Substituted piperidinyl compounds useful as GPR119 agonists
View Patent ↗Substituted piperidinyl compounds of the formula (I): are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. Pharmaceutically acceptable salts are included as well. The compounds are useful as agonists of the g-protein coupled receptor GPR-119.
1. A compound represented by the formula:
or a pharmaceutically acceptable salt thereof, wherein:
ring A is
(1) aryl,
(2) 9 or 10-membered fused aryl, wherein aryl is fused with a heteroaryl or heterocyclyl group,
(3) 6-membered heteroaryl, or
(4) 9 or 10-membered fused heteroaryl,
wherein the heteroaryl or heterocyclyl groups contain 1-2 N atoms;
i or n are independently 0 or 1;
m is 1 or 2;
k is 0, 1, 2, or 3;
each R 1 is selected from the group consisting of
(1) halo,
(2) C 1-6 alkyl,
(3) haloC 1-6 alkyl
(4) hydroxyl,
(5) C 1-6 alkoxyl, and
(6) amino,
wherein the alkyl group is unsubstituted or substituted by hydroxy, C 1-3 alkoxy, or halo;
R 2a and R 2b are independently hydrogen or halo;
each R 3 is independently hydrogen, halo, C 1-6 alkyl, or haloC 1-6 alkyl;
R 4 is hydrogen, halo, C 1-6 alkyl, or haloC 1-6 alkyl; and
R 5 is selected from the group consisting of
(1) oxo,
(2) —COOH,
(3) —NH—C(O)C 1-6 alkyl,
(4) —C(O)C 1-6 alkyl,
(5) —C(O) 2 C 1-6 alkyl,
(6) —C(O)C 1-3 alkyl-heteroaryl,
(7) —C(O)C 1-3 alkyl-heterocyclyl,
(8) —C(O)heterocyclyl,
(9) —C(O)C 3-6 cycloalkyl,
(10) —C(O)NH—C 1-6 alkyl,
(11) —C(O)NH—C 2-6 alkenyl,
(12) —C(O)NH—C 3-6 cycloalkyl,
(13) —C(O)NH-heterocyclyl,
(14) —C(O)NH—C 1-3 alkyl-C 3-6 cycloalkyl,
(15) —C(O)NHC 1-3 alkyl-heterocyclyl,
(16) —C(O)NHC 1-3 alkyl-heteroaryl,
(17) —SO 2 C 1-6 alkyl,
(18) heteroaryl, and
(19) CN;
wherein the heteroaryl group is a 5- or 6-membered ring, containing 1-4 N, O, or S atoms;
wherein the heterocyclyl group is a 3- to 6-membered ring, containing 1-2 N or O atoms; wherein the alkyl group is unsubstituted or substituted by hydroxy, C 1-3 alkoxy, or halo; and wherein the cycloalkyl, heterocyclyl, or heteroaryl groups are unsubstituted or substituted with 1-3 C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, or C 1-6 alkoxyl groups.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is aryl, 9 or 10-membered fused aryl, wherein aryl is fused with a heterocyclyl group, or 6-membered heteroaryl, wherein the heteroaryl or heterocyclyl groups contain 1-2 N atoms.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, 2,3-dihydro-indolyl, pyridinyl, or pyrimidinyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of
(1) oxo,
(2) —COOH,
(3) —C(O)C 1-6 alkyl,
(4) —C(O) 2 C 1-6 alkyl,
(5) —C(O)C 1-3 alkyl-heteroaryl,
(6) —C(O)C 1-3 alkyl-heterocyclyl,
(7) —C(O)-heterocyclyl,
(8) —C(O)C 3-6 cycloalkyl,
(9) —C(O)NHC 1-6 alkyl,
(10) —C(O)NHC 2-6 alkenyl,
(11) —C(O)NHC 3-6 cycloalkyl,
(12) —C(O)NH-heterocyclyl,
(13) —C(O)NHC 1-3 alkyl-heterocyclyl,
(14) —C(O)NHC 1-3 alkyl-heteroaryl,
(15) —C(O)NHC 1-3 alkyl-C 3-6 cyclo alkyl,
(16) —SO 2 C 1-4 alkyl,
(17) heteroaryl, and
(18) CN;
wherein the heteroaryl group is a 5- or 6-membered ring, containing 1-4 N, O, or S atoms;
wherein the heterocyclyl group is a 3- to 6-membered ring, containing 1-2 N or O atoms; wherein the alkyl group is unsubstituted or substituted by hydroxy, C 1-3 alkoxy, or halo; and wherein the cycloalkyl, heterocyclyl, or heteroaryl groups are unsubstituted or substituted with 1-3 C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, or C 1-6 alkoxyl groups.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of oxo, cyano
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently hydrogen or fluoro.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently hydrogen, fluoro or methyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoro or methyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein i is 0; and m is 1.
