U.S. patent application number 11/743200 was filed with the patent office on 2007-11-08 for substituted 1h-benzimidazole-4-carboxamides are potent parp inhibitors.
Invention is credited to Virajkamar B. Gandhi, Vincent L. Giranda, Jianchun Gong, Thomas D. Penning, Sheela A. Thomas, Gui-Dong Zhu.
Application Number | 20070259937 11/743200 |
Document ID | / |
Family ID | 38668505 |
Filed Date | 2007-11-08 |
United States Patent
Application |
20070259937 |
Kind Code |
A1 |
Giranda; Vincent L. ; et
al. |
November 8, 2007 |
SUBSTITUTED 1H-BENZIMIDAZOLE-4-CARBOXAMIDES ARE POTENT PARP
INHIBITORS
Abstract
The present invention relates to 1H-benzimidazole-4-carboxamides
of formula (I), ##STR00001## their preparation, and their use as
inhibitors of the enzyme poly(ADP-ribose)polymerase for the
preparation of drugs.
Inventors: |
Giranda; Vincent L.;
(Gurnee, IL) ; Penning; Thomas D.; (Elmhurst,
IL) ; Gandhi; Virajkamar B.; (Gurnee, IL) ;
Thomas; Sheela A.; (Libertyville, IL) ; Zhu;
Gui-Dong; (Gurnee, IL) ; Gong; Jianchun;
(Deerfield, IL) |
Correspondence
Address: |
ROBERT DEBERARDINE;ABBOTT LABORATORIES
100 ABBOTT PARK ROAD, DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Family ID: |
38668505 |
Appl. No.: |
11/743200 |
Filed: |
May 2, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60796663 |
May 2, 2006 |
|
|
|
Current U.S.
Class: |
514/394 ;
548/305.4 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
35/00 20180101; A61P 25/16 20180101; C07D 409/04 20130101; C07D
403/10 20130101; A61P 31/04 20180101; A61P 19/02 20180101; A61P
29/00 20180101; A61P 1/16 20180101; A61P 25/00 20180101; A61P 43/00
20180101; A61P 3/10 20180101; C07D 235/18 20130101; A61P 19/06
20180101; A61P 1/00 20180101; A61P 31/12 20180101; A61P 11/00
20180101; A61P 37/00 20180101 |
Class at
Publication: |
514/394 ;
548/305.4 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; C07D 403/02 20060101 C07D403/02 |
Claims
1. A compound of Formula (I) ##STR00006## or a therapeutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, and R.sub.3 are
independently selected from the group consisting of hydrogen,
alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR.sub.AR.sub.B,
and (NR.sub.AR.sub.B)carbonyl; Ar.sub.1 is selected from the group
consisting of aryl and heteroaryl, wherein Ar.sub.1 is optionally
substituted with 1, 2, 3, or 4 substituents selected from the group
consisting of alkyl, cyano, halogen, and haloalkyl; X.sub.1 is
alkylenyl; Z is heterocycle, wherein Z is optionally substituted
with 1, 2, 3, or 4 substituents selected from the group consisting
of alkenyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkynyl,
alkoxy, alkoxyalkyl alkoxycarbonyl, alkoxycarbonylalkyl, aryl,
arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl,
cycloalkylalkoxy, cycloalkylcarbonyl, cycloalkylcarbonylalkyl,
halogen, haloalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,
heterocyclealkyl, heterocyclecarbonyl, heterocyclecarbonylalkyl,
hydroxy, hydroxyalkyl, NR.sub.CR.sub.D, NR.sub.CR.sub.Dalkyl,
(NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)carbonylalkyl, and oxo;
R.sub.A and R.sub.B are independently selected from the group
consisting of hydrogen, alkyl, and alkycarbonyl, or R.sub.A and
R.sub.B together with the nitrogen atom to which they are attached
form a heterocycle; and R.sub.C and R.sub.D are independently
selected from the group consisting of hydrogen, alkyl,
alkycarbonyl, cycloalkyl, and cycloalkylalkyl.
2. A compound of Formula (I) ##STR00007## or a therapeutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, and R.sub.3 are
independently selected from the group consisting of hydrogen, and
halogen; Ar.sub.1 is selected from the group consisting of aryl and
heteroaryl, wherein Ar.sub.1 is optionally substituted with
halogen; X.sub.1 is alkylenyl; Z is heterocycle, wherein Z is
optionally substituted with 1, 2, 3, or 4 substituents selected
from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkyl,
hydroxyalkyl, NR.sub.CR.sub.D, and NR.sub.CR.sub.Dalkyl; and
R.sub.C and R.sub.D are independently selected from the group
consisting of hydrogen, alkyl, cycloalkyl, and cycloalkylalkyl.
3. A compound according to claim 1, wherein Ar.sub.1 is phenyl.
4. A compound according to claim 1, wherein Z is pyrrolidinyl
optionally substituted with 1, 2, 3, or 4 substituents selected
from the group consisting of alkenyl, alkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkynyl, alkoxy, alkoxyalkyl alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, carboxy, cyano, cycloalkyl,
cycloalkylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl,
NR.sub.CR.sub.D, NR.sub.CR.sub.Dalkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; and R.sub.C and R.sub.D
are independently selected from the group consisting of hydrogen,
alkyl, alkycarbonyl, cycloalkyl, and cycloalkylalkyl.
5. A compound according to claim 1, wherein Z is pyrrolidinyl
optionally substituted with NR.sub.CR.sub.D.
6. A compound according to claim 1, wherein Z is pyrrolidinyl
optionally substituted with alkyl.
7. A compound according to claim 1, wherein Z is pyrrolidinyl
optionally substituted with NR.sub.CR.sub.Dalkyl.
8. A compound according to claim 1, wherein Z is pyrrolidinyl
optionally substituted with hydroxyalkyl.
9. A compound according to claim 1, wherein Ar.sub.1 is phenyl and
Z is pyrrolidinyl.
10. A compound according to claim 1, wherein Ar.sub.1 is phenyl
substituted with halogen.
11. A compound according to claim 1, wherein R.sub.1, R.sub.2, and
R.sub.3 are hydrogen.
12. A conmpound selected from the group consisting of
6-fluoro-2-[4-(2-methylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-c-
arboxamide;
6-fluoro-2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzim-
idazole-4-carboxamide;
6-fluoro-2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimid-
azole-4-carboxamide;
2-[4-(2-ethylpyrrolidin-1-ylmethyl)phenyl]-6-fluoro-1H-benzimidazole-4-ca-
rboxamide;
6-fluoro-2-[4-(2-isopropylpyrrolidin-1-ylmethyl)phenyl]-1H-benz-
imidazole-4-carboxamide;
6-fluoro-2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzim-
idazole-4-carboxamide;
2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-
-carboxamide;
2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-c-
arboxamide;
2-[4-(2-isopropylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxa-
mide;
2-[4-(2-ethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carbox-
amide;
2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimida-
zole-4-carboxamide;
6-chloro-2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimid-
azole-4-carboxamide;
6-chloro-2-[4-(2-isopropylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole--
4-carboxamide;
6-chloro-2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzim-
idazole-4-carboxamide;
6-chloro-2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzim-
idazole-4-carboxamide;
2-{4-[2-(2-methylpyrrolidin-1-yl)-ethyl]phenyl}-1H-benzimidazole-4-carbox-
amide;
2-[2-fluoro-4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H--
benzimidazole-4-carboxamide;
2-{4-[(3-aminopyrrolidin-1-yl)methyl]phenyl}-1H-benzimidazole-4-carboxami-
de;
2-(4-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazol-
e-4-carboxamide;
2-(4-{[3-(isopropylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole--
4-carboxamide;
2-[4-({3-[(cyclopropylmethyl)amino]pyrrolidin-1-yl}methyl)phenyl]-1H-benz-
imidazole-4-carboxamide;
2-(4-{[3-(cyclobutylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-
-4-carboxamide;
2-(4-{[3-(dicyclobutylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazo-
le-4-carboxamide;
2-(4-{[2-(aminomethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-c-
arboxamide;
2-[4-({2-[(dimethylamino)methyl]pyrrolidin-1-yl}methyl)phenyl]-1H-benzimi-
dazole-4-carboxamide;
2-{4-[(2-{[(cyclopropylmethyl)amino]methyl}pyrrolidin-1-yl)methyl]phenyl}-
-1H-benzimidazole-4-carboxamide;
2-[4-({2-[(dicyclobutylamino)methyl]pyrrolidin-1-yl}methyl)phenyl]-1H-ben-
zimidazole-4-carboxamide;
2-[4-({2-[(isopropylamino)methyl]pyrrolidin-1-yl}methyl)phenyl]-1H-benzim-
idazole-4-carboxamide;
2-(4-{[(2S,5S)-2,5-bis(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-be-
nzimidazole-4-carboxamide;
2-{2-fluoro-4-[(2-methylpyrrolidin-1-yl)methyl]phenyl}-1H-benzimidazole-4-
-carboxamide;
2-(4-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}-2-fluorophenyl)-1H-benzim-
idazole-4-carboxamide;
2-{4-[(3-aminopyrrolidin-1-yl)methyl]-2-fluorophenyl}-1H-benzimidazole-4--
carboxamide;
2-(2-fluoro-4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-b-
enzimidazole-4-carboxamide;
2-[4-(1-pyrrolidin-1-ylethyl)phenyl]-1H-benzimidazole-4-carboxamide;
2-{4-[1-(4-methyl-[1,4]diazepan-1-yl)ethyl]phenyl}-1H-benzimidazole-4-car-
boxamide;
2-[4-(1-(azepan-1-yl-ethyl)phenyl]-1H-benzimidazole-4-carboxamid-
e;
2-[4-(1-(morpholin-4-ylethyl)phenyl]-1H-benzimidazole-4-carboxamide;
2-{4-[1-(4-methyl-piperazin-1-yl)ethyl]phenyl}-1H-benzimidazole-4-carboxa-
mide;
2-{4-[1-(4-isopropylpiperazin-1-yl)ethyl]phenyl}-1H-benzimidazole-4--
carboxamide;
2-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-1H-benzimidazole-4-carboxam-
ide;
2-[5-(1-morpholin-4-ylethyl)thiophen-2-yl]-1H-benzimidazole-4-carboxa-
mide;
2-(2-fluoro-4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-
-1H-benzimidazole-4-carboxamide; and
2-(2-fluoro-4-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-b-
enzimidazole-4-carboxamide.
13. A pharmaceutical composition comprising a compound of Formula
(I) of claim 1 or a therapeutically acceptable salt thereof, in
combination with a therapeutically acceptable carrier.
14. A method of inhibiting poly(ADP-ribose)polymerase (PARP) in a
mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) of claim 1 or a therapeutically
acceptable salt thereof.
15. A method of treating inflammation in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) of
claim 1 or a therapeutically acceptable salt thereof.
16. A method of treating sepsis in a mammal in recognized need of
such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) of
claim 1 or a therapeutically acceptable salt thereof.
17. A method of treating septic shock in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) of
claim 1 or a therapeutically acceptable salt thereof.
18. A method of treating cancer in a mammal in recognized need of
such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
therapeutically acceptable salt thereof.
Description
[0001] This application claims priority from U.S. Provisional
Application Ser. No. 60/796,663, filed May 2, 2006.
TECHNICAL FIELD
[0002] The present invention relates to
1H-benzimidazole-4-carboxamides, their preparation, and their use
as inhibitors of the enzyme poly(ADP-ribose)polymerase for the
preparation of drugs.
BACKGROUND
[0003] Poly(ADP-ribose)polymerase (PARP) or
poly(ADP-ribose)synthase (PARS) has an essential role in
facilitating DNA repair, controlling RNA transcription, mediating
cell death, and regulating immune response. These actions make PARP
inhibitors targets for a broad spectrum of disorders. PARP
inhibitors have demonstrated efficacy in numerous models of
disease, particularly in models of ischemia reperfusion injury,
inflammatory disease, degenerative diseases, protection from
adverse effects of cytoxic compounds, and the potentiation of
cytotoxic cancer therapy. PARP has also been indicated in
retroviral infection and thus inhibitors may have use in
antiretroviral therapy. PARP inhibitors have been efficacious in
preventing ischemia reperfusion injury in models of myocardial
infarction, stroke, other neural trauma, organ transplantation, as
well as reperfusion of the eye, kidney, gut and skeletal muscle.
Inhibitors have been efficacious in inflammatory diseases such as
arthritis, gout, inflammatory bowel disease, CNS inflammation such
as MS and allergic encephalitis, sepsis, septic shock, hemmorhagic
shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also
shown benefit in several models of degenerative disease including
diabetes (as well as complications) and Parkinsons disease. PARP
inhibitors can ameliorate the liver toxicity following
acetominophen overdose, cardiac and kidney toxicities from
doxorubicin and platinum based antineoplastic agents, as well as
skin damage secondary to sulfur mustards. In various cancer models,
PARP inhibitors have been shown to potentiate radiation and
chemotherapy by increasing cell death of cancer cells, limiting
tumor growth, decreasing metastasis, and prolonging the survival of
tumor-bearing animals.
SUMMARY OF THE INVENTION
[0004] In one embodiment, the present invention provides compounds
of Formula (I)
##STR00002##
or a therapeutically acceptable salt thereof, wherein
[0005] R.sub.1, R.sub.2, and R.sub.3 are independently selected
from the group consisting of hydrogen, alkenyl, alkoxy,
alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, nitro, NR.sub.AR.sub.B, and
(NR.sub.AR.sub.B)carbonyl;
[0006] Ar.sub.1 is selected from the group consisting of aryl and
heteroaryl, wherein Ar.sub.1 is optionally substituted with 1, 2,
3, or 4 substituents selected from the group consisting of alkyl,
cyano, halogen, and haloalkyl;
[0007] X.sub.1 is alkylenyl;
[0008] Z is heterocycle, wherein Z is optionally substituted with
1, 2, 3, or 4 substituents selected from the group consisting of
alkenyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkynyl, alkoxy,
alkoxyalkyl alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl,
carboxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,
cycloalkylcarbonyl, cycloalkylcarbonylalkyl, halogen, haloalkyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy,
hydroxyalkyl, NR.sub.CR.sub.D, NR.sub.CR.sub.Dalkyl,
(NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)carbonylalkyl, and
oxo;
[0009] R.sub.A and R.sub.B are independently selected from the
group consisting of hydrogen, alkyl, and alkycarbonyl, or R.sub.A
and R.sub.B together with the nitrogen atom to which they are
attached form a heterocycle; and
[0010] R.sub.C and R.sub.D are independently selected from the
group consisting of hydrogen, alkyl, alkycarbonyl, cycloalkyl, and
cycloalkylalkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0011] In another embodiment, the present invention provides
compounds of Formula (I)
##STR00003##
or a therapeutically acceptable salt thereof, wherein
[0012] R.sub.1, R.sub.2, and R.sub.3 are independently selected
from the group consisting of hydrogen, and halogen;
[0013] Ar.sub.1 is selected from the group consisting of aryl and
heteroaryl, wherein Ar.sub.1 is optionally substituted with
halogen;
[0014] X.sub.1 is alkylenyl;
[0015] Z is heterocycle, wherein Z is optionally substituted with
1, 2, 3, or 4 substituents selected from the group consisting of
alkyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl,
NR.sub.CR.sub.D, and NR.sub.CR.sub.Dalkyl; and
[0016] R.sub.C and R.sub.D are independently selected from the
group consisting of hydrogen, alkyl, cycloalkyl, and
cycloalkylalkyl.
