Heterocyclic amides as rock inhibitors

摘要

The present invention relates to new kinase inhibitors, more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease.;In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases, ophthalmic diseases and Respiratory diseases.

主权项

1. A compound of Formula I or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof,Wherein
R1 is selected form the group comprising hydrogen, alkyl or cycloalkyl; Ar is selected from the group comprising: Wherein X is selected from the group comprising hydrogen or halo; Y is an aryl substituted with a substituent selected from the group consisting of —C(═O)—OR21; —C(═O)—SR22; —C(═O)—NR3R4; —NR5R6; —O—C1-6alkyl; —S—C1-6alkyl; —O—C2-8alkenyl; —S—C2-8alkenyl; —C1-6alkyl; or —C2-8alkenyl;
wherein said —O—C1-6alkyl; —S—C1-6alkyl; —O—C2-8alkenyl; —S—C2-8alkenyl; —C1-6alkyl; or —C2-8alkenyl are each independently substituted with a substituent selected from the group consisting of C(═O)—OR21; —C(═O)—SR22; —C(═O)—NR3R4; Het1; —O-Het2; and —S-Het3; R3 is selected from the group consisting of hydrogen; C2-8alkenyl substituted with O-Het2 or —S-Het3; or C1-20alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of aryl, heteroaryl, C3-6cycloalkenyl, —C(═O)—OR21; —C(═O)—SR22; —C(═O)—NR7R8; Het1; —O-Het2; —S-Het3; C1-6alkyl-S— and C1-6 alkyl-O—;
wherein said —O—C1-6alkyl; —S—C1-6alkyl; or C3-6cycloalkenyl; are each independently substituted with a substituent selected from the group consisting of C(═O)—OR21; —C(═O)—SR22; —C(═O)—NR3R4; Het1; —O-Het2; and —S-Het3; R4 is selected from the group consisting of C2-8alkenyl substituted with O-Het2 or —S-Het3; or C1-20alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of aryl, heteroaryl, C3-6cycloalkenyl, —C(═O)—OR21, —C(═O)—SR22, —C(═O)—NR7R8, Het1, —O-Het2, —S-Het3, —O—C1-6alkyl and —S—C1-6alkyl;
wherein said —O—C1-6alkyl; —S—C1-6alkyl; or C3-6cycloalkenyl; are each independently substituted with a substituent selected from the group consisting of C(═O)—OR21; —C(═O)—SR22; —C(═O)—NR3R4; Het1; —O-Het2; and —S-Het3; or; R3 and R4 together with the nitrogen atom to which they are attached form a heterocycle substituted with one substituent selected from the group consisting of —C(═O)—OR21; —C(═O)—SR22; —C(═O)—NR9R10; Het1; —O-Het2; —S-Het3:
C1-6alkyl; C1-6alkyl-O—C1-4alkyl; or C1-6alkyl-O—C2-4alkenyl; wherein each of said C1-6alkyl; C1-6alkyl-O—C1-4alkyl; or C1-6alkyl-O—C2-4alkenyl is each independently substituted with 1, 2, or 3 substituents each independently selected from the group consisting of aryl, heteroaryl, C3-6cycloalkenyl, —C(═O)—OR21; —C(═O)—SR22; —C(═O)—NR9R10; Het1; —O-Het2; and —S-Het3; R5 or R6 are independently selected from the group consisting of hydrogen; C1-6alkyl; C1-6alkyl-O—C1-6alkyl-; C1-6alkyl-S—C1-6alkyl-; C2-8alkenyl; C1-6alkyl-C(═O)— or C2-8alkenyl-C(═O)—; wherein at least one of R5 or R6 is selected from C1-6alkyl; C1-6alkyl-O—C1-6alkyl-; C1-6alkyl-S—C1-6alkyl-; C2-8alkenyl; C1-6alkyl-C(═O)— or C2-8alkenyl-C(═O)—, and wherein each of said C1-6alkyl; C1-6alkyl-O—C1-6alkyl-; C1-6alkyl-S—C1-6alkyl-; C2-8alkenyl; C1-6alkyl-C(═O)— or C2-8alkenyl-C(═O)— is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of aryl, heteroaryl, C3-6cycloalkenyl, —C(═O)—OR21; —C(═O)—SR22; Het1; —O-Het2; and —S-Het3; R7 or R8 are independently selected from the group consisting of hydrogen; or C1-6alkyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of aryl, heteroaryl, C3-6cycloalkenyl, —C(═O)—OR21; and —C(═O)—NH2; R9 or R10 are independently selected from the group consisting of hydrogen; or C1-6alkyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of aryl, heteroaryl, C3-6cycloalkenyl, —C(═O)—OR21; and —C(═O)—NH2; R13 or R14 are independently selected from the group consisting of hydrogen; C1-6alkyl; C1-6alkyl-O—C1-6alkyl-; C1-6alkyl-S—C1-6alkyl-; or C1-6alkyl-C(═O)— and wherein each of said C1-6alkyl; C1-6 alkyl-O—C1-6 alkyl-; C1-6alkyl-S—C1-6alkyl-; or C1-6alkyl-C(═O)— is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of —C(═O)—OR21; —C(═O)—SR22; Het1; —O-Het2; and —S-Het3; R21 is selected from the group consisting of C1-20alkyl; C1-20alkenyl; C1-20alkynyl; optionally substituted C3-15cycloalkyl; optionally substituted aryl; optionally substituted heterocyclyl; optionally substituted heteroaryl;
wherein said C1-20alkyl is optionally substituted with 1, 2, 3 or more substituents each independently selected from the group consisting of halo, cyano, hydroxy, aryl-O—, aryl-S—, aryl-S(═O)2—, aryl-C(═O), —C(═O)—NR13R14, —O—C(═O)—C1-6alkyl, C1-6alkyl-O—, C1-6alkyl-S—, aryl, heteroaryl, heterocyclyl and C3-15cycloalkyl or from the formula:or
R21 taken together with the oxycarbonyl and aryl to which it is attached forms a cyclic ester comprising from 4 to 9 carbon atoms in the cyclic ester ring; R22 is C1-20alkyl optionally substituted with 1, 2, 3 or more substituents each independently selected from the group consisting of halo, hydroxy, amino, cyano, and mono- or di-(C1-4alkyl)amino; Het1, Het2 or Het3 are independently selected from the group comprising: