Therapeutic isoxazole compounds
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.
1. A compound of formula Ia:
or a pharmaceutically acceptable salt 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;
X is —C(═O)—,—C(═S)—,—S—, or —S(O)—;
Y is—N(R 4 ) 2 where 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, 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 n is independently an integer selected from 0, 1, and 2;
each z is independently an integer selected from 0, 1, and 2;
Z 1 is S (sulfur);
Z 2 , and Z 3 are each independently O (oxygen), N (nitrogen), S (sulfur), or CR 5 ;
each R 5 is independently H (hydrogen), (C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl;
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 ) 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 Z 1 ,Z 2 , and Z 3 is heteroaromatic.
2. The compound of claim 1 , wherein —N(R 4 ) 2 is piperidinyl optionally substituted with one or more R d .
3. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 , wherein X is —C(═O).
5. A compound of formula IIa:
or a pharmaceutically acceptable salt 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 l is N (nitrogen), or 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, A 3 is N and when A 2 is N, A 3 is O;
Z 1 is S (sulfur);
Z 2 , and Z 3 are each independently O (oxygen), N (nitrogen), S (sulfur), or CR 5 ;
each R 5 is independently H (hydrogen), (C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl;
X is —C(═O)—, —C(═S)—, —S—, or —S(O)—;
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 —N(R 4 ) 2 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 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, 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 and the ring comprising Z 1 , Z 2 , and Z 3 is heteroaromatic;
with the proviso that the compound of formula IIa is not selected from the group consisting of:
and
with the proviso that when Z 2 and Z 3 are both CR 5 where each R 5 is H, X is —C(═O), Y is —N(R 4 ) 2 , and one R 4 is H, then the other R 4 is not —OH.
6. The compound of claim 5 with the proviso that 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.
7. The compound of claim 5 having the formula:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 , wherein Y is —N(R 4 ) 2 ; and —N(R 4 ) 2 is piperidinyl optionally substituted with one or more R d .
9. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable diluent or carrier.
11. A method for preparing a pharmaceutically acceptable salt of the compound of claim 1 , comprising:
a) deprotecting a corresponding compound that comprises one or more protecting groups to provide the compound; and
b) forming a pharmaceutically acceptable salt from the compound.
12. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 5 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt thereof.
26. A compound of formula IIa:
or a pharmaceutically acceptable salt 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 ;
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, A 3 is N and when A 2 is N, A 3 is O;
Z 1 is S (sulfur);
Z 2 , and Z 3 are each independently O (oxygen), N (nitrogen), S (sulfur), or CR 5 ;
each R 5 is independently H (hydrogen), (C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl;
X is —C(═O)—, —C(═S)—, —S—, or —S(O)—;
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 —N(R 4 ) 2 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 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, (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, 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 j , —NR k C(O)OR j , 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 and the ring comprising Z 1 , Z 2 , and Z 3 is heteroaromatic;
with the proviso that the compound of formula IIa is not selected from the group consisting of:
and
with the proviso that when Z 2 and Z 3 are both CR 5 where each R 5 is H, X is —C(═O), Y is —N(R 4 ) 2 , and one R 4 is H, then the other R 4 is not —OH.
27. The compound of claim 26 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.