Macrocyclic LRRK2 kinase inhibitors

摘要

The present invention relates to novel macrocylic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of LRRK2 (Leucine-Rich Repeat Kinase 2). Moreover, the present invention provides processes for the preparation of the disclosed compounds, as well as methods of using them, for instance as a medicine or diagnostic agent, in particular for the treatment and/or diagnosis of diseases characterized by LRRK2 kinase activity such as neurological disorders including Parkinson's disease and Alzheimer's disease.;

主权项

1. A compound of Formula I or a stereoisomer, tautomer, racemate, pharmaceutical salt, or N-oxide form thereof, wherein A1 and A2 are C or N; wherein when A1 is C, then A2 is N; and wherein when A2 is C, then A1 is N; R1 is —H, -halo, —OH, —C1-6 alkyl, —C3-6 cycloalkyl, —O—C1-6 alkyl, —S—C1-6 alkyl, —NR9R10, —(C═O)—R4, —SO2—R4, —CN, —NR9—SO2—R4, or -Het1; wherein each of said C1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents of -halo, —OH, —NR11R12, —O—C1-6 alkyl, or —S—C1-6 alkyl; R2 is —H, -halo, —OH, —C1-6 alkyl, —C3-6cycloalkyl, —O—C1-6 alkyl, —S—C1-6 alkyl, —(C═O)—C1-6 alkyl, —(C═O)—O—C1-6 alkyl, —(C═O)—NR27R28, -Het3, —(C═O)-Het3, or —SO2—C1-6 alkyl; wherein each of said C1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents of -halo, —OH, —O—C1-6 alkyl, —S—C1-6 alkyl, -Het3, —Ar2, or —NR13R14; R3 is —H, -halo, —OH, —C1-6 alkyl, —C3-6 cycloalkyl, —O—C1-6 alkyl, —S—C1-6 alkyl, —(C═O)—C1-6 alkyl, —(C═O)—O—C1-6 alkyl, -Het2, —(C═O)-Het2, —(C═O)—NR29R30, or —SO2—C1-6 alkyl; wherein each of said C1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents of -halo, —OH, —OC1-6 alkyl, —SC1-6 alkyl, —NR15R16, -Het2, or —Ar4; R4 is -halo, —OH, —C1-6 alkyl, —O—C1-6 alkyl, —S—C1-6 alkyl, —NR17R18, or -Het4; R5 and R7 are each independently —H, -halo, —C1-6 alkyl, —OC1-6 alkyl, —S—C1-6 alkyl, -Het5, —Ar1, —C3-6 cycloalkyl, —SO2—Ar3, —SO2, —SO2—C1-6 alkyl, —(C═O), —(C═O)—C1-6 alkyl, —O—(C═O)—C1-6 alkyl, or —(C═O)—O—C1-6 alkyl; wherein each of said C1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents of -halo, —OH, —OC1-6 alkyl, —SC1-6 alkyl, -Het5, or —NR23R24; R6 is —SO2, —SO2—C1-6 alkyl, —(C═O), —(C═S), —(C═O)—O—C1-6 alkyl, —(C═S)—O—C1-6 alkyl, —(C═O)—C1-6 alkyl, —(C═O)—C2-6 alkenyl, —(C═S)—C1-6 alkyl, —(C═S)—C2-6 alkenyl, —C1-6 alkyl-(C═O)—NR31R32, —C1-6 alkyl-(C═S)—NR31R32, —C1-6 alkyl-NR33(C═O)—NR31R32, —C1-6 alkyl-NR33(C═S)—NR31R32, —SO2—C3-5 cycloalkyl, —(C═O)—C3-5 cycloalkyl, —(C═S)—C3-5 cycloalkyl, —(C═O)—NR31R32, —(C═S)—NR31R32, —(C═O)-Het5, —(C═S)-Het5, —(C═O)—Ar6, —(C═S)—Ar6, or —(C═O)—NR31—(C═O)—R32; wherein each of said C1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents of -halo, —OH, —OC1-6 alkyl, —SC1-6 alkyl, -Het5, or —NR25R26; R8 is —NR34—(C═O)—R35, —NR36—(C═O)—NR34R35, —NR34—(SO2)-R35, —NR34—(C═O)—O—R35, or —O—(C═O)—NR34R35; R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39 and R40 are each independently —H, -halo, —O, —OH, —O—C1-6 alkyl, —C1-6 alkyl, —C3-6cycloalkyl or -Het1; wherein each of said C1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents of -halo, —OH, —O—C1-6 alkyl, —S—C1-6 alkyl, -Het6, or —Ar5; X1 is —C1-6 alkyl-, —O—C1-6 alkyl-, —S—C1-6 alkyl-, —(C═O)—, —NR3—(C═O)—, —NR3—(C═O)—C1-6 alkyl-, —(C═O)—NR3—C1-6 alkyl-, —NR3—C1-6 alkyl-, —C1-6 alkyl-NR3—C1-6 alkyl-, or —SO2—NR3—; wherein each of said C1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents of -halo, —OH, —C1-6 alkyl, —O—C1-6 alkyl, —S—C1-6 alkyl, or —NR37R38; X2 is —C1-6 alkyl-, —O—C1-6 alkyl-, —O—C1-6 alkyl-O—C1-6 alkyl-, —S—C1-6 alkyl-, —(C═O), —(C═O)—NR2—, —NR2—C1-6 alkyl-, —NR2-5 or —SO2—NR2—; wherein each of said C1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents of -halo, —OH, —C1-6 alkyl, —O—C1-6 alkyl, —S—C1-6 alkyl, or —NR39R40; B is —(C═O)—, —(C═N)—R39—, —(SO2)—, —(C═O)—NR5, —, —(C═S)—NR5, —NR5—(C═O)—NR7, —NR5—(C═S)—NR7—, —SO2—NR5, —NR6—, —NR5—(C═O)—O—, —NR5—(C═S)—O—, or —CHR8—; Ar1, Ar2, Ar3, Ar4, Ar5, and Ar6 are each independently a 5- or 6-membered aryl optionally comprising 1 or 2 heteroatoms of O, N or S; each of said Ar1, Ar2, Ar3, Ar4, and Ar5 being optionally and independently substituted with from 1 to 3 substituents of —NR19R20, —C1-6 alkyl, —O—C1-6 alkyl, or —S—C1-6 alkyl; Het1, Het2, Het3, Het4, Het5, and Het6 are each independently a 5- or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms of O, N or S, wherein each heterocycle is being optionally and independently substituted with from 1 to 3 substituents of -halo, —C1-6 alkyl, —OC1-6 alkyl, —SC1-6 alkyl, or —NR21R22; each of said —C1-6 alkyl being optionally substituted with from 1 to -halo; and Z1, Z2, Z3, Z4 and Z5 are each independently C or N.