Substituted cyclopropyl compounds useful as GPR119 agonists
View Patent ↗Substituted cyclopropyl compounds of the formula (I): and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. The compounds are useful as agonists of the G-protein coupled receptor GPR-119. Pharmaceutical compositions and methods of treatment are also included.
1. A compound represented by the formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 6-membered heteroaryl containing 1-3 N, or phenyl;
ring B is a 6-membered heteroaryl containing 1-3 N;
R′ is selected from the group consisting of
(1) 5- or 6-membered heteroaryl containing 1-4 O, S, or N, optionally substituted by C 1-3 alkyl,
(2) 3-8 membered heterocyclyl containing 1-3 O, S, or N,
(3) C 1-3 alkyl-OH,
(4) C(O) 2 C 1-3 alkyl, and
(5) C(O)NR 4 R 5 ;
each R 2 is selected from the group consisting of
(1) C 1-3 alkyl,
(2) C 1-3 alkoxy,
(3) haloC 1-3 alkyl,
(4) haloC 1-3 alkoxy,
(5) halo, and
(6) cyano;
R 3 is selected from the group consisting of
(1) CN,
(2) halo,
(3) —C 1-6 alkyl,
(4) -haloC 1-6 alkyl,
(5) —C 1-6 alkoxy,
(6) -haloC 1-6 alkoxy,
(7) —C 1-6 alkyl-OH,
(8) —C 1-3 alkyl-O—C 1-3 alkyl, and
(9) —C 1-3 alkyl-S—C 1-3 alkyl;
R 4 and R 5 are independently selected from the group consisting of
(1) hydrogen,
(2) hydroxy,
(3) C 1-6 alkyl,
(4) C 1-6 alkyl-OH,
(5) C 1-6 alkyl-O—C 1-3 alkyl,
(6) haloC 1-6 alkyl,
(7) C 1-6 alkoxy,
(8) C 3-6 cycloalkyl,
(9) C 1-3 alkyl-C 3-6 cycloalkyl, wherein the alkyl group is optionally substituted by hydroxy, or 1-3 fluoro,
(10) C 1-3 alkyl(C 3-6 cycloalkyl) 2 ,
(11) C 1-3 alkyl-C 3-5 heterocyclyl containing 1-3 N, O, or S, wherein the heterocyclyl is optionally substituted by 1-2 oxo,
(12) C 3-5 heterocyclyl containing 1-3 N, O or S, wherein the heterocyclyl is optionally substituted by 1-2 oxo,
(13) C 1-3 alkyl-C(O)NH 2 ,
(14) C 1-3 alkyl-S(O) 2 C 1-3 alkyl,
(15) C 1-3 alkyl-C(O) 2 C 1-3 alkyl,
(16) C(O)C 1-6 alkyl,
(17) C(O)C 3-6 cycloalkyl,
(18) S(O) 2 C 1-6 alkyl, and
(19) S(O) 2 C 3-6 cycloalkyl,
or R 4 and R 5 are linked together with the nitrogen to which they are both attached to form a 3-9 membered monocyclic or bicyclic heterocyclic ring, comprising C, O, N, or S ring atoms, wherein the heterocyclic ring is optionally substituted with 1-3 R 6 ;
each R 6 is selected from the group consisting of:
(1) C 1-3 alkyl,
(2) haloC 1-3 alkyl,
(3) C 1-3 alkoxy,
(4) C 1-3 alkyl-OH,
(5) C 1-3 alkyl-O—C 1-3 alkyl,
(6) halo,
(7) hydroxy,
(8) oxo,
(9) C(O) 2 C 1-3 alkyl,
(10) C(O)NH 2 ,
(11) C(O)N(H)C 1-6 alkyl,
(12) C(O)C 3-6 cycloalkyl,
(13) C 3-6 cycloalkyl,
(14) C 1-3 alkyl-phenyl,
(15) phenyl, and
(16) 5- or 6-membered heteroaryl, containing 1-3 N, O, or S; and
n is 0, 1, 2 or 3.
2. The compound of claim 1 , wherein ring A is pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, or phenyl, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein ring A is pyridinyl, pyrimidinyl, or phenyl, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 , wherein ring A is phenyl, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein ring B is pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , wherein ring B is pyridinyl or pyrimidinyl, or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 , wherein ring B is pyrimidinyl, or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 , wherein ring B is
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein R 3 is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 , wherein R 3 is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 , wherein R 3 is
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein the cyclopropyl ring of formula I is the cis cyclopropyl isomer, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , wherein the cyclopropyl ring of formula I has the 1S and 2R stereocenters, or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein the compound is present in at least 90% diastereomeric excess, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein ring A is phenyl; and ring B is pyrimidinyl, or a pharmaceutically acceptable salt thereof.
16. The compound of claim 15 , wherein R 3 is
or a pharmaceutically acceptable salt thereof.
