Macrocyclic LRRK2 kinase inhibitors

A method of treating Parkinson's disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I

• or a stereoisomer, tautomer, racemate, pharmaceutical salt, or N-oxide thereof,
• wherein:
• A1 and A2 are each individually C or N;
• wherein when A1 is C, then A2 is N, and when A2 is C, then A1 is N;
• 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 said C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —C1-6 alkyl, —O—C1-6 alkyl, —S—C1-6 alkyl, and —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—, or —SO2—NR2—;
• wherein said C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —C1-6 alkyl, —O—C1-6 alkyl, —S—C1-6 alkyl, and —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—;
• 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 said C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —NR11R12, —O—C1-6 alkyl, and —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 said C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —O—C1-6 alkyl, —S—C1-6 alkyl, -Het3, —Ar2, and —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 said C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —OC1-6 alkyl, —SC1-6 alkyl, —NR15R16, -Het2, and —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 said C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —OC1-6 alkyl, —SC1-6 alkyl, -Het5, and —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 said C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —OC1-6 alkyl, —SC1-6 alkyl, -Het5, and —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 said C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —O—C1-6 alkyl, —S—C1-6 alkyl, -Het6, and —Ar5;
• Ar1, Ar2, Ar3, Ar4, Ar5, and Ar6 are each independently a 5- or 6-membered-aryl or a 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms which are independently O, N or S;
• each of said Ar1, Ar2, Ar3, Ar4, and Ar5 being unsubstituted or substituted with 1 to 3 substituents independently selected from —NR19R20, —C1-6 alkyl, —O—C1-6 alkyl, and —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 which are independently O, N or S;
• each heterocycle being unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —C1-6 alkyl, —OC1-6 alkyl, —SC1-6 alkyl, and —NR21R22;
• and each —C1-6 alkyl group being unsubstituted or substituted with 1 to 3 halo substituents;
• and
• Z1, Z2, Z3, Z4 and Z5 are each independently C or N.