H), 7.33 (m, 3H), 7.03 (m, 2H), 6.66 (dd,
1H), 6.37 (m, 1H), 6.19 (d, 1H), 4.27 (s, 1H), 4.05 (d, 2H), 3.40
(m, 2H), 3.17 (s, 1H), 3.07 (m, 3H), 2.79 (m, 1H), 2.24 (m, 3H),
2.14 (m, 2H), 1.94 (m, 2H), 1.71 (m, 3H), 1.52 (m, 2H), 1.38 (m,
4H), 1.22 (m, 2H), 1.09 (s, 3H), 0.91 (s, 6H).
Compound 353
4-(4-{[2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 353A
1,4-dioxaspiro[4.5]decane-8,8-diylbis(methylene)bis(4-methylbenzenesulfona-
te)
[1082] To a 500 ml round-bottomed flask was added Compound 351B (10
g) and dichloromethane (165 ml) to give a colorless solution.
Triethylamine (24.1 ml) and toluene-2-sulfonyl chloride (19.8 g)
were added followed by 4-dimethylaminopyridine (0.604 g). The
reaction was refluxed overnight. Saturated aqueous NH.sub.4Cl was
added followed by dilution with water and additional
dichloromethane. The aqueous layer was extracted with
dichloromethane (2.times.) and the combined organics were dried
(MgSO.sub.4), filtered and concentrated by rotary evaporation. The
residue was purified by regular phase flash column chromatography
(Analogix, 0-55% hexanes/ethyl acetate).
Compound 353B
8,8-bis(fluoromethyl)-1,4-dioxaspiro[4.5]decane
[1083] To a 500 ml round-bottomed flask was added Compound 353A (20
g). tetra-n-Butylammonium fluoride (1M in tetrahydrofuran, 200 ml)
was added and the resulting solution was refluxed for 6 days. The
reaction was cooled, diluted with diethyl ether and washed with
water (3.times.). The organics were dried (Na.sub.2SO.sub.4),
filtered and concentrated by rotary evaporation. The residue was
purified by regular phase flash column chromatography (Analogix,
0-30% hexanes/ethyl acetate).
Compound 353C
[1084] To a 250 ml round bottom flask was added Compound 353B (1.1
g) and 80% aqueous acetic acid (50 ml). The reaction was heated at
65.degree. C. for 3 hours, cooled and concentrated by rotary
evaporation to remove most of the acetic acid and water. The
residue was purified by regular phase flash column chromatography
(Analogix, 0-50% hexanes/ethyl acetate).
Compound 353D
2-chloro-5,5-bis(fluoromethyl)cyclohex-1-enecarbaldehyde
[1085] To a 100 ml pear flask was added N,N-dimethylformamide (498
.mu.l) and dichloromethane (8.9 ml) to give a colorless solution.
The solution was cooled to 0.degree. C. and POCl.sub.3 (550 .mu.l)
was added dropwise and then the mixture was warmed to room
temperature for 30 minutes. In the meantime, to a 100 ml pear
shaped flask was added Compound 353C (870 mg, 5.36 mmol) in
dichloromethane (8941 .mu.l) to give a colorless solution. The
Vilsmeier reagent was then taken up in a syringe and added dropwise
to the 4,4-bis(fluoromethyl)cyclohexanone (870 mg) solution at room
temperature. The resulting solution was stirred overnight. The
reaction was poured into saturated aqueous NaHCO.sub.3 and ice,
warmed to room temperature and extracted with dichloromethane
(3.times.30 ml). The organics were combined, dried over MgSO.sub.4,
filtered and concentrated by rotary evaporation. The residue was
purified by regular phase flash column chromatography (Analogix
(0-60% hexanes/ethyl acetate).
Compound 353E
2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-enecarbaldehyde
[1086] To a 20 ml vial was added Compound 353D (460 mg),
4-chlorophenylboronic acid (414 mg), potassium carbonate (762 mg),
tetrabutylammonium bromide (711 mg), palladium (II) acetate (14.85
mg) and water (2450 .mu.l) to give a suspension which was degassed
with N.sub.2 for 2 minutes. The reaction was stirred at 45.degree.
C. overnight, cooled, and poured over a Supelco silica gel Buchner
funnel, washing with ethyl acetate several times. The filtrate was
concentrated by rotary evaporation and the residue was purified by
regular phase flash column chromatography (Analogix, 0-60%
hexanes/ethyl acetate).
Compound 353F
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5--
bis(fluoro
methyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[1087] To a 20 ml vial was added Compound 353E (240 mg), Compound
15F (297 mg) and dichloromethane (4.2 ml). Sodium
triacetoxyborohydride (268 mg) was added and the reaction was
stirred overnight at room temperature. The reaction was loaded
directly onto silica gel and purified by regular phase flash column
chromatography (Analogix, 0-80% hexanes/ethyl acetate).
Compound 353G
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-bis(flu-
oromethyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[1088] The title compound was prepared by substituting Compound
353F for Compound 15G in the procedure for Compound 15H.
Compound 353H
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-bis(flu-
oromethyl)cyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-
-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide
[1089] Compound 353H was prepared by replacing Compound 3J with
Compound 353G and Compound 11B with Compound 1F in the procedure
for Compound 11D. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.69 (s, 1H) 11.44 (s, 1H) 8.48-8.70 (m, 1H) 8.05 (d, 2H)
7.81 (dd, 1H) 7.46-7.59 (m, 3H) 7.35 (d, 2H) 7.12 (d, 2H) 6.68 (dd,
1H) 6.40 (dd, 1H) 6.16 (d, 1H) 4.39-4.49 (m, 2H) 4.23-4.35 (m, 2H)
3.85 (dd, J=11.87, 2.71 Hz, 2H) 3.20-3.30 (m, 4H) 2.98-3.10 (m, 4H)
2.66-2.77 (m, 2H) 2.11-2.30 (m, 6H) 2.02-2.12 (m, 3 H) 1.99 (s, 1H)
1.82-1.97 (m, 1H) 1.54-1.67 (m, 4H) 1.20-1.34 (m, 2H).
Compound 354
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-cyclopropylmorpholin-2-yl)methoxy]-3-nitrophenyl}sulfonyl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 354A
tert-butyl
2-((2-nitro-4-sulfamoylphenoxy)methyl)morpholine-4-carboxylate
[1090] The title compound was prepared by substituting tert-butyl
2-(hydroxymethyl)-morpholine-4-carboxylate for
tetrahydro-2H-pyran-4-yl-methanol Compound 24A.
Compound 354B
4-(morpholin-2-ylmethoxy)-3-nitrobenzene sulfonamide
[1091] The title compound was prepared by substituting Compound
354A for Compound 113A in the procedure for Compound 134A.
Compound 354C
4-((4-cyclopropylmorpholin-2-yl)methoxy)-3-nitrobenzenesulfonamide
[1092] The title compound was prepared by substituting Compound
354B for Compound 173A in the procedure for Compound 173B.
Compound 354D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-cyclopropylmorpholin-2-yl)methoxy]-3-nitrophenyl}sulfonyl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1093] The title compound was prepared by substituting Compound
354C for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 12.98 (s, 1H), 9.06 (d,
1H), 8.50 (dd, 1H), 8.41 (d, 1H), 8.09 (d, 1H), 7.66 (t, 1H), 7.62
(d, 1H), 7.44 (d, 2H), 7.26 (d, 1H), 7.07 (d, 2H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 4.31 (dd, 1H), 4.22 (dd, 1H), 3.92 (m,
1H), 3.83 (d, 1H), 3.56 (dt, 1H), 3.07 (m, 5H), 2.77 (s, 2H), 2.68
(d, 1H), 2.35 (m, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H),
1.59 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H), 0.40 (m, 4H).
Compound 355
N-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyrid-
in-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 355A
5-chloro-6-((trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine--
3-sulfonamide
[1094] To a cooled (0.degree. C.) solution of Compound 350E (1.2 g)
in tetrahydrofuran (30 ml) was added dropwise a solution of
methylmagnesium bromide (5 ml, 3.0M in ether). Upon addition, the
reaction mixture solidified. More tetrahydrofuran (10 ml) was added
to the mixture and stirring was continued for 1 hour. The mixture
was poured over aqueous NH.sub.4Cl and extracted with ethyl acetate
(3.times.150 ml). The combined organic layers were washed with
water, brine and dried over Na.sub.2SO.sub.4. The mixture was
filtered and concentrated. The residue was dissolved in
dimethylsulfoxide/methanol (20 ml, 1:1) and loaded on loaded on
Gilson, C18(100 A) 250.times.121.2 mm (10 micron), with 30%
acetonitrile to 65% acetonitrile over 40 minutes to separate the
two isomers and isolate the title compound.
Compound 355B
N-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyrid-
in-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1095] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 355A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.63 (s, 1H), 8.47 (s, 1H), 8.17 (s, 1H), 7.54 (d, 1H),
7.48 (m, 2H), 7.35 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.37 (d,
1H), 6.22 (d, 1H), 4.49 (s, 1 H), 4.42 (s, 1H), 4.15 (s, 1H), 3.06
(m, 4H), 2.84 (m, 1H), 2.25 (m, 6H), 1.96 (s, 3H), 1.83 (m, 4H),
1.44 (m, 6H), 1.14 (s, 3H), 0.93 (s, 6H).
Compound 356
N-({5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-
-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 356A
5-chloro-6-((cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine-3--
sulfonamide
[1096] The title compound was prepared as described for Compound
355A.
Compound 356B
N-({5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-
-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1097] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 356A for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (s, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 8.03 (d, 1H),
7.51 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.39 (dd,
1H), 6.21 (d, 1H), 4.55 (s, 1 H), 4.48 (s, 1H), 4.34 (s, 1H), 3.08
(m, 4H), 2.89 (d, 2H), 2.27 (m, 5H), 1.93 (m, 4H), 1.66 (m, 4H),
1.43 (m, 4H), 1.11 (s, 3H), 0.93 (s, 6H).
Compound 357
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-cyano-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 357A
ethyl 4-fluoro-1-(oxetan-3-yl)piperidine-4-carboxylate
[1098] To 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate
(1.000 g) was added HCl (4.0M in dioxane, 4.54 ml). After 1 hour
the reaction was concentrated and dried under high vacuum. The
resulting solid was dissolved in dichloromethane (5 ml) and treated
with sodium triacetoxyborohydride (1.155 g) and oxetan-3-one (0.262
g) and stirred overnight. The reaction was quenched with saturated
NaHCO.sub.3 solution (20 ml) and extracted into dichloromethane
(2.times.25 ml). The organic layer was dried over magnesium
sulfate, filtered, and concentrated. Silica gel chromatography
(Reveleris 80 g) eluting with a gradient of 0.5% to 3.75%
methanol/dichloromethane over 40 minutes (flow=30 ml/min) gave the
title compound.
Compound 357B
(4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methanol
[1099] To a solution of Compound 357A (0.59 g) in tetrahydrofuran
(5 ml) was added lithium aluminum hydride (1.80 ml) at 0.degree. C.
The reaction was removed from the ice bath and allowed to warm to
room temperature. The reaction was quenched by the dropwise
addition of 0.6 ml of water followed by 0.2 ml of 2N aqueous NaOH.
The reaction was filtered through celite and rinsed with ethyl
acetate (50 ml). The mixture and the residue was loaded onto silica
gel (Reveleris 40 g) and eluted using a gradient of 0.75% to 7.5%
methanol/dichloromethane over 30 minutes (flow=40 ml/min) to
provide the title compound.
Compound 357C
3-cyano-4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)benzene
sulfonamide
[1100] The title compound was prepared by substituting Compound
357B for (tetrahydro-2H-pyran-4-yl)methanol in the procedure for
Compound 284A.
Compound 357D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-cyano-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1101] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 357C for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.67 (s, 1H), 11.49-11.14 (m, 1H), 8.17 (d, 1H), 8.03 (d,
2H), 7.51 (dd, 3H), 7.43-7.26 (m, 3H), 7.12-6.96 (m, 2H), 6.67 (dd,
1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.55 (t, 2H), 4.45 (t, 2H), 4.34
(d, 2H), 3.49 (s, 1H), 3.09 (s, 8H), 2.39-1.66 (m, 14H), 1.39 (s,
2H), 0.92 (s, 6H).
Compound 358
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 358A
benzyl (4-ethyl-4-hydroxycyclohexyl)methylcarbamate
[1102] To a vigorous stirring solution of benzyl
(4-oxocyclohexyl)methylcarbamate (1 g) in tetrahydrofuran (20 ml)
at -78.degree. C. was slowly added 1 Methylmagnesium bromide (11.48
ml, 11.48 mmol) in ether. After completion of the addition, the
mixture was stirred at -78.degree. C. for 2 hours and was warmed to
0.degree. C., and stirred in an ice bath for 30 minutes. The
reaction was quenched with a cold NH.sub.4Cl aqueous solution. The
precipitates were filtered off and washed with ethyl acetate. The
filtrate was concentrated. The residue was dissolved in
dichloromethane and loaded onto Analogix purification system, and
was eluted with 0-50% ethyl acetate in dichloromethane to provide
the title compound.
Compound 358B
4-(aminomethyl)-1-ethylcyclohexanol
[1103] A mixture of Compound 358A (500 mg) and 10% Pd/C (100 mg) in
tetrahydrofuran (15 ml) was stirred under H.sub.2 for 3 hours. The
insoluble material was removed by filtration, and the filtrate was
concentrated to provide the title compound.
Compound 358C
4-((trans-4-ethyl-4-hydroxycyclohexyl)methylamino)-3-nitrobenzene
sulfonamide
[1104] Compound 358B (270 mg) and
4-fluoro-3-nitrobenzenesulfonamide (417 mg) in tetrahydrofuran were
treated with triethylamine (0.8 ml) overnight. The reaction was
quenched with water. The resulting mixture was neutralized with
diluted aqueous HCl, and extracted with ethyl acetate. The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by a reverse phase chromatography, eluting
with 40-55% acetonitrile in 0.1% trifluoroacetic acid water to
isolate the title compound.
Compound 358D
4-((cis-4-ethyl-4-hydroxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[1105] The title compound was prepared and isolated as described
for Compound 358C.
Compound 358E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1106] The title compound was prepared as described in the
procedure for Compound 11D using Compound 358C in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 1H), 11.35 (s, 1H), 8.56 (d, 2H), 8.05 (d, 1H), 7.80 (dd, 1 H),
7.45-7.57 (m, 3H), 7.34 (d, 2H), 7.00-7.10 (m, 3H), 6.68 (dd, 1H),
6.39 (dd, 1H), 6.19 (d, 1H), 3.98 (s, 1H), 3.24-3.31 (m, 4H), 3.07
(s, 4H), 2.75 (s, 2H), 2.17 (d, 6H), 1.95 (s, 2H), 1.54-1.73 (m,
5H), 1.35-1.47 (m, 4H), 1.20-1.32 (m, 2H), 1.03-1.18 (m, 2H), 0.92
(s, 6H), 0.81 (t, 3H).
Compound 359
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(cis-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1107] The title compound was prepared as described in the
procedure for Compound 11D using Compound 358D in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 1H), 11.34 (s, 1H), 8.60 (t, 1H), 8.56 (d, 1H), 8.05 (d, 1 H),
7.80 (dd, 1H), 7.54 (d, 1H), 7.47-7.52 (m, 2H), 7.34 (d, 2H),
7.01-7.10 (m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.77
(s, 1H), 3.26 (t, 2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.10-2.26 (m,
6H), 1.95 (s, 2H), 1.46-1.61 (m, 5H), 1.28-1.46 (m, 6H), 1.12-1.24
(m, 2H), 0.92 (s, 6H), 0.82 (t, 3H).
Compound 360
4-(4-{[2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 360A
ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate
[1108] Into a 500 ml round-bottomed flask was added
diisopropylamine (7.98 ml) in tetrahydrofuran (233 ml) to give a
colorless solution. The mixture was cooled to -78.degree. C. under
N.sub.2 and n-BuLi (2.5 M in hexanes, 22.40 ml) was added. The
reaction was stirred for 30 minutes and ethyl
1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g) was added. The
reaction was allowed to stir for 1.5 hours upon which time
CH.sub.3I (4.38 ml) was added. The reaction was allowed to warm to
room temperature overnight with stirring. Water was added and the
aqueous layer was extracted with ethyl acetate. The combined
organics were dried (Na.sub.2SO.sub.4), filtered and concentrated
by rotary evaporation. The residue was purified by normal phase
flash column chromatography (Analogix, 0-50% hexanes/ethyl
acetate).
Compound 360B
(8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol
[1109] In a 500 ml round-bottomed flask was lithium aluminum
hydride (1.772 g) in tetrahydrofuran (234 ml) to give a suspension.
This suspension was cooled to 0.degree. C. and ethyl
8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (10.66 g) was
added via addition funnel. The reaction was stirred overnight at
room temperature and then cooled back down to 0.degree. C. The
excess lithium aluminum hydride was slowly quenched with 1.8 ml
water, 1.8 ml aqueous NaOH (5N) and 5.6 ml water. The suspension
was stirred until the salts turned white and was then filtered
through a plug of silica gel. The filtrate was concentrated by
rotary evaporation and the residue was purified by regular phase
flash column chromatography (Analogix, 0-75% hexanes/ethyl
acetate).
Compound 360C
8-(methoxymethyl)-8-methyl-1,4-dioxaspiro[4.5]decane
[1110] To a 250 ml round-bottomed flask was added NaH (0.902 g) and
tetrahydrofuran (37.6 ml) to give a suspension. Compound 360B was
added as a tetrahydrofuran solution at room temperature. The
suspension was stirred for 30 minutes and then CH.sub.3I (0.611 ml)
was added. The reaction was stirred under N.sub.2 overnight,
carefully quenched with brine and diluted with water and ether. The
aqueous layer was extracted with ether (2.times.) and the combined
organics were dried (Na.sub.2SO.sub.4), filtered and concentrated
by rotary evaporation. The residue was purified by flash column
chromatography (Analogix, 0-60% hexanes/ethyl acetate).
Compound 360D
4-(methoxymethyl)-4-methylcyclohexanone
[1111] The title compound was prepared by substituting Compound
360C for Compound 353B in the procedure for Compound 353C.
Compound 360E
2-chloro-5-(methoxymethyl)-5-methylcyclohex-1-enecarbaldehyde
[1112] The title compound was prepared by substituting Compound
360D for Compound 353C in the procedure for Compound 353D.
Compound 360F
2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-enecarbaldehyde
[1113] The title compound was prepared by substituting Compound
360E for Compound 353D in the procedure for Compound 353E.
Compound 360G
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-(m-
ethoxymethyl)-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[1114] The title compound was prepared by substituting Compound
360F for Compound 353E in the procedure for Compound 353F.
Compound 360H
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-(methoxym-
ethyl)-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic
acid
[1115] The title compound was prepared by substituting Compound
360G for Compound 15G in the procedure for Compound 15H.
Compound 360I
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-(methoxym-
ethyl)-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetra-
hydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide
[1116] The title compound was prepared by replacing Compound 3J
with Compound 360H and Compound 11B with Compound 1F in the
procedure for Compound 11D. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H) 11.43 (s, 1H)
8.45-8.72 (m, 2H) 8.04 (d, 1H) 7.80 (dd, 1H) 7.44-7.61 (m, 3H) 7.34
(d, 2H) 6.99-7.20 (m, 3H) 6.68 (dd, 1H) 6.39 (dd, 1H) 6.18 (d, 1H)
3.85 (dd, 2H) 3.25-3.30 (m, 4H) 3.24 (s, 3H) 3.02-3.17 (m, 6H) 2.72
(dd, 2H) 2.18 (s, 5H) 2.03-2.13 (m, 2H) 1.81-1.93 (m, 2H) 1.57-1.67
(m, 2H) 1.47-1.56 (m, 1H) 1.17-1.41 (m, 3H) 0.91 (s, 3H).
