SUBSTITUTED PYRIMIDINYL PYRROLES ACTIVE AS KINASE INHIBITORS Russian patent published in 2017 - IPC C07D403/04 A61K31/506 A61P35/00 C07F5/02 

FIELD: chemistry.

SUBSTANCE: substituted pyrimidinyl pyrrole compounds or pharmaceutically acceptable salts thereof are selected from the group consisting of 5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide, 5-(2-aminopyrimidin-4-yl)-2-(2,5-dichlorophenyl)-1H-pyrrole-3-carboxamide, 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1H-pyrrole-3-carboxamide, 5-(2-minopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-methyl-1H-pyrrole-3-carboxamide, 5-(2-aminopyrimidin-4-yl)-2-(5 chloro-2-ethylphenyl)-N-ethyl-1H-pyrrole-3-carboxamide, 5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-N-methyl-1H-pyrrole-3-carboxamide, 2-(5-chloro-2-methylphenyl)-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide and 5-(2-aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-N-methyl-1H-pyrrole-3-carboxamide. The invention also relates to versions of the method for preparation of these compounds. For example, the method may include the steps (1): metal-catalyzed coupling reaction of a halogenated derivative of formula

with a substituted phenylboronic acid of formula

or henylboronic acid ester of formula

,

(2) alkaline hydrolysis of the obtained carboxylic acid ester of formula

(3) amidation of the obtained carboxylic acid ester of formula

by a reaction with a derivative of formula (VI) NHR8R9, to obtain a compound of formula

wherein R1, R2, R3, R4, R8 and R9 values are given in the claims, and R12 is hydrogen; and if desired, convertion of a compound of formula (I) to a pharmaceutically acceptable salt or salt convertion to the free compound (I). Method versions include amidation of the carboxylic acid ester of formula (IV) without carboxylic acid (V) isolation or direct preparation of formula I compound without isolation of the intermediate compound of formula (IV) and (V). To prepare the formula I compound, where R12 is hydrogen, the method may include the steps of interaction of pyrrole of formula (VIII) with acetyl chloride to give compound IX, which forms enaminone X by reaction with dimethylformamide dialkyl acetal. Formulas VIII-XII are indicated in the claims.

EFFECT: compound X is reacted with guanidine or its salt of formula XI and hydrolysis of the obtained pyrimidinyl pyrrole nitrile of formula XII is carried out under acidic conditions.

10 cl, 1 tbl, 8 ex

алкил - alkyl