[0017] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein Ar.sub.1 is phenyl.
[0018] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein Z is pyrrolidinyl optionally substituted with 1, 2, 3, or 4
substituents selected from the group consisting of alkenyl, alkyl,
alkylcarbonyl, alkylcarbonylalkyl, alkynyl, alkoxy, alkoxyalkyl
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, carboxy,
cyano, cycloalkyl, cycloalkylalkyl, halogen, haloalkyl, hydroxy,
hydroxyalkyl, NR.sub.CR.sub.D, NR.sub.CR.sub.Dalkyl,
(NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)carbonylalkyl, and oxo;
and
[0019] R.sub.C and R.sub.D are independently selected from the
group consisting of hydrogen, alkyl, alkycarbonyl, cycloalkyl, and
cycloalkylalkyl.
[0020] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein Z is pyrrolidinyl optionally substituted with
NR.sub.CR.sub.D.
[0021] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein Z is pyrrolidinyl optionally substituted with alkyl.
[0022] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein Z is pyrrolidinyl optionally substituted with
NR.sub.CR.sub.Dalkyl.
[0023] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein Z is pyrrolidinyl optionally substituted with
hydroxyalkyl.
[0024] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein Ar.sub.1 is phenyl and Z is pyrrolidinyl.
[0025] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein Ar.sub.1 is phenyl substituted with halogen.
[0026] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I),
wherein R.sub.1, R.sub.2, and R.sub.3 are hydrogen.
[0027] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I), or
a therapeutically acceptable salt thereof, in combination with a
therapeutically acceptable carrier.
[0028] In another embodiment, the present invention provides a
method of inhibiting PARP in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a therapeutically
acceptable salt thereof.
[0029] In another embodiment, the present invention provides a
method of treating cancer in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a therapeutically
acceptable salt thereof.
[0030] In another embodiment, the present invention provides a
method for decreasing tumor volume in a mammal in recognized need
of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
therapeutically acceptable salt thereof.
[0031] In another embodiment, the present invention provides a
method of treating leukemia, colon cancer, glioblastomas,
lymphomas, melanomas, carcinomas of the breast, or cervical
carcinomas in a mammal in recognized need of such treatment
comprising administering to the mammal a therapeutically acceptable
amount of a compound of Formula (I) or a therapeutically acceptable
salt thereof.
[0032] In another embodiment, the present invention provides a
method of potentiation of cytotoxic cancer therapy in a mammal in
recognized need of such treatment comprising administering to the
mammal a therapeutically acceptable amount of a compound of Formula
(I) or a therapeutically acceptable salt thereof.
[0033] In another embodiment, the present invention provides a
method of potentiation of radiation therapy in a mammal in
recognized need of such treatment comprising administering to the
mammal a therapeutically acceptable amount of a compound of Formula
(I) or a therapeutically acceptable salt thereof.
[0034] In another embodiment, the present invention provides a
method of treating ischemia reperfusion injury associated with, but
not limited to, myocardial infarction, stroke, other neural trauma,
and organ transplantation, in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a therapeutically
acceptable salt thereof.
[0035] In another embodiment, the present invention provides a
method of reperfusion including, but not limited to, reperfusion of
the eye, kidney, gut and skeletal muscle, in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
therapeutically acceptable salt thereof.
[0036] In another embodiment, the present invention provides a
method of treating inflammatory diseases including, but not limited
to, arthritis, gout, inflammatory bowel disease, CNS inflammation,
multiple sclerosis, allergic encephalitis, sepsis, septic shock,
hemmorhagic shock, pulmonary fibrosis, and uveitis in a mammal in
recognized need of such treatment comprising administering to the
mammal a therapeutically acceptable amount of a compound of Formula
(I) or a therapeutically acceptable salt thereof.
[0037] In another embodiment, the present invention provides a
method of treating immunological diseases or disorders such as
rheumatoid arthritis and septic shock in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
therapeutically acceptable salt thereof.
[0038] In another embodiment, the present invention provides a
method of treating degenerative disease including, but not limited
to, diabetes and Parkinsons disease, in a mammal in recognized need
of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
therapeutically acceptable salt thereof.
[0039] In another embodiment, the present invention provides a
method of treating hypoglycemia in a mammal in recognized need of
such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
therapeutically acceptable salt thereof.
[0040] In another embodiment, the present invention provides a
method of treating retroviral infection in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
therapeutically acceptable salt thereof.
[0041] In another embodiment, the present invention provides a
method of treating liver toxicity following acetominophen overdose
in a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a therapeutically acceptable salt
thereof.
[0042] In another embodiment, the present invention provides a
method of treating cardiac and kidney toxicities from doxorubicin
and platinum based antineoplastic agents in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
therapeutically acceptable salt thereof.
[0043] In another embodiment, the present invention provides a
method of treating skin damage secondary to sulfur mustards in a
mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a therapeutically acceptable salt
thereof.
[0044] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for inhibiting the PARP enzyme in
a mammal in recognized need of such treatment.
[0045] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for inhibiting tumor growth in a
mammal in recognized need of such treatment.
[0046] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating cancer in a mammal in
recognized need of such treatment.
[0047] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating leukemia, colon
cancer, glioblastomas, lymphomas, melanomas, carcinomas of the
breast, or cervical carcinomas in a mammal in a mammal in
recognized need of such treatment.
[0048] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for potentiation of cytotoxic
cancer therapy in a mammal in recognized need of such treatment
comprising administering to the mammal a therapeutically acceptable
amount of a compound of Formula (I) or a therapeutically acceptable
salt thereof.
[0049] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for potentiation of radiation in a
mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a therapeutically acceptable salt
thereof.
[0050] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating ischemia reperfusion
injury associated with, but not limited to, myocardial infarction,
stroke, other neural trauma, and organ transplantation, in a mammal
in recognized need of such treatment comprising administering to
the mammal a therapeutically acceptable amount of a compound of
Formula (I) or a therapeutically acceptable salt thereof.
[0051] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating reperfusion
including, but not limited to, reperfusion of the eye, kidney, gut
and skeletal muscle, in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a therapeutically
acceptable salt thereof.
[0052] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating inflammatory diseases
including, but not limited to, arthritis, gout, inflammatory bowel
disease, CNS inflammation, multiple sclerosis, allergic
encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary
fibrosis, and uveitis in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a therapeutically
acceptable salt thereof.
[0053] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating immunological
diseases or disorders such as rheumatoid arthritis and septic shock
in a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a therapeutically acceptable salt
thereof.
[0054] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating degenerative disease
including, but not limited to, diabetes and Parkinsons disease, in
a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a therapeutically acceptable salt
thereof.
[0055] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating hypoglycemia in a
mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a therapeutically acceptable salt
thereof.
[0056] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating retroviral infection
in a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a therapeutically acceptable salt
thereof.
[0057] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating liver toxicity
following acetaminophen overdose in a mammal in recognized need of
such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
therapeutically acceptable salt thereof.
[0058] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating cardiac and kidney
toxicities from doxorubicin and platinum based antineoplastic
agents in a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a therapeutically acceptable salt
thereof.
[0059] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating skin damage secondary
to sulfur mustards in a mammal in recognized need of such treatment
comprising administering to the mammal a therapeutically acceptable
amount of a compound of Formula (I) or a therapeutically acceptable
salt thereof.
Definitions
[0060] As used throughout this specification and the appended
claims, the following terms have the following meanings:
[0061] The term "alkenyl" as used herein, means a straight or
branched chain hydrocarbon containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0062] The term "alkoxy" as used herein, means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0063] The term "alkoxyalkyl" as used herein, means at least one
alkoxy group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of alkoxyalkyl include, but are not limited to,
tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and
methoxymethyl.
[0064] The term "alkoxycarbonyl" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
[0065] The term "alkoxycarbonylalkyl" as used herein, means an
alkoxycarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
[0066] The term "alkyl" as used herein, means a straight or
branched chain hydrocarbon containing from 1 to 10 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0067] The term "alkylcarbonyl" as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and
1-oxopentyl.
[0068] The term "alkylcarbonyloxy" as used herein, means an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. Representative examples of
alkylcarbonyloxy include, but are not limited to, acetyloxy,
ethylcarbonyloxy, and tert-butylcarbonyloxy.
[0069] The term "alkylenyl" as used herein, means a divalent group
derived from a straight or branched chain hydrocarbon of from 1 to
6 carbon atoms. Representative examples include, but are not
limited to, --CH.sub.2--, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0070] The term "alkylthio" as used herein, means an alkyl group,
as defined herein, appended to the parent molecular moiety through
a sulfur atom. Representative examples of alkylthio include, but
are not limited, methylthio, ethylthio, tert-butylthio, and
hexylthio.
[0071] The term "alkylthioalkyl" as used herein, means an alkylthio
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of alkylthioalkyl include, but are not limited, methylthiomethyl
and 2-(ethylthio)ethyl.
[0072] The term "alkynyl" as used herein, means a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0073] The term "aryl," as used herein, means a phenyl group or a
naphthyl group.
[0074] The aryl groups of the present invention can be optionally
substituted with one, two, three, four, or five substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy,
cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,
hydroxyalkyl, mercapto, nitro, --NR.sub.ER.sub.F, and
(NR.sub.ER.sub.F)carbonyl.
[0075] The term "arylalkyl" as used herein, means an aryl group, as
defined herein, appended to the parent molecular moiety through an
alkyl group, as defined herein. Representative examples of
arylalkyl include, but are not limited to, benzyl, 2-phenylethyl,
3-phenylpropyl, 1-methyl-3-phenylpropyl, and
2-naphth-2-ylethyl.
[0076] The term "carbonyl" as used herein, means a --C(O)--
group.
[0077] The term "carboxy" as used herein, means a --CO.sub.2H
group.
[0078] The term "cyano" as used herein, means a --CN group.
[0079] The term "cycloalkyl" as used herein, means a saturated
cyclic hydrocarbon group containing from 3 to 8 carbons, examples
of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl.
[0080] The cycloalkyl groups of the present invention are
optionally substituted with 1, 2, 3, or 4 substituents selected
from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl,
alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, mercapto, oxo, --NR.sub.ER.sub.F, and
(NR.sub.ER.sub.F)carbonyl.
[0081] The term "cycloalkylalkyl" as used herein, means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylalkyl include, but are not
limited to, cyclopropylmethyl, 2-cyclobutylethyl,
cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
[0082] The term "formyl" as used herein, means a --C(O)H group.
[0083] The term "halo" or "halogen" as used herein, means --Cl,
--Br, --I or --F.
[0084] The term "haloalkoxy" as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of haloalkoxy include, but are not limited to, chloromethoxy,
2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
[0085] The term "haloalkyl" as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and
2-chloro-3-fluoropentyl.
[0086] The term "heteroaryl," as used herein, means a monocyclic
heteroaryl ring or a bicyclic heteroaryl ring. The monocyclic
heteroaryl ring is a 5 or 6 membered ring. The 5 membered ring has
two double bonds and contains one, two, three or four heteroatoms
independently selected from the group consisting of N, O, and S.
The 6 membered ring has three double bonds and contains one, two,
three or four heteroatoms independently selected from the group
consisting of N, O, and S. The bicyclic heteroaryl ring consists of
the 5 or 6 membered heteroaryl ring fused to a phenyl group or the
5 or 6 membered heteroaryl ring is fused to another 5 or 6 membered
heteroaryl ring. Nitrogen heteroatoms contained within the
heteroaryl may be optionally oxidized to the N-oxide. The
heteroaryl is connected to the parent molecular moiety through any
carbon atom contained within the heteroaryl while maintaining
proper valence. Representative examples of heteroaryl include, but
are not limited to, benzothienyl, benzoxadiazolyl, cinnolinyl,
furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl,
isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,
pyrrolyl, pyridinium N-oxide, quinolinyl, tetrazolyl, thiadiazolyl,
thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl.
[0087] The heteroaryl groups of the present invention are
substituted with 0, 1, 2, 3, or 4 substituents independently
selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl,
alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen,
hydroxy, hydroxyalkyl, mercapto, nitro, --NR.sub.ER.sub.F, and
(NR.sub.ER.sub.F)carbonyl.
[0088] The term "heteroarylalkyl" as used herein, means a
heteroaryl, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of heteroarylalkyl include, but are not limited to,
pyridinylmethyl.
[0089] The term "heterocycle" or "heterocyclic" as used herein,
means a monocyclic or bicyclic heterocyclic ring. The monocyclic
heterocyclic ring consists of a 3, 4, 5, 6, 7, or 8 membered ring
containing at least one heteroatom independently selected from O,
N, and S. The 3 or 4 membered ring contains 1 heteroatom selected
from the group consisting of O, N and S. The 5 membered ring
contains zero or one double bond and one, two or three heteroatoms
selected from the group consisting of O, N and S. The 6 or 7
membered ring contains zero, one or two double bonds and one, two
or three heteroatoms selected from the group consisting of O, N and
S. The bicyclic heterocyclic ring consists of a monocyclic
heterocyclic ring fused to a cycloalkyl group or the monocyclic
heterocyclic ring fused to a phenyl group or the monocyclic
heterocyclic ring fused to another monocyclic heterocyclic ring.
The heterocycle is connected to the parent molecular moiety through
any carbon or nitrogen atom contained within the heterocycle while
maintaining proper valence. Representative examples of heterocycle
include, but are not limited to, azetidinyl, azepanyl, aziridinyl,
diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,
1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,
isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,
oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl,
piperazinyl, piperidinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,
thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl
(thiomorpholine sulfone), thiopyranyl, and trithianyl.
[0090] The heterocycles of this invention are substituted with 0,
1, 2, or 3 substituents independently selected from alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy,
cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,
hydroxyalkyl, mercapto, nitro, --NR.sub.ER.sub.F, and
(NR.sub.ER.sub.F)carbonyl.
