U.S. patent application number 17/167507 was filed with the patent office on 2021-12-30 for apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Andrew Judd, Aaron Kunzer, Andrew Souers, Gerard Sullivan, Zhi-Fu Tao, Xilu Wang, Michael Wendt.
Application Number | 20210403467 17/167507 |
Document ID | / |
Family ID | 1000005839623 |
Filed Date | 2021-12-30 |
United States Patent
Application |
20210403467 |
Kind Code |
A1 |
Tao; Zhi-Fu ; et
al. |
December 30, 2021 |
APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE
AND AUTOIMMUNE DISEASES
Abstract
Disclosed herein are compounds that inhibit the activity of
anti-apoptotic Bcl-2 proteins, compositions containing the
compounds and methods of treating diseases using the compounds.
Inventors: |
Tao; Zhi-Fu; (Vernon Hills,
IL) ; Wang; Xilu; (Libertyville, IL) ; Wendt;
Michael; (Vernon Hills, IL) ; Souers; Andrew;
(Evanston, IL) ; Judd; Andrew; (Grayslake, IL)
; Kunzer; Aaron; (Arlington Heights, IL) ;
Sullivan; Gerard; (Lake Villa, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
1000005839623 |
Appl. No.: |
17/167507 |
Filed: |
February 4, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16707777 |
Dec 9, 2019 |
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17167507 |
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16108346 |
Aug 22, 2018 |
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16707777 |
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15276872 |
Sep 27, 2016 |
10081628 |
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16108346 |
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14789449 |
Jul 1, 2015 |
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15276872 |
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14176506 |
Feb 10, 2014 |
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14789449 |
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61781070 |
Mar 14, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5377 20130101;
C07D 471/04 20130101; A61P 35/00 20180101; A61K 45/06 20130101;
A61K 31/496 20130101; A61P 37/00 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61K 31/5377 20060101 A61K031/5377; A61K 31/496
20060101 A61K031/496; A61K 45/06 20060101 A61K045/06; A61P 37/00
20060101 A61P037/00; A61P 35/00 20060101 A61P035/00 |
Claims
1. A compound selected from the group consisting of:
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(2R)-1,4-dioxan-2-ylmethyl]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-[(3-nitro-4-{[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]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-[(3-nitro-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]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-[(3-nitro-4-{[(5S,8S)-1-oxaspiro[4.5]dec-8-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-[(3-nitro-4-{[(5R,8R)-1-oxaspiro[4.5]dec-8-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-{[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophe-
nyl)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-[(1,4-dioxaspiro[4.5]dec-8-ylmethyl)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-(morpholin-4-yl)-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-{[(2S)-1,4-dioxan-2-ylmethyl]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-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}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-({[3-(hydroxymethyl)oxetan-3-yl]methyl}amino)-3-nitrophenyl]s-
ulfonyl}-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-hydroxy-3-methylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1-
H-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-hydroxytricyclo[3.3.1.1.sup.3,7]dec-1-yl)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-[(3-nitro-4-{[(1R,5S,6S)-3-oxabicyclo[3.1.0]hex-6-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-{[(3-hydroxyoxetan-3-yl)methyl]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-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2-
,3-b]pyridin-5-yloxy)benzamide; methyl
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]sulfamoyl}-2-n-
itrophenyl)amino]methyl}tetrahydro-2H-pyran-4-carboxylate;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)hydrazinyl]phenyl}sulfon-
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-[(3-nitro-4-{[(4R)-oxepan-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-[(3-nitro-4-{[(4S)-oxepan-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-{[(4-methyltetrahydro-2H-pyran-4-yl)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-({3-nitro-4-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]phenyl}sul-
fonyl)-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-[(oxetan-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrr-
olo[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-({[(2R,5R)-5-methyl-1,4-dioxan-2-yl]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-{[(6-hydroxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)su-
lfonyl]-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-{[(4,4-difluoro-1-hydroxycyclohexyl)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-{[(4-methoxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophe-
nyl)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-{[(3,3-difluorocyclobutyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-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-[({1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}methyl-
)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-({[1-(methylsulfonyl)piperidin-4-yl]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-({[(2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}ami-
no)-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-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}p-
henyl)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-({[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}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-({[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}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-({[(2S,6R)-6-methyl-1,4-dioxan-2-yl]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-[(3-nitro-4-{[(3S)-tetrahydrofuran-3-ylmethyl]amino}phenyl)sulfon-
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-({[(2S)-6,6-dimethyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophe-
nyl]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-methyloxetan-3-yl)methyl]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-{[(6-fluoro-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-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-{[(6-methoxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)su-
lfonyl]-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-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfon-
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-{[(cis-3-cyanocyclobutyl)methyl]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-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-ni-
trophenyl)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-({[(2S,5R)-5-methyl-1,4-dioxan-2-yl]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-({[(2S,5S)-5-methyl-1,4-dioxan-2-yl]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-{[(4-cyanotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
N-[(4-{[(1-acetylpiperidin-4-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;
4-(4-{[2-(4-chloro-3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-
piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
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-[(4-{[(4-ethyltetrahydro-2H-pyran-4-yl)methyl]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-({4-[(1,4-dioxepan-6-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-cyclopropylphenyl)-4,4-dimethylcyclohex-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;
4-(4-{[2-(3,4-dichlorophenyl)-4,4-dimethylcyclohex-1-en-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; and
4-[4-({2-[4-(difluoromethyl)phenyl]-4,4-dimethylcyclohex-1-en-1-yl}methyl-
)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phen-
yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, salts of prodrugs and
metabolites thereof.
2. A composition for treating bladder cancer, brain cancer, breast
cancer, bone marrow cancer, cervical cancer, chronic 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, chronic lymphocytic leukemia, myeloma, prostate cancer,
small cell lung cancer or spleen cancer, said composition
comprising an excipient and a therapeutically effective amount of a
compound of claim 1 or a therapeutically acceptable salt of the
compound of claim 1.
3. A method of treating bladder cancer, brain cancer, breast
cancer, bone marrow cancer, cervical cancer, chronic 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, chronic lymphocytic leukemia, myeloma, prostate cancer,
small cell lung cancer or spleen cancer in a subject in need of
treatment, said method comprising administering to the subject a
therapeutically effective amount of a compound of claim 1 or a
therapeutically acceptable salt of the compound of claim 1.
4. A method of treating bladder cancer, brain cancer, breast
cancer, bone marrow cancer, cervical cancer, chronic 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, chronic lymphocytic leukemia, myeloma, prostate cancer,
small cell lung cancer or spleen cancer in a subject in need of
treatment, said method comprising administering to the subject
therapeutically effective amount of a compound of claim 1 or a
therapeutically acceptable salt of the compound of claim 1 and a
therapeutically effective amount of one additional therapeutic
agent or more than one additional therapeutic agent.
5. A composition for treating systemic lupus erythematosus, lupus
nephritis, or Sjogren's Syndrome, said composition comprising an
excipient, a therapeutically effective amount of a compound of
claim 1 or a therapeutically acceptable salt of the compound of
claim 1, and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
6. A method of treating systemic lupus erythematosus, lupus
nephritis, or Sjogren's Syndrome in a subject in need of treatment,
said method comprising administering to the subject a
therapeutically effective amount of a compound of claim 1 or a
therapeutically acceptable salt of the compound of claim 1.
7. A method of treating systemic lupus erythematosus, lupus
nephritis, or Sjogren's Syndrome in a subject in need of treatment,
said method comprising administering to the subject a
therapeutically effective amount of a compound of claim 1 or a
therapeutically acceptable salt of the compound of claim 1 and a
therapeutically effective amount of one additional therapeutic
agent or more than one additional therapeutic agent.
8. The compound of claim 1 selected from the group consisting of:
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(2R)-1,4-dioxan-2-ylmethyl]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-[(3-nitro-4-{[(5R,8R)-1-oxaspiro[4.5]dec-8-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-{[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophe-
nyl)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-[(1,4-dioxaspiro[4.5]dec-8-ylmethyl)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-{[(2S)-1,4-dioxan-2-ylmethyl]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-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}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-{[(3-hydroxyoxetan-3-yl)methyl]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-({[(2S,5R)-5-methyl-1,4-dioxan-2-yl]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-{[(4-cyanotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
4-[4-({2-[4-(difluoromethyl)phenyl]-4,4-dimethylcyclohex-1-en-1-yl}methyl-
)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phen-
yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts thereof.
9. The compound of claim 1 selected from the group consisting of:
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]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-[(3-nitro-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]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-(morpholin-4-yl)-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-[(3-hydroxy-3-methylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1-
H-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-hydroxytricyclo[3.3.1.1.sup.3,7]dec-1-yl)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-{[(4,4-difluoro-1-hydroxycyclohexyl)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-{[(trans-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfon-
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-{[(cis-3-cyanocyclobutyl)methyl]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-{[(4-cyanotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-chloro-3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-
piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
4-(4-{[2-(4-cyclopropylphenyl)-4,4-dimethylcyclohex-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;
4-(4-{[2-(3,4-dichlorophenyl)-4,4-dimethylcyclohex-1-en-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; and
4-[4-({2-[4-(difluoromethyl)phenyl]-4,4-dimethylcyclohex-1-en-1-yl}methyl-
)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phen-
yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 16/707,777, which was filed Dec. 9, 2019 and
which is incorporated by reference in its entirety. U.S.
application Ser. No. 16/707,777 is a divisional application of U.S.
application Ser. No. 16/108,346, which was filed Aug. 22, 2018 and
which is incorporated by reference in its entirety. U.S.
application Ser. No. 16/108,346 is a divisional application of U.S.
application Ser. No. 15/276,872 (issued as U.S. Pat. No.
10,081,628) which was filed Sep. 27, 2016 and which is incorporated
by reference in its entirety. U.S. application Ser. No. 15/276,872
is a continuation application of U.S. application Ser. No.
14/789,449, which was filed Jul. 1, 2015 and which is incorporated
by reference in its entirety. U.S. application Ser. No. 14/789,449
is a divisional application of U.S. application Ser. No.
14/176,506, which was filed Feb. 10, 2014 and which is incorporated
by reference in its entirety. U.S. application Ser. No. 14/176,506
claims priority to U.S. Provisional Application Ser. No.
61/781,070, which was filed Mar. 14, 2013 and which is incorporated
by reference in its entirety.
INCORPORATION OF SEQUENCE LISTING
[0002] A paper copy of the Sequence Listing and a computer readable
form of the sequence containing the file named "ABV11872USD3.txt",
which is 828 bytes in size (as measured in MICROSOFT WINDOWS.RTM.
EXPLORER), are provided herein and are herein incorporated by
reference. This Sequence Listing consists of SEQ ID NO:1.
FIELD OF THE INVENTION
[0003] This invention pertains to compounds that inhibit the
activity of Bcl-2 anti-apoptotic proteins, compositions containing
the compounds, and methods of treating diseases using the
compounds.
BACKGROUND OF THE INVENTION
[0004] The Bcl-2 family of proteins are key regulators of
mitochondria-dependent apoptosis in nucleated cells and includes
both anti-apoptotic (BCl-x.sub.L, Bcl-2, Bcl-w, A1, Mcl-1) and
pro-apoptotic (Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, Puma)
members. Generally, the expression of Bcl-2 protein is associated
with many physiologic functions, including the inhibition of
apoptosis in the body, in some cases resulting in proliferation of
cells affected by to improved outcomes related to the treatment and
prevention of cancer.
[0005] Anti-apoptotic Bcl-2 proteins are associated with a number
of diseases. Bcl-2 proteins may be involved bladder cancer, brain
cancer, breast cancer, bone marrow cancer, cervical cancer, chronic
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, spleen cancer, and the like. Additionally, Bcl-2 may be
involved in immune and auto-immune diseases, as well as arthritis.
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.
[0006] There is a continuing need in the therapeutic arts for
compounds that inhibit the activity of anti-apoptotic Bcl-2
proteins.
SUMMARY OF THE INVENTION
[0007] One embodiment of this invention pertains to compounds and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof, which are useful as inhibitors of
anti-apoptotic Bcl-2 proteins. The compounds include: [0008]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(2R)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0009]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}phenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0010]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}phenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0011]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(5S,8S)-1-oxaspiro[4.5]dec-8-ylmethyl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0012]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(5R,8R)-1-oxaspiro[4.5]dec-8-ylmethyl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0013]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0014]
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-ylmethyl)amino]-3-nitrophenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0015]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(morpholin-4-yl)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]-
pyridin-5-yloxy)benzamide; [0016]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(2S)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0017]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0018]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-{[4-({[3-(hydroxymethyl)oxetan-3-yl]methyl}amino)-3-nitrop-
henyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0019]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3-hydroxy-3-methylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0020]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3-hydroxytricyclo[3.3.1.1.sup.3,7]dec-1-yl)amino]-3-nitroph-
enyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0021]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(1R,5S,6S)-3-oxabicyclo[3.1.0]hex-6-ylmethyl]amino}-
phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0022]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(3-hydroxyoxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0023]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2-
,3-b]pyridin-5-yloxy)benzamide; [0024] methyl
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]sulfamoyl}-2-n-
itrophenyl)amino]methyl}tetrahydro-2H-pyran-4-carboxylate; [0025]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)hydrazinyl]phenyl}sulfon-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0026]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(4R)-oxepan-4-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0027]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(4S)-oxepan-4-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0028]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-methyltetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0029]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]phenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0030]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(oxetan-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrr-
olo[2,3-b]pyridin-5-yloxy)benzamide; [0031]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2R,5R)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0032]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(6-hydroxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0033]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4,4-difluoro-1-hydroxycyclohexyl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0034]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-methoxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0035]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(3,3-difluorocyclobutyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0036]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[({1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}methyl-
)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0037]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-4-yl]methyl}amino)-3-ni-
trophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0038]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}ami-
no)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0039]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]-
amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0040]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-{[4-({[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}am-
ino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide-
; [0041]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-N-{[4-({[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}a-
mino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamid-
e; [0042]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-
piperazin-1-yl)-N-{[4-({[(2S,6R)-6-methyl-1,4-dioxan-2-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0043]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydrofuran-3-ylmethyl]amino}phenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0044]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2S)-6,6-dimethyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophe-
nyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0045]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0046]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(6-fluoro-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0047]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(6-methoxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0048]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(trans-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0049]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(cis-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0050]
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)methyl]amino}-3-ni-
trophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
[0051]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2S,5R)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0052]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2S,5S)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0053]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-cyanotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0054]
N-[(4-{[(1-acetylpiperidin-4-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; [0055]
4-(4-{[2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-
piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0056]
4-(4-{[2-(4-chloro-3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-
piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0057]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-ethyltetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0058]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,4-dioxepan-6-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; [0059]
4-(4-{[2-(4-cyclopropylphenyl)-4,4-dimethylcyclohex-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; [0060]
4-(4-{[2-(3,4-dichlorophenyl)-4,4-dimethylcyclohex-1-en-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; and [0061]
4-[4-({2-[4-(difluoromethyl)phenyl]-4,4-dimethylcyclohex-1-en-1-yl}methyl-
)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phen-
yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.
[0062] Another embodiment pertains to a composition for treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer,
cervical cancer, chronic 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, chronic lymphocytic
leukemia, myeloma, prostate cancer, small cell lung cancer or
spleen cancer, said composition comprising an excipient and a
therapeutically effective amount of a compound of this
invention.
[0063] Another embodiment pertains to a method of treating bladder
cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, chronic 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, chronic lymphocytic leukemia,
myeloma, prostate cancer, small cell lung cancer or spleen cancer
in a subject in need of treatment, said method comprising
administering to the subject a therapeutically effective amount of
a compound of this invention.
[0064] Another embodiment pertains to a method of treating bladder
cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, chronic 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, chronic lymphocytic leukemia,
myeloma, prostate cancer, small cell lung cancer or spleen cancer
in a subject in need of treatment, said method comprising
administering to the subject therapeutically effective amount of
the compound of this invention and a therapeutically effective
amount of one additional therapeutic agent or more than one
additional therapeutic agent.
[0065] Another embodiment pertains to a composition for treating
systemic lupus erythematosus, lupus nephritis, or Sjogren's
Syndrome, said composition comprising an excipient and a
therapeutically effective amount of a compound of this
invention.
[0066] Another embodiment pertains to a method of treating systemic
lupus erythematosus, lupus nephritis, or Sjogren's Syndrome in a
subject in need of treatment, said method comprising administering
to the subject a therapeutically effective amount of a compound of
this invention.
[0067] Another embodiment pertains to a method of treating systemic
lupus erythematosus, lupus nephritis, or Sjogren's Syndrome in a
subject in need of treatment, said method comprising administering
to the subject therapeutically effective amount of the compound of
this invention and a therapeutically effective amount of one
additional therapeutic agent or more than one additional
therapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
[0068] Unless otherwise defined herein, scientific and technical
terms used in connection with the present invention shall have the
meanings that are commonly understood by those of ordinary skill in
the art. The meaning and scope of the terms should be clear,
however, in the event of any latent ambiguity, definitions provided
herein take precedent over any dictionary or extrinsic definition.
In this application, the use of "or" means "and/or" unless stated
otherwise. Furthermore, the use of the term "including", as well as
other forms, such as "includes" and "included", is not limiting.
With reference to the use of the words "comprise" or "comprises" or
"comprising" in this patent application (including the claims),
Applicants note that unless the context requires otherwise, those
words are used on the basis and clear understanding that they are
to be interpreted inclusively, rather than exclusively, and that
Applicants intend each of those words to be so interpreted in
construing this patent application, including the claims below. For
a variable that occurs more than one time in any substituent or in
the compound of the invention or any other formulae herein, its
definition on each occurrence is independent of its definition at
every other occurrence. Combinations of substituents are
permissible only if such combinations result in stable compounds.
Stable compounds are compounds which can be isolated in a useful
degree of purity from a reaction mixture.
[0069] The terms "treat", "treating" and "treatment" refer to a
method of alleviating or abrogating a disease and/or its attendant
symptoms.
[0070] The terms "prevent", "preventing" and "prevention" refer to
a method of preventing the onset of a disease and/or its attendant
symptoms or barring a subject from acquiring a disease. As used
herein, "prevent", "preventing" and "prevention" also include
delaying the onset of a disease and/or its attendant symptoms and
reducing a subject's risk of acquiring a disease.
[0071] The term "therapeutically effective amount" refers to that
amount of the compound being administered sufficient to prevent
development of or alleviate to some extent one or more of the
symptoms of the condition or disorder being treated.
[0072] The term "modulate" refers to the ability of a compound to
increase or decrease the function, or activity, of a Bcl-2
protein.
[0073] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. By "pharmaceutically acceptable" it is meant the
carrier, diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0074] The term "subject" is defined herein to include animals such
as mammals, including, but not limited to, primates (e.g., humans),
cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the
like. In suitable embodiments, the subject is a human.
Compounds
[0075] One embodiment of this invention pertains to compounds and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof, which are useful as inhibitors of
anti-apoptotic Bcl-2 proteins.
[0076] One embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(2R)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and therapeutically
acceptable salts, prodrugs, metabolites, or salts of prodrugs
thereof.
[0077] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}phenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0078] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}phenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0079] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(5S,8S)-1-oxaspiro[4.5]dec-8-ylmethyl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0080] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(5R,8R)-1-oxaspiro[4.5]dec-8-ylmethyl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0081] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0082] Another embodiment pertains to
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-ylmethyl)amino]-3-nitrophenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0083] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(morpholin-4-yl)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]-
pyridin-5-yloxy)benzamide; and therapeutically acceptable salts,
prodrugs, metabolites, or salts of prodrugs thereof.
[0084] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(2S)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and therapeutically
acceptable salts, prodrugs, metabolites, or salts of prodrugs
thereof.
[0085] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
and therapeutically acceptable salts, prodrugs, metabolites, or
salts of prodrugs thereof.
[0086] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[3-(hydroxymethyl)oxetan-3-yl]methyl}amino)-3-nitrophenyl]s-
ulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0087] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3-hydroxy-3-methylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and therapeutically
acceptable salts, prodrugs, metabolites, or salts of prodrugs
thereof.
[0088] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3-hydroxytricyclo[3.3.1.1.sup.37]dec-1-yl)amino]-3-nitrophe-
nyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0089] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(1R,5S,6S)-3-oxabicyclo[3.1.0]hex-6-ylmethyl]amino}-
phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0090] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(3-hydroxyoxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and therapeutically
acceptable salts, prodrugs, metabolites, or salts of prodrugs
thereof.
[0091] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2-
,3-b]pyridin-5-yloxy)benzamide; and therapeutically acceptable
salts, prodrugs, metabolites, or salts of prodrugs thereof.
[0092] Another embodiment pertains to methyl
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]sulfamoyl}-2-n-
itrophenyl)amino]methyl}tetrahydro-2H-pyran-4-carboxylate; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0093] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)hydrazinyl]phenyl}sulfon-
yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0094] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(4R)-oxepan-4-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and therapeutically
acceptable salts, prodrugs, metabolites, or salts of prodrugs
thereof.
[0095] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(4S)-oxepan-4-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and therapeutically
acceptable salts, prodrugs, metabolites, or salts of prodrugs
thereof.
[0096] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-methyltetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0097] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]phenyl}sul-
fonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0098] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(oxetan-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrr-
olo[2,3-b]pyridin-5-yloxy)benzamide; and therapeutically acceptable
salts, prodrugs, metabolites, or salts of prodrugs thereof.
[0099] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2R,5R)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0100] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(6-hydroxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0101] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4,4-difluoro-1-hydroxycyclohexyl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0102] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-methoxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0103] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(3,3-difluorocyclobutyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0104] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[({1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}methyl-
)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
and therapeutically acceptable salts, prodrugs, metabolites, or
salts of prodrugs thereof.
[0105] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-4-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0106] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}ami-
no)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
and therapeutically acceptable salts, prodrugs, metabolites, or
salts of prodrugs thereof.
[0107] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}p-
henyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0108] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
and therapeutically acceptable salts, prodrugs, metabolites, or
salts of prodrugs thereof.
[0109] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
and therapeutically acceptable salts, prodrugs, metabolites, or
salts of prodrugs thereof.
[0110] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2S,6R)-6-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0111] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydrofuran-3-ylmethyl]amino}phenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0112] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2S)-6,6-dimethyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophe-
nyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0113] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and therapeutically
acceptable salts, prodrugs, metabolites, or salts of prodrugs
thereof.
[0114] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(6-fluoro-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0115] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(6-methoxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0116] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(trans-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0117] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(cis-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0118] Another embodiment pertains to
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)methyl]amino}-3-ni-
trophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
and therapeutically acceptable salts, prodrugs, metabolites, or
salts of prodrugs thereof.
[0119] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2S,5R)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0120] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(2S,5S)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0121] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-cyanotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0122] Another embodiment pertains to
N-[(4-{[(1-acetylpiperidin-4-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; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0123] Another embodiment pertains to
4-(4-{[2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-
piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0124] Another embodiment pertains to
4-(4-{[2-(4-chloro-3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-
piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0125] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-ethyltetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0126] Another embodiment pertains to
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,4-dioxepan-6-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1-
H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and therapeutically
acceptable salts, prodrugs, metabolites, or salts of prodrugs
thereof.
[0127] Another embodiment pertains to
4-(4-{[2-(4-cyclopropylphenyl)-4,4-dimethylcyclohex-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; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0128] Another embodiment pertains to
4-(4-{[2-(3,4-dichlorophenyl)-4,4-dimethylcyclohex-1-en-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; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0129] Another embodiment pertains to
4-[4-({2-[4-(difluoromethyl)phenyl]-4,4-dimethylcyclohex-1-en-1-yl}methyl-
)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phen-
yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
therapeutically acceptable salts, prodrugs, metabolites, or salts
of prodrugs thereof.
[0130] The compounds of the invention may comprise geometric
isomers. Compounds of this invention may contain carbon-carbon
double bonds or carbon-nitrogen double bonds in the E or Z
configuration, wherein the term "E" represents higher order
substituents on opposite sides of the carbon-carbon or
carbon-nitrogen double bond and the term "Z" represents higher
order substituents on the same side of the carbon-carbon or
carbon-nitrogen double bond as determined by the Cahn-Ingold-Prelog
Priority Rules. The compounds of this invention may also exist as a
mixture of "E" and "Z" isomers. Substituents around a cycloalkyl or
heterocycloalkyl are designated as being of cis or trans
configuration. Furthermore, the invention contemplates the various
isomers and mixtures thereof resulting from the disposal of
substituents around an adamantane ring system. Two substituents
around a single ring within an adamantane ring system are
designated as being of Z or E relative configuration. For examples,
see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org.
Chem. 1998, 63, 2758-2760.
[0131] Compounds of this invention may contain asymmetrically
substituted carbon atoms in the R or S configuration, in which the
terms "R" and "S" are as defined by the IUPAC 1974 Recommendations
for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976)
45, 13-10. Compounds having asymmetrically substituted carbon atoms
with equal amounts of R and S configurations are racemic at those
carbon atoms. Atoms with an excess of one configuration over the
other are assigned the configuration present in the higher amount,
preferably an excess of about 85%-90%, more preferably an excess of
about 95%-99%, and still more preferably an excess greater than
about 99%. Accordingly, this invention includes racemic mixtures,
relative and absolute stereoisomers, and mixtures of relative and
absolute stereoisomers.
