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US 10,377,772 B2Granted
Macrocyclic LRRK2 kinase inhibitors
AssigneeOncodesign S.A.
InventorsJan Hoflack, Petra Blom, Olivier Lavergne, Sylvie Gomez
Life of this patent
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Abstract
The present invention relates to novel macrocyclic compounds of formula (I) 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.
Claims22
A compound of Formula I or a stereoisomer, tautomer, racemic, salt, hydrate, N-oxide form, or solvate thereof,
- Wherein:
- R1 is selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR9R10, —(C═O)—R4, —(C═S)—R4, —SO2—R4, —CN, —NR9—SO2—R4, —C3-6cycloalkyl, —O—C3-6cycloalkyl, —Ar1 and -Het1;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR35, —NR11R12, —O—C1-6alkyl, and —S—C1-6alkyl;
- R5 is attached to Z1 or Z5 and is selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR6R7, —(C═O)—R8, —(C═S)—R8, —SO2—R8, —CN, —NR6—SO2—R8, —C3-6cycloalkyl, —O—C3-6cycloalkyl, —Ar5 and -Het5;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR36, —NR23R24, —O—C1-6alkyl, and —S—C1-6alkyl;
- R2 is selected from —H, -halo, —OH, —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, —OR27, and —NR13R14;
- R3 is selected from —H, -halo, —OH, —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, —OR28, and —NR15R16;
- R4 and R8 are each independently selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR17R18, —C3-6cycloalkyl, —O—C3-6cycloalkyl, —Ar4 and -Het4;
- R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31, R32, R33, R34, R35 and R36 are each independently selected from —H, -halo, ═O, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —C3-6cycloalkyl, —Ar6 and -Het6;
- 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, —C3-6cycloalkyl, -Het6, —Ar6 and —NR37R38;
- R27 and R28 are each independently selected from —H, —C1-6alkyl, —C3-6cycloalkyl and -Het2:
- R37 and R38 are each independently selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —C3-6cycloalkyl, —Ar7 and -Het7;
- X1 is selected from —C1-6alkyl-, —O—C1-6alkyl-, —S—C1-6alkyl-, —C1-6alkyl-, —NR3-C1-6alkyl-, —NR3—C1-6alkyl-, —NR3—, and —O—;
- 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 —NR33R34;
- X2 is selected from —C1-6alkyl-, —O—C1-6alkyl-, —S—C1-6alkyl-, —C1-6alkyl-NR2—C1-6alkyl-, —NR2—C1-6alkyl-, —NR2—, and —O—;
- 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 —NR31R32;
- Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S;
- each of said Ar1, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, and —NR19R20;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 -halo;
- Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S;
- wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, ═O, —(C═O)—C1-6alkyl, and —NR21R22;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 -halo;
- Het8 is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S;
- wherein said Het8 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —C1-6alkylene, —C1-6alkyl-C3-6cycloalkyl, —C3-6cycloalkyl, —O—C1-6alkyl, —S—C1-6alkyl, ═O, —(C═O)—C1-6alkyl, —C1-6alkyl-O—C1-6alkyl and —NR21R22;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 -halo;
- wherein when R1 is —H, then at least one heteroatom of Het8 is attached to X2;
- Z1, Z2, Z3, Z4 and Z5 are each independently selected from C and N;
- and
- A1 and A2 are each independently selected from C and N.
28 more elements
A compound of Formula Ia or a stereoisomer, tautomer, racemic, salt, hydrate, N-oxide form, or solvate thereof,
- Wherein:
- R1 is selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR9R10, —(C═O)—R4, —(C═S)—R4, —SO2—R4, —CN, —NR9—SO2—R4, —C3-6cycloalkyl, —O—C3-6cycloalkyl, —Ar1 and -Het1;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR35, —NR11R12, —O—C1-6alkyl, and —S—C1-6alkyl;
- R5 is attached to Z1 or Z5 and is selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR6R7, —(C═O)—R8, —(C═S)—R8, —SO2—R8, —CN, —NR6—SO2—R8, —C3-6cycloalkyl, —O—C3-6cycloalkyl, —Ar5 and -Het5;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR36, —NR23R24, —O—C1-6alkyl, and —S—C1-6alkyl;
- R2 is selected from —H, -halo, —OH, —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, —OR27, and —NR13R14;
- R3 is selected from —H, -halo, —OH, —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, —OR28, and —NR15R16;
- R4 and R8 are each independently selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR17R18, —C3-6cycloalkyl, —O—C3-6cycloalkyl, —Ar4 and -Het4;
- R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31, R32, R33 R34, R35 and R36 are each independently selected from —H, -halo, ═O, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —C3-6cycloalkyl, —Ar6 and -Het6;
- 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, —C3-6cycloalkyl, -Het6, —Ar6 and —NR37R38;
- R27 and R28, are each independently selected from —H, —C1-6alkyl, —C3-6cycloalkyl and -Het2:
- R37 and R38, are each independently selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —C3-6cycloalkyl, —Ar7 and -Het7;
- X1 is selected from —C1-6alkyl-, —O—C1-6alkyl-, —S—C1-6alkyl-, —C1-6alkyl-NR3—C1-6alkyl-, —NR3—C1-6alkyl-, —NR—, and —O—;
- 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 —NR33R34;
- X2 is selected from —C1-6alkyl-, —O—C1-6alkyl-, —S—C1-6alkyl-, —C1-6alkyl-NR3—C1-6alkyl-, —NR2—C1-6alkyl-, —NR2—, and —O—;
- 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 —NR31R32;
- Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S;
- each of said Ar1, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, and —NR19R20;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 -halo;
- Het1, Het2, Het4, Het5, Het6, and Het 7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S;
- wherein each of said Het1, Het2, Het4, Het5, Het6, and Het 7 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, ═O, —(C═O)—C1-6alkyl, and —NR21R22;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 -halo;
- Het8 is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S;
- wherein said Het8 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —C1-6alkylene, —C1-6alkyl-C3-6cycloalkyl, —C3-6cycloalkyl, —O—C1-6alkyl, —S—C1-6alkyl, ═O, —(C═O)—C1-6alkyl, —C1-6alkyl-O—C1-6alkyl and —NR21R22;
- wherein each of said —C1-6alkyl is optionally and independently substituted with from 1 to 3 -halo;
- wherein when R1 is —H then at least one heteroatom of Het8 is attached to X2;
- and
- Z1, Z2, Z3, Z4 and Z5 are each independently selected from C and N.
27 more elements
A compound of Formula Ia or a stereoisomer, tautomer, racemic, salt, hydrate, N-oxide form, or solvate thereof,
- Wherein:
- R1 is selected from —H and -halo;
- R5 is attached to Z1 and is selected from —H and —C1-6alkyl;
- R2 is selected from —H and —C1-6alkyl;
- R3 is selected from —H and —C1-6alkyl;
- X1 is selected from—O—C1-6alkyl-, —NR3—C1-6alkyl-, —NR3—, and —O—;
- X2 is selected from—O—C1-6alkyl-, —NR2—C1-6alkyl-, —NR2—, and —O—;
- Het8 is a 3- to 10-membered N-containing heterocycle;
- wherein said Het8 is optionally substituted with 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —C1-6alkylene, —C3-6cycloalkyl, —O—C1-6alkyl, —S—C1-6alkyl, ═O, —(C═O)—C1-6alkyl, —C1-6alkyl—O—C1-6alkyl and —NR21R22;
- and
- Z1, Z2, Z3, Z4 and Z5 are each C.
8 more elements
A compound selected from:
Dependencies are inferred from the claim text.