[0091] The term "heterocycloalkyl" as used herein, means a
heterocycle, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0092] The term "hydroxy" as used herein, means an --OH group.
[0093] The term "hydroxyalkyl" as used herein, means at least one
hydroxy group, as defined herein, is appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of hydroxyalkyl include, but are not
limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
[0094] The term "mercapto" as used herein, means a --SH group.
[0095] The term "nitro" as used herein, means a --NO.sub.2
group.
[0096] The term "nonaromatic" as used herein, means that a 4
membered nonaromatic ring contains zero double bonds, a 5 membered
nonaromatic ring contains zero or one double bond, a 6, 7, or 8
membered nonaromatic ring contains zero, one, or two double
bonds.
[0097] The term "NR.sub.AR.sub.B" as used herein, means two groups,
R.sub.A and R.sub.B, which are appended to the parent molecular
moiety through a nitrogen atom.
[0098] The term "(NR.sub.AR.sub.B)carbonyl" as used herein, means a
NR.sub.AR.sub.B group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of (NR.sub.AR.sub.B)carbonyl include, but
are not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0099] The term "NR.sub.CR.sub.D" as used herein, means two groups,
R.sub.C and R.sub.D, which are appended to the parent molecular
moiety through a nitrogen atom.
[0100] The term "(NR.sub.CR.sub.D)carbonyl" as used herein, means a
NR.sub.CR.sub.D group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of (NR.sub.CR.sub.D)carbonyl include, but
are not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0101] The term "(NR.sub.CR.sub.D)carbonylalkyl" as used herein,
means a (NR.sub.CR.sub.D)carbonyl group, as defined herein,
appended to the parent molecular moiety through an alkyl group, as
defined herein.
[0102] The term "(NR.sub.CR.sub.D)sulfonyl" as used herein, means a
NR.sub.CR.sub.D group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group, as defined herein.
Representative examples of (NR.sub.CR.sub.D)sulfonyl include, but
are not limited to, aminosulfonyl, (methylamino)sulfonyl,
(dimethylamino)sulfonyl, and (ethylmethylamino)sulfonyl.
[0103] The term "NR.sub.ER.sub.F" as used herein, means two groups,
R.sub.E and R.sub.F, which are appended to the parent molecular
moiety through a nitrogen atom. R.sub.E and R.sub.F are each
independently hydrogen, alkyl, and alkylcarbonyl. Representative
examples of NR.sub.ER.sub.F include, but are not limited to, amino,
methylamino, acetylamino, and acetylmethylamino. The term
"(NR.sub.ER.sub.F)carbonyl" as used herein, means a NR.sub.ER.sub.F
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of (NR.sub.ER.sub.F)carbonyl include, but are not limited
to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl,
and (ethylmethylamino)carbonyl.
[0104] The term "oxo" as used herein, means a .dbd.O moiety.
[0105] Compounds of the present invention can exist as
stereoisomers, wherein asymmetric or chiral centers are present.
Stereoisomers are designated (R) or (S) depending on the
configuration of substituents around the chiral carbon atom. The
terms (R) and (S) used herein are configurations as defined in
IUPAC 1974 Recommendations for Section E, Fundamental
Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30, hereby
incorporated by reference. The present invention contemplates
various stereoisomers and mixtures thereof and are specifically
included within the scope of this invention. Stereoisomers include
enantiomers, diastereomers, and mixtures of enantiomers or
diastereomers. Individual stereoisomers of compounds of the present
invention may be prepared synthetically from commercially available
starting materials which contain asymmetric or chiral centers or by
preparation of racemic mixtures followed by resolution well-known
to those of ordinary skill in the art. These methods of resolution
are exemplified by (1) attachment of a mixture of enantiomers to a
chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography and liberation
of the optically pure product from the auxiliary or (2) direct
separation of the mixture of optical enantiomers on chiral
chromatographic columns.
[0106] Compounds of the present invention were named by
ACD/ChemSketch version 5.06 (developed by Advanced Chemistry
Development, Inc., Toronto, ON, Canada) or were given names which
appeared to be consistent with ACD nomenclature.
Determination of Biological Activity
Inhibition of PARP
[0107] Nicotinamide[2,5',8-3H]adenine dinucleotide and streptavidin
SPA beads were purchased from Amersham Biosiences (UK) Recombinant
Human Poly(ADP-Ribose) Polymerase (PARP) purified from E. coli and
6-Biotin-17-NAD.sup.+, were purchase from Trevigen, Gaithersburg,
Md. NAD.sup.+, Histone, aminobenzamide, 3-amino benzamide and Calf
Thymus DNA (dcDNA) were purchased from Sigma, St. Louis, Mo. Stem
loop oligonucleotide containing MCAT sequence was obtained from
Qiagen. The oligos were dissoloved to 1 mM in annealing buffer
containing 10 mM Tris HCl pH 7.5, 1 mM EDTA, and 50 mM NaCl,
incubated for 5 min at 95.degree. C., and followed by annealing at
45.degree. C. for 45 minutes. Histone H1 (95% electrophoretically
pure) was purchased from Roche, Indianapolis, Ind. Biotinylated
histone H1 was prepared by treating the protein with
Sulfo-NHS-LC-Biotin from Pierce Rockford, Ill. The biotinylation
reaction was conducted by slowly and intermittently adding 3
equivalents of 10 mM Sulfo-NHS-LC-Biotin to 100 .mu.M Histone H1 in
phosphate-buffered saline, pH 7.5, at 4.degree. C. with gentle
vortexing over imin followed by subsequent 4.degree. C. incubation
for 1 hr. Streptavidin coated (FlashPlate Plus) microplates were
purchased from Perkin Elmer, Boston, Mass.
[0108] PARP1 assay was conducted in PARP assay buffer containing 50
mM Tris pH 8.0, 1 mM DTT, 4 mM MgCl.sub.2. PARP reactions contained
1.5 .mu.M [.sup.3H]-NAD.sup.+ (1.6uCi/mmol), 200 nM biotinylated
histone H1, 200 nM s1DNA, and 1 nM PARP enzyme. Auto reactions
utilizing SPA bead-based detection were carried out in 100 .mu.l
volumes in white 96 well plates. Reactions were initiated by adding
50 .mu.l of 2.times.NAD.sup.+ substrate mixture to 50 .mu.l of
2.times. enzyme mixture containing PARP and DNA. These reactions
were terminated by the addition of 150 .mu.l of 1.5 mM benzamide
(.about.1000-fold over its IC50). 170 .mu.l of the stopped reaction
mixtures were transferred to streptavidin Flash Plates, incubated
for 1 hr, and counted using a TopCount microplate scintillation
counter. The K.sub.i data was determined from inhibition curves at
various substrate concentrations and are shown in Table 1 for
compounds of the present invention
TABLE-US-00001 TABLE 1 Inhibition of PARP (nM) 12.4 7 2.6 12.5 8.8
43 27 19 55 6.3 1.9 18.4 43 31 13.1 7.6 17.8 13.9 3.5 14.1 18.1 22
13.3 15.6 4.8 3.8 1.5 20.5 55 13.3 10.8 30 25.5 8.1 3.2 21 116 18
18 19.1 31 41 39
[0109] Cellular PARP assay:
[0110] C41 cells were treated with a compound of the present
invention for 30 minutes in 96 well plate. PARP was then activated
by damaging DNA with 1 mM H.sub.2O.sub.2 for 10 minutes. The cells
were then washed with ice-cold PBS once and fixed with pre-chilled
methanol:acetone (7:3) at -20.degree. C. for 10 minutes. After
air-drying, the plates were rehydrated with PBS and blocked 5%
non-fat dry milk in PBS-tween (0.05%) (blocking solution) for 30
minutes at room temperature. The cells were incubated with anti-PAR
antibody 10H (1:50) in Blocking solution at 37.degree. C. for 60
minutes followed by washing with PBS-Tween20 5 times, and
incubation with goat anti-mouse fluorescein
5(6)-isothiocyanate-coupled antibody (1:50) and 1 .mu.g/ml
4',6-diamidino-2-phenylindole (DAPI) in blocking solution at
37.degree. C. for 60 minutes. After washing with PBS-Tween20 5
times, the analysis was performed using an fmax Fluorescence
Microplate Reader (Molecular Devices, Sunnyvalle, Calif.), set at
the excitation wavelength of 490 nm and emission wavelength of 528
nm fluorescein 5(6)-isothiocyanate (FITC) or the excitation
wavelength of 355 nm and emission wavelength of 460 nm (DAPI). The
PARP activity (FITC signal) was normalized with cell numbers
(DAPI).
[0111] The cellular assay measures the formation of poly ADP-ribose
by PARP within cells and demonstrates that compounds of the present
invention penetrate cell membranes and inhibit PARP in intact
cells. The EC.sub.50s, for representative compounds of the present
invention are provided in Table 2.
TABLE-US-00002 TABLE 2 Cellular Activity EC.sub.50 (nM) 0.8 10 2
4.4 34 12.8 1.5 7.9 54 9.5 42 8.7 62 14.3 8.7 41 4.2 9.2 0.8 108 11
3.2 111 51 1.1 2.1 0.8 3.2 5.7 2.6 19 0.2 1 1.7 93 0.9
[0112] As PARP inhibitors, the compounds of the present invention
have numerous therapeutic applications related to, ischemia
reperfusion injury, inflammatory diseases, degenerative diseases,
protection from adverse effects of cytotoxic compounds, and
potentiation of cytotoxic cancer therapy. In particular, compounds
of the present invention potentiate radiation and chemotherapy by
increasing cell death of cancer cells, limiting tumor growth,
decreasing metastasis, and prolonging the survival of tumor-bearing
mammals. Compounds of Formula (I) can treat leukemia, colon cancer,
glioblastomas, lymphomas, melanomas, carcinomas of the breast, and
cervical carcinomas.
[0113] Other therapeutic applications include, but are not limited
to, retroviral infection, arthritis, gout, inflammatory bowel
disease, CNS inflammation, multiple sclerosis, allergic
encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary
fibrosis, uveitis, diabetes, Parkinsons disease, myocardial
infarction, stroke, other neural trauma, organ transplantation,
reperfusion of the eye, reperfusion of the kidney, reperfusion of
the gut, reperfusion of skeletal muscle, liver toxicity following
acetominophen overdose, cardiac and kidney toxicities from
doxorubicin and platinum based antineoplastic agents, and skin
damage secondary to sulfur mustards. (G. Chen et al. Cancer Chemo.
Pharmacol. 22 (1988), 303; C. Thiemermann et al., Proc. Natl. Acad.
Sci. USA 94 (1997), 679-683 D. Weltin et al. Int. J.
Immunopharmacol. 17 (1995), 265-271; H. Kroger et al. Inflammation
20 (1996), 203-215; W. Ehrlich et al. Rheumatol. Int. 15 (1995),
171-172; C. Szabo et al., Proc. Natl. Acad. Sci. USA 95 (1998),
3867-3872; S. Cuzzocrea et al. Eur. J. Pharmacol. 342 (1998),
67-76; V. Burkhart et al., Nature Medicine (1999), 5314-19).
[0114] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
present invention can be employed as a zwitterion or as a
pharmaceutically acceptable salt. By a "therapeutically effective
amount" of the compound of the invention is meant a sufficient
amount of the compound to treat or prevent a disease or disorder
ameliorated by a PARP inhibitor at a reasonable benefit/risk ratio
applicable to any medical treatment. It will be understood,
however, that the total daily usage of the compounds and
compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; activity
of the specific compound employed; the specific composition
employed, the age, body weight, general health, sex and diet of the
patient; the time of administration, route of administration, and
rate of excretion of the specific compound employed; the duration
of the treatment; drugs used in combination or coincidental with
the specific compound employed; and like factors well known in the
medical arts. For example, it is well within the skill of the art
to start doses of the compound at levels lower than those required
to achieve the desired therapeutic effect and to gradually increase
the dosage until the desired effect is achieved.
[0115] By "pharmaceutically acceptable salt" is meant those salts
which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of humans and lower animals without
undue toxicity, irritation, allergic response and the like and are
commensurate with a reasonable benefit/risk ratio. Pharmaceutically
acceptable salts are well-known in the art. The salts can be
prepared in situ during the final isolation and purification of the
compounds of the present invention or separately by reacting the
free base of a compound of the present invention with a suitable
acid. Representative acids include, but are not limited to
acetatic, citric, aspartic, benzoic, benzenesulfonic, butyric,
fumaric, hydrochloric, hydrobromic, hydroiodic, lactic, maleic,
methanesulfonic, pamoic, pectinic, pivalic, propionic, succinic,
tartaric, phosphic, glutamic, and p-toluenesulfonic. Also, the
basic nitrogen-containing groups can be quaternized with such
agents as lower alkyl halides such as methyl, ethyl, propyl, and
butyl chlorides, bromides and iodides; dialkyl sulfates like
dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides
such as decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides; arylalkyl halides like benzyl and phenethyl bromides and
others. Water or oil-soluble or dispersible products are thereby
obtained.
[0116] A compound of the present invention may be administered as a
pharmaceutical composition containing a compound of the present
invention in combination with one or more pharmaceutically
acceptable excipients. A pharmaceutically acceptable carrier or
excipient refers to a non-toxic solid, semi-solid or liquid filler,
diluent, encapsulating material or formulation auxiliary of any
type. The compositions can be administered parenterally,
intracistemally, intravaginally, intraperitoneally, topically (as
by powders, ointments, drops or transdermal patch), rectally, or
bucally. The term "parenteral" as used herein refers to modes of
administration which include intravenous, intramuscular,
intraperitoneal, intrasternal, subcutaneous and intraarticular
injection and infusion.
[0117] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically-acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, as well as
sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and nonaqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), carboxymethylcellulose
and suitable mixtures thereof, vegetable oils (such as olive oil),
and injectable organic esters such as ethyl oleate. Proper fluidity
may be maintained, for example, by the use of coating materials
such as lecithin, by the maintenance of the required particle size
in the case of dispersions, and by the use of surfactants.
[0118] These compositions can also contain adjuvants such as
preservative, wetting agents, emulsifying agents, and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption, such as aluminum
monostearate and gelatin.
[0119] Compounds of the present invention may also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic,
physiologically-acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients, and the like.
The preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art. See, for example, Prescott, Ed.,
Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.
(1976), p. 33 et seq.
[0120] Total daily dose of the compositions of the invention to be
administered to a human or other mammal host in single or divided
doses may be in amounts, for example, from 0.0001 to 300 mg/kg body
weight daily and more usually 1 to 300 mg/kg body weight. The dose,
from 0.0001 to 300 mg/kg body, may be given twice a day.
