Substituted fused pyrazole compounds and their use as LRRK2 inhibitors

Patent metadata

Field	Value
Publication number	US-10975081-B2
Application number	US-201615746817-A
Country	US
Kind code	B2
Filing date	Jul 22, 2016
Priority date	Jul 23, 2015
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

Disclosed are substituted fused pyrazoles, for example substituted indazoles, that inhibit LRRK2 kinase activity, pharmaceutical compositions containing them and their use in the treatment of Parkinson's disease.

First claim

What is claimed is:

1. A compound of Formula (I) or a salt thereof

Wherein
X is selected from CH or N;
Y is selected from CH, N or CR 3 ,
wherein R 3 is selected from the group consisting of halo, C 1-3 alkyl, CN, and C 1-3 haloalkyl;
R 1 is selected from the group consisting of
5 or 6 membered heterocyclyl optionally substituted with one two or three substituents independently selected from the group consisting of
C 1-3 alkyl optionally further substituted with one C 1-3 alkoxyl,
C 1-3 alkoxyl,
halo,
hydroxyl,
—SO 2 CH 3 ,
—COCH 3 ,
oxo group, and
oxetanyl,
—O-4 to 6 membered heterocyclyl optionally substituted with one or two substituents of C 1-3 alkyl, which may be the same or different, and
C 1-6 alkoxyl; and
R 2 is

wherein
Z 1 and Z 2 are independently N or CR 7 , and wherein R 7 is H or C 1-3 alkoxyl, but
Z 1 and Z 2 cannot both be CR 7 ,
R a is selected from the group consisting of
H,
CN,
C 1-3 alkyl,
C 1-3 alkoxyl,
—O—C 1-3 haloalkyl, and
C 3-6 cycloalkyl; and
R b is selected from the group consisting of
2-oxa-6-azaspiro[3.4]octanyl,
C 3-6 cycloalkyl, optionally substituted with one hydroxyl,
—CONHCH 3 ,
—NHCOCH 3 ,
4 to 6 membered heterocyclyl optionally substituted with one or two substituents independently selected from the group consisting of
hydroxyl,
CN,
—CONHCH 3 ,
oxetanyl,
C 1-3 alkyl, optionally substituted with one hydroxyl, and
C 1-3 alkoxyl, optionally substituted with one hydroxyl.

2. A compound according to claim 1 has the structure of Formula (I) or a pharmaceutically acceptable salt thereof.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein X is CH.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein Y is CR 3 and R 3 is F or methyl.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is 5 or 6 membered heterocyclyl optionally substituted with one, two or three substituents independently selected from the group consisting of halo, hydroxyl, SO 2 CH 3 , COCH 3 , oxetanyl, oxo group and C 1-3 alkyl optionally further substituted with one C 1-3 alkoxyl and wherein the 5 or 6 membered heterocyclyl is saturated or contains one double bond and contains one or two heteroatom ring members selected from nitrogen or oxygen.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is 6 membered heterocyclyl optionally substituted with one or two substituents independently selected from the group consisting of halo, oxetanyl and C 1-3 alkyl, and wherein the heterocyclyl is saturated and contains one or two heteroatom ring members selected from nitrogen or oxygen.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is

wherein
R a is selected from the group consisting of
H,
CN,
C 1-3 alkyl,
C 1-3 alkoxyl, and
C 3-6 cycloalkyl; and
R b is selected from the group consisting of
2-oxa-6-azaspiro[3.4]octanyl,
C 3-6 cycloalkyl, optionally substituted with one hydroxyl,
—CONHCH 3 ,
—NHCOCH 3 , and
4 to 6 membered heterocyclyl optionally substituted with one or two substituents independently selected from the group consisting of
hydroxyl,
CN,
—CONHCH 3 ,

C 1-3 alkyl, optionally substituted with one hydroxyl, and
C 1-3 alkoxyl, optionally substituted with one hydroxyl.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is

wherein

R a is C 1-3 alkyl or C 1-3 alkoxyl, and
R b is 4 to 6 membered heterocyclyl optionally substituted with one substituent selected from the group consisting of
hydroxyl,
C 1-3 alkyl optionally substituted with one hydroxyl, and
C 1-3 alkoxyl optionally substituted with one hydroxyl, and
the 4 to 6 membered heterocyclyl is selected from the group consisting of morpholinyl, azetinidyl, piperazinyl, and oxetanyl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof has a structure of Formula (B)

wherein,
R 1 is piperidinyl substituted with one or two substituents independently selected from the group consisting of halo, C 1-3 alkyl and oxetanyl;
R a is C 1-3 alkyl or C 1-3 alkoxyl; and
R b is 4 to 6 membered heterocyclyl substituted with one substituent selected from the group consisting of
hydroxyl,
C 1-3 alkyl optionally substituted with one hydroxyl, and
C 1-3 alkoxyl optionally substituted with one hydroxyl, and
the 4 to 6 membered heterocyclyl is selected from the group consisting of morpholinyl, azetinidyl, piperazinyl, and oxetanyl.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 9 , which is

11. The compound or a pharmaceutically acceptable salt thereof according to claim 9 , which is

12. The compound or a pharmaceutically acceptable salt thereof according to claim 9 , which is

13. The compound or a pharmaceutically acceptable salt thereof according to claim 9 , which is

14. The compound or a pharmaceutically acceptable salt thereof according to claim 9 , which is

15. The compound or a pharmaceutically acceptable salt thereof according to claim 9 , which is

16. A pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

17. A method of treatment of Parkinson's disease which comprises administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1 .

18. The method of claim 17 , wherein the subject is a human.

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Ding Xiao
• Jin Yun
• Liu Qian
• Ren Feng
• Sang Yingxia
• Stasi Luigi Piero
• Wan Zehong
• Wang Hailong
• Xing Weiqiang
• Zhan Yang
• Zhao Baowei

Classifications

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · 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