IP Library › Granted Patent US 9,029,397

Granted Patent B2

US 9,029,397 · App. 13/542,358 · Granted May 12, 2015

Therapeutic isoxazole compounds

Inventors: Alan P. Kaplan (San Diego, CA); Terence P. Keenan (San Diego, CA); Andrew J. McRiner (Melrose, MA)

Assignee: Dart NeuroScience (Cayman) Ltd.

C07D261/08 C07D413/04 C07D413/14 C07D453/02 C07D487/04 C07D491/044

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Quick Facts

Patent No.: US 9,029,397
App. No.: 13/542,358
Granted: May 12, 2015
Kind: B2

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Abstract

The invention provides a compound of formula I: wherein A 1 , A 2 , A 3 , R 1 , X, Y, and B have any of the values described herein, as well as salts of such compounds, compositions comprising such compounds, and therapeutic methods that comprise the administration of such compounds. The compounds are inhibitors of monoamine oxidase B (MAO-B) enzyme function and are useful for improving cognitive function and for treating psychiatric disorders in animals.

Claims (163)

1. A method for inhibiting one or more monoamine oxidase (MAO) enzymes in an animal comprising administering to the animal an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt or prodrug ester thereof,

wherein:

R 1 is H (hydrogen), or is selected from the group consisting of aryl and (C 1 -C 6 )alkyl, each optionally substituted with one or more R h ;

each R h is independently selected from the group consisting of halo, cyano, nitro, and —OH;

A 1 is N (nitrogen), or CR 2 ;

A 2 and A 3 are each independently O (oxygen) or N (nitrogen) with the proviso that when A 2 is O (oxygen), A 3 is N (nitrogen) and when A 2 is N (nitrogen), A 3 is O (oxygen);

R 2 is H (hydrogen), (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or aryl optionally substituted with one or more halo;

B is aryl or heteroaryl, each optionally substituted with one or more R 3 ;

each R 3 is independently (C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl;

X is —C(═O)—, —C(═S)—, —C(R 4 ) 2 —, or —S(O) z —;

each n is independently an integer selected from 0, 1, and 2;

each z is independently an integer selected from 0, 1, and 2;

Y is R 4 , —N(R 4 ) 2 , —OR 4 , —SR 4 , or —C(R 4 ) 3 , each optionally substituted with one or more R d ;

each R 4 is independently selected from the group consisting of hydrogen, —OH, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 8 )cycloalkyl, —(CH 2 ) n (C 3 -C 8 )cycloalkyl, heteroaryl, aryl, aryl(C 1 -C 6 )alkyl, heterocycle, heterocycle(C 1 -C 6 )alkyl, heterocycle(C 1 -C 6 )alkanoyl, and NR a R b ; or when Y is —N(R 4 ) 2 , then two R 4 groups are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from O (oxygen), S(O) z , and NR c wherein each ring system is optionally substituted with one or more R d ;

each R a and R b is independently hydrogen or (C 1 -C 6 )alkyl, or R a and R b are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally substituted with one or more C 1 -C 6 alkyl groups;

each R c is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, (C 1 -C 6 )alkylsulfonyl, arylsulfonyl, (C 1 -C 6 )alkylC(O)—, arylC(O)—, hydroxy(C 1 -C 6 )alkyl, alkoxy(C 1 -C 6 )alkyl, heterocycle, (C 1 -C 6 )alkylOC(O)—, (C 1 -C 6 )alkylaminocarbonyl, and arylaminocarbonyl;

each R d is independently halo, cyano, nitro, oxo, R f R g N(C 1 -C 6 )alkyl, —(CH 2 ) n NR f R g , —C(O)NR f R g , —NR e C(O)R g , arylC(O)NR f R g , —C(O)OH, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(CH 2 ) n OH, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, heterocycle, aryl, heterocycle(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, —NR e S(O) z (C 1 -C 6 )alkyl, —NR e S(O) z aryl, —NR e C(O)NR f R g , —NR e C(O)OR f , or —OC(O)NR f R g ;

each R e is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl;