Compound 361
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[(2S)-4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phe-
nyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 361A
(S)-3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methylamino)benzene
sulfonamide
[1117] The title compound was prepared by substituting Compound
259E for tert-butyl piperazine-1-carboxylate and 3-oxetanone for
4'-chlorobiphenyl-2-carboxaldehyde in the procedure for Compound
1A.
Compound 361B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[3-nitro-4-({[(2S)-4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phe-
nyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1118] The title compound was prepared by substituting Compound
361A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 13.00 (s, 1H), 9.26 (d,
1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H), 7.66
(m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.96 (d, 1H), 6.75 (dd, 1H),
6.54 (d, 1H), 6.48 (m, 1H), 4.64 (m, 4H), 3.93 (m, 1H), 3.89 (d,
1H), 3.68 (dt, 1H), 3.53-3.35 (m, 3H), 3.07 (m, 4H), 2.77 (s, 2H),
2.72 (d, 1H), 2.44 (d, 1H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s,
2H), 1.85 (t, 1H), 1.39 (t, 2H), 0.94 (s, 6H).
Compound 362
N-({3-chloro-4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]phenyl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 362A
3-chloro-4-(((1 r,4r)-4-hydroxy-4-methylcyclohexyl)methoxy)benzene
sulfonamide
[1119] To a solution of Compound 341F (300 mg) in
N,N-dimethylformamide (10 ml) was added sodium hydride (416 mg)
portionwise. The resulting suspension was stirred for 15 minutes.
3-Chloro-4-fluorobenzenesulfonamide (425 mg) was added and stirring
was continued for 72 hours. The reaction was quenched with water
and the pH was adjusted to ca. 7. The mixture was diluted with
brine (75 ml) and extracted with methylene chloride. The crude
product was isolated from the dried methylene chloride layer by
concentration and was purified on silica gel eluted with a 10, 25,
50% ethyl acetate in methylene chloride step gradient to provide
the title compound.
Compound 362B
N-({3-chloro-4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]phenyl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1120] The title compound was prepared by substituting Compound
362A for Compound 130C in the procedure for Compound 130D. .sup.1H
NMR (400 MHz, pyridine-d.sub.5) .delta. 13.07 (m, 1H), 8.58 (d,
1H), 8.45 (d, 1H), 8.31 (dd, 1H), 8.11 (d, 1H), 7.69-7.67 (m, 2H),
7.44 (d, 2H), 7.07 (d, 2H), 6.97 (d, 1H), 6.74 (dd, 1H), 6.52 (m,
2H), 5.34 (br s, 2H), 3.82 (d, 2H), 3.06 (m, 4H), 2.77 (s, 2H),
2.25 (m, 2H), 2.13 (m, 4H), 1.97-1.85 (m, 7H), 1.82-1.73 (m, 2H),
1.44-1.32 (m, 7H), 0.94 (m, 6H).
Compound 363
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]-1-fluorocyclohexyl}meth-
oxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 363A
4-((4'-fluorospiro[benzo[d][1,3]dioxole-2,1'-cyclohexane]-4'-yl)methoxy)-3-
-nitrobenzenesulfonamide
[1121] To a solution of Compound 350C (495 mg) in
N,N-dimethylformamide (6 ml) was added NaH (65% in mineral oil, 320
mg). The mixture was stirred for 30 minutes, and then
4-fluoro-3-nitrobenzenesulfonamide (457 mg) was added. The mixture
was stirred overnight. The mixture was poured over aqueous
NH.sub.4Cl and extracted with ethyl acetate (300 ml). The combined
organic layers were washed with water, brine and dried over
Na.sub.2SO.sub.4. After filtration and evaporation of the solvent,
the residue was loaded on a silica gel cartridge and was eluted
with 30% ethyl acetate in hexane to provide the title compound.
Compound 363B
4-((1-fluoro-4-oxocyclohexyl)methoxy)-3-nitrobenzene
sulfonamide
[1122] To a solution of Compound 363A (860 mg) in ethanol (30 ml)
was added concentrated HCl (10 ml) and the mixture was stirred at
100.degree. C. for 3 hours. The mixture was neutralized with solid
Na.sub.2CO.sub.3 and extracted with dichloromethane (300 ml) and
washed with aqueous NaHCO.sub.3, water, brine and dried over
Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave
the title compound.
Compound 363C
4-((4-((2-cyanoethyl)(cyclopropyl)amino)-1-fluorocyclohexyl)methoxy)-3-nit-
robenzenesulfonamide
[1123] To a solution of Compound 363B (200 mg) in dichloromethane
(6 ml) was added 3-(cyclopropylamino)propanenitrile (64 mg)
followed by sodium triacetoxyborohydride (184 mg). The mixture was
stirred overnight. The reaction mixture was diluted with
dichloromethane (400 ml) and washed with 2N aqueous NaOH, water,
and brine. After drying over Na.sub.2SO.sub.4, the mixture was
filtered and evaporation of the solvent gave the title
compound.
Compound 363D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]-1-fluorocyclohexyl}meth-
oxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1124] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 363C for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.66 (s, 1H), 8.35 (s, 1H), 8.02 (d, 2H), 7.51 (m, 3H),
7.40 (m, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (d,
1H), 6.20 (s, 1H), 4.27 (d, 2H), 3.13 (m, 4H), 2.88 (m, 3H), 2.67
(m, 4H), 2.09 (m, 10H), 1.49 (m, 9H), 0.93 (s, 6H), 0.45 (m,
4H).
Compound 364
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-nitro-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 364A
6-amino-5-nitropyridine-3-sulfonic acid
[1125] 6-Aminopyridine-3-sulfonic acid (20 g) in concentrated
H.sub.2SO.sub.4 (80 ml) was heated at 50.degree. C. until it was
completely dissolved. To this solution was added fuming HNO.sub.3
slowly over 20 minutes, so the internal temperature did not exceed
55.degree. C. After the addition was complete, the reaction mixture
was heated at 50.degree. C. for 1 hour. After it was cooled to room
temperature, it was poured into 150 g of ice. The mixture was
stirred for another hour. The flask was cooled to 0.degree. C., and
was kept at 0.degree. C. for another 2 hours. The solid was
collected by filtration, and washed with cold 1:1 water/ethanol (20
ml), followed by diethyl ether (10 ml). The solid was dried in a
vacuum oven overnight to provide the title compound.
Compound 364B
6-hydroxy-5-nitropyridine-3-sulfonic acid
[1126] Compound 364A (4.0 g) in aqueous HCl (37%, 12 ml) and water
(50 ml) was treated with sodium nitrite (1.19 g) in water (8 ml)
dropwise at 0.degree. C. After the addition was complete, the
reaction mixture was stirred at 0.degree. C. for 1 hour. The
mixture was heated at reflux for 2 hours. Water was distilled off
to give a dry residue. After the residue was cooled to room
temperature, a solution of 1:1 ethano/water (20 ml) was added. The
resulting suspension was cooled to 0.degree. C., and kept at
0.degree. C. for 1 hour. The solid was collected by filtration to
provide the title compound.
Compound 364C
6-chloro-5-nitropyridine-3-sulfonyl chloride
[1127] A mixture of Compound 364B (2.6 g), PCl.sub.5 (5.91 g), and
POCl.sub.3 (10 ml) was heated at 120.degree. C. for 4 hours. The
initial suspension became a clear solution. The excess of
POCl.sub.3 was distilled off. After it was cooled to room
temperature, the residue was poured into 50 g of crushed ice. The
solid was extracted into ethyl acetate. The aqueous layer was
extracted with additional ethyl acetate. The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated to give crude product that was used in the next step
without further purification.
Compound 364D
6-chloro-5-nitropyridine-3-sulfonamide
[1128] Compound 364C in tetrahydrofuran (10 ml) was cooled to
-10.degree. C. To this solution was added concentrated ammonium
hydroxide (0.82 ml) dropwise. The solution was stirred at
-10.degree. C. for 10 minutes. The solvent was removed under
pressure at room temperature. The residue was partitioned between
water and ethyl acetate. The aqueous layer was extracted 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 column chromatography on silica gel
using 5-50% ethyl acetate in hexanes to provide the title
compound.
Compound 364E
5-nitro-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide
[1129] The title compound was prepared by substituting Compound
364D for 4-fluoro-3-nitrobenzenesulfonamide and
(tetrahydro-2H-pyran-4-yl)methanamine for
(4-fluorotetrahydro-2H-pyran-4-yl)methanamine in the procedure for
Compound 138D.
Compound 364F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-nitro-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1130] The title compound was prepared by substituting Compound
364E for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.63 (s, 1H),
8.93 (s, 1H), 8.73 (d, 1H), 8.69 (d, 1H), 8.00 (d, 1H), 7.54 (d,
1H), 7.47-7.48 (m, 2H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H),
6.35 (dd, 1H), 6.22 (d, 1H), 3.83 (dd, 2H), 3.51 (t, 2H), 3.21-3.27
(m, 2H), 3.10 (s, 4H), 2.83 (s, 2H), 1.90-2.27 (m, 12H), 1.58 (dd,
2H), 1.39 (t, 2H), 1.18-1.28 (m, 2H), 0.88-0.93 (m, 8H).
Compound 365
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(2-oxaspiro[3.5]non-7-ylmethyl)amino]phenyl}sulfonyl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 365A
7-(azido methyl)-2-oxaspiro[3.5]nonane
[1131] To a 250 ml round-bottomed flask was Compound 351F (350 mg)
in tetrahydrofuran (75.0 ml) to give a colorless solution. The
solution was cooled to 0.degree. C., triphenylphosphine (2.94 g),
diisopropyl azodicarboxylate (2.18 ml) and diphenyl phosphorazidate
(2.32 ml) were added and the reaction was stirred for 30 minutes at
room temperature. The mixture was concentrated and purified the
residue by regular phase flash column chromatography (Analogix,
0-20% hexanes/ethyl acetate).
Compound 365B
2-oxaspiro[3.5]nonan-7-ylmethanamine
[1132] To a 50 ml round-bottomed flask was added 10% palladium on
carbon (58.7 mg). The flask was flushed with N.sub.2 and Compound
365A (400 mg) was added as a methanol solution (10.5 ml). The flask
was then flushed several times with H.sub.2 (via balloon) and
heated to 45.degree. C. for 2 hours. The reaction was cooled to
room temperature, filtered through celite and the filtrate was
concentrated by rotary evaporation. The residue was used in the
next step without further purification.
Compound 365C
4-(2-oxaspiro[3.5]nonan-7-ylmethylamino)-3-nitrobenzenesulfonamide
[1133] The title compound was prepared by substituting Compound
365B for 1-(tetrahydropyran-4-yl)methylamine in the procedure for
Compound 1F.
Compound 365D
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-(2-oxaspiro[3.5]nonan-7-ylmethyl-
amino)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)benzamide
[1134] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 365C for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.67 (s, 1H) 11.25-11.49 (m, 1H) 8.48-8.66 (m, 2H) 8.03
(d, 1H) 7.79 (dd, 1H) 7.41-7.61 (m, 3H) 7.27-7.40 (m, 2H) 7.05 (t,
3H) 6.67 (dd, 1H) 6.39 (dd, 1H) 6.18 (d, 1H) 4.29 (s, 2H) 4.19 (s,
2H) 3.17-3.27 (m, 2H) 2.99-3.14 (m, 4 H) 2.69-2.79 (m, 2H)
2.09-2.28 (m, 6H) 2.04 (d, 2H) 1.95 (s, 2H) 1.66 (d, 2H) 1.49-1.61
(m, 1H) 1.29-1.45 (m, 4H) 0.93-1.05 (m, 2H) 0.92 (s, 6H).
Compound 366
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-cyano-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 366A
tert-butyl (4-cyano-4-methylcyclohexyl)methylcarbamate
[1135] To a cooled (-78.degree. C.) solution of tert-butyl
(4-cyanocyclohexyl)methylcarbamate (500 mg) in tetrahydrofuran (10
ml) was added lithium diisopropylamide (2.0 ml, 2M in heptane). The
mixture was stirred at -78.degree. C. for 30 minutes before the
addition of CH.sub.3I (1 ml). The mixture was then stirred and the
temperature was allowed to warm to room temperature. The reaction
was quenched with aqueous NH.sub.4Cl and the mixture was extracted
with ethyl acetate (300 ml) and washed with water, brine and dried
over Na.sub.2SO.sub.4. Filtration and evaporation of the solvent
and silica gel chomatography (40% ethyl acetate in hexane) of the
crude material gave the title compound.
Compound 366B
4-(aminomethyl)-1-methylcyclohexanecarbonitrile
[1136] To a solution of Compound 366A (480 mg) in dichloromethane
(10 ml) was added trifluoroacetic acid (10 ml). The mixture was
stirred for 3 hours. The mixture was then concentrated under vacuum
and was used directly in the next reaction without further
purification.
Compound 366C
4-((4-cyano-4-methylcyclohexyl)methylamino)-3-nitrobenzene
sulfonamide
[1137] To a solution of 4-fluoro-3-nitrobenzenesulfonamide (362 mg)
in tetrahydrofuran (10 ml) was added Compound 366B (250 mg) and
N,N-diisopropylethylamine (2 ml). The mixture was stirred
overnight. The mixture was diluted with ethyl acetate (300 ml) and
washed with water, brine and dried over Na.sub.2SO.sub.4.
Filtration and evaporation of the solvent gave the title
compound.
Compound 366D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-cyano-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1138] The title compound was prepared by substituting Compound 3J
for Compound 1E and Compound 366C for Compound 1F in the procedure
for Compound 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.67 (s, 1H), 11.37 (m, 1H), 8.59 (m, 2H), 8.04 (d, 1H),
7.80 (d, 1H), 7.51 (m, 3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.04 (d,
2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.19 (s, 1H), 3.07 (m, 4H), 2.75
(m, 2H), 2.17 (m, 7H), 1.76 (m, 9H), 1.32 (m, 9 H), 0.92 (s,
6H).
Compound 367
[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh
ex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)b-
enzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfo-
nyl)amino}methyl pivalate
[1139] This compound was prepared by substituting chloromethyl
pivalate for chloromethyl butyrate in the procedure for Compound
368. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta.11.72
(s, 1H), 8.43 (d, 1H), 8.22 (dd, 1H), 8.01 (d, 1H), 7.55 (m, 3H),
7.36 (m, 3H), 7.03 (d, 2H), 6.68 (dd, 1H), 6.41 (m, 1H), 6.17 (d,
1H), 5.83 (s, 2H), 4.40 (d, 2H), 3.78 (m, 2H), 3.59 (m, 2H), 3.08
(br m, 4H), 2.73 (br s, 2H), 2.18 (br m, 6H), 1.96 (s, 2H), 1.84
(m, 4H), 1.39 (m, 2H), 1.00 (s, 9H), 0.92 (s, 6H).
Compound 368
{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahyd-
ro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methyl
butyrate
[1140] Compound 37E (500 mg) was dissolved in acetonitrile (3.7 ml)
and chloromethyl butyrate (77 mg) and Hunig's base (73 mg) were
added. The reaction was heated under reflux for one day. After
cooling and dilution with dimethylsulfoxide (4 ml) the reaction was
purified by preparative HPLC using a 250.times.50 mm C18 column and
eluting with 20-100% CH.sub.3CN vs. 0.1% trifluoroacetic acid in
water, giving the product as a trifluoroacetate salt. The
trifluoroacetic acid salt was dissolved in dichloromethane (6 ml)
and washed with 50% aqueous NaHCO.sub.3. The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated
to provide the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.72 (s, 1H), 8.43 (d, 1H),
8.22 (dd, 1H), 8.01 (d, 1H), 7.55 (m, 3H), 7.36 (m, 3H), 7.03 (d,
2H), 6.68 (dd, 1H), 6.41 (m, 1H), 6.17 (d, 1H), 5.83 (s, 2H), 4.40
(d, 2H), 3.78 (m, 2H), 3.59 (m, 2H), 3.08 (br m, 4H), 2.73 (br s,
2H), 2.18 (m, 8H), 1.96 (s, 2H), 1.84 (m, 4H), 1.39 (m, 4H), 0.92
(s, 6H), 0.75 (t, 3H).
Compound 369
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(.sup.2H.s-
ub.8)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 369A
methyl
4-[(2,2,3,3,5,5,6,6-2H.sub.8)piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]py-
ridin-5-yloxy)benzoate
[1141] Into a 40 ml vial were added Compound 3H (1.55 g) and
piperazine-d.sub.8 (2.040 g) in dimethylsulfoxide (13 ml). The
solution was heated to 85.degree. C. for 2.5 hours, and was then
allowed to cool to room temperature overnight. The mixture was
transferred to a 120 ml flask and was cooled to 5-10.degree. C.
Dichloromethane (30 ml) was added, then water (10 ml) was added via
syringe over 5 minutes maintaining temp at no more than 15.degree.
C. The layers were separated and the organic layer was washed with
water (4.times.10-15 ml) until pH of aqueous layer was 8-9. The
organic layer was filtered through Na.sub.2SO.sub.4 and rinsed with
dichloromethane (5 ml), and concentrated to provide the title
compound.
Compound 369B
methyl
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(.s-
up.2H.sub.8)piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate
[1142] In a 100 ml round-bottomed flask, Compound 369A (3.4 g),
Compound 290B (1.321 g) and dichloromethane (3 ml) were added to a
100 ml round bottom flask at room temperature. To a separate 50 ml
3 neck round bottom flask, sodium triacetoxyborohydride (1.330 g)
and dichloromethane (12 ml) were added to give a slurry. After
cooling the 50 ml round bottom flask to 18-20.degree. C., the
piperazine adduct/aldehyde solution was added via syringe over 5
minutes. The triacetoxyborohydride gradually dissolved to give a
clear solution after .about.5 minutes. After an additional 10
minutes, the solution became hazy. After 16 hours, the reaction was
cooled to 5-10.degree. C. Saturated aqueous NaHCO.sub.3 (12 ml) was
added over 5 minutes maintaining the temperature at no more than
10.degree. C. The layers were separated and the organic layer was
washed with saturated aqueous NaHCO.sub.3, and 10% NaCl (12 ml),
and then filtered through Na.sub.2SO.sub.4 and rinsed with
dichloromethane (4 ml). The solution was concentrated on a rotovap,
and chase concentrated with methanol (40 ml). The resulting
solution was cooled to 5-10.degree. C., and the product
precipitated. The solution was mixed at room temperature for 30
minutes, then filtered and rinsed with methanol (5 ml), and the
product was air dried.
Compound 369C
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(.sup.2H.s-
ub.8)piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic
acid
[1143] The title compound was prepared by substituting Compound
369B for Compound 15G in the procedure for Compound 15H.
