Macrocyclic LRRK2 kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9370520-B2
Application number	US-201514747882-A
Country	US
Kind code	B2
Filing date	Jun 23, 2015
Priority date	Sep 30, 2011
Publication date	Jun 21, 2016
Grant date	Jun 21, 2016

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.

First claim

The invention claimed is:

1. 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:
A 1 and A 2 are each individually C or N; wherein when A 1 is C, then A 2 is N, and when A 2 is C, then A 1 is N;
X 1 is —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —(C═O)—, —NR 3 —(C═O)—NR 3 —(C═O)—C 1-6 alkyl-, —(C═O)—NR 3 —C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —C 1-6 alkyl-NR 3 —C 1-6 alkyl-, or —SO 2 —NR 3 —;
wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 37 R 38 ;
X 2 is —C 1-6 alkyl-, —O—C 1-6 alkyl-, —O—C 1-6 alkyl-O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —(C═O)—, —(C═O)—NR 2 —, —NR 2 —C 1-6 alkyl-, —NR 2 —, or —SO 2 —NR 2 —; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 39 R 40 ;
B is —(C═O)—, —(C═N)—R 39 —, —(SO 2 )—, —(C═O)—NR 5 —, —(C═S)—NR 5 —, —NR 5 —(C═O)—NR 7 —, —NR 5 —(C═S)—NR 7 —, —SO 2 —NR 5 —, —NR 6 —, —NR 5 —(C═O)—O—, —NR 5 —(C═S)—O—, or —CHR 8 —;
R 1 is —H, -halo, —OH, —C 1-6 alkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 9 R 10 , —(C═O)—R 4 , —SO 2 —R 4 , —CN, —NR 9 —SO 2 —R 4 , or -Het 1 ; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —NR 11 R 12 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
R 2 is —H, -halo, —OH, —C 1-6 alkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —(C═O)—C 1-6 alkyl, —(C═O)—O—C 1-6 alkyl, —(C═O)—NR 27 R 28 , -Het 3 , —(C═O)-Het 3 , or —SO 2 —C 1-6 alkyl; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -Het 3 , —Ar 2 , and —NR 13 R 14 ;
R 3 is —H, -halo, —OH, —C 1-6 alkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —(C═O)—C 1-6 alkyl, —(C═O)—O—C 1-6 alkyl, -Het 2 , —(C═O)-Het 2 , —(C═O)—NR 29 R 30 , or —SO 2 —C 1-6 alkyl;
wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —OC 1-6 alkyl, —SC 1-6 alkyl, —NR 15 R 16 , -Het 2 , and —Ar 4 ;
R 4 is -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 17 R 18 , or -Het 4 ;
R 5 and R 7 are each independently —H, -halo, —C 1-6 alkyl, —OC 1-6 alkyl, —S—C 1-6 alkyl, -Het 5 , —Ar 1 , C 3-6 cycloalkyl, —SO 2 —Ar 3 , —SO 2 , —SO 2 —C 1-6 alkyl, —(C═O), —(C═O)—C 1-6 alkyl, —O—(C═O)—C 1-6 alkyl, or —(C═O)—O—C 1-6 alkyl; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —OC 1-6 alkyl, —SC 1-6 alkyl, -Het 5 , and —NR 23 R 24 ;
R 6 is —SO 2 , —SO 2 —C 1-6 alkyl, —(C═O), —(C═S), —(C═O)—O—C 1-6 alkyl, —(C═S)—O—C 1-6 alkyl, —(C═O)—C 1-6 alkyl, —(C═O)—C 2-6 alkenyl, —(C═S)—C 1-6 alkyl, —(C═S)—C 2-6 alkenyl, —C 1-6 alkyl-(C—O)—NR 31 R 32 , —C 1-6 alkyl-(C—S)—NR 31 R 32 , —C 1-6 alkyl-NR 33 (C—O)—NR 31 R 32 , —C 1-6 alkyl-NR 33 (C═S)—NR 31 R 32 , —SO 2 —C 3-5 cycloalkyl, —(C═O)—C 3-5 cycloalkyl, —(C═S)—C 3-5 cycloalkyl, —(C—O)—NR 31 R 32 , —(C—S)—NR 31 R 32 , —(C—O)-Het 5 , —(C═S)-Het 5 , —(C—O)—Ar 6 , —(C═S)—Ar 6 , or —(C═O)—NR 31 —(C═O)—R 32 ; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —OC 1-6 alkyl, —SC 1-6 alkyl, -Het 5 , and —NR 25 R 26 ;
R 8 is —NR 34 —(C═O)—R 35 , —NR 36 —(C═O)—NR 34 R 35 , —NR 34 —(SO 2 )—R 35 , —NR 34 —(C—O)—O—R 35 , or —O—(C═O)—NR 34 R 35 ;
R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are each independently —H, -halo, —O, —OH, —O—C 1-6 alkyl, —C 1-6 alkyl, —C 3-6 cycloalkyl or -Het 1 ; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -Het 6 , and —Ar 5 ;
Ar 1 , Ar 2 , Ar 3 , Ar 4 , Ar 5 , and Ar 6 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 Ar 1 , Ar 2 , Ar 3 , Ar 4 , and Ar 5 being unsubstituted or substituted with 1 to 3 substituents independently selected from —NR 19 R 20 , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
Het 1 , Het 2 , Het 3 , Het 4 , Het 5 , and Het 6 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, —C 1-6 alkyl, —OC 1-6 alkyl, —SC 1-6 alkyl, and —NR 21 R 22 ; and each —C 1-6 alkyl group being unsubstituted or substituted with 1 to 3 halo substituents; and
Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each independently C or N.

2. The method of claim 1 , wherein X 1 is —O—CH 2 — and R 5 is not —H.

3. The method of claim 1 , wherein:
A 1 is N;
A 2 is C;
X 1 is —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —(C═O)—, —NR 3 —(C═O)—, —NR 3 —(C═O)—C 1-6 alkyl, —(C═O)—NR 3 —C 1-6 alkyl-, —C 1-6 alkyl-NR 3 —C 1-6 alkyl-, or —SO 2 —NR 3 —; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 37 R 38 ;
X 2 is —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —(C═O)—, —(C═O)—NR 2 —NR 2 —C 1-6 alkyl-, —NR 2 —, or —SO 2 —NR 2 —; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 39 R 40 ;
B is —(C═O)—, —(C═N)R 39 —, —(SO 2 )—, —(C═O)—NR 5 —, —(C═S)—NR 5 —, —NR 5 —(C═O)—NR 7 —, —NR 5 —(C═S)—NR 7 —, —SO 2 —NR 5 —, —NR 6 —, —NR 5 —(C═S)—O—, or —CHR 8 —;
R 1 is —H, —OH, —C 1-6 alkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 9 R 10 , —SO 2 —R 4 , —CN, —NR 9 —SO 2 —R 4 , or -Het 1 ; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from -halo, —OH, —NR 11 R 12 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
R 5 and R 7 are each independently —H, -halo, —C 1-6 alkyl, —OC 1-6 alkyl, —S—C 1-6 alkyl, -Het 5 , —Ar 1 , —C 3-6 cycloalkyl, —SO 2 —Ar 3 , —SO 2 , —SO 2 —C 1-6 alkyl, —(C═O), —(C═O)—C 1-6 alkyl, —O—(C═O)—C 1-6 alkyl, or —(C═O)—O—C 1-6 alkyl; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from —OH, —OC 1-6 alkyl, —SC 1-6 alkyl, -Het 5 , and —NR 23 R 24 ,
R 6 is —SO 2 , —(C═O), —(C═S), —(C═O)—O—C 1-6 alkyl, —(C═O)—C 2-6 alkenyl, —(C═S)—O—C 1-6 alkyl, (C═O)—C 1-6 alkyl, —(C═S)—C 1-6 alkyl, —(C═S)—C 2-6 alkenyl, —C 1-6 alkyl-(C═S)—NR 31 R 32 , —C 1-6 alkyl-NR 33 (C—O)—NR 31 R 32 , —C 1-6 alkyl-NR 33 (C—S)—NR 31 R 32 , —(C—S)—C 3-5 cycloalkyl, —(C—S)—NR 31 R 32 , —(C═O)-Het 5 , —(C═S)-Het 5 , or —(C═O)—NR 31 —(C═O)—R 32 ; wherein said C 1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from —OH, —OC 1-6 alkyl, —SC 1-6 alkyl, -Het 5

Assignees

• Ipsen Pharma Sas
• Oncodesign Sa

Inventors

• Hoflack Jan
• Blom Petra

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D498/16

  Peri-condensed systems · CPC title

• C07D487/18 Primary

  Bridged systems · CPC title