Macrocyclic LRRK2 Kinase Inhibitors

摘要

The present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of LRRK2 kinase, for use in the diagnosis, prevention and/or treatment of LRRK2-kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent. Finally, the present invention also relates to new macrocyclic compounds.

主权项

1. A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, Wherein A1 and A2 are selected from C and N; wherein when A1 is C, then A2 is N; and wherein when A2 is C, then A1 is N; R1 and R7 are each independently selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR9R10, —(C═O)—R4, —SO2—R4, —CN, —NR9—SO2—R4, —C3-6cycloalkyl, and -Het6; wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —NR11R12, —O—C1-6alkyl, and —S—C1-6alkyl; R2 is selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —(C═O)—C1-6alkyl, —(C═O)—O—C1-6alkyl, —(C═O)—NR27R28, -Het3, —(C═O)-Het3, —SO2—C1-6alkyl, and —C3-6cycloalkyl; wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C1-6alkyl, —S—C1-6alkyl, -Het3, —Ar2, and —NR13R14; R3 is selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —(C═O)—C1-6alkyl, —(C═O)—O—C1-6alkyl, -Het2, —C3-6cycloalkyl-(C═O)-Het2, —(C═O)—NR29R30, and —SO2—C1-6alkyl; wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C1-6alkyl, —S—C1-6alkyl, —NR15R16, -Het2, and —Ar3; R4 is independently selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR17R18, and -Het4; R5 is selected from —H, —C1-6alkyl, —C3-6cycloalkyl; wherein each of said C1-6alkyl or —C3-6cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —OC1-6alkyl, —SC1-6alkyl, -Het5, —CN and —NR31R32; R6 is selected from —H, —OH, -halo, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR33R34, and -Het8; 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, R37 and R38 are each independently selected from —H, ═O, —C1-6alkyl, and -Het1; wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C1-6alkyl, —S—C1-6alkyl, —NR35R36, -Het7, and —Ar4; R35 and R36 are each independently selected from —H, ═O, and —C1-6alkyl; wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C1-6alkyl, and —S—C1-6alkyl; X1 is selected from —C1-6alkyl-, —O—C1-6alkyl-, —S—C1-6alkyl-, —(C═O)—, —NR3—(C═O)—, —C1-6alkyl-NR3—, —NR3—, —(C═O)—, —NR3—(C═O)—NR37—, —NR3—C1-6alkyl-, —NR3—SO2—, —NR3—(C═O)—C1-6alkyl-, —(C═O)—NR3—C1-6alkyl-, —O—C1-6alkyl-O—C1-6alkyl- and —C1-6alkyl-NR3—C1-6alkyl-; wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, -phenyl, and —NR23R24 X2 is selected from —C1-6alkyl-, —O—C1-6alkyl-, —S—C1-6alkyl-, —(C═O)—, —NR2—(C═O)—, —C1-6alkyl-NR2—, —NR2—, —(C═O)—, —NR2—(C═O)—NR38—, —NR2—C1-6alkyl-, —NR2—SO2—, —NR2—(C═O)—C1-6alkyl-, —(C═O)—NR2—C1-6alkyl-, —O—C1-6alkyl-O—C1-6alkyl- and —C1-6alkyl-NR2—C1-6alkyl-; wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, -phenyl and —NR25R26; Y is selected from a direct bond, —CHR6—, —O—, —S—, and —NR5—; Ar2, Ar3, and Ar4 are each independently a 5- or 6-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; wherein each of said Ar2, Ar3, and Ar4 is optionally and independently substituted with from 1 to 3 substituents selected from —NR19R20, —C1-6alkyl, —O—C1-6alkyl, and —S—C1-6alkyl; Het1, Het2, Het3, Het4, Het5, Het6, Het7 and Het8 are each independently a 5- or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het1, Het2, Het3, Het4, Het5, Het6, Het7 and Het8 is optionally substituted with from 1 to 3 substituents selected from —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, and —NR21R22; wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3-halo; Z1, Z2, Z3, Z4 and Z5 are each independently selected from C and N; m and n are each independently 0, 1, 2, 3, or 4. for use in the prevention and/or treatment of a LRRK2-kinase associated disease.