N-substituted pyrazolyl guanidine F
The invention provides pyrazolyl guanidine compounds that inhibit F 1 F 0 -ATPase, and methods of using pyrazolyl guanidine compounds as therapeutic agents to treat medical disorders, such as an immune disorder, inflammatory condition, or cancer.
1. A compound represented by Formula I:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A 1 is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 haloalkyl, and C 1 -C 6 alkyl;
R 1 and R 2 are independently hydrogen, halogen, C 1 -C 4 haloalkyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or cyano;
R 3 and R 4 are independently hydrogen, halogen, C 1 -C 4 haloalkyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or cyano;
R 5 is one of the following:
(a) heterocycloalkyl, heteroaryl, phenyl, —(C 1 -C 6 alkylene)-heterocycloalkyl, —(C 1 -C 6 alkylene)-phenyl, —(C 1 -C 6 alkylene)-heteroaryl, or heterocycloalkanonyl, wherein said heterocycloalkyl, heteroaryl, phenyl, and heterocycloalkanonyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, cyano, —CO 2 H, —CO 2 R 6 , —C(O)R 6 , —C(O)N(R 7 )(R 8 ), —N(R 7 )C(O)(R 6 ), —N(R 7 )CO 2 (R 6 ), —N(R 7 )(R 8 ), —O—R 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 7 )(R 8 ), —N(R 7 )SO 2 (R 6 ), —(C 1 -C 6 alkylene)-CO 2 R 7 , and —(C 1 -C 6 alkylene)-C(O)N(R 7 )(R 8 ); or
(b) C 3 -C 6 cycloalkyl or —(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, cyano, —CO 2 H, —CO 2 R 6 , —C(O)R 6 , —C(O)N(R 7 )(R 8 ), —N(R 7 )C(O)(R 6 ), —N(R 7 )CO 2 (R 6 ), —N(R 7 )(R 8 ), —O—R 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 7 )(R 8 ), and —N(R 7 )SO 2 (R 6 );
R 6 represents independently for each occurrence C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, cyano, halogen, —CO 2 H, and aryl; and
R 7 and R 8 each represent independently for each occurrence hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; or R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring.
2. The compound of claim 1 , wherein the compound is a compound of Formula I or a stereoisomer, geometric isomer, or tautomer; or a pharmaceutically acceptable salt of any of the foregoing.
3. The compound of claim 2 , wherein A l is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
4. The compound of claim 3 , wherein R 1 is halogen or C 1 -C 4 haloalkyl.
5. The compound of claim 4 , wherein R 4 is trifluoromethyl.
6. The compound of claim 1 , wherein R 5 is heterocycloalkyl, heteroaryl, phenyl, —(C 1 -C 6 alkylene)-heterocycloalkyl, —(C 1 -C 6 alkylene)-phenyl, or —(C 1 -C 6 alkylene)-heteroaryl, wherein said heterocycloalkyl, heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, cyano, —CO 2 H, —CO 2 R 6 , —C(O)R 6 , —C(O)N(R 7 )(R 8 ), —N(R 7 )C(O)(R 6 ), —N(R 7 )(R 8 ), —O—R 6 , —S(O)R 6 , —SO 2 R 6 , and —SO 2 N(R 7 )(R 8 ).
7. The compound of claim 2 , wherein R 5 is heterocycloalkyl or —(C 1 -C 6 alkylene)-heteroaryl, wherein said heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, cyano, —CO 2 H, —CO 2 R 6 , —C(O)R 6 , —C(O)N(R 7 )(R 8 ), —N(R 7 )C(O)(R 6 ), —N(R 7 )(R 8 ), —O—R 6 , —S(O)R 6 , —SO 2 R 6 , and —SO 2 N(R 7 )(R 8 ).
8. The compound of claim 5 , wherein R 5 is one of the following:
wherein X is —CO 2 R 6 , —C(O)R 6 , —SO 2 R 6 , or —SO 2 N(R 7 )(R 8 ).
9. The compound of claim 5 , wherein R 5 is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, hydroxyl, and methoxy.
10. The compound of claim 1 , wherein said compound is represented by Formula I-A:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt of any of the foregoing; wherein:
A 1 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl;
R 1 and R 2 each represent independently for each occurrence hydrogen, chloro, fluoro, or —CF 3 ;
R 3 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl;
R 4 is C 1 -C 4 haloalkyl;
R 5 is a 3-6 membered heterocycloalkyl, pyridinyl, or phenyl, wherein said heterocycloalkyl, pyridinyl, and phenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CO 2 H, —CO 2 R 6 , —C(O)R 6 , —C(O)N(R 7 )(R 8 ), —SO 2 R 6 , and —SO 2 N(R 7 )(R 8 );
R 6 represents independently for each occurrence C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, each optionally substituted by phenyl; and
R 7 and R 8 each represent independently for each occurrence hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; or R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring.
