U.S. patent application number 13/282826 was filed with the patent office on 2012-02-23 for benzimidazole poly(adp ribose)polymerase inhibitors.
This patent application is currently assigned to ABBOTT LABORATORIES. Invention is credited to Virajkumar B. Gandhi, Vincent L. Giranda, Jianchun Gong, Thomas D. Penning, Gui-Dong Zhu.
Application Number | 20120046303 13/282826 |
Document ID | / |
Family ID | 39828963 |
Filed Date | 2012-02-23 |
United States Patent
Application |
20120046303 |
Kind Code |
A1 |
Gandhi; Virajkumar B. ; et
al. |
February 23, 2012 |
BENZIMIDAZOLE POLY(ADP RIBOSE)POLYMERASE INHIBITORS
Abstract
Compounds which inhibit the activity of
poly(ADP-ribose)polymerase (PARP), compositions containing the
compounds and methods of treating diseases using them are
disclosed.
Inventors: |
Gandhi; Virajkumar B.;
(Gurnee, IL) ; Giranda; Vincent L.; (Gurnee,
IL) ; Gong; Jianchun; (Deerfield, IL) ;
Penning; Thomas D.; (Elmhurst, IL) ; Zhu;
Gui-Dong; (Gurnee, IL) |
Assignee: |
ABBOTT LABORATORIES
Abbott Park
IL
|
Family ID: |
39828963 |
Appl. No.: |
13/282826 |
Filed: |
October 27, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12173213 |
Jul 15, 2008 |
8067613 |
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13282826 |
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60949895 |
Jul 16, 2007 |
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Current U.S.
Class: |
514/255.05 ;
514/322; 514/338; 514/364; 514/365; 514/374; 514/394; 544/405;
546/199; 546/269.4; 546/270.4; 546/271.4; 546/273.4; 548/181;
548/306.1 |
Current CPC
Class: |
A61P 7/04 20180101; A61P
27/02 20180101; A61P 43/00 20180101; A61P 17/00 20180101; A61P
37/06 20180101; A61P 37/08 20180101; A61P 19/06 20180101; C07D
417/14 20130101; A61P 3/08 20180101; A61P 9/10 20180101; A61P 1/04
20180101; A61P 19/02 20180101; A61P 13/12 20180101; A61P 25/28
20180101; A61P 29/00 20180101; C07D 413/14 20130101; A61P 37/00
20180101; A61P 35/00 20180101; C07D 405/14 20130101; A61P 25/00
20180101; A61P 9/00 20180101; A61P 39/02 20180101; A61P 31/14
20180101; A61P 1/16 20180101; A61P 1/00 20180101; A61P 3/10
20180101; C07D 409/14 20130101; A61P 35/04 20180101; A61P 25/16
20180101; A61P 35/02 20180101 |
Class at
Publication: |
514/255.05 ;
546/270.4; 514/338; 544/405; 548/181; 514/365; 546/199; 514/322;
546/273.4; 548/306.1; 514/394; 546/271.4; 514/374; 546/269.4;
514/364 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 31/497 20060101 A61K031/497; A61K 31/427
20060101 A61K031/427; A61K 31/454 20060101 A61K031/454; C07D 409/14
20060101 C07D409/14; A61K 31/4184 20060101 A61K031/4184; C07D
413/14 20060101 C07D413/14; A61K 31/422 20060101 A61K031/422; A61K
31/4245 20060101 A61K031/4245; A61P 37/08 20060101 A61P037/08; A61P
19/02 20060101 A61P019/02; A61P 9/00 20060101 A61P009/00; A61P
35/00 20060101 A61P035/00; A61P 29/00 20060101 A61P029/00; A61P
3/10 20060101 A61P003/10; A61P 19/06 20060101 A61P019/06; A61P 7/04
20060101 A61P007/04; A61P 3/08 20060101 A61P003/08; A61P 1/00
20060101 A61P001/00; A61P 9/10 20060101 A61P009/10; A61P 13/12
20060101 A61P013/12; A61P 35/02 20060101 A61P035/02; A61P 1/16
20060101 A61P001/16; A61P 25/00 20060101 A61P025/00; A61P 37/06
20060101 A61P037/06; A61P 25/16 20060101 A61P025/16; A61P 27/02
20060101 A61P027/02; A61P 31/14 20060101 A61P031/14; A61P 17/00
20060101 A61P017/00; C07D 417/14 20060101 C07D417/14 |
Claims
1-17. (canceled)
18. A compound of Formula III: ##STR00033## or a salt thereof,
wherein A.sup.1 is heteroaryl which is substituted with A.sup.2 and
unfused; A.sup.2 is is heteroaryl; wherein A.sup.2 is unsubstituted
or substituted with one or two or three or four or five
substituents independently selected from R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7,
OC(O)R.sup.7, OC(O)OR.sup.7, NO.sub.2, NH.sub.2, NHR.sup.7,
N(R.sup.7).sub.2, CH.sub.2R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
C(O)N(R.sup.7).sub.2, C(O)NHOH, C(O)NHOR.sup.7,
C(O)NHSO.sub.2R.sup.7, C(O)NR.sup.7SO.sub.2R.sup.7,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2,
CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH, C(N)NH.sub.2,
C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2, CNOH, CNOCH.sub.3, OH, (O),
N.sub.3, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br and I; R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
R.sup.8 is phenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.8A; R.sup.8A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.9 is heteroaryl which
is unfused or fused with benzene, heteroarene or R.sup.9A; R.sup.9A
is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene; R.sup.10 is cycloalkyl, cycloalkenyl,
heterocycloalkyl or heterocycloalkenyl, each of which is unfused or
fused with benzene, heteroarene or R.sup.10A; R.sup.10A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.11 is alkyl, alkenyl, or alkenyl, each of which is
unsubstituted or substituted with one, two, three, four or five
substituents independently selected from R.sup.12, OR.sup.12,
SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, C(O)R.sup.12, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHSO.sub.2R.sup.12, NR.sup.12SO.sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)R.sup.12
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, CN, CF.sub.3, OCF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br and I;
R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16; R.sup.13 is
phenyl which is unfused or fused with benzene, heteroarene or
R.sup.13A; R.sup.13A is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene; R.sup.14 is heteroaryl which is unfused or
fused with benzene, heteroarene or R.sup.14A; R.sup.14A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.15 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.16 is alkyl, alkenyl
or alkenyl, each of which is unsubstituted or substituted with
R.sup.17; and R.sup.17 is phenyl, heteroaryl, cycloalkyl,
cycloalkenyl or heterocycloalkyl.
19. The compound of claim 18, wherein A.sup.1 is selected from the
group consisting of ##STR00034##
20. The compound of claim 18, wherein A.sup.2 is selected from the
group consisting of ##STR00035##
21. The compound of claim 20, wherein A.sup.2 is unsubstituted.
22. The compound of claim 20, wherein A.sup.2 is substituted with
R.sup.10, R.sup.11, or CF.sub.3.
23. The compound of claim 22, wherein A.sup.2 is substituted with
cycloalkyl, heterocycloalkyl, alkyl, or CF.sub.3.
24. The compound of claim 18 which is
2-(4-pyridin-3-yl-1,3-thiazol-2-yl)-1H-benzimidazole-4-carboxamide,
2-(4-pyridin-4-yl-1,3-thiazol-2-yl)-1H-benzimidazole-4-carboxamide,
2-(4-methyl-2-pyrazin-2-yl-1,3-thiazol-5-yl)-1H-benzimidazole-4-carboxami-
de,
2-(2-thien-2-yl-1,3-thiazol-4-yl)-1H-benzimidazole-4-carboxamide,
2-(5-pyridin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
2-(5-pyrazin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
2-(5-pyrimidin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
2-(5-pyridin-3-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
2-(5-pyridin-4-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
2-(5-(1H-pyrrol-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide,
2-[6-(1,3-oxazol-5-yl)pyridin-3-yl]-1H-benzimidazole-4-carboxamide;
2-[5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1H-benzimidazole-4-carboxamide;
2-{5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl}-1H-benzimida-
zole-4-carboxamide;
2-[5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1H-benzimidazole-4-carb-
oxamide; or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising a compound of claim 17
and pharmaceutically acceptable excipient.
Description
[0001] This application claims priority to U.S. Provisional Patent
Application Ser. No. 60/949,895 filed Jul. 16, 2007.
FIELD OF THE INVENTION
[0002] This invention comprises compounds which inhibit the
activity of poly(ADP-ribose)polymerase (PARP), compositions
containing the compounds and methods of treating diseases using
them.
BACKGROUND OF THE INVENTION
[0003] Poly(ADP-ribose)polymerase (PARP) has an essential role in
facilitating DNA repair, controlling RNA transcription, mediating
cell death and regulating immune response. PARP inhibitors have
demonstrated efficacy in disease models for allergic encephalitis,
arthritis, cardiac and kidney toxicities from doxorubicin-based and
platinum-based antineoplastic agents, carcinoma of the breast,
central nervous system inflammation, cervical carcinoma, colon
cancer, diabetes and complications therefrom, glioblastoma, gout,
hemmorhagic shock, hypoglycemia, inflammatory bowel disease,
ischemia reperfusion injury associated with myocardial infarction,
kidney disease, leukemia, liver toxicity following acetominophen
overdose, lymphoma, melanoma, multiple sclerosis, myocardial
infarction, neural trauma, organ transplantation, Parkinsons
disease, potentiation of cytotoxic cancer therapy, pulmonary
fibrosis, reperfusion of the eye, gut, kidney and skeletal muscle,
retroviral infection, rheumatoid arthritis, sepsis, septic shock,
skin damage secondary to sulfur mustards, stroke and other neural
trauma and uveitis.
[0004] In cancer models, PARP inhibitors have been shown to
potentiate radiation and chemotherapy by increasing apoptosis of
cancer cells, limiting tumor growth, decreasing metastasis, and
prolonging the survival of tumor-bearing animals. There is
therefore an existing need in the therapeutic arts for PARP
inhibitors.
SUMMARY OF THE INVENTION
[0005] The present invention has numerous embodiments. One
embodiment this invention, therefore, comprises compounds that are
PARP inhibitors, the compounds having Formula I
##STR00001##
and therapeutically acceptable salts, prodrugs, esters, amides,
salts of prodrugs, salts of esters, and salts of amides thereof,
wherein
[0006] A.sup.1 is heteroaryl which is substituted with A.sup.2 and
unfused or fused with benzene, heteroarene or R.sup.1A; R.sup.1A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0007] A.sup.2 is heteroaryl, heterocycloalkyl, or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0008] B.sup.1 is hydrogen, R.sup.3, CO(O)R.sup.3A, C(O)NH.sub.2,
C(O)NHR.sup.3A, C(O)N(R.sup.3A).sub.2, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3A or SO.sub.2N(R.sup.3A).sub.2;
[0009] R.sup.3A is alkyl or cycloalkyl;
[0010] R.sup.3 is alkyl or alkenyl each of which is unsubstituted
or substituted with one or two of independently selected R.sup.4,
OR.sup.4, NH.sub.2, NHR.sup.4, N(R.sup.4).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.4, C(O)N(R.sup.4).sub.2 or OH;
[0011] R.sup.4 is alkyl or cycloalkyl;
[0012] C.sup.1, D.sup.1, E.sup.1 are each independently hydrogen,
NO.sub.2, CN, R.sup.5, OR.sup.5, CO(O)R.sup.5, C(O)NH.sub.2,
C(O)NHR.sup.5, C(O)N(R.sup.5).sub.2, NH.sub.2, NHR.sup.5,
N(R.sup.5).sub.2, OH, F, Cl, Br or I;
[0013] R.sup.5 is alkyl, alkenyl or alkynyl; each of which is
unsubstituted or substituted with one or two of independently
selected R.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, OH, F, Cl, Br or
I;
[0014] R.sup.6 is alkyl or cycloalkyl;
[0015] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.7, OR.sup.7, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7, OC(O)R.sup.7,
OC(O)OR.sup.7, NO.sub.2, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
CH.sub.2R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2,
C(O)NHOH, C(O)NHOR.sup.7, C(O)NHSO.sub.2R.sup.7,
C(O)NR.sup.7SO.sub.2R.sup.7, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7,
SO.sub.2N(R.sup.7).sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H,
C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2, CNOH,
CNOCH.sub.3, OH, (O), N.sub.3, CF.sub.3, CF.sub.2CF.sub.3,
OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0016] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0017] R.sup.8 is phenyl each of which is unfused or fused with
benzene, heteroarene or R.sup.8A; R.sup.8A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0018] R.sup.9 heteroaryl which is unfused or fused with benzene,
heteroarene or R.sup.9A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0019] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0020] R.sup.11 is alkyl, alkenyl, or alkenyl, each of which is
unsubstituted or substituted with one, two, three, four or five of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, C(O)R.sup.12, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHSO.sub.2R.sup.12, NR.sup.12SO.sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)R.sup.12
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, CN, CF.sub.3, OCF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0021] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0022] R.sup.13 is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0023] R.sup.14 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0024] R.sup.15 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0025] R.sup.16 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with R.sup.17; and
[0026] R.sup.17 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or
heterocycloalkyl.
[0027] Another embodiment pertains to a compound selected from the
group consisting of
[0028]
2-(4-pyridin-3-yl-1,3-thiazol-2-yl)-1H-benzimidazole-4-carboxamide,
[0029]
2-(4-pyridin-4-yl-1,3-thiazol-2-yl)-1H-benzimidazole-4-carboxamide,
[0030]
2-(4-methyl-2-pyrazin-2-yl-1,3-thiazol-5-yl)-1H-benzimidazole-4-car-
boxamide,
[0031]
2-(2-thien-2-yl-1,3-thiazol-4-yl)-1H-benzimidazole-4-carboxamide,
[0032]
2-(2-piperidin-4-yl-1,3-thiazol-4-yl)-1H-benzimidazole-4-carboxamid-
e,
[0033]
2-(2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl)-1H-benzimidazole-4--
carboxamide,
[0034]
2-(2-(1-isopropylpiperidin-4-yl)-1,3-thiazol-4-yl)-1H-benzimidazole-
-4-carboxamide,
[0035]
2-(2-(1-propylpiperidin-4-yl)-1,3-thiazol-4-yl)-1H-benzimidazole-4--
carboxamide,
[0036]
2-(2-(1-cyclobutylpiperidin-4-yl)-1,3-thiazol-4-yl)-1H-benzimidazol-
e-4-carboxamide,
[0037]
2-(5-pyridin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
[0038]
2-(5-pyrazin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
[0039]
2-(5-pyrimidin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
[0040]
2-(5-pyridin-3-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
[0041]
2-(5-pyridin-4-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
[0042]
2-(5-(1H-pyrrol-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide,
[0043]
2-(5-((2R)-pyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxami-
de,
[0044]
2-(5-((2R)-1-methylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-c-
arboxamide,
[0045]
2-(5-((2R)-1-isopropylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole--
4-carboxamide,
[0046]
2-(5-((2R)-1-propylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-c-
arboxamide,
[0047]
2-(5-((2R)-1-(cyclopropylmethyl)pyrrolidin-2-yl)thien-2-yl)-1H-benz-
imidazole-4-carboxamide,
[0048]
2-(5-((2R)-1-cyclobutylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-
-4-carboxamide,
[0049]
2-(5-((2R)-1-cyclopentylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazol-
e-4-carboxamide,
[0050]
2-(5-((2R)-1-cyclohexylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-
-4-carboxamide,
[0051]
2-(5-((2R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-2-yl)thien-2-yl)-1H-
-benzimidazole-4-carboxamide,
[0052]
2-(5-((2R)-1-(pyridin-2-ylmethyl)pyrrolidin-2-yl)thien-2-yl)-1H-ben-
zimidazole-4-carboxamide,
[0053]
2-(5-((2R)-1-(pyridin-4-ylmethyl)pyrrolidin-2-yl)thien-2-yl)-1H-ben-
zimidazole-4-carboxamide,
[0054]
2-(5-((2R)-1-isobutylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-
-carboxamide,
[0055]
2-(5-piperidin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
[0056]
2-(5-(1-methylpiperidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxa-
mide,
[0057]
2-(5-(1-propylpiperidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxa-
mide,
[0058]
2-(5-(1-(cyclopropylmethyl)piperidin-2-yl)thien-2-yl)-1H-benzimidaz-
ole-4-carboxamide,
[0059]
2-(5-(1-cyclobutylpiperidin-2-yl)thien-2-yl)-1H-benzimidazole-4-car-
boxamide,
[0060]
2-(5-(1-isobutylpiperidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carbo-
xamide,
[0061]
2-(5-pyrrolidin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide,
[0062]
2-(5-(1-methylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carbox-
amide,
[0063]
2-(5-(1-isopropylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-car-
boxamide,
[0064]
2-(5-(1-propylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carbox-
amide,
[0065]
2-(5-(1-(cyclopropylmethyl)pyrrolidin-2-yl)thien-2-yl)-1H-benzimida-
zole-4-carboxamide,
[0066]
2-(5-(1-isobutylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carb-
oxamide,
[0067]
2-(5-(1-cyclobutylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-ca-
rboxamide,
[0068]
2-(5-(1-cyclopentylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-c-
arboxamide,
[0069]
2-(5-(1-cyclohexylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-ca-
rboxamide,
[0070]
2-(6-pyrrolidin-2-ylpyridin-3-yl)-1H-benzimidazole-4-carboxamide;
[0071]
2-[6-(1-isopropylpyrrolidin-2-yl)pyridin-3-yl]-1H-benzimidazole-4-c-
arboxamide;
[0072]
2-[6-(1-isobutylpyrrolidin-2-yl)pyridin-3-yl]-1H-benzimidazole-4-ca-
rboxamide;
[0073]
2-[6-(1-cyclobutylpyrrolidin-2-yl)pyridin-3-yl]-1H-benzimidazole-4--
carboxamide;
[0074]
2-[6-(1-cyclopentylpyrrolidin-2-yl)pyridin-3-yl]-1H-benzimidazole-4-
-carboxamide;
[0075]
2-[6-(1-cyclohexylpyrrolidin-2-yl)pyridin-3-yl]-1H-benzimidazole-4--
carboxamide;
[0076]
2-[6-(1-tetrahydro-2H-pyran-4-ylpyrrolidin-2-yl)pyridin-3-yl]-1H-be-
nzimidazole-4-carboxamide;
[0077]
2-[6-(1,3-oxazol-5-yl)pyridin-3-yl]-1H-benzimidazole-4-carboxamide;
[0078]
2-[5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1H-benzimidazole-4-carboxa-
mide;
[0079]
2-{5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl}-1H-ben-
zimidazole-4-20 carboxamide;
[0080]
2-[5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1H-benzimidazole--
4-carboxamide;
and therapeutically acceptable salts, prodrugs, esters, amides,
salts of prodrugs, salts of esters, and salts of amides
thereof.