Compound 369D
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(.sup.2H.s-
ub.8)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1144] To a mixture of Compound 369C (2.0 g), Compound 1F (1.1 g)
and N,N-dimethylpyridin-4-amine (0.7 g) in dichloromethane (20 ml)
was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide
hydrochloride (0.8 g). The reaction mixture was stirred at room
temperature overnight. The reaction was quenched with
N,N-dimethylethane-1,2-diamine (0.6 g) and stirred at room
temperature for 3 hours. The mixture was extracted with 20% aqueous
acetic acid and washed with 5% aqueous NaCl. Methanol (2 ml) and
ethyl acetate (18 ml) were added and the precipitate was collected
by filtration to provide the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) 11.71 (s, 1H), 11.37 (s, br, 1H), 8.60
(t, 1H), 8.55 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.47-7.54 (m,
3H), 7.31-7.34 (m, 2H), 7.09 (d, 1H), 7.01-7.03 (m, 2H), 6.67 (dd,
1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.83 (dd, 2H), 3.21-3.30 (m, 4H),
3.00-3.10 (s, 4H), 2.75 (s, 2H), 2.05-2.24 (m, 6H), 1.95 (s, 2H),
1.80-1.93 (m, 1H), 1.55-1.64 (m, 2H), 1.37 (t, 2H), 1.18-1.31 (m,
2H), 0.90 (s, 6H).
Compound 370
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[3-(tetrahydro-2H-pyran-4-yl-
methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl]sulfonyl}benzamide
Compound 370A
5-amino-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide
[1145] A mixture of Compound 364E (0.16 g) and 5% palladium on
carbon (0.025 g) in ethanol (5 ml) was treated with a balloon of
hydrogen. The reaction mixture was stirred overnight. The solid was
filtered off. The filtrate was concentrated. The residue was
purified by flash chromatography on silica gel to give the title
compound.
Compound 370B
3-((tetrahydro-2H-pyran-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-s-
ulfonamide
[1146] Compound 370A (0.085 g) in water (10 ml) was treated with
concentrated H.sub.2SO.sub.4 (0.5 ml). The solution was cooled to
0.degree. C. To this solution was added NaNO.sub.2 (0.023 g) in
water (1 ml) dropwise. The solution was stirred for 1 hour at
0.degree. C. The reaction mixture was poured into saturated
NaHCO.sub.3 solution, and extracted with ethyl acetate three times.
The combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated to give the title
compound.
Compound 370C
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-((tetrahydro-2H-pyran-4-yl)me-
thyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-ylsulfonyl)benzamide
[1147] This compound was prepared by substituting Compound 370B for
Compound 11B in the procedure for Compound 11D. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.60 (s, 1H), 9.11 (s,
1H), 8.92 (d, 1H), 7.96 (d, 1H), 7.55 (d, 1H), 7.45-7.46 (m, 1H),
7.42 (s, 1H), 7.36 (d, 2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.32 (s,
1H), 6.22 (s, 1H), 4.63 (d, 2H), 3.80 (dd, 2H), 3.21-3.30 (m, 2H),
3.16 (s, 4H), 2.83 (s, 2H), 2.19-2.29 (m, 6H), 1.97 (s, 2H),
1.33-1.41 (m, 6H), 0.93 (s, 2H).
Compound 371
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(6-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyr-
idin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 371A
6-((trans-4-hydroxy-4-methylcyclohexyl)methylamino)-5-nitropyridine-3-sulf-
onamide
[1148] This compound was prepared by substituting Compound 364D for
4-fluoro-3-nitrobenzenesulfonamide and Compound 376B for Compound
138C in the procedure for Compound 138D. The title compound was
isolated by reverse phase Gilson Prep HPLC system with a Phenomenex
prep column (Luna, 5 n, C18(2), 250.times.21.20 mm, 5 .ANG.)
eluting with 20-80% acetonitrile in water with 0.1% TFA.
Compound 371B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(6-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyr-
idin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1149] The title compound was prepared by substituting Compound
371A for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.63 (s, 1H),
11.53-10.99 (m, 1H), 8.91 (s, 1H), 8.71 (dd, 2H), 8.01 (d, 1H),
7.61-7.44 (m, 3H), 7.44-7.28 (m, 2H), 7.12-6.97 (m, 2H), 6.76-6.61
(m, 1H), 6.36 (dd, 1H), 6.21 (d, 1H), 3.92 (s, 1H), 3.48 (t, 2H),
3.10 (s, 4H), 2.83 (s, 2H), 2.24 (dd, 6H), 1.96 (s, 2H), 1.37 (ddd,
11H), 1.07 (s, 3H), 0.93 (s, 6H).
Compound 372
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(5-cyano-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyrid-
in-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 372A
ethyl 4-fluoro-1-(oxetan-3-yl)piperidine-4-carboxylate
[1150] To 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate
(1.00 g) was added HCl (4.0M in dioxane, 4.54 ml). After 1 hour the
reaction was concentrated and dried under high vacuum. The
resulting solid was dissolved in dichloromethane (5 ml) and treated
with sodium triacetoxyborohydride (1.155 g) and oxetan-3-one (0.262
g) and stirred overnight. The reaction was quenched with saturated
NaHCO.sub.3 solution (20 ml) and extracted into dichloromethane
(2.times.25 ml). The organic layer was dried over magnesium
sulfate, filtered, and concentrated. Silica gel chromatography
(Reveleris 80 g) eluting with a gradient of 0.5% to 3.75%
methanol/dichloromethane over 40 minutes (flow=30 ml/minute) gave
the title compound.
Compound 372B
(4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methanol
[1151] To a solution of Compound 372A (0.59 g) in tetrahydrofuran
(5 ml) was added lithium aluminum hydride (1.80 ml) at 0.degree. C.
The reaction was removed from the ice bath and allowed to warm to
room temperature. The reaction was quenched by the dropwise
addition of 0.6 ml of water followed by 0.2 ml of 2N aqueous NaOH.
The reaction was filtered through diatomaceous earth and rinsed
with ethyl acetate (50 ml). The organics were concentrated and
loaded onto silica gel (Reveleris 40 g) and eluted using a gradient
of 0.75% to 7.5% methanol/dichloromethane over 30 minute (flow=40
ml/minutes) to give the title compound.
Compound 372C
5-bromo-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridine-3-sulf-
onamide
[1152] This compound was prepared by substituting Compound 372B for
(tetrahydro-2H-pyran-4-yl)methanol and Compound 36A for
4-fluoro-3-nitrobenzenesulfonamide in the procedure for Compound
24A.
Compound 372D
5-cyano-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridine-3-sulf-
onamide
[1153] This compound was prepared by substituting Compound 372C for
Compound 36B in the procedure for Compound 36C.
Compound 372E
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(5-cyano-6-((4-fluoro-1-(oxetan--
3-yl)piperidin-4-yl)methoxy)pyridin-3-ylsulfonyl)benzamide
[1154] The title compound was prepared by substituting Compound
372D for Compound 11B in the procedure for Compound 11D. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.58 (s, 1H),
8.71 (s, 1H), 8.52 (s, 1H), 7.96 (d, 1H), 7.57 (d, 1H), 7.48-7.30
(m, 4H), 7.06 (d, 2H), 6.68 (d, 1H), 6.37-6.22 (m, 2H), 4.65-4.40
(m, 6H), 3.58 (s, 1H), 3.12 (s, 6H), 2.84-2.59 (m, 4H), 2.17 (s,
6H), 1.96 (d, 6H), 1.41 (s, 2H), 0.93 (s, 6H).
Compound 373
N-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitr-
ophenyl)morpholine-4-carboxamide
Compound 373A
morpholine-4-carboxamide
[1155] A solution of morpholine-4-carbonyl chloride (2.0 g) in
methanol (10 ml) and 7 N NH.sub.3 in methanol (5 ml) was stirred at
45.degree. C. overnight. The mixture was concentrated to give a
solid, which was dried under vacuum.
Compound 373B
N-(2-nitro-4-sulfamoylphenyl)morpholine-4-carboxamide
[1156] This compound was prepared by substituting Compound 373A for
(tetrahydro-2H-pyran-4-yl)methanol in the procedure for Compound
24A.
Compound 373C
N-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitro-
phenyl)morpholine-4-carboxamide
[1157] This compound was prepared by substituting Compound 373B for
Compound 130C in the procedure for Compound 130D. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 13.02 (s, 1H), 10.41 (s, 1H), 9.27
(d, 1H), 8.81 (d, 1H), 8.50 (dd, 1H), 8.40 (d, 1H), 8.09 (d, 1H),
7.65 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.76 (dd, 1H), 6.54 (d,
1H), 6.48 (m, 1H), 3.67 (m, 4H), 3.58 (m, 4H), 3.07 (m, 4H), 2.77
(s, 2H), 2.26 (t, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H),
0.94 (s, 6H).
Compound 374
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(methoxymethyl)cyclohexyl]methyl}amino)-3-nitrophenyl]sul-
fonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 374A
(4,4-diethoxycyclohexyl)methanol
[1158] Ethyl 4,4-diethoxycyclohexanecarboxylate (6.67 g)
synthesized according to a literature procedure (European Journal
of Organic Chemistry (2008) 5:895) in tetrahydrofuran (60 ml) was
treated with 2 M lithium aluminum hydride in tetrahydrofuran (14.5
ml) at 0.degree. C. for 1 hour. Water (3 ml) was slowly added to
quench the reaction. The precipitates were filtered off and washed
with ethyl acetate. The filtrate was dried over Na.sub.2SO.sub.4,
filtered, and concentrated to provide the title compound.
Compound 374B
1,1-diethoxy-4-(methoxymethyl)cyclohexane
[1159] Compound 374A (665 mg) in tetrahydrofuran (20 ml) was
treated with NaH (394 mg) for 30 minutes and then CH.sub.3I (0.267
ml) was slowly added. The resulting mixture was stirred overnight
and the reaction was quenched with a few drops of water. The
mixture was concentrated and the residue was suspended in water and
extracted with dichloromethane. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography, and was eluted with 0-15% ethyl
acetate in dichloromethane to provide the title compound.
Compound 374C
4-(methoxymethyl)cyclohexanone
[1160] Compound 374B (2.2 g) in a mixture of water (3 ml) and
acetic acid (12 ml) was heated at 65.degree. C. for 2 hours. The
reaction mixture was concentrated. The residue was mixed with water
and saturated aqueous NaHCO.sub.3 and extracted with
dichloromethane. The dichloromethane layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide the title
compound.
Compound 374D
4-(methoxymethyl)cyclohexanecarbonitrile
[1161] To a cold (-10.degree. C.) solution of Compound 374C (1.18
g) and toluenesulfonylmethyl isocyanide (2.268 g) in
dimethoxyethane (3 ml) and absolute ethanol (0.1 ml) was added (in
small portions) potassium tert-butoxide (2.235 g). The reaction
mixture was continued to stir at <5.degree. C. for 30 minutes,
warmed to room temperature, heated at 35.degree. C. for 30 minutes
and then at room temperature for 2 hours. The reaction mixture was
concentrated and the residue was dissolved in water-brine, and
extracted with dichloromethane. The dichloromethane layer was
purified by flash chromatography, and was eluted with 5% ethyl
acetate in dichloromethane to provide the title compound.
Compound 374E
(4-(methoxymethyl)cyclohexyl)methanamine
[1162] To a solution of Compound 374D (460 mg) in tetrahydrofuran
(15 ml) was added 2M lithium aluminum hydride in tetrahydrofuran
(2.252 ml) slowly. The reaction mixture was stirred at room
temperature for 1 hour, refluxed for 1 hour and cooled. 2 ml of 2M
aqueous NaOH and water (5 ml) was added. The solid was filtered off
and washed with ether. The filtrate was concentrated. The residue
was mixed with dichloromethane (50 ml) and the resulting mixture
was dried over Na.sub.2SO.sub.4 and concentrated to provide the
title compound.
Compound 374F
4-((4-(methoxymethyl)cyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[1163] Compound 374E (450 mg) and
4-fluoro-3-nitrobenzenesulfonamide (693 mg) in tetrahydrofuran (10
ml) were stirred overnight. The reaction mixture was concentrated
and the residue was suspended in a mixture of CH.sub.3CN, methanol
and water. The precipitates were collected, washed with water and
dried to give the title compound.
Compound 374G
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((4-(methoxymethyl)cyclohexyl-
)methylamino)-3-nitrophenylsulfonyl)benzamide
[1164] The title compound was prepared as described in the
procedure for Compound 11D using Compound 374F in place of Compound
11B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69
(s, 1H), 11.40 (s, 1H), 8.53-8.61 (m, 2H), 8.04 (d, 1H), 7.77-7.82
(m, 1H), 7.47-7.55 (m, 3H), 7.34 (d, 2H), 7.02-7.09 (m, 3H), 6.68
(dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.18-3.27 (m, 5H), 3.04-3.14
(m, 5H), 2.75 (s, 2H), 2.11-2.24 (m, 6H), 1.95 (s, 2H), 1.69-1.84
(m, 3H), 1.33-1.63 (m, 7H), 0.84-1.05 (m, 9H).
Compound 375
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(5-chloro-6-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]methoxy}pyridin--
3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 375A
methyl 1-(thiazol-2-yl)piperidine-4-carboxylate
[1165] A mixture of methyl piperidine-4-carboxylate (2.045 g),
2-bromothiazole (1.64 g), and Cs.sub.2CO.sub.3 (5.86 g) in
dimethylformamide (15 ml) was heated at 100.degree. C. overnight.
After it cooled to room temperature, the reaction mixture was
partitioned between water and ethyl acetate. The organic layer was
separated, and 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 to give
the title compound.
Compound 375B
(1-(thiazol-2-yl)piperidin-4-yl)methanol
[1166] This compound was prepared by substituting Compound 375A for
Compound 339A in the procedure for Compound 339B.
Compound 375C
5-chloro-6-((1-(thiazol-2-yl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide
[1167] This compound was prepared by substituting Compound 375B for
(tetrahydro-2H-pyran-4-yl)methanol and Compound 40A for Compound
36A in the procedure for Compound 36B.
Compound 375D
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(5-chloro-6-((1-(thiazol-2-yl)piper-
idin-4-yl)methoxy)pyridin-3-ylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide
[1168] This compound was prepared by substituting Compound 375C for
Compound 11B in the procedure for Compound 11D. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H), 8.49 (s,
1H), 8.17 (s, 1H), 8.01 (d, 1H), 7.54 (d, 1H), 7.48-7.49 (m, 2H),
7.35 (d, 2H), 7.14 (d, 1H), 7.05 (d, 2H), 6.80 (d, 1H), 6.67 (dd,
1H), 6.38 (dd, 1H), 6.21 (d, 1H), 4.28 (d, 2H), 3.92 (d, 2H),
2.98-3.10 (m, 6H), 2.86 (s, 2H), 2.30 (m, 4H), 2.03-2.15 (m, 3H),
1.96 (s, 2H), 1.96 (s, 2H), 1.82-1.86 (m, 2H), 1.33-1.44 (m, 4H),
0.93 (s, 6H).
Compound 376
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyrid-
in-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 376A
tert-butyl (4-hydroxy-4-methylcyclohexyl)methylcarbamate
[1169] A solution of tert-butyl (4-oxocyclohexyl)methylcarbamate
(1.00 g) was dissolved in tetrahydrofuran (20 ml) and cooled to
-78.degree. C. Methylmagnesium bromide (4.40 ml) was added
dropwise. The reaction was stirred for 2 hours at -78.degree. C.
then allowed to warm to 0.degree. C. and stirred for 30 minutes.
The resulting suspension was quenched with water (10 ml), diluted
with ether (50 ml), washed with ammonium chloride (25 ml), washed
with brine (25 ml), dried over magnesium sulfate, filtered, and
concentrated. Silica gel chromatography (Reveleris 80 g) eluting
using a gradient of 5% to 50% ethyl acetate/dichloromethane over 30
minutes (flow=60 ml/min) gave the title compound as a .about.2:1
mixture of cis and trans isomers.
Compound 376B
4-(aminomethyl)-1-methylcyclohexanol
[1170] To a solution of Compound 376A (0.75 g) in dichloromethane
(3 ml) was added a few drops of water followed by trifluoroacetic
acid (1.19 ml) and the reaction stirred at room temperature. After
stirring for 2 h added added additional trifluoroacetic acid (0.5
ml). After an additional 4 h the reaction was concentrated and
dried under high vacuum. The resulting oily solid was triturated
with diethyl ether with sonication. Filtration and washing with
diethyl ether gave the title compound as a trifluoroacetic acid
salt and a mixture of cis and trans isomers.
Compound 376C
6-((cis-4-hydroxy-4-methylcyclohexyl)methylamino)-5-nitropyridine-3-sulfon-
amide
[1171] This compound was prepared by substituting Compound 364D for
4-fluoro-3-nitrobenzenesulfonamide and Compound 376B for
(4-fluorotetrahydro-2H-pyran-4-yl)methanamine in the procedure for
Compound 138D. The title compound was isolated by reverse phase
Gilson Prep HPLC system with a Phenomenex prep column (Luna, 5.mu.,
C18(2), 250.times.21.20 mm, 5 .ANG.) eluting with 20-80%
acetonitrile in water with 0.1% TFA.
Compound 376D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyrid-
in-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1172] This compound was prepared by substituting Compound 376C for
Compound 11B in the procedure for Compound 11D. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.64 (s, 1H), 8.91 (s,
1H), 8.72 (d, 1H), 8.70 (d, 1H), 8.01 (d, 1H), 7.47-7.54 (m, 3H),
7.35 (d, 2H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.36 (dd, 1H), 6.21 (d,
1H), 3.93 (s, 1H), 3.48 (t, 2H), 3.10 (s, 4H), 2.83 (s, 2H),
2.15-2.33 (m, 6H), 1.96 (s, 1H), 1.34-1.59 (m, 9H), 1.17-1.24 (m,
2H), 1.07 (s, 2H), 0.92 (s, 6H).
Compound 377
4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-ni-
trophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[1173] The title compound was prepared by substituting Compound
378D for Compound 1E and Compound 337M for Compound 1F in the
procedure for Compound 1G. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 13.07 (s, 1H), 9.31 (d, 1H), 8.68 (t, 1H), 8.44 (d, 1H),
8.37 (dd, 1H), 8.10 (d, 1H), 7.68 (m, 1H), 7.66 (d, 1H), 7.41 (m,
2H), 7.09 (m, 2H), 6.92 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.50
(dd, 1H), 3.20 (m, 5H), 3.06 (t, 4H), 2.77 (m, 2H), 2.57 (d, 1H),
2.49 (m, 1H), 2.17 (m, 6H), 1.86 (m, 5H), 1.69 (m, 4H), 1.40 (s,
3H), 1.23 (m, 5H).
Compound 378
4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Compound 378A
2-chloro-5-methoxy-5-methylcyclohex-1-enecarbaldehyde
[1174] Dimethylformamide (1.298 ml) in dichloromethane (2.0 ml) at
-10.degree. C. was treated dropwise with POCl.sub.3 (1.426 ml) to
give a colorless solution. The mixture was stirred 5 minutes and
then warmed to room temperature and stirred 30 minutes. The
solution was cooled to -10.degree. C., treated dropwise with a
solution of 4-methoxy-4-methylcyclohexanone (1.74 g) in
dichloromethane (2.5 ml), and stirred for 4 hours at ambient
temperature. The reaction mixture was poured over a mixture of ice
and 25% aqueous sodium acetate solution. After the ice melted, the
reaction mixture was poured into a separatory funnel and extracted
with diethyl ether (4.times.125 ml). The diethyl ether extracts
were washed with NaHCO.sub.3 solution and brine, dried
(MgSO.sub.4), filtered and concentrated. The concentrate was
chromatographed on silica gel with 0 to 5% ethyl acetate in hexanes
as the eluent.