11. The compound of claim 10 , wherein R 1 is chloro, and R 2 is hydrogen.
12. The compound of claim 11 , wherein R 4 is trifluoromethyl.
13. The compound of claim 12 , wherein R 5 is a 3-6 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of —CO 2 R 6 , —C(O)R 6 , —SO 2 R 6 , and —SO 2 N(R 7 )(R 8 ).
14. The compound of claim 10 , wherein R 5 is one of the following:
wherein X is —CO 2 R 6 , —C(O)R 6 , —SO 2 R 6 , or —SO 2 N(R 7 )(R 8 ).
15. The compound of claim 10 , wherein R 5 is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, hydroxyl, and methoxy.
16. A compound represented by Formula II:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A 1 is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 haloalkyl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
R 1 is halogen, C 1 -C 4 haloalkyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or cyano;
R 2 represents independently for each occurrence hydrogen, halogen, C 1 -C 4 haloalkyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or cyano;
R 3 and R 4 are independently hydrogen, halogen, C 1 -C 4 haloalkyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or cyano;
R 5 is one of the following:
(a) heterocycloalkyl, heteroaryl, phenyl, —(C 1 -C 6 alkylene)-heterocycloalkyl, —(C 1 -C 6 alkylene)-phenyl, —(C 1 -C 6 alkylene)-heteroaryl, or heterocycloalkanonyl, wherein said heterocycloalkyl, heteroaryl, phenyl, and heterocycloalkanonyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, cyano, —CO 2 H, —CO 2 R 6 , —C(O)R 6 , —C(O)N(R 7 )(R 8 ), —N(R 7 )C(O)(R 6 ), —N(R 7 )CO 2 (R 6 ), —N(R 7 )(R 8 ), —O—R 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 7 )(R 8 ), —N(R 7 )SO 2 (R 6 ), —(C 1 -C 6 alkylene)-CO 2 R 7 , and —(C 1 -C 6 alkylene)-C(O)N(R 7 )(R 8 ); or
(b) C 3 -C 6 cycloalkyl or —(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, cyano, —CO 2 H, —CO 2 R 6 , —C(O)R 6 , —C(O)N(R 7 )(R 8 ), —N(R 7 )C(O)(R 6 ), —N(R 7 )CO 2 (R 6 ), —N(R 7 )(R 8 ), —O—R 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 7 )(R 8 ), and —N(R 7 )SO 2 (R 6 );
R 6 represents independently for each occurrence C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, cyano, halogen, —CO 2 H, and aryl;
R 7 and R 8 each represent independently for each occurrence hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; or R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring; and
n is 1 or 2.
17. A compound in Table 1A, 2A, 3A, or 6A below, or a pharmaceutically acceptable salt thereof:
TABLE 1A
No.
Ar
X
Y
I-1
3-chlorophenyl
3-chlorophenyl
I-2
4-chlorophenyl
4-chlorophenyl
I-3
3-fluorophenyl
3,5-dichlorophenyl
I-4
4-fluorophenyl
3-chloro-4-fluorophenyl
I-5
2,4-dichlorophenyl
3-chloro-5-fluorophenyl
I-6
3,4-difluorophenyl
3-trifluoromethylphenyl
I-7
4-trifluoromethylphenyl
3-cyclopropylphenyl
I-8
3-chlorophenyl
3-tert-butylphenyl
I-9
4-chlorophenyl
2-cyclopropylphenyl
I-10
3-fluorophenyl
2-cyclopropyl-4- fluorophenyl
I-11
3-chlorophenyl
3-chlorophenyl
I-12
4-chlorophenyl
4-chlorophenyl
I-13
3-fluorophenyl
3,5-dichlorophenyl
I-14
4-fluorophenyl
3-chloro-4-fluorophenyl
I-15
2,4-dichlorophenyl
3-chloro-5-fluorophenyl
I-16
3,4-difluorophenyl
3-trifluoromethylphenyl
I-17
4-trifluoromethylphenyl
3-cyclopropylphenyl
I-18
3-chlorophenyl
3-tert-butylphenyl