12. The compound of claim 1 represented by the formula:
or a pharmaceutically acceptable salt thereof, wherein:
n is 0 or 1;
k is 0, 1, 2, or 3;
R 1 is selected from the group consisting of fluoro, and methyl;
R 2a and R 2b are independently hydrogen or halo;
each R 3 is independently hydrogen, fluoro or methyl;
R 4 is fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl; and
R 5 is selected from the group consisting of
(1) oxo,
(2) —COOH,
(3) —C(O)C 1-6 alkyl,
(4) —C(O) 2 C 1-6 alkyl,
(5) —C(O)C 1-3 alkyl-heteroaryl,
(6) —C(O)C 1-3 alkyl-heterocyclyl,
(7) —C(O)-heterocyclyl,
(8) —C(O)C 3-6 cycloalkyl,
(9) —C(O)NHC 1-6 alkyl,
(10) —C(O)NHC 2-6 alkenyl,
(11) —C(O)NHC 3-6 cycloalkyl,
(12) —C(O)NH-heterocyclyl,
(13) —C(O)NHC 1-3 alkyl-heterocyclyl,
(14) —C(O)NHC 1-3 alkyl-heteroaryl,
(15) —C(O)NHC 1-3 alkyl-C 3-6 cycloalkyl,
(16) —SO 2 C 1-4 alkyl,
(17) heteroaryl, and
(18) CN;
wherein the heteroaryl group is a 5- or 6-membered ring, containing 1-4 N, O, or S atoms; wherein the heterocyclyl group is a 3- to 6-membered ring, containing 1-2 N or O atoms; wherein the alkyl group is unsubstituted or substituted by hydroxy, C 1-3 alkoxy, or halo; and wherein the cycloalkyl, heterocyclyl, or heteroaryl groups are unsubstituted or substituted with 1-3 C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, or C 1-6 alkoxyl groups.
13. The compound of claim 1 represented by the formula:
or pharmaceutically acceptably salt thereof, wherein:
ring A is selected form the group consisting of pyridinyl or pyrimidinyl;
n is 0 or 1;
k is 0, 1, 2, or 3;
R 1 is selected from the group consisting of fluoro, and methyl;
R 2a and R 2b are independently hydrogen or halo;
each R 3 is independently hydrogen, fluoro or methyl;
R 4 is fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl; and
R 5 is selected from the group consisting of
(1) oxo,
(2) —COOH,
(3) —C(O)C 1-6 alkyl,
(4) —C(O) 2 C 1-6 alkyl,
(5) —C(O)C 1-3 alkyl-heteroaryl,
(6) —C(O)C 1-3 alkyl-heterocyclyl,
(7) —C(O)heterocyclyl,
(8) —C(O)C 3-6 cycloalkyl,
(9) —C(O)NHC 1-6 alkyl,
(10) —C(O)NHC 2-6 alkenyl,
(11) —C(O)NHC 3-6 cycloalkyl,
(12) —C(O)NH-heterocyclyl,
(13) —C(O)NHC 1-3 alkyl-heterocyclyl,
(14) —C(O)NHC 1-3 alkyl-heteroaryl,
(15) —C(O)NHC 1-3 alkyl-C 3-6 cycloalkyl,
(16) —SO 2 C 1-4 alkyl,
(17) heteroaryl, and
(18) CN;
wherein the heteroaryl group is a 5- or 6-membered ring, containing 1-4 N, O, or S atoms; wherein the heterocyclyl group is a 3- to 6-membered ring, containing 1-2 N or O atoms;
wherein the alkyl group is unsubstituted or substituted by hydroxy, C 1-3 alkoxy, or halo; and wherein the cycloalkyl, heterocyclyl, or heteroaryl groups are unsubstituted or substituted with 1-3 C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, or C 1-6 alkoxyl groups.
14. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A compound which is:
or a pharmaceutically acceptable salt thereof.
17. A compound which is:
or a pharmaceutically acceptable salt thereof.
18. A method for treating a condition selected from the group consisting of diabetes and obesity comprising administering to an individual the pharmaceutical composition of claim 15 .