17. A compound represented by the formula Ic:
or a pharmaceutically acceptable salt thereof, wherein:
each R 2 is selected from the group consisting of
(1) C 1-3 alkyl,
(2) C 1-3 alkoxy,
(3) haloC 1-3 alkyl,
(4) haloC 1-3 alkoxy,
(5) halo, and
(6) cyano;
R 3 is selected from the group consisting of
(1) CN,
(2) halo,
(3) —C 1-6 alkyl,
(4) -haloC 1-6 alkyl,
(5) —C 1-6 alkoxy,
(6) -haloC 1-6 alkoxy,
(7) —C 1-6 alkyl-OH,
(8) —C 1-3 alkyl-O—C 1-3 alkyl, and
(9) —C 1-3 alkyl-S—C 1-3 alkyl;
R 4 and R 5 are independently selected from the group consisting of
(1) hydrogen,
(2) hydroxy,
(3) C 1-6 alkyl,
(4) C 1-6 alkyl-OH,
(5) C 1-6 alkyl-O—C 1-3 alkyl,
(6) haloC 1-6 alkyl,
(7) C 1-6 alkoxy,
(8) C 3-6 cycloalkyl,
(9) C 1-3 alkyl-C 3-6 cycloalkyl, wherein the alkyl group is optionally substituted by hydroxy, or 1-3 fluoro,
(10) C 1-3 alkyl(C 3-6 cycloalkyl) 2 ,
(11) C 1-3 alkyl-C 3-5 heterocyclyl containing 1-3 N, O, or S, wherein the heterocyclyl is optionally substituted by 1-2 oxo,
(12) C 3-5 heterocyclyl containing 1-3 N, O or S, wherein the heterocyclyl is optionally substituted by 1-2 oxo,
(13) C 1-3 alkyl-C(O)NH 2 ,
(14) C 1-3 alkyl-S(O) 2 C 1-3 alkyl,
(15) C 1-3 alkyl-C(O) 2 C 1-3 alkyl,
(16) C(O)C 1-6 alkyl,
(17) C(O)C 3-6 cycloalkyl,
(18) S(O) 2 C 1-6 alkyl, and
(19) S(O) 2 C 3-6 cycloalkyl,
or R 4 and R 5 are linked together with the nitrogen to which they are both attached to form a 3-9 membered monocyclic or bicyclic heterocyclic ring, comprising C, O, N, or S ring atoms, wherein the heterocyclic ring is optionally substituted with 1-3 R 6 ;
each R 6 is selected from the group consisting of:
(1) C 1-3 alkyl,
(2) haloC 1-3 alkyl,
(3) C 1-3 alkoxy,
(4) C 1-3 alkyl-OH,
(5) C 1-3 alkyl-O—C 1-3 alkyl,
(6) halo,
(7) hydroxy,
(8) oxo,
(9) C(O) 2 C 1-3 alkyl,
(10) C(O)NH 2 ,
(11) C(O)N(H)C 1-6 alkyl,
(12) C(O)C 3-6 cycloalkyl,
(13) C 3-6 cycloalkyl,
(14) C 1-3 alkyl-phenyl,
(15) phenyl,
(16) 5- or 6-membered heteroaryl, containing 1-3 N, O, or S; and
n is 0, 1, 2, or 3.
18. A compound represented by the formula Id:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of
(1) 5-membered heteroaryl containing 1-4 O, S, or N, optionally substituted by C 1-3 alkyl,
(2) 3-8 membered heterocyclyl containing 1-3 O, S, or N,
(3) C 1-3 alkyl-OH,
(4) C(O) 2 C 1-3 alkyl, and
(5) C(O)NR 4 R 5 ;
each R 2 is selected from the group consisting of
(1) C 1-3 alkyl,
(2) C 1-3 alkoxy,
(3) haloC 1-3 alkyl,
(4) haloC 1-3 alkoxy,
(5) halo, and
(6) cyano;
R 4 and R 5 are independently selected from the group consisting of
(1) hydrogen,
(2) hydroxy,
(3) C 1-6 alkyl,
(4) C 1-6 alkyl-OH,
(5) C 1-6 alkyl-O—C 1-3 alkyl,
(6) haloC 1-6 alkyl,
(7) C 1-6 alkoxy,
(8) C 3-6 cycloalkyl,
(9) C 1-3 alkyl-C 3-6 cycloalkyl, wherein the alkyl group is optionally substituted by hydroxy, or 1-3 fluoro,
(10) C 1-3 alkyl(C 3-6 cycloalkyl) 2 ,
(11) C 1-3 alkyl-C 3-5 heterocyclyl containing 1-3 N, O, or S, wherein the heterocyclyl is optionally substituted by 1-2 oxo,
(12) C 3-5 heterocyclyl containing 1-3 N, O or S, wherein the heterocyclyl is optionally substituted by 1-2 oxo,
(13) C 1-3 alkyl-C(O)NH 2 ,
(14) C 1-3 alkyl-S(O) 2 C 1-3 alkyl,
(15) C 1-3 alkyl-C(O) 2 C 1-3 alkyl,
(16) C(O)C 1-6 alkyl,
(17) C(O)C 3-6 cycloalkyl,
(18) S(O) 2 C 1-6 alkyl, and
(19) S(O) 2 C 3-6 cycloalkyl,
or R 4 and R 5 are linked together with the nitrogen to which they are both attached to form a 3-9 membered monocyclic or bicyclic heterocyclic ring, comprising C, O, N, or S ring atoms, wherein the heterocyclic ring is optionally substituted with 1-3 R 6 ;
each R 6 is selected from the group consisting of:
(1) C 1-3 alkyl,
(2) haloC 1-3 alkyl,
(3) C 1-3 alkoxy,
(4) C 1-3 alkyl-OH,
(5) C 1-3 alkyl-O—C 1-3 alkyl,
(6) halo,
(7) hydroxy,
(8) oxo,
(9) C(O) 2 C 1-3 alkyl,
(10) C(O)NH 2 ,
(11) C(O)N(H)C 1-6 alkyl,
(12) C(O)C 3-6 cycloalkyl,
(13) C 3-6 cycloalkyl,
(14) C 1-3 alkyl-phenyl,
(15) phenyl,
(16) 5- or 6-membered heteroaryl, containing 1-3 N, O, or S; and
n is 0, 1, 2, or 3.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
24. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
25. A method for the treatment of a condition selected from the group consisting of obesity and diabetes comprising administering to an individual a pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.