[0121] Abbreviations which have been used in the descriptions of
the examples that follow are: DBU for
1,8-diazabicyclo[5.4.0]undec-7-ene; DMF for N,N-dimethylformamide;
DMSO for dimethylsulfoxide; Et.sub.2O for diethyl ether; EtOAc for
ethyl acetate; EtOH for ethanol; HPLC for high pressure liquid
chromatography; LDA for lithium diisopropylamide; MeOH for
methanol; psi for pounds per square inch; TFA for trifluoroacetic
acid; THF for tetrahydrofuran, and TMS for trimethylsilane.
[0122] Compounds having formula I may be made by synthetic chemical
processes, examples of which are shown herein below. 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.
Scheme 1
[0123] Compounds of formula 7 wherein X.sub.1 and Ar.sub.1 are as
defined in formula (I), can be prepared from compounds of formula 1
as shown in Scheme 1.
[0124] A benzaldehyde or thiophene carboxaldehyde, containing a
ketone or aldehyde or ketal or acetal (as appropriate), can be
coupled with a compounds of formula 1 using, for example, Pd/C or
sodium bisulfite, with heating, to give compounds of formula 4 (or
5 if starting with a ketone or aldehyde). Alternately, a benzoic
acid or thiophene carboxylic acid, containing a ketone or aldehyde
or ketal or acetal, can be coupled with 1 using standard amide
forming reagents, such as 1,1'-carbonyldiimidazole (CDI), to give
an intermediate amide, which can be treated with acid, such as
acetic acid, with heating, to provide the benzimidazole 4 (or 5 if
starting with a ketone or aldehyde). The ketal or acetal (if
present) can be hydrolysed under acid-catalyzed conditions to give
compounds of formula 5, which can undergo reductive amination using
a cyclic amine (compounds of formula 6) to provide compounds of
formula 7.
##STR00004##
Scheme 2
[0125] Compounds of formula 12 can be prepared from compounds of
formula 8 as shown in Scheme 2.
[0126] Cyclic amines can be added to compounds of formula 8 to give
amides of formula 9. Compounds of formula 9 may be treated with an
alkyl Grignard reagent in the presence of a catalyst such as
zirconium chloride to provide compounds of formula 10. Compounds of
formula 10 may undergo a lithium-halogen exchange of the aryl
bromide with an alkyl lithium reagent such as sec-butyl lithium,
followed by reaction with N,N'-dimethylformamide (DMF), to provide
compounds of formula 11. Compounds of formula 11 can be coupled
with compounds of formula 1 using, for example, Pd/C or sodium
bisulfite, with heating, to give the compounds of formula 12.
##STR00005##
[0127] The following Examples are intended as an illustration of
and not a limitation upon the scope of the invention as defined in
the appended claims. The compounds of this invention can be
prepared by a variety of synthetic routes.
EXAMPLE 1
6-fluoro-2-[4-(2-methylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-ca-
rboxamide
EXAMPLE 1A
2-bromo-4-fluoro-6-nitrophenylamine
[0128] To a solution of 4-fluoro-2-nitroaniline (19.76 g, 126 mmol)
in a mixture of dichloromethane (600 mL) and acetic acid (200 mL)
was slowly added bromine (15 mL) at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 1 hour and at ambient
temperature for 20 hrs. The mixture was concentrated and the
residue partitioned between ethyl acetate and sodium bicarbonate
solution. The organic phase was separated, washed with sodium
bisulphite solution and concentrated. The residue was
recrystallized from hexanes containing some dichloromethane to
provide 22.7 g (76%) of the title compound. MS (DCI/NH.sub.3) m/z
236 (M+H).sup.+.
EXAMPLE 1B
2-amino-5-fluoro-3-nitrobenzonitrile
[0129] To a flask containing EXAMPLE 1A (6.5 g, 27.6 mmol), zinc
cyanide (6.5 g, 55.3 mmol) and palladium
tetrakis(triphenylphosphine) (1.6 g, 1.38 mmol) was added anhydrous
N,N-dimethylformamide (120 mL) and the solution was stirred under
nitrogen at 80.degree. C. for 22 hours. After cooling, the mixture
was partitioned between ethyl acetate and brine. The organic phase
was washed with water and filtered. The filtrate was concentrated
and the crude product recrystallized from methanol to provide 3.3 g
(65%) of the title compound. MS (DCI/NH.sub.3) m/z 182
(M+H).sup.+.
EXAMPLE 1C
2-amino-5-fluoro-3-nitrobenzamide
[0130] A mixture of EXAMPLE 1B (3.3 g, 18.22 mmol) in
polyphosphoric acid (30 g) was stirred at 115.degree. C. for 3
hours. After cooling, water and dichloromethane were added and the
precipitated solid collected by filtration and recrystallized from
methanol to provide 2.6 g (72%) of the title compound. MS
(DCI/NH.sub.3) m/z 200 (M+H).sup.+.
EXAMPLE 1D
2,3-diamino-5-fluorobenzamide
[0131] To a solution of EXAMPLE 1C (1.5 g, 7.5 mmol) in 1:1
tetrahydrofuran/ethanol (100 mL) was added Raney nickel (50% in
water, 1.0 g) and the mixture stirred under hydrogen (60 psi) at
ambient temperature for 16 hours. The solid material was filtered
off and the filtrate concentrated to provide 1.26 g (98%) of the
title compound. MS (DCI/NH.sub.3) m/z 170 (M+H).sup.+.
EXAMPLE 1E
2-(4-diethoxymethylphenyl)-6-fluoro-1H-benzimidazole-4-carboxamide
[0132] A suspension of EXAMPLE 1D (1.5 g, 8.87 mmol) in
dimethylacetamide (20 mL) was stirred for 20 minutes at 50.degree.
C. After partial cooling, terephthaldehyde mono(diethylacetal) (2.0
g, 9.76 mmol) in dimethylacetamide (5 mL) and sodium bisulphite
(1.85 g, 17.74 mmol) were added and the mixture heated at
100.degree. C. for 3 hours. After cooling to ambient temperature,
the solvent was removed. The residue was partitioned between ethyl
acetate and water, and the organic layer washed with brine and
concentrated. The residue was purified by flash chromatography on
silica gel using ethyl acetate to provide 2.4 g (63%) of the title
compound. MS (DCI/NH.sub.3) m/z 358 (M+H).sup.+.
EXAMPLE 1F
6-fluoro-2-(4-formylphenyl)-1H-benzimidazole-4-carboxamide
[0133] To a suspension of EXAMPLE 1E in a mixture of ethanol (40
mL) and water (40 mL) was added concentrated sulfuric acid (1.5 mL)
and the mixture refluxed for 18 hours. After cooling, ethanol was
removed and the residue neutralized with aqueous sodium hydroxide
solution and saturated sodium bicarbonate solution. The green solid
was collected by filtration, washed with water and hot methanol and
dried to provide 1.4 g (88%) of the title compound. MS
(DCI/NH.sub.3) m/z 284 (M+H).sup.+.
EXAMPLE 1G
6-fluoro-2-[4-(2-methylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-ca-
rboxamide
Step A
[0134] A solution of EXAMPLE 1F (60 mg, 0.21 mmol) and
2-methylpyrrolidine (36 mg, 0.42 mmol) in 1:1
methanol/N,N-dimethylformamide (5 mL) was stirred at ambient
temperature for 2 hours. Sodium cyanoborohydride (27 mg, 0.42
mmol), zinc chloride (29 mg, 0.21 mmol) and dimethyl sulfoxide (1
mL) were added and the cloudy mixture stirred at 50.degree. C. for
16 hours. The mixture was concentrated and the residue purified by
HPLC (Zorbax C-8, 0.1% trifluoroacetic acid/acetonitrile/water) to
provide the title compound as the trifluoroacetic acid salt.
Step B
[0135] The trifluoroacetic acid salt from step A was converted to
the hydrochloride salt by dissolving in methanol and treating with
anhydrous hydrogen chloride in diethyl ether to provide 20 mg (27%)
of the title compound as the hydrochloride salt. .sup.1H NMR
(CD.sub.3OD): .delta. 1.50 (d, J=6.7 Hz, 3H), 1.78-1.89 (m, 1H),
1.99-2.09 (m, 1H), 2.10-2.21 (m, 1H), 2.36-2.48 (m, 1H), 3.32-3.37
(m, 1H), 3.40-3.50 (m, 1H), 3.62-3.74 (m, 1H), 4.36 (d, J=13.1 Hz,
1H), 4.76 (d, J=13.1 Hz, 1H), 7.78 (dd, J=7.6, 2.1 Hz, 1H), 7.91
(dd, J=9.9, 2.3 Hz, 1H), 7.94 (d, J=8.2 Hz, 2H), 8.28 (d, J=8.2 Hz,
2H).
EXAMPLE 2
6-fluoro-2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimi-
dazole-4-carboxamide
[0136] The title compound was prepared as the trifluoroacetic acid
salt using the procedure as described in step A of EXAMPLE 1G,
substituting (S)-(-)-pyrrolidin-2-ylmethanol for
2-methylpyrrolidine (41% yield). .sup.1H NMR (CD.sub.3OD): .delta.
1.88-2.04 (m, 2H), 2.10-2.20 (m, 1H), 2.24-2.34 (m, 1H), 3.31-3.37
(m, 1H), 3.41-3.49 (m, 1H), 3.70-3.79 (m, 2H), 3.81-3.86 (m, 1H),
4.35 (d, J=12.8 Hz, 1H), 4.75 (d, J=13.1 Hz, 1H), 7.49 (dd, J=8.1,
2.59 Hz, 1H), 7.70 (dd, J=10.4, 2.4 Hz, 1H), 7.74 (d, J=8.2 Hz,
2H), 8.29 (d, J=8.2 Hz, 2H).
EXAMPLE 3
6-fluoro-2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimida-
zole-4-carboxamide
[0137] The title compound was prepared as the trifluoroacetic acid
salt using the procedure as described in step A of EXAMPLE 1G,
substituting 2-(trifluoromethyl)pyrrolidine for 2-methylpyrrolidine
(34% yield). .sup.1H NMR (CD.sub.3OD): .delta. 1.84-1.96 (m, 2H),
1.99-2.09 (m, 1H), 2.15-2.27 (m, 1H), 2.62-2.70 (m, 1H), 3.05-3.14
(m, 1H), 3.62-3.72 (m, 1H), 3.91-3.99 (m, 1H), 4.35 (d, J=14.0 Hz,
1H), 7.58 (dd, J=7.9, 2.4 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.77
(dd, J=10.1, 2.4 Hz, 1H), 8.15 (d, J=8.5 Hz, 2H).
EXAMPLE 4
2-[4-(2-ethylpyrrolidin-1-ylmethyl)phenyl]-6-fluoro-1H-benzimidazole-4-car-
boxamide
[0138] The title compound was prepared as the hydrochloride salt
using the procedure as described in EXAMPLE 1G, substituting
2-ethylpyrrolidine for 2-methylpyrrolidine (32% yield). .sup.1H NMR
(CD.sub.3OD): .delta. 1.03 (t, J=6.0 Hz, 3H), 1.69-1.76 (m, 1H),
1.83-1.88 (m, 1H), 1.95-2.11 (m, 2H), 2.14-2.22 (m, 1H), 2.41-2.48
(m, 1H), 3.33-3.37 (m, 1H), 3.42-3.50 (m, 1H), 3.51-3.58 (m, 1H),
4.38-4.45 (m, 1H), 4.73-4.81 (m 1H), 7.81 (d, J=6.7 Hz, 1H), 7.93
(d, J=9.8 Hz, 1H), 7.98 (d, J=8.2 Hz, 2H), 8.29 (d, J=8.2 Hz,
2H).
EXAMPLE 5
6-fluoro-2-[4-(2-isopropylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-
-carboxamide
[0139] The title compound was prepared as the trifluoroacetic acid
salt using the procedure as described in step A of EXAMPLE 1G,
substituting 2-isopropylpyrrolidine for 2-methylpyrrolidine (57%
yield). .sup.1H NMR (CD.sub.3OD): .delta. 1.06 (dd, J=19.5, 6.7 Hz,
6H), 1.90-2.04 (m, 2H), 2.06-2.21 (m, 2H), 2.22-2.31 (m, 1H),
3.34-3.41 (m, 1H), 3.41-3.48 (m, 1H), 3.50-3.58 (m, 1H), 4.35 (d,
J=13.1 Hz, 1H), 4.63 (d, J=13.1 Hz, 1H), 7.50 (dd, J=8.2, 2.44 Hz,
1H), 7.70 (dd, J=10.4, 2.4 Hz, 1H), 7.76 (d, J=8.2 Hz, 2H), 8.29
(d, J=8.2 Hz, 2H).
EXAMPLE 6
6-fluoro-2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimi-
dazole-4-carboxamide
[0140] The title compound was prepared as the hydrochloride salt
using the procedure as described in EXAMPLE 1G, substituting
(R)-(+)-pyrrolidin-2-yl-methanol for 2-methylpyrrolidine (72%
yield). .sup.1H NMR (CD.sub.3OD): .delta. 1.90-1.98 (m, 1H),
1.98-2.06 (m, 1H), 2.12-2.21 (m, 1H), 2.26-2.35 (m, 1H), 3.33-3.40
(m, 1H), 3.43-3.51 (m, 1H), 3.73-3.81 (m, 2H), 3.82-3.89 (m, 1H),
4.44 (d, J=13.1 Hz, 1H), 4.81-4.85 (m, 1H), 7.75 (dd, J=7.8, 2.3
Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.91 (d, J=8.2 Hz, 2H), 8.28 (d,
J=8.2 Hz, 2H).
EXAMPLE 7
2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4--
carboxamide
EXAMPLE 7A
2-(4-diethoxymethylphenyl)-1H-benzimidazole-4-carboxamide
[0141] The title compound was prepared using the procedure as
described in EXAMPLE 1E, substituting 2,3-diaminobenzamide
dihydrochloride (synthesized as described in U.S. Pat. No.
6,737,421, column 11, EXAMPLE 2, step (e)) for EXAMPLE 1D (54%
yield). MS (DCI/NH.sub.3) m/z 340 (M+H).sup.+.
EXAMPLE 7B
6-fluoro-2-(4-formylphenyl)-1H-benzimidazole-4-carboxamide
[0142] The title compound was prepared using the procedure as
described in EXAMPLE 1F, substituting EXAMPLE 7A for EXAMPLE 1E
(73% yield). MS (DCI/NH.sub.3) m/z 266 (M+H).sup.+.