[0132] Compounds of the invention can exist in a prodrug form of
the selective Bcl-2 inhibitor compound. Prodrugs are derivatives of
an active drug designed to ameliorate some identified, undesirable
physical or biological property. The physical properties are
usually solubility (too much or not enough lipid or aqueous
solubility) or stability related, while problematic biological
properties include too rapid metabolism or poor bioavailability
which itself may be related to a physicochemical property. Prodrugs
are usually prepared by: a) formation of ester, hemi esters,
carbonate esters, nitrate esters, amides, hydroxamic acids,
carbamates, imines, Mannich bases, phosphates, phosphate esters,
and enamines of the active drug, b) functionalizing the drug with
azo, glycoside, peptide, and ether functional groups, c) use of
aminals, hemi-aminals, polymers, salts, complexes, phosphoramides,
acetals, hemiacetals, and ketal forms of the drug. For example, see
Andrejus Korolkovas's, "Essentials of Medicinal Chemistry", John
Wiley-Interscience Publications, John Wiley and Sons, New York
(1988), pp. 97-118, which is incorporated in its entirety by
reference herein.
Isotope Enriched or Labeled Compounds
[0133] Compounds of the invention can exist in isotope-labeled or
-enriched form containing one or more atoms having an atomic mass
or mass number different from the atomic mass or mass number most
abundantly found in nature. Isotopes can be radioactive or
non-radioactive isotopes. Isotopes of atoms such as hydrogen,
carbon, phosphorous, sulfur, fluorine, chlorine, and iodine
include, but are not limited to, .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.32P, .sup.35S, .sup.18F,
.sup.36Cl, and .sup.125I Compounds that contain other isotopes of
these and/or other atoms are within the scope of this
invention.
[0134] In another embodiment, the isotope-labeled compounds contain
deuterium (2H), tritium (.sup.3H) or .sup.14C isotopes.
Isotope-labeled compounds of this invention can be prepared by the
general methods well known to persons having ordinary skill in the
art. Such isotope-labeled compounds can be conveniently prepared by
carrying out the procedures disclosed in the Examples disclosed
herein and Schemes by substituting a readily available
isotope-labeled reagent for a non-labeled reagent. In some
instances, compounds may be treated with isotope-labeled reagents
to exchange a normal atom with its isotope, for example, hydrogen
for deuterium can be exchanged by the action of a deuteric acid
such as D.sub.2SO.sub.4/D.sub.2O. In addition to the above,
relevant procedures and intermediates are disclosed, for instance,
in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J
et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org
Lett, 5(7), 963 (2003); PCT publications WO1997010223,
WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;
7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013;
and US Patent Application Publication Nos. 20090137457;
20090131485; 20090131363; 20090118238; 20090111840; 20090105338;
20090105307; 20090105147; 20090093422; 20090088416; and
20090082471, the methods are hereby incorporated by reference.
[0135] The isotope-labeled compounds of the invention may be used
as standards to determine the effectiveness of Bcl-2 inhibitors in
binding assays. Isotope containing compounds have been used in
pharmaceutical research to investigate the in vivo metabolic fate
of the compounds by evaluation of the mechanism of action and
metabolic pathway of the nonisotope-labeled parent compound (Blake
et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic
studies are important in the design of safe, effective therapeutic
drugs, either because the in vivo active compound administered to
the subject or because the metabolites produced from the parent
compound prove to be toxic or carcinogenic (Foster et al., Advances
in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985;
Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932
(1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88
(1999).
[0136] In addition, non-radio active isotope containing drugs, such
as deuterated drugs called "heavy drugs," can be used for the
treatment of diseases and conditions related to Bcl-2 activity.
Increasing the amount of an isotope present in a compound above its
natural abundance is called enrichment. Examples of the amount of
enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79,
84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15%
of normal atom with a heavy isotope has been effected and
maintained for a period of days to weeks in mammals, including
rodents and dogs, with minimal observed adverse effects (Czajka D M
and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F,
Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.
Physiol. 1961 201: 357). Acute replacement of as high as 15%-23% in
human fluids with deuterium was found not to cause toxicity
(Blagojevic N et al. in "Dosimetry & Treatment Planning for
Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds.
1994. Advanced Medical Publishing, Madison Wis. pp. 125-134;
Diabetes Metab. 23: 251 (1997)).
[0137] Stable isotope labeling of a drug can alter its
physico-chemical properties such as pKa and lipid solubility. These
effects and alterations can affect the pharmacodynamic response of
the drug molecule if the isotopic substitution affects a region
involved in a ligand-receptor interaction. While some of the
physical properties of a stable isotope-labeled molecule are
different from those of the unlabeled one, the chemical and
biological properties are the same, with one important exception:
because of the increased mass of the heavy isotope, any bond
involving the heavy isotope and another atom will be stronger than
the same bond between the light isotope and that atom. Accordingly,
the incorporation of an isotope at a site of metabolism or
enzymatic transformation will slow said reactions potentially
altering the pharmacokinetic profile or efficacy relative to the
non-isotopic compound.
Pharmaceutical Compositions, Combination Therapies, and
Administration
[0138] Another embodiment pertains to pharmaceutical compositions
comprising a compound of this invention and an excipient.
[0139] Still another embodiment pertains to compositions for
treating diseases during which anti-apoptotic Bcl-2 proteins are
expressed, said compositions comprising an excipient and a
therapeutically effective amount of the compound of this
invention.
[0140] Still another embodiment pertains to compositions for
treating bladder cancer, brain cancer, breast cancer, bone marrow
cancer, cervical cancer, chronic 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, said compositions
comprising an excipient and a therapeutically effective amount of
the compound of this invention.
[0141] Still another embodiment pertains to compositions for
treating diseases during which are expressed anti-apoptotic Bcl-2
proteins, said compositions comprising an excipient and a
therapeutically effective amount of the compound of this invention
and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
[0142] Still another embodiment pertains to compositions for
treating bladder cancer, brain cancer, breast cancer, bone marrow
cancer, cervical cancer, chronic 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, chronic
lymphocytic leukemia, myeloma, prostate cancer, small cell lung
cancer or spleen cancer, said compositions comprising an excipient
and a therapeutically effective amount of the compound of this
invention and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
[0143] Still another embodiment pertains to compositions for
treating systemic lupus erythematosus, lupus nephritis, or
Sjogren's Syndrome, said compositions comprising an excipient and a
therapeutically effective amount of the compound of this
invention.
[0144] Still another embodiment pertains to compositions for
treating systemic lupus erythematosus, lupus nephritis, or
Sjogren's Syndrome, said compositions comprising an excipient and a
therapeutically effective amount of the compound of this invention
and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
[0145] Metabolites of compounds of this invention, produced by in
vitro or in vivo metabolic processes, may also have utility for
treating diseases associated with anti-apoptotic Bcl-2
proteins.
[0146] Certain precursor compounds which may be metabolized in
vitro or in vivo to form compounds of this invention may also have
utility for treating diseases associated with expression of
anti-apoptotic Bcl-2 proteins.
[0147] Compounds of this invention may exist as acid addition
salts, basic addition salts or zwitterions. Salts of the compounds
are prepared during isolation or following purification of the
compounds. Acid addition salts of the compounds are those derived
from the reaction of the compounds with an acid. For example, the
acetate, adipate, alginate, bicarbonate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsufonate, digluconate, formate, fumarate, glycerophosphate,
glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, lactobionate, lactate, maleate,
mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,
nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate,
picrate, propionate, succinate, tartrate, thiocyanate,
trichloroacetic, trifluoroacetic, para-toluenesulfonate, and
undecanoate salts of the compounds are contemplated as being
embraced by this invention. Basic addition salts of the compounds
are those derived from the reaction of the compounds with the
hydroxide, carbonate or bicarbonate of cations such as lithium,
sodium, potassium, calcium, and magnesium.
[0148] The compounds of this invention may be administered, for
example, bucally, ophthalmically, orally, osmotically, parenterally
(intramuscularly, intraperitoneally intrasternally, intravenously,
subcutaneously), rectally, topically, transdermally or
vaginally.
[0149] Therapeutically effective amounts of compounds of this
invention depend on the recipient of the treatment, the disorder
being treated and the severity thereof, the composition containing
the compound, the time of administration, the route of
administration, the duration of treatment, the compound potency,
its rate of clearance and whether or not another drug is
co-administered. The amount of a compound of this invention used to
make a composition to be administered daily to a subject in a
single dose or in divided doses is from about 0.001 to about 1000
mg/kg, or about 0.01 to about 500 mg/kg, or about 0.1 to about 300
mg/kg. Single dose compositions contain these amounts or a
combination of submultiples thereof.
[0150] Dosage regimens may be adjusted to provide the optimum
desired response (e.g., a therapeutic or prophylactic response).
For example, a single bolus may be administered, several divided
doses may be administered over time or the dose may be
proportionally reduced or increased as indicated by the exigencies
of the therapeutic situation. It is especially advantageous to
formulate parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the mammalian subjects to be treated; each unit
containing a predetermined quantity of active compound calculated
to produce the desired therapeutic effect in association with the
required pharmaceutical carrier. The specification for the dosage
unit forms of the invention are dictated by and directly dependent
on (a) the unique characteristics of the active compound and the
particular therapeutic or prophylactic effect to be achieved, and
(b) the limitations inherent in the art of compounding such an
active compound for the treatment of sensitivity in
individuals.
[0151] Compounds of this invention may be administered with or
without an excipient. Excipients include, for example,
encapsulating materials or additives such as absorption
accelerators, antioxidants, binders, buffers, coating agents,
coloring agents, diluents, disintegrating agents, emulsifiers,
extenders, fillers, flavoring agents, humectants, lubricants,
perfumes, preservatives, propellants, releasing agents, sterilizing
agents, sweeteners, solubilizers, wetting agents and mixtures
thereof. The excipients may be pharmaceutically acceptable
excipients.
[0152] Excipients for preparation of compositions comprising a
compound of this invention to be administered orally in solid
dosage form include, for example, agar, alginic acid, aluminum
hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol,
carbomers, castor oil, cellulose, cellulose acetate, cocoa butter,
corn starch, corn oil, cottonseed oil, cross-povidone,
diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl
oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,
groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic
saline, lactose, magnesium hydroxide, magnesium stearate, malt,
mannitol, monoglycerides, olive oil, peanut oil, potassium
phosphate salts, potato starch, povidone, propylene glycol,
Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl
cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium
sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose,
surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol,
triglycerides, water, and mixtures thereof. Excipients for
preparation of compositions comprising a compound of this invention
to be administered ophthalmically or orally in liquid dosage forms
include, for example, 1,3-butylene glycol, castor oil, corn oil,
cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil,
groundnut oil, glycerol, isopropanol, olive oil, polyethylene
glycols, propylene glycol, sesame oil, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of
this invention to be administered osmotically include, for example,
chlorofluorohydrocarbons, ethanol, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of
this invention to be administered parenterally include, for
example, 1,3-butanediol, castor oil, corn oil, cottonseed oil,
dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive
oil, peanut oil, Ringer's solution, safflower oil, sesame oil,
soybean oil, U.S.P. or isotonic sodium chloride solution, water and
mixtures thereof. Excipients for preparation of compositions
comprising a compound of this invention to be administered rectally
or vaginally include, for example, cocoa butter, polyethylene
glycol, wax and mixtures thereof.
[0153] Compounds of this invention are expected to be useful when
used with alkylating agents, angiogenesis inhibitors, antibodies,
antimetabolites, antimitotics, antiproliferatives, antivirals,
aurora kinase inhibitors, other apoptosis promoters (for example,
Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptor
pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell
Engager) antibodies, antibody drug conjugates, biologic response
modifiers, cyclin-dependent kinase inhibitors, cell cycle
inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral
oncogene homolog (ErbB2) receptor inhibitors, growth factor
inhibitors, heat shock protein (HSP)-90 inhibitors, histone
deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,
inhibitors of inhibitors of apoptosis proteins (IAPs),
intercalating antibiotics, kinase inhibitors, kinesin inhibitors,
Jak2 inhibitors, mammalian target of rapamycin inhibitors,
microRNA's, mitogen-activated extracellular signal-regulated kinase
inhibitors, multivalent binding proteins, non-steroidal
anti-inflammatory drugs (NSAIDs), poly ADP (adenosine
diphosphate)-ribose polymerase (PARP) inhibitors, platinum
chemotherapeutics, polo-like kinase (Plk) inhibitors,
phosphoinositide-3 kinase (PI3K) inhibitors, proteosome 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, and in combination with one or
more of these agents.
[0154] BiTE antibodies are bi-specific antibodies that direct
T-cells to attack cancer cells by simultaneously binding the two
cells. The T-cell then attacks the target cancer cell. Examples of
BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab
(Micromet MT103) and the like. Without being limited by theory, one
of the mechanisms by which T-cells elicit apoptosis of the target
cancer cell is by exocytosis of cytolytic granule components, which
include perforin and granzyme B. In this regard, Bcl-2 has been
shown to attenuate the induction of apoptosis by both perforin and
granzyme B. These data suggest that inhibition of Bcl-2 could
enhance the cytotoxic effects elicited by T-cells when targeted to
cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani, J. of
Immunology 1997, 158 (12), 5783).
[0155] 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 Mcl-1 have been shown to enhance the
activity of ABT-263, (i.e.,
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)pip-
erazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-
)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide) or
ABT-737 (i.e.,
N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benz-
oyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3--
nitrobenzenesulfonamide) in multiple tumor cell lines (Tse et. al,
Cancer Research 2008, 68(9), 3421 and references therein).
[0156] 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.
[0157] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, CLORETAZINE.COPYRGT. (laromustine,
VNP 40101M), cyclophosphamide, decarbazine, estramustine,
fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU),
mafosfamide, melphalan, mitobronitol, mitolactol, nimustine,
nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa,
TREANDA.COPYRGT. (bendamustine), treosulfan, rofosfamide and the
like.
[0158] Angiogenesis inhibitors include endothelial-specific
receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth
factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor
(IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors,
matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived
growth factor receptor (PDGFR) inhibitors, thrombospondin analogs,
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
[0159] Antimetabolites include ALIMTA.COPYRGT. (pemetrexed
disodium, LY231514, MTA), 5-azacitidine, XELODA.COPYRGT.
(capecitabine), carmofur, LEUSTAT.COPYRGT. (cladribine),
clofarabine, cytarabine, cytarabine ocfosfate, cytosine
arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine,
EICAR (5-ethynyl-1-.beta.-D-ribofuranosylimidazole-4-carboxamide),
enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or
in combination with leucovorin, GEMZAR.COPYRGT. (gemcitabine),
hydroxyurea, ALKERAN.COPYRGT.(melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,
raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,
tegafur, TS-1, vidarabine, UFT and the like.
[0160] Antivirals include ritonavir, hydroxychloroquine and the
like.
[0161] Aurora kinase inhibitors include ABT-348, AZD-1152,
MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora
B-specific kinase inhibitors and pan-Aurora kinase inhibitors and
the like.
[0162] Bcl-2 protein inhibitors include AT-101 ((-)gossypol),
GENASENSE.COPYRGT. (G3139 or oblimersen (Bcl-2-targeting antisense
oligonucleotide)), IPI-194, IPI-565,
N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4--
(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobe-
nzenesulfonamide) (ABT-737),
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)pip-
erazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-
)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide
(ABT-263),
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 (ABT-199), GX-070
(obatoclax) and the like. Bcr-Abl kinase inhibitors include
DASATINIB.COPYRGT. (BMS-354825), GLEEVEC.COPYRGT. (imatinib) and
the like.
[0163] CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202, R-roscovitine), ZK-304709, dinaciclib and the
like.
[0164] COX-2 inhibitors include ABT-963, ARCOXIA.COPYRGT.
(etoricoxib), BEXTRA.RTM. (valdecoxib), BMS347070,
CELEBREX.COPYRGT. (celecoxib), COX-189 (lumiracoxib), CT-3,
DERAMAXX.COPYRGT. (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.COPYRGT. (rofecoxib) and
the like.
[0165] EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes,
EGF-vaccine, EMD-7200, ERBITUX.COPYRGT. (cetuximab), HR3, IgA
antibodies, IRESSA.COPYRGT. (gefitinib), TARCEVA.COPYRGT.
(erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB.COPYRGT.
(lapatinib) and the like.
[0166] ErbB2 receptor inhibitors include CP-724-714, CI-1033
(canertinib), HERCEPTIN.COPYRGT. (trastuzumab), TYKERB.COPYRGT.
(lapatinib), OMNITARG.COPYRGT. (2C4, petuzumab), TAK-165, GW-572016
(ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine),
APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody,
B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB
AR-209, mAB 2B-1 and the like.
[0167] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[0168] HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101,
CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953,
MYCOGRAB.COPYRGT. (human recombinant antibody to HSP-90),
NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009
and the like.
[0169] Inhibitors of inhibitors of apoptosis proteins include
HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
[0170] Antibody drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC,
MEDI-547, SGN-19Am SGN-35, SGN-75, trastuzumab emtansine and the
like.
[0171] Activators of death receptor pathway include TRAIL,
antibodies or other agents that target TRAIL or death receptors
(e.g., DR4 and DR5) such as Apomab, conatumumab, ETR2-STO1, GDC0145
(lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.
[0172] Kinesin inhibitors include Eg5 inhibitors such as AZD4877,
ARRY-520; CENPE inhibitors such as GSK923295A and the like.
[0173] JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and
INCB018424 and the like.
[0174] MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901,
PD-98059 and the like.
[0175] mTOR inhibitors include AP-23573, CCI-779, everolimus,
RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2
inhibitors, including PI-103, PP242, PP30, Torin 1 and the
like.
[0176] Non-steroidal anti-inflammatory drugs include
AMIGESIC.COPYRGT. (salsalate), DOLOBID.COPYRGT. (diflunisal),
MOTRIN.COPYRGT. (ibuprofen), ORUDIS.COPYRGT. (ketoprofen),
RELAFEN.COPYRGT. (nabumetone), FELDENE.COPYRGT. (piroxicam),
ibuprofen cream, ALEVE.COPYRGT. (naproxen) and NAPROSYN.COPYRGT.
(naproxen), VOLTAREN.COPYRGT. (diclofenac), INDOCIN.COPYRGT.
(indomethacin), CLINORIL.RTM. (sulindac), TOLECTIN.COPYRGT.
(tolmetin), LODINE.COPYRGT. (etodolac), TORADOL.COPYRGT.
(ketorolac), DAYPRO.COPYRGT. (oxaprozin) and the like.
[0177] PDGFR inhibitors include C-451, CP-673, CP-868596 and the
like.
[0178] Platinum chemotherapeutics include cisplatin,
ELOXATIN.COPYRGT. (oxaliplatin) eptaplatin, lobaplatin, nedaplatin,
PARAPLATIN.COPYRGT. (carboplatin), satraplatin, picoplatin and the
like.
[0179] Polo-like kinase inhibitors include BI-2536 and the
like.
[0180] Phosphoinositide-3 kinase (PI3K) inhibitors include
wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658,
PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
[0181] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[0182] VEGFR inhibitors include AVASTIN.COPYRGT. (bevacizumab),
ABT-869, AEE-788, ANGIOZYME.TM. (a ribozyme that inhibits
angiogenesis (Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron,
(Emeryville, Calif.)), axitinib (AG-13736), AZD-2171, CP-547,632,
IM-862, MACUGEN (pegaptamib), NEXAVAR.COPYRGT. (sorafenib,
BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584),
SUTENT.COPYRGT. (sunitinib, SU-11248), VEGF trap, ZACTIMA.TM.
(vandetanib, ZD-6474) and the like.
[0183] Antibiotics include intercalating antibiotics aclarubicin,
actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE.COPYRGT.
(bleomycin), daunorubicin, CAELYX.COPYRGT. or MYOCET.COPYRGT.
(liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin,
ZAVEDOS.COPYRGT. (idarubicin), mitomycin C, nemorubicin,
neocarzinostatin, peplomycin, pirarubicin, rebeccamycin,
stimalamer, streptozocin, VALSTAR.RTM. (valrubicin), zinostatin and
the like.
[0184] Topoisomerase inhibitors include aclarubicin,
9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan,
BN-80915, CAMPTOSAR.COPYRGT. (irinotecan hydrochloride),
camptothecin, CARDIOXANE.COPYRGT. (dexrazoxine), diflomotecan,
edotecarin, ELLENCE.COPYRGT. or PHARMORUBICIN.COPYRGT.
(epirubicin), etoposide, exatecan, 10-hydroxycamptothecin,
gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin,
pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan
and the like.
[0185] Antibodies include AVASTIN.COPYRGT. (bevacizumab),
CD40-specific antibodies, chTNT-1/B, denosumab, ERBITUX.COPYRGT.
(cetuximab), HUMAX-CD4.COPYRGT. (zanolimumab), IGF1R-specific
antibodies, lintuzumab, PANOREX.COPYRGT. (edrecolomab),
RENCAREX.COPYRGT. (WX G250), RITUXAN.COPYRGT. (rituximab),
ticilimumab, trastuzimab, CD20 antibodies types I and II and the
like.
[0186] Hormonal therapies include ARIMIDEX.COPYRGT. (anastrozole),
AROMASIN.COPYRGT. (exemestane), arzoxifene, CASODEX.COPYRGT.
(bicalutamide), CETROTIDE.COPYRGT. (cetrorelix), degarelix,
deslorelin, DESOPAN.COPYRGT. (trilostane), dexamethasone,
DROGENIL.COPYRGT. (flutamide), EVISTA.COPYRGT. (raloxifene),
AFEMA.TM. (fadrozole), FARESTON.COPYRGT. (toremifene),
FASLODEX.COPYRGT. (fulvestrant), FEMARA.COPYRGT. (letrozole),
formestane, glucocorticoids, HECTOROL.COPYRGT. (doxercalciferol),
RENAGEL.COPYRGT. (sevelamer carbonate), lasofoxifene, leuprolide
acetate, MEGACE.COPYRGT. (megesterol), MIFEPREX.COPYRGT.
(mifepristone), NILANDRON.TM. (nilutamide), NOLVADEX.COPYRGT.
(tamoxifen citrate), PLENAXIS.TM. (abarelix), prednisone,
PROPECIA.COPYRGT. (finasteride), rilostane, SUPREFACT.COPYRGT.
(buserelin), TRELSTAR.COPYRGT. (luteinizing hormone releasing
hormone (LHRH)), VANTAS.COPYRGT. (Histrelin implant),
VETORYL.COPYRGT. (trilostane or modrastane), ZOLADEX.COPYRGT.
(fosrelin, goserelin) and the like.
[0187] Deltoids and retinoids include seocalcitol (EB1089, CB1093),
lexacalcitrol (KH1060), fenretinide, PANRETIN.COPYRGT.
(aliretinoin), ATRAGEN.COPYRGT. (liposomal tretinoin),
TARGRETIN.COPYRGT. (bexarotene), LGD-1550 and the like.
[0188] PARP inhibitors include ABT-888 (veliparib), olaparib,
KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231
and the like.
[0189] Plant alkaloids include, but are not limited to,
vincristine, vinblastine, vindesine, vinorelbine and the like.
[0190] Proteasome inhibitors include VELCADE.COPYRGT. (bortezomib),
MG132, NPI-0052, PR-171, carfilzomib and the like.
[0191] 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.COPYRGT. (interferon gamma-1b) or
interferon gamma-n1, combinations thereof and the like. Other
agents include ALFAFERONE.COPYRGT., (IFN-.alpha.), BAM-002
(oxidized glutathione), BEROMUN.COPYRGT. (tasonermin),
BEXXAR.COPYRGT. (tositumomab), CAMPATH.COPYRGT. (alemtuzumab),
CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin,
epratuzumab, GRANOCYTE.COPYRGT. (lenograstim), lentinan, leukocyte
alpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma
vaccine, mitumomab, molgramostim, MYLOTARG.TM. (gemtuzumab
ozogamicin), NEUPOGEN.COPYRGT. (filgrastim), OncoVAC-CL,
OVAREX.COPYRGT. (oregovomab), pemtumomab (Y-muHMFG1),
PROVENGE.COPYRGT.(sipuleucel-T), sargaramostim, sizofilan,
teceleukin, THERACYS.COPYRGT.(Bacillus Calmette-Guerin), ubenimex,
VIRULIZIN.COPYRGT. (immunotherapeutic, Lorus Pharmaceuticals),
Z-100 (Specific Substance of Maruyama (SSM)), WF-10
(Tetrachlorodecaoxide (TCDO)), PROLEUKIN.COPYRGT. (aldesleukin),
ZADAXIN.COPYRGT. (thymalfasin), ZENAPAX.COPYRGT. (daclizumab),
ZEVALIN.COPYRGT. (90Y-Ibritumomab tiuxetan) and the like.
[0192] Biological response modifiers are agents that modify defense
mechanisms of living organisms or biological responses, such as
survival, growth or differentiation of tissue cells to direct them
to have anti-tumor activity and include krestin, lentinan,
sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the
like.
[0193] Pyrimidine analogs include cytarabine (ara C or Arabinoside
C), cytosine arabinoside, doxifluridine, FLUDARA.COPYRGT.
(fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR.COPYRGT.
(gemcitabine), TOMUDEX.COPYRGT. (ratitrexed), TROXATYL.TM.
(triacetyluridine troxacitabine) and the like.
[0194] Purine analogs include LANVIS.COPYRGT. (thioguanine) and
PURI-NETHOL.COPYRGT. (mercaptopurine).
[0195] Antimitotic agents include batabulin, epothilone D
(KOS-862),
N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS 247550), paclitaxel, TAXOTERE.COPYRGT.
(docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel),
vinflunine, ZK-EPO (synthetic epothilone) and the like.
[0196] Ubiquitin ligase inhibitors include MDM2 inhibitors, such as
nutlins, NEDD8 inhibitors such as MLN4924 and the like.