[0081] Still another embodiment comprises compositions comprising a
therapeutically acceptable amount of compound having Formula I, or
a salt, prodrug or salt of a prodrug thereof, and an excipient.
[0082] Still another embodiment comprises methods of inhibiting
poly(ADP-ribose)polymerase in a mammal comprising administering
thereto a therapeutically acceptable amount of a compound having
Formula I, or a salt, prodrug or salt of a prodrug thereof.
[0083] Still another embodiment comprises methods of treating
cancer in a mammal comprising administering thereto a
therapeutically acceptable amount of a compound having Formula
I,
##STR00002##
or a salt, prodrug or salt of a prodrug thereof, wherein
[0084] A.sup.1 is heteroaryl which is substituted with A.sup.2 and
unfused or fused with benzene, heteroarene or R.sup.1A; R.sup.1A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0085] A.sup.2 is heteroaryl, heterocycloalkyl, or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0086] B.sup.1 is hydrogen, R.sup.3, CO(O)R.sup.3A, C(O)NH.sub.2,
C(O)NHR.sup.3A, C(O)N(R.sup.3A).sub.2, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3A or SO.sub.2N(R.sup.3A).sub.2;
[0087] R.sup.3A is alkyl or cycloalkyl;
[0088] R.sup.3 is alkyl or alkenyl each of which is unsubstituted
or substituted with one or two of independently selected R.sup.4,
OR.sup.4, NH.sub.2, NHR.sup.4, N(R.sup.4).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.4, C(O)N(R.sup.4).sub.2 or OH;
[0089] R.sup.4 is alkyl or cycloalkyl;
[0090] C.sup.1, D.sup.1, E.sup.1 are each independently hydrogen,
NO.sub.2, CN, R.sup.5, OR.sup.5, CO(O)R.sup.5, C(O)NH.sub.2,
C(O)NHR.sup.5, C(O)N(R.sup.5).sub.2, NH.sub.2, NHR.sup.5,
N(R.sup.5).sub.2, OH , F, Cl, Br or I;
[0091] R.sup.5 is alkyl, alkenyl or alkynyl; each of which is
unsubstituted or substituted with one or two of independently
selected R.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, OH, F, Cl, Br or
I;
[0092] R.sup.6 is alkyl or cycloalkyl;
[0093] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.7, OR.sup.7, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7, OC(O)R.sup.7,
OC(O)OR.sup.7, NO.sub.2, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
CH.sub.2R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2,
C(O)NHOH, C(O)NHOR.sup.7, C(O)NHSO.sub.2R.sup.7,
C(O)NR.sup.7SO.sub.2R.sup.7, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7,
SO.sub.2N(R.sup.7).sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H,
C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2, CNOH,
CNOCH.sub.3, OH, (O), N.sub.3, CF.sub.3, CF.sub.2CF.sub.3,
OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0094] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0095] R.sup.8 is phenyl each of which is unfused or fused with
benzene, heteroarene or R.sup.8A; R.sup.8A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0096] R.sup.9 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.9A; R.sup.9A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0097] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0098] R.sup.11 is alkyl, alkenyl, or alkenyl, each of which is
unsubstituted or substituted with one, two, three, four or five of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, C(O)R.sup.12, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHSO.sub.2R.sup.12, NR.sup.12SO.sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)R.sup.12
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, CN, CF.sub.3, OCF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0099] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0100] R.sup.13 is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0101] R.sup.14 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0102] R.sup.15 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0103] R.sup.16 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with R.sup.17; and
[0104] R.sup.17 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or
heterocycloalkyl.
[0105] Still another embodiment comprises methods of treating
allergic encephalitis, arthritis, cardiac and kidney toxicities
from doxorubicin-based and platinum-based antineoplastic agents,
carcinoma of the breast, central nervous system inflammation,
cervical carcinoma, colon cancer, diabetes and complications
therefrom, glioblastoma, gout, hemmorhagic shock, hypoglycemia,
inflammatory bowel disease, ischemia reperfusion injury associated
with myocardial infarction, kidney disease, leukemia, liver
toxicity following acetominophen overdose, lymphoma, melanoma,
multiple sclerosis, myocardial infarction, neural trauma, organ
transplantation, Parkinsons disease, potentiation of cytotoxic
cancer therapy, pulmonary fibrosis, reperfusion of the eye, gut,
kidney and skeletal muscle, retroviral infection, rheumatoid
arthritis, sepsis, septic shock, skin damage secondary to sulfur
mustards, stroke and other neural trauma and uveitis in a mammal
comprising administering thereto a therapeutically acceptable
amount of a compound having Formula I
##STR00003##
or a salt, prodrug or salt of a prodrug thereof, wherein
[0106] A.sup.1 is heteroaryl which is substituted with A.sup.2 and
unfused or fused with benzene, heteroarene or R.sup.1A; R.sup.1A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0107] A.sup.2 is heteroaryl, heterocycloalkyl, or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0108] B.sup.1 is hydrogen, R.sup.3, CO(O)R.sup.3A, C(O)NH.sub.2,
C(O)NHR.sup.3A, C(O)N(R.sup.3A).sub.2, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3A or SO.sub.2N(R.sup.3A).sub.2;
[0109] R.sup.3A is alkyl or cycloalkyl;
[0110] R.sup.3 is alkyl or alkenyl each of which is unsubstituted
or substituted with one or two of independently selected R.sup.4,
OR.sup.4, NH.sub.2, NHR.sup.4, N(R.sup.4).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.4, C(O)N(R.sup.4).sub.2 or OH;
[0111] R.sup.14 is alkyl or cycloalkyl;
[0112] C.sup.1, D.sup.1, E.sup.1 are each independently hydrogen,
NO.sub.2, CN, R.sup.5, OR.sup.5, CO(O)R.sup.5, C(O)NH.sub.2,
C(O)NHR.sup.5, C(O)N(R.sup.5).sub.2, NH.sub.2, NHR.sup.5,
N(R.sup.5).sub.2, OH, F, Cl, Br or I;
[0113] R.sup.5 is alkyl, alkenyl or alkynyl; each of which is
unsubstituted or substituted with one or two of independently
selected R.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, OH, F, Cl, Br or
I;
[0114] R.sup.6 is alkyl or cycloalkyl;
[0115] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.7, OR.sup.7, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7, OC(O)R.sup.7,
OC(O)OR.sup.7, NO.sub.2, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
CH.sub.2R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2,
C(O)NHOH, C(O)NHOR.sup.7, C(O)NHSO.sub.2R.sup.7,
C(O)NR.sup.7SO.sub.2R.sup.7, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7,
SO.sub.2N(R.sup.7).sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H,
C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2, CNOH,
CNOCH.sub.3, OH, (O), N.sub.3, CF.sub.3, CF.sub.2CF.sub.3,
OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0116] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0117] R.sup.8 is phenyl each of which is unfused or fused with
benzene, heteroarene or R.sup.8A; R.sup.8A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0118] R.sup.9 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.9A; R.sup.9A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0119] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0120] R.sup.11 is alkyl, alkenyl, or alkenyl, each of which is
unsubstituted or substituted with one, two, three, four or five of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, C(O)R.sup.12, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHSO.sub.2R.sup.12, NR.sup.12SO.sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)R.sup.12
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, CN, CF.sub.3, OCF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0121] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0122] R.sup.13 is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0123] R.sup.14 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0124] R.sup.15 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0125] R.sup.16 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with R.sup.17; and
[0126] R.sup.17 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or
heterocycloalkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0127] This detailed description is intended only to acquaint
others skilled in the art with Applicants' invention, its
principles, and its practical application so that others skilled in
the art may adapt and apply the invention in its numerous forms, as
they may be best suited to the requirements of a particular use.
This description and its specific examples are intended for
purposes of illustration only. This invention, therefore, is not
limited to the embodiments described in this patent application,
and may be variously modified.
[0128] Variable moieties of compounds herein are represented by
identifiers (capital letters with numerical and/or alphabetical
superscripts) and may be specifically embodied.
[0129] It is meant to be understood that proper valences are
maintained for all combinations herein, that monovalent moieties
having more than one atom are attached through their left ends, and
that divalent moieties are drawn from left to right.
[0130] It is also meant to be understood that a specific embodiment
of a variable moiety may be the same or different as another
specific embodiment having the same identifier.
[0131] The term "alkenyl," as used herein, means monovalent,
straight or branched chain hydrocarbon moieties having one or more
than one carbon-carbon double bonds, such as C.sub.2-alkenyl,
C.sub.3-alkenyl, C.sub.4-alkenyl, C.sub.5-alkenyl, C.sub.6-alkenyl
and the like.
[0132] The term "alkenylene," as used herein, means divalent,
straight or branched chain hydrocarbon moieties having one or more
than one carbon-carbon double bonds, such as C.sub.2-alkenylene,
C.sub.3-alkenylene, C.sub.4-alkenylene, C.sub.5-alkenylene,
C.sub.6-alkenylene and the like.
[0133] The term "alkyl," as used herein, means monovalent,
saturated, straight or branched chain hydrocarbon moieties, such as
C.sub.1-alkyl, C.sub.2-alkyl, C.sub.3-alkyl, C.sub.4-alkyl,
C.sub.5-alkyl, C.sub.6-alkyl and the like.
[0134] The term "alkylene," as used herein, means divalent,
saturated, straight or branched chain hydrocarbon moieties, such as
C.sub.1-alkylene, C.sub.2-alkylene, C.sub.3-alkylene,
C.sub.4-alkylene, C.sub.5-alkylene, C.sub.6-alkylene and the
like.
[0135] The term "alkynyl," as used herein, means monovalent,
straight or branched chain hydrocarbon moieties having one or more
than one carbon-carbon triple bonds, such as C.sub.2-alkynyl,
C.sub.3-alkynyl, C.sub.4-alkynyl, C.sub.5-alkynyl, C.sub.6-alkynyl
and the like.
[0136] The term "alkynylene," as used herein, means divalent,
straight or branched chain hydrocarbon moieties having one or more
than one carbon-carbon triple bonds, such as C.sub.2-alkynylene,
C.sub.3-alkynylene, C.sub.4-alkynylene, C.sub.5-alkynylene,
C.sub.6-alkynylene and the like.
[0137] The term "cycloalkane," as used herein, means saturated
cyclic or bicyclic hydrocarbon moieties, such as
C.sub.4-cycloalkane, C.sub.5-cycloalkane, C.sub.6-cycloalkane,
C.sub.7-cycloalkane, C.sub.8-cycloalkane, C.sub.9-cycloalkane,
C.sub.10-cycloalkane, C.sub.11-cycloalkane, C.sub.12-cycloalkane
and the like.
[0138] The term "cycloalkyl," as used herein, means monovalent,
saturated cyclic and bicyclic hydrocarbon moieties, such as
C.sub.3-cycloalkyl, C.sub.4-cycloalkyl, C.sub.5-cycloalkyl,
C.sub.6-cycloalkyl, C.sub.7-cycloalkyl, C.sub.8-cycloalkyl,
C.sub.9-cycloalkyl, C.sub.10-cycloalkyl, C.sub.11-cycloalkyl,
C.sub.12-cycloalkyl and the like.
[0139] The term "cycloalkene," as used herein, means cyclic and
bicyclic hydrocarbon moieties having one or more than one
carbon-carbon double bonds, such as C.sub.5-cycloalkene,
C.sub.6-cycloalkene, C.sub.7-cycloalkene, C.sub.8-cycloalkene,
C.sub.9-cycloalkene, C.sub.10-cycloalkene, C.sub.11-cycloalkene,
C.sub.12-cycloalkene and the like.
[0140] The term "cycloalkenyl," as used herein, means monovalent,
cyclic hydrocarbon moieties having one or more than one
carbon-carbon double bonds, such as C.sub.4-cycloalkenyl,
C.sub.5-cycloalkenyl, C.sub.6-cycloalkenyl, C.sub.7-cycloalkenyl,
C.sub.8-cycloalkenyl, C.sub.9-cycloalkenyl, C.sub.10-cycloalkenyl,
C.sub.11-cycloalkenyl, C.sub.12-cycloalkenyl and the like.
[0141] The term "heteroarene," as used herein, means furan,
imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole,
1,2,5-oxadiazole, 1,3,4-oxadiazole, oxazole, pyrazine, pyrazole,
pyridazine, pyridine, pyrimidine, pyrrole, thiazole,
1,3,4-thiadiazole, thiophene, triazine and 1,2,3-triazole.
[0142] The term "heteroaryl," as used herein, means furanyl,
imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
tetrazolyl, thiazolyl, 1,2,3-thiadiazoyl, 1,2,5-thiadiazolyl,
1,3,4-thiadiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl.
[0143] The term "heterocycloalkane," as used herein, means
cycloalkane having one or two or three CH.sub.2 moieties replaced
with independently selected O, S, S(O), SO.sub.2 or NH and one or
two CH moieties unreplaced or replaced with N and also means
cycloalkane having one or two or three CH.sub.2 moieties unreplaced
or replaced with independently selected O, S, S(O), SO.sub.2 or NH
and one or two CH moieties replaced with N.
[0144] The term "heterocycloalkene," as used herein, means
cycloalkene having one or two or three CH.sub.2 moieties replaced
with independently selected O, S, S(O), SO.sub.2 or NH and one or
two CH moieties unreplaced or replaced with N and also means
cycloalkene having one or two or three CH.sub.2 moieties unreplaced
or replaced with independently selected O, S, S(O), SO.sub.2 or NH
and one or two CH moieties replaced with N.
[0145] The term "heterocycloalkyl," as used herein, means
cycloalkyl having one or two or three CH.sub.2 moieties replaced
with independently selected O, S, S(O), SO.sub.2 or NH and one or
two CH moieties unreplaced or replaced with N and also means
cycloalkyl having one or two or three CH.sub.2 moieties unreplaced
or replaced with independently selected O, S, S(O), SO.sub.2 or NH
and one or two CH moieties replaced with N.
[0146] The term "heterocycloalkenyl," as used herein, means
cycloalkenyl having one or two or three CH.sub.2 moieties replaced
with independently selected O, S, S(O), SO.sub.2 or NH and one or
two CH moieties unreplaced or replaced with N and also means
cycloalkenyl having one or two or three CH.sub.2 moieties
unreplaced or replaced with independently selected O, S, S(O),
SO.sub.2 or NH and one or two CH moieties replaced with N.
[0147] The term "perhaloalkenyl," as used herein, means alkenyl
wherein each of the hydrogens thereof are replaced by independently
selected F, Cl or Br.
[0148] The term "perhaloalkyl," as used herein, means alkyl wherein
each of the hydrogens thereof are replaced by independently
selected F, Cl or Br.
[0149] The term "perhaloalkynyl," as used herein, means alkynyl
wherein each of the hydrogens thereof are replaced by independently
selected F, Cl or Br.
[0150] The term "spiroalkenyl," as used herein, means divalent
hydrocarbon moieties having both ends attached to the same carbon
atom and having one or more than one carbon-carbon double bonds,
such as C.sub.3-spiroalkenyl, C.sub.4-spiroalkenyl,
C.sub.5-spiroalkenyl and the like.
[0151] The term "spiroalkyl," as used herein, means saturated,
divalent hydrocarbon moieties having both ends attached to the same
carbon atom, such as C.sub.2-spiroalkyl, C.sub.3-spiroalkyl, four
C.sub.4-spiroalkyl, C.sub.5-spiroalkyl and the like.
[0152] The term "spiroheteroalkenyl," as used herein, means
spiroalkenyl having one or two CH.sub.2 moieties replaced with
independently selected O, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N and also means spiroalkenyl
having one or two CH.sub.2 moieties unreplaced or replaced with
independently selected O, S, S(O), SO.sub.2 or NH and one or two CH
moieties replaced with N.
[0153] The term "spiroheteroalkyl," as used herein, means
spiroalkyl having one or two CH.sub.2 moieties replaced with
independently selected O, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N and also means spiroalkyl
having one or two CH.sub.2 moieties unreplaced or replaced with
independently selected O, S, S(O), SO.sub.2 or NH and one or two CH
moieties replaced with N.
[0154] The term "cyclic moiety," as used herein, means benzene,
cycloalkane, cycloalkyl, cycloalkene, cycloalkenyl, heteroarene,
heteroaryl, heterocycloalkane, heterocycloalkyl, heterocycloalkene,
heterocycloalkenyl and phenyl, spiroalkyl, spiroalkenyl,
spiroheteroalkyl and spiroheteroalkenyl.
[0155] Compounds of this invention may contain asymmetrically
substituted carbon atoms in the R or S configuration, wherein the
terms "R" and "S" are as defined in Pure Appl. Chem. (1976) 45,
13-10. Compounds having asymmetrically substituted carbon atoms
with equal amounts of R and S configurations are racemic at those
atoms. Atoms having excess of one configuration over the other are
assigned the configuration in excess, preferably an excess of about
85%-90%, more preferably an excess of about 95%-99%, and still more
preferably an excess greater than about 99%. Accordingly, this
invention is meant to embrace racemic mixtures, relative and
absolute diastereoisomers and the compounds thereof.
[0156] Compounds of this invention may also contain carbon-carbon
double bonds or carbon-nitrogen double bonds in the Z or E
configuration, in which the term "Z" represents the larger two
substituents on the same side of a carbon-carbon or carbon-nitrogen
double bond and the term "E" represents the larger two substituents
on opposite sides of a carbon-carbon or carbon-nitrogen double
bond. The compounds of this invention may also exist as a mixture
of "Z" and "E" isomers.
[0157] Compounds of this invention containing NH, C(O)H, C(O)OH,
C(O)NH.sub.2, OH or SH moieties may have attached thereto
prodrug-forming moieties. The prodrug-forming moieties are removed
by metabolic processes and release the compounds having the freed
NH, C(O)H, C(O)OH, C(O)NH.sub.2, OH or SH in vivo. Prodrugs are
useful for adjusting such pharmacokinetic properties of the
compounds as solubility and/or hydrophobicity, absorption in the
gastrointestinal tract, bioavailability, tissue penetration, and
rate of clearance.
[0158] Metabolites of compounds having Formula I, produced by in
vitro or in vivo metabolic processes, may also have utility for
treating diseases associated with overexpressed or unregulated
poly(ADP-ribose)polymerase.
[0159] Certain precursor compounds of compounds having Formula I
may be metabolized in vitro or in vivo to form compounds having
Formula I and may thereby also have utility for treating diseases
caused or exacerbated by overexpressed or unregulated
poly(ADP-ribose)polymerase.
[0160] Compounds having Formula I may also be radiolabeled with a
radioactive isotope such as a radioactive isotope of carbon (i.e.
