Alkylpyrazolyl guanidine F
View Patent ↗The invention provides pyrazolyl guanidine compounds that inhibit F 1 F o -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 thereof; wherein:
A 1 is
A 2 is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, and C 1 -C 3 haloalkyl;
R 1 represents independently for each occurrence chloro, fluoro, C 1 -C 6 alkoxy, trifluoromethyl, or cyano;
R 2 is hydrogen, chloro, fluoro, C 1 -C 6 alkoxy, or trifluoromethyl;
R 3 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or —(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl);
R 4 is C 1 -C 3 haloalkyl;
R 5 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; and
n is 1 or 2.
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 thereof.
3. The compound of claim 2 , wherein n is 1.
4. The compound of claim 3 , wherein R 1 is fluoro.
5. The compound of claim 3 , wherein R 1 is meta-fluoro.
6. The compound of claim 3 , wherein R 1 is chloro, and R 2 is chloro.
7. The compound of claim 4 , wherein R 2 is fluoro.
8. The compound of claim 5 , wherein R 2 is para-fluoro.
9. The compound of claim 2 , wherein R 3 is C 1 -C 6 alkyl.
10. The compound of claim 9 , wherein R 4 is trifluoromethyl.
11. The compound of claim 10 , wherein R 5 is hydrogen.
12. The compound of claim 10 , wherein R 5 is C 1 -C 6 alkyl.
13. The compound of claim 10 , wherein R 5 is C 3 -C 6 cycloalkyl.
14. The compound of claim 2 , wherein A 2 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
15. The compound of claim 10 , wherein A 2 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro and fluoro.
16. The compound of claim 1 , wherein the compound is represented by Formula I-A:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt thereof; wherein:
R 1 is chloro or fluoro;
R 2 is hydrogen, chloro, or fluoro;
R 3 is C 1 -C 6 alkyl;
R 4 is trifluoromethyl;
R 5 is hydrogen or C 1 -C 6 alkyl; and
A 2 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro and fluoro.
17. The compound of claim 16 , wherein R 1 is meta-fluoro, and R 2 is para-fluoro.
18. The compound of claim 16 , wherein R 3 is methyl or ethyl.
19. The compound of claim 16 , wherein R 5 is hydrogen.
20. The compound of claim 16 , wherein R 5 is C 1 -C 6 alkyl.
21. The compound of claim 17 , wherein A 2 is 3-chloro-5-fluorophenyl.
22. The compound of claim 1 , wherein the compound is a compound listed in any one of Tables 1-4 or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
25. A method of treating a disorder selected from the group consisting of an immune disorder, inflammatory disorder, cardiovascular disease, myeloma, lymphoma, cancer, and bacterial infection, 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.
26. The method of claim 25 , 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.
27. The method of claim 25 , wherein the disorder is Crohn's disease or ulcerative colitis.
28. 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.