[0197] Compounds of this invention can also be used as
radiosensitizers that enhance the efficacy of radiotherapy.
Examples of radiotherapy include external beam radiotherapy,
teletherapy, brachytherapy and sealed, unsealed source radiotherapy
and the like.
[0198] Additionally, compounds of this invention may be combined
with other chemotherapeutic agents such as ABRAXANE.TM. (ABI-007),
ABT-100 (farnesyl transferase inhibitor),
ADVEXIN.COPYRGT.(Ad5CMV-p53 vaccine), ALTOCOR.COPYRGT. or
MEVACOR.COPYRGT. (lovastatin), AMPLIGEN.COPYRGT. (poly I:poly C12U,
a synthetic RNA), APTOSYN.COPYRGT. (exisulind), AREDIA.COPYRGT.
(pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE.COPYRGT.
(tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab),
cachectin or cachexin (tumor necrosis factor-alpha), canvaxin
(vaccine), CEAVAC.COPYRGT. (cancer vaccine), CELEUK.COPYRGT.
(celmoleukin), CEPLENE.COPYRGT. (histamine dihydrochloride),
CERVARIX.COPYRGT. (human papillomavirus vaccine), CHOP.COPYRGT. (C:
CYTOXAN.COPYRGT. (cyclophosphamide); H: ADRIAMYCIN.COPYRGT.
(hydroxydoxorubicin); 0: Vincristine (ONCOVIN.COPYRGT.); P:
prednisone), CYPAT.TM. (cyproterone acetate), combrestatin A4P,
DAB(389)EGF (catalytic and translocation domains of diphtheria
toxin fused via a His-Ala linker to human epidermal growth factor)
or TransMID-107R.TM. (diphtheria toxins), dacarbazine,
dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),
eniluracil, EVIZON.TM. (squalamine lactate), DIMERICINE.COPYRGT.
(T4N5 liposome lotion), discodermolide, DX-8951f (exatecan
mesylate), enzastaurin, EP0906 (epithilone B), GARDASIL.COPYRGT.
(quadrivalent human papillomavirus (Types 6, 11, 16, 18)
recombinant vaccine), GASTRIMMUNE.COPYRGT., GENASENSE.COPYRGT., GMK
(ganglioside conjugate vaccine), GVAX.COPYRGT. (prostate cancer
vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic
acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox),
IL-13-pseudomonas exotoxin, interferon-.alpha., interferon-.gamma.,
JUNOVAN.TM. or MEPACT.TM. (mifamurtide), lonafarnib,
5,10-methylenetetrahydrofolate, miltefosine
(hexadecylphosphocholine), NEOVASTAT.COPYRGT.(AE-941),
NEUTREXIN.COPYRGT. (trimetrexate glucuronate), NIPENT.COPYRGT.
(pentostatin), ONCONASE.RTM. (a ribonuclease enzyme),
ONCOPHAGE.COPYRGT. (melanoma vaccine treatment), ONCOVAX.COPYRGT.
(IL-2 Vaccine), ORATHECIN.TM. (rubitecan), OSIDEM.COPYRGT.
(antibody-based cell drug), OVAREX.COPYRGT. MAb (murine monoclonal
antibody), paclitaxel, PANDIMEX.TM. (aglycone saponins from ginseng
comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol
(aPPT)), panitumumab, PANVAC.COPYRGT.-VF (investigational cancer
vaccine), pegaspargase, PEG Interferon A, phenoxodiol,
procarbazine, rebimastat, REMOVAB.COPYRGT. (catumaxomab),
REVLIMID.COPYRGT. (lenalidomide), RSR13 (efaproxiral),
SOMATULINE.COPYRGT. LA (lanreotide), SORIATANE.COPYRGT.
(acitretin), staurosporine (Streptomyces staurospores), talabostat
(PT100), TARGRETIN.COPYRGT. (bexarotene), TAXOPREXIN.COPYRGT.
(DHA-paclitaxel), TELCYTA.COPYRGT. (canfosfamide, TLK286),
temilifene, TEMODAR.COPYRGT. (temozolomide), tesmilifene,
thalidomide, THERATOPE.COPYRGT. (STn-KLH), thymitaq
(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline
dihydrochloride), TNFERADE.TM. (adenovector: DNA carrier containing
the gene for tumor necrosis factor-.alpha.), TRACLEER.COPYRGT. or
ZAVESCA.COPYRGT. (bosentan), tretinoin (Retin-A), tetrandrine,
TRISENOX.COPYRGT. (arsenic trioxide), VIRULIZIN.COPYRGT., ukrain
(derivative of alkaloids from the greater celandine plant), vitaxin
(anti-alphavbeta3 antibody), XCYTRIN.RTM. (motexafin gadolinium),
XINLAY.TM. (atrasentan), XYOTAX.TM. (paclitaxel poliglumex),
YONDELIS.COPYRGT. (trabectedin), ZD-6126, ZINECARD.COPYRGT.
(dexrazoxane), ZOMETA.RTM. (zolendronic acid), zorubicin and the
like.
[0199] Many proteins have been implicated in general autoimmune and
inflammatory responses. Accordingly, it may be possible to combine
the selective Bcl-2 inhibitors of the invention with compounds
capable of altering the function of other proteins implicated in
general autoimmune and inflammatory responses. Examples of proteins
associated with autoimmune and inflammatory response include C5,
CCL1 (I-309), CCL11 (eotaxin), CCL13 (mcp-4), CCL15 (MIP-1d), CCL16
(HCC-4), CCL17 (TARC), CCL18 (PARC), CCL19, CCL2 (mcp-1), CCL20
(MIP-3a), CCL21 (MIP-2), CCL23 (MPIF-1), CCL24 (MPIF-2/eotaxin-2),
CCL25 (TECK), CCL26, CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES),
CCL7 (mcp-3), CCL8 (mcp-2), CXCL1, CXCL10 (IP-10), CXCL 11
(I-TAC/IP-9), CXCL12 (SDF1), CXCL13, CXCL14, CXCL2, CXCL3, CXCL5
(ENA-78/LIX), CXCL6 (GCP-2), CXCL9, IL13, IL8, CCL13 (mcp-4), CCR1,
CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CX3CR1, IL8RA, XCR1
(CCXCR1), IFNA2, IL10, IL13, IL17C, IL1A, IL1B, IL1F10, IL1F5,
IL1F6, IL1F7, IL1F8, IL1F9, IL22, IL5, IL8, IL9, LTA, LTB, MIF,
SCYE1 (endothelial Monocyte-activating cytokine), SPP1, TNF,
TNFSF5, IFNA2, ABCF1, BCL6, C3, C4A, CEBPB, CRP, ICEBERG, IL1R1,
IL1RN, IL8RB, LTB4R, TOLLIP, FADD, IRAK-M, IRAK1, IRAK2, IRAK4,
MYD88, NCK2, TNFAIP3, TRADD, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5,
TRAF6, ACVR1, ACVR1B, ACVR2, ACVR2B, ACVRL1, CD28, CD3E, CD3G,
CD3Z, CD69, CD80, CD86, CNR1, CTLA4, CYSLTR1, FCER1A, FCER2,
FCGR3A, GPR44, HAVCR2, OPRD1, P2RX7, TLR2, TLR3, TLR4, TLR5, TLR6,
TLR7, TLR8, TLR9, TLR10, BLR1, CCL1, CCL2, CCL3, CCL4, CCL5, CCL7,
CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20,
CCL21, CCL22, CCL23, CCL24, CCL25, CCR1, CCR2, CCR3, CCR4, CCR5,
CCR6, CCR7, CCR8, CCR9, CX3CL1, CX3CR1, CXCL1, CXCL2, CXCL3, CXCL5,
CXCL6, CXCL10, CXCL11, CXCL12, CXCL13, CXCR4, GPR2, SCYE1, SDF2,
XCL1, XCL2, XCR1, AMH, AMHR2, BMPR1A, BMPR1B, BMPR2, C19orf10
(IL27w), CER1, CSF1, CSF2, CSF3, DKFZp451J0118, FGF2, GFI1, IFNA1,
IFNB1, IFNG, IGF1, IL1A, IL1B, IL1R1, IL1R2, IL2, IL2RA, IL2RB,
IL2RG, IL3, IL4, IL4R, IL5, IL5RA, IL6, IL6R, IL6ST, IL7, IL8,
IL8RA, IL8RB, IL9, IL9R, IL10, IL10RA, IL10RB, IL11, IL11RA, IL12A,
IL12B, IL12RB1, IL12RB2, IL13, IL13RA1, IL13RA2, IL15, IL15RA,
IL16, IL17, IL17R, IL18, IL18R1, IL19, IL20, KITLG, LEP, LTA, LTB,
LTB4R, LTB4R2, LTBR, MIF, NPPB, PDGFB, TBX21, TDGF1, TGFA, TGFB1,
TGFB1I1, TGFB2, TGFB3, TGFBI, TGFBR1, TGFBR2, TGFBR3, TH1L, TNF,
TNFRSF1A, TNFRSFIB, TNFRSF7, TNFRSF8, TNFRSF9, TNFRSF11A, TNFRSF21,
TNFSF4, TNFSF5, TNFSF6, TNFSF 11, VEGF, ZFPM2, RNF 110 (ZNF144),
FGF family, PLGF, DLL4, NPR-1, Fe gamma receptor IIB modulators,
anti-plasmacytoid cells modulators, Immune-complex clearance
modifiers such as RNase or DNase, proto oncogen inhibitors such as,
but not limited to c-kit and b-raf, Type 1 fibroblasts growth
factor receptor modulators, dihydroorotate dehydrogenase
modulators, estrogen receptor modulators, DNA directed DNA
polymerase inhibitor, CD85gamma modulators, and epigenetic
modifiers.
[0200] Combinations for treating autoimmune and inflammatory
diseases may include compounds of the invention and non-steroidal
anti-inflammatory drug(s), also referred to as NSAIDS, which
include drugs like ibuprofen. Other combinations may include
corticosteroids including prednisolone; the well known side-effects
of steroid use can be reduced or even eliminated by tapering the
steroid dose required when treating subjects in combination with
this invention.
[0201] Non-limiting examples of therapeutic agents that may be used
in combination with selective Bcl-2 inhibitors of this invention
for treating lupus include the following: cytokine suppressive
anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of
other human cytokines or growth factors, for example, TNF, LT,
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11,
IL-12, IL-13, IL-15, IL-16, IL-17A, IL-17F, IL-18, IL-21, IL-22,
IL-23, IL-25, IL-33, interferons (for example, alpha, beta, gamma
etc.), Tweak, BAFF/BLyS, April, chemokines. Compounds of the
invention can also be combined with antibodies to cell surface
molecules such as CD2, CD3, CD4, CD8, CD16, CD19, CD20, CD22, CD25,
CD28, CD30, CD32, CD40, CD45, CD47, CD52, CD54, CD64, CD69, CD72,
CD79, CD80 (B7.1), CD86 (B7.2), CD90, CD100, CD200, CTLA, ICOS-1,
B7RP, BR3, TACI, BCMA, or their ligands including CD154 (gp39 or
CD40L).
[0202] Compounds of the invention may also be combined with other
agents, such as cytoxan, 6-MP, azathioprine sulphasalazine,
mesalazine, olsalazine chloroquinine, penicillamine, aurothiomalate
(intramuscular and oral), azathioprine, cochicine, corticosteroids
(oral, inhaled and local injection), selective glucocorticoid
receptor modulators (SGRMs), O beta-2 adrenoreceptor agonists
(salbutamol, terbutaline, salmeterol), xanthines (theophylline,
aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium
and oxitropium, cyclosporin, FK506, leflunomide, corticosteroids
such as prednisolone, phosphodiesterase inhibitors, adensosine
agonists, antithrombotic agents, complement inhibitors, adrenergic
agents, agents which interfere with signaling by proinflammatory
cytokines such as TNF-.alpha. or IL-1 (e.g., IRAK, NIK, IKK, p38 or
MAP kinase inhibitors), IL-10 converting enzyme inhibitors, JAK
inhibitors, BTK inhibitors, SYK inhibitors, PKC family inhibitors,
TNF-.alpha. converting enzyme (TACE) inhibitors, T-cell signaling
inhibitors such as kinase inhibitors, metalloproteinase inhibitors,
sulfasalazine, 6-mercaptopurines, angiotensin converting enzyme
inhibitors, soluble cytokine receptors and derivatives thereof
(e.g., soluble p55 or p75 TNF receptors and the derivatives
p75TNFRIgG (Enbrel.TM. and p55TNFRIgG (Lenercept)), sIL-1RI,
sIL-1RII, sIL-6R), antiinflammatory cytokines (e.g., IL-4, IL-6,
IL-10, IL-11, IL12, IL-13, IL-17, IL-18, IL-33 and TGF.beta.),
folic acid, hydroxychloroquine sulfate, etanercept, infliximab,
methylprednisolone, meloxicam, methylprednisolone acetate, gold
sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene
napsylate/apap, folate, diclofenac sodium, oxycodone HCl,
hydrocodone bitartrate/apap, diclofenac sodium/misoprostol,
fentanyl, anakinra, human recombinant, tramadol HCl,
cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium,
prednisolone, morphine sulfate, lidocaine hydrochloride,
glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine,
olopatadine HCl, misoprostol, omeprazole, IL-1 TRAP, MRA, CTLA4-IG,
IL-18 BP, anti-IL-18, Anti-IL15, BIRB-796, SCIO-469, VX-702,
AMG-548, VX-740, Roflumilast, IC-485, CDC-801, Mesopram.
Combinations may additionally include leflunomide, cyclosporine and
SiP agonists.
[0203] Examples of therapeutic agents for SLE (Lupus) and lupus
nephritis, with which the compounds of the invention can be
combined include the following: NSAIDs, for example, diclofenac,
naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for
example, Celecoxib, rofecoxib, valdecoxib; anti-malarials, for
example, hydroxychloroquine; Steroids, for example, prednisone,
prednisolone, budenoside, dexamethasone; Cytotoxics, for example,
azathioprine, cyclophosphamide, mycophenolate mofetil,
methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for
example Cellcept. binding proteins incorporated into the methods of
the invention, may also be combined with agents such as
sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran and agents
which interfere with synthesis, production or action of
proinflammatory cytokines such as IL-1, for example, caspase
inhibitors like IL-1.beta. converting enzyme inhibitors and IL-1ra.
The invention may also be used with T cell signaling inhibitors,
for example, tyrosine kinase inhibitors; or molecules that target T
cell activation molecules, for example, CTLA-4-IgG or anti-B7
family antibodies such as B7RP, anti-PD-1 family antibodies. The
invention, can be combined with IL-11 or anti-cytokine antibodies,
for example, fonotolizumab (anti-IFNg antibody), anti-interferon
alpha, or anti-receptor receptor antibodies, for example, anti-TL-6
receptor antibody (including gp130) and antibodies to B-cell
surface molecules. The invention may also be used with inhibitors
of HMGB1, HDGF. The invention may also be used with inhibitors of
toll receptors 1, 2, 3, 4, 7, and 9. The invention may also be used
with inhibitors of dendritic cell makers BDCA-1, 2 and 3, DEC205,
CD11c, Bst2 (PDCA-1), Langerin, and SiglecH. The invention may also
be used with agents which promote regulatory T cell function. The
invention may also be used with UP 394 (abetimus), agents that
inhibit complement, for example, anti-C5, anti-C5a, deplete or
inactivate B-cells, for example, Rituximab (anti-CD20 antibody),
lymphostat-B (anti-BlyS antibody), anti-CD22, TNF antagonists, for
example, anti-TNF antibodies, Adalimumab (PCT Publication No. WO
97/29131; HUMIRA), CA2 (REMICADE), CDP 571, TNFR-Ig constructs,
(p75TNFRIgG (ENBREL) and p55TNFRIgG (LENERCEPT)) and inhibitors of
other bcl-2 family members such as Bcl-x.sub.L, Mcl-1, A-1 etc.
[0204] Examples of therapeutic agents used to treat Sjogren's
Syndrome, that may be combined with the selective Bcl-2 inhibitors
of the invention include, but are not limited to artificial tears,
cyclosporine, cevimeline, pilocarpine, NSAIDs, corticosteroids,
immunosuppressants, disease-modifying anti-rheumatic drugs (DMARDs)
such as methotrexate, and hydroxychloroquine.
Methods of Treatment
[0205] An embodiment of the invention pertains to methods of
treating cancer in a mammal comprising administering thereto a
therapeutically acceptable amount of a compound of this
invention.
[0206] Still another embodiment pertains to methods of treating
autoimmune disease in a mammal comprising administering thereto a
therapeutically acceptable amount of a compound of this
invention.
[0207] Still another embodiment pertains to methods of treating
disease in a subject during which anti-apoptotic Bcl-2 proteins are
expressed, said methods comprising administering to the subject a
therapeutically effective amount of a compound of this
invention.
[0208] Still another embodiment pertains to methods of treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer,
cervical cancer, chronic 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 in a subject, said methods
comprising administering to the subject a therapeutically effective
amount of a compound of this invention.
[0209] Still another embodiment pertains to methods of treating
disease in a subject during which are expressed anti-apoptotic
Bcl-2 proteins, said methods comprising administering to the
subject a therapeutically effective amount of a compound of this
invention and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
[0210] Still another embodiment pertains to methods of treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer,
cervical cancer, chronic 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, chronic lymphocytic
leukemia, myeloma, prostate cancer, small cell lung cancer or
spleen cancer in a subject, said methods comprising administering
to the subject a therapeutically effective amount of the compound
of this invention and a therapeutically effective amount of one
additional therapeutic agent or more than one additional
therapeutic agent.
[0211] Still another embodiment pertains to methods of treating
systemic lupus erythematosus, lupus nephritis, or Sjogren's
Syndrome in a subject, said methods comprising administering to the
subject a therapeutically effective amount of a compound of this
invention.
[0212] Still another embodiment pertains to methods of treating
systemic lupus erythematosus, lupus nephritis, and Sjogren's
Syndrome in a subject, said methods comprising administering to the
subject a therapeutically effective amount of the compound of this
invention and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
[0213] It is expected that, because compounds of this invention
bind to Bcl-2, they would also have utility as binders to
anti-apoptotic proteins having close structural homology to Bcl-2,
such as, for example, anti-apoptotic Bcl-X.sub.L, Bcl-w, Mcl-1 and
Bfl-1/A1 proteins.
[0214] Involvement of Bel-2 proteins in bladder cancer, brain
cancer, breast cancer, bone marrow cancer, cervical cancer, chronic
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, spleen cancer, and the like is described in commonly-owned
PCT/US2004/036770, published as WO 2005/049593, in
PCT/US2004/037911, published as WO 2005/049594, and in
PCT/US01/29432, published as WO02/24636.
[0215] Involvement of Bel-2 proteins in immune and autoimmune
diseases is described in Current Allergy and Asthma Reports 2003,
3, 378-384; British Journal of Haematology 2000, 110(3), 584-90;
Blood 2000, 95(4), 1283-92; and New England Journal of Medicine
2004, 351(14), 1409-1418. Involvement of Bel-2 proteins in
arthritis is disclosed in commonly-owned PCT/US2008/083478,
published as WO 2009/064938. Involvement of Bel-2 proteins in
methods of treating systemic lupus erythematosus, lupus nephritis,
and Sjogren's Syndrome is described in commonly-owned
PCT/US2011/061769, published as WO 2012/071374. Involvement of
Bel-2 proteins in bone marrow transplant rejection is disclosed in
commonly-owned U.S. patent application Ser. No. 11/941,196.
[0216] 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. Cancers include, but are not limited to,
hematologic and solid tumor types such as acoustic neuroma, acute
leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia
(monocytic, myeloblastic, adenocarcinoma, angiosarcoma,
astrocytoma, myelomonocytic and promyelocytic), acute t-cell
leukemia, basal cell carcinoma, bile duct carcinoma, bladder
cancer, brain cancer, breast cancer (including estrogen-receptor
positive breast cancer), bronchogenic carcinoma, Burkitt's
lymphoma, cervical cancer, chondrosarcoma, chordoma,
choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia,
chronic myelocytic (granulocytic) leukemia, chronic myelogenous
leukemia, colon cancer, colorectal cancer, craniopharyngioma,
cystadenocarcinoma, dysproliferative changes (dysplasias and
metaplasias), embryonal carcinoma, endometrial cancer,
endotheliosarcoma, ependymoma, epithelial carcinoma,
erythroleukemia, esophageal cancer, estrogen-receptor positive
breast cancer, essential thrombocythemia, Ewing's tumor,
fibrosarcoma, gastric carcinoma, germ cell testicular cancer,
gestational trophobalstic disease, glioblastoma, head and neck
cancer, heavy chain disease, hemangioblastoma, hepatoma,
hepatocellular cancer, hormone insensitive prostate cancer,
leiomyosarcoma, liposarcoma, lung cancer (including small cell lung
cancer and non-small cell lung cancer),
lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic
leukemia, lymphoma (lymphoma, including diffuse large B-cell
lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's
lymphoma), malignancies and hyperproliferative disorders of the
bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and
uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia,
medullary carcinoma, medulloblastoma, melanoma, meningioma,
mesothelioma, multiple myeloma, myelogenous leukemia, myeloma,
myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma,
pinealoma, polycythemia vera, prostate cancer (including
hormone-insensitive (refractory) prostate cancer), rectal cancer,
renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma,
sebaceous gland carcinoma, seminoma, skin cancer, small cell lung
carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,
squamous cell carcinoma, synovioma, sweat gland carcinoma,
testicular cancer (including germ cell testicular cancer), thyroid
cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine
cancer, Wilms' tumor and the like.
[0217] It is also expected that compounds of this invention would
inhibit growth of cells expressing Bcl-2 proteins derived from a
pediatric cancer or neoplasm including embryonal rhabdomyosarcoma,
pediatric acute lymphoblastic leukemia, pediatric acute myelogenous
leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic
ependymoma, pediatric anaplastic large cell lymphoma, pediatric
anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid
tumor of the central nervous system, pediatric biphenotypic acute
leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's
family of tumors such as primitive neuroectodermal rumors,
pediatric diffuse anaplastic Wilm's tumor, pediatric favorable
histology Wilm's tumor, pediatric glioblastoma, pediatric
medulloblastoma, pediatric neuroblastoma, pediatric
neuroblastoma-derived myelocytomatosis, pediatric pre-B-cell
cancers (such as leukemia), pediatric psteosarcoma, pediatric
rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric
T-cell cancers such as lymphoma and skin cancer and the like.
[0218] Autoimmune disorders include acquired immunodeficiency
disease syndrome (AIDS), autoimmune lymphoproliferative syndrome,
hemolytic anemia, inflammatory diseases, and thrombocytopenia,
acute or chronic immune disease associated with organ
transplantation, Addison's disease, allergic diseases, alopecia,
alopecia areata, 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 hypoglycaemia,
autoimmune neutropaenia, autoimmune thrombocytopaenia, 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, common varied immunodeficiency (common variable
hypogammaglobulinaemia), conjunctivitis, connective tissue disease
associated interstitial lung disease, contact dermatitis, Coombs
positive haemolytic anaemia, 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, 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, Grave's disease, haemosiderosis associated lung
disease, hairy cell leukemia, 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 purpurea, 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 leucopaenia, idiopathic pulmonary
fibrosis, idiopathic thrombocytopaenia, idiosyncratic liver
disease, infantile spinal muscular atrophy, infectious diseases,
inflammation of the aorta, inflammatory bowel disease, irritable
bowel disease, insulin dependent diabetes mellitus, interstitial
pneumonitis, iridocyclitis/uveitis/optic neuritis,
ischemia-reperfusion injury, ischemic stroke, juvenile pernicious
anaemia, 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 Shi-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 supranucleo 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,
Sjorgren's syndrome, skin allograft rejection, skin changes
syndrome, small bowel transplant rejection, sperm autoimmunity,
multiple sclerosis (all subtypes), spinal ataxia, spinocerebellar
degenerations, spondyloarthopathy, 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, 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
Experimentals
[0219] The following abbreviations have the meanings indicated.
ADDP means 1,1'-(azodicarbonyl)dipiperidine; AD-mix-.beta. means a
mixture of (DHQD).sub.2PHAL, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3,
and K.sub.2SO.sub.4; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc
means tert-butoxycarbonyl; (DHQD).sub.2PHAL means hydroquinidine
1,4-phthalazinediyl diethyl ether; DBU means
1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminum
hydride; DIEA means diisopropylethylamine; DMAP means
N,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe
means 1,2-bis(dimethylphosphino)ethane; DMSO means
dimethylsulfoxide; dppb means 1,4-bis(diphenylphosphino)-butane;
dppe means 1,2-bis(diphenylphosphino)ethane; dppf means
1,1'-bis(diphenylphosphino)ferrocene; dppm means
1,1-bis(diphenylphosphino)methane; EDAC HCl means
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc
means fluorenylmethoxycarbonyl; HATU means
0-(7-azabenzotriazol-1-yl)-N,N'N'N'-tetramethyluronium
hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means
isopropyl alcohol; MP-BH.sub.3 means macroporous triethylammonium
methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA
means trifluoroacetic acid; THF means tetrahydrofuran; NCS means
N-chlorosuccinimide; NN means N-methylmorpholine; NMP means
N-methylpyrrolidine; PPh.sub.3 means triphenylphosphine.
[0220] Compounds of this invention may be made by synthetic
chemical processes, examples of which are shown herein. Exemplary
schemes of the most useful and readily understood description of
procedures and conceptual aspects of this invention are disclosed
in commonly-owned U.S. patent application Ser. No. 12/951,344. It
is meant to be understood that the order of the steps in the
processes may be varied, that reagents, solvents and reaction
conditions may be substituted for those specifically mentioned, and
that vulnerable moieties may be protected and deprotected, as
necessary.
