N-substituted pyrazolyl guanidine F
View Patent ↗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) C 1 -C 6 alkyl substituted by 1 or 2 substituents independents from the group consisting of hydroxyl, C 1 -C 6 alkoxy, 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 ), —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 7 )(R 8 ), and —N(R 7 )SO 2 (R 6 ); or
(b) C 2 -C 6 alkenyl;
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 1 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 2 is hydrogen.
6. The compound of claim 4 , wherein R 3 is hydrogen.
7. The compound of claim 4 , wherein R 4 is trifluoromethyl.
8. The compound of claim 1 , wherein R 5 is C 1 -C 6 alkyl substituted by 1 or 2 substituents independently selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, 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 ), —S(O)R 6 , —SO 2 R 6 , and —SO 2 N(R 7 )(R 8 ).
9. The compound of claim 7 , wherein R 5 is C 1 -C 6 alkyl substituted by 1 or 2 substituents independently selected from the group consisting of hydroxyl, cyano, —CO 2 H, —CO 2 —(C 1 -C 6 alkyl), and —C(O)N(R 7 )(R 8 ).
10. The compound of claim 1 , wherein said compound is represented by Formula I-B:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt 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 C 1 -C 6 alkyl substituted by 1 or 2 substituents independently selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, cyano, —CO 2 H, —CO 2 R 6 , —C(O)R 6 , and —C(O)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 A 1 is 3-chloro-5-fluoro-phenyl.
12. The compound of claim 10 , wherein R 3 is hydrogen, methyl, or ethyl.
13. The compound of claim 12 , wherein R 4 is trifluoromethyl.
14. 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) C 1 -C 6 alkyl substituted by 1 or 2 substituents independently selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, 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 ), —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 7 )(R 8 ), and —N(R 7 )SO 2 (R 6 ); or
(b) C 2 -C 6 alkenyl;
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.
15. A compound in Table 2-A below, or a pharmaceutically acceptable salt thereof:
TABLE 2-A
Compound
No.
Chemical Structure
A-1
A-2
A-3
A-4
A-5
A-6
A-7
A-8
A-9
A-10*
A-11*
A-12
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A method of treating a disorder, 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, wherein the disorder is 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, or epidermal hyperplasia.
18. The method of claim 17 , wherein the disorder is Crohn's disease or ulcerative colitis.
19. 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.
20. A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier.
21. A pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier.