Ip receptor agonist heterocyclic compounds

摘要

Disclosed are (2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)alkane carboxylic acid derivatives as represented by the general formula (Ia), or a pharmaceutically acceptable salt thereof, wherein: A is N or CH; R1 is H or alkyl; or R1 is -X-Y; or R1 is -W-R7-X-Y; or R2 is H, alkyl; or R2 is -X-Y; or R2 is -W-R7-X-Y; wherein either R1 or R2 is -X-Y or -W-R7-X-Y; R2a is hydrogen; or R2 and R2a taken together are oxo; R3 is H, alkoxy, OH or alkyl optionally substituted by one to 17 halogen atoms; R4 is H, alkoxy, OH or alkyl; R5 is aryl; -(C0-C4 alkyl)-4 to 14 membered heteroaryl, wherein the heteroaryl contains at least one heteroatom selected from N, O and S, wherein the aryl and heteroaryl are each optionally substituted by one to five Z substituents; R6 is aryl; -(C0-C4 alkyl)-4 to 14 membered heteroaryl, wherein the heteroaryl contains at least one heteroatom selected from N, O and S, wherein the aryl and heteroaryl are each optionally substituted by one to five Z substituents; W is alkylene optionally substituted by hydroxy, halogens or alkyl; X is alkylene optionally substituted by hydroxy, halogens or alkyl; Y is carboxy and alkoxycarbonyl; R7 is a divalent moiety represented by -O-, -NHC(O)-, -CH2=CH2- , -aryl-D-; -3 to 14 membered heterocyclyl-D-, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein D is 0, S, NH or not present; Z is independently alkyl optionally substituted by one to 13 halogen atoms, alkoxy or halogen; R19 and R21 are each independently H or alkyl. Representative compounds include 7-(2-phenyl-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid, 7-(8-hydroxy-2,3-di-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid; 7-(7-hydroxy-6-oxo-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid; 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b ]pyrazin-5(6H)-yl)heptanoic acid, 2-(3-((2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)methyl)phenoxy)acetic acid or 7-(3-phenyl-2-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid. Further disclosed is a pharmaceutical composition, comprising a therapeutically effective amount of a compound as defined above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, for the treatment of a disorder or disease selected from the group consisting of PAH, disorders in need of anti-platelet therapy, atherosclerosis, asthma, COPD, hyperglycemia, inflammatory disease, or fibrotic diseases.