[0221] It will be readily apparent to those skilled in the art that
other suitable modifications and adaptations of the compounds of
the invention described herein are obvious and may be made using
suitable equivalents without departing from the scope of the
invention or the embodiments disclosed herein. Having now described
the present invention in detail, the same will be more clearly
understood by reference to the following examples, which are
included for purposes of illustration only and are not intended to
be limiting of the invention.
[0222] The following examples are presented to provide what is
believed to be the most useful and readily understood description
of procedures and conceptual aspects of this invention. Each
exemplified compound and intermediate was named using
ACD/ChemSketch Build 59026 (3 Sep. 2012), Advanced Chemistry
Development Inc., Toronto, Ontario), or ChemDraw.RTM. Ver. 9.0.7
(CambridgeSoft, Cambridge, Mass.).
Example 1
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(2R)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 1A
methyl
4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylat-
e
[0223] 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 triflic 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 afford the title
compound.
Example 1B
methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[0224] EXAMPLE 1A (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 afford the title compound.
Example 1C
(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[0225] To a mixture of LiBH.sub.4 (13 g), EXAMPLE 1B (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.
Example 1D
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piper-
azine-1-carboxylate
[0226] Mesyl Chloride (7.5 mL) was added via syringe to EXAMPLE 1C
(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.
Example 1E
1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
[0227] EXAMPLE 1D (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 afford the title compound.
Example 1F
5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine
[0228] 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.
Example 1G
1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol
[0229] To a mixture of EXAMPLE 1F (24.3 g) in tetrahydrofuran (500
mL) at -78.degree. C. was added 2.5M BuLi in hexanes (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 thee 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.
Example 1H
methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate
[0230] A mixture of EXAMPLE 1G (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.
Example 1I
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
[0231] A mixture of EXAMPLE 1H (1.55 g), EXAMPLE 1E (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.
Example 1J
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
[0232] EXAMPLE 1I (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 afford the title compound.
Example 1K
(S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate
[0233] To 2-chloroethanol (9.1 mL) in toluene (17 mL) was added
Et.sub.2O.BF.sub.3 (0.30 mL), and a warm water bath was used to
warm the mixture to 38.degree. C. S-(+)-epichlorohydrin (3.4 mL)
was added dropwise, keeping the temperature <45.degree. C. The
reaction was stirred at .about.35.degree. C. for 20 minutes, cooled
to 15.degree. C., and 20% NaOH (21 mL) was added dropwise, keeping
the temperature <18.degree. C. The reaction was then allowed to
warm to room temperature for 1 hour. Water was added (10 mL), the
layers were separated, the aqueous layer was extracted with
toluene, the combined toluene layers washed with water, and the
organic layer was concentrated down to an oil. NaOH (20% (wt)
aqueous, 50 g) was heated to 90.degree. C., then the above oil was
added, and the mixture was heated for 1 hour, and cooled to room
temperature. Then dichloromethane (12 mL) was added, followed by
p-toluenesulfonyl chloride (8.0 g). The biphasic reaction was
stirred at room temperature overnight. Water was added (10 mL), and
the aqueous layer was extracted twice with dichloromethane (10 mL).
The combined dichloromethane layers were washed with 1/1
water/brine and dried over Na.sub.2SO.sub.4. After filtration and
concentration, the crude material was chromatographed on silica gel
with 65/35 heptanes/ethyl acetate to afford the title compound.
Example 1L
(R)-2-(azidomethyl)-1,4-dioxane
[0234] EXAMPLE 1K (2.5 g) was dissolved in N,N-dimethylformamide
(12 mL), then sodium azide (1.0 g) was added and the reaction was
heated at 80.degree. C. for 3 hours. The reaction was then cooled
and diluted with water and extracted with ethyl acetate. The
organic layer was washed with brine and the combined aqueous layers
were extracted with ethyl acetate. The combined organic layers were
dried over Na.sub.2SO.sub.4. After filtration and concentration,
the crude material was chromatographed on silica gel with 3/1
heptanes/ethyl acetate to afford the title compound.
Example 1M
(R)-(1,4-dioxan-2-yl)methanamine
[0235] EXAMPLE 1L (916 mg) was dissolved in tetrahydrofuran (20 mL)
and water (5 mL). Then trimethylphosphine (6.4 mL, 1.0M in
tetrahydrofuran) was added and the reaction mixture was stirred at
room temperature for 90 minutes. Then 2N aqueous LiOH (6 mL) was
added, and extracted with ethyl acetate. The organic layer was
washed twice with brine, then dried over Na.sub.2SO.sub.4. After
filtration and concentration, the product was used in the next step
without purification.
Example 1N
(R)-4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide
[0236] EXAMPLE 1M (160 mg) was dissolved in tetrahydrofuran (3 mL),
then 4-fluoro-3-nitrobenzenesulfonamide (164 mg) was added,
followed by N-ethyl-N-isopropylpropan-2-amine (0.25 mL), and the
mixture was heated at 45.degree. C. overnight. The reaction mixture
was then concentrated and methanol (3 mL) was added and the mixture
was stirred overnight. The solids were filtered off, and the filter
cake was washed with more methanol to afford the title
compound.
Example 1O
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(2R)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0237] EXAMPLE 1N (170 mg), EXAMPLE 1J (340 mg),
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (150
mg), and 4-dimethylaminopyridine (130 mg) were stirred in
CH.sub.2Cl.sub.2 (5 mL) overnight. N',N'-dimethylethane-1,2-diamine
(0.19 mL) was then added and the mixture was stirred for 90
minutes. Dichloromethane (15 mL) was added, and the reaction
mixture was washed with 10% acetic acid:0.75% NaCl in water
(2.times.12 mL). The combined aqueous layers were back-extracted
with dichloromethane, and the combined organics were washed with
brine, and dried over Na.sub.2SO.sub.4. After filtration and
concentration, the crude material was chromatographed on silica gel
with 3/7 dichloromethane/ethyl acetate. The material was then
chromatographed on silica gel with 1.5-2.5% CH.sub.3OH in
dichloromethane. The material was triturated with CH.sub.3CN to
afford the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.65 (s, 1H), 8.55 (t, 1H),
8.54 (d, 1H), 8.01 (d, 1H), 7.81 (dd, 1H), 7.50 (m, 3H), 7.32 (d,
2H), 7.07 (d, 1H), 7.02 (d, 2H), 6.66 (dd, 1H), 6.37 (m, 1H), 6.18
(d, 1H), 3.77 (m, 3H), 3.63 (m, 2H), 3.47 (m, 2H), 3.31 (m, 2H),
3.06 (br m, 4H), 2.74 (br s, 2H), 2.19 (br m, 4H), 2.13 (br m, 2H),
1.94 (br m, 2H), 1.37 (t, 2H), 0.90 (s, 6H).
Example 2
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 2A
(S)-3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)benzenesulfonamide
[0238] The title compound was prepared by substituting
(S)-1-(tetrahydro-2H-pyran-4-yl)ethanamine for EXAMPLE 1M in
EXAMPLE 1N.
Example 2B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0239] The title compound was prepared by substituting EXAMPLE 2A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.68 (s, 1H), 11.36 (bs,
1H), 8.57 (d, 1H), 8.30 (d, 1H), 8.06 (d, 1H), 7.82 (dd, 1H), 7.56
(d, 1H), 7.52-7.48 (m, 2H), 7.34 (dt, 2H), 7.16 (d, 1H), 7.03 (dt,
2H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.18 (d, 1H), 3.92-3.82 (m, 2H),
3.76 (q, 1H), 3.27 (td, 2H), 3.07 (bs, 4H), 2.75 (bs, 2H),
2.25-2.10 (m, 6H), 1.95 (bs, 2H), 1.80 (m, 1H), 1.71-1.53 (m, 2H),
1.38 (t, 2H), 1.33-1.23 (m, 2H), 1.19 (d, 3H), 0.92 (s, 6H).
Example 3
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 3A
(R)-3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)benzenesulfonamide
[0240] The title compound was prepared by substituting
(R)-1-(tetrahydro-2H-pyran-4-yl)ethanamine for EXAMPLE 1M in
EXAMPLE 1N.
Example 3B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}phenyl)-
sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0241] The title compound was prepared by substituting EXAMPLE 3A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.68 (s, 1H), 11.36 (bs,
1H), 8.57 (d, 1H), 8.30 (d, 1H), 8.06 (d, 1H), 7.82 (dd, 1H), 7.56
(d, 1H), 7.52-7.48 (m, 2H), 7.34 (dt, 2H), 7.16 (d, 1H), 7.03 (dt,
2H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.18 (d, 1H), 3.92-3.82 (m, 2H),
3.76 (q, 1H), 3.27 (td, 2H), 3.07 (bs, 4H), 2.75 (bs, 2H),
2.25-2.10 (m, 6H), 1.95 (bs, 2H), 1.80 (m, 1H), 1.71-1.53 (m, 2H),
1.38 (t, 2H), 1.33-1.23 (m, 2H), 1.19 (d, 3H), 0.92 (s, 6H).
Example 4
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(5S,8S)-1-oxaspiro[4.5]dec-8-ylmethyl]amino}phenyl)s-
ulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 4A
1-oxaspiro[4.5]decane-8-carbonitrile
[0242] Potassium t-butoxide (1.68 g) was added portionwise to a
mixture of 1-oxaspiro[4.5]decan-8-one (0.96 g) and TosMIC reagent
(p-toluenesulfonylmethyl isocyanide, 1.46 g) in 1,2-dimethoxyethane
(30 mL) and ethanol (0.5 mL) at 0.degree. C. The reaction mixture
was allowed to warm to room temperature and stirred for 4 hours,
then heated to 40.degree. C. for 24 hours. The reaction mixture was
cooled, diluted with ether (600 mL), washed twice with water and
brine, and concentrated. The crude product was chromatographed on
silica gel with 1-20% ethyl acetate/hexanes to afford the title
compound.
Example 4B
1-oxaspiro[4.5]decane-8-ylmethylamine
[0243] LiAlH.sub.4 (9.1 mL, 1M in tetrahydrofuran) was added to
EXAMPLE 4A (0.96 g) in tetrahydrofuran (30 mL) at 0.degree. C. The
reaction mixture was allowed to warm to room temperature and
stirred for 1 hour. The reaction mixture was quenched with the
addition of 2 mL water and 10 mL 1M aqueous NaOH, and the mixture
was stirred for 1 hour. The reaction mixture was diluted with ether
(100 mL), filtered, and concentrated to afford the title
compound.
Example 4C
4-(((5S,8S)-1-oxaspiro[4.5]decan-8-ylmethyl)amino)-3-nitrobenzenesulfonami-
de
[0244] 4-Fluoro-3-nitrobenzenesulfonamide (650 mg), EXAMPLE 4B (500
mg) and triethylamine (0.41 mL) in tetrahydrofuran (12 mL) were
heated at 50.degree. C. for 2 hours. The reaction mixture was
concentrated. The crude product was chromatographed on silica gel
with 50% ethyl acetate/hexanes to afford the title compound.
Example 4D
4-(((5R,8R)-1-oxaspiro[4.5]decan-8-ylmethyl)amino)-3-nitrobenzenesulfonami-
de
[0245] The title compound was also isolated from EXAMPLE 4C as the
later-eluting fraction.
Example 4E
N-((4-(((5S,8S)-1-oxaspiro[4.5]decan-8-ylmethyl)amino)-3-nitrophenyl)sulfo-
nyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl--
3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide
[0246] The title compound was prepared by substituting EXAMPLE 4C
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.35 (br s, 1H),
8.59 (m, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.79 (d, 1H), 7.51 (m,
2H), 7.34 (d, 2H), 7.07 (d, 1H), 7.04 (d, 2H), 6.67 (d, 1H), 6.38
(d, 1H), 6.19 (s, 1H), 3.68 (t, 2H), 3.26 (m, 6H), 3.07 (m, 4H),
2.74 (s, 2H), 2.19 (s, 2H), 2.14 (m, 2H), 1.97 (s, 2H), 1.82 (m,
2H), 1.60 (m, 2H), 1.57 (m, 4H), 1.36 (m, 2H), 1.32 (m, 4H), 0.92
(m, 6H).
Example 5
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(5R,8R)-1-oxaspiro[4.5]dec-8-ylmethyl]amino}phenyl)s-
ulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0247] The title compound was prepared by substituting EXAMPLE 4D
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.35 (br s, 1H),
8.60 (m, 1H), 8.57 (s, 1H), 8.05 (s, 1H), 7.81 (d, 1H), 7.51 (m,
2H), 7.34 (d, 2H), 7.09 (d, 1H), 7.03 (d, 2H), 6.67 (d, 1H), 6.39
(d, 1H), 6.19 (s, 1H), 3.67 (t, 2H), 3.27 (m, 6H), 3.07 (m, 4H),
2.75 (s, 2H), 2.20 (s, 2H), 2.14 (m, 2H), 1.95 (s, 2H), 1.81 (m,
2H), 1.75 (m, 2H), 1.65 (m, 2H), 1.63 (m, 2H), 1.38 (m, 2H), 1.32
(m, 2H), 1.09 (m, 2H), 0.92 (m, 6H).
Example 6
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 6A
4-(((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfona-
mide
[0248] The title compound was prepared by substituting
4-(aminomethyl)tetrahydro-2H-pyran-4-ol for EXAMPLE 1M in EXAMPLE
1N.
Example 6B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0249] The title compound was prepared by substituting EXAMPLE 6A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 8.66 (t, 1H),
8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.52 (d, 1H), 7.49 (d,
2H), 7.34 (d, 2H), 7.16 (d, 1H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.39
(dd, 1H), 6.19 (d, 1H), 4.99 (bs, 1H), 3.63 (d, 4H), 3.38 (d, 2H),
3.07 (bs, 4H), 2.75 (bs, 2H), 2.23-2.11 (m, 6H), 1.95 (bs, 2H),
1.66-1.57 (m, 2H), 1.54-1.48 (m, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Example 7
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-ylmethyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 7A
1,4-dioxaspiro[4.5]decane-8-carbonitrile
[0250] The title compound was prepared by substituting
1,4-dioxaspiro[4.5]decan-8-one for 1-oxaspiro[4.5]decan-8-one in
EXAMPLE 4A.
Example 7B
1,4-dioxaspiro[4.5]decan-8-ylmethanamine
[0251] The title compound was prepared by substituting EXAMPLE 7A
for EXAMPLE 4A in EXAMPLE 4B.
Example 7C
4-((1,4-dioxaspiro[4.5]decan-8-ylmethyl)amino)-3-nitrobenzenesulfonamide
[0252] The title compound was prepared by substituting EXAMPLE 7B
for EXAMPLE 1M in EXAMPLE 1N.
Example 7D
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-ylmethyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0253] The title compound was prepared by substituting EXAMPLE 7C
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.60 (s, 1H), 8.48 (d, 2H),
7.99 (d, 1H), 7.71 (dd, 1H), 7.53 (d, 1H), 7.38-7.48 (m, 1H), 7.34
(d, 2H), 7.04 (d, 2H), 6.95 (d, 1H), 6.65 (dd, 1H), 6.35 (dd, 1H),
6.21 (d, 1H), 3.84 (s, 4H), 3.25 (t, 3H), 3.04 (s, 4H), 2.72 (s,
2H), 2.08-2.25 (m, 6H), 1.95 (s, 2H), 1.69 (t, 5H), 1.34-1.52 (m,
4H), 1.25 (d, 2H), 0.85-1.00 (m, 6H).
Example 8
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(morpholin-4-yl)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]p-
yridin-5-yloxy)benzamide
Example 8A
4-morpholino-3-nitrobenzenesulfonamide
[0254] The title compound was prepared by substituting morpholine
for EXAMPLE 1M in EXAMPLE 1N.
Example 8B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(morpholin-4-yl)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]p-
yridin-5-yloxy)benzamide
[0255] The title compound was prepared by substituting EXAMPLE 8A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.68 (s, 1H), 11.42 (bs,
1H), 8.27 (d, 1H), 8.03 (d, 1H), 7.86 (d, 1H), 7.53-7.48 (m, 3H),
7.35 (d, 2H), 7.24 (d, 1H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.40 (dd,
1H), 6.20 (d, 1H), 3.69 (t, 4H), 3.16-3.02 (m, 8H), 2.76 (bs, 2H),
2.28-2.11 (m, 6H), 1.96 (bs, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Example 9
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(2S)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 9A
(R)-(1,4-dioxan-2-yl)methyl methanesulfonate
[0256] The title compound was prepared by substituting
R-(-)-epichlorohydrin for S-(+)-epichlorohydrin in EXAMPLE 1K.
Example 9B
(S)-2-(azidomethyl)-1,4-dioxane
[0257] The title compound was prepared by substituting EXAMPLE 9A
for EXAMPLE 1K in EXAMPLE 1L.
Example 9C
(S)-(1,4-dioxan-2-yl)methanamine
[0258] EXAMPLE 9B (400 mg) was dissolved in tetrahydrofuran (15
mL), cooled to 0.degree. C., and lithium aluminum hydride (2.0 mL,
2.0M in tetrahydrofuran) was added. The reaction mixture was
stirred at 0.degree. C. for 50 minutes, then at room temperature
for another 75 minutes. The reaction mixture was cooled to
0.degree. C., then water (0.16 mL) was carefully added, followed by
20% aqueous NaOH (0.16 mL), and additional water (0.48 mL). The
mixture was stirred for 15 minutes, MgSO.sub.4 was added and
diethylether was added (20 mL). The mixture was stirred for 15
minutes, filtered through diatomaceous earth, and rinsed with
diethylether. Concentration of the filtrate gave the title compound
which was used in the next step without additional
purification.
Example 9D
(S)-4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide
[0259] The title compound was prepared by substituting EXAMPLE 9C
for EXAMPLE 1M in EXAMPLE 1N.
Example 9E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(2S)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0260] The title compound was prepared by substituting EXAMPLE 9D
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.65 (s, 1H), 8.55 (t, 1H),
8.54 (d, 1H), 8.01 (d, 1H), 7.81 (dd, 1H), 7.50 (m, 3H), 7.32 (d,
2H), 7.07 (d, 1H), 7.02 (d, 2H), 6.66 (dd, 1H), 6.37 (m, 1H), 6.18
(d, 1H), 3.77 (m, 3H), 3.63 (m, 2H), 3.47 (m, 2H), 3.31 (m, 2H),
3.06 (br m, 4H), 2.74 (br s, 2H), 2.19 (br m, 4H), 2.13 (br m, 2H),
1.94 (br m, 2H), 1.37 (t, 2H), 0.90 (s, 6H).
Example 10
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 10A
4-(((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzen-
esulfonamide
[0261] The title compound was prepared by substituting
(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol for EXAMPLE 1M in
EXAMPLE 1N.
Example 10B
4-(((4-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-4-yl)meth-
yl)amino)-3-nitrobenzenesulfonamide
[0262] EXAMPLE 10A (648 mg) was dissolved in N,N-dimethylformamide
(9 mL), and tert-butyldimethylsilyl trifluoromethanesulfonate (546
mg) was added. The solution was stirred at room temperature for 16
hours, and the solvent was removed under vacuum. The crude material
was purified by flash column chromatography on silica gel using
50-70% ethyl acetate in heptanes.
Example 10C
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-(((tert-butyldimethylsil-
yl)oxy)methyl)tetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfony-
l)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)m-
ethyl)piperazin-1-yl)benzamide
[0263] The title compound was prepared by substituting EXAMPLE 10B
for EXAMPLE 1N in EXAMPLE 1O.
Example 10D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0264] EXAMPLE 10C (488 mg) was dissolved in tetrahydrofuran (3
mL). Tetrabutylammonium fluoride (1M in tetrahydrofuran, 1.45 mL)
was added, and the solution was stirred at room temperature for 30
minutes. The reaction mixture was quenched with a saturated aqueous
solution of sodium bicarbonate and diluted with ethyl acetate. The
phases were separated, and the organic phase was washed with brine,
and then dried on anhydrous sodium sulfate. After filtration and
concentration, the crude material was purified by flash column
chromatography on silica gel using ethyl acetate, increasing to
5-10% methanol in dichloromethane. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.69 (s, 1H), 9.08 (t, 1H),
8.59 (d, 1H), 8.08 (d, 1H), 7.83 (dd, 1H), 7.56-7.52 (m, 3H), 7.38
(d, 2H), 7.18 (d, 1H), 7.08 (d, 2H), 6.72 (dd, 1H), 6.43 (dd, 1H),
6.24 (d, 1H), 5.26 (t, 1H), 3.68-3.58 (m, 4H), 3.56 (d, 2H), 3.10
(bs, 4H), 3.05 (m, 2H), 2.77 (bs, 2H), 2.27-2.15 (m, 6H), 1.99 (bs,
2H), 1.51 (m, 4H), 1.42 (t, 2H), 0.96 (s, 6H).
Example 11
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[3-(hydroxymethyl)oxetan-3-yl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 11A
4-(((3-(hydroxymethyl)oxetan-3-yl)methyl)amino)-3-nitrobenzenesulfonamide
[0265] The title compound was prepared by substituting
(3-(aminomethyl)oxetan-3-yl)methanol for EXAMPLE 1M in EXAMPLE
1N.
Example 11B
4-(((3-(((tert-butyldimethylsilyl)oxy)methyl)oxetan-3-yl)methyl)amino)-3-n-
itrobenzenesulfonamide
[0266] The title compound was prepared by substituting EXAMPLE 11A
for EXAMPLE 10A in EXAMPLE 10B.
Example 11C
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((3-(((tert-butyldimethylsil-
yl)oxy)methyl)oxetan-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'--
chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperaz-
in-1-yl)benzamide
[0267] The title compound was prepared by substituting EXAMPLE 11B
for EXAMPLE 1N in EXAMPLE 1O.
Example 11D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[3-(hydroxymethyl)oxetan-3-yl]methyl}amino)-3-nitrophenyl]su-
lfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0268] The title compound was prepared by substituting EXAMPLE 11C
for EXAMPLE 10C in EXAMPLE 10D. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.65 (s, 1H), 11.40 (bs,
1H), 8.90 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.83 (dd, 1H),
7.53-7.47 (m, 3H), 7.34 (d, 2H), 7.13 (d, 1H), 7.04 (d, 2H), 6.68
(dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 5.34 (t, 1H), 4.37 (s, 4H),
3.77 (d, 2H), 3.69 (d, 2H), 3.07 (bs, 4H), 2.74 (bs, 2H), 2.25-2.11
(m, 6H), 1.95 (bs, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 12
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-hydroxy-3-methylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 12A
4-((3-hydroxy-3-methylbutyl)amino)-3-nitrobenzenesulfonamide
[0269] The title compound was prepared by substituting
4-amino-2-methylbutan-2-ol for EXAMPLE 1M in EXAMPLE 1N.
Example 12B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-hydroxy-3-methylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0270] The title compound was prepared by substituting EXAMPLE 12A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.37 (bs,
1H), 8.95 (t, 1H), 8.56 (d, 1H), 8.05 (d, 1H), 7.82 (dd, 1H), 7.54
(d, 1H), 7.52-7.48 (m, 2H), 7.34 (d, 2H), 7.06-6.98 (m, 3H), 6.68
(dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 4.67 (s, 1H), 3.45 (q, 2H),
3.07 (bs, 4H), 2.75 (bs, 2H), 2.25-2.11 (m, 6H), 1.95 (bs, 2H),
1.74 (t, 2H), 1.38 (t, 2H), 1.18 (s, 6H), 0.92 (s, 6H).
Example 13
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-hydroxytricyclo[3.3.1.1.sup.3,7]dec-1-yl)amino]-3-nitrophe-
nyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 13A
4-((3-hydroxyadamantan-1-yl)amino)-3-nitrobenzenesulfonamide
[0271] The title compound was prepared by substituting
3-aminoadamantan-1-ol for EXAMPLE 1M in EXAMPLE 1N.
Example 13B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-hydroxytricyclo[3.3.1.1.sup.3,7]dec-1-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0272] The title compound was prepared by substituting EXAMPLE 13A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.45 (bs,
1H), 8.57 (d, 1H), 8.45 (s, 1H), 8.04 (d, 1H), 7.82 (dd, 1H),
7.57-7.47 (m, 3H), 7.41-7.32 (m, 3H), 7.04 (d, 2H), 6.68 (dd, 1H),
6.39 (dd, 1H), 6.18 (d, 1H), 4.68 (s, 1H), 3.06 (bs, 4H), 2.75 (bs,
2H), 2.28-2.10 (m, 8H), 1.97-1.88 (m, 8H), 1.72-1.55 (m, 4H), 1.48
(d, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 14
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1R,5S,6S)-3-oxabicyclo[3.1.0]hex-6-ylmethyl]amino}p-
henyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 14A
tert-butyl (1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate
[0273] Tert-butyl diazoacetate (135 g, 15% in toluene) was added to
2,5-dihydrofuran (100 g) and rhodium (II) acetate dimer (0.95 g) in
dichloromethane (250 mL) over 4 hours, and the reaction mixture was
stirred for 24 hours. The reaction mixture was concentrated and the
crude product was chromatographed on silica gel with 1-15% ethyl
acetate/hexanes to separately give the product and its diastereomer
in a 2:1 ratio.
