Compounds for inhibiting LRRK2 kinase activity

Patent metadata

Field	Value
Publication number	US-11034696-B2
Application number	US-201816480762-A
Country	US
Kind code	B2
Filing date	Jan 23, 2018
Priority date	Jan 25, 2017
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

Abstract

Compounds of Formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising these compounds, the use of these compounds and compositions in the treatment of diseases in which LRRK-2 kinase is involved.

First claim

What is claimed is:

1. A compound of Formula (I):

wherein:
R 1 is
a) an N-linked 6-9 membered fused bicyclic heterocyclyl ring optionally substituted with one, two or three substituents independently selected from the group consisting of oxo, halo, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy;
wherein:
 C 1-3 alkyl and C 1-3 alkoxy optionally is substituted with one or two substituents independently selected from the group consisting of halo, hydroxyl, unsubstituted C 1-3 alkyl and unsubstituted C 1-3 alkoxy; or

b) an N-linked 7-10 membered heterospirane ring optionally substituted with one, two or three substituents independently selected from the group consisting of oxo, halo, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy,
wherein:
 C 1-3 alkyl and C 1-3 alkoxy optionally is substituted with one or two substituents independently selected from the group consisting or halo, hydroxyl, unsubstituted C 1-3 alkyl and unsubstituted C 1-3 alkoxy; and
provided that:
 R 1 is not 2-oxa-6-azaspiro[3.4]octan-6-yl;

R 2 is selected from the group consisting of:
a) a 4-7 membered heterocyclyl ring optionally substituted with one, two or three substituents independently selected from the group consisting of C 1-3 alkyl
wherein:
 the C 1-3 alkyl group optionally is substituted with one, two or three substituents independently selected from the group consisting of halo, hydroxyl, CO 2 H, —CH 2 CH 2 —, C 1-3 alkoxy, cyano, hydroxyl, —SO 2 CH 3 , —COCH 3 , and —COCH 2 OH;
 wherein:
 when the 4-7 membered heterocyclyl ring contains a substitutable nitrogen atom, the group of substituents identified for R 2 above further includes a 4-6 membered heterocyclyl ring;
wherein:
 the 4-6 membered heterocyclyl ring optionally is substituted with one or two substituents independently selected from the group consisting of: cyano, halo, hydroxyl, C 1-3 alkyl, C 1-3 alkoxyl, CH 2 OH and C 3-6 cycloalkyl which C 3-6 cycloalkyl group is optionally substituted with one or two substituents independently selected from the group consisting of halo, hydroxyl, cyano, CH 2 OH, unsubstituted C 1-3 alkyl and unsubstituted C 1-3 alkoxyl;
 provided that:
 the 4-6 membered heterocyclyl ring is attached to the substitutable nitrogen atom of the 4-7 membered heterocyclyl ring as defined above;

b) —O-4-6 membered heterocyclyl ring;
wherein:
 the heterocyclyl ring is optionally substituted with one or two substituents independently selected from the group consisting of: cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxyl, CH 2 OH and —CO 2 H;

c) C3-6 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of cyano, halo, hydroxyl, C 1-3 alkyl, C 1-3 alkoxyl, CO 2 H and a 4-6 membered heterocyclyl ring;
d) —O—C 3-6 cycloalkyl;
wherein:
 the cycloalkyl group is optionally substituted with one or two substituents independently selected from the group consisting of cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxyl, CH 2 OH and CO 2 H; and

e) C 1-6 alkoxy optionally substituted by one or two substituents independently selected from the group consisting of halo, hydroxyl, C 1-3 alkyl, C 1-3 alkoxyl, CO 2 H and a 4-6 membered heterocyclyl ring;

R 3 is selected from the group consisting of halo, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy and C 3-6 cycloalkyl; and
R 4 is selected from the group consisting of H, halo, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy and C 3-6 cycloalkyl; or

a pharmaceutically acceptable salt thereof.

2. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 1 , wherein:
R 1 is an N-linked 6-9 membered fused bicyclic heterocyclyl ring selected from the group consisting of hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, hexahydropyrrolo[1,2-a]pyrazine-6(2H)-yl, 3-azabicyclo[3.1.0]hexanyl and hexahydro-2H-furo[2,3-c]pyrrolyl;
wherein:
the fused bicyclic heterocyclyl optionally is substituted with one, two or three substituents independently selected from the group consisting of: oxo, halo, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy.

3. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 1 , wherein:
R 1 is an N-linked 7-10 membered heterospirane ring;
wherein:
the N-linked 7-10 membered heterospirane ring optionally is substituted with one substituent selected from the group consisting of: oxo, hydroxyl and C 1-3 alkyl, and with the proviso that R 1 is not 2-oxa-6-azaspiro[3.4]octan-6-yl.

4. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 3 , wherein:
R 1 is an N-linked 7-10 membered heterospirane ring selected from the group consisting of oxazasprio[2.5]octanyl, dioxazaspiro[2.6]nonanyl, dioxazaspiro[3.5]nonanyl, dioxazaspiro[4.4]nonanyl, diazaspiro[2.7]decanyl, diazasprio[3.6]decanyl, diazasprio[4.5]decanyl, oxaadiazaspiro[2.7]decanyl, oxadiazasprio[3.6]decanyl and oxadiazasprio[4.5]decanyl;
wherein:
the N-linked 7-10 membered heterospirane ring of R 1 optionally is substituted with one oxo group.

5. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 4 , wherein:
R 1 is an N-linked 7-10 membered heterospirane ring selected from the group consisting of 1-oxa-4,8-diazaspiro[4.5]decan-8-yl, 3-oxa-1,8-diazaspiro[4.5]decan-8-yl, 1,8-diazaspiro[4.5]decan-8-yl, 2,8-diazaspiro[4.5]decan-8-yl, 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl and 4-oxa-7-azaspiro[2.5]octan-7-yl;
wherein:
the N-linked 7-10 membered heterospirane ring of R 1 is optionally substituted with one oxo group.

6. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 5 , wherein:
R 1 is selected from the group consisting of 3-oxo-1-oxa-4,8-diazaspiro[4.5]decan-8-yl, 2-oxo-3-oxa-1,8-diazaspiro[4.5]decan-8-yl, 2-oxo-1,8-diazaspiro[4.5]decan-8-yl, 1-oxo-2,8-diazaspiro[4.5]decan-8-yl, 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl and 4-oxa-7-azaspiro[2.5]octan-7-yl.

7. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 1 , wherein:
R 2 is a 4-7 membered heterocyclyl ring optionally is substituted with one, two or three substituents independently selected from the group consisting of C 1-3 alkyl, cyano, halo, hydroxyl, —SO 2 CH 3 , —COCH 3 , and —COCH 2 OH,
wherein:
the C 1-3 alkyl group of R 2 optionally is substituted with one, two or three substituents independently selected from the group consisting of: halo, hydroxyl, CO 2 H, —CH 2 CH 2 — and C 1-3 alkoxy;
when the 4-7 membered heterocyclyl ring contains a substitutable nitrogen atom, the group of substituents identified for R 2 above further includes an 4-6 membered heterocyclyl ring;
wherein:
the 4-6 membered heterocyclyl ring optionally is substituted with one or two substituents independently selected from the group consisting of: cyano, halo, hydroxyl, C 1-3 alkyl, C 1-3 alkoxyl and CH 2 OH;
provided that:
the 4-6 membered heterocyclyl ring is attached to the substitutable nitrogen atom of the 4-7 membered heterocyclyl ring.

8. The compound or a pharmaceutically acceptable salt according to claim 7 , wherein:
R 2 is a 5-6 membered heterocyclyl ring optionally substituted with one, two or three substituents independently selected from the group consisting of C 1-3 alkyl, halo, hydroxyl, —SO 2 CH 3 , —COCH 3 , and —COCH 2 OH,
wherein:
the C 1-3 alkyl group is optionally substituted with one halo, hydroxyl or C 1-3 alkoxy group,
when the 5-6 membered heterocyclyl ring contains a substitutable nitrogen atom, the group of substituents identified for R 2 above further includes an oxygen containing 4-6 memb

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Ren Feng
• Sang Yingxia
• Xing Weiqiang
• Zhan Yang
• Zhao Baowei

Classifications

• C07D407/14

  containing three or more hetero rings · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title