I-19
4-chlorophenyl
2-cyclopropylphenyl
I-20
3-fluorophenyl
2-cyclopropyl-4- fluorophenyl
I-21
3-chlorophenyl
3-chlorophenyl
I-22
4-chlorophenyl
4-chlorophenyl
I-23
3-fluorophenyl
3,5-dichlorophenyl
I-24
4-fluorophenyl
3-chloro-4-fluorophenyl
I-25
2,4-dichlorophenyl
3-chloro-5-fluorophenyl
I-26
3,4-difluorophenyl
3-trifluoromethylphenyl
I-27
4-trifluoromethylphenyl
3-cyclopropylphenyl
I-28
3-chlorophenyl
3-tert-butylphenyl
I-29
4-chlorophenyl
2-cyclopropylphenyl
I-30
3-fluorophenyl
2-cyclopropyl-4- fluorophenyl
I-31
3-chlorophenyl
3-chlorophenyl
I-32
4-chlorophenyl
4-chlorophenyl
I-33
3-fluorophenyl
3,5-dichlorophenyl
I-34
4-fluorophenyl
3-chloro-4-fluorophenyl
I-35
2,4-dichlorophenyl
3-chloro-5-fluorophenyl
I-36
3,4-difluorophenyl
3-trifluoromethylphenyl
I-37
4-trifluoromethylphenyl
3-cyclopropylphenyl
I-38
3-chlorophenyl
3-tert-butylphenyl
I-39
4-chlorophenyl
2-cyclopropylphenyl
I-40
3-fluorophenyl
2-cyclopropyl-4- fluorophenyl
I-41
3-chlorophenyl
3-chlorophenyl
I-42
4-chlorophenyl
4-chlorophenyl
I-43
3-fluorophenyl
3,5-dichlorophenyl
I-44
4-fluorophenyl
3-chloro-4-fluorophenyl
I-45
2,4-dichlorophenyl
3-chloro-5-fluorophenyl
I-46
3,4-difluorophenyl
3-trifluoromethylphenyl
I-47
4-trifluoromethylphenyl
3-cyclopropylphenyl
I-48
3-chlorophenyl
3-tert-butylphenyl
I-49
4-chlorophenyl
2-cyclopropylphenyl
I-50
3-fluorophenyl
2-cyclopropyl-4- fluorophenyl
I-51
3-chlorophenyl
3-chlorophenyl
I-52
4-chlorophenyl
4-chlorophenyl
I-53
3-fluorophenyl
3,5-dichlorophenyl
I-54
4-fluorophenyl
3-chloro-4-fluorophenyl
I-55
2,4-dichlorophenyl
3-chloro-5-fluorophenyl
I-56
3,4-difluorophenyl
3-trifluoromethylphenyl
I-57
4-trifluoromethylphenyl
3-cyclopropylphenyl
I-58
3-chlorophenyl
3-tert-butylphenyl
I-59
4-chlorophenyl
2-cyclopropylphenyl
I-60
3-fluorophenyl
2-cyclopropyl-4- fluorophenyl
I-61
3-chlorophenyl
3-chlorophenyl
I-62
4-chlorophenyl
4-chlorophenyl
I-63
3-fluorophenyl
3,5-dichlorophenyl
I-64
4-fluorophenyl
3-chloro-4-fluorophenyl
I-65
2,4-dichlorophenyl
3-chloro-5-fluorophenyl
I-66
3,4-difluorophenyl
3-trifluoromethylphenyl
I-67
4-trifluoromethylphenyl
3-cyclopropylphenyl
I-68
3-chlorophenyl
3-tert-butylphenyl
I-69
4-chlorophenyl
2-cyclopropylphenyl
I-70
3-fluorophenyl
2-cyclopropyl-4- fluorophenyl
I-71
3-chlorophenyl
3-chlorophenyl
I-72
4-chlorophenyl
4-chlorophenyl
I-73
3-fluorophenyl
3,5-dichlorophenyl
I-74
4-fluorophenyl
3-chloro-4-fluorophenyl
I-75
2,4-dichlorophenyl
3-chloro-5-fluorophenyl
I-76
3,4-difluorophenyl
3-trifluoromethylphenyl
I-77
4-trifluoromethylphenyl
3-cyclopropylphenyl
I-78
3-chlorophenyl
3-tert-butylphenyl
I-79
4-chlorophenyl
2-cyclopropylphenyl
I-80
3-fluorophenyl
2-cyclopropyl-4- fluorophenyl
I-81
3-chlorophenyl
3-chloro-5-fluorophenyl
I-82
3-chlorophenyl
3-chloro-5-fluorophenyl
I-83
3-chlorophenyl
3-chloro-5-fluorophenyl
I-84
3-chlorophenyl
3-chloro-5-fluorophenyl
I-85
3-chlorophenyl
3-chloro-5-fluorophenyl
I-86
3-chlorophenyl
3-chloro-5-fluorophenyl
I-87
3-chlorophenyl
3-chloro-5-fluorophenyl
I-88
3-chlorophenyl
3-chloro-5-fluorophenyl
I-89
3-chlorophenyl
3-chloro-5-fluorophenyl
I-90
3-chlorophenyl
3-chloro-5-fluorophenyl
I-91
3-chlorophenyl
3-chloro-5-fluorophenyl
I-92
3-chlorophenyl
3-chloro-5-fluorophenyl
I-93
3-chlorophenyl
3-chloro-5-fluorophenyl
I-94
3-chlorophenyl
3-chloro-5-fluorophenyl