Compound 378B
2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-enecarbaldehyde
[1175] Compound 378A (1.55 g), 4-chlorophenylboronic acid (1.542
g), PdOAc.sub.2 (0.055 g), K.sub.2CO.sub.3 (2.84 g) and
tetrabuylammonium bromide (2.65 g) were combined in a 50-ml
round-bottomed flask equipped with a magnetic stir bar. Water (9.13
ml) was added. The vial was flushed with nitrogen, capped and
stirred at 45.degree. C. for 14 hours. The reaction mixture was
cooled to room temperature and partitioned between brine and
diethyl ether. The organic layer was washed with brine, dried
(MgSO.sub.4), filtered through a plug of celite, concentrated and
chromatographed on silica gel with 5 to 20% ethyl acetate in
hexanes as the eluent.
Compound 378C
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-me-
thoxy-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[1176] The title compound was prepared by substituting Compound
378B for 4'-chlorobiphenyl-2-carboxaldehyde and Compound 15F for
tert-butyl piperazine-1-carboxylate in the procedure for Compound
1A except that a small amount of DMSO was added to the reaction
mixture.
Compound 378D
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-methoxy-5-
-methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[1177] The title compound was prepared by substituting Compound
378C for Compound 15G in the procedure for Compound 15H.
Compound 378E
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-methoxy-5-
-methylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-
-pyran-4-yl)methylamino)phenylsulfonyl)benzamide
[1178] The title compound was prepared by substituting Compound
378D for Compound 1E in the procedure for Compound 1G. .sup.1H NMR
(500 MHz, pyridine-d.sub.5) .delta. 13.07 (s, 1H), 9.31 (d, 1H),
8.68 (t, 1H), 8.43 (d, 1H), 8.37 (dd, 1H), 8.09 (d, 1H), 7.68 (m,
1H), 7.66 (d, 1H), 7.41 (m, 2H), 7.09 (m, 2H), 6.90 (d, 1H), 6.74
(dd, 1H), 6.52 (d, 1H), 6.50 (dd, 1H), 3.97 (dd, 2H), 3.30 (td,
2H), 3.21 (s, 3H), 3.15 (m, 2H), 3.06 (t, 4H), 2.77 (m, 2H), 2.57
(d, 1H), 2.50 (m, 1H), 2.16 (m, 6H), 1.81 (m, 2H), 1.63 (m, 1H),
1.57 (dd, 2H), 1.32 (m, 2H), 1.21 (s, 3H).
[1179] Table 1 below presents the inhibition constant (K.sub.i) for
binding of representative compounds to Bcl-2 protein, as determined
by a TR-FRET (Time-Resolved Fluorescence-Resonance-Energy-Transfer)
assay. The smaller the K.sub.i value, the greater is the binding
affinity. It will be noted that the overwhelming majority of the
compounds have K.sub.i<0.0001 .mu.M (<0.1 nM), and very many
have K.sub.i<0.00001 .mu.M (<0.01 nM).
TABLE-US-00001 TABLE 1 Bc1-2 binding K.sub.i (.mu.M) Compound Ki
Compound Ki 1 0.000225 190 0.000026 2 <0.000010 191 <0.000010
3 0.000013 192 <0.000010 4 <0.000010 193 <0.000010 5
<0.000010 194 <0.000010 6 0.000018 195 <0.000010 7 0.00492
196 <0.000010 8 0.000153 197 <0.000010 9 <0.000010 198
<0.000010 10 <0.000010 199 <0.000010 11 0.000016 200
<0.000010 12 <0.000010 201 0.000014 13 <0.000010 202
<0.000010 14 0.002798 203 <0.000010 15 <0.000010 204
<0.000010 16 0.000219 205 <0.000010 17 0.00009 206 0.000036
18 0.000017 207 0.00003 19 0.000226 208 0.000104 20 0.000181 209
<0.000010 21 0.000912 210 0.000011 22 0.000291 211 0.000058 23
0.000083 212 0.0001330 24 <0.000010 213 <0.000010 25
<0.000010 214 <0.000010 26 0.000011 215 <0.000010 27
0.000134 216 <0.000010 28 <0.000010 217 <0.000010 29
<0.000010 218 0.000013 30 <0.000010 219 0.001192 31
<0.000010 220 0.000988 32 <0.000010 221 0.000049 33
<0.000010 222 0.000938 34 0.00001 223 0.000053 35 <0.000010
224 <0.000010 36 0.000017 225 0.000196 37 <0.000010 226
0.000139 38 0.0003 227 <0.000010 39 0.000012 228 0.026761 40
<0.000010 229 0.002109 41 <0.000010 230 0.000031 42 0.000439
231 0.000770 43 0.000012 232 0.001631 44 <0.000010 233 0.001654
45 <0.000010 234 0.000115 46 0.000935 235 0.000023 47
<0.000010 236 0.000033 48 <0.000010 237 0.000024 49 0.000074
238 <0.000010 50 0.000021 239 0.000026 51 <0.000010 240
<0.000010 52 0.000114 241 <0.000010 53 <0.000010 242
0.000057 54 0.002071 243 0.000546 55 <0.000010 244 0.000281 56
0.000037 245 0.000015 57 0.000063 246 0.000144 58 <0.000010 247
0.000019 59 0.000203 248 0.000029 60 <0.000010 250 0.000412 61
0.000091 251 0.000571 62 <0.000010 252 <0.000010 63
<0.000010 253 0.000052 64 <0.000010 254 <0.000010 65
<0.000010 255 <0.000010 66 <0.000010 256 <0.000010 67
<0.000010 257 0.000052 68 0.000012 258 <0.000010 69 0.001157
259 <0.000010 70 0.003964 260 0.000016 71 0.00001 261 0.000134
72 <0.000010 262 <0.000010 73 <0.000010 263 0.000156 74
0.000029 264 0.000036 75 <0.000010 265 <0.000010 76 0.000196
266 <0.000010 77 0.000213 267 0.000035 78 <0.000010 268
<0.000010 79 <0.000010 269 0.000016 80 <0.000010 270
<0.000010 81 <0.000010 271 0.000039 82 0.000328 272 0.000031
83 0.000071 273 0.000035 84 0.000123 274 0.000040 85 0.000391 275
<0.000010 86 0.000498 276 <0.000010 87 0.000618 277
<0.000010 88 0.000672 278 0.000252 89 0.000073 279 0.000035 90
0.000013 280 0.000071 91 0.000487 281 0.000145 92 0.000128 282
<0.000010 93 0.003461 283 <0.000010 94 0.000678 284 0.000024
95 0.000014 285 <0.000010 96 0.000014 286 <0.000010 97
0.000017 287 0.000081 98 <0.000010 288 0.000251 99 0.000233 289
0.000090 100 <0.000010 290 <0.000010 101 0.000021 291
<0.000010 102 0.000094 292 0.000190 103 <0.000010 293
0.000093 104 0.000016 294 0.000046 105 <0.000010 295
<0.000010 106 0.000895 296 0.000512 107 0.000035 297 0.000174
108 <0.000010 298 <0.000010 109 0.000127 299 0.000039 110
0.000557 300 0.001627 111 <0.000010 301 0.002065 112
<0.000010 302 0.000332 113 <0.000010 303 0.000044 114
<0.000010 304 nd 115 <0.000010 305 0.000033 116 <0.000010
306 0.002067 117 <0.000010 307 0.000130 118 <0.000010 308
0.000141 119 <0.000010 309 0.000023 120 <0.000010 310
0.000165 121 <0.000010 311 <0.000010 122 <0.000010 312
<0.000010 123 <0.000010 313 0.001102 124 <0.000010 314
0.000042 125 <0.000010 315 0.000052 126 <0.000010 316
0.000601 127 <0.000010 317 <0.000010 128 <0.000010 318
<0.000010 129 0.000002 319 <0.000010 130 <0.000010 320
<0.000010 131 <0.000010 321 <0.000010 132 <0.000010 322
<0.000010 133 <0.000010 323 0.000104 134 <0.000010 324
<0.000010 135 <0.000010 325 <0.000010 136 <0.000010 326
<0.000010 137 <0.000010 327 <0.000010 138 <0.000010 328
<0.000010 139 <0.000010 329 0.000030 140 <0.000010 330
<0.000010 141 <0.000010 331 0.001086 142 0.00013 332 0.000621
143 <0.000010 333 0.000511 144 <0.000010 334 0.000572 145
<0.000010 335 0.000150 146 <0.000010 336 0.000198 147
<0.000010 337 <0.000010 148 <0.000010 338 0.000013 149
<0.000010 339 0.000036 150 <0.000010 340 <0.000010 151
0.000017 341 <0.000010 152 <0.000010 342 <0.000010 153
<0.000010 343 <0.000010 154 <0.000010 344 <0.000010 155
0.000059 345 <0.000010 156 <0.000010 346 0.000042 157
<0.000010 347 0.000013 158 <0.000010 348 0.000034 159
<0.000010 349 0.000023 160 <0.000010 350 <0.000010 161
<0.000010 351 <0.000010 162 <0.000010 352 0.000014 163
<0.000010 353 <0.000010 164 <0.000010 354 0.000010 165
<0.000010 355 0.000014 166 <0.000010 356 0.000039 167
<0.000010 357 <0.000010 168 <0.000010 358 <0.000010 169
0.000021 359 <0.000010 170 0.000022 360 <0.000010 171
<0.000010 361 <0.000010 172 <0.000010 362 0.000016 173
<0.000010 363 0.000017 174 <0.000010 364 <0.000010 175
0.000119 365 <0.000010 176 0.000023 366 0.000024 177 0.000111
367 nd 178 0.000076 368 nd 179 <0.000010 369 <0.000010 180
<0.000010 370 0.000285 181 0.000017 371 <0.0000010 182
0.000068 372 nd 183 <0.000010 373 <0.0000010 184 <0.000010
374 <0.0000010 185 0.000022 375 0.00010999 186 0.000047 376
<0.0000010 187 0.00008 377 <0.0000010 188 <0.000010 378
<0.0000010 189 0.000018 nd = not determined
[1180] Table 2 below presents data for log D (a parameter related
to lipophilicity) at pH 7.4, as determined by an HPLC method, for
representative compounds. It will be noted that all compounds have
high log D values (most in excess of 5.3), indicating a high degree
of lipophilicity and very poor solubility in water at pH 7.4.
TABLE-US-00002 TABLE 2 log D at pH 7.4 Compound log D 5 5.37 6 5.74
9 5.71 12 5.17 18 6.35 20 6.24 24 5.72 37 5.27 87 5.86 89 6.21 90
6.69 91 6.59 92 5.60 120 5.40 208 5.57 239 5.92 242 5.51 276 5.59
277 5.26 286 5.66 303 6.24 311 5.60 312 6.47 322 5.48 337 5.48 338
5.67
[1181] B. Exemplary Compounds
[1182] Compounds believed to be particularly useful in preparation
of solid dispersions of the invention include without limitation:
[1183]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpipe-
ridin-4-yl)amino]phenyl}-sulfonyl)benzamide--Compound 89; [1184]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrop-
henyl}sulfonyl)-benzamide--Compound 91; [1185]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 5;
[1186]
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 9;
[1187]
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 29;
[1188]
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 34;
[1189]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 37;
[1190]
N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-
-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compoun-
d 277; [1191]
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3--
yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
61; [1192]
4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
378; [1193]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitr-
ophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
149; [1194]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitroph-
enyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
337;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitr-
ophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
338;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-{[4-({3-[cyclopropyhoxetan-3-yl)amino]propyl}amino)-3-nitrop-
henyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
311; [1195]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]met-
hyl}amino)phenyl]-sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--
-Compound 118; [1196]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 134;
[1197]
N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
253; [1198]
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
108; [1199]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
234; and pharmaceutically acceptable salts thereof.
[1200] C. Compound Forms
[1201] In some embodiments, a compound of Formula I is present in
the solid dispersion in its parent-compound form, alone or together
with a salt form of the compound.
[1202] Compounds of Formula I may form acid addition salts, basic
addition salts or zwitterions. Salts of compounds of Formula I can
be prepared during isolation or following purification of the
compounds.
[1203] Acid addition salts are those derived from reaction of a
compound of Formula I with an acid. For example, salts including
the acetate, adipate, alginate, ascorbate, bicarbonate, citrate,
aspartate, benzoate, benzenesulfonate (besylate), bisulfate,
butyrate, camphorate, camphorsulfonate, digluconate,
ethanedisulfonate, formate, fumarate, glycerophosphate, glutamate,
hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride,
hydroiodide, 1-hydroxy-2-naphthoate, lactate, lactobionate, malate,
maleate, malonate, mesitylenesulfonate, methanesulfonate,
naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,
persulfate, phosphate, picrate, propionate, succinate, sulfate,
tartrate, thiocyanate, trichloroacetate, trifluoroacetate,
para-toluenesulfonate and undecanoate salts of a compound of
Formula I can be used in a composition of the invention.
[1204] Basic addition salts, including those derived from reaction
of a compound with the bicarbonate, carbonate, hydroxide or
phosphate of cations such as lithium, sodium, potassium, calcium
and magnesium, can likewise be used.
[1205] A compound of Formula I typically has more than one
protonatable nitrogen atom and is consequently capable of forming
acid addition salts with more than one, for example about 1.2 to
about 2, about 1.5 to about 2 or about 1.8 to about 2, equivalents
of acid per equivalent of the compound.
[1206] A compound of Formula I typically has more than one
protonatable nitrogen atom and is consequently capable of forming
acid addition salts with more than one, for example about 1.2 to
about 2, about 1.5 to about 2 or about 1.8 to about 2, equivalents
of acid per equivalent of the compound.
[1207] Without being bound by theory, it is believed that the
therapeutic efficacy of compounds of Formula I is due at least in
part to their ability to bind to a Bcl-2 family protein such as
Bcl-2, Bcl-X.sub.L or Bcl-w in a way that inhibits the
anti-apoptotic action of the protein, for example by occupying the
BH3 binding groove of the protein. It will generally be found
desirable to select a compound having high binding affinity for a
Bcl-2 family protein, for example a K.sub.i<1 nM, preferably
<0.1 nM, more preferably <0.01 nM.
[1208] A compound of Formula I or a salt thereof is present in a
solid dispersion of the invention in an amount that can be
therapeutically effective when the composition is administered to a
subject in need thereof according to an appropriate regimen. Dosage
amounts are expressed herein as parent-compound-equivalent amounts
unless the context requires otherwise. Typically, a unit dose (the
amount administered at a single time), which can be administered at
an appropriate frequency, e.g., twice daily to once weekly, is
about 10 to about 1,000 mg, depending on the compound in question.
Where frequency of administration is once daily (q.d.), unit dose
and daily dose are the same. Illustratively, the unit dose is
typically about 25 to about 1,000 mg, more typically about 50 to
about 500 mg, for example about 50, about 100, about 150, about
200, about 250, about 300, about 350, about 400, about 450 or about
500 mg. Where the dosage form comprises a capsule shell enclosing
the solid dispersion, or a tablet wherein the solid dispersion is
formulated with other ingredients, a unit dose can be deliverable
in a single dosage form or a plurality of dosage forms, most
typically 1 to about 10 dosage forms.
[1209] D. Formulations
[1210] The higher the unit dose, the more desirable it becomes to
prepare a solid dispersion having a relatively high concentration
of the drug therein. Typically, the concentration of drug in the
solid dispersion is at least about 1%, e.g., about 1% to about 50%,
by parent-compound-equivalent weight, but lower and higher
concentrations can be acceptable or achievable in specific cases.
Illustratively, the drug concentration in various embodiments is at
least about 2%, e.g., about 2% to about 50%, or at least about 5%,
e.g., about 5% to about 40%, for example about 5%, about 10%, about
15%, about 20%, about 25%, about 30%, about 35% or about 40%, by
parent-compound-equivalent weight. In some embodiments, the drug
concentration may be between about 5% and about 15%, such as
between about 5% and about 12%, such as about 5%, about 6%, about
7%, about 8%, about 9%, about 10%, about 11%, or about 12%.
[1211] The major component of the matrix of a solid dispersion
product is a polymer that is hydrophilic or water-soluble at least
in a part of the pH scale, more particularly at a pH occurring in
the gastrointestinal (GI) tract, or a combination of such polymers.
A polymer or polymer mixture useful herein is solid at ambient
temperature and, in the interests of good storage stability at a
range of temperatures, should remain solid even at the highest
temperatures typically experienced during storage, transport and
handling of the product. A useful property of a polymer determining
its usefulness herein is therefore its glass transition temperature
(T.sub.g). Suitable water-soluble polymers include, but are not
limited to, those having a T.sub.g of at least about 40.degree. C.,
at least about 50.degree. C., at least about 60.degree. C., or
more, and more particularly about 80.degree. C. to about
180.degree. C. Methods for determining T.sub.g values of organic
polymers are described for example in Sperling, ed. (1992)
Introduction To Physical Polymer Science, 2nd edition, John Wiley
& Sons, Inc.
[1212] Polymers are considered water-soluble if they form a clear
homogeneous solution in water (e.g., a solution that is essentially
uniform throughout, and that appears clear under visual inspection
or alternatively using an instrument such as a turbidimeter, the
solution for example exhibiting little or no scattering of a light
beam going therethrough). When dissolved at 20.degree. C. in an
aqueous solution at 2% (w/v), a suitable water-soluble polymer
illustratively has an apparent viscosity of about 1 to about 5000
mPas, for example about 1 to about 700 mPas, or about 5 to about
100 mPas. Water-dispersable or water-swellable polymers can also be
used.
[1213] Non-limiting examples of polymeric carriers useful herein
include: [1214] homopolymers and copolymers of N-vinyl lactams,
especially homopolymers and copolymers of N-vinyl pyrrolidone,
e.g., the homopolymer polyvinylpyrrolidone (PVP or povidone) and
copolymers such as those comprising monomers of N-vinyl pyrrolidone
and vinyl acetate (copovidone) or N-vinyl pyrrolidone and vinyl
propionate; [1215] cellulose esters and cellulose ethers, in
particular methylcellulose, ethylcellulose,
(hydroxyalkyl)celluloses such as hydroxypropylcellulose,
(hydroxyalkyl)alkyl-celluloses such as hydroxypropylmethylcellulose
(HPMC or hypromellose), cellulose phthalates and succinates such as
cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate
(HPMC-P), hydroxypropylmethylcellulose succinate (HPMC-S) and
hydroxypropylmethylcellulose acetate succinate (HPMC-AS); [1216]
high molecular weight polyalkylene oxides such as polyethylene
oxides (PEGs or PEOs) and copolymers of ethylene oxide and
propylene oxide (poloxamers); [1217] polyacrylates and
polymethacrylates such as methacrylic acid/ethyl acrylate
copolymers, methacrylic acid/methyl methacrylate copolymers, butyl
methacrylate/2-dimethylaminoethyl methacrylate copolymers,
poly(hydroxyalkyl acrylates) and poly(hydroxyalkyl methacrylates);
[1218] polyacrylamides; [1219] vinyl acetate polymers such as
copolymers of vinyl acetate and crotonic acid, polyvinyl acetate,
polyvinyl alcohol and partially hydrolyzed polyvinyl acetate (also
referred to as partially saponified polyvinyl alcohol); [1220]
graft copolymers of polyethylene glycol, polyvinyl caprolactam and
polyvinyl acetate (e.g., Soluplus.TM. of BASF or equivalent
product); [1221] oligo- and polysaccharides such as carrageenans,
galactomannans and xanthan gum; and mixtures of two or more
thereof.
[1222] Suitable povidones include, without limitation, those having
a K-value (a measure of viscosity of an aqueous solution of the
povidone) of about 12, about 15, about 17, about 25, about 30 or
about 90, and mixtures thereof. A particular example of a useful
povidone is povidone (or PVP) K30. A particular example of a useful
copovidone is one consisting of about 60% N-vinyl pyrrolidone and
about 40% vinyl acetate monomers, referred to herein as "copovidone
60/40".