.sup.13C), hydrogen (i.e. .sup.3H), nitrogen (i.e. .sup.15N),
phosphorus (i.e. .sup.32P), sulfur (i.e. .sup.35S) or iodide (i.e.
.sup.125I). Radioactive isotopes may be incorporated into the
compounds having Formula I by reacting the same and a radioactive
derivitizing agent or by incorporating a radiolabeled intermediate
into their syntheses. The radiolabeled compounds of Formula I are
useful for both prognostic and diagnostic applications as well as
for in vivo and in vitro imaging.
[0161] Compounds having Formula I may exist as acid addition salts,
basic addition salts or zwitterions. Salts of compounds having
Formula I are prepared during their isolation or following their
purification. Acid addition salts are those derived from the
reaction of a compound having Formula I with acid. Accordingly,
salts including the acetate, adipate, alginate, bicarbonate,
citrate, aspartate, benzoate, benzenesulfonate (besylate),
bisulfate, butyrate, camphorate, camphorsufonate, digluconate,
formate, fumarate, glycerophosphate, glutamate, hemisulfate,
heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
lactobionate, lactate, maleate, mesitylenesulfonate,
methanesulfonate, naphthylenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, phosphate, picrate, propionate,
succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic,
para-toluenesulfonate and undecanoate salts of the compounds having
Formula I are meant to be embraced by this invention. Basic
addition salts of compounds are those derived from the reaction of
the compounds having Formula I with the bicarbonate, carbonate,
hydroxide, or phosphate of cations such as lithium, sodium,
potassium, calcium and magnesium.
[0162] Compounds having Formula I may be administered, for example,
bucally, ophthalmically, orally, osmotically, parenterally
(intramuscularly, intraperintoneally intrasternally, intravenously,
subcutaneously), rectally, topically, transdermally and
vaginally.
[0163] Therapeutically effective amounts of a compound having
Formula I depend on recipient of treatment, disease treated and
severity thereof, composition comprising it, time of
administration, route of administration, duration of treatment,
potency, rate of clearance and whether or not another drug is
co-administered. The amount of a compound having Formula I used to
make a composition to be administered daily to a patient in a
single dose or in divided doses is from about 0.001 to about 200
mg/kg body weight. Single dose compositions contain these amounts
or a combination of submultiples thereof.
[0164] Compounds having Formula I may be administered with or
without an excipient. Excipients include, for example,
encapsulators and additives such as absorption accelerators,
antioxidants, binders, buffers, coating agents, coloring agents,
diluents, disintegrating agents, emulsifiers, extenders, fillers,
flavoring agents, humectants, lubricants, perfumes, preservatives,
propellants, releasing agents, sterilizing agents, sweeteners,
solubilizers, wetting agents and mixtures thereof.
[0165] Compounds having Formula I may be radiolabeled with a
radioactive isotope such as carbon (i.e. .sup.13C), hydrogen (i.e.
.sup.3H), nitrogen (i.e. .sup.15N), phosphorus (i.e. .sup.32P),
sulfur (i.e. .sup.35S), iodide (i.e. .sup.125I) and the like.
Radioactive isotopes may be incorporated into the compounds having
Formula I by reacting the same and a radioactive derivitizing agent
or by incorporating a radiolabeled intermediate into their
syntheses. The radiolabeled compounds of Formula I are useful for
both prognostic and diagnostic applications and for in vivo and in
vitro imaging.
[0166] Compounds having Formula I may be incorporated into devices
such as, but not limited to, arterio-venous grafts, billiary
stents, by-pass grafts, catheters, central nervous system shunts,
coronary stents, drug delivery balloons, peripheral stents and
ureteural stents, each of which may be used in areas such as, but
not limited to, the vasculature for introduction of a compound
having Formula I into selected tissues or organs in the body. One
measure of the effectiveness of compounds having Formula I is
reduction or elimination of device-associated thrombi and
complications associated therewith.
[0167] Compounds having Formula I can used as a radiosensitizers
which enhance the efficacy of radiotherapy. Examples of
radiotherapy include, but are not limited to, external beam
radiotherapy, teletherapy, brachtherapy and sealed and unsealed
source radiotherapy.
[0168] Excipients for preparation of compositions comprising a
compound having Formula I to be administered orally include, for
example, agar, alginic acid, aluminum hydroxide, benzyl alcohol,
benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil,
cellulose, cellulose acetate, cocoa butter, corn starch, corn oil,
cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl
cellulose, ethyl laureate, ethyl oleate, fatty acid esters,
gelatin, germ oil, glucose, glycerol, groundnut oil,
hydroxypropylmethyl celluose, isopropanol, isotonic saline,
lactose, magnesium hydroxide, magnesium stearate, malt, mannitol,
monoglycerides, olive oil, peanut oil, potassium phosphate salts,
potato starch, povidone, propylene glycol, Ringer's solution,
safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium
phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean
oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc,
tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water and
mixtures thereof. Excipients for preparation of compositions
comprising a compound having Formula I to be administered
ophthalmically or orally include, for example, 1,3-butylene glycol,
castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of
sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive
oil, polyethylene glycols, propylene glycol, sesame oil, water and
mixtures thereof. Excipients for preparation of compositions
comprising a compound having Formula I to be administered
osmotically include, for example, chlorofluoro-hydrocarbons,
ethanol, water and mixtures thereof. Excipients for preparation of
compositions comprising a compound having Formula I to be
administered parenterally include, for example, 1,3-butanediol,
castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut
oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's
solution, safflower oil, sesame oil, soybean oil, U.S.P. or
isotonic sodium chloride solution, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound
having Formula I to be administered rectally or vaginally include,
for example, cocoa butter, polyethylene glycol, wax and mixtures
thereof.
[0169] Nicotinamide[2,5',8-3H]adenine dinucleotide and strepavidin
SPA beads were obtained from Amersham Biosciences (UK). Recombinant
Human Poly(ADP-Ribose)Polymerase (PARP), purified from E. coli and
6-Biotin-17-NAD.sup.+, were obtained from Trevigen (Gaithersburg,
Md.). NAD.sup.+, histone, aminobenzamide, 3-aminobenzamide and Calf
Thymus DNA (dcDNA) were obtained from Sigma (St. Louis, Mo.). Stem
loop oligonucleotide containing MCAT sequence was obtained from
Qiagen. The oligos were dissolved to 1 mM in annealing buffer
containing 10 mM Tris HCl (pH 7.5), 1 mM EDTA, and 50 mM NaCl,
incubated for 5 minutes at 95.degree. C. and annealed at 45.degree.
C. for 45 minutes. Histone H1 (95% electrophoretically pure) was
obtained from Roche (Indianapolis, Ind. Biotinylated histone H1 was
prepared by treating the protein with Sulfo-NHS-LC-Biotin (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 1 minute
then incubation at 4.degree. C. for 1 hour. Streptavidin coated
(FlashPlate Plus) microplates were obtained from Perkin Elmer
(Boston, Mass.).
[0170] PARP1 assay was conducted in PARP assay buffer containing 50
mM tris (pH 8.0), 1 mM DTT and 4 mM MgCl.sub.2. PARP reactions
contained 1.5 .mu.M [.sup.3H]-NAD.sup.+ (1.6 .mu.Ci/mmol), 200 nM
biotinylated histone H1, 200 nM slDNA, 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 (1000-fold over its IC.sub.50). 170 .mu.L of the stopped
reaction mixtures were transferred to streptavidin Flash Plates,
incubated for 1 hour and counted using a TopCount microplate
scintillation counter. The K.sub.i data (in nM) for representative
compounds of this invention were determined from inhibition curves
at various substrate concentrations and are shown in TABLE 1.
TABLE-US-00001 TABLE 1 Example PARP-1 (K.sub.i, nM) 1 14.5 2 11.8 3
28 4 20.9 5 32 6 45 7 61 8 50 9 44 10 3.1 11 2 12 9 13 2.4 14 3.2
15 5 16 6 17 10 18 6 19 8 20 5 21 4 22 3 23 8 24 12 25 10 26 6 27 8
28 7 29 14 30 16 31 11 32 23 33 21 34 7 35 7 36 5 37 7 38 6 39 11
40 10 41 5 42 12 43 3 44 41 45 11 46 17 47 14 48 14 49 17 50 0.8 51
1.8 52 14 53 317
[0171] These data demonstrate the utility of representative
compounds having Formula I as inhibitors of
poly(ADP-ribose)polymerase.
[0172] Involvement of PARP in cancer, stroke, ischemia and
inflammation is described in Pharm. Res. 52, 2005. Involvement of
PARP in other disease states is reported in Cancer Chemo.
Pharmacol. 22 (1988), 303; Proc. Natl. Acad. Sci. USA 94 (1997),
679-683 D; Int. J. Immunopharmacol. 17 (1995), 265-271;
Inflammation 20 (1996), 203-215; Rheumatol. Int. 15 (1995),
171-172; Proc. Natl. Acad. Sci. USA 95 (1998), 3867-3872; Eur. J.
Pharmacol. 342 (1998), 67-76 and Nature Medicine (1999),
5314-19.
[0173] Compounds having Formula I are also expected to be useful
when used with alkylating agents, angiogenesis inhibitors,
antibodies, antimetabolites, antimitotics, antiproliferatives,
aurora kinase inhibitors, Bcr-Abl kinase inhibitors, biologic
response modifiers, cyclin-dependent kinase inhibitors, cell cycle
inhibitors, cyclooxygenase-2 inhibitors, leukemia viral oncogene
homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat
shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC)
inhibitors inhibitors, hormonal therapies, immunologicals,
intercalating antibiotics, kinase inhibitors, mammalian target of
rapomycin inhibitors, mitogen-activated extracellular
signal-regulated kinase inhibitors, non-steroidal anti-inflammatory
drugs (NSAID's), platinum chemotherapeutics, polo-like kinase
inhibitors, proteasome inhibitors, purine analogs, pyrimidine
analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids
plant alkaloids, topoisomerase inhibitors and the like.
[0174] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, Cloretazine.TM. (VNP 40101M),
cyclophosphamide, decarbazine, estramustine, fotemustine,
glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,
melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard
N-oxide, ranimustine, temozolomide, thiotepa, treosulfan,
trofosfamide and the like.
[0175] Angiogenesis inhibitors include endothelial-specific
receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth
factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor
(IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors,
matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived
growth factor receptor (PDGFR) inhibitors, thrombospondin analogs
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
[0176] Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680
and the like.
[0177] Bcr-Abl kinase inhibitors include DASATINIB.RTM.
(BMS-354825), GLEEVEC.RTM. (imatinib) and the like.
[0178] CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
[0179] COX-2 inhibitors include ABT-963, ARCOXIA.RTM. (etoricoxib),
BEXTRA.RTM. (valdecoxib), BMS347070, CELEBREX.TM. (celecoxib),
COX-189 (lumiracoxib), CT-3, DERAMAXX.RTM. (deracoxib), JTE-522,
4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole),
MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125,
SD-8381, SVT-2016, S-2474, T-614, VIOXX.RTM. (rofecoxib) and the
like.
[0180] EGFR inhibitors include ABX-EGF, anti-EGFr immunoliposomes,
EGF-vaccine, EMD-7200, ERBITUX.RTM. (cetuximab), HR3, IgA
antibodies, IRESSA.RTM. (gefitinib), TARCEVA.RTM. (erlotinib or
OSI-774), TP-38, EGFR fusion protein, TYKERB.RTM. (lapatinib) and
the like.
[0181] ErbB2 receptor inhibitors include CP-724-714, CI-1033
(canertinib), Herceptin.RTM. (trastuzumab), TYKERB.RTM.
(lapatinib), OMNITARG.RTM. (2C4, petuzumab), TAK-165, GW-572016
(ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine),
APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody,
B7.her2IgG3, AS HER2 trifunctional bispecific antibodies, mAB
AR-209, mAB 2B-1 and the like.
[0182] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[0183] HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101,
CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953,
MYCOGRAB.RTM., NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112,
STA-9090 VER49009 and the like.
[0184] MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901,
PD-98059 and the like.
[0185] mTOR inhibitors include AP-23573, CCI-779, everolimus,
RAD-001, rapamycin, temsirolimus and the like.
[0186] Non-steroidal anti-inflammatory drugs include AMIGESIC.RTM.
(salsalate), DOLOBID.RTM. (diflunisal), MOTRIN.RTM. (ibuprofen),
ORUDIS.RTM. (ketoprofen), RELAFEN.RTM. (nabumetone), FELDENE.RTM.
(piroxicam) ibuprofin cream, ALEVE.RTM. and NAPROSYN.RTM.
(naproxen), VOLTAREN.RTM. (diclofenac), INDOCIN.RTM.
(indomethacin), CLINORIL.RTM. (sulindac), TOLECTIN.RTM. (tolmetin),
LODINE.RTM. (etodolac), TORADOL.RTM. (ketorolac), DAYPRO.RTM.
(oxaprozin) and the like.
[0187] PDGFR inhibitors include C-451, CP-673, CP-868596 and the
like.
[0188] Platinum chemotherapeutics include cisplatin, ELOXATIN.RTM.
(oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN.RTM.
(carboplatin), satraplatin and the like.
[0189] Polo-like kinase inhibitors include BI-2536 and the
like.
[0190] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[0191] VEGFR inhibitors include AVASTIN.RTM. (bevacizumab),
ABT-869, AEE-788, ANGIOZYME.TM., axitinib (AG-13736), AZD-2171,
CP-547,632, IM-862, Macugen (pegaptamib), NEXAVAR.RTM. (sorafenib,
BAY43-9006), pazopanib (GW-786034), (PTK-787, ZK-222584),
SUTENT.RTM. (sunitinib, SU-11248), VEGF trap, vatalanib,
ZACTIMA.TM. (vandetanib, ZD-6474) and the like.
[0192] Antimetabolites include ALIMTA.RTM. (premetrexed disodium,
LY231514, MTA), 5-azacitidine, XELODA.RTM. (capecitabine),
carmofur, LEUSTAT.RTM. (cladribine), clofarabine, cytarabine,
cytarabine ocfosfate, cytosine arabinoside, decitabine,
deferoxamine, doxifluridine, eflornithine, EICAR, enocitabine,
ethnylcytidine, fludarabine, hydroxyurea, 5-fluorouracil (5-FU)
alone or in combination with leucovorin, GEMZAR.RTM. (gemcitabine),
hydroxyurea, ALKERAN.RTM. (melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosate, pelitrexol, pentostatin,
raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,
tegafur, TS-1, vidarabine, UFT and the like.
[0193] Antibiotics include intercalating antibiotics aclarubicin,
actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE.RTM.
(bleomycin), daunorubicin, CAELYX.RTM. or MYOCET.RTM.
(doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS.RTM.
(idarubicin), mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
VALSTAR.RTM. (valrubicin), zinostatin and the like.
[0194] Topoisomerase inhibitors include aclarubicin,
9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan,
BN-80915, CAMPTOSAR.RTM. (irinotecan hydrochloride), camptothecin,
CARDIOXANE.RTM. (dexrazoxine), diflomotecan, edotecarin,
ELLENCE.RTM. or PHARMORUBICIN.RTM. (epirubicin), etoposide,
exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,
mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan,
sobuzoxane, SN-38, tafluposide, topotecan and the like.
[0195] Antibodies include AVASTIN.RTM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, ERBITUX.RTM. (cetuximab),
HUMAX-CD4.RTM. (zanolimumab), IGF1R-specific antibodies,
lintuzumab, PANOREX.RTM. (edrecolomab), RENCAREX.RTM. (WX G250),
RITUXAN.RTM. (rituximab), ticilimumab, trastuzimab and the
like.
[0196] Hormonal therapies include ARIMIDEX.RTM. (anastrozole),
AROMASIN.RTM. (exemestane), arzoxifene, CASODEX.RTM.
(bicalutamide), CETROTIDE.RTM. (cetrorelix), degarelix, deslorelin,
DESOPAN.RTM. (trilostane), dexamethasone, DROGENIL.RTM.,
(flutamide), EVISTA.RTM. (raloxifene), fadrozole, FARESTON.RTM.
(toremifene), FASLODEX.RTM. (fulvestrant), FEMARA.RTM.,
(letrozole), formestane, glucocorticoids, HECTOROL.RTM. or
RENAGEL.RTM. (doxercalciferol), lasofoxifene, leuprolide acetate,
MEGACE.RTM. (megesterol), MIFEPREX.RTM. (mifepristone),
NILANDRON.TM. (nilutamide), NOLVADEX.RTM. (tamoxifen citrate),
PLENAXIS.TM. (abarelix), predisone, PROPECIA.RTM. (finasteride),
rilostane, SUPREFACT.RTM. (buserelin), TRELSTAR.RTM. (luteinizing
hormone releasing hormone (LHRH)), vantas, VETORYL.RTM.,
(trilostane or modrastane), ZOLADEX.RTM. (fosrelin, goserelin) and
the like.
[0197] Deltoids and retinoids include seocalcitol (EB1089, CB1093),
lexacalcitrol (KH1060), fenretinide, PANRETIN.RTM. (aliretinoin),
ATRAGEN.RTM. (liposomal tretinoin), TARGRETIN.RTM. (bexarotene),
LGD-1550 and the like.
[0198] Plant alkaloids include, but are not limited to,
vincristine, vinblastine, vindesine, vinorelbine and the like.
[0199] Proteasome inhibitors include VELCADE.RTM. (bortezomib),
MG132, NPI-0052, PR-171 and the like.
[0200] Examples of immunologicals include interferons and other
immune-enhancing agents. Interferons include interferon alpha,
interferon alpha-2a, interferon alpha-2b, interferon beta,
interferon gamma-1a, ACTIMMUNE.RTM. (interferon gamma-1b), or
interferon gamma-n1, combinations thereof and the like. Other
agents include ALFAFERONE.RTM., BAM-002, BEROMUN.RTM. (tasonermin),
BEXXAR.RTM. (tositumomab), CamPath.RTM. (alemtuzumab), CTLA4
(cytotoxic lymphocyte antigen 4), decarbazine, denileukin,
epratuzumab, GRANOCYTE.RTM. (lenograstim), lentinan, leukocyte
alpha interferon, imiquimod, MDX-010, melanoma vaccine, mitumomab,
molgramostim, MYLOTARG.TM. (gemtuzumab ozogamicin), NEUPOGEN.RTM.
(filgrastim), OncoVAC-CL, OvaRex.RTM. (oregovomab), pemtumomab
(Y-muHMFG1), PROVENGE.RTM., sargaramostim, sizofilan, teceleukin,
TheraCys.RTM., ubenimex, VIRULIZIN.RTM., Z-100, WF-10,
PROLEUKIN.RTM. (aldesleukin), ZADAXIN.RTM. (thymalfasin),
ZENAPAX.RTM. (daclizumab), ZEVALIN.RTM. (90Y-Ibritumomab tiuxetan)
and the like.
