Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors

Patent metadata

Field	Value
Publication number	US-10039753-B2
Application number	US-201615262112-A
Country	US
Kind code	B2
Filing date	Sep 12, 2016
Priority date	Sep 14, 2015
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

Abstract

The present invention provides novel imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives of Formula (I), and the pharmaceutically acceptable salts thereof

wherein R 1 , R 1a , R 1b , R 2 , R 4 , R 5 , R 6 , X and Z are as defined in the specification. The invention is also directed to pharmaceutical compositions comprising the compounds of Formula (I) and to use of the compounds in the treatment of diseases associated with LRRK2, such as neurodegenerative diseases including Parkinson's disease or Alzheimer's disease, cancer, Crohn's disease or leprosy.

First claim

We claim:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof; wherein
X is CR 7 or N;
Z is CR 3 or N;
R 1 is selected from the group consisting of cyano and a 5- to 10-membered heteroaryl which contains 1 to 5 heteroatoms independently selected from N, O and S; wherein the 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 8 ;
R 1a and R 1b are each independently hydrogen, halo, hydroxy or C 1 -C 3 alkyl;
R 2 is a C 3 -C 7 cycloalkyl or a 4- to 7-membered heterocycloalkyl which contains 1 to 3 heteroatoms independently selected from NR, O and S; wherein the C 3 -C 7 cycloalkyl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1 to 3 R 9 ; and wherein the C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 10 ;
R is hydrogen, C 1 -C 6 alkyl or absent;
R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, deutero, amino, halo, hydroxy, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 6 alkoxy; wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 6 alkoxy are each optionally substituted with 1 to 3 halo or C 1 -C 3 alkoxy;
R 8 at each occurrence is independently selected from the group consisting of halo, —C(O)NH 2 , —C(O)NH(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 -C 6 cycloalkyl; wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 -C 6 cycloalkyl are each optionally substituted with 1 to 3 halo, cyano, hydroxy or C 1 -C 3 alkoxy;
R 9 at each occurrence is independently selected from the group consisting of halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkoxyC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkoxyC 1 -C 6 alkyl are optionally substituted with one to three halo or a cyano; and
R 10 at each occurrence is independently selected from the group consisting of halo, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, amino, C 1 -C 6 alkylamino and di(C 1 -C 6 alkyl)amino.

2. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof; wherein
X is CR 7 or N;
Z is CR 3 or N;
R 1 is selected from the group consisting of cyano and a 5- to 10-membered heteroaryl which contains 1 to 5 heteroatoms independently selected from N, O and S; wherein the 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 8 ;
R 1a and R 1b are each independently hydrogen, halo, hydroxy or C 1 -C 3 alkyl;
R 2 is a C 3 -C 7 cycloalkyl or a 4- to 7-membered heterocycloalkyl which contains 1 to 3 heteroatoms independently selected from NR, O and S; wherein the C 3 -C 7 cycloalkyl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1 to 3 R 9 ; and wherein the C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 10 ;
R is hydrogen, C 1 -C 6 alkyl or absent;
R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, deutero, amino, halo, hydroxy, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 6 alkoxy; wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 6 alkoxy are each optionally substituted with 1 to 3 halo or C 1 -C 3 alkoxy;
R 8 at each occurrence is independently selected from the group consisting of halo, —C(O)NH 2 , —C(O)NH(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 -C 6 cycloalkyl; wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 -C 6 cycloalkyl are each optionally substituted with 1 to 3 halo, cyano, hydroxy or C 1 -C 3 alkoxy;
R 9 at each occurrence is independently selected from the group consisting of halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkoxyC 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkoxyC 1 -C 6 alkyl are optionally substituted with one to three halo or a cyano; and
R 10 at each occurrence is independently selected from the group consisting of halo, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, amino, C 1 -C 6 alkylamino and di(C 1 -C 6 alkyl)amino.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein
X is CR 7 ;
Z is CR 3 ;
R 3 is hydrogen, bromo, chloro, fluoro, methoxy or cyano; and
R 4 , R 5 , R 6 and R 7 are each hydrogen or deutero.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein
R 1 is a 5- to 10-membered heteroaryl which contains 1 to 4 heteroatoms independently selected from N, O and S; wherein the 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R 8 ;
R 1a and R 1b are each hydrogen; and
R 8 at each occurrence is independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 3 -C 6 cycloalkyl; wherein the C 1 -C 3 alkyl is optionally substituted with 1 to 3 fluoro, hydroxy or C 1 -C 3 alkoxy.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein
R 1 is a 5- to 10-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, benzoxazolyl, benzoisoxazolyl, benzopyrazolyl, benzotriazolyl, imidazothiazolyl and imidazothiadiazolyl; each of which is optionally substituted with an R 8 ; and R 8 is selected from the group consisting of methyl, trifluoromethyl, isopropyl, 2-hydroxyisopropyl, methoxy, methoxymethyl, cyclopropyl and chloro.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R 1 is selected from the group consisting of

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R 1 is selected from the group consisting of

8. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R 2 is tetrahydropyranyl, cyclopentyl or cyclohexyl; each of which is optionally substituted with 1 to 2 R 9 ; and
R 9 at each occurrence is independently methyl, ethyl, cyanomethyl, hydroxy or fluoro.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein
R 2 is selected from the group consisting of

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof wherein R 2 is

11. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting of

12. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein
X is N;
Z is CR 3 ;
R 1 is a 5- to 10-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, benzoxazolyl, benzoisoxazolyl, benzopyrazolyl, benzotriazolyl, imidazothiazolyl and imidazothiadiazolyl; each of which is optionally substituted with an R 8 ;
R 1a and R 1b are each hydrogen; and
R 8 is methyl, trifluoromethyl, isopro

Assignees

• Pfizer

Inventors

• Coffman Karen Jean
• Galatsis Paul
• Garnsey Michelle Renee
• Henderson Jaclyn Louise
• Kormos Bethany Lyn
• Kurumbail Ravi G
• Pettersson Martin Youngjin
• Reese Matthew Richard
• Stepan Antonia Friederike
• Verhoest Patrick Robert
• Wager Travis T

Classifications

• A61P43/00

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

• A61P31/08

  for leprosy · 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

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title