Bicyclic dihydroisoquinoline-1-one derivatives

摘要

The invention provides novel compounds having the general formula (I);
wherein R1, R2, R3, R4, R5, R6, A1, A2, A3, A4, A5 and n are as described herein, compositions including the compounds and methods of using the compounds. The compounds are useful, for example, as aldosterone synthase (CYP11B2 or CYP11B1) inhibitors for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome.

主权项

1. A compound according to formula (I), wherein R1, R2, R3 and R4 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halocycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, halocycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl are substituted with R12, R13and R14; or R2 and R4 together form a double bond, wherein in case R2 and R4 together form a double bond, then R5 is H; or R1 and R2 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R22, R23and R24; or R3 and R4 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R29, R30and R31; or R1 and R3 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R44, R45and R46; A1 is CR8 or N; A2 is CR9 or N; A3 is CR10 or N; A4 is CR11 or N; A5 is CR6 ; one of R5, R6, R7 and R8 is selected from the group consisting of halogen, cyano, alkoxy, hydroxyalkoxy, haloalkyl, haloalkoxy and hydroxy and the others are each independently selected from the group consisting of H, halogen, cyano, alkoxy, hydroxyalkoxy, haloalkoxy and hydroxy; R9 is selected from the group consisting of H, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl, substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl and substituted heteroarylalkyl, wherein substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl and substituted heteroarylalkyl are substituted with R32, R33and R34; R10 is —Om—(CR15R16)p—(CR17R18)q—(CR19R20)r—R21; or R9 and R10 together with the carbon atoms to which they are attached form a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl or a substituted heteroaryl, wherein substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl are substituted with R35, R36and R37; R11 is H; R15, R17 and R19 are each independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl and halocycloalkyl; R16, R18 and R20 are each independently selected from the group consisting of H, hydroxy, halogen and alkyl; or R15 and R16 together with the carbon atom to which they are attached form a cycloalkyl; or R17 and R18 together with the carbon atom to which they are attached form a cycloalkyl; or R19 and R20 together with the carbon atom to which they are attached form a cycloalkyl; or R15 and R17 together form —(CH2)v—; or R15 and R19 together form —(CH2)w—; or R17 and R19 together form —(CH2)x—; R21 is selected from the group consisting of H, halogen, cyano, —OR25, —SR25, —S(O)R25, —S(O)2R25, —NR25R26, —NR26SO2R25, —NR26 SO2NR25R27, —NR26C(O)R25, —HR26C(O)NR25R27, —C(O)R28, —C(O)NR25R26, cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl and substituted aryl, wherein substituted heterocycloalkyl, substituted heteroaryl, substituted heteroarylalkyl and substituted aryl are substituted with R38, R39and R40; R25 is selected from the group consisting of H, alkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxyalkyl, cycloalkoxyalkyl, halocycloalkoxyalkyl, alkylcycloalkoxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkoxyalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R41, R42and R43; R26 and R27 are each independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl and halocycloalkyl; or R15 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49; or R17 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49; or R19 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49; R28 is selected from the group consisting of H, hydroxy, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R50, R51and R52; R12, R13, R14, R22, R23, R24, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51 and R52 are each independently selected from the group consisting of H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkylcarbonylamino, alkylsulfonyl, alkylsulfonylamino, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxycarbonyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl, chloropyridinylcarbonyl and heterocycloalkyl; n is zero or 1; m is zero or 1; p, q and r are independently selected from zero and 1; v and x are independently 1, 2, 3 or 4; and w is zero, 1, 2 or 3; with the proviso that no more than one of A2, A3 and A4 is N; or a pharmaceutically acceptable salt thereof.