[1223] Another suitable polymer is a mixture of PVP and polyvinyl
acetate, such as that sold under the name Kollidon.TM. SR by BASF
AG. In some embodiments, a vinylpyrrolidone-vinyl acetate copolymer
commercially available as Kollidon VA 64, which is soluble both in
water and in alcohol, is suitable in the formulations of the
present invention.
[1224] Suitable HPMCs and derivatives thereof include, without
limitation, HPMC E3, HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4,
HPMC A15, HPMC-AS LF, HPMC-AS MF, HPMC-AS HF, HPMC-AS LG, HPMC-AS
MG, HPMC-AS HG, HPMC-P 50, HPMC-P 55 and mixtures thereof.
[1225] Suitable ethylcelluloses include, without limitation, those
sold under the Ethocel.TM. trademark of Dow Chemical Company as
Ethocel.TM. 4, Ethocel.TM. 7, Ethocel.TM. 10, Ethocel.TM. 14 and
Ethocel.TM. 20, products of other manufacturers equivalent thereto,
and mixtures thereof.
[1226] Suitable methacrylic acid/methyl methacrylate copolymers
include, without limitation, those sold under the Eudragit.TM.
trademark of Rohm GmbH as Eudragit.TM. L100, Eudragit.TM. L100-55
and Eudragit.TM. S 100, products of other manufacturers equivalent
thereto, and mixtures thereof.
[1227] Suitable PEGs include, without limitation, PEG 400, PEG 600,
PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and
mixtures thereof. Lower molecular-weight PEGs such as PEG 400 and
PEG 600 may be unsuitable as the sole polymeric carrier but can be
useful in combination with other polymers.
[1228] Suitable poloxamers include, without limitation, poloxamer
124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 and
mixtures thereof. It will be noted that poloxamers have surfactant
properties and can be included primarily for these properties as
well as their polymeric nature.
[1229] In one embodiment, the solid dispersion matrix comprises one
or more polymeric carriers selected from the group consisting of
povidones, copovidones, HPMCs, polyethylene glycol/polyvinyl
caprolactam/polyvinyl acetate graft copolymers and mixtures
thereof. In a more particular embodiment, the solid dispersion
matrix comprises one or more polymeric carriers selected from the
group consisting of povidone K30, copovidone 60/40, HPMC E5,
Soluplus.TM. polyethylene glycol/polyvinyl caprolactam/polyvinyl
acetate graft copolymer and products equivalent to Soluplus.TM.
[1230] One or more polymeric carriers typically constitute in total
about 20% to about 95%, such as about 20% to about 90%, for example
about 40% to about 85%, or about 60% to about 85%, or about 70% to
about 85%, or even about 75% to about 85%, by weight of the solid
dispersion.
[1231] Upon oral administration and exposure to GI fluid, it is
believed without being bound by theory that, through interplay
between the polymeric carrier and a surfactant component of the
solid dispersion, a suitable release rate and inhibition of
crystallization or recrystallization of the active ingredient are
provided, thereby permitting bioabsorption.
[1232] The surfactant component can be anionic, non-ionic or can
comprise a combination of anionic and non-ionic surfactants. Useful
pharmaceutically acceptable anionic surfactants include alkyl
sulfates (e.g., sodium lauryl sulfate), alkylcarboxylates,
alkylbenzole sulfates and secondary alkane sulfonates.
[1233] Particularly useful as surfactants herein are
pharmaceutically acceptable non-ionic surfactants, especially those
having a hydrophilic-lipophilic balance (HLB) value of about 12 to
about 18, for example about 13 to about 17, or about 14 to about
16. The HLB system (see Fiedler (2002) Encyclopedia of Excipients,
5th edition, Aulendorf: ECV-Editio-Cantor-Verlag) assigns numeric
values to surfactants, with lipophilic substances receiving lower
HLB values and hydrophilic substances receiving higher HLB
values.
[1234] Non-limiting examples of non-ionic surfactants useful herein
include: [1235] polyoxyethylene castor oil derivatives such as
PEG-35 castor oil (e.g., Cremophor
[1236] EL.TM. of BASF or equivalent product), PEG-40 hydrogenated
castor oil (e.g., Cremophor RH.TM. 40 or equivalent product) and
PEG-60 hydrogenated castor oil (e.g., Cremophor RH.TM. 60 or
equivalent product); [1237] other polyoxyethylene glycerides such
as PEG-32 glyceryl laurate (e.g., Gelucire.TM. 44/14 of Gattefosse
or equivalent product) and PEG-32 glyceryl palmitostearate (e.g.,
Gelucire.TM. 50/13 or equivalent product), and Labrafil M1944 CS
(oleoyl macrogol 6 glycerides prepared by transesterification of
apricot kernel oil with PEG 300); [1238] fatty acid monoesters of
sorbitan, for example sorbitan monooleate (e.g., Span.TM. 80 or
equivalent product), sorbitan monostearate (e.g., Span.TM. 60 or
equivalent product), sorbitan monopalmitate (e.g., Span.TM. 40 or
equivalent product) and sorbitan monolaurate (e.g., Span.TM. 20 or
equivalent product); [1239] other fatty acid esters of sorbitan,
for example, sorbitan tristearate and sorbitan trioleate; [1240]
fatty acid monoesters of polyoxyethylene sorbitan (polysorbates)
such as PEG-20 sorbitan monooleate (polysorbate 80, e.g., Tween.TM.
80 or equivalent product) PEG-20 sorbitan monostearate (polysorbate
60, e.g., Tween.TM. 60 or equivalent product), PEG-20 sorbitan
monopalmitate (polysorbate 40, e.g., Tween.TM. 40 or equivalent
product), or PEG-20 sorbitan monolaurate (polysorbate 20, e.g.,
Tween.TM. 20 or equivalent product); [1241] other fatty acid esters
of polyoxyethylene sorbitan, for example, polyoxyethylene (20)
sorbitan tristearate (Tween 65), polyoxyethylene (20) sorbitan
trioleate (Tween 85); [1242] fatty acid ester of polyalkylene
glycols such as, for example, PEG 660 hydroxy-stearic acid
(polyglycol ester of 12-hydroxystearic acid (70 mol %) with 30 mol
% ethylene glycol); [1243] polyalkoxylated ethers of fatty alcohols
such as, for example, PEG (2) stearyl ether (Brij 72), macrogol 6
cetylstearyl ether or macrogol 25 cetylstearyl ether; [1244] A
tocopheryl compound corresponding to the structure below:
[1244] ##STR00002## [1245] wherein Z is a linking group, R.sup.1
and R.sup.2 are, independently of one another, hydrogen or
C.sub.1-C.sub.4 alkyl and n is an integer from 5 to 100, preferably
10 to 50. Typically, Z is the residue of an aliphatic dibasic acid
such as glutaric, succinic, or adipic acid. Preferably, both
R.sup.1 and R.sup.2 are hydrogen. The preferred tocopheryl compound
is .alpha.-tocopheryl polyethylene glycol succinate, which is
commonly abbreviated as vitamin E-TPGS. Vitamin E-TPGS is a
water-soluble form of natural-source vitamin E prepared by
esterifying d-alpha-tocopheryl acid succinate with polyethylene
glycol 1000; and mixtures of two or more thereof.
[1246] In one embodiment, the solid dispersion comprises one or
more surfactants selected from the group consisting of
polyoxyethylene glycerides (including polyoxyethylene castor oil
derivatives), polysorbates, TPGS and mixtures thereof. In a more
particular embodiment, the solid dispersion matrix comprises one or
more polymeric carriers selected from the group consisting of
PEG-40 hydrogenated castor oil, polysorbate 80, polysorbate 20 and
TPGS.
[1247] One or more surfactants typically constitute in total about
2% to about 25%, for example about 5% to about 20%, such as between
about 5% and about 15%, or between about 5% and about 10%, by
weight of the solid dispersion.
[1248] Other, optional, components of the solid dispersion include,
without limitation, one or more lubricants, glidants or flow
regulators. Such a material, for example colloidal silicon dioxide
or fumed silica (e.g., Aerosil), can reduce adhesion of the
extrudable mixture to the screw and wall of the extruder and can
facilitate the smooth passage of extrudate through the die.
Illustratively, colloidal silicon dioxide can constitute zero to
about 5%, for example about 0.1% to about 2%, by weight of the
solid dispersion. The solid dispersion can also optionally contain
one or more bulking agents (fillers), disintegrants, cosolvents
such as propylene glycol esters of fatty acids (e.g., propylene
glycol laurate), plasticizers and/or stabilizers such as
antioxidants, light stabilizers, free radical scavengers or
antimicrobial agents.
[1249] A dosage form of the invention can consist of, or consist
essentially of, a solid dispersion as described above. However, in
some embodiments a dosage form contains additional excipients and
requires additional processing of the solid dispersion. For
example, the solid dispersion can be ground to a powder and filled
into a capsule shell or molded or compressed to form a tablet, with
additional excipients as may be conventionally used in such dosage
forms.
[1250] Thus orally deliverable solid dosage forms of the invention
include but are not limited to capsules, dragees, granules, pills,
powders and tablets. Excipients commonly used to formulate such
dosage forms include encapsulating materials or formulation
additives such as absorption accelerators, antioxidants, binders,
buffers, coating agents, coloring agents, diluents, disintegrating
agents, emulsifiers, extenders, fillers, flavoring agents,
humectants, lubricants, preservatives, propellants, releasing
agents, sterilizing agents, sweeteners, solubilizers and mixtures
thereof. Many excipients have two or more functions in a
pharmaceutical composition. Characterization herein of a particular
excipient as having a certain function, e.g., diluent,
disintegrant, binding agent, etc., should not be read as limiting
to that function. Further information on excipients can be found in
standard reference works such as Handbook of Pharmaceutical
Excipients, 3rd ed. (Kibbe, ed. (2000), Washington: American
Pharmaceutical Association).
[1251] Suitable diluents illustratively include, either
individually or in combination, lactose, including anhydrous
lactose and lactose monohydrate; lactitol; maltitol; mannitol;
sorbitol; xylitol; dextrose and dextrose monohydrate; fructose;
sucrose and sucrose-based diluents such as compressible sugar,
confectioner's sugar and sugar spheres; maltose; inositol;
hydrolyzed cereal solids; starches (e.g., corn starch, wheat
starch, rice starch, potato starch, tapioca starch, etc.), starch
components such as amylose and dextrates, and modified or processed
starches such as pregelatinized starch; dextrins; celluloses
including powdered cellulose, microcrystalline cellulose,
silicified microcrystalline cellulose, food grade sources of
.alpha.- and amorphous cellulose and powdered cellulose, and
cellulose acetate; calcium salts including calcium carbonate,
tribasic calcium phosphate, dicalcium phosphate (e.g., dibasic
calcium phosphate dihydrate), monobasic calcium sulfate
monohydrate, calcium sulfate and granular calcium lactate
trihydrate; magnesium carbonate; magnesium oxide; bentonite;
kaolin; sodium chloride; and the like. Such diluents, if present,
typically constitute in total about 1% to about 95%, for example
about 5% to about 50%, or about 10% to about 30%, by weight of the
composition. The diluent or diluents selected preferably exhibit
suitable flow properties and, where tablets are desired,
compressibility.
[1252] Microcrystalline cellulose and silicified microcrystalline
cellulose are particularly useful diluents, and are optionally used
in combination with a water-soluble diluent such as mannitol.
Illustratively, a suitable weight ratio of microcrystalline
cellulose or silicified microcrystalline cellulose to mannitol is
about 10:1 to about 1:1, but ratios outside this range can be
useful in particular circumstances.
[1253] Suitable disintegrants include, either individually or in
combination, starches including pregelatinized starch and sodium
starch glycolate; clays; magnesium aluminum silicate;
cellulose-based disintegrants such as powdered cellulose,
microcrystalline cellulose, methylcellulose, low-substituted
hydroxypropylcellulose, carmellose, carmellose calcium, carmellose
sodium and croscarmellose sodium; alginates; povidone;
crospovidone; polacrilin potassium; gums such as agar, guar, locust
bean, karaya, pectin and tragacanth gums; colloidal silicon
dioxide; and the like. One or more disintegrants, if present,
typically constitute in total about 0.2% to about 30%, for example
about 0.5% to about 20%, or about 1% to about 10%, by weight of the
composition.
[1254] Sodium starch glycolate is a particularly useful
disintegrant, and typically constitutes in total about 1% to about
20%, for example about 2% to about 15%, or about 5% to about 10%,
by weight of the composition.
[1255] Binding agents or adhesives are useful excipients,
particularly where the composition is in the form of a tablet. Such
binding agents and adhesives should impart sufficient cohesion to
the blend being tableted to allow for normal processing operations
such as sizing, lubrication, compression and packaging, but still
allow the tablet to disintegrate and the composition to be absorbed
upon ingestion. Suitable binding agents and adhesives include,
either individually or in combination, acacia; tragacanth; glucose;
polydextrose; starch including pregelatinized starch; gelatin;
modified celluloses including methylcellulose, carmellose sodium,
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose,
hydroxyethylcellulose and ethylcellulose; dextrins including
maltodextrin; zein; alginic acid and salts of alginic acid, for
example sodium alginate; magnesium aluminum silicate; bentonite;
polyethylene glycol (PEG); polyethylene oxide; guar gum;
polysaccharide acids; polyvinylpyrrolidone (povidone or PVP), for
example povidone K-15, K-30 and K-29/32; polyacrylic acids
(carbomers); polymethacrylates; and the like. One or more binding
agents and/or adhesives, if present, typically constitute in total
about 0.5% to about 25%, for example about 1% to about 15%, or
about 1.5% to about 10%, by weight of the composition.
[1256] Povidone and hydroxypropylcellulose, either individually or
in combination, are particularly useful binding agents for tablet
formulations, and, if present, typically constitute about 0.5% to
about 15%, for example about 1% to about 10%, or about 2% to about
8%, by weight of the composition.
[1257] Wetting agents can be added to the formulation if desired,
in addition to the surfactant component of the solid dispersion.
Non-limiting examples of surfactants that can be used as wetting
agents include, either individually or in combination, quaternary
ammonium compounds, for example benzalkonium chloride, benzethonium
chloride and cetylpyridinium chloride; dioctyl sodium
sulfosuccinate; polyoxyethylene alkylphenyl ethers, for example
nonoxynol 9, nonoxynol 10 and octoxynol 9; poloxamers
(polyoxyethylene and polyoxypropylene block copolymers);
polyoxyethylene fatty acid glycerides and oils, for example
polyoxyethylene (8) caprylic/capric mono- and diglycerides,
polyoxyethylene (35) castor oil and polyoxyethylene (40)
hydrogenated castor oil; polyoxyethylene alkyl ethers, for example
ceteth-10, laureth-4, laureth-23, oleth-2, oleth-10, oleth-20,
steareth-2, steareth-10, steareth-20, steareth-100 and
polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid
esters, for example polyoxyethylene (20) stearate, polyoxyethylene
(40) stearate and polyoxyethylene (100) stearate; sorbitan esters,
for example sorbitan monolaurate, sorbitan monooleate, sorbitan
monopalmitate and sorbitan monostearate; polyoxyethylene sorbitan
esters, for example polysorbate 20 and polysorbate 80; propylene
glycol fatty acid esters, for example propylene glycol laurate;
sodium lauryl sulfate; fatty acids and salts thereof, for example
oleic acid, sodium oleate and triethanolamine oleate; glyceryl
fatty acid esters, for example glyceryl monooleate, glyceryl
monostearate and glyceryl palmitostearate; .alpha.-tocopherol
polyethylene glycol (1000) succinate (TPGS); tyloxapol; and the
like. One or more wetting agents, if present, typically constitute
in total about 0.1% to about 15%, for example about 0.2% to about
10%, or about 0.5% to about 7%, by weight of the composition,
excluding surfactant present in the solid dispersion.
[1258] Nonionic surfactants, more particularly poloxamers, are
examples of wetting agents that can be useful herein.
Illustratively, a poloxamer such as Pluronic.TM. F 127, if present,
can constitute about 0.1% to about 10%, for example about 0.2% to
about 7%, or about 0.5% to about 5%, by weight of the composition,
excluding surfactant present in the solid dispersion.
[1259] Lubricants reduce friction between a tableting mixture and
tableting equipment during compression of tablet formulations.
Suitable lubricants include, either individually or in combination,
glyceryl behenate; stearic acid and salts thereof, including
magnesium, calcium and sodium stearates; hydrogenated vegetable
oils; glyceryl palmitostearate; talc; waxes; sodium benzoate;
sodium acetate; sodium fumarate; sodium stearyl fumarate; PEGs
(e.g., PEG 4000 and PEG 6000); poloxamers; polyvinyl alcohol;
sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and
the like. One or more lubricants, if present, typically constitute
in total about 0.05% to about 10%, for example about 0.1% to about
5%, or about 0.2% to about 2%, by weight of the composition. Sodium
stearyl fumarate is a particularly useful lubricant.
[1260] Anti-adherents reduce sticking of a tablet formulation to
equipment surfaces. Suitable anti-adherents include, either
individually or in combination, talc, colloidal silicon dioxide,
starch, DL-leucine, sodium lauryl sulfate and metallic stearates.
One or more anti-adherents, if present, typically constitute in
total about 0.05% to about 10%, for example about 0.1% to about 7%,
or about 0.2% to about 5%, by weight of the composition. Colloidal
silicon dioxide is a particularly useful anti-adherent.
[1261] Glidants improve flow properties and reduce static in a
tableting mixture. Suitable glidants include, either individually
or in combination, colloidal silicon dioxide, starch, powdered
cellulose, sodium lauryl sulfate, magnesium trisilicate and
metallic stearates. One or more glidants, if present, typically
constitute in total about 0.05% to about 10%, for example about
0.1% to about 7%, or about 0.2% to about 5%, by weight of the
composition, excluding glidant present in the solid dispersion.
Colloidal silicon dioxide is a particularly useful glidant.
[1262] Other excipients such as buffering agents, stabilizers,
antioxidants, antimicrobials, colorants, flavors and sweeteners are
known in the pharmaceutical art and can be used in compositions of
the present invention. Tablets can be uncoated or can comprise a
core that is coated, for example with a nonfunctional film or a
release-modifying or enteric coating. Capsules can have hard or
soft shells comprising, for example, gelatin (in the form of hard
gelatin capsules or soft elastic gelatin capsules), starch,
carrageenan and/or HPMC, optionally together with one or more
plasticizers.
[1263] E. Method of Preparation
[1264] A solvent process for preparing a solid dispersion as
described above comprises dissolving the API, the polymeric carrier
and the surfactant in a suitable solvent; and removing the solvent
to provide the solid dispersion. Optionally, where the API is in
free base (parent-compound) form and it is desired to provide a
solid dispersion of the drug at least partly in the form of an acid
addition salt, an acid is added before solvent removal to effect
conversion of the API to the corresponding salt. For example, one
or more acids selected from the group consisting of acetic, adipic,
alginic, ascorbic, carbonic, citric, aspartic, benzoic,
benzenesulfonic, sulfuric, butyric, camphoric, camphorsulfonic,
gluconic, ethanedisulfonic, formic, fumaric, glycerophosphoric,
glutamic, heptanoic, hexanoic, hydrobromic, hydrochloric,
hydroiodic, 1-hydroxy-2-naphthoic, lactic, lactobionic, malic,
maleic, malonic, mesitylenesulfonic, methanesulfonic,
naphthalenesulfonic, nicotinic, oxalic, pamoic, pectinic,
phosphoric, picric, propionic, succinic, sulfuric, tartaric,
thiocyanic, trichloroacetic, trifluoroacetic, para-toluenesulfonic
and undecanoic acids can be added before solvent removal, resulting
in at least partial formation of the corresponding acid addition
salt of the API. Such one or more acids can be added in any
suitable amount, for example from 0 to about 10 molar equivalents
per molar equivalent of the compound of Formula I.