Example 14B
(1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid
[0274] EXAMPLE 14A (4 g) was stirred in dichloromethane (20 mL) and
TFA (20 mL) for 2 hours, and was concentrated. The crude material
was taken up in dichloromethane (200 mL) and saturated
Na.sub.2CO.sub.3 solution (20 mL). The reaction mixture was stirred
for 10 minutes, and the organic layer was separated and dried over
Na.sub.2SO.sub.4. After filtration, the mixture was concentrated to
afford the title compound.
Example 14C
(1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxamide
[0275] Oxalyl chloride (2.05 mL) was added to EXAMPLE 14B (4 g) in
dichloromethane (40 mL) and the reaction mixture was stirred for 24
hours, and concentrated. The crude material was taken up in
dichloromethane (30 mL), saturated NH.sub.4OH solution (3 mL) was
added, and the reaction mixture was stirred for 30 minutes.
Dichloromethane (30 mL) and saturated Na.sub.2CO.sub.3 solution (20
mL) were added, and the organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford the title
compound.
Example 14D
3-nitro-4-{[(1R,5S,6S)-3-oxabicyclo[3.1.0]hex-6-ylmethyl]amino}benzenesulf-
onamide
[0276] Borane-tetrahydrofuran complex (2.5 mL, 1M in
tetrahydrofuran) was added to EXAMPLE 14C (160 mg) in
tetrahydrofuran (2 mL) and the reaction mixture was stirred for 24
hours at 50.degree. C. The reaction mixture was quenched by the
slow addition of 1M aqueous HCl, diluted with dichloromethane (20
mL), and minimal concentrated NaOH solution was added to basicify
the solution. To this mixture 4-fluoro-3-nitrobenzenesulfonamide
(277 mg) and triethylamine (2 mL) were added and the reaction
mixture was stirred for 1 hours. The reaction mixture was
concentrated and the crude product was chromatographed on silica
gel with 10-100% ethyl acetate/hexanes to afford the title
compound.
Example 14E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1R,5S,6S)-3-oxabicyclo[3.1.0]hex-6-ylmethyl]amino}p-
henyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0277] The title compound was prepared by substituting EXAMPLE 14D
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 11.40 (br s, 1H),
8.60 (m, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.83 (d, 1H), 7.51 (m,
2H), 7.34 (d, 2H), 7.09 (d, 1H), 7.04 (d, 2H), 6.69 (d, 1H), 6.39
(d, 1H), 6.20 (s, 1H), 3.74 (d, 2H), 3.54 (m, 2H), 3.31 (m, 3H),
3.07 (m, 4H), 2.76 (s, 2H), 2.20 (s, 4H), 2.14 (m, 2H), 1.95 (s,
2H), 1.71 (m, 2H), 1.38 (m, 2H), 1.05 (m, 1H), 0.92 (m, 6H).
Example 15
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3-hydroxyoxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 15A
4-(((3-hydroxyoxetan-3-yl)methyl)amino)-3-nitrobenzenesulfonamide
[0278] The title compound was prepared by substituting
3-(aminomethyl)oxetan-3-ol for EXAMPLE 1M in EXAMPLE 1N.
Example 15B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3-hydroxyoxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0279] The title compound was prepared by substituting EXAMPLE 15A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.66 (s, 1H), 11.38 (bs,
1H), 8.56 (d, 1H), 8.54 (t, 1H), 8.05 (d, 1H), 7.83 (dd, 1H),
7.54-7.48 (m, 3H), 7.34 (dt, 2H), 7.19 (d, 1H), 7.04 (dt, 2H), 6.68
(dd, 1H), 6.39 (dd, 1H), 6.35 (s, 1H), 6.20 (d, 1H), 4.47 (dd, 4H),
3.72 (d, 2H), 3.07 (bs, 4H), 2.75 (bs, 2H), 2.25-2.10 (m, 6H), 1.95
(bs, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 16
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,-
3-b]pyridin-5-yloxy)benzamide
Example 16A
4-(morpholinoamino)-3-nitrobenzenesulfonamide
[0280] The title compound was prepared by substituting
morpholin-4-amine for EXAMPLE 1M in EXAMPLE 1N.
Example 16B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,-
3-b]pyridin-5-yloxy)benzamide
[0281] The title compound was prepared by substituting EXAMPLE 16A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.43 (bs,
1H), 9.26 (s, 1H), 8.54 (d, 1H), 8.04 (d, 1H), 7.83 (dd, 1H), 7.64
(d, 1H), 7.54-7.47 (m, 3H), 7.34 (d, 2H), 7.04 (d, 2H), 6.67 (dd,
1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.90-3.52 (m, 4H), 3.07 (bs, 4H),
2.85 (bs, 4H), 2.75 (bs, 2H), 2.26-2.11 (m, 6H), 1.95 (bs, 2H),
1.38 (t, 2H), 0.92 (s, 6H).
Example 17
methyl
4-{[(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}tetrahydro-2H-pyran-4-carboxylate
Example 17A
methyl
4-(((2-nitro-4-sulfamoylphenyl)amino)methyl)tetrahydro-2H-pyran-4-c-
arboxylate
[0282] The title compound was prepared by substituting methyl
4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate for EXAMPLE 1M in
EXAMPLE 1N.
Example 17B
methyl
4-{[(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}tetrahydro-2H-pyran-4-carboxylate
[0283] The title compound was prepared by substituting EXAMPLE 17A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.41 (bs,
1H), 8.56 (d, 1H), 8.54 (t, 1H), 8.04 (d, 1H), 7.84 (dd, 1H),
7.53-7.46 (m, 3H), 7.34 (d, 2H), 7.13 (d, 1H), 7.04 (d, 2H), 6.68
(dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.79 (dt, 2H), 3.62 (s, 3H),
3.59 (d, 2H), 3.33 (m, 2H), 3.07 (bs, 4H), 2.75 (bs, 2H), 2.25-2.11
(m, 6H), 2.02 (d, 2H), 1.95 (bs, 2H), 1.62 (m, 2H), 1.38 (t, 2H),
0.92 (s, 6H).
Example 18
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)hydrazinyl]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 18A
4-hydrazinyl-3-nitrobenzenesulfonamide
[0284] The title compound was prepared by substituting hydrazine
monohydrate for EXAMPLE 1M in EXAMPLE 1N.
Example 18B
3-nitro-4-(2-(tetrahydro-2H-pyran-4-yl)hydrazinyl)benzenesulfonamide
[0285] EXAMPLE 18A (250 mg) was taken up in dichloromethane (10 mL)
and 1-methylpyrrolidinone (5 mL), then dihydro-2H-pyran-4(3H)-one
(119 mg) was added, and the solution was stirred at room
temperature for 20 minutes. Sodium triacetoxyborohydride (479 mg)
was added, and the mixture was stirred at room temperature for 16
hours. The mixture was diluted with ethyl acetate, washed with a
saturated aqueous sodium bicarbonate solution, washed with water
two times, washed with brine, and dried on anhydrous sodium
sulfate. After filtration and concentration, the crude material was
recrystallized from ethyl acetate. The solid material was washed
with diethyl ether, and dried under vacuum to afford the title
compound.
Example 18C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)hydrazinyl]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0286] The title compound was prepared by substituting EXAMPLE 18B
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.65 (s, 1H), 10.81 (s,
1H), 8.56 (d, 1H), 8.02 (d, 1H), 7.90 (dd, 1H), 7.72 (d, 1H),
7.51-7.47 (m, 3H), 7.34 (d, 2H), 7.03 (d, 2H), 6.68 (dd, 1H), 6.37
(dd, 1H), 6.21 (d, 1H), 3.79 (m, 4H), 3.27 (td, 2H), 3.08 (bs, 4H),
2.77 (bs, 2H), 2.55 (dt, 4H), 2.25-2.11 (m, 6H), 1.95 (bs, 2H),
1.38 (t, 2H), 0.92 (s, 6H).
Example 19
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(4R)-oxepan-4-ylmethyl]amino}phenyl)sulfonyl]-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 19A
oxepan-4-one
[0287] To a stirred solution of dihydro-2H-pyran-4(3H)-one (8.5 g)
and boron trifluoride diethyl etherate (15 mL) in dichloromethane
(400 mL) at -25.degree. C. was added (trimethylsilyl)diazomethane
(60 mL, 120 mmol, 2.0 M in hexanes) slowly via syringe. The
reaction mixture was stirred at -25.degree. C. for 2.5 hours. The
reaction mixture was diluted with water (300 mL) and extracted with
dichloromethane (300 mL). The organic layer was separated, washed
with 10:1 saturated aqueous NH.sub.4Cl: saturated aqueous
NH.sub.4OH, washed with brine, dried over magnesium sulfate,
filtered, and concentrated in vacuo. The resulting crude product
was purified by silica gel chromatography to afford the title
compound.
Example 19B
oxepane-4-carbonitrile
[0288] The title compound was prepared by substituting EXAMPLE 19A
for 1-oxaspiro[4.5]decan-8-one in EXAMPLE 4A.
Example 19C
oxepan-4-ylmethanamine
[0289] The title compound was prepared by substituting EXAMPLE 19B
for EXAMPLE 4A in EXAMPLE 4B.
Example 19D
(R)-3-nitro-4-(oxepan-4-ylmethylamino)benzenesulfonamide
[0290] The title compound was prepared by substituting EXAMPLE 19C
for EXAMPLE 1M in EXAMPLE 1N. The enantiomers were separated using
a modified Berger Instruments PrepSFC.TM. system. A manual version
of the Berger system was integrated with a Gilson 232 autosampler
for sample injection and a Cavro MiniPrep.TM. pipettor customized
for fraction collection at atmospheric pressure (Olson, J.; Pan,
J.; Hochlowski, J.; Searle, P.; Blanchard, D. JALA 2002, 7, 69-74).
Custom designed collection shoes allowed collection into
18.times.150 mm tubes and a methanol wash system allows washing of
shoes between fractions to maximize recovery and avoid
cross-contamination of fractions. The system was controlled using
SFC ProNTo.TM. software (version 1.5.305.15) and an AbbVie
developed Visual Basic application for autosampler and fraction
collector control. The outlet pressure was 100 bar, oven
temperature at 35.degree. C., and mobile phase flow rate at 40
mL/minute. The column used was a Chiralpak IA, 21.times.250 mm, 5
micron. The mobile phase was 35% CH.sub.3OH (containing 0.3%
diethylamine)/65% supercritical CO.sub.2. Samples were injected as
solutions in 1.9 mL CH.sub.3OH:DMSO 1:1. The preparative SFC system
was controlled using SFC ProNTo.TM. software (version 1.5.305.15)
and custom software for autosampler and fraction collector control.
Fractions were collected based upon UV signal threshold and on-line
Thermo MSQ mass spectrometry was used for molecular mass
confirmation, using ESI ionization in positive mode. Mass spectra
were acquired using a Navigator 4.0 software and an AbbVie
developed Visual Basic interface to communicate with SFC
controlling software.
Example 19E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(4R)-oxepan-4-ylmethyl]amino}phenyl)sulfonyl]-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0291] The title compound was prepared by substituting EXAMPLE 19D
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 8.49-8.67 (m,
2H), 8.04 (d1H), 7.80 (dd, 1H), 7.45-7.58 (m, 3H), 7.34 (d, 2H),
6.97-7.14 (m, 3H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H),
3.44-3.76 (m, 4H), 3.00-3.13 (m, 4H), 2.74 (s, 2H), 2.07-2.27 (m,
6H), 1.83-2.00 (m, 3H), 1.68-1.85 (m, 3H), 1.54-1.65 (m, 1H),
1.27-1.47 (m, 4H), 0.92 (s, 6H).
Example 20
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(4S)-oxepan-4-ylmethyl]amino}phenyl)sulfonyl]-2-(1H--
pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 20A
(S)-3-nitro-4-((oxepan-4-ylmethyl)amino)benzenesulfonamide
[0292] The title compound was also obtained as described in EXAMPLE
19D.
Example 20B
[0293]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-[(3-nitro-4-{[(4S)-oxepan-4-ylmethyl]amino}phenyl)sulfonyl]-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0294] The title compound was prepared by substituting EXAMPLE 20A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 8.49-8.67 (m,
2H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.45-7.58 (m, 3H), 7.34 (d, 2H),
6.97-7.14 (m, 3H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H),
3.44-3.76 (m, 4H), 3.00-3.13 (m, 4H), 2.74 (s, 2H), 2.07-2.27 (m,
6H), 1.83-2.00 (m, 3H), 1.68-1.85 (m, 3H), 1.54-1.65 (m, 1H),
1.27-1.47 (m, 4H), 0.92 (s, 6H).
Example 21
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-methyltetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 21A
4-(((4-methyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonam-
ide
[0295] Sodium triacetoxyborohydride (3513 mg) was added to
trifluoromethylacetic acid (30 mL).
4-Amino-3-nitrobenzenesulfonamide (800 mg) was added and the
solution was stirred at room temperature for 10 minutes.
4-Methyltetrahydro-2H-pyran-4-carbaldehyde (991 mg) dissolved in
dichloromethane (10 mL) was added drop-wise. After the addition,
the mixture was stirred at room temperature for 16 hours. The
mixture was poured over an ice-cold saturated solution of sodium
bicarbonate and extracted with ethyl acetate. The organic layer was
washed with water and brine and dried on anhydrous sodium sulfate.
After filtration and concentration, the crude material was purified
by recrystallization from ethyl acetate.
Example 21B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-methyltetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0296] The title compound was prepared by substituting EXAMPLE 21A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.38 (bs,
1H), 8.56 (d, 1H), 8.48 (t, 1H), 8.03 (d, 1H), 7.80 (dd, 1H),
7.54-7.46 (m, 3H), 7.34 (d, 2H), 7.22 (d, 1H), 7.04 (d, 2H), 6.68
(dd, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 3.72-3.63 (m, 2H), 3.52 (m,
2H), 3.30 (m, 2H), 3.07 (bs, 4H), 2.75 (bs, 2H), 2.25-2.10 (m, 6H),
1.95 (bs, 2H), 1.53 (m, 2H), 1.38 (t, 2H), 1.31 (d, 2H), 1.06 (s,
3H), 0.92 (s, 6H).
Example 22
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 22A
3-nitro-4-(((tetrahydro-2H-thiopyran-4-yl)methyl)amino)benzenesulfonamide
[0297] The title compound was prepared by substituting
(tetrahydro-2H-thiopyran-4-yl)methanamine hydrochloride for EXAMPLE
1M in EXAMPLE 1N.
Example 22B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-thiopyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0298] The title compound was prepared by substituting EXAMPLE 22A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.68 (s, 1H), 11.37 (bs,
1H), 8.59 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H),
7.55-7.47 (m, 3H), 7.34 (d, 2H), 7.08 (d, 1H), 7.04 (d, 2H), 6.68
(dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.28 (t, 2H), 3.07 (bs, 4H),
2.75 (bs, 2H), 2.58 (m, 4H), 2.25-2.11 (m, 6H), 2.02 (dd, 2H), 1.95
(bs, 2H), 1.70 (m, 1H), 1.38 (t, 2H), 1.36-1.28 (m, 2H), 0.92 (s,
6H).
Example 23
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(oxetan-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrro-
lo[2,3-b]pyridin-5-yloxy)benzamide
Example 23A
3-nitro-4-((oxetan-3-ylmethyl)amino)benzenesulfonamide
[0299] The title compound was prepared by substituting
oxetan-3-ylmethanamine for EXAMPLE 1M in EXAMPLE 1N.
Example 23B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(oxetan-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrro-
lo[2,3-b]pyridin-5-yloxy)benzamide
[0300] The title compound was prepared by substituting EXAMPLE 23A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.39 (bs,
1H), 8.66 (t, 1H), 8.55 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H),
7.54-7.46 (m, 3H), 7.34 (d, 2H), 7.09 (d, 1H), 7.03 (d, 2H), 6.68
(dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 4.66 (dd, 2H), 4.36 (t, 2H),
4.01 (bs, 1H), 3.71 (t, 2H), 3.07 (bs, 4H), 2.75 (bs, 2H),
2.26-2.10 (m, 6H), 1.95 (bs, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 24
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2R,5R)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 24A
(R)-((2-(allyloxy)propoxy)methyl)benzene
[0301] (R)-1-(benzyloxy)propan-2-ol (5 g) and allyl bromide (3.5
mL) were dissolved in tetrahydrofuran (45 mL). The mixture was
cooled to 5.degree. C., and 95% NaH (1.1 g) was added in four
portions over 10 minutes. The mixture was allowed to warm
temperature and stirred under a drying tube overnight. The reaction
was diluted with water and extracted with ether. The organic layer
was washed with brine and the combined aqueous layers were
back-extracted with ether. The combined organic layers were dried
over Na.sub.2SO.sub.4. Filtration and concentration of the filtrate
afforded the title compound which was used in the next step without
further purification.
Example 24B
2-(((R)-1-(benzyloxy)propan-2-yloxy)methyl)oxirane
[0302] EXAMPLE 24A (6.2 g) was dissolved in dichloromethane (200
mL), cooled to 0.degree. C., m-chloroperoxybenzoic acid (13.5 g)
was added. The reaction mixture was stirred cold for 1 hour, then
stirred at room temperature overnight. Aqueous Na.sub.2SO.sub.3
(10%, 100 mL) was added, the mixture was stirred for 5 minutes, and
the layers were separated. The organic layer was washed with
saturated NaHCO.sub.3 (2.times.150 mL), and with brine. After
drying over Na.sub.2SO.sub.4, filtration and concentration, the
crude material was dissolved in diethylether, then washed with 10%
Na.sub.2S.sub.2O.sub.3, 3 times with saturated NaHCO.sub.3, and
brine. After drying over Na.sub.2SO.sub.4, filtration and
concentration gave a crude oil. The crude material was
chromatographed on silica gel with 85/15 heptanes/ethyl acetate to
afford the title compound.
Example 24C
(S)-2-(((R)-1-(benzyloxy)propan-2-yloxy)methyl)oxirane
[0303] R,R-(salen)Co(II) complex (56 mg) was added to neat EXAMPLE
24B (4.0 g), then tetrahydrofuran was added (180 .mu.L), followed
by acetic acid (20.7 .mu.L). The mixture was cooled to 0.degree.
C., water was added (180 .mu.L) and the reaction was allowed to
come to room temperature overnight in an open 25 mL flask. The
reaction was then directly chromatographed on silica gel with 85/15
heptanes/ethyl acetate to afford the title compound.
Example 24D
(R)-2-((S)-oxiran-2-ylmethoxy)propan-1-ol
[0304] EXAMPLE 24C (2.3 g) was dissolved in ethyl acetate (65 mL),
Pd(OH).sub.2 on carbon (20% Pd dry wt/overall 50% water, 100 mg)
was added and the reaction mixture was stirred under a hydrogen
balloon for 2 hours. After filtration through diatomaceous earth
and concentration the incomplete reaction was rerun, this time
using tetrahydrofuran in place of ethyl acetate. The crude material
was chromatographed on silica gel with 35/65 heptanes/ethyl acetate
to afford the title compound.
Example 24E
((2R,5R)-5-methyl-1,4-dioxan-2-yl)methanol
[0305] EXAMPLE 24D (800 mg) was dissolved in dichloromethane (45
mL), (1S)-(+)-camphorsulfonic acid (415 mg) was added, and the
reaction mixture was stirred at room temperature overnight.
Saturated NaHCO.sub.3 was added, the layers were separated, and the
aqueous layer was extracted with dichloromethane (3.times.50 mL).
The combined organic layers were dried over Na.sub.2SO.sub.4. After
filtration and concentration, the crude material was
chromatographed on silica gel with 35/65 heptanes/ethyl acetate to
afford the title compound.
Example 24F
((2S,5R)-5-methyl-1,4-dioxan-2-yl)methyl methanesulfonate
[0306] EXAMPLE 24E (400 mg) and triethylamine (0.58 mL) were
dissolved in dichloromethane (12 mL). The reaction mixture was
cooled to 0.degree. C., and methanesulfonyl chloride (0.28 mL) was
added dropwise. The reaction mixture was stirred at room
temperature for 1 hour. Saturated NaHCO.sub.3 (10 mL) was added,
and the aqueous layer was extracted with dichloromethane (3.times.7
mL). The combined organic layers were dried over Na.sub.2SO.sub.4.
Filtration and concentration of the filtrate gave the title
compound that was used in the next step without further
purification.
Example 24G
(2R,5R)-2-(azidomethyl)-5-methyl-1,4-dioxane
[0307] The title compound was prepared by substituting EXAMPLE 24F
for EXAMPLE 1K in EXAMPLE 1L.
Example 24H
((2R,5R)-5-methyl-1,4-dioxan-2-yl)methanamine
[0308] The title compound was prepared by substituting EXAMPLE 24G
for EXAMPLE 9B in EXAMPLE 9C.
Example 241
4-(((2R,5R)-5-methyl-1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[0309] The title compound was prepared by substituting EXAMPLE 24H
for EXAMPLE 1M in EXAMPLE 1N.
Example 24J
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2R,5R)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0310] The title compound was prepared by substituting EXAMPLE 241
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.65 (s, 1H), 8.57 (d, 1H),
8.55 (t, 1H), 8.03 (d, 1H), 7.83 (dd, 1H), 7.50 (m, 3H), 7.34 (d,
2H), 7.10 (d, 1H), 7.02 (d, 2H), 6.67 (dd, 1H), 6.38 (m, 1H), 6.20
(d, 1H), 3.86, 3.78, 3.70, 3.67 (all m, 5H), 3.54, 3.49 (both m,
3H), 3.08 (br m, 4H), 2.76 (br s, 2H), 2.20 (br m, 4H), 2.13 (br m,
2H), 1.94 (br m, 2H), 1.37 (t, 2H), 1.09 (d, 3H), 0.92 (s, 6H).
Example 25
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(6-hydroxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 25A
1,4-dioxepan-6-one
[0311] To a cooled (0.degree. C.) solution of ethane-1,2-diol (12.9
g) and ethyl 2-diazoacetate (47.5 g) in dichloromethane (400 mL)
was added dropwise BF.sub.3Et.sub.2O (0.3 mL). Gas evolution was
observed upon the addition. The temperature was allowed to rise to
room temperature and the mixture was stirred for 24 hours. The
mixture was then concentrated under vacuum and the residue was used
directly in the next reaction without further purification. To a
solution of diethyl 2,2'-(ethane-1,2-diylbis(oxy))diacetate (52.75
g) in DMF was added tert-butoxylithium (36 g). The mixture was
stirred at 90.degree. C. overnight. The mixture was poured over 10%
aqueous HCl (200 mL) and extracted three times with ethyl acetate.
The combined extracts were washed three times with water, and
brine, and dried over Na.sub.2SO.sub.4. Filtration and
concentration gave crude product which was used in the next
reaction without further purification. A mixture of ethyl
6-oxo-1,4-dioxepane-5-carboxylate (16.2 g) in 10% aqueous HCl (100
mL) was stirred at reflux for 4 hours. The mixture was cooled, and
extracted three times with ethyl ether. The combined extracts were
washed with brine, and dried over Na.sub.2SO.sub.4. After
filtration, concentration afforded the title compound.
Example 25B
6-(nitromethyl)-1,4-dioxepan-6-ol
[0312] To a solution of sodium ethoxide (14 g, 21% w) in ethanol
(20 mL) was added a solution of EXAMPLE 25A (3.2 g) and
nitromethane (3.75 g). The reaction mixture was stirred for 4
hours. The reaction mixture was poured in aqueous NH.sub.4Cl (200
mL). The aqueous layer was extracted three times with ethyl
acetate. The organic layers were combined and dried with
MgSO.sub.4. After filtration and concentration, the crude material
was purified with on an Analogix System with a 600 g column,
eluting with 0-40% ethyl acetate in hexanes to afford the title
compound.
Example 25C
6-(aminomethyl)-1,4-dioxepan-6-ol
[0313] To a solution of EXAMPLE 25B (1.2 g) in ethanol (60 mL) was
added Pd/C (10%, 120 mg). The mixture was stirred under a hydrogen
balloon overnight. The mixture was filtered and concentrated to
afford the crude product which was used directly in the next
reaction without further purification.
Example 25D
4-(((6-hydroxy-1,4-dioxepan-6-yl)methyl)amino)-3-nitrobenzenesulfonamide
[0314] The title compound was prepared by substituting EXAMPLE 25C
for EXAMPLE 1M in EXAMPLE 1N.
Example 25E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(6-hydroxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0315] The title compound was prepared by substituting EXAMPLE 25D
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 8.64 (t, 1H),
8.57 (d, 1H), 8.05 (d, 1H), 7.81 (dd, 1H), 7.45-7.57 (m, 3H), 7.33
(t, 2H), 7.11 (d, 1H), 6.97-7.07 (m, 2H), 6.68 (dd, 1H), 6.39 (dd,
1H), 6.19 (d, 1H), 5.46-5.58 (m, 1H), 3.58-3.83 (m, 9H), 3.34-3.46
(m, 3H), 2.99-3.16 (m, 5H), 2.67-2.83 (m, 2H), 2.08-2.31 (m, 7H),
1.86-1.98 (m, 2H), 1.32-1.44 (m, 2H), 0.92 (s, 6H).
Example 26
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4,4-difluoro-1-hydroxycyclohexyl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 26A
4-(((4,4-difluoro-1-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonam-
ide
[0316] The title compound was prepared by substituting
1-(aminomethyl)-4,4-difluorocyclohexanol for EXAMPLE 1M in EXAMPLE
1N.
Example 26B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4,4-difluoro-1-hydroxycyclohexyl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0317] The title compound was prepared by substituting EXAMPLE 26A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.73 (s, 1H), 11.40 (bs,
1H), 8.73 (t, 1H), 8.63 (d, 1H), 8.11 (d, 1H), 7.87 (dd, 1H),
7.62-7.53 (m, 3H), 7.40 (d, 2H), 7.25 (d, 1H), 7.10 (d, 2H), 6.74
(dd, 1H), 6.45 (dd, 1H), 6.25 (d, 1H), 5.12 (s, 1H), 3.49-3.42 (m,
2H), 3.13 (bs, 4H), 2.81 (bs, 2H), 2.30-2.18 (m, 6H), 2.15-1.90 (m,
6H), 1.81 (d, 2H), 1.66 (td, 2H), 1.44 (t, 2H), 0.98 (s, 6H).
Example 27
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-methoxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 27A
4-(((4-methoxytetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfona-
mide
[0318] The title compound was prepared by substituting
(4-methoxytetrahydro-2H-pyran-4-yl)methanamine for EXAMPLE 1M in
EXAMPLE 1N.
Example 27B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-methoxytetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0319] The title compound was prepared by substituting EXAMPLE 27A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.69 (s, 1H), 11.36 (bs,
1H), 8.58 (d, 1H), 8.42 (t, 1H), 8.05 (d, 1H), 7.87 (dd, 1H),
7.56-7.48 (m, 3H), 7.34 (d, 2H), 7.12 (d, 1H), 7.04 (d, 2H), 6.68
(d, 1H), 6.40 (dd, 1H), 6.19 (d, 1H), 3.68-3.62 (m, 2H), 3.56 (td,
2H), 3.47 (d, 2H), 3.17 (s, 3H), 3.07 (bs, 4H), 2.76 (bs, 2H), 2.20
(bs, 4H), 2.14 (t, 2H), 1.95 (bs, 2H), 1.75 (d, 2H), 1.60 (m, 2H),
1.38 (t, 2H), 0.92 (s, 6H).
Example 28
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3,3-difluorocyclobutyl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 28A
4-(((3,3-difluorocyclobutyl)methyl)amino)-3-nitrobenzenesulfonamide
[0320] The title compound was prepared by substituting
(3,3-difluorocyclobutyl)methanamine hydrochloride for EXAMPLE 1M in
EXAMPLE 1N.
Example 28B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3,3-difluorocyclobutyl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0321] The title compound was prepared by substituting EXAMPLE 28A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.41 (bs,
1H), 8.62 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H),
7.54-7.46 (m, 3H), 7.34 (d, 2H), 7.11 (d, 1H), 7.04 (d, 2H), 6.68
(d, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 3.53 (t, 2H), 3.07 (bs, 4H),
2.74 (bs, 2H), 2.70-2.59 (m, 2H), 2.46-2.35 (m, 2H), 2.25-2.10 (m,
7H), 1.95 (bs, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 29
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[({1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}methyl)-
amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 29A
3-nitro-4-(((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)amino)benz-
enesulfonamide
[0322] The title compound was prepared by substituting
(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methanamine for
EXAMPLE 1M in EXAMPLE 1N.
Example 29B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[({1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}methyl)-
amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0323] The title compound was prepared by substituting EXAMPLE 29A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.39 (bs,
1H), 8.63 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.81 (dd, 1H),
7.54-7.48 (m, 3H), 7.34 (d, 2H), 7.13 (d, 1H), 7.04 (d, 2H), 6.68
(d, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.82 (d, 2H), 3.36 (t, 2H),
3.17 (t, 2H), 3.07 (bs, 4H), 2.75 (bs, 2H), 2.25-2.11 (m, 6H), 1.95
(bs, 2H), 1.86 (m, 3H), 1.38 (t, 2H), 1.27 (m, 2H), 0.92 (s,
6H).
Example 30
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-4-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 30A
4-(((1-(methylsulfonyl)piperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonam-
ide
[0324] The title compound was prepared by substituting
(1-(methylsulfonyl)piperidin-4-yl)methanamine for EXAMPLE 1M in
EXAMPLE 1N.
Example 30B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-4-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0325] The title compound was prepared by substituting EXAMPLE 30A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.40 (bs,
1H), 8.62 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H),
7.54-7.48 (m, 3H), 7.34 (d, 2H), 7.12 (d, 1H), 7.04 (d, 2H), 6.68
(d, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.56 (d, 2H), 3.34 (t, 2H),
3.07 (bs, 4H), 2.83 (s, 3H), 2.75 (bs, 2H), 2.67 (td, 2H),
2.25-2.10 (m, 6H), 1.95 (bs, 2H), 1.81 (m, 3H), 1.38 (t, 2H), 1.27
(m, 2H), 0.92 (s, 6H).
Example 31
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}amin-
o)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 31A
(2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one
[0326] 2,6-Dimethyl-4H-pyran-4-one (14 g) and tetrahydrofuran (140
mL) were added to 10% Pd/C, dry (2.8 g) in a 250 mL SS pressure
bottle and the mixture was stirred for 2 hours at 50 psi. The
mixture was filtered through a nylon membrane and concentrated. The
crude product was chromatographed on silica gel with 5-50% ethyl
acetate/hexanes to afford the title compound.
Example 31B
rac-(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-carbonitrile
[0327] The title compound was prepared by substituting EXAMPLE 31A
for 1-oxaspiro[4.5]decan-8-one in EXAMPLE 4A
Example 31C
4-({[(2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitro-
benzenesulfonamide
[0328] LiAlH.sub.4 (14.4 mL, 1M in tetrahydrofuran) was added to
EXAMPLE 31B (2 g) in tetrahydrofuran (40 mL) and the mixture was
stirred for 1 hour. The reaction mixture was quenched by the
addition of saturated sodium potassium tartrate solution (5 mL),
and the mixture was stirred for 30 minutes. The solution was
decanted away from the salts and concentrated. The crude material
was taken up in tetrahydrofuran (50 mL) and triethylamine (2.0 mL)
and 4-fluoro-3-nitrobenzenesulfonamide (3.16 g) were added. The
reaction mixture was stirred for 1 hour. The reaction mixture was
diluted with ethyl acetate (200 mL), washed twice with
NaH.sub.2PO.sub.4 solution and brine, and concentrated. The crude
product was chromatographed on silica gel with 10-50% ethyl
acetate/hexanes to separately afford the title compound and its
diastereomer.
Example 31D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}amin-
o)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0329] The title compound was prepared by substituting EXAMPLE 31C
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.69 (s, 1H), 11.40 (br s, 1H),
8.60 (m, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.80 (d, 1H), 7.51 (m,
2H), 7.34 (d, 2H), 7.09 (d, 1H), 7.04 (d, 2H), 6.68 (d, 1H), 6.40
(d, 1H), 6.19 (s, 1H), 3.39 (m, 2H), 3.28 (m, 2H), 3.07 (m, 4H),
2.75 (s, 2H), 2.19 (s, 4H), 2.14 (m, 2H), 1.95 (s, 2H), 1.65 (m,
2H), 1.38 (m, 2H), 1.09 (s, 6H), 0.92 (m, 6H), 0.84 (m, 4H).
Example 32
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}ph-
enyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0330] EXAMPLE 22B (450 mg) was dissolved in dichloromethane (8
mL), and 3-chloroperoxybenzoic acid (76%, 88 mg) was added. The
reaction mixture was stirred at room temperature for three days.
The crude material was purified by flash column chromatography on
silica gel using 10-20% methanol in dichloromethane. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H),
11.41 (bs, 1H), 8.68-8.56 (m, 1H), 8.55 (d, 1H), 8.03 (d, 1H), 7.78
(d, 1H), 7.52-7.47 (m, 3H), 7.34 (d, 2H), 7.09 (m, 1H), 7.04 (d,
2H), 6.67 (d, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 3.25 (m, 2H), 3.06
(bs, 4H), 2.86 (d, 2H), 2.73 (bs, 2H), 2.66-2.53 (m, 2H), 2.25-2.00
(m, 6H), 1.95 (bs, 2H), 1.87 (m, 3H), 1.69 (m, 2H), 1.38 (t, 2H),
0.92 (s, 6H).
Example 33
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 33A
(S)-4-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene-
sulfonamide
[0331] The title compound was prepared by substituting racemic
(2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamine hydrochloride for
EXAMPLE 1M in EXAMPLE 1N, and performing chiral purification as
described in EXAMPLE 19D.
Example 33B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0332] The title compound was prepared by substituting EXAMPLE 33A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.41 (bs,
1H), 8.60-8.52 (m, 2H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.53-7.47 (m,
3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.04 (d, 2H), 6.68 (d, 1H), 6.39
(dd, 1H), 6.19 (d, 1H), 3.59 (td, 1H), 3.52 (td, 1H), 3.25 (t, 2H),
3.07 (bs, 4H), 2.74 (bs, 2H), 2.28-2.00 (m, 8H), 1.95 (bs, 2H),
1.58 (dd, 2H), 1.38 (t, 2H), 1.25 (m, 1H), 1.12 (s, 6H), 0.92 (s,
6H).
Example 34
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 34A
(R)-4-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzene-
sulfonamide
[0333] The title compound was also prepared as described in EXAMPLE
33A.
Example 34B
[0334]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-{[4-({[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]methyl}ami-
no)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0335] The title compound was prepared by substituting EXAMPLE 34A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.40 (bs,
1H), 8.60-8.52 (m, 2H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.53-7.47 (m,
3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.04 (d, 2H), 6.68 (d, 1H), 6.39
(dd, 1H), 6.19 (d, 1H), 3.59 (td, 1H), 3.52 (td, 1H), 3.25 (t, 2H),
3.07 (bs, 4H), 2.74 (bs, 2H), 2.28-2.00 (m, 8H), 1.95 (bs, 2H),
1.58 (dd, 2H), 1.38 (t, 2H), 1.25 (m, 1H), 1.12 (s, 6H), 0.92 (s,
6H).
Example 35
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S,6R)-6-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 35A
(R)-1-(tert-butyldiphenylsilyloxy)propan-2-ol
[0336] (R)-propane-1,2-diol (5 g) and imidazole (4.5 g) were
dissolved in dichloromethane (200 mL). The mixture was cooled to
0.degree. C., and a solution of tert-butylchlorodiphenylsilane
(18.1 g) in dichloromethane (50 mL) was added dropwise. The
reaction mixture was maintained at 0.degree. C. under a drying tube
overnight. The reaction mixture was filtered through diatomaceous
earth, and concentrated. The crude material was chromatographed on
silica gel with 9/1 heptanes/ethyl acetate to afford the title
compound.
Example 35B
(R)-(2-(benzyloxy)propoxy)(tert-butyl)diphenylsilane
[0337] EXAMPLE 35A (16.8 g), benzyl bromide (9.5 mL),
N-ethyl-N-isopropylpropan-2-amine (15.0 mL), and sodium iodide
(0.82 g) were heated at 150.degree. C. under N.sub.2 for 3 days.
The reaction was cooled to room temperature and partitioned between
ethyl acetate and 1M KHSO.sub.4. The organic layer was washed with
brine, and dried over Na.sub.2SO.sub.4. After filtration and
concentration, the crude material was chromatographed on silica gel
with 98.5/1.5 heptanes/ethyl acetate to afford the title
compound.
Example 35C
(R)-2-(benzyloxy)propan-1-ol
[0338] EXAMPLE 35B (5.6 g) was dissolved in tetrahydrofuran (50
mL), tetrabutyl ammonium fluoride (15 mL, 1.0M in 95/5
tetrahydrofuran/H.sub.2O) was added and the reaction was stirred
overnight. The reaction mixture was concentrated and the crude
material was chromatographed on silica gel with 3/1 heptanes/ethyl
acetate to afford the title compound.
Example 35D
(R)-((1-(allyloxy)propan-2-yloxy)methyl)benzene
[0339] The title compound was prepared by substituting EXAMPLE 35C
for (R)-1-(benzyloxy)propan-2-ol in EXAMPLE 24A.
Example 35E
2-(((R)-2-(benzyloxy)propoxy)methyl)oxirane
[0340] The title compound was prepared by substituting EXAMPLE 35D
for EXAMPLE 24A in EXAMPLE 24B.
Example 35F
(R)-2-(((R)-2-(benzyloxy)propoxy)methyl)oxirane
[0341] The title compound was prepared by substituting EXAMPLE 35E
for EXAMPLE 24B and S,S-(salen)Co(II) complex (CAS #188264-84-8)
for R,R-(salen)Co(II) complex in EXAMPLE 24C.
Example 35G
(R)-1-((R)-oxiran-2-ylmethoxy)propan-2-ol
[0342] EXAMPLE 35F (780 mg) was dissolved in tetrahydrofuran (20
mL), and Pd(OH).sub.2 on carbon (20% Pd dry wt/overall 50% water,
80 mg) was added. The reaction mixture was stirred under a hydrogen
balloon for 3 hours. Filtration through diatomaceous earth and
concentration gave the title compound that was used in the next
step without further purification.
Example 35H
((2S,6R)-6-methyl-1,4-dioxan-2-yl)methanol
[0343] The title compound was prepared by substituting EXAMPLE 35G
for EXAMPLE 24D in EXAMPLE 24E.
Example 351
((2R,6R)-6-methyl-1,4-dioxan-2-yl)methyl methanesulfonate
[0344] The title compound was prepared by substituting EXAMPLE 35H
for EXAMPLE 24E in EXAMPLE 24F.
Example 35J
(2S,6R)-2-(azidomethyl)-6-methyl-1,4-dioxane
[0345] The title compound was prepared by substituting EXAMPLE 351
for EXAMPLE 1K in EXAMPLE 1L.
Example 35K
((2S,6R)-6-methyl-1,4-dioxan-2-yl)methanamine
[0346] The title compound was prepared by substituting EXAMPLE 35J
for EXAMPLE 9B in EXAMPLE 9C.
Example 35L
4-(((2S,6R)-6-methyl-1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[0347] The title compound was prepared by substituting EXAMPLE 35J
for EXAMPLE 1M in EXAMPLE 1N.
Example 35M
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S,6R)-6-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0348] The title compound was prepared by substituting EXAMPLE 35L
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.66 (s, 1H), 11.35 (v br
s, 1H), 8.59 (t, 1H), 8.55 (d, 1H), 8.03 (d, 1H), 7.81 (dd, 1H),
7.50 (m, 3H), 7.34 (d, 2H), 7.08 (d, 1H), 7.03 (d, 2H), 6.68 (dd,
1H), 6.38 (m, 1H), 6.20 (d, 1H), 3.86 (m, 1H), 3.79 (dd, 1H), 3.70
(m, 2H), 3.48 (m, 1H), 3.35 (m, 2H), 3.21 (t, 1H), 3.06 (br m, 5H),
2.76 (br s, 2H), 2.20 (br m, 4H), 2.14 (br m, 2H), 1.95 (br m, 2H),
1.38 (t, 2H), 1.01 (d, 3H), 0.92 (s, 6H).
Example 36
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydrofuran-3-ylmethyl]amino}phenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 36A
(S)-(tetrahydrofuran-3-yl)methanol
[0349] (R)-tetrahydrofuran-3-carboxylic acid (0.50 g) in
tetrahydrofuran (7.5 mL) was cooled to 0.degree. C., and borane
tetrahydrofuran complex (14 mL 1.0M in tetrahydrofuran) was added
dropwise, keeping the temperature <6.degree. C. The reaction
mixture was allowed to stir at room temperature under nitrogen for
45 minutes. The reaction mixture was cooled to 0.degree. C. and 5N
NaOH (2.3 mL) was carefully added. The reaction mixture was stirred
for a few minutes, and water and diethylether were added. The
separated organic layer was washed with brine and the combined
aqueous layers were back-extracted with diethylether. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude material was chromatographed on silica gel
with 3/7 heptanes/ethyl acetate to afford the title compound.
Example 36B
(R)-(tetrahydrofuran-3-yl)methyl methanesulfonate
[0350] The title compound was prepared by substituting EXAMPLE 36A
for EXAMPLE 24E in EXAMPLE 24F.
Example 36C
(S)-3-(azidomethyl)tetrahydrofuran
[0351] The title compound was prepared by substituting EXAMPLE 36B
for EXAMPLE 1K in EXAMPLE 1L.
Example 36D
(S)-(tetrahydrofuran-3-yl)methanamine
[0352] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 9B in EXAMPLE 9C.
Example 36E
(S)-3-nitro-4-((tetrahydrofuran-3-yl)methylamino)benzenesulfonamide
[0353] The title compound was prepared by substituting EXAMPLE 36D
for EXAMPLE 1M in EXAMPLE 1N.
Example 36F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydrofuran-3-ylmethyl]amino}phenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0354] The title compound was prepared by substituting EXAMPLE 36E
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.68 (s, 1H), 11.33 (v br
s, 1H), 8.62 (t, 1H), 8.57 (d, 1H), 8.03 (d, 1H), 7.81 (dd, 1H),
7.50 (m, 3H), 7.34 (d, 2H), 7.09 (d, 1H), 7.03 (d, 2H), 6.68 (dd,
1H), 6.39 (m, 1H), 6.19 (d, 1H), 3.80 (m, 1H), 3.71 (dd, 1H), 3.63
(dd, 1H), 3.52 (m, 2H), 3.08 (br m, 4H), 2.76 (br s, 2H), 2.58 (m,
1H), 2.20 (br m, 4H), 2.00 (m, 1H), 2.14 (br m, 2H), 1.65 (m, 1H),
1.95 (br m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 37
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S)-6,6-dimethyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 37A
methyl 2-(allyloxy)acetate
[0355] Methyl glycolate (25 g) was added dropwise over 10-15
minutes to a 0.degree. C. suspension of NaH (7.7 g, 95%) in DMF
(280 mL). Methyl glycolate (25 g) was then added dropwise over
10-15 minutes. The reaction was allowed to warm to room
temperature, stirred for 1 hour, and cooled back down to 0.degree.
C. Allyl bromide (36.7 g) was added dropwise over 10-15 minutes,
and the reaction was stirred at room temperature for 1 hour. The
reaction mixture was poured into saturated aqueous NH.sub.4Cl
solution (700 mL) and extracted with ethyl acetate (3.times.350
mL). The combined organic layers were washed with brine and dried
over Na.sub.2SO.sub.4. After filtration and concentration, the
crude product was distilled using a Vigeraux head and vac=3.4 mmHg
to get the title compound as a mixture with DMF. This was dissolved
in ether (10 mL), washed with water (2.times.10 mL) and brine, then
dried over MgSO.sub.4. Filtration and concentration gave the title
compound.
Example 37B
1-(allyloxy)-2-methylpropan-2-ol
[0356] EXAMPLE 37A (12 g) was dissolved in tetrahydrofuran (200 mL)
and cooled to 0.degree. C. CH.sub.3MgCl (100 mL, 3.0 M in
tetrahydrofuran) was added dropwise. The reaction mixture was
stirred cold under N.sub.2 for 3.5 hours. Saturated NH.sub.4Cl (60
mL) was slowly added followed by the addition of water and
diethylether. The organic layer was washed with brine and dried
over Na.sub.2SO.sub.4. Filtration and concentration of the filtrate
afforded the title compound which was used in the next step without
further purification.
Example 37C
((1-(allyloxy)-2-methylpropan-2-yloxy)methyl)benzene
[0357] The title compound was prepared by substituting EXAMPLE 37B
for EXAMPLE 35A in EXAMPLE 35B.
Example 37D
2-((2-(benzyloxy)-2-methylpropoxy)methyl)oxirane
[0358] The title compound was prepared by substituting EXAMPLE 37C
for EXAMPLE 24A in EXAMPLE 24B.
Example 37E
(R)-2-((2-(benzyloxy)-2-methylpropoxy)methyl)oxirane
[0359] The title compound was prepared by substituting EXAMPLE 37D
for EXAMPLE 24B and S,S-(salen)Co(II) complex (CAS #188264-84-8)
for R,R-(salen)Co(II) complex in EXAMPLE 24C.
Example 37F
(R)-2-methyl-1-(oxiran-2-ylmethoxy)propan-2-ol
[0360] The title compound was prepared by substituting EXAMPLE 37E
for EXAMPLE 35F in EXAMPLE 35G.
Example 37G
(S)-(6,6-dimethyl-1,4-dioxan-2-yl)methanol
[0361] The title compound was prepared by substituting EXAMPLE 37F
for EXAMPLE 24D in EXAMPLE 24E.
Example 37H
(R)-(6,6-dimethyl-1,4-dioxan-2-yl)methyl methanesulfonate
[0362] The title compound was prepared by substituting EXAMPLE 37G
for EXAMPLE 24E in EXAMPLE 24F.
Example 371
(S)-6-(azidomethyl)-2,2-dimethyl-1,4-dioxane
[0363] The title compound was prepared by substituting EXAMPLE 37H
for EXAMPLE 1K in EXAMPLE 1L.
Example 37J
(S)-(6,6-dimethyl-1,4-dioxan-2-yl)methanamine
[0364] The title compound was prepared by substituting EXAMPLE 371
for EXAMPLE 9B in EXAMPLE 9C.
Example 37K
(S)-4-((6,6-dimethyl-1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[0365] The title compound was prepared by substituting EXAMPLE 37J
for EXAMPLE 1M in EXAMPLE 1N.
Example 37L
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S)-6,6-dimethyl-1,4-dioxan-2-yl]methyl}amino)-3-nitrophen-
yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0366] The title compound was prepared by substituting EXAMPLE 37K
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.66 (s, 1H), 11.33 (v br
s, 1H), 8.57 (t, 1H), 8.56 (d, 1H), 8.03 (d, 1H), 7.82 (dd, 1H),
7.50 (m, 3H), 7.34 (d, 2H), 7.06 (d, 1H), 7.03 (d, 2H), 6.69 (dd,
1H), 6.38 (m, 1H), 6.20 (d, 1H), 4.06 (m, 1H), 3.81 (dd, 1H), 3.49
(d, 1H), 3.43 (m, 1H), 3.29 (m, 1H), 3.18 (m, 2H), 3.08 (br m, 4H),
2.76 (br s, 2H), 2.20 (br m, 4H), 2.14 (br m, 2H), 1.95 (br m, 2H),
1.38 (t, 2H), 1.27 (s, 3H), 1.08 (s, 3H), 0.92 (s, 6H).
Example 38
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 38A
4-(((3-methyloxetan-3-yl)methyl)amino)-3-nitrobenzenesulfonamide
[0367] The title compound was prepared by substituting
(3-methyloxetan-3-yl)methanamine for EXAMPLE 1M in EXAMPLE 1N.
Example 38B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0368] The title compound was prepared by substituting EXAMPLE 38A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.66 (s, 1H), 11.41 (bs,
1H), 8.67 (t, 1H), 8.57 (d, 1H), 8.03 (d, 1H), 7.83 (dd, 1H),
7.52-7.47 (m, 3H), 7.34 (d, 2H), 7.17 (d, 1H), 7.04 (d, 2H), 6.68
(d, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.45 (d, 2H), 4.31 (d, 2H),
3.57 (td, 2H), 3.07 (bs, 4H), 2.75 (bs, 2H), 2.25-2.11 (m, 6H),
1.95 (bs, 2H), 1.38 (t, 2H), 1.32 (s, 3H), 0.92 (s, 6H).
Example 39
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(6-fluoro-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 39A
6-((dibenzylamino)methyl)-1,4-dioxepan-6-ol
[0369] To a solution of EXAMPLE 25C (1.8 g) in dichloromethane (30
mL) was added benzaldehyde (3.82 g) and acetic acid (0.5 mL)
followed by sodium cycanoborohydride on resin (2.4 mmol/g, 4.5 g).
The mixture was stirred overnight. The mixture was then filtered
and the filtrate was concentrated under vacuum. The residue was
loaded on a silica gel column and eluted with 30% ethyl acetate in
hexane to afford the title compound.
Example 39B
N,N-dibenzyl-1-(6-fluoro-1,4-dioxepan-6-yl)methanamine
[0370] To a solution of EXAMPLE 39A (256 mg) in dichloromethane (33
mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (2 mL, 1M
solution in tetrahydrofuran). The mixture was stirred overnight.
The mixture was then poured into ice-water and extracted three
times with dichloromethane (50 mL). The combined organic extracts
were washed with aqueous NaHCO.sub.3, water and brine, and dried
over Na.sub.2SO.sub.4. After filtration and concentration, the
crude material was purified by column chromatography using 20%
ethyl acetate in heptane to afford the title compound.
Example 39C
(6-fluoro-1,4-dioxepan-6-yl)methanamine
[0371] To a solution of EXAMPLE 39B (200 mg) in methanol (20 mL)
was added Raney Ni (30 mg). The mixture was stirred under 30 psi
hydrogen overnight. Filtration and concentration afforded the title
compound.
Example 39D
4-(((6-fluoro-1,4-dioxepan-6-yl)methyl)amino)-3-nitrobenzenesulfonamide
[0372] The title compound was prepared by substituting EXAMPLE 39C
for EXAMPLE 1M in EXAMPLE 1N.
Example 39E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(6-fluoro-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0373] The title compound was prepared by substituting EXAMPLE 39D
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz
dimethylsulfoxide-d.sub.6) .delta. ppm 11.70 (s, 1H), 11.60-11.67
(m, 1H), 9.48-9.71 (m, 1H), 8.52-8.70 (m, 2H), 8.04 (d, 1H), 7.83
(dd, 1H), 7.46-7.62 (m, 3H), 7.39 (d, 2H), 7.20 (d, 1H), 7.08 (d,
2H), 6.71 (dd, 1H), 6.40 (dd, 1H), 6.25 (s, 1H), 3.49-4.03 (m, 9H),
2.99-3.19 (m, 2H), 2.62-2.84 (m, 2H), 2.15-2.31 (m, 4H), 1.97-2.05
(m, 4H), 1.37-1.53 (m, 4H), 0.94 (s, 6H).
