Aldosterone synthase inhibitors

摘要

This invention relates to tricyclic triazole analogs of the formula I or their pharmaceutically acceptable salts, wherein the variable are defined herein. The inventive compounds selectively inhibit aldosterone synthetase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as to methods for the treatment, amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthetase.;

主权项

1. A compound of the formula I or a pharmaceutically acceptable salt thereofwherein:
X is N or C(R6); R1 is H; alkyl optionally independently substituted one or more times by halogen, —OR7, NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, or —S(O)m—R7; cycloalkyl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; aryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9 —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, or —S(O)m—R7; or heteroaryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; R2 is H; halogen; —CN; alkyl optionally independently substituted one or more times by halogen; or cycloalkyl optionally independently substituted once or twice by alkyl or halogen; R3 is H; halogen; —CN; alkyl optionally independently substituted one or more times by halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen; R4 is H; halogen; —CN; alkyl optionally independently substituted one or more times by halogen; or cycloalkyl optionally independently substituted once or twice by alkyl or halogen; R5 is H; halogen; —CN; —OR7; —NR8R9; —N(R11)C(O)R7; —C(O)R7; —C(O)N(R8)(R9); —C(O)OR7; —N(R11)S(O)2R7; —S(O)2N(R8)(R9); —S(O)m—R7; alkyl optionally independently substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; cycloalkyl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, aryl (optionally substituted once or twice by halogen, alkyl, haloalkyl, cycloalkyl or aryl), heteroaryl (optionally substituted one or twice by halogen, alkyl, haloalkyl, cycloalkyl or aryl), —OR7, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; aryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, aryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), heteroaryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), —CN, —NR8R9 —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; aralkyl wherein the aryl ring is optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, aryl (optionally substituted one or twice by halogen, alkyl, or haloalkyl), heteroaryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), —OR7, —CN, —NR8R9 —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7 and the alkyl chain is straight or branched and optionally substituted one or more times by halogen or —OR7; heterocycloalkyl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9 —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; heteroaryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, aryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), heteroaryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), —OR7, —CN, —NR8R9, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; or heteroaralkyl wherein the heteroaryl ring is optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, aryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), heteroaryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), —OR7, —CN, —NR8R9 —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7 and the alkyl chain is straight or branched and optionally substituted one or more times by halogen or —OR7; R6 is H; halogen; —CN; —OR7; —NR8R9; —N(R11)C(O)R7; —C(O)N(R8)(R9); —C(O)R7; —C(O)OR7; —N(R11)S(O)2R7; —S(O)2N(R8)(R9); —S(O)m—R7; alkyl optionally independently substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; cycloalkyl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, aryl (optionally substituted once or twice by halogen, alkyl, haloalkyl, cycloalkyl or aryl), heteroaryl (optionally substituted once or twice by halogen, alkyl, haloalkyl, cycloalkyl or aryl), —OR7, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR8 or —S(O)m—R8; aryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, aryl (optionally substituted one or twice by halogen, alkyl, or haloalkyl), heteroaryl (optionally substituted one or twice by halogen, alkyl, or haloalkyl), —OR7, —CN, —NR8R9 —N(R11)C(O)(R7), —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; aralkyl wherein the aryl ring is optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, aryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), heteroaryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), —OR7, —CN, —NR8R9 —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7 and the alkyl chain is straight or branched and optionally substituted one or more times by halogen or —OR7; heterocycloalkyl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9 —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; heteroaryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, aryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), heteroaryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), —OR7, —CN, —NR8R9, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; heteroaralkyl wherein the heteroaryl ring is optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, aryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), heteroaryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), —OR7, —CN, —NR8R9 —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7 and the alkyl chain is straight or branched and optionally substituted one or more times by halogen or —OR7;or R5 and R6 are joined together to form a 5-7 membered carbocyclic or heterocyclic ring that is fused to the pyridyl ring to which R5 and R6 are attached, wherein the ring formed by R5 and R6 is optionally independently substituted by 1 to 3 R10;
R7 is independently selected from the group consisting of H; alkyl optionally independently substituted one or more times by halogen, —OR11, —NR8R9, —CN, —N(R11)C(O)R11, —C(O)N(R8)(R9), —C(O)OR11 or —S(O)m—R11, aryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl), heteroaryl (optionally substituted once or twice by halogen, alkyl, or haloalkyl); cycloalkyl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, —OR11, —NR8R9, —CN, —N(R11)C(O)R11, —C(O)N(R8)(R9), —C(O)OR11 or —S(O)m—R11, aryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OH, —OR11, —NR8R9, —CN, —N(R11)C(O)R11, —C(O)N(R8)(R9), —C(O)OR11 or —S(O)m—R11; or heteroaryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR11, —NR8R9, —CN, —N(R9)C(O)R11, —C(O)N(R8)(R9), —C(O)OR11 or —S(O)m—R11; R8 is independently H or alkyl; R9 is independently H or alkyl; R10 is independently H; halogen; —CN; —OR7; —NR8R9; —N(R11)C(O)R7; —C(O)N(R7)(R8); —C(O)N(R8)(R9); —C(O)OR7; —S(O)m—R7; alkyl optionally independently substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; cycloalkyl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, —OR1, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR8 or —S(O)m—R8; aryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9 —N(R11)C(O)(R7), —C(O)N(R7)(R8), —C(O)OR7 or —S(O)m—R7; heterocycloalkyl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9 —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; or heteroaryl optionally independently substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; R11 is independently H or alkyl; is an optional double bond; n is 1 or 2; and m is 0, 1 or 2.