[0201] Biological response modifiers are agents that modify defense
mechanisms of living organisms or biological responses, such as
survival, growth, or differentiation of tissue cells to direct them
to have anti-tumor activity and include krestin, lentinan,
sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the
like.
[0202] Pyrimidine analogs include cytarabine (ara C or Arabinoside
C), cytosine arabinoside, doxifluridine, FLUDARA.RTM.
(fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR.RTM.
(gemcitabine), TOMUDEX.RTM. (ratitrexed), TROXATYL.TM.
(triacetyluridine troxacitabine) and the like.
[0203] Purine analogs include LANVIS.RTM. (thioguanine) and
PURI-NETHOL.RTM. (mercaptopurine).
[0204] Antimitotic agents include batabulin, epothilone D
(KOS-862),
N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS 247550), paclitaxel, TAXOTERE.RTM. (docetaxel),
PNU100940 (109881), patupilone, XRP-9881, vinflunine, ZK-EPO and
the like.
[0205] Compounds of the present invention are also intended to be
used as a radiosensitizer that enhances the efficacy of
radiotherapy. Examples of radiotherapy include, but are not limited
to, external beam radiotherapy, teletherapy, brachtherapy and
sealed and unsealed source radiotherapy.
[0206] Additionally, compounds having Formula I may be combined
with other chemotherapeutic agents such as ABRAXANE.TM. (ABI-007),
ABT-100 (farnesyl transferase inhibitor), ADVEXIN.RTM.,
ALTOCOR.RTM. or MEVACOR.RTM. (lovastatin), AMPLIGEN.RTM. (poly
I:poly C12U, a synthetic RNA), APTOSYN.TM. (exisulind), AREDIA.RTM.
(pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE.RTM. (tazarotne),
AVE-8062, BEC2 (mitumomab), cachectin or cachexin (tumor necrosis
factor), canvaxin (vaccine), CeaVac.TM. (cancer vaccine),
CELEUK.RTM. (celmoleukin), CEPLENE.RTM. (histamine
dihydrochloride), CERVARIX.TM. (human papillomavirus vaccine),
CHOP.RTM. (C: CYTOXAN.RTM. (cyclophosphamide); H: ADRIAMYCIN.RTM.
(hydroxydoxorubicin); O: Vincristine (ONCOVIN.RTM.); P:
prednisone), CyPat.TM., combrestatin A4P, DAB(389)EGF or
TransMID-107R.TM. (diphtheria toxins), dacarbazine, dactinomycin,
5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil,
EVIZON.TM. (squalamine lactate), DIMERICINE.RTM. (T4N5 liposome
lotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,
EP0906, GARDASIL.RTM. (quadrivalent human papillomavirus (Types 6,
11, 16, 18) recombinant vaccine), gastrimmune, genasense, GMK
(ganglioside conjugate vaccine), GVAX.RTM. (prostate cancer
vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic
acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox),
IL-13-pseudomonas exotoxin, interferon-.alpha., interferon-.gamma.,
JUNOVAN.TM. or MEPACT.TM. (mifamurtide), lonafarnib,
5,10-methylenetetrahydrofolate, miltefosine
(hexadecylphosphocholine), NEOVASTAT.RTM. (AE-941), NEUTREXIN.RTM.
(trimetrexate glucuronate), NIPENT.RTM. (pentostatin),
ONCONASE.RTM. (a ribonuclease enzyme), ONCOPHAGE.RTM. (melanoma
vaccine treatment), OncoVAX (IL-2 Vaccine), ORATHECIN.TM.
(rubitecan), OSIDEM.RTM. (antibody-based cell drug), OvaRex.RTM.
MAb (murine monoclonal antibody), paditaxel, PANDIMEX.TM. (aglycone
saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and
20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC.RTM.-VF
(investigational cancer vaccine), pegaspargase, PEG Interferon A,
phenoxodiol, procarbazine, rebimastat, REMOVAB.RTM. (catumaxomab),
REVLIMID.RTM. (lenalidomide), RSR13 (efaproxiral), SOMATULINE.RTM.
LA (lanreotide), SORIATANE.RTM. (acitretin), staurosporine
(Streptomyces staurospores), talabostat (PT100), TARGRETIN.RTM.
(bexarotene), Taxoprexin.RTM. (DHA-paclitaxel), TELCYTA.TM.
(TLK286), temilifene, TEMODAR.RTM. (temozolomide), tesmilifene,
thalidomide, THERATOPE.RTM. (STn-KLH), thymitaq
(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline
dihydrochloride), TNFerade.TM. (adenovector: DNA carrier containing
the gene for tumor necrosis factor-.alpha.), TRACLEER.RTM. or
ZAVESCA.RTM. (bosentan), tretinoin (Retin-A), tetrandrine,
TRISENOX.RTM. (arsenic trioxide), VIRULIZIN.RTM., ukrain
(derivative of alkaloids from the greater celandine plant), vitaxin
(anti-alphavbeta3 antibody), XCYTRIN.RTM. (motexafin gadolinium),
XINLAY.TM. (atrasentan), XYOTAX.TM. (paclitaxel poliglumex),
YONDELIS.TM. (trabectedin), ZD-6126, ZINECARD.RTM. (dexrazoxane),
zometa (zolendronic acid), zorubicin and the like.
[0207] It is also expected that compounds having Formula I would
inhibit growth of cells derived from a pediatric cancer or neoplasm
including embryonal rhabdomyosarcoma, pediatric acute lymphoblastic
leukemia, pediatric acute myelogenous leukemia, pediatric alveolar
rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric
anaplastic large cell lymphoma, pediatric anaplastic
medulloblastoma, pediatric atypical teratoid/rhabdoid tumor of the
central nervous system, pediatric biphenotypic acute leukemia,
pediatric Burkitts lymphoma, pediatric cancers of Ewing's family of
tumors such as primitive neuroectodermal rumors, pediatric diffuse
anaplastic Wilm's tumor, pediatric favorable histology Wilm's
tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric
neuroblastoma, pediatric neuroblastoma-derived myelocytomatosis,
pediatric pre-B-cell cancers (such as leukemia), pediatric
osteosarcoma, pediatric rhabdoid kidney tumor, pediatric
rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and
skin cancer and the like (commonly-owned U.S. application Ser. No.
10/988,338), Cancer Res., 2000, 60, 6101-10); and autoimmune
disorders include, acquired immunodeficiency disease syndrome,
autoimmune lymphoproliferative syndrome, hemolytic anemia,
inflammatory diseases, thrombocytopenia and the like (Current
Allergy and Asthma Reports 2003, 3:378-384; Br. J. Haematol. 2000
September; 110(3): 584-90; Blood 2000 Feb. 15; 95(4):1283-92; and
New England Journal of Medicine 2004 September; 351(14):
1409-1418).
[0208] Compounds having Formula I may be made by synthetic chemical
processes, examples of which are shown hereinbelow. 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 such as C(O)OH, C(O) and C(O)H, NH, C(O)NH.sub.2, OH and
SH moieties may be protected and deprotected, as necessary.
[0209] Protecting groups for C(O)OH moieties include, but are not
limited to, acetoxymethyl, allyl, benzoylmethyl, benzyl,
benzyloxymethyl, tert-butyl, tert-butyldiphenylsilyl,
diphenylmethyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl,
diphenylmethylsilyl, ethyl, para-methoxybenzyl, methoxymethyl,
methoxyethoxymethyl, methyl, methylthiomethyl, naphthyl,
para-nitrobenzyl, phenyl, n-propyl, 2,2,2-trichloroethyl,
triethylsilyl, 2-(trimethylsilyl)ethyl,
2-(trimethylsilyl)ethoxymethyl, triphenylmethyl and the like.
[0210] Protecting groups for C(O) and C(O)H moieties include, but
are not limited to, 1,3-dioxylketal, diethylketal, dimethylketal,
1,3-dithianylketal, O-methyloxime, O-phenyloxime and the like.
[0211] Protecting groups for NH moieties include, but are not
limited to, acetyl, alanyl, benzoyl, benzyl (phenylmethyl),
benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc),
3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoryl,
formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl,
phenylacetyl, phthaloyl, succinyl, trichloroethoxycarbonyl,
triethylsilyl, trifluoroacetyl, trimethylsilyl, triphenylmethyl,
triphenylsilyl, para-toluenesulfonyl and the like.
[0212] Protecting groups for OH and SH moieties include, but are
not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl
(Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, 3,4-dimethoxybenzyl,
3,4-dimethoxybenzyloxycarbonyl, 1,1-dimethyl-2-propenyl,
diphenylmethyl, formyl, methanesulfonyl, methoxyacetyl,
4-methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl,
methyl, para-toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl,
2,2,2-trichloroethyl, triethylsilyl, trifluoroacetyl,
2-(trimethylsilyl)ethoxycarbonyl, 2-trimethylsilylethyl,
triphenylmethyl, 2-(triphenylphosphonio)ethoxycarbonyl and the
like.
[0213] A discussion protecting groups is provided in T. H. Greene
and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed.,
John Wiley & Sons, New York (1999).
[0214] The following abbreviations have the meanings indicated.
ADDP means 1,1'-(azodicarbonyl)dipiperidine; AD-mix-.beta. means a
mixture of (DHQD).sub.2PHAL, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3
and K.sub.2SO.sub.4); 9-BBN means 9-borabicyclo[3.3.1]nonane; CDI
means carbonyldiimidazole; (DHQD).sub.2PHAL means hydroquinidine
1,4-phthalazinediyl diethyl ether; DBU means
1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminum
hydride; DIEA means diisopropylethylamine; DMAP means
N,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe
means 1,2-bis(dimethylphosphino)ethane; DMSO means
dimethylsulfoxide; dppb means 1,4-bis(diphenylphosphino)butane;
dppe means 1,2-bis(diphenylphosphino)ethane; dppf means
1,1'-bis(diphenylphosphino)ferrocene; dppm means
1,1-bis(diphenylphosphino)methane; EDAC means
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; Fmoc means
fluorenylmethoxycarbonyl; HATU means
O-(7-azabenzotriazol-1-yl)-N,N'N'N'-tetramethyluronium
hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means
isopropyl alcohol; MP-BH.sub.3 means macroporus triethylammonium
methylpolystyrene cyanoborohydride; PyBOP means
benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate;
TEA means triethylamine; TFA means trifluoroacetic acid; THF means
tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means
N-methylmorpholine; NMP means N-methylpyrrolidine; PPh.sub.3 means
triphenylphosphine; BOC means Di-tert-butyl dicarbonate; C-18 means
dimethyl-octadecylsilane; DCI means chemical ionization for direct
introduction; DME means 1,2-dimethoxyethane; ESI means electrospray
ionization; HPLC means high performance liquid chromatography; MS
means mass spectrometry; as used in reference to .sup.1H NMR, the
symbol ".delta." refers to a .sup.1H NMR chemical shift; as used in
reference to .sup.1H NMR, the abbreviation "br" refers to a broad
.sup.1H NMR signal; as used in reference to .sup.1H NMR, the
abbreviation "d" refers to a doublet .sup.1H NMR peak; as used in
reference to .sup.1H NMR, the abbreviation "dd" refers to a doublet
of doublets .sup.1H NMR peak; as used in reference to .sup.1H NMR,
the abbreviation "m" refers to a multiplet .sup.1H NMR peak; as
used in reference to .sup.1H NMR, the abbreviation "q" refers to a
quartet .sup.1H NMR peak; as used in reference to .sup.1H NMR, the
abbreviation "s" refers to a singlet .sup.1H NMR peak; and as used
in reference to .sup.1H NMR, the abbreviation "t" refers to a
triplet .sup.1H NMR peak.
Compounds of Formula I
[0215] One embodiment comprises compounds of Formula I,
##STR00004##
and therapeutically acceptable salts, prodrugs, esters, amides,
salts of prodrugs, salts of esters, and salts of amides thereof,
wherein
[0216] A.sup.1 is heteroaryl which is substituted with A.sup.2 and
unfused or fused with benzene, heteroarene or R.sup.1A; R.sup.1A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0217] A.sup.2 is heteroaryl, heterocycloalkyl, or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0218] B.sup.1 is hydrogen, R.sup.3, CO(O)R.sup.3A, C(O)NH.sub.2,
C(O)NHR.sup.3A, C(O)N(R.sup.3A).sub.2, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3A or SO.sub.2N(R.sup.3A).sub.2;
[0219] R.sup.3A is alkyl or cycloalkyl;
[0220] R.sup.3 is alkyl or alkenyl each of which is unsubstituted
or substituted with one or two of independently selected R.sup.4,
OR.sup.4, NH.sub.2, NHR.sup.4, N(R.sup.4).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.4, C(O)N(R.sup.4).sub.2 or OH;
[0221] R.sup.4 is alkyl or cycloalkyl;
[0222] C.sup.1, D.sup.1, E.sup.1 are each independently hydrogen,
NO.sub.2, CN, R.sup.5, OR.sup.5, CO(O)R.sup.5, C(O)NH.sub.2,
C(O)NHR.sup.5, C(O)N(R.sup.5).sub.2, NH.sub.2, NHR.sup.5,
N(R.sup.5).sub.2, OH, F, Cl, Br or I;
[0223] R.sup.5 is alkyl, alkenyl or alkynyl; each of which is
unsubstituted or substituted with one or two of independently
selected R.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, OH, F, Cl, Br or
I;
[0224] R.sup.6 is alkyl or cycloalkyl;
[0225] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.7, OR.sup.7, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7, OC(O)R.sup.7,
OC(O)OR.sup.7, NO.sub.2, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
CH.sub.2R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2,
C(O)NHOH, C(O)NHOR.sup.7, C(O)NHSO.sub.2R.sup.7,
C(O)NR.sup.7SO.sub.2R.sup.7, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7,
SO.sub.2N(R.sup.7).sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H,
C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2, CNOH,
CNOCH.sub.3, OH, (O), N.sub.3, CF.sub.3, CF.sub.2CF.sub.3,
OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0226] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0227] R.sup.8 is phenyl each of which is unfused or fused with
benzene, heteroarene or R.sup.8A; R.sup.8A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0228] R.sup.9 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.9A; R.sup.9A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0229] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0230] R.sup.11 is alkyl, alkenyl, or alkenyl, each of which is
unsubstituted or substituted with one, two, three, four or five of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, C(O)R.sup.12, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHSO.sub.2R.sup.12, NR.sup.12SO.sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)R.sup.12
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, CN, CF.sub.3, OCF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0231] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0232] R.sup.13 is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0233] R.sup.14 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0234] R.sup.15 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0235] R.sup.16 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with R.sup.17; and
[0236] R.sup.17 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or
heterocycloalkyl.
Embodiments of Formula I
[0237] Selected subclasses of compounds of interest that fall
within the scope of the compounds of Formula I are shown in the
various embodiments described below, wherein A.sup.1, A.sup.2,
R.sup.1A, R.sup.2A, B.sup.1, R.sup.3, R.sup.3A, R.sup.4, C.sup.1,
D.sup.1, E.sup.1, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A,
R.sup.14A, and R.sup.15A can be as defined for the compounds of
Formula I and as defined in the various embodiments described
throughout this specification.
[0238] In one embodiment of Formula I, exactly one of B.sup.1,
C.sup.1, D.sup.1, and E.sup.1 is hydrogen and the remaining are as
described in Formula I.
[0239] In another embodiment of Formula I, exactly two of B.sup.1,
C.sup.1, D.sup.1, and E.sup.1 are hydrogen and the remaining are as
described in Formula I.
[0240] In another embodiment of Formula I, exactly three of
B.sup.1, C.sup.1, D.sup.1, and E.sup.1 are hydrogen and the
remaining are as described in Formula I.
Embodiments of Formula II
[0241] In one embodiment, the present invention is directed, in
part, to a class of compounds having a structure of Formula II
##STR00005##
and therapeutically acceptable salts, prodrugs, esters, amides,
salts of prodrugs, salts of esters, and salts of amides thereof,
wherein
[0242] A.sup.1 is heteroaryl which is substituted with A.sup.2 and
unfused or fused with benzene, heteroarene or R.sup.1A; R.sup.1A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0243] A.sup.2 is heteroaryl, heterocycloalkyl, or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0244] B.sup.1 is hydrogen, R.sup.3, CO(O)R.sup.3A, C(O)NH.sub.2,
C(O)NHR.sup.3A, C(O)N(R.sup.3A).sub.2, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3A or SO.sub.2N(R.sup.3A).sub.2;
[0245] R.sup.3A is alkyl or cycloalkyl;
[0246] R.sup.3 is alkyl or alkenyl each of which is unsubstituted
or substituted with one or two of independently selected R.sup.4,
OR.sup.4, NH.sub.2, NHR.sup.4, N(R.sup.4).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.4, C(O)N(R.sup.4).sub.2 or OH;
[0247] R.sup.4 is alkyl or cycloalkyl;
[0248] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.7, OR.sup.7, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7, OC(O)R.sup.7,
OC(O)OR.sup.7, NO.sub.2, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
CH.sub.2R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2,
C(O)NHOH, C(O)NHOR.sup.7, C(O)NHSO.sub.2R.sup.7,
C(O)NR.sup.7SO.sub.2R.sup.7, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7,
SO.sub.2N(R.sup.7).sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H,
C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2, CNOH,
CNOCH.sub.3, OH, (O), N.sub.3, CF.sub.3, CF.sub.2CF.sub.3,
OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0249] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0250] R.sup.8 is phenyl each of which is unfused or fused with
benzene, heteroarene or R.sup.8A; R.sup.8A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0251] R.sup.9 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.9A; R.sup.9A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0252] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0253] R.sup.11 is alkyl, alkenyl, or alkenyl, each of which is
unsubstituted or substituted with one, two, three, four or five of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, C(O)R.sup.12, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHSO.sub.2R.sup.12, NR.sup.12SO.sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)R.sup.12
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, CN, CF.sub.3, OCF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0254] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0255] R.sup.13 is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0256] R.sup.14 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0257] R.sup.15 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0258] R.sup.16 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with R.sup.17; and
[0259] R.sup.17 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or
heterocycloalkyl.