Example 40
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(6-methoxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 40A
N,N-dibenzyl-1-(6-methoxy-1,4-dioxepan-6-yl)methanamine
[0374] To a solution of EXAMPLE 39A (300 mg) in tetrahydrofuran (3
mL) and HMPA (hexamethylphosphoramide, 3 mL) was added NaH (200 mg,
60% in mineral oil). The mixture was stirred for 30 minutes before
the addition of CH.sub.3I (0.6 g). The mixture was then stirred at
50.degree. C. overnight. The mixture was poured over aqueous
NH.sub.4Cl and extracted three times with ethyl acetate (100 mL).
The combined organic extracts were washed three times with water,
and brine, and dried over Na.sub.2SO.sub.4. After filtration and
concentration, evaporation of the solvent gave crude product which
was loaded on a silica gel column and eluted with 20% ethyl acetate
in hexane to afford the title compound.
Example 40B
(6-methoxy-1,4-dioxepan-6-yl)methanamine
[0375] To a solution of EXAMPLE 40A (200 mg) in methanol (20 mL)
was added Raney Ni (50 mg). The mixture was stirred under 30 psi
hydrogen overnight. After filtration, vacuum evaporation of the
solvent afforded the title compound.
Example 40C
4-(((6-methoxy-1,4-dioxepan-6-yl)methyl)amino)-3-nitrobenzenesulfonamide
[0376] The title compound was prepared by substituting EXAMPLE 40B
for EXAMPLE 1M in EXAMPLE 1N.
Example 40D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(6-methoxy-1,4-dioxepan-6-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0377] The title compound was prepared by substituting EXAMPLE 40C
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.68 (s, 1H), 8.57 (d, 1H),
8.49 (t, 1H), 8.05 (d, 1H), 7.43-7.58 (m, 3H), 7.34 (d, 2H), 7.12
(d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H),
3.87-4.09 (m, 3H), 3.61-3.81 (m, 5H), 3.38-3.51 (m, 2H), 2.99-3.15
(m, 4H), 2.70-2.90 (m, 2H), 2.08-2.33 (m, 5H), 1.90-2.01 (m, 3H),
1.39 (t, 2H), 1.17 (t, 2H), 0.92 (s, 6H).
Example 41
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 41A
trans-3-(hydroxymethyl)cyclobutanecarbonitrile
[0378] Catecholborane (7.1 mL) was added to
3-methylenecyclobutanecarbonitrile (5.6 g) in tetrahydrofuran (25
mL) and the mixture was stirred for 24 hours. The reaction mixture
was quenched by the slow addition of ethanol (25 mL), and the
mixture was poured into ethanol (75 mL) and tetrahydrofuran (100
mL). To this was added 2M aqueous NaOH (150 mL) and 30% aqueous
H.sub.2O.sub.2 (150 mL) was added slowly over 1 hour. The mixture
was stirred another 3 hours, and was diluted with ethyl acetate
(500 mL). The layers were separated and the organic layer was
washed twice with 1M aqueous NaOH and brine, and concentrated. The
crude product was chromatographed on silica gel with 5-100% ethyl
acetate/hexanes to separately afford the title compound and its
cis-diastereomer.
Example 41B
trans-3-cyanocyclobutyl)methyl methanesulfonate
[0379] Mesyl chloride (1.0 mL) was added to EXAMPLE 41A (1.35 g)
and diisopropylethylamine (2.33 mL) in dichloromethane (50 mL) at
-20.degree. C. The mixture was stirred for 1 hour. The reaction
mixture was poured into dichloromethane (200 mL) and washed twice
with water and brine, and concentrated. The crude product was
chromatographed on silica gel with 10-100% ethyl acetate/hexanes to
separately afford the title compound.
Example 41C
4-(((trans-3-cyanocyclobutyl)methyl)amino)-3-nitrobenzenesulfonamide
[0380] Sodium azide (1.1 g) was added to EXAMPLE 41B (5.6 g) in
N,N-dimethylformamide (15 mL) and the mixture was stirred for 24
hours. The reaction mixture was poured into water (75 mL) and
extracted twice with ether (100 mL). The organic layers were
combined and concentrated to 10 mL. Tetrahydrofuran (25 mL) was
added and to the resulting mixture triphenylphosphine (2.2 g) and
water (0.3 mL) were added, and the reaction was stirred for 24
hours. Sodium sulfate (5 g) and 4-fluoro-3-nitrobenzenesulfonamide
(1.86 g) were added and the reaction was stirred for 2 hours at
40.degree. C. The mixture was diluted with ethyl acetate (300 mL).
The layers were separated and the organic layer was washed with
brine, and concentrated. The crude product was chromatographed on
silica gel with 50% ethyl acetate/hexanes to afford the title
compound.
Example 41D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(trans-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0381] The title compound was prepared by substituting EXAMPLE 41C
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 11.35 (br s, 1H),
8.56 (m, 1H), 8.54 (s, 1H), 8.04 (s, 1H), 7.80 (d, 1H), 7.51 (m,
2H), 7.34 (d, 2H), 7.09 (d, 1H), 7.04 (d, 2H), 6.69 (d, 1H), 6.39
(d, 1H), 6.19 (s, 1H), 3.51 (m, 2H), 3.40 (m, 1H), 3.07 (m, 4H),
2.78 (m, 1H), 2.75 (m, 2H), 2.38 (m, 2H), 2.20 (m, 6H), 1.95 (s,
2H), 1.38 (t, 2H), 1.24 (m, 1H), 0.92 (m, 6H), 0.85 (m, 2H).
Example 42
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(cis-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfonyl]-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 42A
cis-3-(hydroxymethyl)cyclobutanecarbonitrile
[0382] The title compound was also isolated from EXAMPLE 41A.
Example 42B
cis-3-cyanocyclobutyl)methyl methanesulfonate
[0383] The title compound was prepared by substituting EXAMPLE 42A
for EXAMPLE 41A in EXAMPLE 41B.
Example 42C
4-(((cis-3-cyanocyclobutyl)methyl)amino)-3-nitrobenzenesulfonamide
[0384] The title compound was prepared by substituting EXAMPLE 42B
for EXAMPLE 41B in EXAMPLE 41C.
Example 42D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(cis-3-cyanocyclobutyl)methyl]amino}-3-nitrophenyl)sulfonyl]-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0385] The title compound was prepared by substituting EXAMPLE 42C
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 11.35 (br s, 1H),
8.55 (m, 2H), 8.04 (s, 1H), 7.81 (d, 1H), 7.51 (m, 2H), 7.34 (d,
2H), 7.06 (d, 1H), 7.04 (d, 2H), 6.69 (d, 1H), 6.39 (d, 1H), 6.19
(s, 1H), 3.47 (m, 2H), 3.32 (m, 1H), 3.07 (m, 4H), 2.75 (m, 2H),
2.65 (m, 1H), 2.38 (m, 2H), 2.20 (m, 6H), 1.95 (s, 2H), 1.38 (t,
2H), 1.24 (m, 1H), 0.92 (m, 6H), 0.86 (m, 2H).
Example 43
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)methyl]amino}-3-nit-
rophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 43A
4-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)amino)-3-nitrobenzenes-
ulfonamide
[0386] The title compound was prepared by substituting
4-(aminomethyl)tetrahydro-2H-thiopyran 1,1-dioxide hydrochloride
for EXAMPLE 1M in EXAMPLE 1N.
Example 43B
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)methyl]amino}-3-nit-
rophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0387] The title compound was prepared by substituting EXAMPLE 43A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 11.67 (s, 1H), 11.42 (bs,
1H), 8.66 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.81 (dd, 1H),
7.56-7.48 (m, 3H), 7.34 (d, 2H), 7.13 (d, 1H), 7.04 (d, 2H), 6.68
(d, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.37 (t, 2H), 3.17-3.00 (m,
8H), 2.73 (bs, 2H), 2.26-2.03 (m, 9H), 1.95 (bs, 2H), 1.68 (m, 2H),
1.38 (t, 2H), 0.92 (s, 6H).
Example 44
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S,5R)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 44A
(R)-2-(((R)-1-(benzyloxy)propan-2-yloxy)methyl)oxirane
[0388] The title compound was prepared by substituting
S,S-(salen)Co(II) complex (CAS #188264-84-8) for R,R-(salen)Co(II)
complex (CAS #176763-62-5) in EXAMPLE 24C.
Example 44B
(R)-2-((R)-oxiran-2-ylmethoxy)propan-1-ol
[0389] The title compound was prepared by substituting EXAMPLE 44A
for EXAMPLE 35F in EXAMPLE 35G.
Example 44C
((2S,5R)-5-methyl-1,4-dioxan-2-yl)methanol
[0390] The title compound was prepared by substituting EXAMPLE 44B
for EXAMPLE 24D in EXAMPLE 24E.
Example 44D
((2R,5R)-5-methyl-1,4-dioxan-2-yl)methyl methanesulfonate
[0391] The title compound was prepared by substituting EXAMPLE 44C
for EXAMPLE 24E in EXAMPLE 24F.
Example 44E
(2S,5R)-2-(azidomethyl)-5-methyl-1,4-dioxane
[0392] The title compound was prepared by substituting EXAMPLE 44D
for EXAMPLE 1K in EXAMPLE 1L.
Example 44F
((2S,5R)-5-methyl-1,4-dioxan-2-yl)methanamine
[0393] The title compound was prepared by substituting EXAMPLE 44E
for EXAMPLE 9B in EXAMPLE 9C.
Example 44G
4-(((2S,5R)-5-methyl-1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[0394] The title compound was prepared by substituting EXAMPLE 44F
for EXAMPLE 1M in EXAMPLE 1N.
Example 44H
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S,5R)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0395] The title compound was prepared by substituting EXAMPLE 44G
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H), 8.57 (t, 1H),
8.55 (d, 1H), 8.03 (d, 1H), 7.83 (dd, 1H), 7.50 (m, 3H), 7.34 (d,
2H), 7.10 (d, 1H), 7.03 (d, 2H), 6.67 (dd, 1H), 6.38 (m, 1H), 6.19
(d, 1H), 3.81 (ddd, 2H), 3.72 (m, 1H), 3.52 (m, 2H), 3.36 (m, 2H),
3.20 (dd, 1H), 3.07 (br m, 4H), 2.76 (br s, 2H), 2.20 (br m, 4H),
2.14 (br m, 2H), 1.95 (br m, 2H), 1.38 (t, 2H), 0.98 (d, 3H), 0.92
(s, 6H).
Example 45
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S,5S)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 45A
(S)-((2-(allyloxy)propoxy)methyl)benzene
[0396] The title compound was prepared by substituting
(S)-1-(benzyloxy)propan-2-ol for (R)-1-(benzyloxy)propan-2-ol in
EXAMPLE 24A.
Example 45B
(S)-2-((R)-oxiran-2-ylmethoxy)propan-1-ol
[0397] The title compound was prepared by substituting EXAMPLE 45A
for EXAMPLE 24A in EXAMPLE 24B.
Example 45C
(R)-2-(((S)-1-(benzyloxy)propan-2-yloxy)methyl)oxirane
[0398] The title compound was prepared by substituting
S,S-(salen)Co(II) complex (CAS #188264-84-8) for R,R-(salen)Co(II)
complex (CAS #176763-62-5) and EXAMPLE 45B for EXAMPLE 24B in
EXAMPLE 24C.
Example 45D
(S)-2-((S)-oxiran-2-ylmethoxy)propan-1-ol
[0399] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 35F in EXAMPLE 35G.
Example 45E
((2S,5S)-5-methyl-1,4-dioxan-2-yl)methanol
[0400] The title compound was prepared by substituting EXAMPLE 45D
for EXAMPLE 24D in EXAMPLE 24E.
Example 45F
((2R,5S)-5-methyl-1,4-dioxan-2-yl)methyl methanesulfonate
[0401] The title compound was prepared by substituting EXAMPLE 45E
for EXAMPLE 24E in EXAMPLE 24F.
Example 45G
(2S,5S)-2-(azidomethyl)-5-methyl-1,4-dioxane
[0402] The title compound was prepared by substituting EXAMPLE 45F
for EXAMPLE 1K in EXAMPLE 1L.
Example 45H
((2S,5S)-5-methyl-1,4-dioxan-2-yl)methanamine
[0403] The title compound was prepared by substituting EXAMPLE 45G
for EXAMPLE 9B in EXAMPLE 9C.
Example 45I
4-(((2S,5S)-5-methyl-1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[0404] The title compound was prepared by substituting EXAMPLE 45H
for EXAMPLE 1M in EXAMPLE 1N.
Example 45J
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(2S,5S)-5-methyl-1,4-dioxan-2-yl]methyl}amino)-3-nitropheny-
l]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0405] The title compound was prepared by substituting EXAMPLE 451
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 8.57 (d, 1H),
8.55 (t, 1H), 8.03 (d, 1H), 7.83 (dd, 1H), 7.50 (m, 3H), 7.34 (d,
2H), 7.11 (d, 1H), 7.03 (d, 2H), 6.68 (dd, 1H), 6.38 (m, 1H), 6.20
(d, 1H), 3.84, 3.78, 3.70, 3.66 (all m, 5H), 3.54, 3.49 (both m,
3H), 3.08 (br m, 4H), 2.76 (br s, 2H), 2.20 (br m, 4H), 2.14 (br m,
2H), 1.95 (br m, 2H), 1.38 (t, 2H), 1.09 (d, 3H), 0.92 (s, 6H).
Example 46
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-cyanotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 46A
(4-carbamoyl-tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl
ester
[0406] 4-(Aminomethyl)tetrahydro-2H-pyran-4-carboxamide (1000 mg)
was stirred in acetonitrile (30 mL) and 1-methylpyrrolidinone (10
mL). N,N-dimethylpyridin-4-amine (77 mg) was added followed by
di-tert-butyl dicarbonate (1.45 g). The mixture was stirred for one
hour at room temperature, and then the acetonitrile portion of the
solvent was removed by evaporation at reduced pressure. The mixture
was added to ethyl acetate and washed three times with water. The
mixture was then washed with brine and dried on anhydrous sodium
sulfate. After filtration, the solvent was removed, and the
material was utilized with no further purification.
Example 46B
(4-cyano-tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl
ester
[0407] EXAMPLE 46A (1.63 g) was dissolved in tetrahydrofuran (60
mL), and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (1.58 g)
was added. The mixture was stirred at room temperature for 16
hours. The solvent was removed under vacuum and the material taken
up in ethyl acetate. The solution was washed with water three
times, washed with brine, and dried on anhydrous sodium sulfate.
After filtration, the solvent was removed, and the material was
utilized with no further purification.
Example 46C
4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile trifluoroacetic
acid salt
[0408] EXAMPLE 46B (610 mg) was dissolved in dichloromethane (20
mL). 2,2,2-Trifluoroacetic acid (1.95 mL) was added, and the
mixture was stirred at room temperature for four hours. The solvent
was removed under vacuum, the crude material was taken up in
dichloromethane, and the solvents were removed under vacuum again.
The material was then triturated with diethyl ether, and dried on
vacuum.
Example 46D
4-[(4-cyano-tetrahydro-pyran-4-ylmethyl)-amino]-3-nitro-benzenesulfonamide
[0409] The title compound was prepared by substituting EXAMPLE 46C
for EXAMPLE 1M in EXAMPLE 1N.
Example 46E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-cyanotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0410] The title compound was prepared by substituting EXAMPLE 46D
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.66 (s, 1H), 11.37 (bs, 1H),
8.65 (t, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.85 (dd, 1H), 7.52 (dd,
2H), 7.49 (d, 1H), 7.44 (d, 1H), 7.34 (d, 2H), 7.04 (d, 2H), 6.68
(dd, 1H), 6.38 (t, 1H), 6.20 (d, 1H), 3.92 (dd, 2H), 3.83 (d, 2H),
3.46 (t, 2H), 3.08 (s, 4H), 2.76 (s, 2H), 2.27-2.12 (m, 6H), 1.95
(s, 2H), 1.89 (d, 2H), 1.74 (td, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Example 47
N-[(4-{[(1-acetylpiperidin-4-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
Example 47A
(1-Acetyl-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester
[0411] Tert-butyl (piperidin-4-ylmethyl)carbamate (600 mg) was
dissolved in dichloromethane (20 mL). Triethylamine (1.17 mL) was
added, and acetic anhydride (0.26 mL) was added. The solution was
mixed at room temperature for 16 hours, and the solvent was removed
under vacuum. The material was carried on with no further
purification.
Example 47B
1-(4-(aminomethyl)piperidin-1-yl)ethanone trifluoroacetic acid
salt
[0412] EXAMPLE 47A (718 mg) was dissolved in dichloromethane (20
mL). 2,2,2-Trifluoroacetic acid (4.32 mL) was added, and the
solution was stirred at room temperature for four hours. The
solvent was removed under vacuum, the material taken up in
dichloromethane, and the solvents were removed under vacuum again.
The material was then triturated with diethyl ether, and dried on
vacuum.
Example 47C
4-[(1-Acetyl-piperidin-4-ylmethyl)-amino]-3-nitro-benzenesulfonamide
[0413] The title compound was prepared by substituting EXAMPLE 47B
for EXAMPLE 1M in EXAMPLE 1N.
Example 47D
N-[(4-{[(1-acetylpiperidin-4-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
[0414] The title compound was prepared by substituting EXAMPLE 47C
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 11.35 (bs, 1H),
8.62 (t, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.81 (dd, 1H), 7.52 (dd,
2H), 7.49 (d, 1H), 7.34 (d, 2H), 7.11 (d, 1H), 7.04 (d, 2H), 6.68
(dd, 1H), 6.39 (t, 1H), 6.19 (d, 1H), 4.38 (d, 1H), 3.81 (d, 1H),
3.07 (s, 4H), 2.98 (t, 1H), 2.75 (s, 2H), 2.48 (t, 1H), 2.24-2.11
(m, 6H), 1.98 (s, 3H), 1.95 (s, 2H), 1.88 (m, 2H), 1.72 (t, 2H),
1.38 (t, 2H), 1.22-0.98 (m, 3H), 0.92 (s, 6H).
Example 48
4-(4-{[2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-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
Example 48A
methyl
2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[0415] The title compound was prepared by substituting
2-fluoro-4-chlorophenyl boronic acid for 4-chlorophenyl boronic
acid in EXAMPLE 1B.
Example 48B
(2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[0416] The title compound was prepared by substituting EXAMPLE 48A
for EXAMPLE 1B in EXAMPLE 1C.
Example 48C
2-(4-chloro-2-fluorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde
[0417] EXAMPLE 48B (500 mg) was dissolved in dichloromethane (19
mL), Dess-Martin periodinane (950 mg) was added and the reaction
was stirred at room temperature for 2 hours. The reaction was then
concentrated and and the crude material was partitioned between
diethyl ether and 2M aqueous Na.sub.2CO.sub.3. The organic layer
was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude material was chromatographed on silica gel
with 9/1 heptanes/ethyl acetate to give the title compound.
Example 48D
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(piperazin-1-yl)benzoate
[0418] A mixture of EXAMPLE 1H (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) and extracted thee times with
dichloromethane. The combined extracts were washed twice with
water, washed with brine, filtered, and concentrated to give the
title compound.
Example 48E
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chloro-2-fluorophe-
nyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0419] To a solution of EXAMPLE 48C (450 mg) and EXAMPLE 48D (600
mg) in dichloromethane (6 mL) was added sodium
triacetoxyborohydride (540 mg). The mixture was stirred overnight.
The mixture was diluted with ethyl acetate (200 mL) and washed with
saturated aqueous NaHCO.sub.3, water and brine. After drying over
Na.sub.2SO.sub.4, the crude material was filtered, and
chromatographed on silica gel with 1/1 heptanes/ethyl acetate to
give the title compound.
Example 48F
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chloro-2-fluorophenyl)-4,-
4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0420] The title compound was prepared by substituting EXAMPLE 48E
for EXAMPLE 1I in EXAMPLE 1J.
Example 48G
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(piperazin-1-yl)benzoate
[0421] The title compound was prepared by substituting
(tetrahydro-2H-pyran-4-yl)methanamine for EXAMPLE 1M in EXAMPLE
1N.
Example 48H
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chloro-2-fluorophenyl)-4,-
4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-
-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide
[0422] The title compound was prepared by substituting EXAMPLE 48F
for EXAMPLE 1J and EXAMPLE 48G for EXAMPLE 1N in EXAMPLE 1O.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s,
1H), 8.61 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.50
(m, 3H), 7.35 (dd, 1H), 7.21 (dd, 1H), 7.10 (m, 2H), 6.68 (dd, 1H),
6.39 (m, 1H), 6.20 (d, 1H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.07 (br
m, 4H), 2.67 (br s, 2H), 2.17 (br m, 6H), 1.90 (br m, 2H), 1.88 (m,
1H), 1.61 (dd, 2H), 1.40 (t, 2H), 1.27 (ddd, 2H), 0.92 (s, 6H).
Example 49
4-(4-{[2-(4-chloro-3-fluorophenyl)-4,4-dimethylcyclohex-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
Example 49A
methyl
2-(4-chloro-3-fluorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[0423] The title compound was prepared by substituting
3-fluoro-4-chlorophenyl boronic acid for 4-chlorophenyl boronic
acid in EXAMPLE 1B.
Example 49B
(2-(4-chloro-3-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[0424] The title compound was prepared by substituting EXAMPLE 49A
for EXAMPLE 1B in EXAMPLE 1C.
Example 49C
2-(4-chloro-3-fluorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde
[0425] The title compound was prepared by substituting EXAMPLE 49B
for EXAMPLE 48B in EXAMPLE 48C.
Example 49D
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chloro-3-fluorophe-
nyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0426] The title compound was prepared by substituting EXAMPLE 49C
for EXAMPLE 48C in EXAMPLE 48E.
Example 49E
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chloro-3-fluorophenyl)-4,-
4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0427] The title compound was prepared by substituting EXAMPLE 49D
for EXAMPLE 1I in EXAMPLE 1J.
Example 49F
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chloro-3-fluorophenyl)-4,-
4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-
-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide
[0428] The title compound was prepared by substituting EXAMPLE 49E
for EXAMPLE 1J and EXAMPLE 48G for EXAMPLE 1N in EXAMPLE 1O.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.69 (s,
1H), 8.61 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.50
(m, 3H), 7.32 (dd, 1H), 7.23 (dd, 1H), 7.11 (d, 1H), 7.03 (m, 1H),
6.68 (dd, 1H), 6.39 (m, 1H), 6.20 (d, 1H), 3.85 (dd, 2H), 3.27 (m,
4H), 3.07 (br m, 4H), 2.75 (br s, 2H), 2.21 (br m, 4H), 2.14 (br m,
2H), 1.96 (s, 2H), 1.89 (m, 1H), 1.61 (dd, 2H), 1.38 (t, 2H), 1.26
(ddd, 2H), 0.92 (s, 6H).
Example 50
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-ethyltetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 50A
4-[(4-Ethyl-tetrahydro-pyran-4-ylmethyl)-amino]-3-nitro-benzenesulfonamide
[0429] The title compound was prepared by substituting
(4-ethyltetrahydro-2H-pyran-4-yl)methanamine for EXAMPLE 1M in
EXAMPLE 1N.
Example 50B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-ethyltetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0430] The title compound was prepared by substituting EXAMPLE 50A
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 11.37 (bs, 1H),
8.57 (d, 1H), 8.37 (t, 1H), 8.05 (d, 1H), 7.84 (dd, 1H), 7.52 (dd,
2H), 7.49 (d, 1H), 7.34 (d, 2H), 7.22 (d, 1H), 7.04 (d, 2H), 6.68
(dd, 1H), 6.39 (t, 1H), 6.19 (d, 1H), 3.68-3.52 (m, 4H), 3.35 (q,
2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.25-2.11 (m, 6H), 1.95 (s, 2H),
1.55-1.35 (m, 8H), 0.92 (s, 6H), 0.82 (t, 3H).
Example 51
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,4-dioxepan-6-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 51A
tert-butyl 2-(1,4-dioxepan-6-ylidene)acetate
[0431] To a cooled (0.degree. C.) solution of tert-butyl
2-(diethoxyphosphoryl)acetate (16.9 g) in THE (250 mL) was added
sodium hydride (60% in mineral oil, 2.7 g) in portions over 20
minutes, and the mixture was stirred for an additional 10 minutes.
EXAMPLE 25A (6.5 g) in THE (10 mL) was added and the reaction
mixture was stirred for 1 hour, while the temperature was allowed
to rise to room temperature. The mixture was then poured into water
(200 mL) and extracted with ether (2.times.300 mL). The combined
ether extracts were washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Chromatography on
silica gel using 10% ethyl acetate in heptanes provided the title
compound.
Example 51B
tert-butyl 2-(1,4-dioxepan-6-yl)acetate
[0432] EXAMPLE 51A (8.4 g) and THE (100 mL) were added to 5% Pd/C
(wet JM #9, 1.6 g) in a 250 mL SS pressure bottle and the mixture
was stirred for 30 minutes at 30 psi. The mixture was filtered
through a nylon membrane and concentrated.
Example 51C
2-(1,4-dioxepan-6-yl)acetic acid
[0433] EXAMPLE 51B (8.4 g) was stirred in dichloromethane (100
mL)/TFA (100 mL) for 1 hour, and the mixture was concentrated to
give the title compound.
