Benzamide glucokinase activators
View Patent ↗The present invention relates to N-heteroaryl-benzamides, pharmaceutical compositions comprising the same, and methods of using the same. The N-heteroaryl-benzamides are useful in diseases or medical conditions mediated by glucokinase.
1. A pharmaceutical composition comprising a compound of Formula I or a salt thereof
wherein B is a direct bond or —O—;
R 1 is C 1-6 -alkyl, C 1-4 -alkoxy-C 1-4 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-4 -alkyl or C 3-7 -cycloalkyl-oxy-C 1-4 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 3 ;
R 3 is independently selected from hydroxy, —CF 3 , methyl and F;
with the proviso that Y—X— cannot be CH 3 —O—, C 2 H 5 —O—, or CH 3 C(O)—O—;
X is a linker independently selected from —O—Z— and —O—Z—O—Z—, wherein the O is attached to the phenyl ring;
each Z is independently selected from a direct bond, C 2-6 alkenylene, and —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —;
Y is selected from aryl-Z 1 —, a 5-10 membered heterocyclyl-Z 1 —, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O) t , C 3-7 cycloalkyl-Z 1 —, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) 1-4 CH 2 F, —(CH 2 ) 1-4 CHF 2 , —(CH 2 ) 1-4 CF 3 , —CH(OH)CH 2 F, —CH(OH)CHF 2 , and —CH(OH)CF 3 , wherein each Y is optionally substituted with 1-3 substituents independently selected from R 4 ;
Z 1 is independently selected from a direct bond, C 2-6 -alkenylene, and) —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —;
p is independently selected from 0, 1, 2, and 3;
q is independently selected from 0, 1, 2, and 3;
p+q is selected from 0, 1, 2, and 3;
R 4 is independently selected from R 5 —X 1 —, Cl, F, Br, I, CH 2 F, CHF 2 , CF 3 , cyano, amino, C 1-6 alkyl, —OC 1-6 -alkyl, carboxy, —C(O)OR 7 , hydroxy, and phenyl optionally substituted by C 1-6 alkyl or —C(O)OR 7 , wherein X 1 is defined as X above;
R 5 is selected from H; C 1-6 alkyl; CH 2 F; CHF 2 ; CF 3 ; phenyl; naphthyl; a 5-10 membered heterocyclyl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O) t ; and a C 3-7 cycloalkyl, and each R 5 is optionally substituted by one or more substituents independently selected from R 6 ;
R 6 is independently selected from Cl, F, Br, I, C 1-6 alkyl, —OC 1-6 alkyl, CH 2 F, CHF 2 , CF 3 , cyano, hydroxy, amino, C(O)OH, and —C(O)OC 1-6 alkyl;
R 7 is independently selected from C 1-8 -alkyl and C 3-8 -cycloalkyl;
A is a 5-10 membered heterocyclyl, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O) t , substituted with R 8 ;
R 8 is —(CH 2 ) 1-2 —COOH, optionally substituted with one or more substituents independently selected from R 9 ;
R 9 is independently selected from C 1-4 -alkyl, hydroxy and F;
R 10 is independently selected from H, Cl, F, Br, I, C 1-6 -alkyl, and —C 2-4 -alkyl-O—C 1-4 alkyl;
t is independently selected from 0, 1, and 2; and
a pharmaceutically acceptable diluent or carrier.
2. A compound according to Formula Ib or a salt thereof:
wherein B is a direct bond or —O—;
R 1 is C 1-6 -alkyl, C 1-4 -alkoxy-C 1-4 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-4 -alkyl or C 3-7 -cycloalkyl-oxy-C 1-4 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 3 ;
R 3 is independently selected from hydroxy, —CF 3 , methyl and F;
with the proviso that Y—X— cannot be CH 3 —O—, C 2 H 5 —O—, or CH 3 C(O)—O—;
X is a linker independently selected from —O—Z— and —O—Z—O—Z—, wherein the O is attached to the phenyl ring;
each Z is independently selected from a direct bond, C 2-6 alkenylene, and —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —;
Y is selected from aryl-Z 1 —, a 5-10 membered heterocyclyl-Z 1 —, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O) t , C 3-7 cycloalkyl-Z 1 —, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) 1-4 —CH 2 F, —(CH 2 ) 1-4 CHF 2 , —(CH 2 ) 14 CF 3 , —CH(OH)CH 2 F, —CH(OH)CHF 2 , and —CH(OH)CF 3 , wherein each Y is optionally substituted with 1-3 substituents independently selected from R 4 ;
Z 1 is independently selected from a direct bond, C 2-6 -alkenylene, and —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —;
p is independently selected from 0, 1, 2, and 3;
q is independently selected from 0, 1, 2, and 3;
p+q is selected from 0, 1, 2, and 3;
R 4 is independently selected from R 5 —X 1 —, Cl, F, Br, I, CH 2 F, CHF 2 , CF 3 , cyano, amino, C 1-6 -alkyl, carboxy, —C(O)OR 7 , hydroxy, and phenyl optionally substituted by C 1-6 alkyl or —C(O)OR 7 , wherein X 1 is defined as X above;
