IP Library › Granted Patent US 10,370,370

Granted Patent B2

US 10,370,370 · App. 15/736,235 · Granted Aug 6, 2019

Aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors

Inventors: Raksha Acharya (Bedford, MA); Duane A. Burnett (Wayland, MA); Matthew Gregory Bursavich (Needham, MA); Andrew Simon Cook (Stow, MA); Bryce Alden Harrison (Framingham, MA); Andrew J. McRiner (Melrose, MA)

Assignee: Axovant Sciences GmbH

C07D453/02 A61P25/00

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Quick Facts

Patent No.: US 10,370,370
App. No.: 15/736,235
Granted: Aug 6, 2019
Kind: B2

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Abstract

The present invention relates to novel aminobenzisoxazole compounds, and pharmaceutical compositions of the same, that are suitable as agonists or partial agonists of Alpha7-nAChR, and methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function. In particular, methods of administering the compound or composition to a patient in need thereof, for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.

Claims (174)

1. A compound represented by Formula (Ia) or Formula (Ib):

wherein:

R 1 , R 2 , R 3 , and R 4 independently represent —H, -D, halogen radical, —CN, an unbranched C 1 -C 4 -alkyl radical, a branched C 3 -C 4 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, an unbranched —OC 1 -C 4 -alkyl, a branched or cyclic —OC 3 -C 4 -alkyl, —N(R 5 )(R 6 ), —(CO)N(R 5 )(R 6 ), —NR 5 (CO)(R 6 ), —SO 2 C 1 -C 4 -alkyl, —SO 2 N(R 5 )(R 6 ), —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, —(CH 2 ) m SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 C 1 -C 4 -alkyl, an aryl radical, or a heteroaryl radical; wherein the alkyl portion of the unbranched C 1 -C 4 -alkyl radical, the branched C 3 -C 4 -alkyl radical, the C 3 -C 6 -cycloalkyl radical, the unbranched —OC 1 -C 4 -alkyl, the branched or cyclic —OC 3 -C 4 -alkyl, the —SO 2 C 1 -C 4 -alkyl, the —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, or the —N(R 5 )SO 2 C 1 -C 4 -alkyl, may be independently substituted with up to 5 radical substituents comprising: -D, halogen radical, ═O, —OR 5 , —(CH 2 ) m OR 5 , —N(R 5 )(R 6 ), —NR 5 (CO)(R 6 ), —(CH 2 ) m N(R 5 )(R 6 ), —SO 2 C 1 -C 4 -alkyl, —SO 2 N(R 5 )(R 6 ), —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, —(CH 2 ) m SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 C 1 -C 4 -alkyl, —(CO)(CH 2 ) m R 5 , —(CO)N(R 5 )(R 6 ), an unbranched C 1 -C 6 -alkyl radical, a branched C 3 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a C 1 -C 6 -hydroxyalkyl radical, a C 1 -C 2 -haloalkyl radical, or —OC 1 -C 2 -haloalkyl radical; and wherein the aryl radical or the heteroaryl radical may be independently substituted with up to 5 radical substituents comprising: -D, halogen radical, —CN, —OR 5 , —(CH 2 ) m OR 5 , —N(R 5 )(R 6 ), —NR 5 (CO)(R 6 ), —(CH 2 ) m N(R 5 )(R 6 ), —SO 2 C 1 -C 4 -alkyl, —SO 2 N(R 5 )(R 6 ), —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, —(CH 2 ) m SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 C 1 -C 4 -alkyl, —(CO)(CH 2 ) m R 5 , —(CO)N(R 5 )(R 6 ), an unbranched C 1 -C 6 -alkyl radical, a branched C 3 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a C 1 -C 6 -hydroxyalkyl radical, a C 1 -C 2 -haloalkyl radical, or —OC 1 -C 2 -haloalkyl radical;

R 5 and R 6 independently represent —H; an unbranched C 1 -C 6 -alkyl radical, a branched C 3 -C 6 -alkyl radical; a C 3 -C 6 -cycloalkyl radical; or the N(R 5 )(R 6 ) moiety forms a cycle, wherein R 5 and R 6 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical; wherein the (3-6 membered)-heteroalkyl di-radical comprises at least one ring atom selected from the group consisting of oxygen, nitrogen, and sulfur, with the proviso that when the at least one ring atom is nitrogen, the nitrogen is independently substituted with —H, an unbranched C 1 -C 4 -alkyl radical, a branched C 3 -C 4 -alkyl radical, a C 3 -C 4 -cycloalkyl radical, —(CO)-unbranched C 1 -C 4 -alkyl, —(CO)-branched C 3 -C 4 -alkyl, —(SO 2 )-unbranched C 1 -C 4 -alkyl, or —(SO 2 )-branched C 3 -C 4 -alkyl, and with the further proviso that when the at least one ring atom is sulfur, the sulfur may be independently substituted with 0 to 2 ═O; wherein the C 2 -C 6 -alkyl di-radical or the alkyl portion of said (3-6 membered)-heteroalkyl di-radical may be independently substituted with up to 5 radical substituents comprising: -D, halogen radical, ═O, an unbranched C 1 -C 6 -alkyl radical, or a branched C 3 -C 6 -alkyl radical; and

m independently represents an integer from 1 to 6;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 independently represents —H, -D, or halogen radical.

3. The compound of claim 1 , where R 2 independently represents —H, -D, or halogen radical.

4. The compound of claim 1 , wherein R 3 independently represents —H, -D, —F, —Cl, —Br, —CN, an unbranched C 1 -C 4 -alkyl radical, a branched C 3 -C 4 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, an unbranched —OC 1 -C 4 -alkyl, a branched or cyclic —OC 3 -C 4 -alkyl, —N(R 5 )(R 6 ), —(CO)N(R 5 )(R 6 ), —NR 5 (CO)(R 6 ), —SO 2 C 1 -C 4 -alkyl, —SO 2 N(R 5 )(R 6 ), —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, —(CH 2 ) m SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 C 1 -C 4 -alkyl, an aryl radical, or a heteroaryl radical; wherein the alkyl portion of the unbranched C 1 -C 4 -alkyl radical, the branched C 3 -C 4 -alkyl radical, the C 3 -C 6 -cycloalkyl radical, the unbranched —OC 1 -C 4 -alkyl, the branched or cyclic —OC 3 -C 4 -alkyl, the —SO 2 C 1 -C 4 -alkyl, the —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, or the —N(R 5 )SO 2 C 1 -C 4 -alkyl, may be independently substituted with up to 5 radical substituents comprising: -D, —F, —Cl, —Br, ═O, —OR, —(CH 2 ) m OR 5 , —N(R 5 )(R 6 ), —NR 5 (CO)(R 6 ), —(CH 2 ) m N(R 5 )(R 6 ), —SO 2 C 1 -C 4 -alkyl, —SO 2 N(R 5 )(R 6 ), —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, —(CH 2 ) m SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 C 1 -C 4 -alkyl, —(CO)(CH 2 ) m R 5 , —(CO)N(R 5 )(R 6 ), an unbranched C 1 -C 6 -alkyl radical, a branched C 3 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a C 1 -C 6 -hydroxyalkyl radical, a C 1 -C 2 -haloalkyl radical, or —OC 1 -C 2 -haloalkyl radical; and wherein the aryl radical or the heteroaryl radical may be independently substituted with up to 5 radical substituents comprising: -D, —F, —Cl, —Br, —CN, —OR 5 , —(CH 2 ) m OR 5 , —N(R 5 )(R 6 ), —NR 5 (CO)(R 6 ), —(CH 2 ) m N(R 5 )(R 6 ), —SO 2 C 1 -C 4 -alkyl, —SO 2 N(R 5 )(R 6 ), —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, —(CH 2 ) m SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 C 1 -C 4 -alkyl, —(CO)(CH 2 ) m R 5 , —(CO)N(R 5 )(R 6 ), an unbranched C 1 -C 6 -alkyl radical, a branched C 3 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a C 1 -C 6 -hydroxyalkyl radical, a C 1 -C 2 -haloalkyl radical, or —OC 1 -C 2 -haloalkyl radical.