Example 51D
benzyl ((1,4-dioxepan-6-yl)methyl)carbamate
[0434] A solution of EXAMPLE 51C (3.88 g), diphenylphosphoryl azide
(6.67 g), benzyl alcohol (5.04 mL), and triethylamine (3.4 mL) in
toluene (50 mL) was stirred at 90.degree. C. for 48 hours. The
mixture was cooled and poured into water (100 mL) and extracted
with ether (2.times.200 mL). The combined extracts were washed with
water and brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Chromatography on silica gel using 5-20% ethyl
acetate in heptanes provided the title compound.
Example 51E
(1,4-dioxepan-6-yl)methanamine
[0435] EXAMPLE 51D (4 g) and ethanol (60 mL) were added to 20%
Pd(OH).sub.2/C (wet, 0.4 g) in a 250 mL SS pressure bottle and the
reaction mixture was stirred for 30 minutes at 30 psi and
50.degree. C. The mixture was filtered through a nylon membrane and
concentrated to give the title compound.
Example 51F
4-(((1,4-dioxepan-6-yl)methyl)amino)-3-nitrobenzenesulfonamide
[0436] The title compound was prepared by substituting EXAMPLE 51E
for EXAMPLE 1M in EXAMPLE 1N.
Example 51G
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,4-dioxepan-6-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0437] The title compound was prepared by substituting EXAMPLE 51F
for EXAMPLE 1N in EXAMPLE 1O. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.68 (s, 1H), 11.35 (br s, 1H),
8.70 (m, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.81 (d, 1H), 7.50 (m,
3H), 7.34 (d, 2H), 7.07 (d, 1H), 7.04 (d, 2H), 6.69 (d, 1H), 6.39
(d, 1H), 6.19 (s, 1H), 3.86 (dd, 2H), 3.68 (m, 4H), 3.64 (dd, 2H),
3.37 (m, 2H), 3.07 (m, 4H), 2.76 (m, 2H), 2.35 (m, 1H), 2.20 (m,
4H), 2.14 (m, 2H), 1.95 (m, 2H), 1.38 (m, 2H), 0.92 (m, 6H).
Example 52
4-(4-{[2-(4-cyclopropylphenyl)-4,4-dimethylcyclohex-1-en-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
Example 52A
methyl
2-(4-cyclopropylphenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[0438] The title compound was prepared by substituting
4-cyclopropylphenyl boronic acid for 4-chlorophenyl boronic acid in
EXAMPLE 1B.
Example 52B
(2-(4-cyclopropylphenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[0439] The title compound was prepared by substituting EXAMPLE 52A
for EXAMPLE 1B in EXAMPLE 1C.
Example 52C
2-(4-cyclopropylphenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde
[0440] The title compound was prepared by substituting EXAMPLE 52B
for EXAMPLE 48B in EXAMPLE 48C.
Example 52D
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-cyclopropylphenyl)-
-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0441] The title compound was prepared by substituting EXAMPLE 52C
for EXAMPLE 48C in EXAMPLE 48E.
Example 52E
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-cyclopropylphenyl)-4,4-di-
methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0442] The title compound was prepared by substituting EXAMPLE 52D
for EXAMPLE 1I in EXAMPLE 1J.
Example 52F
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-cyclopropylphenyl)-4,4-di-
methylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H--
pyran-4-yl)methylamino)phenylsulfonyl)benzamide
[0443] The title compound was prepared by substituting EXAMPLE 52E
for EXAMPLE 1J and EXAMPLE 48G for EXAMPLE 1N in EXAMPLE 1O.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s,
1H), 8.59 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.50
(m, 3H), 7.09 (d, 1H), 6.97 (d, 2H), 6.87 (d, 2H), 6.68 (dd, 1H),
6.39 (m, 1H), 6.20 (d, 1H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.08 (br
m, 4H), 2.78 (br s, 2H), 2.20 (br m, 4H), 2.13 (br m, 2H), 1.93 (s,
2H), 1.86 (m, 2H), 1.61 (dd, 2H), 1.37 (t, 2H), 1.27 (ddd, 2H),
0.92 (s, 6H), 0.89 (m, 2H), 0.61 (m, 2H).
Example 53
4-(4-{[2-(3,4-dichlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 53A
methyl
2-(3,4-dichlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[0444] The title compound was prepared by substituting
3,4-dichlorophenyl boronic acid for 4-chlorophenyl boronic acid in
EXAMPLE 1B.
Example 53B
(2-(3,4-dichlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[0445] The title compound was prepared by substituting EXAMPLE 53A
for EXAMPLE 1B in EXAMPLE 1C.
Example 53C
2-(3,4-dichlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde
[0446] The title compound was prepared by substituting EXAMPLE 53B
for EXAMPLE 48B in EXAMPLE 48C.
Example 53D
methyl
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(3,4-dichlorophenyl)--
4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[0447] The title compound was prepared by substituting EXAMPLE 53C
for EXAMPLE 48C in EXAMPLE 48E.
Example 53E
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(3,4-dichlorophenyl)-4,4-dim-
ethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[0448] The title compound was prepared by substituting EXAMPLE 53D
for EXAMPLE 1I in EXAMPLE 1J.
Example 53F
2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(3,4-dichlorophenyl)-4,4-dim-
ethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-p-
yran-4-yl)methylamino)phenylsulfonyl)benzamide
[0449] The title compound was prepared by substituting EXAMPLE 53E
for EXAMPLE 1J and EXAMPLE 48G for EXAMPLE 1N in EXAMPLE 1O.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s,
1H), 8.60 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.52
(m, 4H), 7.29 (d, 1H), 7.11 (d, 1H), 7.02 (dd, 1H), 6.68 (dd, 1H),
6.39 (m, 1H), 6.20 (d, 1H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.07 (br
m, 4H), 2.76 (br s, 2H), 2.21 (br m, 4H), 2.14 (br m, 2H), 1.96 (s,
2H), 1.89 (m, 1H), 1.61 (dd, 2H), 1.38 (t, 2H), 1.26 (ddd, 2H),
0.92 (s, 6H).
Example 54
4-[4-({2-[4-(difluoromethyl)phenyl]-4,4-dimethylcyclohex-1-en-1-yl}methyl)-
piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
Example 54A
2-(4-Difluoromethyl-phenyl)-4,4-dimethyl-cyclohex-1-enecarboxylic
acid methyl ester
[0450] The title compound was prepared by substituting
(4-(difluoromethyl)phenyl)boronic acid for 4-chlorophenyl boronic
acid in EXAMPLE 1B.
Example 54B
[2-(4-difluoromethyl-phenyl)-4,4-dimethyl-cyclohex-1-enyl]-methanol
[0451] The title compound was prepared by substituting EXAMPLE 54A
for EXAMPLE 1B in EXAMPLE 1C.
Example 54C
2-(4-difluoromethyl-phenyl)-4,4-dimethyl-cyclohex-1-enecarbaldehyde
[0452] The title compound was prepared by substituting EXAMPLE 54B
for EXAMPLE 48B in EXAMPLE 48C.
Example 54D
4-{4-[2-(4-Difluoromethyl-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-pipe-
razin-1-yl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzoic acid
methyl ester
[0453] The title compound was prepared by substituting EXAMPLE 54C
for EXAMPLE 48C in EXAMPLE 48E.
Example 54E
4-{4-[2-(4-difluoromethyl-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-pipe-
razin-1-yl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzoic acid
[0454] The title compound was prepared by substituting EXAMPLE 54D
for EXAMPLE 1I in EXAMPLE 1J.
Example 54F
4-[4-({2-[4-(difluoromethyl)phenyl]-4,4-dimethylcyclohex-1-en-1-yl}methyl)-
piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0455] The title compound was prepared by substituting EXAMPLE 54E
for EXAMPLE 1J and EXAMPLE 48G for EXAMPLE 1N in EXAMPLE 1O.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.67 (s,
1H), 11.38 (bs, 1H), 8.59 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80
(dd, 1H), 7.53-7.47 (m, 5H), 7.16 (d, 2H), 7.11 (d, 1H), 6.99 (t,
1H), 6.68 (dd, 1H), 6.39 (t, 1H), 6.19 (d, 1H), 3.85 (dd, 2H), 3.27
(m, 4H), 3.07 (s, 4H), 2.75 (s, 2H), 2.23-2.13 (m, 6H), 1.97 (s,
2H), 1.89 (m, 1H), 1.62 (d, 2H), 1.40 (t, 2H), 1.36 (m, 2H), 0.93
(s, 6H).
Bcl-2 Binding Data
[0456] Determination of the utility of compounds of this invention
as binders to and inhibitors of anti-apoptotic Bcl-2 proteins was
performed using the Time Resolved-Fluorescence Resonance Energy
Transfer (TR-FRET) Assay. Tb-anti-GST antibody was purchased from
Invitrogen (Catalog No. PV4216).
Probe Synthesis
[0457] All reagents were used as obtained from the vendor unless
otherwise specified. Peptide synthesis reagents including
diisopropylethylamine (DIEA), dichloromethane (DCM),
N-methylpyrrolidone (NMP),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU), N-hydroxybenzotriazole (HOBt) and
piperidine were obtained from Applied Biosystems, Inc. (ABI),
Foster City, Calif. or American Bioanalytical, Natick, Mass.
Preloaded 9-Fluorenylmethyloxycarbonyl (Fmoc) amino acid cartridges
(Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH,
Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH,
Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Asn(Trt)-OH,
Fmoc-Pro-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH,
Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH)
were obtained from ABI or Anaspec, San Jose, Calif. The peptide
synthesis resin (Fmoc-Rink amide MBHA resin) and Fmoc-Lys(Mtt)-OH
were obtained from Novabiochem, San Diego, Calif. Single-isomer
6-carboxyfluorescein succinimidyl ester (6-FAM-NHS) was obtained
from Anaspec. Trifluoroacetic acid (TFA) was obtained from Oakwood
Products, West Columbia, S.C. Thioanisole, phenol,
triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) and
isopropanol were obtained from Aldrich Chemical Co., Milwaukee,
Wis. Matrix-assisted laser desorption ionization mass-spectra
(MALDI-MS) were recorded on an Applied Biosystems Voyager DE-PRO
MS). Electrospray mass-spectra (ESI-MS) were recorded on Finnigan
SSQ7000 (Finnigan Corp., San Jose, Calif.) in both positive and
negative ion mode.
General Procedure for Solid-Phase Peptide Synthesis (SPPS)
[0458] Peptides were synthesized with, at most, 250 .mu.mol
preloaded Wang resin/vessel on an ABI 433A peptide synthesizer
using 250 .mu.mol scale Fastmoc.TM. coupling cycles. Preloaded
cartridges containing 1 mmol standard Fmoc-amino acids, except for
the position of attachment of the fluorophore, where 1 mmol
Fmoc-Lys(Mtt)-OH was placed in the cartridge, were used with
conductivity feedback monitoring. N-terminal acetylation was
accomplished by using 1 mmol acetic acid in a cartridge under
standard coupling conditions.
Removal of 4-Methyltrityl (Mtt) from Lysine
[0459] The resin from the synthesizer was washed thrice with DCM
and kept wet. 150 mL of 95:4:1
dichloromethane:triisopropylsilane:trifluoroacetic acid was flowed
through the resin bed over 30 minutes. The mixture turned deep
yellow then faded to pale yellow. 100 mL of DMF was flowed through
the bed over 15 minutes. The resin was then washed thrice with DMF
and filtered. Ninhydrin tests showed a strong signal for primary
amine.
Resin Labeling with 6-Carboxyfluorescein-NHS (6-FAM-NHS)
[0460] The resin was treated with 2 equivalents 6-FAM-NHS in 1%
DIEA/DMF and stirred or shaken at ambient temperature overnight.
When complete, the resin was drained, washed thrice with DMF,
thrice with (1.times.DCM and 1.times.methanol) and dried to provide
an orange resin that was negative by ninhydrin test.
General Procedure for Cleavage and Deprotection of Resin-Bound
Peptide
[0461] Peptides were cleaved from the resin by shaking for 3 hours
at ambient temperature in a cleavage cocktail consisting of 80%
TFA, 5% water, 5% thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1
mL/0.1 g resin). The resin was removed by filtration and rinsing
twice with TFA. The TFA was evaporated from the filtrates, and
product was precipitated with ether (10 mL/0.1 g resin), recovered
by centrifugation, washed twice with ether (10 mL/0.1 g resin) and
dried to give the crude peptide.
General Procedure for Purification of Peptides
[0462] The crude peptides were purified on a Gilson preparative
HPLC system running Unipoint.RTM. analysis software (Gilson, Inc.,
Middleton, Wis.) on a radial compression column containing two
25.times.100 mm segments packed with Delta-Pak.TM. C18 15 m
particles with 100 .ANG. pore size and eluted with one of the
gradient methods listed below. One to two milliliters of crude
peptide solution (10 mg/mL in 90% DMSO/water) was purified per
injection. The peaks containing the product(s) from each run were
pooled and lyophilized. All preparative runs were run at 20 mL/min
with eluents as buffer A: 0.1% TFA-water and buffer B:
acetonitrile.
General Procedure for Analytical HPLC
[0463] Analytical HPLC was performed on a Hewlett-Packard 1200
series system with a diode-array detector and a Hewlett-Packard
1046A fluorescence detector running HPLC 3D ChemStation software
version A.03.04 (Hewlett-Packard. Palo Alto, Calif.) on a
4.6.times.250 mm YMC column packed with ODS-AQ 5 .mu.m particles
with a 120 .ANG. pore size and eluted with one of the gradient
methods listed below after preequilibrating at the starting
conditions for 7 minutes. Eluents were buffer A: 0.1% TFA-water and
buffer B: acetonitrile. The flow rate for all gradients was 1
mL/min.
F-Bak: Peptide Probe Acetyl-(SEQ ID NO:
1)GQVGRQLAIIGDK(6-FAM)-INR-NH.sub.2
[0464] Fmoc-Rink amide MBHA resin was extended using the general
peptide synthesis procedure to provide the protected resin-bound
peptide (1.020 g). The Mtt group was removed, labeled with
6-FAM-NHS and cleaved and deprotected as described hereinabove to
provide the crude product as an orange solid (0.37 g). This product
was purified by RP-HPLC. Fractions across the main peak were tested
by analytical RP-HPLC, and the pure fractions were isolated and
lyophilized, with the major peak providing the title compound
(0.0802 g) as a yellow solid; MALDI-MS m/z=2137.1
[(M+H).sup.+].
Alternative Synthesis of Peptide Probe F-Bak: Acetyl-(SEQ ID NO:
1)GQVGRQLAIIGDK(6-FAM)-INR-NH.sub.2
[0465] The protected peptide was assembled on 0.25 mmol Fmoc-Rink
amide MBHA resin (Novabiochem) on an Applied Biosystems 433A
automated peptide synthesizer running Fastmoc.TM. coupling cycles
using pre-loaded 1 mmol amino acid cartridges, except for the
fluorescein (6-FAM)-labeled lysine, where 1 mmol
Fmoc-Lys(4-methyltrityl) was weighed into the cartridge. The
N-terminal acetyl group was incorporated by putting 1 mmol acetic
acid in a cartridge and coupling as described hereinabove.
Selective removal of the 4-methyltrityl group was accomplished with
a solution of 95:4:1 DCM:TIS:TFA (v/v/v) flowed through the resin
over 15 minutes, followed by quenching with a flow of
dimethylformamide. Single-isomer 6-carboxyfluorescein-NHS was
reacted with the lysine side-chain in 1% DIEA in DMF and confirmed
complete by ninhydrin testing. The peptide was cleaved from the
resin and side-chains deprotected by treating with 80:5:5:5:2.5:2.5
TFA/water/phenol/thioanisole/triisopropylsilane:
3,6-dioxa-1,8-octanedithiol (v/v/v/v/v/v), and the crude peptide
was recovered by precipitation with diethyl ether. The crude
peptide was purified by reverse-phase high-performance liquid
chromatography, and its purity and identity were confirmed by
analytical reverse-phase high-performance liquid chromatography and
matrix-assisted laser-desorption mass-spectrometry (m/z=2137.1
((M+H).sup.+)).
Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)
Assay
[0466] Representative compounds were serially diluted in dimethyl
sulfoxide (DMSO) starting at 50 .mu.M (2.times.starting
concentration; 10% DMSO) and 10 .mu.L were transferred into a
384-well plate. Then 10 .mu.L of a protein/probe/antibody mix was
added to each well at final concentrations listed in TABLE 1. The
samples are then mixed on a shaker for 1 minute and incubated for
an additional 3 hours at room temperature. For each assay, the
probe/antibody and protein/probe/antibody were included on each
assay plate as negative and positive controls, respectively.
Fluorescence was measured on the Envision (Perkin Elmer) using a
340/35 nm excitation filter and 520/525 (F-Bak peptide) and 495/510
nm (Tb-labeled anti-Histidine antibody) emission filters.
Dissociation constants (K.sub.i) are shown in TABLE 2 below and
were determined using Wang's equation (Wang Z.-X., An Exact
Mathematical Expression For Describing Competitive Binding Of Two
Different Ligands To A Protein Molecule. FEBS Lett. 1995,
360:111-4).
TABLE-US-00001 TABLE 1 Protein, Probe And Antibody Used For TR-FRET
Assays Protein Probe Antibody Protein Probe (nM) (nM) Antibody (nM)
GST-Bcl-2 F-Bak Peptide Probe 1 100 Tb-anti-GST 1 Acetyl-(SEQ ID
NO: 1 GQVGRQLAIIGDK(6- FAM)-INR-amide) 6-FAM =
6-carboxyfluorescein.; Tb = terbium; GST = glutathione
S-transferase
[0467] The samples were then mixed on a shaker for 1 minute and
incubated for an additional 3 hours at room temperature. For each
assay, the probe/antibody and protein/probe/antibody were included
on each assay plate as negative and positive controls,
respectively. Fluorescence was measured on the Envision (Perkin
Elmer) using a 340/35 nm excitation filter and 520/525 (F-Bak
peptide) and 495/510 nm (Tb-labeled anti-Histidine antibody)
emission filters.
[0468] Inhibition constants (K.sub.i) for compounds were determined
using Wang's equation (Wang Zx. An Exact Mathematical Expression
For Describing Competitive Binding Of Two Different Ligands To A
Protein Molecule. FEBS Lett. 1995, 360:111-4). Where the K.sub.i
for a compound is represented as "<" (less than) a certain
numerical value, it is intended to mean that the binding affinity
value (e.g., for Bcl-2) is lower than the limit of detection of the
assay used. Inhibition constants (K.sub.i) for compounds of the
invention are shown in Table 2.
TABLE-US-00002 TABLE 2 TR-FRET Bcl-2 Binding K.sub.i (nM) EXAMPLE
Ki (nM) 1 <0.1 2 0.1 3 <0.1 4 <0.1 5 <0.1 6 <0.1 7
0.1 8 0.7 9 <0.1 10 <0.1 11 <0.1 12 <0.1 13 0.1 14
<0.1 15 <0.1 16 <0.1 17 0.1 18 <0.1 19 0.1 20 <0.1
21 <0.1 22 <0.1 23 <0.1 24 <0.1 25 <0.1 26 <0.1
27 <0.1 28 <0.1 29 <0.1 30 <0.1 31 <0.1 32 <0.1
33 <0.1 34 <0.1 35 <0.1 36 <0.1 37 <0.1 38 <0.1
38 <0.1 40 <0.1 41 <0.1 42 <0.1 43 <0.1 44 <0.1
45 <0.1 46 <0.1 47 <0.1 48 0.1 49 0.1 50 0.1 51 <0.1 52
0.1 53 0.2 54 nd nd = no data
The inhibition constant (K.sub.i) is the dissociation constant of
an enzyme-inhibitor complex or a protein/small molecule complex,
wherein the small molecule is inhibiting binding of one protein to
another protein or peptide. So a large K.sub.i value indicates a
low binding affinity and a small K.sub.i value indicates a high
binding affinity. TABLE 2 shows inhibition constants for the
inhibition of a Bak BH3 peptide probe to Bcl-2 protein and indicate
that compounds according to the invention have high binding
affinities for anti-apoptotic Bcl-2 protein. The compounds are
therefore expected to have utility in treatment of diseases during
which anti-apoptotic Bcl-2 protein is expressed.
Biological Data
RS4;11 Cell Viability Assay
[0469] The acute lymphoblastic leukemia (ALL) cell line RS4;11 was
used as the primary human cell line to assess the cellular activity
of Bcl-2 selective agents in vitro and their efficacy in vivo.
Previous studies have shown by BH3 profiling, a mitochondrial assay
that classifies blocks in the intrinsic apoptotic pathway, that
RS4;11 cells were highly dependent on BCL-2 for survival and
sensitive to the Bcl-2 family member inhibitor ABT-737 (Blood,
2008, Vol. 111, 2300-2309). The prevalence of Bcl-2 complexed to
the proapoptotic BH3 protein Bim in RS4;11 suggests that these
cells are "primed" or more susceptible to cell death by antagonism
of the antiapoptotic protein Bcl-2 for which they depend on for
survival.
[0470] RS4;11 cells were cultured in RPMI-1640 supplemented with 2
mM L-glutamine, 10% FBS, 1 mM sodium pyruvate, 2 mM HEPES, 1%
penicillin/streptomycin (Invitrogen), 4.5 g/L glucose and
maintained at 37 C containing 5% CO.sub.2. To test for the cellular
activity of compounds in vitro, cells were treated at 50,000 cells
per well in 96-well microtiter plates in the presence of 10% human
serum for 48 hours in a humidified chamber with 5% CO.sub.2. Cell
cytotoxicity EC.sub.50 values were assessed using CellTiter Glo
(Promega) according to the manufacturer's recommendations. The
EC.sub.50 values were determined as a percentage of viable cells
following treatment compared to the untreated control cells.
TABLE-US-00003 TABLE 3 RS4; 11 EC.sub.50 Values (.mu.M) EXAMPLE #
EC.sub.50 (.mu.M) 1 0.0053 2 0.16 3 0.15 4 0.057 5 0.0052 6 0.0076
7 0.0068 8 >1.0 9 0.0022 10 0.0081 11 0.015 12 0.030 13 0.13 14
0.010 15 0.0093 16 0.067 17 0.085 18 0.047 19 0.014 20 0.019 21
0.019 22 0.028 23 0.023 24 0.014 25 0.036 26 0.044 27 0.097 28 0.12
29 0.057 30 0.027 31 0.016 32 0.043 33 0.044 34 0.013 35 0.012 36
0.032 37 0.25 38 0.030 39 0.040 40 0.076 41 0.047 42 0.056 43 0.031
44 0.0047 45 0.019 46 0.0069 47 0.014 48 0.0033 49 0.046 50 0.052
51 0.039 52 0.016 53 0.046 54 0.0099
[0471] TABLE 3 shows the utility of compounds of this invention to
functionally inhibit anti-apoptotic Bcl-2 protein in a cellular
context. The acute lymphoblastic leukemia (ALL) cell line RS4;11
has been shown by BH3 profiling, a mitochondrial assay that
classifies blocks in the intrinsic apoptotic pathway, to be highly
dependent on Bcl-2 for survival and is sensitive to the Bcl-2
family member inhibitor ABT-737 (Blood, 2008, Vol. 111, 2300-2309).
The ability of compounds to kill RS4;11 cells is a direct measure
of the compounds ability to inhibit anti-apoptotic Bcl-2 protein
function. Compounds of this invention are very effective in killing
RS4;11 cells as demonstrated by low EC.sub.50 values.
[0472] It is known within the art that inhibition of certain
members of the Bcl-2 family of proteins may induce dose-limiting
thrombocytopenia. The dose-limiting thrombocytopenia that severely
limited the therapeutic use of some non-selective Bcl-2 inhibitors
for autoimmune indications is thought to be due to inhibition of
Bcl-x.sub.L (See Mason, K. D., et al., Programmed a nuclear cell
death delimits platelet life span. CELL, 2007. 128(6): p.
1173-86.
[0473] An experiment was performed to evaluate the effect of Bcl-2
selective/Bcl-x.sub.L sparing compounds on immune cells and
platelets, as evaluated in C57Bl/6 mice. Mice were treated four
days with compounds (doses of 30 mg/kg, administered by
intraperitoneal injection every day) and cell numbers were measured
with a Cell Dyn hematology analyzer 24 hours after the first and
last doses. Exposure of the compound (area under the curve) was
calculated by using time points of 1, 6, 10 and 24 hours after the
last dose. The results of this experiment are illustrated in Table
4.
TABLE-US-00004 TABLE 4 Lymphocyte Reduction in C57BL/6 Mice Treated
with 1 and 4 Doses of a Bcl-2 Selective Inhibitor (30 mg/kg)
EXAMPLE # % inh. day 1 % inh. day 4 1 41 41 2 <15 <15 3
<15 <15 5 47 45 6 <15 24 7 64 55 9 69 58 10 <15 <15
12 41 27 14 61 54 15 <15 <15 16 <15 <15 18 <15 25 19
49 45 20 20 57 21 61 61 22 40 44 23 37 15 24 48 58 25 29 15 26 38
23 27 23 21 31 53 55 34 <15 61 35 54 49 36 47 42 37 28 22 44 66
60 46 46 35 48 76 78 52 54 51 nd = no decrease of lymphocytes
[0474] These data are consistent with the in vitro selectivity
profile and underscore the essential role of Bcl-2 on lymphocyte
and Bcl-x.sub.L on platelet survival respectively. This
pharmacodynamic study illustrates the ability of these compounds as
selective Bcl-2 inhibitors to effectively reduce lymphocytes,
without the adverse effects associated with non-selective Bcl-2
inhibitors.
Sequence CWU 1
1
1113PRTArtificial SequenceSynthetic 1Gly Gln Val Gly Arg Gln Leu
Ala Ile Ile Gly Asp Lys1 5 10
* * * * *