[0260] In another embodiment of Formula II, B.sup.1 is H, as
described in Formula III:
##STR00006##
wherein
[0261] A.sup.1 is heteroaryl which is substituted with A.sup.2 and
unfused or fused with benzene, heteroarene or R.sup.1A; R.sup.1A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0262] A.sup.2 is heteroaryl, heterocycloalkyl, or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0263] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.7, OR.sup.7, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7, OC(O)R.sup.7,
OC(O)OR.sup.7, NO.sub.2, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
CH.sub.2R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2,
C(O)NHOH, C(O)NHOR.sup.7, C(O)NHSO.sub.2R.sup.7,
C(O)NR.sup.7SO.sub.2R.sup.7, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7,
SO.sub.2N(R.sup.7).sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H,
C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2, CNOH,
CNOCH.sub.3, OH, (O), N.sub.3, CF.sub.3, CF.sub.2CF.sub.3,
OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0264] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0265] R.sup.8 is phenyl each of which is unfused or fused with
benzene, heteroarene or R.sup.8A; R.sup.8A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0266] R.sup.9 heteroaryl which is unfused or fused with benzene,
heteroarene or R.sup.9A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0267] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.1OA is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0268] R.sup.11 is alkyl, alkenyl, or alkenyl, each of which is
unsubstituted or substituted with one, two, three, four or five of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, C(O)R.sup.12, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHSO.sub.2R.sup.12, NR.sup.12SO.sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)R.sup.12
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, CN, CF.sub.3, OCF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0269] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0270] R.sup.13 is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0271] R.sup.14 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0272] R.sup.15 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0273] R.sup.16 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with R.sup.17; and
[0274] R.sup.17 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or
heterocycloalkyl.
[0275] In another embodiment of Formula II, B.sup.1 is H, as in
Formula III wherein A.sup.1 is heteroaryl which is substituted with
A.sup.2 and unfused or fused with benzene, heteroarene or R.sup.1A;
R.sup.1A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0276] A.sup.2 is is heteroaryl, heterocycloalkyl, or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0277] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.7, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I;
[0278] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0279] R.sup.8 is phenyl each of which is unfused or fused with
benzene, heteroarene or R.sup.8A; R.sup.8A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0280] R.sup.9 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.9A; R.sup.9A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0281] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0282] R.sup.11 is alkyl, alkenyl, or alkenyl, each of which is
unsubstituted or substituted with one, two, three, four or five of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, C(O)R.sup.12, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHSO.sub.2R.sup.12, NR.sup.12SO.sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)R.sup.12
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, CN, CF.sub.3, OCF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0283] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0284] R.sup.13 is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0285] R.sup.14 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0286] R.sup.15 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0287] R.sup.16 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with R.sup.17; and
[0288] R.sup.17 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or
heterocycloalkyl.
Embodiments of A.sup.1 in Formula III
[0289] In one embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; and A.sup.2, R.sup.2A, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A,
R.sup.14A, and R.sup.15A are as described in Formula III wherein
A.sup.1 and A.sup.2 are unsubstituted or substituted as described
in Formula III.
[0290] In another embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; A.sup.2 is heteroaryl or heterocycloalkyl, each
of which is unfused or fused with R.sup.2A; and R.sup.2A, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.8A, R.sup.9A,
R.sup.10A, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A are as described in
Formula III wherein A.sup.1 and A.sup.2 are unsubstituted or
substituted as described in Formula III.
[0291] In another embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; A.sup.2 is heteroaryl or heterocycloalkyl, each
of which is unfused; and R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and
R.sup.15A are as described in Formula III wherein A.sup.1 and
A.sup.2 are unsubstituted or substituted as described in Formula
III.
[0292] In another embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; A.sup.2 is heteroaryl which is unfused or fused
with R.sup.2A; and R.sup.2A, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and
R.sup.15A are as described in Formula III wherein A.sup.1 and
A.sup.2 are unsubstituted or substituted as described in Formula
III.
[0293] In another embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; A.sup.2 is heteroaryl which is unfused; and
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.8A, R.sup.9A,
R.sup.10A, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A are as described in
Formula III wherein A.sup.1 and A.sup.2 are unsubstituted or
substituted as described in Formula III.
[0294] In another embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; A.sup.2 is heterocycloalkyl which is unfused or
fused with R.sup.2A; and R.sup.2A, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A,
R.sup.14A, and R.sup.15A are as described in Formula III wherein
A.sup.1 and A.sup.2 are unsubstituted or substituted as described
in Formula III.
[0295] In another embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; A.sup.2 is heterocycloalkyl which is unfused; and
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.8A, R.sup.9A,
R.sup.10A, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A are as described in
Formula III wherein A.sup.1 and A.sup.2 are unsubstituted or
substituted as described in Formula III.
[0296] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00007##
[0297] wherein A.sup.2, R.sup.2A, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A,
R.sup.14A, and R.sup.15A are as described in Formula III wherein
A.sup.1 and A.sup.2 are unsubstituted or substituted as described
in Formula III.
[0298] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00008##
[0299] wherein A.sup.2 is heteroaryl or heterocycloalkyl, each of
which is unfused or fused with R.sup.2A; and R.sup.2A, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.8A, R.sup.9A,
R.sup.10A, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A are as described in
Formula III wherein A.sup.1 and A.sup.2 are unsubstituted or
substituted as described in Formula III.
[0300] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00009##
[0301] wherein A.sup.2 is heteroaryl or heterocycloalkyl, each of
which is unfused; and R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and
R.sup.15A are as described in Formula III wherein A.sup.1 and
A.sup.2 are unsubstituted or substituted as described in Formula
III.
[0302] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00010##
[0303] wherein A.sup.2 is heteroaryl which is unfused or fused with
R.sup.2A; and R.sup.2A, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and
R.sup.15A are as described in Formula III wherein A.sup.1 and
A.sup.2 are unsubstituted or substituted as described in Formula
III.
[0304] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00011##
[0305] wherein A.sup.2 is heteroaryl which is unfused; and R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.8A, R.sup.9A,
R.sup.10A, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A are as described in
Formula III wherein A.sup.1 and A.sup.2 are unsubstituted or
substituted as described in Formula III.
[0306] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00012##
[0307] wherein A.sup.2 is heterocycloalkyl which is unfused or
fused with R.sup.2A; and R.sup.2A, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A,
R.sup.14A, and R.sup.15A are as described in Formula III wherein
A.sup.1 and A.sup.2 are unsubstituted or substituted as described
in Formula III.
[0308] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00013##
[0309] wherein A.sup.2 is heterocycloalkyl which is unfused; and
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.8A, R.sup.9A,
R.sup.10A, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A are as described in
Formula III wherein A.sup.1 and A.sup.2 are unsubstituted or
substituted as described in Formula III.
Embodiments of A.sup.2 in Formula III
[0310] In one embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; A.sup.2 is selected from the group consisting
of
##STR00014##
wherein R.sup.2A, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A
are as described in Formula III wherein A.sup.1 and A.sup.2 are
unsubstituted or substituted as described in Formula III.
[0311] In another embodiment of Formula III, A.sup.1 is selected
from the groun consisting of
##STR00015##
A.sup.2 is selected from the group consisting of
##STR00016##
wherein R.sup.2A, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A
are as described in Formula III wherein A.sup.1 and A.sup.2 are
unsubstituted or substituted as described in Formula III.
[0312] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00017##
[0313] wherein A.sup.2 is selected from the group consisting
##STR00018##
each of which is unfused; and R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.8A, R.sup.9A, R.sup.10A, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and
R.sup.15A are as described in Formula III wherein A.sup.1 and
A.sup.2 are unsubstituted or substituted as described in Formula
III.
Optional Substituents on Rings
[0314] In one embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; A.sup.2 is selected from the group consisting
of
##STR00019##
wherein R.sup.2A, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.8A,
R.sup.9A, R.sup.10A, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A are as
described in Formula III wherein A.sup.1 and A.sup.2 are
unsubstituted or substituted with R.sup.7 or CF.sub.3 as described
in Formula III.
[0315] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00020##
A.sup.2 is selected from the group consisting of
##STR00021##
wherein R.sup.2A, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.8A,
R.sup.9A, R.sup.10A, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and R.sup.15A are as
described in Formula III wherein A.sup.1 and A.sup.2 are
unsubstituted or substituted with R.sup.7 or CF.sub.3 as described
in Formula III.
[0316] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00022##
[0317] wherein A.sup.2 is selected from the group consisting of
##STR00023##
each of which is unfused; and R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.8A, R.sup.9A, R.sup.10A, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.13A, R.sup.14A, and
R.sup.15A are as described in Formula III wherein A.sup.1 and
A.sup.2 are unsubstituted or substituted with R.sup.7 or CF.sub.3
as described in Formula III.
[0318] In one embodiment of Formula III, A.sup.1 is heteroaryl,
which is unfused; A.sup.2 is selected from the group consisting
of
##STR00024##
wherein A.sup.1 and A.sup.2 are unsubstituted or substituted with
R.sup.7 or CF.sub.3 as described in Formula III; each R.sup.7 is
R.sup.10 or R.sup.11; R.sup.10 is cycloalkyl or heterocycloalkyl;
each of which is unfused; each R.sup.11 is alkyl which is
unsubstituted or substituted with R.sup.12; each R.sup.12 is
R.sup.14 or R.sup.15; each of which is unfused; R.sup.14 is
heteroaryl and R.sup.15 is cycloalkyl each of which which are
unfused.
[0319] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00025##
A.sup.2 is selected from the group consisting of
##STR00026##
wherein A.sup.1 and A.sup.2 are unsubstituted or substituted with
R.sup.7 or CF.sub.3 as described in Formula III; each R.sup.7 is
R.sup.10 or R.sup.11; R.sup.10 is cycloalkyl or heterocycloalkyl;
each of which is unfused; each R.sup.11 is alkyl which is
unsubstituted or substituted with R.sup.12; each R.sup.12 is
R.sup.14 or R.sup.15; each of which is unfused; R.sup.14 is
heteroaryl and R.sup.15 is cycloalkyl each of which is unfused.
[0320] In another embodiment of Formula III, A.sup.1 is selected
from the group consisting of
##STR00027##
[0321] wherein A.sup.2 is selected from the group consisting
##STR00028##
each of which is unfused; wherein A.sup.1 and A.sup.2 are
unsubstituted or substituted with R.sup.7 or CF.sub.3 as described
in Formula III; each R.sup.7 is R.sup.10 or R.sup.11; R.sup.10 is
cycloalkyl or heterocycloalkyl; each of which is unfused; each
R.sup.11 is alkyl which is unsubstituted or substituted with
R.sup.12; each R.sup.12 is R.sup.14 or R.sup.15; each of which is
unfused; R.sup.14 is heteroaryl and R.sup.15 is cycloalkyl each of
which is unfused.
Schemes
[0322] The starting materials used herein are commercially
available or may be prepared by routine methods well known to those
of ordinary skill in the art. The compounds of the present
invention may be prepared using the methods illustrated in the
general synthetic schemes and experimental procedures detailed
below. The general synthetic schemes are presented for purposes of
illustration and are not intended to be limiting.
##STR00029##
[0323] As shown in SCHEME 1, compounds having formula (1) can be
converted to compounds having formula (3) by reacting the former,
compounds having Formula (2), wherein X is H, I, Br, Cl, or
OSO.sub.2CF.sub.3, 1,1'-carbonyldiimidazole and pyridine followed
by reacting the product therefrom and glacial acetic acid.
##STR00030##
[0324] As shown in SCHEME 2, compounds having formula (3) wherein X
is I, Br, Cl, or OSO.sub.2CF.sub.3, can be converted to compounds
having Formula I using methods such as those described in Palladium
Reagents And Catalysts: New Perspectives For The 21st Century, By
J. Tsuji, John Wiley & Sons, Ltd., Chichester, 2004, 1-670.
##STR00031##
[0325] As shown in SCHEME 3, compounds having formula (2) can be
converted to compounds having formula (5) using methods such as
those described in Tsuji, op. cit.
##STR00032##
[0326] As shown in SCHEME 4, compounds having formula (4) can be
converted to compounds having Formula I by reacting the former,
compounds having formula (6), and a base. Bases include sodium
hydride, potassium carbonate and the like. The reaction is
typically run in a solvent such as DMF or THF at low temperatures
between about 0.degree. C. and 25.degree. C.
[0327] The following examples are presented to provide what is
believed to be the most useful and readily understood description
of procedures and conceptual aspects of this invention.
EXAMPLE 1
2-(4-pyridin-3-yl-1,3-thiazol-2-yl)-1H-benzimidazole-4-carboxamide
[0328] To a mixture of 2-(3-pyridyl)-1,3-thiazole-4-carboxylic acid
(300 mg) in pyridine (5 mL) and DMF (5 mL) at ambient temperature
was added CDI (248 mg). The mixture was heated at 40.degree. C. for
2 hours, treated with 2,3-diaminobenzamide dihydrochloride (326
mg), stirred at ambient temperature for 16 hours and concentrated.
The concentrate was heated in glacial acetic acid (20 mL) at
110.degree. C. for 2 hours, cooled and concentrated. The
concentrate was partitioned between ethyl acetate and sodium
bicarbonate solution, and the solid that precipitated was filtered
and washed with water and ethyl acetate. .sup.1H NMR (DMSO-d.sub.6)
.delta. 7.38 (t, J=7.8 Hz, 1H), 7.60-7.67 (m, 1H), 7.78 (d, J=7.8
Hz, 1H), 7.81 (brs, 1H), 7.90 (dd, J=7.46, 1.0 Hz, 1H), 8.44-8.50
(m, 1H), 8.74-8.76 (m, 1H), 8.74 (s, 1H), 9.29 (brs, 1H), 9.34 (d,
J=1.7 Hz, 1H), 13.44 (brs, 1H).
EXAMPLE 2
2-(4-pyridin-4-yl-1,3-thiazol-2-yl)-1H-benzimidazole-4-carboxamide
[0329] This example was prepared as described in EXAMPLE 1,
substituting 2-(4-pyridyl)-1,3-thiazole-4-carboxylic acid for
2-(3-pyridyl)-1,3-thiazole-4-carboxylic acid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.38 (t, J=7.8 Hz, 1H), 7.78 (d, J=8.1 Hz,
1H), 7.83 (brs, 1H), 7.91 (d, J=7.8 Hz, 1H), 8.05-8.06 (m, 1H),
8.07-8.08 (m, 1H), 8.80-8.81 (m, 1H), 8.81-8.83 (m, 2H), 9.28 (brs,
1H), 13.48 (brs, 1H).
EXAMPLE 3
2-(4-methyl-2-pyrazin-2-yl-1,3-thiazol-5-yl)-1H-benzimidazole-4-carboxamid-
e
[0330] This example was prepared as described in EXAMPLE 1,
substituting 4-methyl-2-(2-pyrazinyl)-1,3-thiazole-5-carboxylic
acid for 2-(3-pyridyl)-1,3-thiazole-4-carboxylic acid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.89 (s, 3H) 7.37 (t, J=7.8 Hz, 1H), 7.75
(s, 1H), 7.77 (brs, 1H), 7.89 (d, J=7.7 Hz, 1H), 8.74-8.76 (m, 1H),
8.78 (d, J=2.8 Hz, 1H), 9.08 (brs, 1H), 9.34 (d, J=1.5 Hz, 1H),
13.09 (brs, 1H).
EXAMPLE 4
2-(2-thien-2-yl-1,3-thiazol-4-yl)-1H-benzimidazole-4-carboxamide
[0331] This example was prepared as described in EXAMPLE 1,
substituting 2-(2-thienyl)-1,3-thiazole-4-carboxylic acid for
2-(3-pyridyl)-1,3-thiazole-4-carboxylic acid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.23 (t, J=4.3 Hz, 1H), 7.36 (t, J=7.7 Hz,
1H), 7.75 (d, J=7.7 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.81 (s, 1H),
7.82 (brs, 1H), 7.89 (d, J=7.4 Hz, 1H), 8.57 (s, 1H), 9.27 (brs,
1H), 13.30 (brs, 1H).
EXAMPLE 5
2-(2-piperidin-4-yl-1,3-thiazol-4-yl)-1H-benzimidazole-4-carboxamide
[0332] To a solution of
2-(1-(tertert-butoxycarbonyl)piperid-4-yl)-1,3-thiazole-4-carboxylic
acid (1.03 g) in pyridine (8 mL) and DMF (8 mL) at ambient
temperature was added CDI (562 mg). The mixture was heated at
40.degree. C. for 2 hours, treated with 2,3-diaminobenzamide
dihydrochloride (739 mg), stirred at ambient temperature for 16
hours and concentrated. The concentrate was stirred in glacial
acetic acid (30 mL) at 110.degree. C. for 2 hours, cooled and
concentrated. The concentrate was stirred in dichloromethane (20
mL) and TFA (8 mL) at ambient temperature for 1 hour, treated with
acetonitrile and concentrated. The concentrate was purified by HPLC
(Zorbax C-8, 0.1% TFA/acetonitrile/water). The product was
dissolved in dichloromethane (5 mL) and methanol (5 mL), treated
with 1M hydrochloric acid in ether (10 mL) and concentrated .sup.1H
NMR (DMSO-d.sub.6) .delta. 1.93-2.09 (m, 2H), 2.26-2.37 (m, 2H),
3.02-3.16 (m, 2H), 3.38-3.47 (m, 2H), 3.49-3.55 (m, 1H), 7.38 (t,
J=7.8 Hz, 1H), 7.77 (d, J=7.1 Hz, 1H), 7.80 (s, 1H), 7.90 (d, J=7.5
Hz, 1H), 8.64 (s, 1H), 8.72 (brs, 1H), 8.94 (brs, 1H), 9.11 (brs,
1H).
EXAMPLE 6
2-(2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl)-1H-benzimidazole-4-carboxa-
mide
[0333] To a solution of EXAMPLE 5 (50 mg) in methanol (8 mL) was
added 37 wt % formaldehyde in water (28 .mu.L) and TEA (21 .mu.L).
The solution was stirred for 1 hour, treated with sodium
cyanoborohydride (28 mg) and zinc (II) chloride (20 mg), stirred
for 60 hours and was concentrated. The concentrate was purified by
HPLC (Zorbax C-8, 0.1% TFA/acetonitrile/water). The salt was
dissolved in dichloromethane (2 mL) and methanol (2 mL), treated
with 1M hydrochloric acid in ether (4 mL) and concentrated. .sup.1H
NMR (DMSO-d.sub.6) .delta. 2.12-2.23 (m, 2H), 2.32-2.41 (m, 2H),
2.78 (d, J=4.6 Hz, 3H), 3.10-3.20 (m, 2H), 3.41-3.48 (m, 1H),
3.50-3.59 (m, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.80-7.82 (m, 1H),
7.82-7.85 (m, 1H), 7.94 (d, J=6.7 Hz, 1H), 8.82 (brs, 1H), 8.98
(brs, 1H), 10.84 (brs, 1H).
EXAMPLE 7
2-(2-(1-isopropylpiperidin-4-yl)-1,3-thiazol-4-yl)-1H-benzimidazole-4-carb-
oxamide
[0334] This example was prepared as the hydrochloride salt as
described in EXAMPLE 6, substituting acetone for formaldehyde.