5. The compound of claim 1 , wherein R 3 independently represents —Cl, —CH 3 , or —OCH 3 .

6. The compound of claim 1 , wherein R 4 independently represents —H, -D, —F, —Cl, —Br, —CN, an unbranched C 1 -C 4 -alkyl radical, a branched C 3 -C 4 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, an unbranched —OC 1 -C 4 -alkyl, a branched or cyclic —OC 3 -C 4 -alkyl, —N(R 5 )(R 6 ), —(CO)N(R 5 )(R 6 ), —NR 5 (CO)(R 6 ), —SO 2 C 1 -C 4 -alkyl, —SO 2 N(R 5 )(R 6 ), —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, —(CH 2 ) m SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 C 1 -C 4 -alkyl, an aryl radical, or a heteroaryl radical; wherein the alkyl portion of the unbranched C 1 -C 4 -alkyl radical, the branched C 3 -C 4 -alkyl radical, the C 3 -C 6 -cycloalkyl radical, the unbranched —OC 1 -C 4 -alkyl, the branched or cyclic —OC 3 -C 4 -alkyl, the —SO 2 C 1 -C 4 -alkyl, the —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, or the —N(R 5 )SO 2 C 1 -C 4 -alkyl, may be independently substituted with up to 5 radical substituents comprising: -D, —F, —Cl, —Br, ═O, —OR 5 , —(CH 2 ) m OR 5 , —N(R 5 )(R 6 ), —NR 5 (CO)(R 6 ), —(CH 2 ) m N(R 5 )(R 6 ), —SO 2 C 1 -C 4 -alkyl, —SO 2 N(R 5 )(R 6 ), —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, —(CH 2 ) m SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 C 1 -C 4 -alkyl, —(CO)(CH 2 ) m R 5 , —(CO)N(R 5 )(R 6 ), —OCF 3 , an unbranched C 1 -C 6 -alkyl radical, a branched C 3 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a C 1 -C 6 -hydroxyalkyl radical, a C 1 -C 2 haloalkyl radical, or —OC 1 -C 2 -haloalkyl radical; and wherein aryl radical or the heteroaryl radical may be independently substituted with up to 5 radical substituents comprising: -D, —F, —Cl, —Br, —CN, —OR 5 , —(CH 2 ) m OR 5 , —N(R 5 )(R 6 ), —NR 5 (CO)(R 6 ), —(CH 2 ) m N(R 5 )(R 6 ), —SO 2 C 1 -C 4 -alkyl, —SO 2 N(R 5 )(R 6 ), —(CH 2 ) m SO 2 C 1 -C 4 -alkyl, —(CH 2 ) m SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 C 1 -C 4 -alkyl, —(CO)(CH 2 ) m R 5 , —(CO)N(R 5 )(R 6 ), —OCF 3 , an unbranched C 1 -C 6 -alkyl radical, a branched C 3 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a C 1 -C 6 -hydroxyalkyl radical, a C 1 -C 2 -haloalkyl radical, or —OC 1 -C 2 -haloalkyl radical.

7. The compound of claim 1 , wherein R 4 independently represents —H, -D, —F, —Cl, —CH 3 , —OCH 3 , —OCH 2 CH 3 , or —CF 3 .

8. The compound of claim 1 , wherein the compound is a single enantiomer or a single diastereomer.

9. The compound of claim 1 , wherein the compound is selected from the group consisting of:

N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

7-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

5-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-cyclopropyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

N-(quinuclidin-3-yl)-6-(trifluoromethyl)benzo[d]isoxazol-3-amine;

6,7-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

4-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

3-(quinuclidin-3-ylamino)benzo[d]isoxazole-6-carbonitrile;

6-(methylsulfonyl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-(tert-butyl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

5,6-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

N-(quinuclidin-3-yl)-6-(trifluoromethoxy)benzo[d]isoxazol-3-amine;

7-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

5-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

4-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

7-fluoro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6,7-difluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

5-fluoro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-chloro-7-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-chloro-7-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-chloro-N-(quinuclidin-3-yl)-7-(trifluoromethyl)benzo[d]isoxazol-3-amine;

6-chloro-7-cyclopropyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

4-fluoro-6-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

4,6-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

7-fluoro-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

7-chloro-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

7-chloro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-isopropoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-ethoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-chloro-3-(quinuclidin-3-ylamino)benzo[d]isoxazole-7-carbonitrile;

7-chloro-6-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-(IH-pyrazol-I -yl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

7-methoxy-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-chloro-7-ethoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6,7-dimethyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-chloro-7-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

6-chloro-5-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine; and

6-bromo-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

and single enantiomers and pharmaceutically acceptable salts thereof.