I-95
3-chlorophenyl
3-chloro-5-fluorophenyl
I-96
3-chlorophenyl
3-chloro-5-fluorophenyl
I-97
3-chlorophenyl
3-chloro-5-fluorophenyl
I-98
3-chlorophenyl
3-chloro-5-fluorophenyl
I-99
3-chlorophenyl
3-chloro-5-fluorophenyl
I-100
3-chlorophenyl
3-chloro-5-fluorophenyl
I-101
3-chlorophenyl
3-chloro-5-fluorophenyl
I-102
3-chlorophenyl
3-chloro-5-fluorophenyl
I-103
3-chlorophenyl
3-chloro-5-fluorophenyl
I-104
3-chlorophenyl
3-chloro-5-fluorophenyl
I-105
3-chlorophenyl
3-chloro-5-fluorophenyl
I-106
3-chlorophenyl
3-chloro-5-fluorophenyl
I-107
3-cyanophenyl
3-chloro-5-fluorophenyl
I-108
3,4-difluorophenyl
3-chloro-5-fluorophenyl
I-109
3-chlorophenyl
3-chloro-5-fluorophenyl
I-110
3-chlorophenyl
3-chloro-5-fluorophenyl
I-111
3,4-difluorophenyl
3-chloro-5-fluorophenyl
I-112
3,4-difluorophenyl
3-chloro-5-fluorophenyl
I-113
3,4-difluorophenyl
3-chloro-5-fluorophenyl
I-114
3,4-difluorophenyl
3-chloro-5-fluorophenyl
I-115
3-chlorophenyl
3-chloro-5-fluorophenyl
I-116
3-chlorophenyl
3-chloro-5-fluorophenyl
I-117
3-chlorophenyl
3-chloro-5-fluorophenyl
I-118
3-chlorophenyl
3-chloro-5-fluorophenyl
I-119
3-chlorophenyl
3-chloro-5-fluorophenyl
I-120
3-chlorophenyl
3-chloro-5-fluorophenyl
I-121
3-chlorophenyl
3-chloro-5-fluorophenyl
I-122
3-chlorophenyl
3-chloro-5-fluorophenyl
I-123
3-chlorophenyl
3-chloro-5-fluorophenyl
I-124
3-chlorophenyl
3-chloro-5-fluorophenyl
I-125
3-chlorophenyl
3-chloro-5-fluorophenyl
I-126
3-chlorophenyl
3-chloro-5-fluorophenyl
I-127
3-chlorophenyl
3-chloro-5-fluorophenyl
I-128
3-chlorophenyl
3-chloro-5-fluorophenyl
I-129
3-chlorophenyl
3-chloro-5-fluorophenyl
I-130
3-chlorophenyl
3-chloro-5-fluorophenyl
I-131
3-chlorophenyl
3-chloro-5-fluorophenyl
I-132
3-chlorophenyl
3-chloro-5-fluorophenyl
I-133
3-chlorophenyl
3-chloro-5-fluorophenyl
I-134
3-chlorophenyl
3-chloro-5-fluorophenyl
TABLE 2A
Com-
pound
No.
Chemical Structure
A-13
A-14
A-15
A-16
A-17
A-18
A-19
A-20
A-21
A-22
A-23
A-24
A-25
A-26
A-27
A-28
A-29
A-30
A-31
A-32
A-33
A-34
A-35
A-36
A-37
A-38
TABLE 3A
Compound
No.
Chemical Structure
A-39
A-40
A-41
A-42
A-43
A-44
A-45
A-46
A-47
A-48
A-49
A-50
A-51
A-52
A-53
A-54
A-55
A-56
A-57
TABLE 6A
Compound
No.
Chemical Structure
A-58
18. The compound of claim 17 , wherein the compound is one of the following or a pharmaceutically acceptable salt thereof:
19. The compound of claim 17 , wherein the compound is
20. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
21. A method of treating a disorder selected from the group consisting of rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, uveitis, and epidermal hyperplasia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 in order to ameliorate a symptom of the disorder.
22. The method of claim 21 , wherein the disorder is Crohn's disease or ulcerative colitis.
23. A method of inhibiting a F 1 F 0 -ATPase, comprising exposing a F 1 F 0 -ATPase to a compound of claim 1 to inhibit said F 1 F 0 -ATPase.
24. The compound of claim 1 , wherein R 5 is C 3 -C 6 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 1 -C 4 haloalkyl.
25. The compound of claim 5 , wherein R 5 is C 3 -C 6 cycloalkyl or —(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 1 -C 4 haloalkyl.
26. A pharmaceutical composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier.