US 9,096,609 B2Granted

Macrocyclic LRRK2 kinase inhibitors

AssigneesIpsen Pharma S.A.S., Oncodesign S.A.

InventorsJan Hoflack, Petra Blom

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Abstract

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.

Claims10

Dependent claims

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.

26 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/348,138Filed 28 Sep 2012
Priority: WO PCT/EP2011/06708630 Sep 2011
Published: US 2014/0206683 A124 Jul 2014
Granted: 4 Aug 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00

Family

US 2014/0206683 A1Pre-grant publication · published 24 Jul 2014
US 9,096,609 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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.

26 more elements

Facts

Application

14/348,138Filed 28 Sep 2012

Priority

WO PCT/EP2011/06708630 Sep 2011

Published

US 2014/0206683 A124 Jul 2014

Granted

4 Aug 2015

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00