2-PHENYLAMINOPYRIMIDINE DERIVATIVES AS LEUCINE-RICH REPEAT KINASE 2 (LRRK2) MODULATORS FOR TREATMENT OF PARKINSON'S DISEASE

摘要

FIELD: chemistry.;SUBSTANCE: invention relates to novel compounds of formula I and formula II or pharmaceutically acceptable salts thereof, having the properties of a leucine repeat kinase inhibitor 2 (LRRK2, id est "Leucine Rich Repeat Kinase"). Compounds of formula I and formula II correspond to structures; ;or ;In the compound of formula I, m is 0, 1 or 2; X is -NR^a- or -O-, and R^a represents a hydrogen atom or C_1-6alkyl; R¹ is C_1-6alkyl or C_3-6cycloalkyl optionally substituted with a halogen atom, or, if X is NH, R¹ is deuterated C_3-6cycloalkyl; or R¹ and R^a together with the atoms to which they are attached, can form a three-six-membered ring; R² is a halogen atom, cyano or halo-C_1-6alkyl; R³ is -OR⁴, a halogen atom or C_1-6alkyl; R⁴ is a hydrogen atom, C_1-6alkyl, halogen-C_1-6alkyl, C_3-6cycloalkyl or C_3-6cycloalkyl-C_1-6alkyl; R⁵ is a hydrogen atom or C_1-6alkyl; R⁶ is a hydrogen atom, C_1-6alkyl, hydroxy-C_1-6alkyl, C_3-6cycloalkyl-C_1-6alkyl, optionally substituted with hydroxy, 5-6 membered heteroaryl or heterocyclyl with 1 to 2 nitrogen atoms as ring heteroatoms; where heteroaryl and heterocyclyl each may be optionally substituted with C_1-6alkyl; or R⁵ and R⁶ together with the nitrogen atom to which they are attached, form a four-seven-membered ring, optionally including an additional heteroatom selected from O and N, and optionally substituted with one or two groups independently selected from the following groups: C_1-6alkyl, C_1-6alkoxy, halogen-C_1-6alkoxy, C_1-6alkoxy-C_1-6alkyl, hydroxy-C_1-6alkyl, halogen atom, C_3-6cycloalkyl-C_1-6alkyl and 4-6 membered heterocyclyl with 1 to 2 heteroatoms selected from N and O; or R⁵ and R⁶ together with the nitrogen atom to which they are attached, and an additional heteroatom O form a deuterated morpholino group; or hexahydro-pyrrolo [1,2-a]pyrazinyl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 1-oxa-6-aza-spiro[3.3]hept-6-yl or 2-oxa-6-aza-spiro[3.3]hept-6-yl; and R⁷ is a hydroxy group, a halogen atom, C_1-6alkyl, C_1-6alkoxy, halogen-C_1-6alkyl or halogen-C_1-6alkoxy; wherein said compound is selected from the group of compounds indicated in claim 1 of the invention. Preferably such a compound may be [4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-2-fluoro-5-methoxy-phenyl]-morpholin-4-yl-methanone or [4-(4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-5-methoxy-2-methyl-phenyl]-morpholin-4-yl-methanone. In the compound of formula II, A is a five- or six-membered ring containing one or two heteroatoms, each independently selected from O; m is 0, 1 or 2; X is -NR^a- or -O-, and R^a represents a hydrogen atom or C_1-6alkyl; R¹ is C_1-6alkyl or C_3-6cycloalkyl; or R¹ and R^a together with the atoms to which they are attached, can form a three-six-membered ring; R² is a halogen atom, cyano or halo-C_1-6alkyl; R⁵ is a hydrogen atom or C_1-6alkyl; R⁶ is a hydrogen atom, C_1-6alkyl, hydroxy-C_1-6alkyl, C_3-6cycloalkyl-C_1-6alkyl or heterocyclyl with 1 to 2 nitrogen atoms as heteroatoms in the ring, where heterocyclyl may be optionally substituted with C_1-6alkyl; or R⁵ and R⁶ together with the nitrogen atom to which they are attached, form a four to six membered ring optionally including an additional heteroatom selected from O or N, and optionally substituted with one or two groups independently selected from the following groups: C_1-6alkyl, C_1-6alkoxy, halogen-C_1-6alkoxy, C_1-6alkoxy-C_1-6alkyl, hydroxy-C_1-6alkyl, halogen atom, C_3-6cycloalkyl-C_1-6alkyl and 4-6 membered heterocyclyl with 1 to 2 heteroatoms selected from N and O; or hexahydro-pyrrolo[1,2-a]pyrazinyl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 1-oxa-6-aza-spiro[3.3]hept-6-yl or 2-oxa-6-aza-spiro [3.3] hept-6-yl; and R⁷ is a halogen atom, C_1-6alkyl, C_1-6alkoxy, halogen-C_1-6alkyl or halogen-C_1-6alkoxy.;EFFECT: compounds can be used to treat Parkinson's disease mediated by the activity of said kinase.;11 cl, 6 tbl, 20 ex