EXAMPLE 7C
2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4--
carboxamide
[0143] The title compound was prepared as the hydrochloride salt
using the procedure as described in EXAMPLE 1G, substituting
(S)-(-)-pyrrolidin-2-ylmethanol for 2-methylpyrrolidine and
substituting EXAMPLE 7B for EXAMPLE 1F (7% yield). .sup.1H NMR
(CD.sub.3OD): .delta. 1.88-2.08 (m, 2H), 2.11-2.23 (m, 1H),
2.25-2.38 (m, 1H), 3.33-3.41 (m, 1H), 3.43-3.54 (m, 1H), 3.75-3.82
(m, 2H), 3.82-3.87 (m, 1H), 4.45 (d, J=13.2 Hz, 1H), 4.84-4.87 (m,
1H), 7.65-7.71 (m, 1H), 7.93 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.3 Hz,
1H), 8.07 (dd, J=7.7, 0.9 Hz, 1H), 8.31 (d, J=8.3 Hz, 2H).
EXAMPLE 8
2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-ca-
rboxamide
[0144] The title compound was prepared as the hydrochloride salt
using the procedure as described in EXAMPLE 1G, substituting
2-(trifluoromethyl)pyrrolidine for 2-methylpyrrolidine and EXAMPLE
7B for EXAMPLE 1F (45% yield). .sup.1H NMR (CD.sub.3OD): .delta.
2.01-2.11 (m, 1H), 2.12-2.28 (m, 2H), 2.39-2.54 (m, 1H), 3.17-3.27
(m, 1H), 3.39-3.52 (m, 1H), 4.22-4.35 (m, 1H), 4.44 (d, J=13.5 Hz,
1H), 4.63 (d, J=13.8 Hz, 1H), 7.70-7.75 (m, 1H), 7.91 (d, J=8.6 Hz,
2H), 8.03 (dd, J=8.3, 0.92 Hz, 1H), 8.08 (dd, J=7.7, 0.9 Hz, 1H),
8.26 (d, J=8.6 Hz, 2H).
EXAMPLE 9
2-[4-(2-isopropylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxam-
ide
[0145] The title compound was prepared as the hydrochloride salt
using the procedure as described in EXAMPLE 1G, substituting
2-isopropylpyrrolidine for 2-methylpyrrolidine and substituting
EXAMPLE 7B for EXAMPLE 1F (40% yield). .sup.1H NMR (CD.sub.3OD):
.delta. 1.06 (d, J=12.9 Hz, 6H), 1.91-2.06 (m, 2H), 2.06-2.22 (m,
2H), 2.22-2.33 (m, 1H), 3.34-3.43 (m, 1H), 3.46-3.54 (m, 1H),
3.54-3.62 (m, 1H), 4.47 (d, J=13.2 Hz, 1H), 4.71 (d, J=12.9 Hz,
1H), 7.70-7.77 (m, 1H), 8.00 (d, J=8.3 Hz, 2H), 8.05 (dd, J=8.3,
0.9 Hz, 1H), 8.09 (dd, J=7.7, 0.9 Hz, 1H), 8.31 (d, J=8.3 Hz,
2H).
EXAMPLE 10
2-[4-(2-ethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-carboxamide
[0146] The title compound was prepared as the hydrochloride salt
using the procedure as described in EXAMPLE 1G, substituting
2-ethylpyrrolidine for 2-methylpyrrolidine and substituting EXAMPLE
7B for EXAMPLE 1F (17% yield). .sup.1H NMR (CD.sub.3OD): .delta.
1.03 (t, J=7.4 Hz, 3H), 1.63-1.76 (m, 1H), 1.79-1.91 (m, 1H),
1.94-2.08 (m, 2H), 2.11-2.24 (m, 1H), 2.36-2.51 (m, 1H), 3.34-3.38
(m, 1H), 3.41-3.58 (m, 2H), 4.40 (d, J=13.2 Hz, 1H), 4.76 (d,
J=13.2 Hz, 1H), 7.7 (t, J=8.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 8.04
(dd, J=8.3, 0.6 Hz, 1H), 8.09 (dd, J=7.7, 0.6 Hz, 1H), 8.30 (d,
J=8.6 Hz, 2H).
EXAMPLE 11
2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4--
carboxamide
[0147] The title compound was prepared as the hydrochloride salt
using the procedure as described in EXAMPLE 1G, substituting
(R)-(+)-pyrrolidin-2-ylmethanol for 2-methylpyrrolidine and
substituting EXAMPLE 7B for EXAMPLE 1F (55% yield). .sup.1H NMR
(CD.sub.3OD): .delta. 1.90-1.98 (m, 1H), 1.99-2.07 (m, 1H),
2.13-2.23 (m, 1H), 2.27-2.37 (m, 1H), 3.33-3.41 (m, 1H), 3.43-3.52
(m, 1H), 3.76-3.80 (m, 1H), 3.80-3.83 (m, 1H), 3.83-3.88 (m, 1H),
4.47 (d, J=13.1 Hz, 1H), 4.84-4.86 (m, 1H), 7.72 (t, J=7.9 Hz, 1H),
7.95 (d, J=8.2 Hz, 2H), 8.04 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.3 Hz,
1H), 8.30 (d, J=8.2 Hz, 2H).
EXAMPLE 12
6-chloro-2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimida-
zole-4-carboxamide
EXAMPLE 12A
2-amino-5-chloro-3-nitrobenzamide
Step A
Preparation of 2-amino-3-nitrobenzamide
[0148] To a solution of 2-amino-3-nitrobenzoic acid (prepared using
the procedure as described in U.S. Pat. No. 6,737,421, EXAMPLE 2,
part b) in dimethoxyethane (7.1 mL/g), was added thionyl chloride
(1.33 equivalents). The mixture was stirred at 50.degree. C. for 12
hours, cooled and slowly added to concentrated ammonium hydroxide
(22 equivalents). The mixture was stirred at 50.degree. C. for 2
hours, water was added, and the mixture was cooled and filtered.
The solid was washed with water and isopropanol and dried to give
the title compound (89% yield).
Step B
Preparation of 2-amino-5-chloro-3-nitrobenzamide
[0149] To a solution of 2-amino-3-nitrobenzamide (4.0 g, 22 mmol)
in warm acetonitrile (1250 mL) was added N-chlorosuccinimide (3.1
g, 23 mmol) and the mixture stirred at 60.degree. C. for 20 hours.
After cooling, the orange crystalline material was collected by
filtration, washed with acetonitrile and dried. The filtrate was
concentrated and the solid recrystallized from acetonitrile to
provide a second crop of the title compound. (3.98 g, 84%). MS
(DCI/NH.sub.3) m/z 216 (M+H).sup.+.
EXAMPLE 12B
2,3-diamino-5-chlorobenzamide
[0150] The title compound was prepared using the procedure as
described in EXAMPLE 1D, substituting EXAMPLE 12A for EXAMPLE 1C
(99% yield). MS (DCI/NH.sub.3) m/z 186 (M+H).sup.+.
EXAMPLE 12C
6-chloro-2-(4-diethoxymethylphenyl)-1H-benzimidazole-4-carboxamide
[0151] The title compound was prepared using the procedure as
described in EXAMPLE 1E, substituting EXAMPLE 12B for EXAMPLE 1D
(47% yield). MS (DCI/NH.sub.3) m/z 374 (M+H).sup.+.
EXAMPLE 12D
6-chloro-2-(4-formylphenyl)-1H-benzimidazole-4-carboxamide
[0152] The title compound was prepared using the procedure as
described in EXAMPLE 1F, substituting EXAMPLE 12C for EXAMPLE 1E
(82% yield). MS (DCI/NH.sub.3) m/z 300 (M+H).sup.+.
EXAMPLE 12E
6-chloro-2-[4-(2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimida-
zole-4-carboxamide
[0153] The title compound was prepared as the trifluoroacetic acid
salt using the procedure as described in step A of EXAMPLE 1G,
substituting 2-(trifluoromethyl)pyrrolidine for
2-methylpyrrolidine, and substituting EXAMPLE 12D for EXAMPLE 1F
(28% yield). .sup.1H NMR (DMSO-d.sub.6): .delta. 1.72-1.81 (m, 1H),
1.83-1.98 (m, 2H), 2.12-2.25 (m, 1H), 2.64-2.68 (m, 1H), 3.01-3.07
(m, 1H), 3.78-3.84 (m, 1H), 3.97 (d, J=13.4 Hz, 1H), 4.25 (d,
J=13.7 Hz, 1H), 7.63 (d, J=7.9 Hz, 2H), 7.84 (s, 1H), 7.85 (s, 1H),
7.97 (br s, 1H), 8.29 (d, J=7.9 Hz, 2H), 9.07 (br s, 1H).
EXAMPLE 13
6-chloro-2-[4-(2-isopropylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimidazole-4-
-carboxamide
[0154] The title compound was prepared as the trifluoroacetic acid
salt using the procedure as described in step A of EXAMPLE 1G,
substituting 2-isopropylpyrrolidine for 2-methylpyrrolidine, and
substituting EXAMPLE 12D for EXAMPLE.1F (8% yield). .sup.1H NMR
(DMSO-d.sub.6): .delta. 0.92 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.9 Hz,
3H), 1.76-1.83 (m, 1H), 1.83-1.90 (m, 1H), 1.92-2.04 (m, 2H),
2.05-2.15 (m, 1H), 3.18-3.26 (m, 1H), 3.34-3.43 (m, 2H), 4.23-4.62
(m, 2H), 7.82-7.83 (m, 2H), 7.89 (d, J=8.2 Hz, 2H), 7.98 (br s,
1H), 8.38 (d, J=8.2 Hz, 2H), 9.12 (br s, 1H), 10.06 (br s, 1H).
EXAMPLE 14
6-chloro-2-[4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimi-
dazole-4-carboxamide
[0155] The title compound was prepared as the hydrochloride salt
using the procedure as described in EXAMPLE 1G, substituting
(S)-(-)-pyrrolidin-2-ylmethanol for 2-methylpyrrolidine and
substituting EXAMPLE 12D for EXAMPLE 1F (9% yield). .sup.1H NMR
(DMSO-d6): .delta. 1.75-1.91 (m, 2H), 1.95-2.06 (m, 1H), 2.08-2.20
(m, 1H), 3.15-3.23 (m, 1H), 3.27-3.35 (m, 1H), 3.65-3.76 (m, 3H),
4.37 (dd, J=12.9, 6.8 Hz, 1H), 4.67 (dd, J=12.9, 4.3 Hz, 1H),
7.81-7.82 (m, 2H), 7.83-7.85 (m, 2H), 7.94 br (s, 1H), 8.36 (d,
J=8.6 Hz, 2H), 9.12 (br s, 1H), 10.29 (br s, 1H).
EXAMPLE 15
6-chloro-2-[4-((R)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimi-
dazole-4-carboxamide
[0156] The title compound was prepared as the hydrochloride salt
using the procedure as described in EXAMPLE 1G, substituting
(R)-(+)-pyrrolidin-2-ylmethanol for 2-methylpyrrolidine and
substituting EXAMPLE 12D for EXAMPLE 1F (24% yield). .sup.1H NMR
(CD.sub.3OD): .delta. 1.89-1.98 (m, 1H), 1.98-2.06 (m, 1H),
2.12-2.21 (m, 1H), 2.26-2.36 (m, 1H), 3.33-3.40 (m, 1H), 3.43-3.50
(m, 1H), 3.73-3.81 (m, 2H), 3.82-3.88 (m, 1H), 4.44 (d, J=13.1 Hz,
1H), 4.83 (d, J=13.1 Hz, 1H), 7.90 (d, J=8.5 Hz, 2H), 7.98 (d,
J=1.8 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 8.29 (d, J=8.2 Hz, 2H).
EXAMPLE 16
2-{4-[2-(2-methylpyrrolidin-1-yl)-ethyl]phenyl}-1H-benzimidazole-4-carboxa-
mide
EXAMPLE 16A
2-(4-[1,3]-Dioxolan-2-ylmethylphenyl)-1H-benzimidazole-4-carboxamide
[0157] A solution of 4-(1,3-dioxolan-2-ylmethyl)benzoic acid (1.0
g, 4.80 mmol) in pyridine (5 mL) and N,N-dimethylformamide (5 mL)
was treated with 1,1'-carbonyldiimidazole (0.856 g, 5.28 mmol) at
45.degree. C. for 2 hours. 2,3-Diaminobenzamide dihydrochloride
(synthesized as described in U.S. Pat. No. 6,737,421, column 11,
EXAMPLE 2, step (e), 1.08 g, 4.80 mmol) was added and the mixture
stirred at ambient temperature overnight. The mixture was
concentrated and the residue heated in acetic acid (30 mL) at
80.degree. C. for 3 hours. After cooling, the mixture was
concentrated and the residue partitioned between ethyl acetate and
sodium bicarbonate solution. After filtering, the filtrate was
concentrated and the residue purified by flash chromatography on
silica gel (0-15% methanol in 2:1 ethyl acetate/hexane) to give
1.14 g of the title compound. MS (DCI) m/z 324 (M+H).sup.+.
EXAMPLE 16B
2-{4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl}-1H-benzimidazole-4-carboxam-
ide
[0158] A solution of EXAMPLE 16A (750 mg, 2.32 mmol) in acetic acid
(30 mL) and water (60 mL) was heated at 70.degree. C. for 18 hours.
After cooling, the solution was concentrated to give a light yellow
solid. To a solution of the crude aldehyde (170 mg) in
N,N-dimethylformamide (1 mL) and methanol (3.5 mL) was added
2-methylpyrrolidine (125 .mu.L, 1.22 mmol) and the mixture stirred
at ambient temperature for 1 hour. Sodium cyanoborohydride (77 mg,
1.22 mmol) was added and the mixture heated at 55.degree. C.
overnight. The methanol was removed and the residue purified by
flash chromatography (silica gel, 1:10:80 ammonium
hydroxide/methanol/dichloromethane) followed by HPLC (Zorbax, C-18,
250.times.2.54 column, Mobile phase A: 0.1% trifluoroacetic acid in
water; B: 0.1% trifluoroacetic acid in acetonitrile; 0-100%
gradient) to provide the title compound as a trifluoroacetate salt.
This material was dissolved in 1:1 methanol/dichloromethane (2 mL)
and was treated with a 1M solution of hydrochloric acid in ether (5
mL). Concentration afforded 135 mg of the title compound as the
hydrochloride salt. .sup.1H NMR (CD.sub.3OD) 1.52 (d, J=6.4 Hz,
3H), 1.76-1.85 (m, 1H), 2.07-2.19 (m, 2H), 2.37 (m, 1H), 3.26-3.38
(m, 4H), 3.55-3.61 (m, 1H), 3.66-3.73 (m, 1H), 3.80 (m, 1H),
7.68-7.78 (m, 3H), 8.02 (d, J=8.2 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H),
8.19 (d, J=7.9 Hz, 2H).