R 5 is selected from H; C 1-6 alkyl; CH 2 F; CHF 2 ; CF 3 ; phenyl; naphthyl; a 5-10 membered heterocyclyl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O) t ; and a C 3-7 cycloalkyl, and each R 5 is optionally substituted by one or more substituents independently selected from R 6 ;
R 6 is independently selected from Cl, F, Br, I, C 1-6 alkyl, —OC 1-6 alkyl, CH 2 F, CHF 2 , CF 3 , cyano, hydroxy, amino, C(O)OH, and —C(O)OC 1-6 alkyl;
R 7 is independently selected from C 1-8 -alkyl and C 3-8 -cycloalkyl;
A is a 5-10 membered heterocyclyl, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O) t , substituted with R 8 ;
R 8 is —(CH 2 ) 1-2 —COOH, optionally substituted with one or more substituents independently selected from R 9 ;
R 9 is independently selected from C 1-4 -alkyl, hydroxy and F;
R 10 is independently selected from H, Cl, F, Br, I, C 1-6 -alkyl, and —C 2-4 -alkyl-O—C 1-4 -alkyl; and
t is independently selected from 0, 1, and 2.
3. A compound according to claim 1 wherein B is a direct bond.
4. A compound according to claim 1 wherein B is —O—.
5. A compound according to claim 2 , wherein R 1 is C 1-6 -alkyl or C 1-4 -alkoxy-C 1-4 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 3 .
6. A compound according to claim 1 wherein R 1 is C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-4 -alkyl or C 3-7 -cycloalkyl-oxy-C 1-4 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 3 .
7. A compound according to claim 1 wherein R 3 is —CF 3 , methyl or F.
8. A compound according to claim 1 wherein Z is a direct bond or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —.
9. A compound according to claim 1 wherein Y is phenyl-Z 1 —, naphthyl-Z 1 —, a 5-10 membered heterocyclyl-Z 1 —, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O) t , or C 3-7 cycloalkyl-Z 1 —, wherein each Y is optionally substituted with 1-3 substituents independently selected from R 4 .
10. A compound according to claim 1 wherein Z 1 is a direct bond or —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —.
11. A compound according to claim 1 wherein p and q are both 0.
12. A compound according to claim 1 wherein R 4 is independently selected from R 5 —X 1 —, Cl, F, and —OC 1-6 -alkyl.
13. A compound according to claim 1 wherein A is thiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl substituted with R 8 .
14. A compound according to claim 13 wherein A is
15. A compound according to Formula Ic or a salt thereof:
wherein B is a direct bond or —O—;
R 1 is C 1-6 -alkyl, C 1-4 -alkoxy-C 1-4 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-4 -alkyl or C 3-7 -cycloalkyl-oxy-C 1-4 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 3 ;
R 3 is independently selected from hydroxy, —CF 3 , methyl and F;
Y is selected from —CH 3 and —C 2 H 5 ;
A is a 5-10 membered heterocyclyl, wherein the heterocyclyl consists of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O) t , substituted with R 8 ;
Z 1 is independently selected from a direct bond, C 2-6 -alkenylene, and —(CH 2 ) p —C(R 10 ) 2 —(CH 2 ) q —;
p is independently selected from 0, 1, 2, and 3;
q is independently selected from 0, 1, 2, and 3;
p+q is selected from 0, 1, 2, and 3;
R 8 is —(CH 2 ) 1-2 —COOH, optionally substituted with one or more substituents independently selected from R 9 ;
R 9 is independently selected from C 1-4 -alkyl, hydroxy and F;
R 10 is independently selected from H, Cl, F, Br, I, C 1-6 -alkyl, and —C 2-4 -alkyl-O—C 1-4 alkyl; and
t is independently selected from 0, 1, and 2.
16. A compound according to claim 15 wherein B is a direct bond.
17. A compound according to claim 15 wherein B is —O—.
18. A compound according to claim 15 wherein R 1 is C 1-6 -alkyl or C 1-4 -alkoxy-C 1-4 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 3 .
19. A compound according to claim 15 wherein R 1 is C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-4 -alkyl or C 3-7 -cycloalkyl-oxy-C 1-4 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 3 .
20. A compound according to claim 15 wherein R 3 is —CF 3 , methyl or F.
21. A compound according to claim 15 wherein Y is —CH 3 .
22. A compound according to claim 15 wherein Y is —C 2 H 5 .
23. A compound according to claim 15 wherein A is thiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl substituted with R 8 .
24. A compound according to claim 23 wherein A is