Preparation of tyrosine amide derivatives as Rho-​kinase inhibitors

Abstract

The invention relates to compds. of formula I and pharmaceutically acceptable salts and solvates thereof (wherein X1 and X2 are independently CH and N; p = 1 - 3; each R when present is halo; R0 and R1 are independently H, halo, CN, etc.; R2 and R3 are independently H, C1-​6 alkyl, C3-​10 cycloalkyl, etc.; R4 and R5 are independently H, C1-​6 alkyl, C1-​6 aminoalkyl, etc.; R6 is H, C1-​6 (halo)​alkyl, etc.;) as Rho kinase inhibitors, methods of prepg. such compds., pharmaceutical compns. contg. them and therapeutic use thereof. Particularly the compds. of the invention may be useful in the treatment of many disorders assocd. with ROCK enzymes mechanisms, such as pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD)​, idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH)​. Example compd. II was prepd. by a multistep procedure (procedure given)​. The invention compds. were evaluated for their ROCK1 and ROCK2 inhibitory activities. From the assay, it was detd. that compd. II exhibited Ki value of < 3 nM.