Compounds for inhibiting LRRK2 kinase activity

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 membered heterocyclyl ring;

provided that:

the oxygen containing heterocyclyl ring is attached to said substitutable nitrogen atom of the 5-6 membered heterocyclyl ring.

9. The compound of Formula (I) or pharmaceutically acceptable salt according to claim 8 , wherein:

R 2 is a 5-6 membered heterocyclyl ring optionally substituted with one, two or three substituents, which substituents are selected from halo

wherein:

when the 5-6 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 an oxygen containing 4-6 membered heterocyclyl ring; and

provided that:

the oxygen containing heterocyclyl ring is attached to said substitutable nitrogen atom of the 5-6 membered heterocyclyl ring.

10. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 1 , wherein:

R 2 is C 3-6 cycloalkyl 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 CO 2 H.

11. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 1 , wherein:

R 2 is —O-4-6 membered heterocyclyl ring;

wherein:

the —O-4-6 membered heterocyclyl ring optionally is 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.

12. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from the group consisting of C 1-3 alkyl and C 1-3 alkoxyl.

13. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 12 , wherein R 3 is selected from the group consisting of methyl and methoxy.

14. The compound of Formula (I) or a pharmaceutically acceptable salt according to claim 1 , wherein R 4 is selected from the group consisting of H, chloro and methyl.

15. A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and at least one pharmaceutically acceptable excipient.

16. A method for treating a neurodegenerative disease, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt according to claim 1 , wherein the neurodegenerative disease is Parkinson's disease.

17. The method for treating a neurodegenerative disease according to claim 16 , wherein the subject is a human.

18. The method for treating a neurodegenerative disease according to claim 17 , wherein the subject is a human expressing G2019S mutation in LRRK2 kinase.