Indoline compounds as aldosterone synthase inhibitors

摘要

This invention relates to indo line compounds of the structural formula I, or their pharmaceutically acceptable salts, wherein the variables 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 formula or a pharmaceutically acceptable salt thereofwherein:
R1 is —C(O)R7; —C(O)OR7; —C(S)R7; R2 is H; halogen; —CN; —OR7; —N(R10)C(O)R7; —NR11R12; —C(O)R7; —C(O)N(R11)(R12); —N(R10)C(O)—R7; —C(O)OR7; —OC(O)R7; —SO2N(R11)(R12); —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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —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(R8)(R9), —N(R10)SO2—R7 or —S(O)mR7; 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(R8)(R9), —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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —N(R10)SO2—R7 or —S(O)m—R7; R3 is H; halogen; —CN; —OR7; —N(R10)C(O)R7; —NR11R12; —C(O)R7; —C(O)N(R11)(R12); —N(R10)C(O)—R7; —C(O)OR7; —OC(O)R7; —SO2N(R11)(R12); —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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —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(R8)(R9), —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(R8)(R9), —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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —N(R10)SO2—R7 or —S(O)m—R7; R4 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen; R5 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen; R6 is H; halogen; —CN; alkyl optionally substituted one or more times by halogen or cycloalkyl optionally substituted once or twice by alkyl or halogen; or cycloalkyl optionally substituted once or twice by alkyl or halogen; 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)R10, —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, —OR10, —NR8R9, —CN, —N(R10)C(O)R10, —C(O)N(R8)(R9), —C(O)R10, —C(O)OR10—OC(O)R10, 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)R10, —C(O)OR10—OC(O)R10 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, alkyl or haloalkyl; 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)R7, —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)OR8 or —S(O)m—R8; 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)R7, —C(O)OR7, —OC(O)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)R7, —C(O)OR7, —OC(O)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)R7, —C(O)OR7, —OC(O)R7 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)R7, —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)OR8 or —S(O)m—R8; 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)R7, —C(O)OR7, —OC(O)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)R7, —C(O)OR7, —OC(O)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)R7, —C(O)OR7, —OC(O)R7 or —S(O)m—R7;
or R11 and R12 are joined together with the nitrogen to which they are attached form a saturated 5- to 7-membered heterocyclic ring; R13 is H; halogen; —CN; —OR7; —NR11R12; —N(R10)C(O)R7; —C(O)N(R11)(R12); —C(O)R7; —C(O)OR7; —OC(O)R7; —SO2N(R11)(R12); —N(R10)SO2—R7; —S(O)m—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, —OC(O)R7, —SO2N(R8)(R9), —N(R10)SO2—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(R8)(R9), —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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —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(R8)(R9), —N(R10)SO2—R7 or —S(O)m—R7; or monocyclic 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(R8)(R9), —N(R10)SO2—R7 or —S(O)m—R7; R14 is H; halogen; —CN; —OR7; —NR11R12; —N(R10)C(O)R7; —C(O)N(R11)(R12); —C(O)R7; —C(O)OR7; —OC(O)R7; —SO2N(R11)(R12); —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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —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(R8)(R9), —N(R10)SO2—R7 or —S(O)m—R7; aryl 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(R7)(R8), —C(O)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —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(R8)(R9), —N(R10)SO2—R7 or —S(O)m—R7; or monocyclic 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(R8)(R9), —N(R10)SO2—R7 or —S(O)m—R7; R15 is independently H; halogen; —CN; —OR7; —C(O)N(R8)(R9); —C(O)R7; —C(O)OR7; —OC(O)R7; —SO2N(R8)(R9); —N(R10)SO2—R7; —S(O)m—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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —N(R10)S(O)2—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)OR8, —SO2N(R8)(R9), —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)R7—C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —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)R7, —C(O)OR7, —OC(O)R7, —SO2N(R8)(R9), —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)R7, —OC(O)R7, —SO2N(R8)(R9), —N(R10)SO2—R7 or —S(O)m—R7; is a single or double bond; and m is 0, 1 or 2; provided that when R1 is benzyl or —C(O)alkyl, R5, R6 R13 and R14 cannot all be hydrogen at the same time and further provided that monocyclic heteroaryl cannot be a tetrazole ring.