[1265] Alternatively, where the API is in salt form and it is
desired to provide a solid dispersion of the drug in free base
(parent-compound) form, a base is added before solvent removal to
effect conversion of the API to its corresponding free base. The
salt by-product of such conversion can remain in the product or is
optionally extracted before solvent removal.
[1266] In the dissolving step, the various components can be added
in any order. For example, each ingredient can be added to the
solvent separately and then dissolved therein. Alternatively, the
polymeric carrier and/or surfactant can be pre-mixed with the API,
and the resulting mixture then added to the solvent. In some
embodiments, the polymeric carrier and the API may be dissolved in
the solvent prior to adding the surfactant. The polymeric carrier
and the API may be pre-mixed prior to addition of the solvent.
[1267] In principle any solvent can be used so long as it is
effective to dissolve the active ingredient, polymer carrier and
surfactant. Non-limiting examples of solvents that can be useful
include methanol, ethanol, acetone, tetrahydrofuran (THF),
dichloromethane and mixtures thereof. Optionally a cosolvent can be
included. Dual solvent systems that have been found particularly
useful include dichloromethane/methanol, for example 95 parts
dichloromethane to 5 parts methanol, and THF/water, for example 90
parts THF to 10 parts water.
[1268] Solvent removal can be accomplished using heat, vacuum or a
combination thereof. In some embodiments, heating at a temperature
between about 40.degree. C. to about 90.degree. C., such as about
50.degree. C. to about 80.degree. C., for example about 55.degree.
C. to about 75.degree. C., may be found suitable. In some
embodiments, solvent removal may be accomplished using a
combination of heat and vacuum. In some embodiments, the solvent
may be removed by heating at a temperature between about 40.degree.
C. to about 90.degree. C., such as about 50.degree. C. to about
80.degree. C., for example about 55.degree. C. to about 75.degree.
C. while simultaneously subjecting the composition to a vacuum. A
vacuum gradient may be used. For example, the vacuum may be
increased during solvent evaporation in, e.g., a rotary evaporator,
starting conveniently at ambient pressure and slowly increasing the
vacuum over an extended duration. In some embodiments, the pressure
may be decreased from ambient pressure to about 100 mm Hg over a
period sufficient to evaporate the solvent, which may be, for
example, between about 1 hour and about 5 hours. In some preferred
embodiments, the pressure may be decreased from ambient pressure to
about 200 mm Hg over a period sufficient to evaporate the solvent,
which may be, for example, between about 1 hour and about 5 hours,
such as between about 1 hours and about 3 hours. The duration
necessary to adequately remove solvent is, in part, dependent upon
the volatility of the solvent in which volatile solvents, e.g.,
methanol, may be removed more quickly. After solvent removal, the
resulting product is cooled (if necessary) to ambient temperature.
Illustrative methods of solvent removal include without limitation
rotary evaporation and spray-drying.
[1269] In some embodiments, the composition may be subjected to an
additional solvent evaporation method, for example, oven drying at
a temperature exceeding about 40.degree. C., such as between about
50.degree. C. and about 80.degree. C. for a duration sufficient to
provide a solid dispersion.
[1270] Solvent evaporation according to the present invention
yields a pharmaceutical composition in which the active
pharmaceutical ingredient is "essentially non-crystalline," meaning
that no more than about 5%, for example no more than about 2% or no
more than about 1% crystallinity is observed by X-ray diffraction
analysis. In a particular embodiment, no detectable crystallinity
is observed by one or both of X-ray diffraction analysis or
polarization microscopy.
[1271] F. Dosage Forms and Regimen
[1272] The terms "orally deliverable", "oral administration" and
"orally administered" herein refer to administration to a subject
per os (p.o.), that is, administration wherein the composition is
immediately swallowed, for example with the aid of a suitable
volume of water or other potable liquid. "Oral administration" is
distinguished herein from intraoral administration, e.g.,
sublingual or buccal administration or topical administration to
intraoral tissues such as periodontal tissues, that does not
involve immediate swallowing of the composition.
[1273] The active ingredient form (e.g., parent compound or salt),
the polymeric carrier(s), surfactant(s) and other optional
ingredients should be selected, and relative amounts of these
components should be used, to provide a solid dispersion or dosage
form having acceptable bioabsorption when administered orally. Such
bioabsorption can be evidenced, for example, by the pharmacokinetic
(PK) profile of the solid dispersion or dosage form, more
particularly by the C.sub.max or AUC, for example AUC.sub.0-24 or
AUC.sub.0 at a particular dose or over a range of doses.
Illustratively, bioavailability can be expressed as a percentage,
for example using the parameter F, which computes AUC for oral
delivery of a test composition as a percentage of AUC for
intravenous (i.v.) delivery of the drug in a suitable solvent,
taking into account any difference between oral and i.v. doses.
[1274] Bioavailability can be determined by PK studies in humans or
in any suitable model species. For present purposes, a dog model is
generally suitable. In various illustrative embodiments,
compositions of the invention exhibit oral bioavailability of at
least about 15%, at least about 20%, at least about 25% or at least
about 30%, up to or exceeding about 50%, in a dog model, when
administered as a single dose of about 2.5 to about 10 mg/kg to
fasting or non-fasting animals.
[1275] Compositions embraced herein, including compositions
described generally or with specificity herein, are useful for
orally delivering a drug that is a compound of Formula I or a
pharmaceutically acceptable salt thereof to a subject. Accordingly,
a method of the invention for delivering such a drug to a subject
comprises orally administering a composition as described
above.
[1276] The subject can be human or non-human (e.g., a farm, zoo,
work or companion animal, or a laboratory animal used as a model)
but in an important embodiment the subject is a human patient in
need of the drug, for example to treat a disease characterized by
apoptotic dysfunction and/or overexpression of an anti-apoptotic
Bcl-2 family protein. A human subject can be male or female and of
any age. The patient is typically an adult, but a method of the
invention can be useful to treat a childhood cancer such as
leukemia, for example acute lymphocytic leukemia, in a pediatric
patient.
[1277] The composition is normally administered in an amount
providing a therapeutically effective daily dose of the drug. The
term "daily dose" herein means the amount of drug administered per
day, regardless of the frequency of administration. For example, if
the subject receives a unit dose of 150 mg twice daily, the daily
dose is 300 mg. Use of the term "daily dose" will be understood not
to imply that the specified dosage amount is necessarily
administered once daily. However, in a particular embodiment the
dosing frequency is once daily (q.d.), and the daily dose and unit
dose are in this embodiment the same thing.
[1278] What constitutes a therapeutically effective dose depends on
the particular compound, the subject (including species and body
weight of the subject), the disease (e.g., the particular type of
cancer) to be treated, the stage and/or severity of the disease,
the individual subject's tolerance of the compound, whether the
compound is administered in monotherapy or in combination with one
or more other drugs, e.g., other chemotherapeutics for treatment of
cancer, and other factors. Thus the daily dose can vary within wide
margins, for example from about 10 to about 1,000 mg. Greater or
lesser daily doses can be appropriate in specific situations. It
will be understood that recitation herein of a "therapeutically
effective" dose herein does not necessarily require that the drug
be therapeutically effective if only a single such dose is
administered; typically therapeutic efficacy depends on the
composition being administered repeatedly according to a regimen
involving appropriate frequency and duration of administration. It
is strongly preferred that, while the daily dose selected is
sufficient to provide benefit in terms of treating the cancer, it
should not be sufficient to provoke an adverse side-effect to an
unacceptable or intolerable degree. A suitable therapeutically
effective dose can be selected by the physician of ordinary skill
without undue experimentation based on the disclosure herein and on
art cited herein, taking into account factors such as those
mentioned above. The physician may, for example, start a cancer
patient on a course of therapy with a relatively low daily dose and
titrate the dose upwards over a period of days or weeks, to reduce
risk of adverse side-effects.
[1279] Illustratively, suitable doses of a compound of Formula I
are generally about 25 to about 1,000 mg/day, more typically about
50 to about 500 mg/day or about 200 to about 400 mg/day, for
example about 50, about 100, about 150, about 200, about 250, about
300, about 350, about 400, about 450 or about 500 mg/day,
administered at an average dosage interval of about 3 hours to
about 7 days, for example about 8 hours to about 3 days, or about
12 hours to about 2 days. In most cases a once-daily (q.d.)
administration regimen is suitable.
[1280] An "average dosage interval" herein is defined as a span of
time, for example one day or one week, divided by the number of
unit doses administered over that span of time. For example, where
a drug is administered three times a day, around 8 am, around noon
and around 6 pm, the average dosage interval is 8 hours (a 24-hour
time span divided by 3). If the drug is formulated as a discrete
dosage form such as a tablet or capsule, a plurality (e.g., 2 to
about 10) of dosage forms administered at one time is considered a
unit dose for the purpose of defining the average dosage
interval.
[1281] Where the composition is in the form of a capsule, one to a
small plurality of capsules can be swallowed whole, typically with
the aid of water or other imbibable liquid to help the swallowing
process. Suitable capsule shell materials include, without
limitation, gelatin (in the form of hard gelatin capsules or soft
elastic gelatin capsules), starch, carrageenan and HPMC.
[1282] Administration can be with or without food, i.e., in a
non-fasting or fasting condition. It is generally preferred to
administer the present compositions to a non-fasting patient.
[1283] G. Monotherapies and Combination Therapies
[1284] Compositions of the invention are suitable for use in
monotherapy or in combination therapy, for example with other
chemotherapeutics or with ionizing radiation. A particular
advantage of the present invention is that it permits once-daily
oral administration, a regimen which is convenient for the patient
who is undergoing treatment with other orally administered drugs on
a once-daily regimen. Oral administration is easily accomplished by
the patient him/herself or by a caregiver in the patient's home; it
is also a convenient route of administration for patients in a
hospital or residential care setting.
[1285] Combination therapies illustratively include administration
of a composition of the present invention concomitantly with one or
more of bortezomib, carboplatin, cisplatin, cyclophosphamide,
dacarbazine, dexamethasone, docetaxel, doxorubicin, etoposide,
fludarabine, irinotecan, paclitaxel, rapamycin, rituximab,
vincristine and the like, for example with a polytherapy such as
CHOP (cyclophosphamide+doxorubicin+vincristine+prednisone), RCVP
(rituximab+cyclophosphamide+vincristine+prednisone), R-CHOP
(rituximab+CHOP) or DA-EPOCH-R (dose-adjusted etoposide,
prednisone, vincristine, cyclophosphamide, doxorubicin and
rituximab).
[1286] A composition of the invention can be administered in
combination therapy with one or more therapeutic agents that
include, but are not limited to, alkylating agents, angiogenesis
inhibitors, antibodies, antimetabolites, antimitotics,
antiproliferatives, antivirals, aurora kinase inhibitors, other
apoptosis inducing agents (for example, Bcl-xL, Bcl-w and Bfl-1
inhibitors), activators of a death receptor pathway, Bcr-Abl kinase
inhibitors, BiTE (bi-specific T-cell engager) antibodies,
antibody-drug conjugates, biological response modifiers,
cyclin-dependent kinase (CDK) inhibitors, cell cycle inhibitors,
cyclooxygenase-2 (COX-2) inhibitors, dual variable domain binding
proteins (DVDs), human epidermal growth factor receptor 2 (ErbB2 or
HER/2neu) receptor inhibitors, growth factor inhibitors, heat shock
protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors,
hormonal therapies, immunologicals, inhibitors of apoptosis
proteins (IAPB), intercalating antibiotics, kinase inhibitors,
kinesin inhibitors, JAK2 inhibitors, mammalian target of rapamycin
(mTOR) inhibitors, microRNAs, mitogen-activated extracellular
signal-regulated kinase (MEK) inhibitors, multivalent binding
proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly-ADP
(adenosine diphosphate)-ribose polymerase (PARP) inhibitors,
platinum chemotherapeutics, polo-like kinase (Pik) inhibitors,
phosphoinositide-3 kinase (PI3K) inhibitors, proteasome inhibitors,
purine analogs, pyrimidine analogs, receptor tyrosine kinase
inhibitors, retinoids, deltoids, plant alkaloids, small inhibitory
ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin
ligase inhibitors, and the like.
[1287] 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, but are not limited to, 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 (Sutton
et al. (1997) J. Immunol. 158:5783-5790).
[1288] 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. For
example, siRNAs targeting Mc1-1 have been shown to enhance the
activity of ABT-263 or ABT-737 in various tumor cell lines (Tse et
al. (2008) Cancer Res. 68:3421-3428 and references therein).
[1289] 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.
[1290] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, Cloretazine.TM. (laromustine, VNP
40101M), cyclophosphamide, dacarbazine, estramustine, fotemustine,
glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,
melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard
N-oxide, ranimustine, temozolomide, thiotepa, treosulfan,
trofosfamide and the like.
[1291] Angiogenesis inhibitors include epidermal growth factor
receptor (EGFR) inhibitors, endothelial-specific receptor tyrosine
kinase (Tie-2) 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.
[1292] Antimetabolites include Alimta.TM. (pemetrexed disodium,
LY231514, MTA), 5-azacitidine, Xeloda.TM. (capecitabine), carmofur,
Leustat.TM. (cladribine), clofarabine, cytarabine, cytarabine
ocfosfate, cytosine arabinoside, decitabine, deferoxamine,
doxifluridine, eflornithine, EICAR
(5-ethynyl-1-(3-D-ribofuranosylimidazole-4-carboxamide),
enocitabine, ethenylcytidine, fludarabine, 5-fluorouracil (5-FU)
alone or in combination with leucovorin, Gemzar.TM. (gemcitabine),
hydroxyurea, Alkeran.TM. (melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,
raltitrexed, ribavirin, S-1, triapine, trimetrexate, TS-1,
tiazofurin, tegafur, vidarabine, UFT and the like.
[1293] Antivirals include ritonavir, hydroxychloroquine and the
like.
[1294] Aurora kinase inhibitors include ABT-348, AZD-1152,
MLN-8054, VX-680, aurora A-specific kinase inhibitors, aurora
B-specific kinase inhibitors, pan-aurora kinase inhibitors and the
like.
[1295] Bcl-2 family protein inhibitors other than compounds of
Formula I herein include AT-101 ((-)gossypol), Genasense.TM.
Bcl-2-targeting antisense oligonucleotide (G3139 or oblimersen),
IPI-194, IPI-565, ABT-737, ABT-263, GX-070 (obatoclax) and the
like.
[1296] Bcr-Abl kinase inhibitors include dasatinib (BMS-354825),
Gleevec.TM. (imatinib) and the like.
[1297] CDK inhibitors include AZD-5438, BMI-1040, BMS-387032,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202 or R-roscovitine), ZK-304709 and the like.
[1298] COX-2 inhibitors include ABT-963, Arcoxia.TM. (etoricoxib),
Bextra.TM. (valdecoxib), BMS-347070, Celebrex.TM. (celecoxib),
COX-189 (lumiracoxib), CT-3, Deramaxx.TM. (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.TM. (rofecoxib) and the
like.
[1299] EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes,
EGF-vaccine, EMD-7200, Erbitux.TM. (cetuximab), HR3, IgA
antibodies, Iressa.TM. (gefitinib), Tarceva.TM. (erlotinib or
OSI-774), TP-38, EGFR fusion protein, Tykerb.TM. (lapatinib) and
the like.
[1300] ErbB2 receptor inhibitors include CP-724714, CI-1033
(canertinib), Herceptin.TM. (trastuzumab), Tykerb.TM. (lapatinib),
Omnitarg.TM. (2C4, petuzumab), TAK-165, GW-572016 (ionafamib),
GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER2
vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2
trifunctional bispecific antibodies, mAB AR-209, mAB 2B-1 and the
like.
[1301] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[1302] HSP-90 inhibitors include 17AAG, CNF-101, CNF-1010,
CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, Mycograb.TM.
(human recombinant antibody to HSP-90), nab-17AAG, NCS-683664,
PU24FC1, PU-3, radicicol, SNX-2112, STA-9090, VER-49009 and the
like.
[1303] Inhibitors of apoptosis proteins include HGS-1029, GDC-0145,
GDC-0152, LCL-161, LBW-242 and the like.
[1304] Antibody-drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-veMMAE, PSMA-ADC,
MEDI-547, SGN-19A, SGN-35, SGN-75 and the like.
[1305] Activators of death receptor pathway include TRAIL and
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, trastuzumab and the
like.
[1306] Kinesin inhibitors include Eg5 inhibitors such as AZD-4877
and ARRY-520, CENPE inhibitors such as GSK-923295A, and the
like.
[1307] JAK2 inhibitors include CEP-701 (lesaurtinib), XL019,
INCB-018424 and the like.
[1308] MEK inhibitors include ARRY-142886, ARRY-438162, PD-325901,
PD-98059 and the like.
[1309] mTOR inhibitors include AP-23573, CCI-779, everolimus,
RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2
inhibitors, including PI-103, PP242, PP30 and Torin 1, and the
like.
[1310] Non-steroidal anti-inflammatory drugs include Amigesic.TM.
(salsalate), Dolobid.TM. (diflunisal), Motrin.TM. (ibuprofen),
Orudis.TM. (ketoprofen), Relafen.TM. (nabumetone), Feldene.TM.
(piroxicam), ibuprofen cream, Aleve.TM. and Naprosyn.TM.
(naproxen), Voltaren.TM. (diclofenac), Indocin.TM. (indomethacin),
Clinoril.TM. (sulindac), Tolectin.TM. (tolmetin), Lodine.TM.
(etodolac), Toradol.TM. (ketorolac), Daypro.TM. (oxaprozin) and the
like.
[1311] PDGFR inhibitors include CP-673451, CP-868596 and the
like.
[1312] Platinum chemotherapeutics include cisplatin, Eloxatin.TM.
(oxaliplatin), eptaplatin, lobaplatin, nedaplatin, Paraplatin.TM.
(carboplatin), picoplatin, satraplatin and the like.
[1313] Polo-like kinase inhibitors include BI-2536 and the
like.
[1314] Phosphoinositide-3 kinase inhibitors include wortmannin,
LY-294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,
GDC-0941, BGT226, BEZ235, XL765 and the like.
[1315] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[1316] VEGFR inhibitors include Avastin.TM. (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-547632, IM-862,
Macugen.TM. (pegaptanib), Nexavar.TM. (sorafenib, BAY43-9006),
pazopanib (GW-786034), vatalanib (PTK-787 or ZK-222584), Sutent.TM.
(sunitinib or SU-11248), VEGF trap, Zactima.TM. (vandetanib or
ZD-6474) and the like.
[1317] Antibiotics include intercalating antibiotics such as
aclarubicin, actinomycin D, amrubicin, annamycin, Adriamycin.TM.
(doxorubicin), Blenoxane.TM. (bleomycin), daunorubicin, Caelyx.TM.
and Myocet.TM. (liposomal doxorubicin), elsamitrucin, epirubicin,
glarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
Valstar.TM. (valrubicin), zinostatin and the like.
[1318] Topoisomerase inhibitors include aclarubicin,
9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan,
BN-80915, Camptosar.TM. (irinotecan hydrochloride), camptothecin,
Cardioxane.TM. (dexrazoxane), diflomotecan, edotecarin, Ellence.TM.
and Pharmorubicin.TM. (epirubicin), etoposide, exatecan,
10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone,
orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38,
tafluposide, topotecan and the like.
[1319] Antibodies include Avastin.TM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, Erbitux.TM. (cetuximab),
Humax-CD4.TM. (zanolimumab), IGF1R-specific antibodies, lintuzumab,
Panorex.TM. (edrecolomab), Rencarex.TM. (WX G250), Rituxan.TM.
(rituximab), ticilimumab, trastuzumab, CD20 antibodies types I and
II and the like.
[1320] Hormonal therapies include Arimidex.TM. (anastrozole),
Aromasin.TM. (exemestane), arzoxifene, Casodex.TM. (bicalutamide),
Cetrotide.TM. (cetrorelix), degarelix, deslorelin, Desopan.TM.
(trilostane), dexamethasone, Drogenil.TM. (flutamide), Evista.TM.
(raloxifene), Afema.TM. (fadrozole), Fareston.TM. (toremifene),
Faslodex.TM. (fulvestrant), Femara.TM. (letrozole), formestane,
glucocorticoids, Hectorol.TM. (doxercalciferol), Renagel.TM.
(sevelamer carbonate), lasofoxifene, leuprolide acetate, Megace.TM.
(megestrol), Mifeprex.TM. (mifepristone), Nilandron.TM.
(nilutamide), tamoxifen including Nolvadex.TM. (tamoxifen citrate),
Plenaxis.TM. (abarelix), prednisone, Propecia.TM. (finasteride),
rilostane, Suprefact.TM. (buserelin), luteinizing hormone releasing
hormone (LHRH) including Trelstar.TM. (triptorelin), histrelin
including Vantas.TM. (histrelin implant), Modrastane.TM.
(trilostane), Zoladex.TM. (goserelin) and the like.
[1321] Deltoids and retinoids include seocalcitol (EB1089 or
CB1093), lexacalcitol (KH1060), fenretinide, Panretin.TM.
(alitretinoin), tretinoin including Atragen.TM. (liposomal
tretinoin), Targretin.TM. (bexarotene), LGD-1550 and the like.
[1322] PARP inhibitors include ABT-888, olaparib, KU-59436,
AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the
like.
[1323] Plant alkaloids include vincristine, vinblastine, vindesine,
vinorelbine and the like.
[1324] Proteasome inhibitors include Velcade.TM. (bortezomib),
MG132, NPI-0052, PR-171 and the like.
[1325] 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.TM. (interferon gamma-1b),
interferon gamma-nl, combinations thereof and the like. Other
agents include Alfaferone (IFN-.alpha.), BAM-002 (oxidized
glutathione), Beromun.TM. (tasonermin), Bexxar.TM. (tositumomab),
Campath.TM. (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4),
dacarbazine, denileukin, epratuzumab, Granocyte.TM. (lenograstim),
lentinan, leukocyte alpha interferon, imiquimod, MDX-010
(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim,
Mylotarg.TM. (gemtuzumab ozogamicin), Neupogen.TM. (filgrastim),
OncoVAC-CL, Ovarex.TM. (oregovomab), pemtumomab (Y-muHMFG1),
Provenge.TM. (sipuleucel-T), sargaramostim, sizofuran, teceleukin,
Theracys.TM. (BCG or Bacillus Calmette-Guerin), ubenimex,
Virulizin.TM. (immunotherapeutic, Lorus Pharmaceuticals), Z-100
(Specific Substance of Maruyama or SSM), WF-10
(tetrachlorodecaoxide or TCDO), Proleukin.TM. (aldesleukin),
Zadaxin.TM. (thymalfasin), Zenapax.TM. (daclizumab), Zevalin.TM.
(90Y-ibritumomab tiuxetan) and the like.
[1326] 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,
sizofuran, picibanil, PF-3512676 (CpG-8954), ubenimex and the like.
Pyrimidine analogs include cytarabine (cytosine arabinoside, ara C
or arabinoside C), doxifluridine, Fludara.TM. (fludarabine), 5-FU
(5-fluorouracil), floxuridine, Gemzar.TM. (gemcitabine),
Tomudex.TM. (raltitrexed), triacetyluridine, Troxatyl.TM.
(troxacitabine) and the like.
[1327] Purine analogs include Lanvis.TM. (thioguanine),
Purinethol.TM. (mercaptopurine) and the like.
[1328] Antimitotic agents include batabulin, epothilone D
(KOS-862),
N-(2-((4-hydroxy-phenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS-247550), paclitaxel, Taxotere.TM. (docetaxel),
larotaxel (PNU-100940, RPR-109881 or XRP-9881), patupilone,
vinflunine, ZK-EPO (synthetic epothilone) and the like.
[1329] Ubiquitin ligase inhibitors include MDM2 inhibitors such as
nutlins, NEDD8 inhibitors such as MLN4924, and the like.
[1330] Compositions of this invention can also be used as
radiosensitizers that enhance the efficacy of radiotherapy.
Examples of radiotherapy include, but are not limited to, external
beam radiotherapy (XBRT), teletherapy, brachytherapy, sealed-source
radiotherapy, unsealed-source radiotherapy and the like.
[1331] Additionally or alternatively, a composition of the present
invention can be administered in combination therapy with one or
more antitumor or chemotherapeutic agents selected from
Abraxane.TM. (ABI-007), ABT-100 (farnesyl transferase inhibitor),
Advexin.TM. (Ad5CMV-p53 vaccine or contusugene ladenovec),
Altocor.TM. or Mevacor.TM. (lovastatin), Ampligen.TM.
(poly(I)-poly(C12U), a synthetic RNA), Aptosyn.TM. (exisulind),
Aredia.TM. (pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), Avage.TM. (tazarotene),
AVE-8062 (combretastatin derivative), BEC2 (mitumomab), cachectin
or cachexin (tumor necrosis factor), Canvaxin.TM. (melanoma
vaccine), CeaVac.TM. (cancer vaccine), Celeuk.TM. (celmoleukin),
histamine including Ceplene.TM. (histamine dihydrochloride),
Cervarix.TM. (AS04 adjuvant-adsorbed human papilloma virus (HPV)
vaccine), CHOP (Cytoxan.TM. (cyclophosphamide)+Adriamycin.TM.
(doxorubicin)+Oncovin.TM. (vincristine)+prednisone), combretastatin
A4P, Cypat.TM. (cyproterone), DAB(389)EGF (catalytic and
translocation domains of diphtheria toxin fused via a His-Ala
linker to human epidermal growth factor), dacarbazine,
dactinomycin, Dimericine.TM. (T4N5 liposome lotion),
5,6-dimethylxanthenone-4-acetic acid (DMXAA), discodermolide,
DX-8951f (exatecan mesylate), eniluracil (ethynyluracil),
squalamine including Evizon.TM. (squalamine lactate), enzastaurin,
EPO-906 (epothilone B), Gardasil.TM. (quadrivalent human papilloma
virus (Types 6, 11, 16, 18) recombinant vaccine), Gastrimmune.TM.,
Genasense.TM. (oblimersen), GMK (ganglioside conjugate vaccine),
GVAX.TM. (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. and Mepact.TM.
(mifamurtide), lonafarnib, 5,10-methylenetetrahydro fo late,
miltefosine (hexadecylphosphocholine), Neovastat.TM. (AE-941),
Neutrexin.TM. (trimetrexate glucuronate), Nipent.TM. (pentostatin),
Onconase.TM. (ranpirnase, a ribonuclease enzyme), Oncophage.TM.
(vitespen, melanoma vaccine treatment), OncoVAX.TM. (IL-2 vaccine),
Orathecin.TM. (rubitecan), Osidem.TM. (antibody-based cell drug),
Ovarex.TM. MAb (murine monoclonal antibody), paclitaxel
albumin-stabilized nanoparticle, paclitaxel, Pandimex.TM. (aglycone
saponins from ginseng comprising 20(S)-protopanaxadiol (aPPD) and
20(S)-protopanaxatriol (aPPT)), panitumumab, Panvac.TM.-VF
(investigational cancer vaccine), pegaspargase, peginterferon alfa
(PEG interferon A), phenoxodiol, procarbazine, rebimastat,
Removab.TM. (catumaxomab), Revlimid.TM. (lenalidomide), RSR13
(efaproxiral), Somatuline.TM. LA (lanreotide), Soriatane.TM.
(acitretin), staurosporine (Streptomyces staurospores), talabostat
(PT100), Targretin.TM. (bexarotene), Taxoprexin.TM.
(docosahexaenoic acid (DHA)+paclitaxel), Telcyta.TM. (canfosfamide,
TLK-286), Temodar.TM. (temozolomide), tesmilifene, tetrandrine,
thalidomide, Theratope.TM. (STn-KLH vaccine), Thymitaq.TM.
(nolatrexed dihydrochloride), TNFerade.TM. (adenovector: DNA
carrier containing the gene for tumor necrosis factor-.alpha.),
Tracleer.TM. or Zavesca.TM. (bosentan), TransMID-107R.TM. (KSB-311,
diphtheria toxins), tretinoin (retin-A), Trisenox.TM. (arsenic
trioxide), Ukrain.TM. (derivative of alkaloids from the greater
celandine plant), Virulizin.TM. Vitaxin.TM. (anti-.alpha.v.beta.3
antibody), Xcytrin.TM. (motexafin gadolinium), Xinlay.TM.
(atrasentan), Xyotax.TM. (paclitaxel poliglumex), Yondelis.TM.
(trabectedin), ZD-6126 (N-acetylcolchino1-O-phosphate),
Zinecard.TM. (dexrazoxane), zoledronic acid, zorubicin and the
like.
[1332] In one embodiment, a composition of the invention is
administered in a therapeutically effective amount to a subject in
need thereof to treat a disease during which is overexpressed one
or more of antiapoptotic Bcl-2 protein, antiapoptotic Bcl-X.sub.L
protein and antiapoptotic Bcl-w protein.
[1333] In another embodiment, a composition of the invention is
administered in a therapeutically effective amount to a subject in
need thereof to treat a disease of abnormal cell growth and/or
dysregulated apoptosis.
[1334] Examples of such diseases include, but are not limited to,
cancer, mesothelioma, bladder cancer, pancreatic cancer, skin
cancer, cancer of the head or neck, cutaneous or intraocular
melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma
of the fallopian tubes, carcinoma of the endometrium, carcinoma of
the cervix, carcinoma of the vagina, carcinoma of the vulva, bone
cancer, colon cancer, rectal cancer, cancer of the anal region,
stomach cancer, gastrointestinal (gastric, colorectal and/or
duodenal) cancer, chronic lymphocytic leukemia, acute lymphocytic
leukemia, esophageal cancer, cancer of the small intestine, cancer
of the endocrine system, cancer of the thyroid gland, cancer of the
parathyroid gland, cancer of the adrenal gland, sarcoma of soft
tissue, cancer of the urethra, cancer of the penis, testicular
cancer, hepatocellular (hepatic and/or biliary duct) cancer,
primary or secondary central nervous system tumor, primary or
secondary brain tumor, Hodgkin's disease, chronic or acute
leukemia, chronic myeloid leukemia, lymphocytic lymphoma,
lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies
of T-cell or B-cell origin, melanoma, multiple myeloma, oral
cancer, non-small-cell lung cancer, prostate cancer, small-cell
lung cancer, cancer of the kidney and/or ureter, renal cell
carcinoma, carcinoma of the renal pelvis, neoplasms of the central
nervous system, primary central nervous system lymphoma,
non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma,
pituitary adenoma, adrenocortical cancer, gall bladder cancer,
cancer of the spleen, cholangiocarcinoma, fibrosarcoma,
neuroblastoma, retinoblastoma or a combination thereof.
[1335] In a more particular embodiment, a composition of the
invention is administered in a therapeutically effective amount to
a subject in need thereof to treat bladder cancer, brain cancer,
breast cancer, bone marrow cancer, cervical cancer, chronic
lymphocytic leukemia, acute lymphocytic leukemia, colorectal
cancer, esophageal cancer, hepatocellular cancer, lymphoblastic
leukemia, follicular lymphoma, lymphoid malignancies of T-cell or
B-cell origin, melanoma, myelogenous leukemia, myeloma, oral
cancer, ovarian cancer, non-small-cell lung cancer, prostate
cancer, small-cell lung cancer or spleen cancer.
[1336] According to any of these embodiments, the composition is
administered in monotherapy or in combination therapy with one or
more additional therapeutic agents.
[1337] For example, a method for treating mesothelioma, bladder
cancer, pancreatic cancer, skin cancer, cancer of the head or neck,
cutaneous or intraocular melanoma, ovarian cancer, breast cancer,
uterine cancer, carcinoma of the fallopian tubes, carcinoma of the
endometrium, carcinoma of the cervix, carcinoma of the vagina,
carcinoma of the vulva, bone cancer, colon cancer, rectal cancer,
cancer of the anal region, stomach cancer, gastrointestinal
(gastric, colorectal and/or duodenal) cancer, chronic lymphocytic
leukemia, acute lymphocytic leukemia, esophageal cancer, cancer of
the small intestine, cancer of the endocrine system, cancer of the
thyroid gland, cancer of the parathyroid gland, cancer of the
adrenal gland, sarcoma of soft tissue, cancer of the urethra,
cancer of the penis, testicular cancer, hepatocellular (hepatic
and/or biliary duct) cancer, primary or secondary central nervous
system tumor, primary or secondary brain tumor, Hodgkin's disease,
chronic or acute leukemia, chronic myeloid leukemia, lymphocytic
lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoid
malignancies of T-cell or B-cell origin, melanoma, multiple
myeloma, oral cancer, non-small-cell lung cancer, prostate cancer,
small-cell lung cancer, cancer of the kidney and/or ureter, renal
cell carcinoma, carcinoma of the renal pelvis, neoplasms of the
central nervous system, primary central nervous system lymphoma,
non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma,
pituitary adenoma, adrenocortical cancer, gall bladder cancer,
cancer of the spleen, cholangiocarcinoma, fibrosarcoma,
neuroblastoma, retinoblastoma or a combination thereof in a subject
comprises administering to the subject therapeutically effective
amounts of (a) a composition of the invention and (b) one or more
of etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP,
RCVP, DA-EPOCH-R or bortezomib.
[1338] In particular embodiments, a composition of the invention is
administered in a therapeutically effective amount to a subject in
need thereof in combination therapy with etoposide, vincristine,
CHOP, rituximab, rapamycin, R-CHOP, RCVP, DA-EPOCH-Ror bortezomib
in a therapeutically effective amount, for treatment of a lymphoid
malignancy such as B-cell lymphoma or non-Hodgkin's lymphoma.
[1339] In other particular embodiments, a composition of the
invention is administered in a therapeutically effective amount to
a subject in need thereof in monotherapy or in combination therapy
with etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP,
RCVP, DA-EPOCH-R or bortezomib in a therapeutically effective
amount, for treatment of chronic lymphocytic leukemia or acute
lymphocytic leukemia.
[1340] The present invention also provides a method for maintaining
in bloodstream of a human cancer patient a therapeutically
effective plasma concentration of a compound of Formula I and/or
one or more metabolites thereof, comprising administering to the
subject a solid dispersion of the compound or a pharmaceutically
acceptable salt thereof in essentially non-crystalline form in a
matrix that comprises a pharmaceutically acceptable water-soluble
polymeric carrier and a pharmaceutically acceptable surfactant, in
a parent-compound-equivalent dosage amount of about 50 to about 500
mg per day, at an average dosage interval of about 3 hours to about
7 days.
[1341] What constitutes a therapeutically effective plasma
concentration depends inter alia on the particular compound of
Formula I, the particular cancer present in the patient, the stage,
severity and aggressiveness of the cancer, and the outcome sought
(e.g., stabilization, reduction in tumor growth, tumor shrinkage,
reduced risk of metastasis, etc.). It is strongly preferred that,
while the plasma concentration is sufficient to provide benefit in
terms of treating the cancer, it should not be sufficient to
provoke an adverse side-effect to an unacceptable or intolerable
degree.
