Saturated acyl guanidine for inhibition of F₁F₀-ATPase

摘要

The invention provides saturated acyl guanidine compounds that inhibit F1F0-ATPase, and methods of using saturated acyl guanidine compounds as therapeutic agents to treat medical disorders, such as an immune disorder, inflammatory condition, or cancer.

主权项

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: A1 is pyrazolyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of phenyl, alkyl, haloalkyl, cycloalkyl, halogen, hydroxyl, hydroxyalkyl, and C1-6alkoxy, 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, C1-6alkoxy, and cyano; R1 is alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, alkylene-O-alkyl, alkylene-cycloalkyl, alkylene-heterocycloalkyl, aralkyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, or 1,2,3,4-tetrahydronaphthalen-2-yl, wherein the cycloalkyl, heterocycloalkyl, aralkyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, and 1,2,3,4-tetrahydronaphthalen-2-yl are optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, hydroxyl, alkoxyl, and cyano; R2 and R4 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(R5)2)m-alkoxyl, —N(R6)(R7), heterocycloalkyl, —N(R6)C(O)-alkyl, —C(O)N(R6)(R7), —N(R6)C(O)N(R6)(R7), halogen, haloalkyl, and cyano; or(ii) cycloalkyl, —(C(R5)2)m-cycloalkyl, aryl, or aralkyl, 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; R5 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl; or two occurrences of R5 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring; 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 C1-6alkoxy; and m is 1, 2, 3, 4, or 5.