PYRAZOLOPYRIDYL COMPOUNDS AS ALDOSTERONE SYNTHASE INHIBITORS

摘要

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

主权项

1. A compound of the structural formula or a pharmaceutically acceptable salt thereofwherein:
Ring A is attached to Ring B via positions D and E and is: D is C; E is N; R1 is H or alkyl; R2 is halogen; —CN; —OR7; —N(R10)C(O)R7; —NR11R12; —C(O)R7; —C(O)N(R11)(R12); —C(O)OR7; —SO2N(R10)—R7; —N(R10)SO2—R7; —S(O)m—R7; alkyl optionally substituted one or more times by halogen, —OR7, NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; R3 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; cycloalkyl optionally substituted once or twice by alkyl or halogen; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)(R7), —C(O)N(R8)(R9), —C(O)OR7—SO2N(R10)—R7, —N(R10)SO2—R7, or —S(O)m—R7; or —C(O)OR7; R4 is H; halogen; —CN; —OR7; —NR8R9; —N(R10)C(O)R7; —C(O)N(R8)(R9); —C(O)R7; —C(O)OR7; —SO2N(R10)—R7; —N(R10)S(O)2—R7; —S(O)o—R7; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)S(O)2—R7, or —S(O)n—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR8, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)(R7), —C(O)N(R8)(R9), —C(O)OR7—SO2N(R10)—R7, —N(R10)SO2—R7, or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7—SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; R5 is H; halogen; —CN; —OR7; —NR8R9; —N(R10)C(O)R7; —C(O)N(R8)(R9); —C(O)R7; —C(O)OR7; —SO2N(R10)—R7; —N(R10)S(O)2—R7; —S(O)n—R7; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)S(O)2—R7, or —S(O)n—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)(R7), —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7;
or R4 and R5 are joined together to form a 5-7 membered carbocyclic or heterocyclic ring that is fused to the pyridyl ring to which R4 and R5 are attached, wherein the ring formed by R4 and R5 is optionally substituted by 1 to 3 R6; R6 is independently H; halogen; —CN; —OR7; —NR8R9; —N(R10)C(O)R7; —C(O)N(R7)(R8); —C(O)N(R8)(R9); —C(O)OR7; —SO2N(R10)—R7; —N(R10)SO2—R7; —S(O)m—R7; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7—SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)(R7), —C(O)N(R7)(R8), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —SO2N(R10)—R7, —N(R10)SO2—R7 or —S(O)m—R7; R7 is independently H; alkyl optionally substituted one or more times by halogen, —OR10, —NR8R9, —CN, —N(R10)C(O)R10, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR10, —NR8R9, —CN, —N(R10)C(O)R10, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OH, —OR10, —NR8R9, —CN, —N(R10)C(O)R10, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR10, —NR8R9, —CN, —N(R9)C(O)R10, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10; R8 is independently H or alkyl; R9 is independently H or alkyl;
or R8 and R9 are joined together with the nitrogen to which they are attached form a saturated 5- to 7-membered heterocyclic ring; R10 is independently H or alkyl; R11 is independently H; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)(R7), —C(O)N(R7)(R8), —C(O)OR7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; R12 is independently H; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)(R7), —C(O)N(R7)(R8), —C(O)OR7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; a is 0, 1, 2, 3 or 4; n is 1 or 2; and m is 0, 1 or 2.