Therapeutic isoxazole compounds

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is (C 1 -C 6 )alkyl substituted with one or more R h ;

each R h is independently selected from the group consisting of fluoro, bromo, iodo, cyano, and nitro;

A 1 is 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)— or —C(═S)—

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

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

Y is —N(R 4 ) 2 ;

the two R 4 groups are 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 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, (C 1 -C 6 )alkylC(O)—, (C 1 -C 6 )alkylOC(O)—, (C 1 -C 6 )alkylC(O)O—, 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, (C 1 -C 6 )alkylC(O)—, (C 1 -C 6 )alkylOC(O)—, (C 1 -C 6 )alkylC(O)O—, 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. The compound of claim 1 , wherein

B is heteroaryl optionally substituted with one or more R 3 .

3. The compound of claim 2 having the formula:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 having the formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 having the formula:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , wherein X is —C(═O)—.

7. A compound of the Formula Ie:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is (C 1 -C 6 )alkyl substituted with one or more R h ;

each R h is independently selected from the group consisting of fluoro, bromo, iodo, cyano, and nitro;

A l is CR 2 ;

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;

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 0 (oxygen);

Z 1 is N (nitrogen), or CR 5 ;

Z 2 is N (nitrogen), or CR 5 ;

Z 3 is N (nitrogen), or CR 5 ;

Z 4 is N (nitrogen), or CR 5 ;

each R 5 is independently H (hydrogen), (C 1 -C 6 )alkyl, —NR i R j , —C(O)NR i R j , or aryl(C 1 -C 6 )alkyl;

X is —C(═O)—or —C(═S)—;

Y is —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, aryl sulfonyl, (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, (C 1 -C 6 )alkylC(O)—, (C 1 -C 6 )alkylOC(O)—, (C 1 -C 6 )alkylC(O)O—, heterocycle, aryl, heterocycle(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, —NR,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 n is independently an integer selected from 0, 1, and 2;

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

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, 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 ),OH, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylC(O)—, (C 1 -C 6 )alkylOC(O)—, (C 1 C 6 )alkylC(O)O—, 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),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 i 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 and the ring comprising Z 1 , Z 2 , Z 3 and Z 4 is aromatic or heteroaromatic.

8. The compound of claim 7 having the formula:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 7 selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 7 having the formula:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 , wherein R 1 is CF 3 and A l is CR 2 .

12. The compound of claim 7 having the formula:

or a pharmaceutically acceptable salt thereof.

13. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is (C 1 -C 6 )alkyl substituted with one or more R h ;

each R h is independently selected from the group consisting of fluoro, iodo, bromo, cyano, and nitro;

A l is 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)— or —C(═S)—;

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

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

Y is R 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, (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 ;

each R a and R b is independently (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 chloro, bromo, iodo, cyano, nitro, oxo, R f R g N(C 1 -C 6 )alkyl, —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, (C 1 -C 6 )alkylC(O)—, (C 1 -C 6 )alkylOC(O)—, (C 1 -C 6 )alkylC(O)O—, 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 ) nOH, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylC(O)—, (C 1 -C 6 )alkylOC(O)—, (C 1 —C 6 )alkylC(O)O—, 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.

14. The compound of claim 13 , wherein X is —C(═O)—.

15. The compound of claim 13 having the formula:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 13 having the formula:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 13 having the structure of formula Id:

or a pharmaceutically acceptable salt thereof,

wherein:

Z 1 is S (sulfur), and Z 2 Z 3 are each independently CR 5 ;

each R 5 is independently H (hydrogen), (C 1 -C 6 )alkyl, —NR i R j , —C(O)NR i R j , or aryl(C 1 -C 6 )alkyl;

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 Z 1 , Z 2 , and Z 3 is heteroaromatic.

18. The compound of claim 17 having the formula:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 17 having the formula:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 13 , wherein B is heteroaryl optionally substituted with one or more R 3 .

21. A pharmaceutical composition comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 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 l is 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 —, —S(O)— or —S—;

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

each z is independently an integer selected from 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 —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, and heterocycle(C 1 -C 6 )alkanoyl; 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 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, (C 1 -C 6 )alkylC(O)—, (C 1 -C 6 )alkylOC(O)—, (C 1 -C 6 )alkylC(O)O—, 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, (C 1 -C 6 )alkylC(O)—, (C 1 -C 6 )alkylOC(O)—, (C 1 -C 6 )alkylC(O)O—, 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;

with the proviso that when Y is —N(R 4 ) 2 , then R 4 is not a 7-azabicyclo[2.2.1]heptane or 1-azabicyclo[2.2.2]octane, each optionally substituted with (C 1 -C 6 )alkyl,

with the proviso that the compound of formula I is not:

and a pharmaceutically acceptable excipient or carrier.