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.33 (d, J=6.7 Hz, 6H),
2.27-2.43 (m, 4H), 3.12-3.23 (m, 2H), 3.46-3.56 (m, 4H), 7.46 (t,
J=7.8 Hz, 1H), 7.80-7.83 (m, 1H), 7.83-7.87 (m, 1H), 7.94 (d, J=7.6
Hz, 1H), 8.85 (brs, 1H), 8.97 (brs, 1H), 10.68 (brs, 1H).
EXAMPLE 8
2-(2-(1-propylpiperidin-4-yl)-1,3-thiazol-4-yl)-1H-benzimidazole-4-carboxa-
mide
[0335] This example was prepared as the hydrochloride salt as
described in EXAMPLE 6, substituting propionaldehyde for
formaldehyde. .sup.1H NMR (DMSO-d.sub.6) .delta. 0.94 (t, J=7.3 Hz,
3H), 1.73-1.83 (m, 2H), 2.17-2.28 (m, 2H), 2.33-2.40 (m, 2H),
2.97-3.05 (m, 2H), 3.05-3.17 (m, 2H), 3.43-3.51 (m, 1H), 3.56-3.65
(m, 2H), 7.44 (t, J=7.8 Hz, 1H), 7.79-7.82 (m, 1H), 7.82-7.85 (m,
1H), 7.93 (d, J=7.6 Hz, 1H), 8.79 (brs, 1H), 9.00 (brs, 1H), 10.69
(brs, 1H).
EXAMPLE 9
2-(2-(1-cyclobutylpiperidin-4-yl)-1,3-thiazol-4-yl)-1H-benzimidazole-4-car-
boxamide
[0336] This example was prepared as the hydrochloride salt as
described in EXAMPLE 6, substituting cyclobutanone for
formaldehyde. .sup.1H NMR (DMSO-d.sub.6) .delta. 1.71-1.81 (m, 2H),
2.16-2.26 (m, 4H), 2.33-2.41 (m, 3H), 2.42-2.48 (m, 2H), 2.89-2.98
(m, 2H), 3.44-3.50 (m, 2H), 3.60-3.67 (m, 1H), 7.45 (t, J=7.8 Hz,
1H), 7.79-7.82 (m, 1H), 7.82-7.86 (m, 1H), 7.94 (d, J=7.0 Hz, 1H),
8.82 (brs, 1H), 8.98 (brs, 1H), 11.24 (brs, 1H).
EXAMPLE 10
2-(5-pyridin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
EXAMPLE 10A
2-(5-bromothiophen-2-yl)-1H-benzimidazole-4-carboxamide
[0337] This example was prepared as described in EXAMPLE 1,
substituting 5-bromo-2-thiophenecarboxylic acid for
2-(3-pyridyl)-1,3-thiazole-4-carboxylic acid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.33 (brs, 1H), 7.39 (d, J=3.1 Hz, 1H), 7.71
(m, 3H), 7.84 (brs, 1H), 8.99 (brs, 1H), 13.48 (brs, 1H).
EXAMPLE 10B
2-(5-pyridin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
[0338] A mixture of EXAMPLE 10A (184 mg), tri-ortho-tolylphosphine
(52 mg), tris(dibenzylidineacetone)dipalladium(0) (52 mg),
2-(tri-n-butylstannyl)pyridine (420 mg) and triethylamine (238
.mu.L) in DMF (5 mL) was heated at 75.degree. C. overnight. The
mixture was cooled, diluted with dichloromethane and flash
chromatographed (with 0-15% methanol in 2:1 ethyl acetate/hexane).
Additional purification by HPLC (Zorbax, C-18, Mobile phase A: 0.1%
TFA in H.sub.2O; B: 0.1% TFA in acetonitrile; 0-100% gradient)
provided the title compound. .sup.1H NMR (DMSO-d.sub.6) .delta.
7.34-7.39 (m, 2H), 7.74-7.76 (m, 2H), 7.86-7.95 (m, 3H), 8.00-8.05
(m, 1H), 8.02 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 9.04 (brs, 1H).
EXAMPLE 11
2-(5-pyrazin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
[0339] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 10B, substituting
2-(tri-n-butylstannyl)pyrazine for 2-(tri-n-butylstannyl)pyridine.
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.35 (t, J=7.8 Hz, 1H), 7.73 (s,
1H), 7.75 (d, J=7.7 Hz, 1H), 7.86 (d, J=7.7 Hz, 1H), 8.03 (d, J=3.7
Hz, 1H), 8.09 (d, J=4.0 Hz, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.63 (s,
1H), 8.99 (s, 1H), 9.31 (d, J=1.2 Hz, 1H).
EXAMPLE 12
2-(5-pyrimidin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
[0340] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 10B, substituting
2-(tri-n-butylstannyl)pyrimidine for
2-(tri-n-butylstannyl)pyridine. .sup.1H NMR (DMSO-d.sub.6) .delta.
7.37 (t, J=7.8 Hz, 1H), 7.44 (t, J=4.9 Hz, 1H), 7.75 (s, 1H), 7.77
(d, J=7.4 Hz, 1H), 7.88 (d, J=7.4 Hz, 1H), 8.02-8.06 (m, 2H), 8.87
(d, J=4.9 Hz, 2H), 9.04 (s, 1H).
EXAMPLE 13
2-(5-pyridin-3-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
[0341] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 10B, substituting
3-(tri-n-butylstannyl)pyridine for 2-(tri-n-butylstannyl)pyridine.
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.37 (t, J=7.6 Hz, 1H), 7.67
(dd, J=7.9, 4.9 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.82 (s, 1H), 7.87
(d, J=4.0 Hz, 1H), 7.88 (s, 1H), 8.05 (d, J=3.7 Hz, 1H), 8.39 (d,
J=8.24 Hz, 1H), 8.65 (d, J=4.9 Hz, 1H), 8.99 (brs, 1H), 9.13 (d,
J=2.1 Hz, 1H).
EXAMPLE 14
2-(5-pyridin-4-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
[0342] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 10B, substituting
4-(tri-n-butylstannyl)pyridine for 2-(tri-n-butylstannyl)pyridine.
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.38 (t, J=7.7 Hz, 1H), 7.78 (d,
J=7.1 Hz, 1H), 7.81 (brs, 1H), 7.88 (d, J=7.7 Hz, 1H), 8.11 (d,
J=6.4 Hz, 2H), 8.16 (d, J=7.7 Hz, 1H), 8.77 (d, J=6.4 Hz, 2H), 8.94
(brs, 1H).
EXAMPLE 15
2-(5-(1H-pyrrol-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide
[0343] To EXAMPLE 10A (100 mg),
1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (100 mg) and
dichlorobis(triphenylphosphine)palladium(II) (21 mg) in
1,2-dimethoxyethane/water/ethanol (7/3/2, 10 mL) was added 2M
sodium carbonate solution (1.5 mL). The mixture was heated at
80.degree. C. for 1 hour and concentrated. The concentrate was
partitioned between ethyl acetate and brine, and the organic phase
was washed with brine, dried over magnesium sulfate, filtered and
concentrated. The concentrate in THF (10 mL) was treated TFA (1 mL)
and stirred overnight and concentrated. The concentrate was
purified by HPLC (Zorbax, C-18, Mobile phase A: 0.1% TFA in water;
B: 0.1% TFA in acetonitrile; 0-100% gradient). .sup.1H NMR
(DMSO-d.sub.6) .delta. 6.15-6.17 (m, 1H), 6.53-6.54 (m, 1H),
6.93-6.94 (m, 1H), 7.19-7.43 (m, 3H), 7.72 (d, J=7.0 Hz, 1), 7.79
(s, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.92 (d, J=3.7 Hz, 1H), 9.02 (s,
1H), 11.57 (s, 1H).
EXAMPLE 16
2-(5-((2R)-pyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide
EXAMPLE 16A
(R)-tert-butyl
2-(5-methoxycarbonylthiophen-2-yl)pyrrolidine-1-carboxylate
[0344] To a solution of N-Boc-pyrrolidine (3 mL) and (-)-sparteine
(3.9 mL) in tert-butyl methyl ether (36 mL) at -78.degree. C. was
added 1.4M sec-butyl lithium in cyclohexane (12.21 mL). The
solution was stirred for 3 hours and 1M zinc chloride in ether
(10.2 mL) was added. The mixture was stirred for 30 minutes and
warmed to ambient temperature for 30 minutes. Methyl
5-bromothiophene-2-carboxylate (3.15 g), tri-tert-butylphosphine
tetrafluoroborate (249 mg) and palladium(II) acetate (153 mg) were
added, and the mixture was stirred at ambient temperature
overnight, treated with concentrated ammonium hydroxide (1 mL) and
stirred for 30 minutes, and filtered through diatomaceous earth
(Celite.RTM.). The filtrate was washed with 0.5M hydrochloric acid
solution and water and concentrated. The concentrate was flash
chromatographed on silica gel with ethyl acetate/hexane.
EXAMPLE 16B
(R)-2-(5-carboxythiophen-2-yl)pyrrolidine-1-carboxylic acid
tert-butyl ester
[0345] To a mixture of EXAMPLE 16A (2.8 g) in THF (20 mL) was added
lithium hydroxide monohydrate (500 mg) in water (5 mL). The mixture
stirred at ambient temperature overnight and partitioned between
ethyl acetate and 0.5 M hydrochloric acid. The extract was washed
with water, dried over magnesium sulfate, filtered and
concentrated.
EXAMPLE 16C
(R)-tert-butyl
2-(5-(4-carbamoyl-1H-benzimidazol-2-yl)thiophen-2-yl)pyrrolidine-1-carbox-
ylate
[0346] To a solution of EXAMPLE 16B (2.4 g) in pyridine (20 mL) and
DMF (20 mL) was added CDI (1.6 g), and the mixture was stirred at
40.degree. C. for 1 hour. 2,3-Diaminobenzamide dihydrochloride (1.8
g) was added, and the mixture stirred at ambient temperature
overnight and concentrated. The concentrate was stirred in of
acetic acid (20 mL) at 80.degree. C. for 4 hours and concentrated.
The concentrate was partitioned between ethyl acetate and saturated
sodium bicarbonate solution, and the extract was washed with water
and concentrated. The concentrate was purified by flash
chromatography on silica gel with 40-80% ethyl acetate in
hexane.
EXAMPLE 16D
2-(5-((2R)-pyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide
[0347] A solution of EXAMPLE 16C (2.2 g) in TFA (50 mL) was stirred
at ambient temperature for 30 minutes. After concentration, the
concentrate was purified by HPLC (Zorbax, C-18, Mobile phase A:
0.1% TFA in water; B: 0.1% TFA in acetonitrile; 0-100% gradient).
.sup.1H NMR (CD.sub.3OD) .delta. 2.19-2.29 (m, 1H), 2.28-2.41 (m,
2H), 2.55-2.67 (m, 1H), 3.43-3.56 (m, 2H), 5.01 (dd, J=9.3, 6.9 Hz,
1H), 7.36 (d, J=3.7 Hz, 1H), 7.39 (d, J=4.6 Hz, 1H), 7.71 (d, J=7.6
Hz, 1H), 7.79 (d, J=3.7 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H).
EXAMPLE 17
2-(5-((2R)-1-methylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxam-
ide
[0348] A solution of EXAMPLE 16D (50 mg) in methanol (20 mL) was
treated with 37 wt % formaldehyde in water (114 .mu.L) and stirred
overnight. Sodium cyanoborohydride (315 mg) was added, and the
solution was stirred for 3 hours and concentrated. The concentrate
was dissolved in methanol and TFA, and purified by HPLC (Zorbax
C-8, 0.1% TFA/acetonitrile/water). .sup.1H NMR (CD.sub.3OD) .delta.
2.30 (m, 2H), 2.47 (m, 1H), 2.74 (m, 1H), 2.94 (s, 3H), 3.31-3.40
(m, 1H), 3.88 (m, 1H), 4.81 (m, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.51
(d, J=3.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.86 (d, J=4.0 Hz, 1H),
7.95 (d, J=7.6 Hz, 1H).
EXAMPLE 18
2-(5-((2R)-1-isopropylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carbo-
xamide
[0349] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting acetone for formaldehyde.
.sup.1H NMR (CD.sub.3OD) .delta. 1.40 (dd, J=11.6, 6.7 Hz, 6H),
2.26-2.31 (m, 2H), 2.35-2.48 (m, 1H), 2.62-2.68 (m, 1H), 3.40-3.47
(m, 1H), 3.55-3.73 (m, 2H), 4.98-5.10 (m, 1H), 7.39 (t, J=7.8 Hz,
1H), 7.50 (d, J=4.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.84 (d, J=4.0
Hz, 1H), 7.95 (d, J=7.6 Hz, 1H).
EXAMPLE 19
2-(5-((2R)-1-propylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxam-
ide
[0350] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting propionaldehyde for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 0.99 (t, J=6.9 Hz,
3H), 1.59-1.73 (m, 1H), 1.75-1.85 (m, 1H), 2.25-2.37 (m, 2H),
2.36-2.49 (m, 1H), 2.60-2.75(m, 1H), 3.02-3.13 (m, 1H), 3.18-3.30
(m, 1H), 3.31-3.42 (m, 1H), 3.80-3.98 (m, 1H), 4.78-4.89 (m, 1H),
7.40 (t, J=7.8 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.74 (d, J=7.9 Hz,
1H), 7.86 (d, J=4.0 Hz, 1H), 7.95 (d, J=6.7 Hz, 1H).
EXAMPLE 20
2-(5-((2R)-1-(cyclopropylmethyl)pyrrolidin-2-yl)thien-2-yl)-1H-benzimidazo-
le-4-carboxamide
[0351] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting cyclopropanecarbaldehyde for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 0.24-0.33 (m, 1H),
0.40-0.45 (m, 1H), 0.65-0.79 (m, 2H), 1.01-1.17 (m, 2H), 2.26-2.38
(m, 2H), 2.38-2.49 (m, 1H), 2.63-2.76 (m, 1H), 3.03-3.10 (m, 1H),
3.11-3.20 (m, 1H), 3.38-3.49 (m, 1H), 3.95-4.05 (m, 1H), 7.39 (t,
J=7.8 Hz, 1H), 7.49 (d, J=3.7 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.84
(d, J=4.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H).
EXAMPLE 21
2-(5-((2R)-1-cyclobutylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carb-
oxamide
[0352] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting cyclobutanone for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 1.76-1.89 (m, 2H),
1.95-2.04 (m, 1H), 2.12-2.22 (m, 1H), 2.23-2.35 (m, 4H),
2.40-2.45(m, 1H), 2.63-2.76 (m, 1H), 3.25-3.36 (m, 2H),
3.70-3.75(m, 1H), 3.93-4.05 (m, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.47
(d, J=3.7 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.82 (d, J=4.0 Hz, 1H),
7.95 (d, J=7.6 Hz, 1H).
EXAMPLE 22
2-(5-((2R)-1-cyclopentylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-car-
boxamide
[0353] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting cyclopentanone for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 1.60-1.69 (m, 2H),
1.73-1.91 (m, 3H), 2.02-2.13 (m, 1H), 2.12-2.24 (m, 1H), 2.27-2.36
(m, 2H), 2.35-2.48 (m, 2H), 2.60-2.74 (m, 1H), 3.38-3.54 (m, 1H),
3.66-3.76 (m, 1H), 3.78-3.89 (m, 1H), 4.94-5.07 (m, 1H), 7.39 (t,
J=7.9 Hz, 1H), 7.49 (d, J=4.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.83
(d, J=4.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H).
EXAMPLE 23
2-(5-((2R)-1-cyclohexylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carb-
oxamide
[0354] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting cyclohexanone for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 1.17-1.26 (m, 1H),
1.27-1.45 (m, 2H), 1.45-1.68 (m, 3H), 1.67-1.95 (m, 2H), 1.85-1.93
(m, 1H), 1.94-2.09 (m, 2H), 2.10-2.20 (m, 1H), 2.22-2.34 (m, 1H),
2.34-2.47 (m, 1H), 2.59-2.72 (m, 1H), 3.44-3.55 (m, 1H), 3.59-3.71
(m, 1H), 5.10-5.20 (m, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.50 (d, J=3.7
Hz, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.85 (d, J=4.0 Hz, 1H), 7.95 (d,
J=7.6 Hz, 1H).
EXAMPLE 24
2-(5-((2R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-2-yl)thien-2-yl)-1H-benzim-
idazole-4-carboxamide
[0355] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting tetrahydro-pyran-4-one for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 1.70-1.77 (m, 1H),
1.77-1.91 (m, 2H), 1.95-2.03 (m, 1H), 2.05-2.19 (m, 1H), 2.25-2.37
(m, 1H), 2.37-2.50 (m, 2H), 2.57-2.75 (m, 1H), 3.37-3.51 (m, 1H),
3.59-3.74 (m, 2H), 3.90-3.97 (m, 1H), 3.97-4.04 (m, 1H), 4.04-4.12
(m, 1H), 5.10-5.19 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.52 (d, J=3.7
Hz, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.85 (d, J=4.0 Hz, 1H), 7.95 (d,
J=7.6 Hz, 1H).
EXAMPLE 25
2-(5-((2R)-1-(pyridin-2-ylmethyl)pyrrolidin-2-yl)thien-2-yl)-1H-benzimidaz-
ole-4-carboxamide
[0356] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting pyridine-2-carbaldehyde for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 2.25-2.38 (m, 2H),
2.42-2.54 (m, 1H), 2.66-2.80 (m, 1H), 3.39-3.52 (m, 1H), 3.68-3.79
(m, 1H), 4.42 (d, J=7.7 Hz, 1H), 4.55 (d, J=7.7 Hz, 1H), 5.09 (dd,
J=9.8, 7.3 Hz, 1H), 7.38 (d, J=3.7 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H),
7.41-7.46 (m, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.69-7.75 (m, 1H), 7.77
(d, J=4.0 Hz, 1H), 7.84-7.92 (m, 1H), 7.95 (dd, J=7.6, 1.2 Hz, 1H),
8.63 (d, J=4.0 Hz, 1H).
EXAMPLE 26
2-(5-((2R)-1-(pyridin-4-ylmethyl)pyrrolidin-2-yl)thien-2-yl)-1H-benzimidaz-
ole-4-carboxamide
[0357] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting pyridine-4-carbaldehyde for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 2.03-2.21 (m, 3H),
2.40-2.58 (m, 1H), 2.65-2.80 (m, 1H), 3.31-3.38 (m, 1H), 3.98 (d,
J=15.6 Hz, 1H), 4.34 (d, J=15.6 Hz, 1H), 4.39 (t, J=7.0 Hz, 1H),
7.28 (d, J=3.7 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.74 (d, J=7.0 Hz,
1H), 7.79 (d, J=4.0 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 8.00 (d, J=6.4
Hz, 2H), 8.73 (d, J=6.7 Hz, 2H).