[1342] In another embodiment, a composition of the invention is
administered in a therapeutically effective amount to a subject in
need thereof to treat an immune or autoimmune disorder. Such
disorders include acquired immunodeficiency disease syndrome
(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia,
inflammatory diseases, thrombocytopenia, acute and chronic immune
diseases associated with organ transplantation, Addison's disease,
allergic diseases, alopecia, alopecia greata, atheromatous
disease/arteriosclerosis, atherosclerosis, arthritis (including
osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme
arthritis, psoriatic arthritis and reactive arthritis), autoimmune
bullous disease, abetalipoprotemia, acquired
immunodeficiency-related diseases, acute immune disease associated
with organ transplantation, acquired acrocyanosis, acute and
chronic parasitic or infectious processes, acute pancreatitis,
acute renal failure, acute rheumatic fever, acute transverse
myelitis, adenocarcinomas, aerial ectopic beats, adult (acute)
respiratory distress syndrome, AIDS dementia complex, alcoholic
cirrhosis, alcohol-induced liver injury, alcohol-induced hepatitis,
allergic conjunctivitis, allergic contact dermatitis, allergic
rhinitis, allergy and asthma, allograft rejection,
alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic
lateral sclerosis, anemia, angina pectoris, ankylosing
spondylitis-associated lung disease, anterior horn cell
degeneration, antibody mediated cytotoxicity, antiphospholipid
syndrome, anti-receptor hypersensitivity reactions, aortic and
peripheral aneurysms, aortic dissection, arterial hypertension,
arteriosclerosis, arteriovenous fistula, arthropathy, asthenia,
asthma, ataxia, atopic allergy, atrial fibrillation (sustained or
paroxysmal), atrial flutter, atrioventricular block, atrophic
autoimmune hypothyroidism, autoimmune haemolytic anaemia,
autoimmune hepatitis, type-1 autoimmune hepatitis (classical
autoimmune or lupoid hepatitis), autoimmune mediated hypoglycemia,
autoimmune neutropenia, autoimmune thrombocytopenia, autoimmune
thyroid disease, B-cell lymphoma, bone graft rejection, bone marrow
transplant (BMT) rejection, bronchiolitis obliterans, bundle branch
block, burns, cachexia, cardiac arrhythmias, cardiac stun syndrome,
cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation
response, cartilage transplant rejection, cerebellar cortical
degenerations, cerebellar disorders, chaotic or multifocal atrial
tachycardia, chemotherapy-associated disorders, chlamydia,
choleosatatis, chronic alcoholism, chronic active hepatitis,
chronic fatigue syndrome, chronic immune disease associated with
organ transplantation, chronic eosinophilic pneumonia, chronic
inflammatory pathologies, chronic mucocutaneous candidiasis,
chronic obstructive pulmonary disease (COPD), chronic salicylate
intoxication, colorectal common varied immunodeficiency (common
variable hypogammaglobulinemia), conjunctivitis, connective tissue
disease-associated interstitial lung disease, contact dermatitis,
Coombs-positive hemolytic anemia, cor pulmonale, Creutzfeldt-Jakob
disease, cryptogenic autoimmune hepatitis, cryptogenic fibrosing
alveolitis, culture-negative sepsis, cystic fibrosis, cytokine
therapy-associated disorders, Crohn's disease, dementia
pugilistica, demyelinating diseases, dengue hemorrhagic fever,
dermatitis, dermatitis scleroderma, dermatologic conditions,
dermatomyositis/polymyositis-associated lung disease, diabetes,
diabetic arteriosclerotic disease, diabetes mellitus, diffuse Lewy
body disease, dilated cardiomyopathy, dilated congestive
cardiomyopathy, discoid lupus erythematosus, disorders of the basal
ganglia, disseminated intravascular coagulation, Down's Syndrome in
middle age, drug-induced interstitial lung disease, drug-induced
hepatitis, drug-induced movement disorders induced by drugs which
block CNS dopamine receptors, drug sensitivity, eczema,
encephalomyelitis, endocarditis, endocrinopathy, enteropathic
synovitis, epiglottitis, Epstein-Barr virus infection,
erythromelalgia, extrapyramidal and cerebellar disorders, familial
hematophagocytic lymphohistiocytosis, fetal thymus implant
rejection, Friedreich's ataxia, functional peripheral arterial
disorders, female infertility, fibrosis, fibrotic lung disease,
fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis,
glomerular nephritis, glomerulonephritides, Goodpasture's syndrome,
goitrous autoimmune hypothyroidism (Hashimoto's disease), gouty
arthritis, graft rejection of any organ or tissue, graft versus
host disease, gram-negative sepsis, gram-positive sepsis,
granulomas due to intracellular organisms, group B streptococci
(GBS) infection, Graves' disease, hemosiderosis-associated lung
disease, hairy cell leukemia, Hallerrorden-Spatz disease,
Hashimoto's thyroiditis, hay fever, heart transplant rejection,
hemachromatosis, hematopoietic malignancies (leukemia and
lymphoma), hemolytic anemia, hemolytic uremic syndrome/thrombolytic
thrombocytopenic purpura, hemorrhage, Henoch-Schoenlein purpura,
hepatitis A, hepatitis B, hepatitis C, HIV infection/HIV
neuropathy, Hodgkin's disease, hypoparathyroidism, Huntington's
chorea, hyperkinetic movement disorders, hypersensitivity
reactions, hypersensitivity pneumonitis, hyperthyroidism,
hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis
evaluation, idiopathic Addison's disease, idiopathic leucopenia,
idiopathic pulmonary fibrosis, idiopathic thrombocytopenia,
idiosyncratic liver disease, infantile spinal muscular atrophy,
infectious diseases, inflammation of the aorta, inflammatory bowel
disease, insulin dependent diabetes mellitus, interstitial
pneumonitis, iridocyclitis/uveitis/optic neuritis,
ischemia-reperfusion injury, ischemic stroke, juvenile pernicious
anemia, juvenile rheumatoid arthritis, juvenile spinal muscular
atrophy, Kaposi's sarcoma, Kawasaki's disease, kidney transplant
rejection, legionella, leishmaniasis, leprosy, lesions of the
corticospinal system, linear IgA disease, lipidema, liver
transplant rejection, Lyme disease, lymphederma, lymphocytic
infiltrative lung disease, malaria, male infertility idiopathic or
NOS, malignant histiocytosis, malignant melanoma, meningitis,
meningococcemia, microscopic vasculitis of the kidneys, migraine
headache, mitochondrial multisystem disorder, mixed connective
tissue disease, mixed connective tissue disease-associated lung
disease, monoclonal gammopathy, multiple myeloma, multiple systems
degenerations (Mencel, Dejerine-Thomas, Shy-Drager and
Machado-Joseph), myalgic encephalitis/Royal Free Disease,
myasthenia gravis, microscopic vasculitis of the kidneys,
mycobacterium avium intracellulare, mycobacterium tuberculosis,
myelodyplastic syndrome, myocardial infarction, myocardial ischemic
disorders, nasopharyngeal carcinoma, neonatal chronic lung disease,
nephritis, nephrosis, nephrotic syndrome, neurodegenerative
diseases, neurogenic I muscular atrophies, neutropenic fever,
non-alcoholic steatohepatitis, occlusion of the abdominal aorta and
its branches, occlusive arterial disorders, organ transplant
rejection, orchitis/epidydimitis, orchitis/vasectomy reversal
procedures, organomegaly, osteoarthrosis, osteoporosis, ovarian
failure, pancreas transplant rejection, parasitic diseases,
parathyroid transplant rejection, Parkinson's disease, pelvic
inflammatory disease, pemphigus vulgaris, pemphigus foliaceus,
pemphigoid, perennial rhinitis, pericardial disease, peripheral
atherlosclerotic disease, peripheral vascular disorders,
peritonitis, pernicious anemia, phacogenic uveitis, pneumocystis
carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin
changes syndrome), post-perfusion syndrome, post-pump syndrome,
post-MI cardiotomy syndrome, postinfectious interstitial lung
disease, premature ovarian failure, primary biliary cirrhosis,
primary sclerosing hepatitis, primary myxoedema, primary pulmonary
hypertension, primary sclerosing cholangitis, primary vasculitis,
progressive supranuclear palsy, psoriasis, psoriasis type 1,
psoriasis type 2, psoriatic arthropathy, pulmonary hypertension
secondary to connective tissue disease, pulmonary manifestation of
polyarteritis nodosa, post-inflammatory interstitial lung disease,
radiation fibrosis, radiation therapy, Raynaud's phenomenon and
disease, Raynoud's disease, Refsum's disease, regular narrow QRS
tachycardia, Reiter's disease, renal disease NOS, renovascular
hypertension, reperfusion injury, restrictive cardiomyopathy,
rheumatoid arthritis-associated interstitial lung disease,
rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome,
scleroderma, senile chorea, senile dementia of Lewy body type,
sepsis syndrome, septic shock, seronegative arthropathies, shock,
sickle cell anemia, Sjogren's disease-associated lung disease,
Sjogren's syndrome, skin allograft rejection, skin changes
syndrome, small bowel transplant rejection, sperm autoimmunity,
multiple sclerosis (all subtypes), spinal ataxia, spinocerebellar
degenerations, spondyloarthropathy, sporadic polyglandular
deficiency type I, sporadic polyglandular deficiency type II,
Still's disease, streptococcal myositis, stroke, structural lesions
of the cerebellum, subacute sclerosing panencephalitis, sympathetic
ophthalmia, syncope, syphilis of the cardiovascular system,
systemic anaphylaxis, systemic inflammatory response syndrome,
systemic onset juvenile rheumatoid arthritis, systemic lupus
erythematosus, systemic lupus erythematosus-associated lung
disease, lupus nephritis, systemic sclerosis, systemic
sclerosis-associated interstitial lung disease, T-cell or FAB ALL,
Takayasu's disease/arteritis, telangiectasia, Th2-type and Th1-type
mediated diseases, thromboangitis obliterans, thrombocytopenia,
thyroiditis, toxicity, toxic shock syndrome, transplants,
trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibody
hepatitis), type B insulin resistance with acanthosis nigricans,
type III hypersensitivity reactions, type IV hypersensitivity,
ulcerative colitic arthropathy, ulcerative colitis, unstable
angina, uremia, urosepsis, urticaria, uveitis, valvular heart
diseases, varicose veins, vasculitis, vasculitic diffuse lung
disease, venous diseases, venous thrombosis, ventricular
fibrillation, vitiligo acute liver disease, viral and fungal
infections, vital encephalitis/aseptic meningitis, vital-associated
hemaphagocytic syndrome, Wegener's granulomatosis,
Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection
of any organ or tissue, yersinia and salmonella-associated
arthropathy and the like.
EXAMPLES
[1343] The following examples are merely illustrative, and do not
limit this disclosure in any way. For example, it will be
appreciated that lab-scale compositions or formulations, or solid
dispersions, referenced herein may in general be scaled up in view
of the details provided without departing from the intended scope
of the present application.
[1344] Trademarked ingredients used in the examples, which can be
substituted with comparable ingredients from other suppliers,
include: [1345] Cremophor RH.TM. 40 of BASF: PEG-40 hydrogenated
castor oil; [1346] Soluplus.TM. of BASF: graft copolymer of
polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate;
[1347] Tween.TM. 20 of Uniqema: polysorbate 20 surfactant; [1348]
Tween.TM. 80 of Uniqema: polysorbate 80 surfactant.
[1349] In the examples, "API" (active pharmaceutical ingredient)
can be any compound of Formula I, added in essentially anhydrous
parent-compound (i.e., not salt) form. In solid dispersions to
which citric acid is added during preparation, the presence of
citrate salt of the API is possible but has not been conclusively
determined. The following compounds are more specifically
contemplated for formulation according to the examples: [1350]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}-sulfonyl)benzamide--Compound 89;
[1351]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrop-
henyl}sulfonyl)-benzamide--Compound 91; [1352]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 5;
[1353]
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 9;
[1354]
cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 29;
[1355]
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 34;
[1356]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 37;
[1357]
N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-
-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compoun-
d 277; [1358]
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3--
yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
61; [1359]
4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
378; [1360]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitr-
ophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
149; [1361]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitroph-
enyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
337; [1362]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
338; [1363]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nit-
rophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
311; [1364]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]met-
hyl}amino)phenyl]-sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--
-Compound 118; [1365]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound 134;
[1366]
N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
253; [1367]
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
108; and [1368]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}su-
lfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide--Compound
234.
Example 1
[1369] A solid dispersion comprising API, TPGS surfactant and
Soluplus.TM. polymer in a weight ratio of approximately 21:5:74 is
prepared as follows.
[1370] The following solid components are combined in a 100 ml
amber glass scintillation vial: 1.0 g API and 3.5 g Soluplus.TM.
polymer. Approximately 45.5 g solvent mixture (THF/water, 90:10) is
added to the solids with agitation until the solids are dissolved
(this takes approximately 15 minutes), forming a drug/polymer
solution. TPGS surfactant (0.05 g) is weighed into a separate 20 ml
amber glass scintillation vial, and an aliquot of 10 g of the
drug/polymer solution is added to the surfactant, with mixing. The
resulting solution is placed in a Genevac rotary evaporator for
solvent removal at 80.degree. C. by slowly increasing applied
vacuum from ambient to approximately 200 mm Hg over a period of
about 3 hours. The powder that remains after solvent removal is
collected, with scraping as necessary, from the bottom of the vial,
and is screened through a #50-mesh sieve. The sieved powder is then
incubated at 50.degree. C. for 30 minutes as a secondary drying
step, to provide the solid dispersion.
Example 2
[1371] A solid dispersion comprising API, Tween.TM. 20 surfactant
and Soluplus.TM. polymer in a weight ratio of approximately
20:10:70 is prepared as in Example 1, except that 0.1 g Tween.TM.
20 is substituted for 0.05 g TPGS.
Example 3
[1372] A solid dispersion comprising API, Tween.TM. 80 surfactant
and Soluplus.TM. polymer in a weight ratio of approximately
20:10:70 is prepared as in Example 1, except that 0.1 g Tween.TM.
80 is substituted for 0.05 g TPGS.
Example 4
[1373] A solid dispersion comprising API, Cremophor RH.TM. 40
surfactant and Soluplus.TM. polymer in a weight ratio of
approximately 20:10:70 is prepared as in Example 1, except that 0.1
g Cremophor RH.TM. 40 is substituted for 0.05 g TPGS.
Example 5
[1374] A solid dispersion comprising API, TPGS surfactant and HPMC
E5 polymer in a weight ratio of approximately 21:5:74 is prepared
as in Example 1, except that 3.5 g HPMC E5 is substituted for 3.5 g
Soluplus.TM.
Example 6
[1375] A solid dispersion comprising API, Tween.TM. 20 surfactant
and HPMC E5 polymer in a weight ratio of approximately 20:10:70 is
prepared as in Example 1, except that 3.5 g HPMC E5 is substituted
for 3.5 g Soluplus.TM., and 0.1 g Tween.TM. 20 is substituted for
0.05 g TPGS.
Example 7
[1376] A solid dispersion comprising API, Tween.TM. 80 surfactant
and HPMC E5 polymer in a weight ratio of approximately 20:10:70 is
prepared as in Example 1, except that 3.5 g HPMC E5 is substituted
for 3.5 g Soluplus.TM., and 0.1 g Tween.TM. 80 is substituted for
0.05 g TPGS.
Example 8
[1377] A solid dispersion comprising API, Cremophor RH.TM. 40
surfactant and HPMC E5 polymer in a weight ratio of approximately
20:10:70 is prepared as in Example 1, except that 3.5 g HPMC E5 is
substituted for 3.5 g Soluplus.TM., and 0.1 g Cremophor RH.TM. 40
is substituted for 0.05 g TPGS.
Example 9
[1378] A solid dispersion comprising API, TPGS surfactant, povidone
K30 polymer and citric acid in a weight ratio of approximately
21:5:65:9 is prepared as follows.
[1379] The following solid components are combined in a 100 ml
amber glass scintillation vial: 1.0 g API, 3.05 g povidone K30
polymer and 0.45 g citric acid. Approximately 70.5 g solvent
mixture (dichloromethane/methanol, 95:5) is added to the solids
with agitation until the solids are dissolved (this takes
approximately 15 minutes), forming a drug/polymer solution. TPGS
surfactant (0.05 g) is weighed into a separate 20 ml amber glass
scintillation vial, and an aliquot of 15 g of the drug/polymer
solution is added to the surfactant, with mixing. The resulting
solution is placed in a Genevac rotary evaporator for solvent
removal at 80.degree. C. by slowly increasing applied vacuum from
ambient to approximately 200 mm Hg over a period of about 1 hour.
The powder that remains after solvent removal is collected, with
scraping as necessary, from the bottom of the vial, and is screened
through a #50-mesh sieve. The sieved powder is then incubated at
50.degree. C. for 30 minutes as a secondary drying step, to provide
the solid dispersion.
[1380] Note: solid dispersions prepared according to Examples 9-12,
although believed to be operative according to the invention, may
be suboptimal due to formation of a precipitate in the
dichloromethane/methanol solution.
Example 10
[1381] A solid dispersion comprising API, Tween.TM. 20 surfactant,
HPMC E5 polymer and citric acid in a weight ratio of approximately
20:10:61:9 is prepared as in Example 9, except that 0.1 g Tween.TM.
20 is substituted for 0.05 g TPGS and that 3.05 g HPMC E5 is
substituted for 3.05 g povidone K30.
Example 11
[1382] A solid dispersion comprising API, Tween.TM. 80 surfactant,
HPMC E5 polymer and citric acid in a weight ratio of approximately
20:10:61:9 is prepared as in Example 9, except that 0.1 g Tween.TM.
80 is substituted for 0.05 g TPGS and that 3.05 g HPMC E5 is
substituted for 3.05 g povidone K30.
Example 12
[1383] A solid dispersion comprising API, Cremophor RH.TM. 40
surfactant, HPMC E5 polymer and citric acid in a weight ratio of
approximately 20:10:61:9 is prepared as in Example 9, except that
0.1 g Cremophor RH.TM. 40 is substituted for 0.05 g TPGS and that
3.05 g HPMC E5 is substituted for 3.05 g povidone K30.
[1384] A sample of the solid dispersion of Example 12 is submitted
for determination of crystallinity or lack thereof by powder X-ray
diffraction (PXRD). No sharp peaks are observed, indicating an
absence of crystallinity.
Example 13
[1385] A solid dispersion comprising API, Tween.TM. 20 surfactant
and copovidone 60/40 polymer in a weight ratio of approximately
20:10:70 is prepared as follows.
[1386] The following solid components are combined in a 100 ml
amber glass scintillation vial: 1.0 g API and 3.5 g copovidone
polymer. Approximately 70.5 g solvent mixture
(dichloromethane/methanol, 95:5) is added to the solids with
agitation until the solids are dissolved (this takes approximately
15 minutes), forming a drug/polymer solution. Tween.TM. 20
surfactant (0.1 g) is weighed into a separate 20 ml amber glass
scintillation vial, and an aliquot of 15 g of the drug/polymer
solution is added to the surfactant, with mixing. The resulting
solution is placed in a Genevac rotary evaporator for solvent
removal at 80.degree. C. by slowly increasing applied vacuum from
ambient to approximately 200 mm Hg over a period of about 1 hour.
The powder that remains after solvent removal is collected, with
scraping as necessary, from the bottom of the vial, and is screened
through a #50-mesh sieve. The sieved powder is then incubated at
50.degree. C. for 30 minutes as a secondary drying step, to provide
the solid dispersion.
[1387] A sample of the solid dispersion of Example 13 is submitted
for determination of crystallinity or lack thereof by PXRD. No
sharp peaks are observed, indicating an absence of
crystallinity.
Example 14
[1388] A solid dispersion comprising API, Cremophor RH.TM. 40
surfactant and copovidone 60/40 polymer in a weight ratio of
approximately 20:10:70 is prepared as in Example 13, except that
0.1 g Cremophor RH.TM. 40 is substituted for 0.1 g Tween.TM.
20.
[1389] A sample of the solid dispersion of Example 14 is submitted
for determination of crystallinity or lack thereof by PXRD. No
sharp peaks are observed, indicating an absence of
crystallinity.
Example 15
[1390] The solid dispersion of any of Examples 1-14 is blended with
siliconized microcrystalline cellulose, croscarmellose sodium and
sodium stearyl fumarate at a weight ratio of 82:15:2:1.
Approximately 300-900 mg of the resulting blend contains 50-150 mg
of a compound of Formula I, and can be filled into a hard gelatin
capsule of suitable size to provide a 50-150 mg dosage form
suitable for oral administration.
Example 16
[1391] A solid dispersion comprising API, TPGS surfactant, and
copovidone 60/40 polymer in a weight ratio of approximately
15:20:65 is prepared as follows.
[1392] The following solid components are combined in a 250 ml
round-bottom flask: 1.0 g API, 1.33 g TPGS surfactant and 4.33 g
copovidone 60/40. Approximately 80 g solvent mixture
(dichloromethane/methanol, 95:5) is added to the solids with
agitation until the solids are dissolved (this takes approximately
15 minutes), forming a drug/polymer/surfactant solution. The
resulting solution is placed in a Biichi rotary evaporator for
solvent removal at 60.degree. C. by slowly increasing applied
vacuum in stages from ambient to approximately 500 mbar to
ultimately 10 mbar over a period of about 1 hour. The solid that
remains after solvent removal is collected, with scraping as
necessary, from the round-bottom flask, and is ground by hand with
a mortar and pestle. The powder is then incubated at 50.degree. C.
for 24 hours as a secondary drying step, to provide the solid
dispersion.
Example 17
[1393] A solid dispersion comprising API, TPGS surfactant, and
copovidone 60/40 polymer in a weight ratio of approximately
15:20:65 is prepared as follows.
[1394] The following solid components are combined in a 20 ml
scintillation vial: 0.18 g API, 0.24 g TPGS surfactant and 0.78 g
copovidone 60/40. Approximately 18 g solvent mixture
(dichloromethane/methanol, 95:5) is added to the solids with
agitation until the solids are dissolved (this takes approximately
5 minutes), forming a drug/polymer/surfactant solution. The
resulting solution is placed in a 20 ml glass syringe and delivered
to a Microcapacity spray drying unit (Pro-Cept, Belgium)at 2
ml/min. At the unit the solution is atomized using a bi-fluid
nozzle with an atomization gas flow rate of 8 ml/min. The inlet air
flow is approximately 0.4 m.sup.3/min and inlet temperature about
40.degree. C. The powder is collected from the instrument and
incubated for 37.degree. C. for 24 hours as a secondary drying
step, to provide the solid dispersion.
[1395] When introducing elements of the present disclosure or the
preferred embodiments(s) thereof, the articles "a", "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[1396] As various changes could be made in the above apparatus and
methods without departing from the scope of the disclosure, it is
intended that all matter contained in the above description and
shown in the accompanying figures shall be interpreted as
illustrative and not in a limiting sense.
* * * * *