HETEROCYCLIC COMPOUNDS AND METHODS OF THEIR USE

摘要

The present invention relates generally to compounds that are useful in antagonizing the angiotensin II type 2 (AT2) receptor. More particularly, the invention relates to substituted isoquinoline compounds and their use as AT2 receptor antagonists. Pharmaceutical compositions comprising the compounds and their use in modulating the AT2 receptor and therapies that require modulation of the AT2 receptor are described.

主权项

1. A compound of formula (I): wherein R1 is —C(═O)CHR6R7, —C(═O)NR6R7, —C(═O)CH2CHR6R7, —C(═O)CH═CR6R7, —C(═S)CHR6R7, —C(═S)NR6R7, —C(═S)CH2CHR6R7, —C(═S)CH═CR6R7, —C(═NR8)CHR6R7, —C(═NR8)NR6R7, —C(═NR8)CH2CHR6R7 and —C(═NR8)CH═CR6R7; one of R2 and R3 is hydrogen or oxo (═O) and the other is a carboxylic acid, —CH2CO2H, —C(═O)-2-glucuronic acid, —C(═O)C(═O)OH, —CH2OH, —C(═O)NH2, —CH2C(═O)NH2, —CN, —CH2CN, a carboxylic acid bioisostere or a —CH2-carboxylic acid bioisostere; R4 is hydrogen, R9, —C1-6alkylR9, —C2-6alkenylR9, —C2-6alkynylR9, —OH, —OR9, —OC1-6alkylR9, —OC2-6alkenylR9, —OC2-6alkynylR9, —NHC(═O)R9, —NHC(═O)C1-6 alkylR9, —NHC(═O)C2-6alkenylR9, —NHC(═O)C2-6alkynylR9, —NHC(═O)NHR9, —NHC(═O)NHC1-6alkylR9, —NHC(═O)NHC2-6alkenylR9, —NHC(═O)NHC2-6 alkynylR9, —NHC(═O)OR9, —NHC(═O)OC1-6alkylR9, —NHC(═O)OC2-6 alkenylR9, —NHC(═O)OC2-6alkynylR9, —NHSO2R9, —NHSO2C1-6alkylR9, —NHSO2C2-6 alkenylR9, —NHSO2C2-6alkynylR9, —SO2NHR9, —SO2NHC1-6alkylR9, —SO2NHC2-6 alkenylR9, —SO2NHC2-6alkynylR9, —C(═O)NHR9, —C(═O)NHC1-6alkylR9, —C(═O)NHC2-6 alkenylR9, —C(═O)NHC2-6alkynyl R9, —C(═O)R9, —C(═O)C1-6alkylR9, —C(═O)C2-6 alkenylR9, —C(═O)C2-6alkynylR9, —C(═O)OR9, —C(═O)OC1-6alkylR9, —C(═O)OC2-6 alkenylR9, —C(═O)OC2-6alkynylR9, —C(═O)NHR9, —C(═O)NHC1-6alkylR9, —C(═O)NHC2-6alkenylR9 or —C(═O)NHC2-6alkynylR9; R5 is hydrogen, —OH, —C1-6alkyl, —OC1-6alkyl, —C(R10)3, —OC(R10)3, aryl, —C1-6alkylaryl or —OC1-6 alkylaryl; R6 and R7 are independently hydrogen, —C1-6alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —CH2aryl, —CH2cycloalkyl, —CH2cycloalkenyl, —CH2heterocyclyl or —CH2heteroaryl; provided that R6 and R7 are not both hydrogen; R8 is hydrogen, —C1-6alkyl, aryl or —C1-6alkylaryl; R9 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl; each R10 is independently selected from the group consisting of hydrogen and halogen; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl may be optionally substituted; or a pharmaceutically acceptable salt thereof; provided that:
(i) R4 and R5 are not both hydrogen; and(ii) when R2 is —CH2OH, CO2H or a carboxylic acid bioisostere and R4 is hydrogen, phenyl, —Ophenyl, —C1-4alkylphenyl or —OC1-4alkylphenyl in which the alkyl group is unsubstituted, biphenyl, —Obiphenyl, naphthyl or —Onaphthyl, R5 is not hydrogen, —OC1-6alkyl, phenyl, benzyl, naphthyl, biphenyl or —Oaryl.