Scheme summarizes the synthesis of compounds Compound

Scheme 2 summarizes the synthesis of compounds 15-34–15-44. Compound 15-34 was prepared by selective N-methylation of the amide of 15-20. The common intermediate 13 was reacted with phenylcarbonochloridate. The addition of (3,4-dichlorophenyl)methanol followed by hydrolysis of the resulting ester moiety generated 15-35. With regard to the synthesis of compounds 15-36, 13 was treated with 3,4-dichlorobenzylbromide in the presence of potassium carbonate, and the ester moiety was hydrolyzed by sodium hydroxide. Compound 15-37 was synthesized by the reaction of the aniline intermediate 13 with 3,4-dichlorobenzene-1-sulfonyl chloride in the presence of pyridine followed by basic hydrolysis of the ester moiety. Intermediate 12b was prepared from methyl 1-chloroisoquinoline-4-carboxylate and t-butyl 4-(cyanomethyl)benzoate, in a manner similar to the synthesis of 12a as described in Scheme 1. Using 12b, compounds 15-38–15-41 were prepared as follows: (1) acidic removal of the ester moiety (TFA); (2) conversion to acyl chloride (oxalyl chloride); (3) condensation of the acyl chloride with 3,4-dichloroaniline; and (4) hydrolysis of the ester moiety. 15-42–15-44 were achieved by demethylation of 12c by boron tribromide, which was derived from methyl 1-chloroisoquinoline-4-carboxylate and 2-(4-methoxyphenyl)acetonitrile in a procedure similar to the synthesis of 12a (Scheme 1), and the subsequent etherification of the resulting phenol followed by hydrolysis. Compounds 15-45 and 15-46, in which the acetic SU6668 moiety at the 4-position of the isoquinoline core was modified, were synthesized as shown in Scheme 3, Scheme 4. Geminal dimethylation of 12b by sodium hydride and iodomethane resulted in 16 with a 72% yield. Deprotection of the t-butyl ester moiety using TFA, followed by the condensation reaction of 17 with 4-chlorophenethylamine (WSC·HCl, HOBT·H2O), gave 18 in a 44% yield. Finally, hydrolysis of the ester moiety afforded the target derivative 15-45. Compound 15-46 was synthesized from commercially available 4-bromo-1-chloroisoquinoline (19), which was reacted with methyl 4-(cyanomethyl)benzoate in the presence of sodium hexamethyldisilazane. Subsequent oxidative decyanation afforded 20. Compound 20 was converted to 22 using the boronic acid ester 21 by the following two-step reaction method: (1) treatment with bis(pinacolato)diboron in the presence of PdCl2(dppf) and potassium acetate; and (2) oxidation of 21 using oxone. Transformation of 22 into the target compound 15-46 was accomplished using the following conventional method: (1) alkylation of the hydroxyl moiety in 22 with t-butyl 2-bromoacetate in the presence of potassium carbonate; (2) basic hydrolysis of the methyl ester (NaOH); (3) condensation of the acid with 4-chlorophenethylamine (WSC–HCl and HOBT–H2O); and (4) hydrolysis of the t-butyl ester moiety.
Results and discussion Compounds were tested for their binding affinity to human CRTH2 in a radioligand binding assay (3H-PGD2) using CHO cells stably transfected with human CRTH2. In addition, these compounds were assessed for their functional activity in PGD2 driven Ca2+ flux in KB8 cells expressing human CRTH2.