OXADIAZINE COMPOUNDS AND METHODS OF USE THEREOF

1 . A compound of Formula (I)

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is phenyl, 5- to 6-membered aromatic heterocycle, 8- to 10-membered bicyclic heterocycle or 11- to 14-membered tricyclic heterocycle, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkyl, —C3-C8 monocyclic cycloalkyl, halo-substituted C1-C4 alkyl, —CN, —OH, —C1-C4 alkoxy, —O—C3-C8 monocyclic cycloalkyl, halo-substituted C1-C4 alkoxy and 3- to 7-membered monocyclic heterocycle;

each R 2 is independently hydrogen, —C1-C4 alkyl or —C3-C6 monocyclic cycloalkyl with the proviso that both R 2 are not hydrogen, or both R 2 together with the carbon atom they are attached to form a C3-C6 monocyclic cycloalkyl, wherein each —C1-C4 alkyl and —C3-C6 monocyclic cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —OH, —C1-C4 alkoxy, —O—C3-C8 monocyclic cycloalkyl which is unsubstituted or substituted with halo, halo-substituted C1-C4 alkyl or halo-substituted C1-C4 alkoxy;

Y is pyridinyl or phenyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, —CN and —OH; and

Z is nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, —C1-C4 alkoxy and —OCF 3 .

2 . (canceled)

3 . A compound of claim 1 , wherein R 1 is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkyl, —C3-C8 monocyclic cycloalkyl and halo-substituted C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

4 - 6 . (canceled)

7 . A compound of claim 1 , wherein R 1 is 5- to 6-membered aromatic heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkyl, —C3-C8 monocyclic cycloalkyl and halo-substituted C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

8 - 10 . (canceled)

11 . A compound of claim 1 , wherein R 1 is 8-to 10-membered bicyclic heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkyl, —C3-C8 monocyclic cycloalkyl and halo-substituted C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

12 - 21 . (canceled)

22 . A compound of claim 21 , wherein one R 2 is hydrogen and the other R 2 is —C1-C4 alkyl or cyclopropyl; or a pharmaceutically acceptable salt thereof.

23 - 29 . (canceled)

30 . A compound of claim 1 , wherein Y is pyridinyl or phenyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, —CN and —OH; or a pharmaceutically acceptable salt thereof.

31 - 33 . (canceled)

34 . The compound of claim 1 , wherein Y is

wherein the left most radical is connected to the Z group in Formula (I); or a pharmaceutically acceptable salt thereof.

35 - 39 . (canceled)

40 . A compound of claim 1 , wherein Z is

or a pharmaceutically acceptable salt thereof.

41 . A compound selected from the group consisting of:

(+)-(5S,6R)-5-(4-chlorophenyl)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazine;

(+)-cis-5-(3,4-dichlorophenyl)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazine;

(+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6-dihydro-4H-1,2,4-oxadiazin;

(−)-5-chloro-6-fluoro-3-[3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl]-1-methyl-1H-indole;

(+)-5-chloro-6-fluoro-3-[3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl]-1-methyl-1H-indole;

(+)-5-chloro-6-fluoro-3-[3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl]-1-methyl-1H-indole;

(+)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6,6-dimethyl-5-phenyl-5,6-dihydro-4H-1,2,4-oxadiazin;

(+)-5-(4-chlorophenyl)-3-[6-methoxy-5-(4-m ethyl-1H-imidazol-1-yl)pyridin-2-yl]-6,6-dimethyl-5,6-dihydro-4H-1,2,4-oxadiazine;

(+)-trans-5-(4-chlorophenyl)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazine; and

(+)-8-(4-chlorophenyl)-6-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-4-oxa-5,7-diazaspiro[2.5]oct-5-ene;

or a pharmaceutically acceptable salt thereof.

42 . The compound of claim 41 , selected from the group consisting of:

(+)-(5 S,6R)-5-(4-chlorophenyl)-3-[6-methoxy-5-(4-methyl-1H-imidazol -1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazine;

(+)-cis-5-(3,4-dichlorophenyl)-3-[6-methoxy-5-(4-methyl-1H-imidazol -1-yl)pyridin-2-yl]-6-methyl -5,6-dihydro-4H-1,2,4-oxadiazine;

(+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6-dihydro-4H-1,2,4-oxadiazin;

(−)-5-chloro-6-fluoro-3-[3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl]-1-methyl-1H-indole;

(+)-5-chloro-6-fluoro-3-[3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl]-1-methyl-1H-indole;

(+)-5-chloro-6-fluoro-3-[3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl]-1-methyl-1H-indole;

(+)-5-(4-chlorophenyl)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6,6-dimethyl-5,6-dihydro-4H-1,2,4-oxadiazine;

(+)-trans-5-(4-chlorophenyl)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazine; and

(+)-8-(4-chlorophenyl)-6-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-4-oxa-5,7-diazaspiro [2.5]oct-5-ene;

or a pharmaceutically acceptable salt thereof

43 . The compound of claim 42 , wherein the compound is (+)-(5S,6R)-5-(4-chlorophenyl)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazine; or a pharmaceutically acceptable salt thereof.

44 . The compound of claim 42 , wherein the compound is (+)-5-chloro-6-fluoro-3-[3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-6-methyl-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl]-1-methyl-1H-indole; or a pharmaceutically acceptable salt thereof.

45 . The compound of claim 42 , wherein the compound is (+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6-dihydro-4H-1,2,4-oxadiazine; or a pharmaceutically acceptable salt thereof.

46 . A compound of Formula (II)

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is phenyl, 5- to 6-membered aromatic heterocycle, 8- to 10-membered bicyclic heterocycle or 11- to 14-membered tricyclic heterocycle, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkyl, —C3-C8 monocyclic cycloalkyl, halo-substituted C1-C4 alkyl, —CN, —OH, —C1-C4alkoxy, —O—C3-C8 monocyclic cycloalkyl, halo-substituted C1-C4alkoxy and 3- to 7-membered monocyclic heterocycle;

each R 2 is independently hydrogen, —C1-C4 alkyl or —C3-C6 monocyclic cycloalkyl, or both R 2 together with the carbon atom they are attached to form a C3-C6 monocyclic cycloalkyl, wherein each —C1-C4 alkyl and —C3-C6 monocyclic cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —OH, —C1-C4alkoxy, —O—C 3 -C8 monocyclic cycloalkyl which is unsubstituted or substituted with halo, halo-substituted C1-C4 alkyl or halo-substituted C1-C4alkoxy;

R 3 is —C1-C4 alkyl or —C3-C6 monocyclic cycloalkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —OH, —C1-C4 alkoxy, —O—C3-C8 monocyclic cycloalkyl which is unsubstituted or substituted with halo, halo-substituted C1-C4 alkyl or halo-substituted C1-C4alkoxy;

Y is pyridinyl or phenyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, —CN and —OH; and

Z is nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, —C1-C4 alkoxy and —OCF 3 .

47 - 88 . (canceled)

89 . The compound of claim 46 , wherein the compound is (+)-3-[3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5-methyl-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl]-1-methyl-1H-indole; or a pharmaceutically acceptable salt thereof.

90 . The compound of claim 46 , wherein the compound is (−)-3-[3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5-methyl-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl]-1-methyl-1H-indole; or a pharmaceutically acceptable salt thereof.

91 - 92 . (canceled)

93 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or vehicle and an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

94 . A method for treating a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

95 - 104 . (canceled)

105 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or vehicle and an effective amount of a compound of claim 46 or a pharmaceutically acceptable salt thereof.

106 . A method for treating a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound of claim 46 or a pharmaceutically acceptable salt thereof.

107 - 108 . (canceled)