EXAMPLE 17
2-[2-fluoro-4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimi-
dazole-4-carboxamide
EXAMPLE 17A
methyl 4-cyano-2-fluoro-benzoate
[0159] A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43
mmol), zinc cyanide (10.0 g, 86 mmol) and palladium
tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in
N,N-dimethylformamide (100 mL) was stirred at 80.degree. C.
overnight. After cooling, the mixture was partitioned between ethyl
acetate and brine and the organic phase washed with water and
concentrated. The residue was purified by flash chromatography on
silica gel (1:5 ethyl acetate/hexane) to afford 6.1 g (80%) of the
title compound. MS (DCI): m/z 180 (M+H).sup.+.
EXAMPLE 17B
methyl 2-fluoro-4-formyl-benzoate
[0160] EXAMPLE 17A (310 mg, 1.73 mmol) was dissolved in 60% aqueous
acetic acid (10 mL) with gentle heating. Raney nickel (60 mg) was
added and the mixture stirred under hydrogen at ambient temperature
for 18 hours. Solid material was filtered off and the filtrate
concentrated. The residue was purified by flash chromatography on
silica gel (1:4 ethyl acetate/hexane) to give 220 mg (70%) of the
title compound. MS (DCI): m/z 183 (M+H).sup.+.
EXAMPLE 17C
methyl 4-[1,3]dioxolan-2-yl-2-fluorobenzoate
[0161] A solution of EXAMPLE 17B (2.0 g, 11 mmol), 1,2-ethanediol
(1.0 g, 16 mmol), and p-toluenesulfonic acid monohydrate (10 mg) in
benzene (10 mL) was heated under reflux with a Dean-Stark apparatus
for 6 hours. After cooling, the mixture was partitioned between
ethyl acetate and brine and the organic phase washed with 10%
sodium hydroxide solution, water and concentrated. The residue was
purified by flash chromatography on silica gel (1:5 ethyl
acetate/hexane) to give 2.1 g (80%) of the title compound. MS
(DCI): m/z 227 (M+H).sup.+.
EXAMPLE 17D
4-[1,3]dioxolan-2-yl-2-fluorobenzoic acid
[0162] To a solution of EXAMPLE 17C (2.0 g) in tetrahydrofuran (10
mL) and water (5 mL) was added a solution of lithium hydroxide
monohydrate (1 g) in water (5 mL). Methanol was added until a
homogeneous solution formed. The solution was stirred at ambient
temperature for 4 hours and concentrated to 5 mL. This was
acidified with 2N hydrochloric acid to pH 2 and partitioned between
ethyl acetate and water. The organic phase was washed with water,
dried over magnesium sulfate, filtered and concentrated to give 1.5
g (79%) of the title compound. MS (DCI): m/z 213 (M+H).sup.+.
EXAMPLE 17E
2-(4-[1,3]dioxolan-2-yl-2-fluorophenyl)-1H-benzimidazole-4-carboxamide
[0163] A solution of EXAMPLE 17D (1.5 g, 7.1 mmol) in pyridine (5
mL) and N,N-dimethylformamide (20 mL) was treated with
1,1'-carbonyldiimidazole (1.4 g, 8.5 mmol) at 40.degree. C. for 30
minutes. 2,3-Diaminobenzamide dihydrochloride (synthesized as
described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step
(e), 1.58 g, 7.1 mmol) was added and the mixture stirred at ambient
temperature overnight. Solvents were removed and the residue was
stirred in acetic acid (10 mL) at 80.degree. C. overnight. After
concentration, the residue was purified by flash chromatography on
silica gel (ethyl acetate) to give 500 mg (22%) of the title
compound. MS (DCI/NH.sub.3) m/z 329 (M+H).sup.+.
EXAMPLE 17F
2-(2-fluoro-4-formylphenyl)-1H-benzimidazole-4-carboxamide
[0164] A solution of EXAMPLE 17E (500 mg, 1.5 mmol) in acetic acid
(5 mL) and water (10 mL) was heated at 70.degree. C. overnight.
After cooling, the mixture was concentrated to give 400 mg (94%) of
the title compound. MS (DCI/NH.sub.3) m/z 285 (M+H).sup.+.
EXAMPLE 17G
2-[2-fluoro-4-((S)-2-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]-1H-benzimi-
dazole-4-carboxamide
[0165] To a solution of EXAMPLE 17F (70 mg, 0.25 mmol) in
N,N-dimethylformamide (2 mL) and methanol (4 mL) was added
(S)-pyrrolidin-2-ylmethanol (37 mg, 0.37 mmol) and the solution
stirred at ambient temperature for 10 minutes. Sodium
cyanoborohydride (38 mg) was added and the mixture heated at
55.degree. C. overnight. After cooling, the mixture was
concentrated and the residue purified by HPLC (Zorbax, C-18,
250.times.2.54 column, Mobile phase A: 0.1% trifluoroacetic acid in
water; B: 0.1% trifluoroacetic acid in acetonitrile; 0-100%
gradient) to provide 65 mg of the title compound as a
trifluoroacetic acid salt. .sup.1H NMR (CD.sub.3OD): .delta.
1.87-2.07 (m, 2H); 2.15 (d, J=4.0 Hz, 1H); 2.30 (dd, J=12.5, 6.41
Hz, 1H); 3.25-3.38 (m, 1H); 3.50 (s, 1H); 3.77 (d, J=7.3 Hz, 2H);
3.87 (d, J=7.6 Hz, 1H); 4.35 (d, J=12.8 Hz, 1H); 4.75 (d, J=13.1
Hz, 1H); 7.42 (s, 1H); 7.55 (s, 2H); 7.82 (s, 1H); 7.97 (s, 1H);
8.39 (d, J=1.2 Hz, 1H).
EXAMPLE 18
2-{4-[(3-aminopyrrolidin-1-yl)methyl]phenyl}-1H-benzimidazole-4-carboxamid-
e
EXAMPLE 18A
tert-butyl
1-{4-[4-(aminocarbonyl)-1H-benzimidazol-2-yl]benzyl}pyrrolidin--
3-ylcarbamate
[0166] A solution of EXAMPLE 7B (300 mg, 1.13 mmol) and
3-(tert-butoxycarbonylamino)pyrrolidine (631 mg, 3.39 mmol) in 1:1
methanol/N,N'-dimethylformamide (20 mL) was stirred at ambient
temperature for 2 hours. Sodium cyanoborohydride (213 mg, 3.39
mmol) and zinc chloride (154 mg, 1.13 mmol) were added and the
mixture stirred at 50.degree. C. for 18 hours. The mixture was
concentrated and the residue purified by HPLC (Zorbax C-8, 0.1%
trifluoroacetic acid/acetonitrile/water) to provide the title
compound (415 mg, 84%). MS (DCI/NH.sub.3) m/z 436 (M+H).sup.+.
EXAMPLE 18B
2-{4-[(3-aminopyrrolidin-1-yl)methyl]phenyl}-1H-benzimidazole-4-carboxamid-
e
[0167] A solution of EXAMPLE 18A (410 mg, 0.94 mmol) in
dichloromethane (40 mL) was treated with trifluoroacetic acid (15
mL) at 0.degree. C. and the mixture stirred at ambient temperature
for 3 hours. The solution was diluted with acetonitrile and
concentrated to provide the title compound as a trifluoroacetate
salt (300 mg, 96%). .sup.1H NMR (CD.sub.3OD) .delta. 2.17-2.29 (m,
1H), 2.59-2.71 (m, 1H), 3.43-3.51 (m, 1H), 3.56 (dd, J=12.7, 4.4
Hz, 1H), 3.64-3.73 (m, 1H), 3.80 (dd, J=12.8, 8.2 Hz, 1H),
4.14-4.24 (m, 1H), 4.55 (d, J=5.5 Hz, 2H), 7.45 (t, J=7.8 Hz, 1H),
7.77 (d, J=8.5 Hz, 2H), 7.81 (dd, J=7.9, 0.9 Hz, 1H), 7.98 (dd,
J=7.6, 0.9 Hz, 1H), 8.30 (d, J=8.2 Hz, 2H).
EXAMPLE 19
2-(4-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}phenyl)
1H-benzimidazole-4-carboxamide
[0168] A solution of EXAMPLE 18B (50 mg, 0.15 mmol), triethylamine
(52 .mu.L, 0.37 mmol) and formaldehyde (37% in water, 8 .mu.L, 0.30
mmol) in 1:1 methanol/N,N'-dimethylformamide (6 mL) was stirred at
ambient temperature for 2 hours. Sodium cyanoborohydride (28 mg,
0.45 mmol) and zinc chloride (20 mg, 0.15 mmol) were added and the
mixture stirred at 50.degree. C. for 18 hours. The mixture was
concentrated and the residue purified by HPLC (Zorbax C-8, 0.1%
trifluoroacetic acid/acetonitrile/water) to provide the
trifluoroacetate salt of the title compound. The hydrochloride salt
(18 mg, 33%) was obtained by treatment of a methanol solution of
the purified trifluoroacetate salt with a solution of hydrochloric
acid in ether. .sup.1H NMR (CD.sub.3OD) .delta. 2.46-2.59 (m, 1H),
2.63-2.76 (m, 1H), 2.99 (s, 6H), 3.53-3.65 (m, 1H), 3.70-3.83 (m,
1H), 3.92-4.08 (m, 2H), 4.23-4.38 (m, 1H), 4.73 (s, 2H), 7.69-7.75
(m, 1H), 8.03 (dd, J=8.3, 0.9 Hz, 3H), 8.08 (dd, J=7.5, 0.8 Hz,
1H), 8.30 (d, J=8.6 Hz, 2H).
EXAMPLE 20
2-(4-{[3-(isopropylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-
-carboxamide
[0169] The title compound as the hydrochloride salt was prepared
according to the procedure for EXAMPLE 19, substituting acetone for
formaldehyde (26% yield). .sup.1H NMR (CD.sub.3OD): .delta. 1.40
(d, J=6.4 Hz, 6H), 2.31-2.51 (m, 1H), 2.69-2.85 (m, 1H), 3.45-3.57
(m, 2H), 3.76-3.84 (m, 2H), 3.85-3.94 (m, 1H), 4.31-4.48 (m, 1H),
4.73 (s, 2H), 7.66-7.72 (m, 1H), 7.99-8.03 (m, 3H), 8.07 (dd,
J=7.7, 0.9 Hz, 1H), 8.29 (d, J=8.6 Hz, 2H).
EXAMPLE 21
2-[4-({3-[(cyclopropylmethyl)amino]pyrrolidin-1-yl}methyl)phenyl]-1H-benzi-
midazole-4-carboxamide
[0170] The title compound as the hydrochloride salt was prepared
according to the procedure for EXAMPLE 19, substituting
cyclopropanecarboxaldehyde for formaldehyde. (24% yield). .sup.1H
NMR (CD.sub.3OD) .delta. 0.40-0.54 (m, 2H), 0.73 (d, J=8.0 Hz, 2H),
1.09-1.22 (m, 1H), 2.33-2.47 (m, 1H), 2.65-2.86 (m, 1H), 3.00 (d,
J=7.36 Hz, 2H), 3.41-3.56 (m, 1H), 3.73-3.85 (m, 2H), 3.88-4.03 (m,
1H), 4.17-4.36 (m, 1H), 4.71 (s, 2H), 7.69 (t, J=7.8 Hz, 1H), 8.00
(d, J=8.0 Hz, 3H), 8.07 (d, J=7.7 Hz, 1H), 8.30 (d, J=8.3 Hz,
2H).
EXAMPLE 22
2-(4-{[3-(cyclobutylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole--
4-carboxamide
[0171] The title compound as the hydrochloride salt was prepared
according to the procedure for EXAMPLE 19, substituting
cyclobutanone for formaldehyde (31% yield). .sup.1H NMR
(CD.sub.3OD) .delta. 1.86-2.02 (m, 2H), 2.25-2.44 (m, 5H),
2.58-2.78 (m, 1H), 3.46-3.63 (m, 1H), 3.71-3.82 (m, 2H), 3.84-3.95
(m, 2H), 4.10-4.22 (m, 1H), 4.71 (s, 2H), 7.64-7.70 (m, 1H), 7.99
(d, J=8.3 Hz, 3H), 8.06 (dd, J=7.5, 0.8 Hz, 1H), 8.30 (d, J=8.3 Hz,
2H).
EXAMPLE 23
2-(4-{[3-(dicyclobutylamino)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazol-
e-4-carboxamide
[0172] The title compound as the hydrochloride salt was prepared
according to the procedure for EXAMPLE 19, substituting
cyclobutanone for formaldehyde (14% yield). .sup.1H NMR
(CD.sub.3OD): .delta. 1.75-1.92 (m, 4H), 2.30-2.44 (m, 4H),
2.44-2.59 (m, 6H), 3.39-3.50 (m, 1H), 3.60-3.71 (m, 1H), 3.76-3.88
(m, 2H), 3.96-4.06 (m, 3H), 4.27-4.43 (m, 1H), 4.65-4.71 (m, 2H),
7.67 (t, J=8.0 Hz, 1H), 7.99 (d, J=7.4 Hz, 1H), 8.00 (d, J=8.0 Hz,
2H), 8.07 (d, J=6.8 Hz, 1H), 8.29 (d, J=8.6 Hz, 2H);
EXAMPLE 24
2-(4-{[2-(aminomethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-ca-
rboxamide
EXAMPLE 24A
tert-butyl
(1-{4-[4-(aminocarbonyl)-1H-benzimidazol-2-yl]benzyl}pyrrolidin-
-2-yl)methylcarbamate
[0173] The title compound was prepared according to the procedure
for EXAMPLE 18A, substituting tert-butyl
pyrrolidin-2-ylmethylcarbamate for
3-(tert-butoxycarbonylamino)pyrrolidine. (85% yield). MS
(DCI/NH.sub.3) m/z 450 (M+H).sup.+.
EXAMPLE 24B
2-(4-{[2-(aminomethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-benzimidazole-4-ca-
rboxamide
[0174] The title compound as the trifluoroacetate salt was prepared
according to the procedure for EXAMPLE 18B, substituting EXAMPLE
24A for EXAMPLE 18A. (94% yield). .sup.1H NMR (CD.sub.3OD): .delta.
1.97-2.11 (m, 2H), 2.12-2.23 (m, 1H), 2.41-2.53 (m, 1H), 3.24-3.29
(m, 1H), 3.33-3.37 (m, 1H), 3.43-3.55 (m, 2H), 3.79-3.89 (m, 1H),
4.35 (d, J=12.9 Hz, 1H), 4.70 (d, J=12.9 Hz, 1H), 7.46 (t, J=7.8
Hz, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.83 (d, J=7.4 Hz, 1H), 7.99 (dd,
J=7.7, 0.9 Hz, 1H), 8.30 (d, J=8.3 Hz, 2H).