10. The compound of claim 1 , wherein the compound is selected from the group consisting of:

(R)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-7-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-7-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-5-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-5-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-cyclopropyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-cyclopropyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R) N-(quinuclidin-3-yl)-6-(trifluoromethyl)benzo[d]isoxazol-3-amine;

(S)-N-(quinuclidin-3-yl)-6-(trifluoromethyl)benzo[d]isoxazol-3-amine;

(R)-6,7-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6,7-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-4-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-4-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-3-(quinuclidin-3-ylamino)benzo[d]isoxazole-6-carbonitrile;

(S)-3-(quinuclidin-3-ylamino)benzo[d]isoxazole-6-carbonitrile;

(R)-6-(methylsulfonyl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-(methylsulfonyl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-(tert-butyl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-(tert-butyl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-5,6-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-5,6-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R) N-(quinuclidin-3-yl)-6-(trifluoromethoxy)benzo[d]isoxazol-3-amine;

(S)-N-(quinuclidin-3-yl)-6-(trifluoromethoxy)benzo[d]isoxazol-3-amine;

(R)-7-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-7-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-5-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-5-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-4-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-4-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-7-fluoro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-7-fluoro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6,7-difluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6,7-difluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-5-fluoro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-5-fluoro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-methy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-chloro-7-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-chloro-7-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-N-(quinuclidin-3-yl)-7-(trifluoromethyl)benzo[d]isoxazol-3-amine;

(S)-6-chloro-N-(quinuclidin-3-yl)-7-(trifluoromethyl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-cyclopropyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-chloro-7-cyclopropyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-4-fluoro-6-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-4-fluoro-6-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-4,6-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-4,6-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-7-fluoro-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-7-fluoro-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-7-chloro-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-7-chloro-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-7-chloro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-7-chloro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-isopropoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-isopropoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-ethoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-ethoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-3-(quinuclidin-3-ylamino)benzo[d]isoxazole-7-carbonitrile;

(S)-6-chloro-3-(quinuclidin-3-ylamino)benzo[d]isoxazole-7-carbonitrile;

(R)-7-chloro-6-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-7-chloro-6-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-(lH-pyrazol-l-yl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-(lH-pyrazol-1-yl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-(5-methyl-l,3,4-oxadiazol-2-yl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-(5-methyl-l,3,4-oxadiazol-2-yl)-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-7-methoxy-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-7-methoxy-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-ethoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-chloro-7-ethoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6,7-dimethyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6,7-dimethyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-chloro-7-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-5-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-chloro-5-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-bromo-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine; and

(S)-6-bromo-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

and pharmaceutically acceptable salts thereof.

11. The compound of claim 1 , wherein the compound is selected from the group consisting of:

(R)-6-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(S)-6-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6,7-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-7-fluoro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-5-fluoro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-N-(quinuclidin-3-yl)-7-(trifluoromethyl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine; and

(R)-6-chloro-5-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

and pharmaceutically acceptable salts thereof.

12. The compound of claim 1 , wherein the compound is selected from the group consisting of:

(R)-6-chloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6,7-dichloro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-7-fluoro-6-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-methyl-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-7-methoxy-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

(R)-6-chloro-N-(quinuclidin-3-yl)-7-(trifluoromethyl)benzo[d]isoxazol-3-amine; and

(R)-6-chloro-7-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine;

and pharmaceutically acceptable salts thereof.

13. A pharmaceutical composition, comprising:

i) the compound, or pharmaceutically acceptable salt thereof, of claim 1 ; and

ii) at least one pharmaceutically acceptable carrier, excipient or diluent.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 15, 2019

From: ACHARYA, RAKSHA; BURNETT, DUANE A.; BURSAVICH, MATTHEW GREGORY; COOK, ANDREW SIMON; HARRISON, BRYCE ALDEN; MCRINER, ANDREW J.

To: FORUM PHARMACEUTICALS, INC.

Reel/Frame 048015/0100 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 15, 2019

From: FORUM PHARMACEUTICALS, INC.

To: AXOVANT SCIENCES GMBH

Reel/Frame 048015/0215 →

Continuity (2)

Provisional Application 62173717 · Jun 10, 2015

Related Publication 20180134696A1 · May 17, 2018