Heterocyclic guanidine F1F0-atpase inhibitors and therapeutic uses thereof

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:
• A1 is a five-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C1-C6alkoxy, cyano, —CO2R4, —C(O)R5, —S(O)R5, —SO2R5, —SO2N(R6)(R7), —C(O)N(R6)(R7), —N(R6)(R7), and —N(R4)C(O)(R5);
• A2 is one of the following:
• (i) heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of phenyl, alkyl, haloalkyl, cycloalkyl, halogen, hydroxyl, hydroxyalkyl, and C1-C6alkoxy, wherein the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, C1-C6alkoxy, and cyano;
• or
• (ii) aryl or aralkyl, each of which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, C1-C6alkoxy, and cyano;
• R1 and R2 each represent independently hydrogen or alkyl;
• R3 is one of the following:
• (i) alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, alkoxyl, —O—(C(R4)2)m-alkoxyl, —N(R6)(R7), heterocycloalkyl, —N(R6)C(O)R8, —C(O)N(R6)(R7), —N(R6)C(O)N(R6)(R7), halogen, haloalkyl, and cyano;
• (ii) aryl, aralkyl, cycloalkyl, or —(C(R4)2)m-cycloalkyl, each of which are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, alkoxy, —S-alkyl, and cyano;
• (iii) aryl substituted by heterocycloalkyl, wherein the aryl and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, and alkyl;
• or
• (iv) heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, alkoxy, —S-alkyl, cyano, amino, and oxo;
• R4 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl;
• or two occurrences of R4 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring;
• R5 represents independently for each occurrence alkyl or cycloalkyl;
• R6 and R7 each represent independently for each occurrence hydrogen, alkyl, or cycloalkyl;
• or R6 and R7 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 C1-C6alkoxy;
• R8 is alkyl, cycloalkyl, aryl, or aralkyl;
• and
• m is 1, 2, 3, 4, or 5.