Pyridonyl guanidine F
View Patent ↗The invention provides pyridonyl guanidine compounds that inhibit F 1 F 0 -ATPase, and methods of using pyridonyl 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 phenylene or a six-membered heteroarylene;
A 2 is
X is halogen, haloalkyl, C 1 -C 6 alkoxy, —N(H)(R 8 ), or —OP(O)(OR 11 ) 2 ;
R 1 represents independently for each occurrence halogen, alkyl, haloalkyl, hydroxyl, C 1 -C 6 alkoxy, or cyano;
R 2 is hydrogen or alkyl;
R 3 is aryl, aralkyl, cycloalkyl, —(C(R 6 ) 2 ) m -cycloalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, —(C(R 6 ) 2 ) m -heterocycloalkyl, alkyl, haloalkyl, hydroxylalkyl, —(C(R 6 ) 2 ) m -alkoxyl, or —(C(R 8 ) 2 ) m —CN, wherein said aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, C 1 -C 6 alkoxy, and cyano;
R 4 is hydrogen, alkyl, or —C(O)R 7 ; or R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy;
R 5 is hydrogen, halogen, alkyl, alkoxyl, or —C(O)R 7 ;
R 6 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl;
R 7 represents independently for each occurrence alkyl or cycloalkyl;
R 8 is hydrogen or alkyl;
R 9 is alkyl, cycloalkyl, haloalkyl, —(C(R 6 ) 2 ) m -cycloalkyl, —(C(R 6 ) 2 ) m —CN, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 10 is alkyl, cycloalkyl, —(C(R 6 ) 2 ) m -cycloalkyl, haloalkyl, or C 1 -C 6 alkoxy;
R 11 represents independently for each occurrence hydrogen or an alkali metal;
n is 0, 1, 2, or 3; and
m is 1, 2, 3, 4, or 5.
2. The compound of claim 1 , wherein A 1 is phenylene.
3. The compound of claim 1 , wherein A 2 is
4. The compound of claim 2 , wherein A 2 is
5. The compound of claim 1 , wherein R 1 is halogen or haloalkyl.
6. The compound of claim 4 , wherein R 1 is chloro, fluoro, or trifluoromethyl.
7. The compound of claim 4 , wherein R 2 and R 4 are hydrogen.
8. The compound of claim 1 , wherein R 3 is aryl or aralkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and cycloalkyl.
9. The compound of claim 1 , wherein R 3 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and cycloalkyl.
10. The compound of claim 1 , wherein R 3 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
11. The compound of claim 1 , wherein R 3 is benzyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and cycloalkyl.
12. The compound of claim 1 , wherein R 3 is alkyl, hydroxyalkyl, cycloalkyl, or —(C(R 6 ) 2 ) m -alkoxyl, wherein said cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, and alkyl.
13. The compound of claim 4 , wherein R 5 is hydrogen.
14. The compound of claim 1 , wherein n is 1 or 2.
15. The compound of claim 1 , wherein said compound is represented by Formula I-A:
including all stereoisomers, geometric isomers, tautomers, or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
R 1 and R 2 each represent independently for each occurrence hydrogen, chloro, fluoro, or —CF 3 ; and
R 3 is aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein said aryl, aralkyl, heteroaryl, and heteroaralkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, C 1 -C 6 alkoxy, and cyano.
16. The compound of claim 15 , wherein R 1 and R 2 are independently chloro or fluoro.
17. The compound of claim 16 , wherein R 3 is aryl or aralkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, and alkyl.
18. The compound of claim 16 , wherein R 3 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
19. The compound of 16 , wherein R 3 is benzyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
20. The compound of claim 1 , wherein the compound is one of compounds listed in Table 1 or 2, or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 , wherein the compound is
23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
24. The pharmaceutical composition of claim 23 , wherein the compound is
25. A method of treating a disorder selected from the group consisting of an immune disorder, inflammatory disorder, cardiovascular disease, myeloma, lymphoma, 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. 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.