EXAMPLE 27
2-(5-((2R)-1-isobutylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carbox-
amide
[0358] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting 2-methyl-propionaldehyde for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 1.00 (dd, J=13.7,
6.7 Hz, 6H), 2.01-2.13 (m, 1H), 2.28-2.38 (m, 2H), 2.38-2.52 (m,
1H), 2.59-2.74 (m, 1H), 3.00-3.12 (m, 2), 3.32-3.41 (m, 1H),
3.90-4.12 (m, 1H), 4.80-4.92 (m, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.52
(d, J=3.7 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.86 (d, J=4.0 Hz, 1H),
7.96 (d, J=7.6 Hz, 1H).
EXAMPLE 28
2-(5-piperidin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
EXAMPLE 28A
methyl 5-(pyridin-2-yl)thiophene-2-carboxylate
[0359] To methyl 5-bromo-thiophene-2-carboxylate (2 g),
tri-2-furylphosphine (400 mg), and
tris(dibenzylidineacetone)dipalladium(0) (400 mg) was added DMF (50
mL), 2-(tributylstannyl)pyridine (4 g) and TEA (1 mL) The mixture
was heated at 80.degree. C. for 7 hours, cooled and partitioned
between ethyl acetate and brine. The aqueous phase was extracted
with ethyl acetate, and the extract was dried, filtered and
concentrated. The concentrate was flash chromatographed on silica
gel with a 20-70% ethyl acetate in hexane.
EXAMPLE 28B
methyl 5-(piperidin-2-yl)thiophene-2-carboxylate
[0360] EXAMPLE 28A (1.7 g) in methanol (100 mL) and 10% palladium
on carbon (170 mg) was stirred under 60 psi of hydrogen until all
starting material was consumed, filtered and concentrated.
EXAMPLE 28C
benzyl
2-(5-(methoxycarbonyl)thiophen-2-yl)piperidine-1-carboxylate
[0361] To a mixture of EXAMPLE 28B (0.3 g), potassium carbonate
(0.36 g), dioxane (20 mL) and water (5 mL) was added benzyl
chloroformate (0.23 mL), and the mixture stirred for 4 hours.
Piperazine was added, and the mixture stirred for 30 minutes and
partitioned between ethyl acetate and brine. The extract was washed
with brine, dried over magnesium sulfate, filtered and
concentrated. The concentrate was flash chromatographed on silica
gel with 10-50% ethyl acetate in hexane.
EXAMPLE 28D
5-(1-(benzyloxycarbonyl)piperidin-2-yl)thiophene-2-carboxylic
acid
[0362] To EXAMPLE 28C (0.4 g) in THF (10 mL) was added lithium
hydroxide hydrate (132 mg) in water (3 mL). The mixture was stirred
at ambient temperature overnight and partitioned between ethyl
acetate and 0.5 M hydrochloric acid. The extract was washed with
water, dried over magnesium sulfate, filtered, and concentrated.
The concentrate was flash chromatographed silica gel withethyl
acetate.
EXAMPLE 28E
benzyl
2-(5-(4-carbamoyl-1H-benzimidazol-2-yl)thiophen-2-yl)piperidine-1-c-
arboxylate
[0363] To a solution of EXAMPLE 28D (0.35 g) in pyridine (10 mL)
and DMF (10 mL) was added CDI (0.23 g), and the mixture was heated
at 40.degree. C. for 1 hour. 2,3-Diaminobenzamide dichloride (0.22
g) was added, and the mixture stirred at ambient temperature
overnight and concentrated. The concentrate was stirred in acetic
acid (20 mL) at 80.degree. C. for 4 hours and concentrated. The
concentrate was partitioned between ethyl acetate and saturated
sodium bicarbonate solution. The extract was washed with water and
concentrated, and the concentrate was flash chromatographed on
silica gel with 40-80% ethyl acetate in hexane.
EXAMPLE 28F
2-(5-piperidin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
[0364] A solution of EXAMPLE 28E (0.21 g) in TFA (10 mL) was
stirred at ambient temperature overnight and concentrated. The
concentrate was purified by HPLC (Zorbax, C-18, Mobile phase A:
0.1% TFA in water; B: 0.1% TFA in acetonitrile; 0-100% gradient).
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.62-1.76 (m, 1H), 1.84-1.96 (m,
2H), 2.00-2.08 (m, 1H), 2.10-2.20 (m, 1H), 2.19-2.28 (m, 1H),
3.06-3.13 (m, 1H), 3.34-3.47 (m, 1H), 4.36-4.50 (m, 1H), 7.02 (s,
1H), 7.28 (t,
[0365] J=7.9 Hz, 1H), 7.38 (d, J=4.0 Hz, 1H), 7.65 (d, J=7.0 Hz,
1H), 7.81 (d, J=4.0 Hz, 1H), 7.98 (d, J=7.3 Hz, 1H), 9.40 (s, 1H),
9.50 (s, 1H), 10.10 (s, 1H).
EXAMPLE 29
2-(5-(1-methylpiperidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide
[0366] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting EXAMPLE 28F for EXAMPLE 16D.
.sup.1H NMR (CD.sub.3OD) .delta. 1.63-1.86 (m, 1H), 1.86-2.00 (m,
1H), 2.00-2.11 (m, 2H), 2.11-2.23 (m, 1H), 2.30-2.39 (m, 1H), 2.75
(s, 3H), 3.17-3.28 (m, 1H), 3.68-3.73 (m, 1H), 4.58 (dd, J=12.3,
2.8 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 7.43 (d, J=3.7 Hz, 1H), 7.75
(dd, J=8.0, 1.2 Hz, 1H), 7.85 (d, J=3.7 Hz, 1H), 7.95 (dd, J=7.7,
1.2 Hz, 1H).
EXAMPLE 30
2-(5-(1-propylpiperidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide
[0367] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting EXAMPLE 28F for EXAMPLE 16D
and propionaldehyde for formaldehyde. .sup.1H NMR (CD.sub.3OD)
.delta. 0.89 (t, J=7.4 Hz, 3H), 1.47-1.63 (m, 1H), 1.70-1.98 (m,
3H), 1.99-2.15 (m, 2H), 2.17-2.23 (m, 1H), 2.26-2.35 (m, 1H),
2.83-2.95 (m, 1H), 2.96-3.10 (m, 1H), 3.10-3.25 (m, 1H), 3.78 (d,
J=12.9 Hz, 1H), 4.70 (dd, J=12.0, 2.8 Hz, 1H), 7.36 (t, J=7.6 Hz,
1H), 7.43 (d, J=3.7 Hz, 1H), 7.75 (dd, J=8.0, 1.2 Hz, 1H), 7.85 (d,
J=3.7 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H).
EXAMPLE 31
2-(5-(1-(cyclopropylmethyl)piperidin-2-yl)thien-2-yl)-1H-benzimidazole-4-c-
arboxamide
[0368] This example was prepared as described in EXAMPLE 17,
substituting EXAMPLE 28F for EXAMPLE 16D and
cyclopropanecarbaldehyde for formaldehyde. .sup.1H NMR (CD.sub.3OD)
.delta. 0.22-0.30 (m, 1H), 0.30-0.40 (m, 1H), 0.66-0.81 (m, 2H),
1.00-1.10 (m, 1H), 1.72-1.84 (m, 1H), 1.91-2.15 (m, 3H), 2.15-2.26
(m, 1H), 2.28-2.36 (m, 1H), 2.82-2.90 (m, 1H), 2.95-3.02 (m, 1H),
3.19-3.28 (m, 1H), 4.01 (d, J=13.1 Hz, 1H), 4.69 (dd, J=12.2, 2.7
Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.42 (d, J=3.7 Hz, 1H), 7.75 (dd,
J=8.0, 1.2 Hz, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.95 (d, J=7.6 Hz,
1H).
EXAMPLE 32
2-(5-(1-cyclobutylpiperidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamid-
e
[0369] This example was prepared as described in EXAMPLE 17,
substituting EXAMPLE 28F for EXAMPLE 16D and cyclobutanone for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 1.34-1.48 (m, 1H),
1.51-1.81 (m, 3H), 1.82-2.12 (m, 4H), 2.11-2.37 (m, 4H), 2.88-3.00
(m, 1H), 3.66 (d, J=12.6 Hz, 1H), 3.74-3.88 (m, 1H), 4.60 (dd,
J=12.0, 2.8 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.42 (d, J=3.7 Hz,
1H), 7.74 (dd, J=8.1, 1.1 Hz, 1H), 7.81 (d, J=3.7 Hz, 1H), 7.95
(dd, J=7.5, 1.1 Hz, 1H).
EXAMPLE 33
2-(5-(1-isobutylpiperidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide
[0370] This example was prepared as described in EXAMPLE 17,
substituting EXAMPLE 28F for EXAMPLE 16D and
2-methyl-propionaldehyde for formaldehyde. .sup.1H NMR (CD.sub.3OD)
.delta. 0.91 (d, J=6.7 Hz, 3H), 0.96 (d, J=6.4 Hz, 3H), 1.00-1.07
(m, 2H), 1.87-1.97 (m, 1H), 1.97-2.11 (m, 4H), 2.92 (d, J=7.1 Hz,
2H), 2.98-3.21 (m, 1H), 3.86 (d, J=12.6 Hz, 1H), 4.57-4.71 (m, 1H),
7.40 (t, J=7.7 Hz, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.74 (dd, J=8.1,
1.1 Hz, 1H), 7.85 (d, J=4.0 Hz, 1H), 7.96 (dd, J=7.7, 1.2 Hz,
1H).
EXAMPLE 34
2-(5-pyrrolidin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
EXAMPLE 34A
tert-butyl
2-(5-(methoxycarbonyl)thiophen-2-yl)-1H-pyrrole-1-carboxylate
[0371] A mixture of methyl 5-bromothiophene-2-carboxylate (4 g),
1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (3.8 g), dichlorobis
(triphenylphosphine)palladium(II) (1.2 g) and 2M sodium carbonate
solution (18 mL) in DME/water/ethanol (7/3/2, 200 mL) was heated at
60.degree. C. for 4 hours, cooled and partitioned between ethyl
acetate and brine. The extract was washed with water and
concentrated, and the concentrate was flash chromatographed on
silica gel with 5-40% ethyl acetate in hexane.
EXAMPLE 34B
tert-butyl
2-(5-(methoxycarbonyl)thiophen-2-yl)pyrrolidine-1-carboxylate
[0372] To a solution of EXAMPLE 34A (3.7 g) in acetic acid (200 mL)
was added 5% platinum on carbon (370 mg). The mixture was shaken
under 60 psi of hydrogen until all starting material was consumed,
filtered and concentrated. The concentrate was partitioned between
ethyl acetate and saturated sodium bicarbonate solution. The
extract was washed with water and concentrated. The concentrate was
flash chromatographed on silica gel with 10-30% ethyl acetate in
hexane.
EXAMPLE 34C
5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiophene-2-carboxylic
acid
[0373] To a mixture of EXAMPLE 34B (2.7 g) in THF (50 mL) was added
lithium hydroxide (0.2 g) in water (5 mL). The mixture was stirred
at ambient temperature overnight and partitioned between ethyl
acetate and 0.5 M hydrochloric acid. The extract was washed with
water, dried over magnesium sulfate, filtered and concentrated. The
concentrate was flash chromatographed on silica gel with ethyl
acetate.
EXAMPLE 34D
tert-butyl
2-(5-(4-carbamoyl-1H-benzimidazol-2-yl)thiophen-2-yl)pyrrolidin-
e-1-carboxylate
[0374] To a solution of EXAMPLE 34C (2.4 g) in pyridine (100 mL)
and DMF (100 mL) was added CDI (1.6 g). The mixture was heated at
40.degree. C. for 1 hour, treated with 2,3-diaminobenzamide
dihydrochloride (1.8 g), stirred at ambient temperature overnight
and concentrated. The concentrate was heated in acetic acid (50 mL)
at 80.degree. C. overnight and concentrated. The concentrate was
flash chromatographed on silica gel with ethyl acetate.
EXAMPLE 34E
2-(5-pyrrolidin-2-ylthien-2-yl)-1H-benzimidazole-4-carboxamide
[0375] A solution of EXAMPLE 34D (2.1 g) in dichloromethane (20 mL)
and TFA (5 mL) was stirred at ambient temperature overnight and
concentrated. The concentrate was purified by HPLC (Zorbax, C-18,
Mobile phase A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile;
0-100% gradient). .sup.1H NMR (CD.sub.3OD) .delta. 2.19-2.27 (m,
1H), 2.27-2.41 (m, 2H), 2.57-2.68 (m, 1H), 3.43-3.57 (m, 2H), 5.01
(dd, J=9.4, 6.9 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.42 (d, J=4.6 Hz,
1H), 7.73 (dd, J=8.1, 1.1 Hz, 1H), 7.81 (d, J=4.0 Hz, 1H), 7.94
(dd, J=7.7, 0.9 Hz, 1H).
EXAMPLE 35
2-(5-(1-methylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide
[0376] This example was prepared as described in EXAMPLE 17,
substituting EXAMPLE 34E for EXAMPLE 16D. .sup.1H NMR (CD.sub.3OD)
.delta. 2.30 (m, 2H), 2.47 (m, 1H), 2.74 (m, 1H), 2.94 (s, 3H),
3.31-3.40 (m, 1H), 3.88 (m, 1H), 4.81 (m, 1H), 7.40 (t, J=7.7 Hz,
1H), 7.51 (d, J=3.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.86 (d, J=4.0
Hz, 1H), 7.95 (d, J=7.6 Hz, 1H).
EXAMPLE 36
2-(5-(1-isopropylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamid-
e
[0377] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting EXAMPLE 34E for EXAMPLE 16D
and acetone for formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 1.40
(dd, J=12.2, 6.7 Hz, 6H), 2.20-2.35 (m, 2H), 2.34-2.46 (m, 1H),
2.67 (dd,
[0378] J=12.0, 4.73 Hz, 1H), 3.39-3.52 (m, 1H), 3.58-3.64 (m, 1H),
3.64-3.73 (m, 1H), 5.00-5.08 (m, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.51
(d, J=3.7 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.85 (d, J=4.0 Hz, 1H),
7.95 (d, J=6.7 Hz, 1H).
EXAMPLE 37
2-(5-(1-propylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide
[0379] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting EXAMPLE 34E for EXAMPLE 16D
and propionaldehyde for formaldehyde. .sup.1H NMR (CD.sub.3OD)
.delta. 0.99 (t, J=7.4 Hz, 3H), 1.56-1.74 (m, 1H), 1.74-1.81 (m,
1H), 2.25-2.38 (m, 2H), 2.37-2.50 (m, 1H), 2.64-2.76 (m, 1H),
3.02-3.07 (m, 1H), 3.18-3.28 (m, 1H), 3.32-3.41 (m, 1H), 3.80-3.90
(m, 1H), 4.78-4.89 (m, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.51 (d, J=3.7
Hz, 1H), 7.75 (d, J=7.1 Hz, 1H), 7.86 (d, J=3.7 Hz, 1H), 7.96 (d,
J=6.7 Hz, 1H).
EXAMPLE 38
2-(5-(1-(cyclopropylmethyl)pyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4--
carboxamide
[0380] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting EXAMPLE 34E for EXAMPLE 16D
and cyclopropanecarbaldehyde for formaldehyde. .sup.1H NMR
(CD.sub.3OD) .delta. 0.30-0.33 (m, 1H), 0.40-0.44 (m, 1H),
0.63-0.81 (m, 2H), 0.98-1.18 (m, 1H), 2.26-2.39 (m, 2H), 2.39-2.51
(m, 1H), 2.61-2.80 (m, 1H), 3.01-3.11 (m, 1H), 3.11-3.21 (m, 1H),
3.38-3.53 (m, 1H), 3.92-4.07 (m, 1H), 4.80-4.90 (m, 1H), 7.40 (t,
J=7.8 Hz, 1H), 7.49 (d, J=4.0 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.85
(d, J=3.7 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H).
EXAMPLE 39
2-(5-(1-isobutylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxamide
[0381] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting EXAMPLE 34E for EXAMPLE 16D
and 2-methylpropionaldehyde for formaldehyde. .sup.1H NMR
(CD.sub.3OD) .delta. 1.00 (dd, J=13.7, 6.7 Hz, 6H), 2.01-2.15 (m,
1H), 2.27-2.39 (m, 2H), 2.39-2.55 (m, 1H), 2.59-2.76 (m, 1H),
3.00-3.12 (m, 2H), 3.32-3.41 (m, 1H), 3.90-4.12 (m, 1H), 4.80-4.92
(m, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.52 (d, J=3.7 Hz, 1H), 7.74 (d,
J=8.0 Hz, 1H), 7.86 (d, J=4.0 Hz, 1H), 7.95 (d, J=6.7 Hz, 1H).
EXAMPLE 40
2-(5-(1-cyclobutylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxami-
de
[0382] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting EXAMPLE 34E for EXAMPLE 16D
and cyclobutanone for formaldehyde. .sup.1H NMR (CD.sub.3OD)
.delta. 1.75-1.90 (m, 2H), 1.95-2.04 (m, 1H), 2.10-2.23 (m, 1H),
2.23-2.35 (m, 4H), 2.40-2.45(m, 1H), 2.63-2.76 (m, 1H), 3.25-3.36
(m, 2H), 3.70-3.75 (m, 1H), 3.93-4.05 (m, 1H), 7.40 (t, J=7.8 Hz,
1H), 7.47 (d, J=4.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.82 (d, J=3.7
Hz, 1H), 7.95 (d, J=7.7 Hz, 1H).
EXAMPLE 41
2-(5-(1-cyclopentylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxam-
ide
[0383] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting EXAMPLE 34E for EXAMPLE 16D
and cyclopentanone for formaldehyde. .sup.1H NMR (CD.sub.3OD)
.delta. 1.60-1.69 (m, 2H), 1.72-1.91 (m, 3H), 1.97-2.13 (m, 1H),
2.13-2.25 (m, 1H), 2.25-2.36 (m, 2H), 2.35-2.48 (m, 2H), 2.60-2.74
(m, 1H), 3.38-3.56 (m, 1H), 3.66-3.89 (m, 2H), 4.94-5.06 (m, 1H),
7.39 (t, J=7.9 Hz, 1H), 7.50 (d, J=4.0 Hz, 1H), 7.74 (d, J=7.1 Hz,
1H), 7.84 (d, J=3.99 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H).
EXAMPLE 42
2-(5-(1-cyclohexylpyrrolidin-2-yl)thien-2-yl)-1H-benzimidazole-4-carboxami-
de
[0384] This example was prepared as the trifluoroacetate salt as
described in EXAMPLE 17, substituting EXAMPLE 34E for EXAMPLE 16D
and cyclohexanone for formaldehyde. .sup.1H NMR (CD.sub.3OD)
.delta. 1.17-1.26 (m, 1H), 1.30-1.40 (m, 2H), 1.40-1.60 (m, 3H),
1.69-1.75 (m, 1H), 1.85-1.93 (m, 1H), 1.93-2.01 (m, 1H), 2.02-2.05
(m, 1H), 2.13-2.24 (m, 1H), 2.25-2.32 (m, 1H), 2.38-2.48 (m, 1H),
2.60-2.72 (m, 1H), 3.20-3.39 (m, 1H), 3.50-3.56 (m, 1H), 3.60-3.68
(m, 1H), 5.10-5.18 (m, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.50 (d, J=3.7
Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.85 (d, J=3.7 Hz, 1H), 7.95 (d,
J=7.4 Hz, 1H).
EXAMPLE 43
2-(6-pyrrolidin-2-ylpyridin-3-yl)-1H-benzimidazole-4-carboxamide
[0385] To a mixture of
6-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)nicotinic acid (3 g, 10.6
mmol) in pyridine (10 mL) and N,N-dimethylformamide (50 mL) at
ambient temperature was added 1,1'-carbonyldiimidazole (2.2 g, 16
mmol). The mixture was heated at 40.degree. C. for 1 hour, treated
with 2,3-diaminobenzamide dihydrochloride (2.4 g, 10.6 mmol),
stirred at ambient temperature, for 16 hours and concentrated. The
residue was heated in acetic acid (100 mL) at 110.degree. C. for 2
hours, cooled and concentrated. The residue was purified by flash
chromatography on silica gel using ethyl acetate to provide the
acyclic intermediate. This intermediate was dissolved in
dichloromethane (100 mL) and trifluoroacetic acid (20 mL) and the
mixture was stirred at room temperature for 16 hours and was
concentrated. The residue was purified by HPLC (Zorbax C-8, 0.1%
trifluoroacetic acid/acetonitrile/water) to provide the title
compound. .sup.1H NMR (methanol-d.sub.4) .delta. 2.04-2.36 (m, 3H),
2.49-2.74 (m, 1H), 3.39-3.72 (m, 2H), 4.98 (t, J=7.63 Hz, 1H),
7.17-7.49 (m, 1H), 7.69 (d, J=8.14 Hz, 1H), 7.81 (d, J=8.14 Hz,
1H), 7.99 (d, J=7.46 Hz, 1H), 8.64 (dd, J=8.31, 2.20 Hz, 1H), 9.42
(s, 1H).
EXAMPLE 44
2-[6-(1-isopropylpyrrolidin-2-yl)pyridin-3-yl]-1H-benzimidazole-4-carboxam-
ide
[0386] The title compound was prepared as the trifluoroacetic acid
salt as described in EXAMPLE 6, substituting acetone for
formaldehyde and EXAMPLE 43 for EXAMPLE 5. .sup.1H NMR
(methanol-d.sub.4) .delta. 1.34 (dd, J=7.97, 6.61 Hz, 6H),
1.98-2.31 (m, 3H), 2.56-2.77 (m, 1H), 3.41-3.57 (m, 1H), 3.58-3.84
(m, 2H), 4.99-5.13 (m, 1H), 7.31-7.52 (m, 1H), 7.73 (d, J=7.46 Hz,
1H), 7.82 (d, J=7.12 Hz, 1H), 8.00 (d, J=7.46 Hz, 1H), 8.67 (dd,
J=8.31, 2.20 Hz, 1H), 9.46 (d, J=2.37 Hz, 1H).
EXAMPLE 45
2-[6-(1-isobutylpyrrolidin-2-yl),pyridin-3-yl]-1H-benzimidazole-4-carboxam-
ide
[0387] The title compound was prepared as the trifluoroacetic acid
salt as described in EXAMPLE 6, substituting isobutyraldehyde for
formaldehyde and EXAMPLE 43 for EXAMPLE 5. .sup.1H NMR
(methanol-d.sub.4) .delta. 0.97 (d, J=6.74 Hz, 3H), 1.10 (d, J=6.74
Hz, 3H), 1.86-2.39 (m, 3H), 2.50-2.82 (m, 1H), 3.12 (d, J=7.14 Hz,
2H), 3.24-3.52 (m, 2H), 3.88-4.10 (m, 1H), 4.66-4.96 (m, 1H),
7.20-7.54 (m, 1H), 7.70 (d, J=7.93 Hz, 1H), 7.81 (d, J=7.93 Hz,
1H), 8.00 (d, J=6.74 Hz, 1H), 8.68 (dd, J=8.13, 2.18 Hz, 1H), 9.48
(d, J=1.98 Hz, 1H).
EXAMPLE 46
2-[6-(1-cyclobutylpyrrolidin-2-yl),pyridin-3-yl]-1H-benzimidazole-4-carbox-
amide
[0388] The title compound was prepared as the trifluoroacetic acid
salt as described in EXAMPLE 6, substituting cyclobutanone for
formaldehyde and EXAMPLE 43 for EXAMPLE 5. .sup.1H NMR
(methanol-d.sub.4) .delta. 1.63-1.89 (m, 2H), 1.84-2.04 (m, 2H),
2.08-2.45 (m, 6H), 2.47-2.72 (m, 1H), 3.66-3.88 (m, 1H), 3.97 (t,
J=8.53 Hz, 1H), 4.67-4.98 (m, 1H), 7.23-7.55 (m, 1H), 7.70 (d,
J=8.33 Hz, 1H), 7.81 (d, J=7.14 Hz, 1H), 8.00 (d, J=6.74 Hz, 1H),
8.64 (dd, J=8.13, 2.18 Hz, 1H), 9.50 (d, J=2.38 Hz, 1H).
EXAMPLE 47
2-[6-(1-cyclopentylpyrrolidin-2-yl),pyridin-3-yl]-1H-benzimidazole-4-carbo-
xamide
[0389] The title compound was prepared as the trifluoroacetic acid
salt as described in EXAMPLE 6, substituting cyclopentanone for
formaldehyde and EXAMPLE 43 for EXAMPLE 5. .sup.1H NMR
(methanol-d.sub.4) .delta. 1.37-1.52 (m, 1H), 1.51-1.69 (m, 2H),
1.67-2.01 (m, 4H), 2.02-2.38 (m, 4H), 2.56-2.80 (m, 1H), 3.41-3.56
(m, 1H), 3.69-3.96 (m, 2H), 4.92-5.05 (m, 1H), 7.43 (t, J=7.73 Hz,
1H), 7.72 (d, J=7.93 Hz, 1H), 7.81 (d, J=7.14 Hz, 1H), 8.00 (d,
J=7.54 Hz, 1H), 8.67 (dd, J=8.13, 2.18 Hz, 1H), 9.48 (d, J=1.98 Hz,
1H).
EXAMPLE 48
2-[6-(1-cyclohexylpyrrolidin-2-yl),pyridin-3-yl]-1H-benzimidazole-4-carbox-
amide
[0390] The title compound was prepared as the trifluoroacetic acid
salt as described in EXAMPLE 6, substituting cyclohexanone for
formaldehyde and EXAMPLE 43 for EXAMPLE 5. .sup.1H NMR
(methanol-d.sub.4) .delta. 1.10-1.58 (m, 5 H), 1.68 (d, J=12.29 Hz,
1H), 1.77-1.94 (m, 2H), 1.96-2.29 (m, 5H), 2.57-2.75 (m, 1H),
3.32-3.41 (m, 1H), 3.42-3.61 (m, 1H), 3.65-3.93 (m, 1H), 5.13 (dd,
J=8.53, 6.54 Hz, 1H), 7.32-7.48 (m, 1H), 7.72 (d, J=8.33 Hz, 1H),
7.81 (d, J=7.14 Hz, 1H), 7.99 (d, J=7.54 Hz, 1H), 8.67 (dd, J=8.13,
2.18 Hz, 1H), 9.46 (d, J=1.59 Hz, 1H).
EXAMPLE 49
2-[6-(1-tetrahydro-2H-pyran-4-ylpyrrolidin-2-yl),pyridin-3-yl]-1H-benzimid-
azole-4-carboxamide
[0391] The title compound was prepared as the trifluoroacetic acid
salt as described in EXAMPLE 6, substituting
dihydro-2H-pyran-4(3H)-one for formaldehyde and EXAMPLE 43 for
EXAMPLE 5. .sup.1H NMR (methanol-d.sub.4) .delta. 1.57-1.75 (m,
1H), 1.75-1.94 (m, 2H), 1.95-2.08 (m, 1H), 2.08-2.32 (m, 3H),
2.55-2.84 (m, 1H), 3.25-3.46 (m, 2H), 3.46-3.77 (m, 2H), 3.72-4.14
(m, 3H), 5.15 (dd, J=8.65, 6.27 Hz, 1H), 7.13-7.59 (m, 1H), 7.72
(d, J=7.80 Hz, 1H), 7.81 (d, J=7.12 Hz, 1H), 7.99 (d, J=6.44 Hz,
1H), 8.68 (dd, J=8.31, 2.20 Hz, 1H), 9.47 (d, J=1.36 Hz, 1H).
EXAMPLE 50
2-[6-(1,3-oxazol-5-yl)pyridin-3-yl]-1H-benzimidazole-4-carboxamide
EXAMPLE 50A
6-(oxazol-5-yl)nicotinic acid
[0392] To a suspension of methyl 6-formylnicotinate (60 mg, 0.363
mmol) in methanol (3 mL) was added sodium methoxide in methanol
(0.5M, 2.91 mL, 1.45 mmol). Tosylmethyl isocyanide (85 mg, 0.436
mmol) was added to the reaction and the mixture was heated at
reflux overnight. After cooling, the reaction mixture was
concentrated. The residue was treated with 5% citric acid/50% brine
(1:1) and extracted with ethyl acetate. The suspension was
filtered, washed with water, and dried under vacuum to provide the
title compound. MS (DCI/NH.sub.3) m/z: 191.0 (M+1).sup.-.
EXAMPLE 50B
N-(2-amino-3-carbamoylphenyl)-6-(oxazol-5-yl)nicotinamide
[0393] A solution of EXAMPLE 50A (60.0 mg, 0.316 mmol) in a mixture
of pyridine (1.5 mL) and N,N-dimethylformamide (1.5 mL) was treated
with 1,1'-carbonyldiimidazole (56.3 mg, 0.347 mmol) at 45.degree.
C. for 2 hours. After cooling, 2,3-diaminobenzamide (HCl salt)
(70.7 mg, 0.316 mmol) was added and the mixture stirred at room
temperature for 5 hours. After concentration, the residue was
treated with 20% brine and ethyl acetate. The solid was filtered,
washed with ethyl acetate and water, and dried under vacuum to
provide the title compound. This material was used in the next step
without further purification.
EXAMPLE 50C
2-[6-(1,3-oxazol-5-yl)pyridin-3-yl]-1H-benzimidazole-4-carboxamide
[0394] A suspension of EXAMPLE 50B (24.0 mg, 0.074 mmol) in acetic
acid (1 mL) was heated to 80.degree. C. for 3 hours and cooled. The
solution was concentrated and purified by HPLC (Zorbax, C-18,
250.times.2.54 column, Mobile phase A: 0.1% trifluoroacetic acid in
H.sub.2O; B: 0.1% trifluoroacetic acid in CH.sub.3CN; 0-100%
gradient) to provide the title compound as the trifluoroacetic acid
salt. MS (DCI/NH.sub.3) m/z: 306.2 (M+H).sup.+. .sup.1H NMR
(dimethylsulfoxide-d.sub.6/D.sub.2O) .delta. 7.45 (t, J=7.78 Hz,
1H), 7.84 (d, J=8.24 Hz, 1H), 7.93 (d, J=7.63 Hz, 1H), 7.96 (s,
1H), 8.01 (d, J=8.24 Hz, 1H), 8.60 (s, 1H), 8.71 (dd, J=8.39, 2.29
Hz, 1H), 9.44 (d, J=1.53 Hz, 1H).
EXAMPLE 51
2-[5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1H-benzimidazole-4-carboxamide
EXAMPLE 51A
methyl 6-(2-amino-3-carbamoylphenylcarbamoyl)nicotinate
[0395] A solution of 5-(methoxycarbonyl)picolinic acid (3.33 g,
18.4 mmol) in a mixture of pyridine (20 mL) and
N,N-dimethylformamide (35 mL) was treated with
1,1'-carbonyldiimidazole (3.28 g, 20.2 mmol) at 45.degree. C. for 2
hours. After cooling, 2,3-diaminobenzamide (HCl salt) (4.12 g, 18.4
mmol) was added and the mixture stirred at room temperature
overnight. The mixture was concentrated and the residue used in the
next step without further purification.
EXAMPLE 51B
methyl 6-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)nicotinate
[0396] The crude product from EXAMPLE 51A in acetic acid (40 ml)
was heated to 90.degree. C. for 1.5 hours. After cooling, the
suspension was filtered. The filter cake was washed with acetic
acid, and stirred in saturated NaHCO.sub.3 for 30 minutes. The
solid was filtered, washed with water and ether, and dried under
vacuum to provide the title compound as an off-white solid. MS
(DCI/NH.sub.3) m/z: 297.1 (M+H).sup.+.
EXAMPLE 51C
6-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)nicotinic acid
[0397] To a suspension of EXAMPLE 51B (2.00 g, 6.75 mmol) in
tetrahydrofuran (36 ml) and methanol (12 mL) was added an emulsion
of lithium hydroxide (0.850 g, 20.3 mmol) in water (8 mL) at room
temperature. After 4 hours, most of the solvent was evaporated. The
residue was dissolved in water and acidified with 5% citric acid
until pH 5. The precipitate was filtered, washed with water and
dried under vacuum to provide the title compound. MS (DCI/NH.sub.3)
m/z: 283.1 (M+H).sup.-.
EXAMPLE 51D
2-(5-(hydrazinecarbonyl)pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxamide
[0398] To a suspension of EXAMPLE 51C (1.40 g, 4.96 mmol) and TFFH
(fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate,
1.57 g, 5.95 mmol) in N,N-dimethylformamide (18 mL) at 0.degree. C.
was added triethylamine (1.38 mL, 9.92 mmol) and hydrazine (0.311
mL, 9.92 mmol). The mixture was stirred at room temperature
overnight. Water (60 mL) was added to the suspension and the solid
was filtered, washed with water and ether and dried under vacuum to
provide the title compound. MS (DCI/NH.sub.3) m/z: 297.1
(M+H)+.
EXAMPLE 51E
2-[5-(1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1H-benzimidazole-4-carboxamide
[0399] A mixture of EXAMPLE 51D (70.0 mg, 0.236 mmol) and trimethyl
orthoformate (1.50 mL, 13.6 mmol) in dimethylsulfoxide (0.5 mL) was
heated at 150.degree. C. for 30 minutes in a microwave reactor (CEM
Explorer). After concentration the residue was purified by
supercritical fluid chromatography (SFC) using a Princeton SFC
pyridine 60 .ANG. 5 .mu.m (21.2 mm.times.150 mm) column and a
gradient of 10-50% methanol (A) and carbon dioxide (B), at a flow
rate of 40 mL/min. to provide the title compound. MS (APCI) m/z:
307.1 (M+H).sup.+. .sup.1H NMR (dimethylsulfoxide-d.sub.6) .delta.
7.38 (t, J=7.83 Hz, 1H), 7.73-7.82 (m, 2H), 7.91 (d, J=7.06 Hz,
1H), 8.55-8.70 (m, 2H), 9.31 (s, 1H, brd), 9.36 (d, J=1.84 Hz, 1H),
9.49 (s, 1H).
EXAMPLE 52
2-{5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl}-1H-benzimidaz-
ole-4-carboxamide
[0400] To a suspension of EXAMPLE 51D (70 mg, 0.236 mmol) in
N,N-dimethylformamide (6 mL) was added trifluoroacetic acid (0.018
mL, 0.236 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (84
mg, 0.496 mmol). After 15 minutes, triethylamine (0.165 mL, 1.18
mmol) was added dropwise and the reaction stirred overnight. Water
was added to the suspension and the solid was filtered, washed with
water and ether and concentrated. The crude product was purified by
HPLC (Zorbax, C-18, 250.times.2.54 column, Mobile phase A: 0.1%
trifluoroacetic acid in H.sub.2O; B: 0.1% trifluoroacetic acid in
CH.sub.3CN; 0-100% gradient) to provide the title compound as the
trifluoroacetic acid salt. MS (DCI/NH.sub.3) m/z: 375.1
(M+H).sup.+. .sup.1H NMR (dimethylsulfoxide-d.sub.6) .delta. 7.43
(t, J=7.67 Hz, 1H), 7.80 (d, J=7.06 Hz, 1H), 7.84 (s, 1H), 7.94 (d,
J=8.29 Hz, 1H), 8.63-8.74 (m, 2H), 9.15 (s, 1H, brd), 9.41 (s,
1H).
EXAMPLE 53
2-[5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1H-benzimidazole-4-carbo-
xamide
[0401] To a suspension of EXAMPLE 51D (70 mg, 0.236 mmol) in
N,N-dimethylformamide (6 mL) was added acetic acid (0.014 mL, 0.236
mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (84 mg, 0.496
mmol). After 15 minutes, triethylamine (0.165 mL, 1.181 mmol) was
added dropwise. The reaction was stirred for 5 hours. Water was
added to the suspension and the solid was filtered. The filtrate
was concentrated and purified by HPLC (Zorbax, C-18, 250.times.2.54
column, Mobile phase A: 0.1% trifluoroacetic acid in H.sub.2O; B:
0.1% trifluoroacetic acid in CH.sub.3CN; 0-100% gradient) to
provide the title compound as trifluoroacetic acid salt. MS
(DCI/NH.sub.3) m/z: 321.1 (M+H).sup.+. .sup.1H NMR
(dimethylsulfoxide-d.sub.6) .delta. 2.34 (s, 3H), 7.43 (t, J=7.82
Hz, 1H), 7.81 (d, J=7.36 Hz, 1H), 7.85 (s, 1H), 7.94 (d, J=7.36 Hz,
1H), 8.50 (d, J=8.29 Hz, 1H), 8.66 (d, J=8.29 Hz, 1H), 9.13 (s, 1H,
brd), 9.24 (s, 1H), 12.34 (s, 1H).
[0402] The foregoing is meant to illustrate the invention but not
to limit it. Variations and changes obvious to one skilled in the
art are intended to be within the scope of the invention as defined
in the appended claims.
* * * * *