IP Library › Granted Patent US 8,377,931
Granted Patent B2
US 8,377,931 · App. 12/584,373 · Granted Feb 19, 2013

Benzoxazine derivatives and uses thereof

Inventors: Jacob Berger (Los Altos Hills, CA); Robin Douglas Clark (Lawai, HI); Shu-Hai Zhao (Sunnyvale, CA)
Assignee: Roche Palo Alto LLC
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Quick Facts
Patent No.
US 8,377,931
App. No.
12/584,373
Granted
Feb 19, 2013
Kind
B2
Abstract

The present invention provides a compound of the formula: a pharmaceutically acceptable salt or a prodrug thereof, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Y, Z 1 , m, n, and p are as defined herein. The present invention also provides compositions comprising, methods for using, and methods for preparing Compound of Formula I.

Claims (104)

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R 3 is alkyl, aryl, haloalkyl, heterocyclyl, or heteroaryl; and

R 9 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or benzyl.

2. The compound of claim 1 , wherein R 3 is aryl or heteroaryl.

3. The compound of claim 2 , wherein R 9 is hydrogen or alkyl.

4. The compound of claim 3 , wherein R 3 is optionally substituted phenyl.

5. The compound of claim 4 , wherein R 9 is hydrogen or methyl.

6. The compound of claim 5 , wherein R 3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-methanesulfonylaminophenyl, 2-methanesulfonylphenyl, 2-carbamoylphenyl, 3-methanesulfonylphenyl, 4-methanesulfonylphenyl, 3-fluorophenyl, naphthylene-1-yl, 2,4-difluorophenyl, 2-cyanophenyl, 2-chloro-4-fluorophenyl, 5-fluoro-2-methylphenyl, 5-chloronaphthyl, naphthylene-2-yl, 4-fluoro-2-methylphenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 4-(piperazin-1-yl)-phenyl, or 2,3-dihydrobenzo[1,4]dioxinyl.

7. The compound of claim 5 , wherein R 3 is optionally substituted heteroaryl.

8. The compound of claim 7 , wherein R 3 is quinolin-8-yl, thiophen-2-yl, 5-chlorothiophen-2-yl, isoquinolin-5-yl, 4-(Benzo[1,2,5]thiadiazole-4-yl, 1-methyl-1H-imidazole-4-yl, or 4-(Benzo[1,2,5]oxadiazole-4-yl.

9. The compound of claim 4 , wherein R 3 is 2-halophenyl.

10. The compound of claim 1 , wherein R 3 is 2-fluorophenyl.

11. The compound of claim 1 , wherein R 9 is hydrogen.

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

4-Benzenesulfonyl-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Chloro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(3,4-Dichloro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(4-Chloro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(4-Chloro-benzenesulfonyl)-8-(3,5-dimethyl-piperazin-1-yl)-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(2-chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(4-Chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(4-Methoxy-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

8-piperazin-1-yl-4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(3,4-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(3-Chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(3,5-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2,3-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2,6-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2,4-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

N-[3-(8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenyl]-methanesulfonamide;

N-[2-(8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenyl]-methanesulfonamide;

2-(8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzamide;

4-(3-Methanesulfonyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(4-methanesulfonyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-Benzenesulfonyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(3-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-Benzenesulfonyl-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(naphthalene-1-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-methanesulfonyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-8-piperazin-1-yl-4-(thiophene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-8-piperazin-1-yl-4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(3-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(2,4-difluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(5-chloro-thiophene-2-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(3-chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(2,3-dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

2-(6-Chloro-8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile;

6-Chloro-4-(2-chloro-4-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(5-fluoro-2-methyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(5-chloro-naphthalene-1-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(isoquinoline-5-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(1-methyl-1H-imidazole-4-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(Benzo[1,2,5]oxadiazole-4-sulfonyl)-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

2-(6-Methyl-8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile;

6-Methyl-8-piperazin-1-yl-4-(thiophene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Methyl-8-piperazin-1-yl-4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(3-Fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2,4-Difluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Chloro-4-fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(5-Fluoro-2-methyl-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(Isoquinoline-5-sulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Methyl-4-(1-methyl-1H-imidazole-4-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Fluoro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(2-fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Fluoro-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(3-Methanesulfonyl-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-8-(4-methyl-piperazin-1-yl)-4-(naphthalene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine;

4-Benzenesulfonyl-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine;

4-Benzenesulfonyl-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-Benzenesulfonyl-6-fluoro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

2-(8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenol;

4-(2-Methoxy-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2,3-Dihydro-benzo[1,4]dioxine-6-sulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2,3-Dihydro-benzo[1,4]dioxine-6-sulfonyl)-6-fluoro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Methoxy-4-(naphthalene-1-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Chloro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(3-Chloro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(5-Fluoro-2-methyl-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Methoxy-8-piperazin-1-yl-4-(toluene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine;

2-(6-Methyl-8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenol;

6-tert-Butyl-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine; and

6-piperazin-1-yl-4-(4-piperazin-1-yl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine.

13. A composition comprising:

(a) a therapeutically effective amount of a compound of claim 1 ; and

(b) a pharmaceutically acceptable carrier.

14. The compound of claim 12 , wherein said compound is selected from:

4-(2-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Fluoro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Chloro-4-(2-fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine;

6-Fluoro-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-(2-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine; and

6-tent-Butyl-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine.

15. The compound 4-(2-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine, or a pharmaceutically acceptable salt thereof.

16. The compound 4-(2-Fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine, or a pharmaceutically acceptable salt thereof.

Continuity (4)
Continuation 11047284 · Jan 31, 2005
Continuation 10435732 · May 9, 2003
Provisional Application 60378003 · May 13, 2002
Related Publication 20090325950A1 · Dec 31, 2009