EXAMPLE 25
2-[4-({2-[(dimethylamino)methyl]pyrrolidin-1-yl}methyl)phenyl]-1H-benzimid-
azole-4-carboxamide
[0175] The title compound as the hydrochloride salt was prepared
according to the procedure for EXAMPLE 19, substituting EXAMPLE 24B
for EXAMPLE 18B. (27% yield). .sup.1H NMR (CD.sub.3OD): .delta.
2.08-2.21 (m, 2H), 2.23-2.34 (m, 1H), 2.59-2.72 (m, 1H), 3.04 (s,
6H), 3.34-3.51 (m, 2H), 3.72 (dd, J=13.4, 8.8 Hz, 1H), 3.99 (dd,
J=13.5, 4.3 Hz, 1H), 4.18-4.30 (m, 1H), 4.42-4.53 (m, 1H), 4.99 (d,
J=9.5 Hz, 1H), 7.66-7.71 (m, 1H), 8.00 (dd, J=8.3, 0.9 Hz, 1H),
8.06 (d, J=4.0 Hz, 1H), 8.06-8.09 (m, 2H), 8.30 (d, J=8.3 Hz,
2H).
EXAMPLE 26
2-{4-[(2-{[(cyclopropylmethyl)amino]methyl}pyrrolidin-1-yl)methyl]phenyl}--
1H-benzimidazole-4-carboxamide
[0176] The title compound as the hydrochloride salt was prepared
according to the procedure for EXAMPLE 19 substituting cyclopropane
carboxaldehyde for formaldehyde and EXAMPLE 24B for EXAMPLE 18B
(14% yield). .sup.1H NMR (CD.sub.3OD): .delta. 0.46-0.56 (m, 2H),
0.71-0.79 (m, 2H), 1.14-1.29 (m, 1H), 2.16 (d, J=6.4 Hz, 2H),
2.20-2.30 (m, 1H), 2.53-2.65 (m, 1H), 2.99-3.16 (m, 2H), 3.34-3.41
(m, 1H), 3.43-3.50 (m, 1H), 3.62 (dd, J=13.4, 7.5 Hz, 1H), 3.78
(dd, J=13.5, 4.6 Hz, 1H), 4.07-4.20 (m, 1H), 4.47 (d, J=12.6 Hz,
1H), 4.99 (d, J=12.9 Hz, 1H), 7.65-7.71 (m, 1H), 8.00 (dd, J=8.3,
0.9 Hz, 1H), 8.07 (dd, J=7.5, 0.8 Hz, 3H), 8.29 (d, J=8.3 Hz,
2H).
EXAMPLE 27
2-[4-({2-[(dicyclobutylamino)methyl]pyrrolidin-1-yl}methyl)phenyl]-1H-benz-
imidazole-4-carboxamide
[0177] The title compound as the hydrochloride salt was prepared
according to the procedure for EXAMPLE 19 substituting
cyclobutanone for formaldehyde and EXAMPLE 24B for EXAMPLE 18B (39%
yield). .sup.1H NMR (CD.sub.3OD): .delta. 1.77-1.98 (m, 4H),
2.09-2.20 (m, 2H), 2.23-2.30 (m, 1H), 2.36 (d, J=2.2 Hz, 4H),
2.45-2.60 (m, 4H), 2.72-2.83 (m, 1H), 3.33-3.45 (m, 2H), 3.65 (dd,
J=13.7, 10.3 Hz, 1H), 3.84 (dd, J=13.8, 3.1 Hz, 1H), 3.90-4.01 (m,
2H), 4.08-4.19 (m, 1H), 4.48 (d, J=12.9 Hz, 1H), 4.99 (d, J=12.0
Hz, 1H), 7.66-7.71 (m, 1H), 8.00 (dd, J=8.3, 0.9 Hz, 1H), 8.03-8.09
(m, 3H), 8.29 (d, J=8.3 Hz, 2H).
EXAMPLE 28
2-[4-({2-[(isopropylamino)methyl]pyrrolidin-1-yl}methyl)phenyl]-1H-benzimi-
dazole-4-carboxamide
[0178] The title compound as the hydrochloride salt was prepared
according to the procedure for EXAMPLE 19 substituting acetone for
formaldehyde and EXAMPLE 24B for EXAMPLE 18B (27% yield). .sup.1H
NMR (CD.sub.3OD): .delta. 1.43 (d, J=6.4 Hz, 6H), 2.09-2.19 (m,
2H), 2.20-2.30 (m, 1H), 2.50-2.62 (m, 1H), 3.35-3.42 (m, 1H),
3.43-3.50 (m, 1H), 3.51-3.57 (m, 1H), 3.60 (dd, J=13.2, 7.7 Hz,
1H), 3.69-3.78 (m, 1H), 4.06-4.14 (m, 1H), 4.46 (d, J=13.5 Hz, 1H),
4.99 (d, J=13.2 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz,
1H), 8.07 (d, J=7.7 Hz, 3H), 8.29 (d, J=8.3 Hz, 2H).
EXAMPLE 29
2-(4-{[(2S,5S)-2,5-bis(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-ben-
zimidazole-4-carboxamide
[0179] To a solution of EXAMPLE 7B (75 mg, 0.28 mmol) in
N,N'-dimethylformamide (4 mL) and methanol (4 mL) was added
(S,S)-(+)-2,5-bis(methoxymethyl)pyrrolidine (134 mg, 0.84 mmol) and
the mixture stirred at ambient temperature for 1.5 hours. Sodium
cyanoborohydride (53 mg, 0.28 mmol) was added and the mixture
heated at 55.degree. C. overnight. After cooling, the mixture was
concentrated and the residue purified by HPLC (Zorbax, C-18,
250.times.2.54 column, Mobile phase A: 0.1% trifluoroacetic acid in
water; B: 0.1% trifluoroacetic acid in acetonitrile; 0-100%
gradient) to provide the title compound as the trifluoroacetate
salt. Dissolution in methanol and treatment with a 1M hydrochloric
acid solution in ether, followed by concentration, afforded the
title compound as the hydrochloride salt (20 mg, 18%). .sup.1H NMR
(CD.sub.3OD) .delta. 1.91-1.99 (m, 1H), 2.13-2.19 (m, 1H),
2.18-2.26 (m, 1H), 2.32-2.40 (m, 1H), 3.22 (s, 3H), 3.23-3.27 (m,
1H), 3.45-3.51 (m, 1H), 3.49 (s, 3H), 3.78-3.83 (m, 1H), 3.87-3.93
(m, 1H), 3.99 (m, 1H), 4.07-4.13 (m, 1H), 4.52 (d, J=13.4 Hz, 1H),
4.71 (d, J=13.7 Hz, 1H), 7.66 (t, J=7.9 Hz, 1H), 7.95 (d, J=8.2 Hz,
2H), 7.99 (d, J=8.2 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 8.31 (d, J=8.2
Hz, 2H).
EXAMPLE 30
2-{2-fluoro-4-[(2-methylpyrrolidin-1-yl)methyl]phenyl}-1H-benzimidazole-4--
carboxamide
[0180] To a suspension of EXAMPLE 17F (50 mg, 0.17 mmol) in
methanol (10 mL) was added 2-methylpyrrolidine (43 mg, 0.5 mmol)
and the mixture stirred at 50.degree. C. until complete
dissolution. Sodium cyanoborohydride (38 mg) was added and the
mixture heated at 55.degree. C. overnight. After cooling, the
mixture was concentrated and the residue purified by HPLC (Zorbax,
C-1 8, 250.times.2.54 column, Mobile phase A: 0.1% trifluoroacetic
acid in water; B: 0.1% trifluoroacetic acid in acetonitrile; 0-100%
gradient) to provide the title compound as the trifluoroacetate
salt (44 mg). .sup.1H NMR (DMSO-D6) .delta. 1.39 (d, J=6.4 Hz, 3H);
1.59-1.74 (m, 1H); 1.84-1.93 (m, 1H); 1.95-2.09 (m, 1H); 2.18-2.38
(m, 1H); 3.18-3.29 (m, 1H); 3.30-3.44 (m, 1H); 3.48-3.63 (m, 1H);
4.29 (dd, J=12.9, 7.1 Hz, 1H); 4.67 (dd, J=13.2, 2.5 Hz, 1H); 7.40
(t, J=8.3 Hz, 1H); 7.61 (dd, J=8.3, 1.53 Hz, 1H); 7.72 (d, J=12.0
Hz, 1H); 7.78 (d, J=8.3 Hz,1H); 7.84 (d, J=1.5 Hz 1H); 7.92 (d,
J=8.0 Hz 1H); 8.40 (t, J=8.0 Hz, 1H); 9.15 (s, 1H); 9.98 (s,
1H).
EXAMPLE 31
2-(4-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}-2-fluorophenyl)-1H-benzimi-
dazole-4-carboxamide
[0181] The title compound was prepared as the trifluoroacetate salt
according to the procedure for EXAMPLE 30, substituting
3-dimethylaminopyrrolidine for 2-methylpyrrolidine. .sup.1H NMR
(DMSO-D.sub.6) .delta. 2.05-2.26 (m, 1H); 2.29-2.43 (m, 1H); 2.83
(s, 6H); 3.20-3.31 (m, 1H); 3.33-3.49 (m, 2H); 3.65 (dd, J=12.6,
8.3 Hz, 1H); 3.92-4.11 (m, 2H); 4.26 (m, 1H); 7.39 (t, J=8.0 Hz,
1H); 7.52 (d, J=8.0 Hz, 1H); 7.59 (d, J=11.7 Hz, 1H); 7.78 (d,
J=1.8 Hz, 1H); 7.83 (d, J=7.1 Hz, 1H); 7.92 (d, J=7.1 Hz, 1H); 8.35
(t, J=8.0 Hz, 1H); 9.20 (s, 1H); 9.65 (s, 1H).
EXAMPLE 32
2-{4-[(3-aminopyrrolidin-1-yl)methyl]-2-fluorophenyl}-1H-benzimidazole-4-c-
arboxamide
[0182] To a solution of EXAMPLE 17F (100 mg, 0.3 mmol) in
N,N'-dimethylformamide (5 mL) and methanol (10 mL) was added
tert-butyl pyrrolidin-3-yl-carbamate (111 mg, 0.6 mmol) and the
mixture stirred at ambient temperature for 10 minutes. Sodium
cyanoborohydride (38 mg) was added and the mixture heated at
55.degree. C. overnight. After cooling, the mixture was
concentrated and the residue was treated with dichloromethane (4
mL) and trifluoroacetic acid (1 mL) for 1 hour and concentrated.
The residue was purified by HPLC (Zorbax, C-18, 250.times.2.54
column, Mobile phase A: 0.1% trifluoroacetic acid in water; B: 0.1%
trifluoroacetic acid in acetonitrile; 0-100% gradient) to provide
the title compound as the trifluoroacetate salt (79 mg). .sup.1H
NMR (DMSO-D.sub.6) .delta. 2.02-2.17 (m, 1H); 2.35-2.48 (m, 1H);
3.40 (s, 2H); 3.46-3.61 (m, 1H); 3.64-3.82 (m, 1H); 3.92-4.12 (m,
1H); 4.45-4.62 (m, 2H); 7.41 (t, J=7.7 Hz, 1H); 7.59 (dd, J=8.0,
1.2 Hz, 1H); 7.68 (d, J=12.0 Hz, 1H); 7.78 (s, 1H); 7.84 (d, J=8.0
Hz, 1H); 7.93 (d, J=8.3 Hz, 1H); 8.27-8.52 (m, J=7.8, 7.8 Hz, 2H);
9.16 (s, 1H).
EXAMPLE 33
2-(2-fluoro-4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-be-
nzimidazole-4-carboxamide
[0183] The title compound was prepared as trifluoroacetate salt
according to the procedure for EXAMPLE 30, substituting
(R)-2-hydroxymethylpyrrolidine for 2-methylpyrrolidine. .sup.1H NMR
(DMSO-D.sub.6) .delta. 1.75-1.83 (m, 1H), 1.82-1.90 (m, 1H),
1.98-2.05 (m, 1H), 2.12-2.21 (m, 1H), 3.21-3.28 (m, 1H), 3.34-3.40
(m, 1H), 3.65 (m, 2H), 4.41 (d, J=12.8 Hz, 1H), 4.67 (d, J=12.8 Hz,
1H), 7.40 (t, J=7.8 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.71 (d,
J=11.9 Hz, 1H), 7.81 (br s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.92 (d,
J=7.3 Hz, 1H), 8.40 (t, J=7.8 Hz, 1H), 9.15 (br s, 1H), 9.74 (br s,
1H).
EXAMPLE 34
2-[4-(1-pyrrolidin-1-ylethyl)phenyl]-1H-benzimidazole-4-carboxamide
EXAMPLE 34A
2-(4-acetylphenyl)-1H-benzimidazole-4-carboxamide
[0184] 4-Acetylbenzoic acid (1.64 g, 10 mmol) in
N,N-dimethylformamide (10 mL) and pyridine (10 mL) was stirred at
40.degree. C. for 10 minutes. 1,1'-carbonyldiimidazole (1.7 g, 10.5
mmol) was added and the mixture was stirred at 40.degree. C. for 30
minutes. 2,3-diaminobenzamide dihydrochloride (synthesized as
described in U.S. Pat. No. 6,737,421, 2.2 g, 10 mmol) was added and
the mixture was stirred at ambient temperature for 2.5 hours.
Isopropyl alcohol (20 mL) was added and the mixture was stirred at
ambient temperature for 20 hours. The resulting solid was filtered,
washed with isopropyl alcohol and dried to give 2.1 g of a yellow
solid. The crude material was stirred in water (30 mL) with 50%
sodium hydroxide (1 mL) at ambient temperature for 7.5 hours. The
solution was filtered and the solid (1.84 g) collected and stirred
in refluxing acetic acid (25 mL) for 4 hours. The mixture was
concentrated, stirred in dichloromethane, filtered, and dried to
give the title compound (1.78 g, 64%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.27 (br, 1H), 8.40 (d, J=8.4 Hz, 2H), 8.16 (d, J=8.5 Hz,
2H), 7.89 (d, J=7.5 Hz, 1H), 7.78 (d, J=6.8 Hz, 1H), 7.78 (br, 1H),
7.37 (t, J=7.8 Hz, 1H), 2.66 (s, 3H).
EXAMPLE 34B
2-[4-(1-pyrrolidin-1-ylethyl)phenyl]-1H-benzimidazole-4-carboxamide
[0185] A solution of EXAMPLE 34A (0.1 g, 0.4 mmol) and pyrrolidine
(0.13 mL, 1.6 mmol) in methanol (1 mL) was treated with sodium
cyanoborohydride (0.05 g, 0.8 mmol) and acetic acid (0.2 mL) and
the mixture stirred overnight at 70.degree. C. The residue was
concentrated and purified by flash chromatography on silica gel
using 0-10% dichloromethane/methanol/0.1% ammonium hydroxide to
provide the title compound, which was dissolved in methanol (1 mL),
treated with a solution of 1M hydrochloric acid in ether (2 mL) and
stirred at ambient temperature for 2 hours. The precipitate was
filtered to give the title compound as the hydrochloride salt.
.sup.1H NMR (DMSO-d.sub.6) .delta. 11.26 (s, 1H), 8.34 (d, J=8.4
Hz, 2H), 7.85-7.91 (m, 3H), 7.79 (d, J=7.2 Hz, 2H), 7.39 (t, J=7.8
Hz, 1H), 4.51 (qd, J=7.4, 7.2 Hz, 1H), 3.70 (dd, J=11.4, 4.5 Hz,
1H), 3.12-3.20 (m, 1 Hz), 2.95-3.02 (m, 1H), 2.89 (dq, J=11.2, 8.1
Hz, 1H), 1.91-2.00 (m, 2H), 1.79-1.88 (m, 1H), 1.69 (d, J=6.9 Hz,
3H).
EXAMPLE 35
2-{4-[1-(4-methyl-[1,4]diazepan-1-yl)ethyl]phenyl}-1H-benzimidazole-4-carb-
oxamide
[0186] The title compound as the hydrochloride salt was prepared as
described in EXAMPLE 34B by substituting 1-methyl-[1,4]diazepane
for pyrrolidine. .sup.1H NMR (DMSO-d.sub.6) .delta. 11.42 (s, 1H)
9.70 (s, 1H), 8.37 (d, J=7.5 Hz, 2H), 7.84-7.92 (m, 3H), 7.79 (d,
J=8.1 Hz, 2H), 7.38 (t, J=7.8 Hz, 1H), 3.64 (s, 1H), 3.51-3.58 (m,
3H), 3.48 (s, 1H), 3.17 (s, 4H), 2.73-2.80 (m, 5H), 2.11-2.20 (m,
3H).
EXAMPLE 36
2-[4-(1-(azepan-1-yl-ethyl)phenyl]-1H-benzimidazole-4-carboxamide
[0187] The title compound as the hydrochloride salt was prepared as
described in EXAMPLE 34B by substituting azepane for pyrrolidine.
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.34 (d, J=8.4 Hz,
2H), 7.85-7.90 (m, 3H), 7.72-7.79 (m, 2H), 7.37 (t, J=7.8 Hz, 1H),
4.65-4.70 (m, 1H) 3.51 (s, 1H), 3.02-3.06 (m, 5H), 2.96 (d, J=6.2
Hz, 2H), 1.73-1.83 (m, 4H), 1.47-1.67 (m, 4H).
EXAMPLE 37
2-[4-(1-(morpholin-4-ylethyl)phenyl]-1H-benzimidazole-4-carboxamide
[0188] The title compound was prepared as described in EXAMPLE 34B
by substituting morpholine for pyrrolidine. The product was
purified by HPLC on a C18 column using 0-100%
acetonitrile/water/0.1% trifluoroacetic acid to provide the title
compound as the trifluoroacetate salt. .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.24 (s, 1H), 8.36 (d, J=8.2 Hz, 2H), 7.89 (d, J=7.6 Hz,
1H), 7.72-7.81 (m, 4H), 7.38 (t, J=7.6 Hz, 1H), 4.61 (d, J=7.6 Hz
1H) 3.60-3.77 (m, 5H), 2.94-3.02 (m 3 Hz), 1.71 (d, J=7.0 Hz,
4H).
EXAMPLE 38
2-{4-[1-(4-methyl-piperazin-1-yl)ethyl]phenyl}-1H-benzimidazole-4-carboxam-
ide
[0189] The title compound was prepared as described in EXAMPLE 34B
by substituting 1-methylpiperazine for pyrrolidine. The product was
purified by HPLC on a C18 column using 0-100%
acetonitrile/water/0.1% trifluoroacetic acid to provide the title
compound as the trifluoroacetate salt. .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.25 (s, 1H), 8.26 (d, J=8.2 Hz, 2H), 7.88 (d, J=6.7 Hz,
1H), 7.73-7.81 (m, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.36 (t, J=7.8 Hz,
1H), 3.75-3.82 (m, 4H), 3.36-3.42 (m, 1H), 3.31 (s, 1H), 3.03 (s,
1H), 2.78 (s, 3H), 2.40 (s, 1H), 1.45 (d, J=6.7 Hz, 3H), 1.03-1.11
(m, 1H).
EXAMPLE 39
2-{4-[1-(4-isopropylpiperazin-1-yl)ethyl]phenyl}-1H-benzimidazole-4-carbox-
amide
[0190] The title compound was prepared as described in EXAMPLE 34B
by substituting 1-isopropylpiperazine for pyrrolidine. The product
was purified by HPLC on a C18 column using 0-100%
acetonitrile/water/0.1% trifluoroacetic acid to provide the title
compound as the trifluoroacetate salt. .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.25 (s, 1H), 8.27 (d, J=8.2 Hz, 2H), 7.88 (d, J=7.6 Hz,
1H), 7.73-7.80 (m, 2H), 7.61 (d, J=8.2 Hz, 2H), 7.37 (t, J=7.8 Hz,
1H), 3.42-3.49 (m, 2H), 3.38 (dd, J=14.0, 7.0 Hz, 3H), 3.07 (s, 3
Hz), 2.41 (s, 1H), 1.48 (d, J=6.7 Hz, 3H), 1.18-1.24 (m, 6H).
EXAMPLE 40
2-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-1H-benzimidazole-4-carboxami-
de
EXAMPLE 40A
(4-bromopheny)pyrrolidin-1-ylmethanone
[0191] A solution of 4-bromobenzoyl chloride (3 g, 13.7 mmol)) in
dichloromethane (25 mL) was cooled to 0.degree. C. and treated with
pyrrolidine (2.5 mL, 30.3 mmol) and triethylamine (2 mL, 14.4
mmol). The mixture was warmed to ambient temperature over 3 hours
and concentrated. The residue was purified by flash chromatography
on silica gel using 10-60% hexane/ethyl acetate to provide the
title compound (3.1 g, 89%). MS (ESI) m/e 256 (M+H).sup.+.
EXAMPLE 40B
1-[1-(4-bromopheny)-1-methylethyl]pyrrolidine
[0192] A solution of EXAMPLE 40A (0.5 g, 2 mmol)) in
tetrahydrofuran (5 mL) was cooled to -15.degree. C. and treated
with zirconium(IV) chloride (0.46 g, 2 mmol). The mixture was
stirred at -15.degree. C. for 30 minutes and a 3M solution of
methylmagnesium bromide in ether (4 mL, 12 mmol) was slowly added.
The mixture was warmed to ambient temperature overnight then cooled
to 0.degree. C. 25% sodium hydroxide was added, the mixture
extracted with dichloromethane, and the organic layer separated,
washed with water and brine, and concentrated. The residue was
purified by flash chromatography on silica gel using 10-60%
hexane/ethyl acetate to give the title compound (0.2 g, 38%). MS
(ESI) m/e 270 (M+H).sup.+.
EXAMPLE 40C
4-(1-methyl-1-pyrrolidin-1-ylethyl)benzaldehyde
[0193] A solution of EXAMPLE 40B (0.4 g, 1.5 mmol)) in
tetrahydrofuran (5 mL) was cooled to -78.degree. C. and treated
with a 1.3 M solution of sec-butyl lithium in cyclohexane (1.8 mL,
2.3 mmol). The mixture was stirred for 30 minutes at -78.degree. C.
and treated with N,N'-dimethylformamide (0.4 mL, 5.2 mmol). The
mixture was warmed to ambient temperature over 1.5 hours, acetic
acid (1 mL) added and the mixture stirred at ambient temperature
for 10 minutes. Water (2 mL) was added and the mixture diluted with
ethyl acetate. The organic layer was separated, washed with
saturated sodium bicarbonate, water and brine, and concentrated.
The residue was purified by flash chromatography on silica gel
using 10-60% hexane/ethyl acetate to give the title compound (0.135
g, 42%). MS (ESI) m/e 218 (M+H).sup.+.
EXAMPLE 40D
2-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-1H-benzimidazole-4-carboxami-
de
[0194] A solution of 2,3-diamino-benzamide dihydrochloride (0.134
g, 0.6 mmol) (2.2 g, 10 mmol) and EXAMPLE 40C (0.13 g, 0.6 mmol) in
methanol (4 mL) was treated with 10% palladium on carbon (0.04 g).
The mixture was refluxed overnight, filtered through celite and
concentrated. The residue was purified by flash chromatography on
silica gel using 0-10% dichloromethane/methanol/0.1% ammonium
hydroxide to provide the title compound. .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.12 (s, 1H), 8.36 (d, J=8.5 Hz, 2H), 8.06 (d, J=8.5 Hz,
2H), 7.90 (d, J=7.3 Hz, 1H), 7.75-7.84 (m, 2H), 7.40 (t, J=7.8 Hz,
1H), 3.39 (s, 1H), 3.17 (s, 2H), 1.82-1.88 (m, 4H), 1.81 (s, 6H)
1.72 (s, 1H), 1.09 (t, J=6.9 Hz, 1H).
EXAMPLE 41
2-[5-(1-morpholin-4-ylethyl)thiophen-2-yl]-1H-benzimidazole-4-carboxamide
EXAMPLE 41A
5-acetylthiophene-2-carboxylic acid
(2-amino-3-carbamoylphenyl)amide
[0195] A solution of 5-acetylthiophene-2-carboxylic acid (1.80 g,
10.55 mmol) in pyridine (12 mL) and N,N'-dimethylformamide (12 mL)
was treated with 1,1'-carbonyldiimidazole (1.88 g, 11.60 mmol) at
45.degree. C. for 4 hours. 2,3-Diaminobenzamide dihydrochloride
(2.36 g, 10.55 mmol) was added and the mixture stirred at ambient
temperature overnight. The mixture was concentrated and the residue
stirred in ethyl acetate and water, filtered, and the yellow solid
washed with water and ethyl acetate and dried to give the title
compound (2.91 g, 91%). MS(APCI): 304 (M+1).sup.+.
EXAMPLE 41B
2-(5-acetylthiophen-2-yl)-1H-benzimidazole-4-carboxamide
[0196] To a solution of EXAMPLE 41A (1.70 g) in hot
N,N'-dimethylformamide (60 mL) was added acetic acid (50 mL) and
the solution heated at 125.degree. C. for 3 hours. After cooling,
the solution was filtered, and the yellow solid washed with
methanol and dried to give the title compound (1.52 g, 95%).
MS(APCI): 286 (M+1).sup.+.
EXAMPLE 41C
2-[5-(1-morpholin-4-ylethyl)thiophen-2-yl]-1H-benzimidazole-4-carboxamide
[0197] A solution of EXAMPLE 41B (100 mg, 0.35 mmol) and morpholine
(61 .mu.L, 0.70 mmol) in dimethylsulfoxide (3 mL) was stirred at
ambient temperature overnight. Zinc chloride (48 mg, 0.35 mmol) was
added and the mixture stirred at ambient temperature for 1 hour.
Sodium cyanoborohydride (44 mg, 0.70 mmol) and methanol (3 mL) were
added and the suspension heated at 80.degree. C. for 2 days. After
cooling, solvent was removed and the residue purified by HPLC
(Zorbax, C-1 8, 250.times.2.54 column, Mobile phase A: 0.1%
trifluoroacetic acid in water; B: 0.1% trifluoroacetic acid in
acetonitrile; 0-100% gradient) to provide the title compound as the
trifluoroacetate salt (77.6 mg, 34%). .sup.1H NMR (CD.sub.3OD):
.delta. 1.89 (d, J=7.2 Hz, 3H), 3.23-3.33 (m, 4H), 3.82-4.06 (m,
4H), 4.93 (q, J=7.0 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.46 (d, J=3.7
Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.85 (d, J=3.7 Hz, 1H), 7.96 (d,
J=7.8 Hz, 1H).
EXAMPLE 42
2-(2-fluoro-4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-be-
nzimidazole-4-carboxamide
[0198] The title compound was prepared as the trifluoroacetate salt
according to the procedure for Example 17G, substituting
(S)-(+)-2-(methoxymethyl)pyrrolidine for
(S)-pyrrolidin-2-ylmethanol. .sup.1H NMR (CD.sub.3OD) .delta.
1.86-1.96 (m, 1H), 1.96-2.09 (m, 1H), 2.11-2.22 (m, 1H), 2.32 (dd,
J=13.1, 6.7 Hz, 1H), 3.34-3.36 (m, 1H), 3.44 (s, 3H), 3.47-3.55 (m,
1H), 3.64 (s, 2H), 3.87 (d, J=4.9 Hz, 1H), 4.38 (d, J=13.1 Hz, 1H),
4.71 (d, J=13.1 Hz, 1H), 7.44 (t, J=7.93 Hz, 1H), 7.53-7.60 (m,
2H), 7.85 (d, J=7.6 Hz, 1H), 8.00 (d, J=6.7 Hz, 1H), 8.45 (t, J=7.9
Hz, 1H).
EXAMPLE 43
2-(2-fluoro-4-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-1H-be-
nzimidazole-4-carboxamide
[0199] The title compound was prepared as the trifluoroacetate salt
according to the procedure for Example 17G, substituting
(R)-(-)-2-(methoxymethyl)pyrrolidine for
(S)-pyrrolidin-2-ylmethanol. .sup.1H NMR (CD.sub.3OD) .delta.
1.86-1.96 (m, 1H) 1.96-2.09 (m, 1H) 2.11-2.22 (m, 1H) 2.32 (dd,
J=13.1, 6.7 Hz, 1H) 3.34-3.36 (m, 1H) 3.44 (s, 3H) 3.47-3.55 (m,
1H), 3.64 (s, 2H), 3.87 (d, J=4.9 Hz, 1H), 4.38 (d, J=13.1 Hz, 1H),
4.71 (d, J=13.1 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.53-7.60 (m, 2H),
7.85 (d, J=7.6 Hz, 1H), 8.00 (d, J=6.7 Hz, 1H), 8.45 (t, J=7.9 Hz,
1H).
* * * * *