each R f and R g is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl, or R f and R g are optionally taken together with the nitrogen to which they are attached to form a 3-8 membered monocyclic or a 7-12 membered bicyclic ring system, each optionally comprising one or more additional heteroatom groups selected from O (oxygen), S(O) z , and NR c wherein each ring system is optionally substituted with one or more R q ;

each R q is independently halo, cyano, nitro, oxo, —NR i R j , R i R j N(C 1 -C 6 )alkyl, —(CH 2 ) n NR i R j , —C(O)NR i R j , —NR k C(O)R j , arylC(O)NR i R j , —C(O)OH, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(CH 2 ) n OH, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, heterocycle, aryl, heterocycle (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, —NR e S(O) z (C 1 -C 6 )alkyl, —NR k S(O) z aryl, —NR k C(O)NR i R j , —NR k C(O)OR I , or —OC(O)NR i R j ;

each R k is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl;

each R i and R j is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl; and

the dashed line represents an optional double bond wherein the ring comprising A 1 , A 2 , and A 3 is heteroaromatic.

2. A method for improving cognitive function in an animal in need of such treatment comprising administering to the animal an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt or prodrug ester thereof,

wherein:

R 1 is H (hydrogen), or is selected from the group consisting of aryl and (C 1 -C 6 )alkyl, each optionally substituted with one or more R h ;

each R h is independently selected from the group consisting of halo, cyano, nitro, and —OH;

A 1 is N (nitrogen), or CR 2 ;

A 2 and A 3 are each independently O (oxygen) or N (nitrogen) with the proviso that when A 2 is O (oxygen), A 3 is N (nitrogen) and when A 2 is N (nitrogen), A 3 is O (oxygen);

R 2 is H (hydrogen), (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or aryl optionally substituted with one or more halo;

B is aryl or heteroaryl, each optionally substituted with one or more R 3 ;

each R 3 is independently (C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl;

X is —C(═O)—, —C(═S)—, —C(R 4 ) 2 —, or —S(O) z —;

each n is independently an integer selected from 0, 1, and 2;

each z is independently an integer selected from 0, 1, and 2;

Y is R 4 , —N(R 4 ) 2 , —OR 4 , —SR 4 , or —C(R 4 ) 3 , each optionally substituted with one or more R d ;

each R d is independently halo, cyano, nitro, oxo, R f R g N(C 1 -C 6 )alkyl, —(CH 2 ) n NR f R g , —C(O)NR f R g , —NR e C(O)R g , arylC(O)NR f R g , —C(O)OH, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(CH 2 ) n OH, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, heterocycle, aryl, heterocycle (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, —NR e S(O) z (C 1 -C 6 )alkyl, —NR e S(O) z aryl, —NR e C(O)NR f R g , —NR e C(O)OR f , or —OC(O)NR f R g ;

each R e is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl;

each R q is independently halo, cyano, nitro, oxo, —NR i R j , R i R j N(C 1 -C 6 )alkyl, —(CH 2 )—NR i R j , —C(O)NR i R j , —NR k C(O)R i , arylC(O)NR i R j , —C(O)OH, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(CH 2 ) n OH, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, heterocycle, aryl, heterocycle (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, —NR e S(O) z (C 1 -C 6 )alkyl, —NR k S(O) z aryl, —NR k C(O)NR i R j , —NR k C(O)OR i , or —OC(O)NR i R j ;

each R k is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl;

each R i and R j is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl; and

the dashed line represents an optional double bond wherein the ring comprising A 1 , A 2 , and A 3 is heteroaromatic.

3. A method for treating a psychiatric disorder in an animal comprising administering to an animal in need thereof an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt or prodrug ester thereof,

wherein:

R 1 is H (hydrogen), or is selected from the group consisting of aryl and (C 1 -C 6 )alkyl, each optionally substituted with one or more R h ;

each R h is independently selected from the group consisting of halo, cyano, nitro, and —OH;

A 1 is N (nitrogen), or CR 2 ;

A 2 and A 3 are each independently O (oxygen) or N (nitrogen) with the proviso that when A 2 is O (oxygen), A 3 is N (nitrogen) and when A 2 is N (nitrogen), A 3 is O (oxygen);

R 2 is H (hydrogen), (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or aryl optionally substituted with one or more halo;

B is aryl or heteroaryl, each optionally substituted with one or more R 3 ;

each R 3 is independently (C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl;

X is —C(═O)—, —C(═S)—, —C(R 4 ) 2 —, or —S(O) z —;

each n is independently an integer selected from 0, 1, and 2;

each z is independently an integer selected from 0, 1, and 2;

Y is R 4 , —N(R 4 ) 2 , —OR 4 , —SR 4 , or —C(R 4 ) 3 , each optionally substituted with one or more R d ;

each R e is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl;

each R q is independently halo, cyano, nitro, oxo, —NR i R j , R i R j N(C 1 -C 6 )alkyl, —(CH 2 )—NR i R j , —C(O)NR i R j , —NR k C(O)R j , arylC(O)NR i R j , —C(O)OH, (C 1 -C 6 )alkyl, (C 3 -C 8 )cyclo alkyl, —(CH 2 ) n OH, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, heterocycle, aryl, heterocycle(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, —NR e S(O) z (C 1 -C 6 )alkyl, —NR k S(O) z aryl, —NR k C(O)NR i R j , —NR k C(O)OR i , or —OC(O)NR i R j ;

each R k is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl;

each R i and R j is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl; and

the dashed line represents an optional double bond wherein the ring comprising A 1 , A 2 , and A 3 is heteroaromatic.

4. The method of claim 3 , wherein the psychiatric disorder is a disorder of the central nervous system.

5. The method of claim 4 , wherein the disorder of the central nervous system is age-associated memory impairment, mild cognitive impairment, Alzheimer's disease or Parkinson's disease.

6. The method of claim 3 , wherein the psychiatric disorder is associated with head trauma, brain trauma or cerebrovascular disease.

7. The method of claim 3 , wherein the psychiatric disorder is attention deficit disorder.

8. A method for treating memory impairment in an animal with a psychiatric disorder comprising administering to the animal an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt or prodrug ester thereof,

wherein:

R 1 is H (hydrogen), or is selected from the group consisting of aryl and (C 1 -C 6 )alkyl, each optionally substituted with one or more R h ;

each R h is independently selected from the group consisting of halo, cyano, nitro, and —OH;

A 1 is N (nitrogen), or CR 2 ;

A 2 and A 3 are each independently O (oxygen) or N (nitrogen) with the proviso that when A 2 is O (oxygen), A 3 is N (nitrogen) and when A 2 is N (nitrogen), A 3 is O (oxygen);

R 2 is H (hydrogen), (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or aryl optionally substituted with one or more halo;

B is aryl or heteroaryl, each optionally substituted with one or more R 3 ;

each R 3 is independently (C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl;

X is —C(═O)—, —C(═S)—, —C(R 4 ) 2 —, or —S(O) z —;

each n is independently an integer selected from 0, 1, and 2;

each z is independently an integer selected from 0, 1, and 2;

Y is R 4 , —N(R 4 ) 2 , —OR 4 , —SR 4 , or —C(R 4 ) 3 , each optionally substituted with one or more R d ;

each R d is independently halo, cyano, nitro, oxo, R f R g N(C 1 -C 6 )alkyl, —(CH 2 ) a NR f R g , —C(O)NR f R g , —NR e C(O)R g , arylC(O)NR f R g , —C(O)OH, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(CH 2 ) n OH, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, heterocycle, aryl, heterocycle (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, —NR e S(O) z (C 1 -C 6 )alkyl, —NR e S(O) z aryl, —NR e C(O)NR f R g , —NR e C(O)OR f , or —OC(O)NR f R g ;

each R e is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl;

each R k is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl;

each R i and R j is independently hydrogen, (C 1 -C 6 )alkyl, aryl or heteroaryl; and

the dashed line represents an optional double bond wherein the ring comprising A 1 , A 2 , and A 3 is heteroaromatic.

9. The method of claim 8 , wherein the psychiatric disorder is a psychotic disorder, a neurological disorder, or a neurotic disorder.

10. The method of claim 1 , wherein the compound has the formula: