Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
View Patent ↗Substituted cyclopropyl compounds of formula (I) are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. Pharmaceutically acceptable salts and solvates 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 represents a 6-membered aryl or heteroaryl group containing 1 nitrogen atom, and optionally 1-2 additional nitrogen atoms;
Ring B represents a 6 membered heteroaryl ring containing 1-2 nitrogen atoms;
i and j independently represent integers selected from 0, 1 and 2, such that i plus j is 1 or 2;
R 1 represents a member selected from the group consisting of H, halo, C 1-6 alkyl, haloC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)haloC 1-6 alkyl, C(O)NH—C 1-6 alkyl, S(O)C 1-6 alkyl, SO 2 C 1-6 alkyl, SO 2 NH 2 , SO 2 NHC 1-6 alkyl, SO 2 N(C 1-6 alkyl) 2 , CN, and HAR optionally substituted with 1-3 C 1-6 alkyl, halo or halo C 1-6 alkyl groups;
and each R 2 , R 3 and R 4 is independently selected from H, halo, C 1-6 alkyl and haloC 1-6 alkyl.
2. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of Aryl which is phenyl, and Heteroaryl selected from the group consisting of pyridine, pyrimidine and pyrazine.
3. A compound in accordance with claim 2 , or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of phenyl and pyrimidine.
4. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein ring A is a pyrimidine ring.
5. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of pyridine, pyrimidine and pyrazine.
6. A compound in accordance with claim 5 , or a pharmaceutically acceptable salt thereof, wherein ring B is pyrimidine.
7. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein i and j represent 0, 1 or 2, such that the sum of i and j is 2.
8. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: H, halo which is F or Br, C 1-3 alkyl, haloC 1-3 alkyl, C(O)NHC 2-4 alkyl, S(O)C 1-3 alkyl, SO 2 C 1-3 alkyl, SO 2 NHC 1-3 alkyl, CN and HAR which is a 5 membered heteroaromatic ring containing one nitrogen atom, optionally 1-3 additional nitrogen atoms, and optionally one oxygen atom, said heteroaryl being optionally substituted with one C 1-3 alkyl group.
9. A compound in accordance with claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: H, halo which is F or Br, C 1-3 alkyl, CF 3 , C(O)NH-cyclopropyl, S(O)CH 3 , SO 2 CH 3 , SO 2 NHcyclopropyl, CN and HAR which is selected from the group consisting of: oxadiazole, triazole and tetrazole, said group being optionally substituted with methyl or cyclopropyl.
10. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A represents a phenyl ring and R 1 represents a five membered heteroaryl ring selected from the group consisting of oxadiazole, triazole and tetrazole, said ring being optionally substituted with methyl or cyclopropyl.
11. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A represents a pyridine or pyrimidine ring and R 1 represents CN, CF 3 , or a five membered heteroaryl ring selected from the group consisting of oxadiazole, triazole and tetrazole, said ring being optionally substituted with methyl or cyclopropyl.
12. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 represents H, halo selected from F and Cl, CH 3 or CF 3 .
13. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are selected from the group consisting of: H, halo selected from F and Cl, CH 3 and CF 3 .
14. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cyclopropyl ring is the cis cyclopropyl isomer.
15. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof wherein:
ring A is selected from the group consisting of Aryl which is phenyl, and Heteroaryl selected from the group consisting of pyridine, pyrimidine and pyrazine;
ring B is selected from the group consisting of pyridine, pyrimidine and pyrazine;
i and j represent 0, 1 or 2, such that the sum of i and j is 2;
R 1 is selected from the group consisting of: H, halo which is F or Br, C 1-3 alkyl, haloC 1-3 alkyl, C(O)NHC 2-4 alkyl, S(O)C 1-3 alkyl, SO 2 C 1-3 alkyl, SO 2 NHC 1-3 alkyl, CN and HAR which is a 5 membered heteroaromatic ring containing one nitrogen atom, optionally 1-3 additional nitrogen atoms, and optionally one oxygen atom, said heteroaryl being optionally substituted with one C 1-3 alkyl group;
R 2 represents H, halo selected from F and Cl, CH 3 and CF 3 ;
and R 3 and R 4 represent H, halo selected from F and Cl, CH 3 and CF 3 .
16. A compound in accordance with claim 1 selected from the group consisting of:
Compound Name
rac cis-5-chloro-2-[4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl} cyclopropyl)piperidin-1-
yl]pyrimidine, 5-chloro-2-[4-((1S,2R)-2-{2-[4-
(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-chloro-2-[4-
((1R,2S)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl) piperidin-1-yl]pyrimidine
rac-cis 5-chloro-2-{4-[2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-
1-yl}pyrimidine, cis 5-chloro-2-{4-[(1S,2R)-2-(2-{[5-(methylsulfonyl)pyridin-2-
yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine, cis 5-chloro-2-{4-[(1R,2S)-2-(2-{[5-
(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-(1H-1,2,4-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-(1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-N-
cyclopropyl-2-fluorobenzamide
rac cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
fluorobenzonitrile
rac cis-5-chloro-2-[4-(2-{2-[4-(cyclopropylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-
1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1,2,4-oxadiazol-3-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1,2,4-oxadiazol-5-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1,3-oxazol-4-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-(4-{2-[2-(4-isoxazol-4-ylphenoxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
rac cis-5-chloro-2-(4-{2-[2-(4-isoxazol-5-ylphenoxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-pyrazol-3-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-pyrazol-4-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-pyrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-1,2,4-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(4H-1,2,4-triazol-4-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac-cis-5-fluoro-2-[4-(2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-methyl-2-[4-(2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(2H-1,2,3-triazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-1,2,3-triazol-5-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-fluoro-4-(1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-fluoro-2-[4-(2-{2-[3-fluoro-4-(1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-2-[4-(2-{2-[3-fluoro-4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]-5-methylpyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(2H-tetrazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(5-methyl-2H-tetrazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidine-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(5-methyl-1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac-cis-5-chloro-2-[4-(2-{2-[4-(methylsulfinyl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
Chiral-cis-6-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile, cis 6-(2-{(1S,2R)-2-{1-(5-chloropyrimidin-2-
yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-methylpyrimidine-4-carbonitrile, cis 6-(2-{(1R,
2S)-2-{1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-methylpyrimidine-
4-carbonitrile
Rac-cis-1-[4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)phenyl]ethanone
Rac-cis-2-methyl-6-(2-{2-[1-(5-methylpyrazin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)pyrimidine-
4-carbonitrile
Rac-cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)pyrimidine-
2-carbonitrile
Chiral-cis-2-methyl-6-(2-{2-[1-(5-methylpyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile, cis-2-methyl-6-(2-{(1S,2R)-2-[1-(5-
methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile, cis-2-
methyl-6-(2-{(1R,2S)-2-[1-(5-methylpyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile
Rac-cis-2-methyl-6-(2-{2-[1-(5-methylpyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile
Rac-cis-2,4-dimethyl-6-(2-{2-[1-(5-methylpyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine
Rac-cis-6-(2-{2-[1-(5-chloro-4-methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-
2-methylpyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(5-chloropyridin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(4,5-dimethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(5-chloro-4-methylpyridin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(5-fluoro-4-methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-
2-methylpyrimidine-4-carbonitrile
Rac-cis-2-methyl-6-[2-(2-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-
yl}cyclopropyl)ethoxy]pyrimidine-4-carbonitrile
Rac-cis-5-chloro-2-(4-{2-[2-(pyridin-3-yloxy)ethyl]cyclopropyl}piperidin-1-yl)pyrimidine
Rac-cis-5-chloro-2-(4-{2-[2-(pyrimidin-4-yloxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
Rac-cis-5-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)nicotinonitrile
Rac-cis-6-(2-{2-[1-(5-chloropyrimidin-2-yl) piperidin-4-yl] cyclopropyl} ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl} ethoxy)-6-
methylpyrimidine-2-carbonitrile
Rac-cis-6-(2-{2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-5-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)pyridine-2-
carbonitrile
Rac-cis-5-chloro-2-(4-{2-[2-(pyridin-4-yloxy)ethyl]cyclopropyl}piperidin-1-yl)pyrimidine
Chiral cis-5-chloro-2-{4-[2-(2-{[5-(1H-1,2,3-triazol-1-yl)pyridin-2-
yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine, cis-5-chloro-2-{4-(1S,2R)-[2-(2-{[5-
(1H-1,2,3-triazol-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine, cis-
5-chloro-2-{4-(1R,2S)-[2-(2-{[5-(1H-1,2,3-triazol-1-yl)pyridin-2-
yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine
5-chloro-2-[4-((1R,2S)-2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-
1-yl]pyrimidine and 5-chloro-2-[4-((1S,2R)-2-{2-[3-fluoro-4-(5-
methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-chloro-2-[4-((1S,2R)-2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-chloro-2-[4-((1R,2S)-2-{2-
[4-(1H-1,2,3-triazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-fluoro-2-[4-((1R,2S)-2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-fluoro-2-[4-((1S,2R)-2-{2-
[4-(1H-1,2,3-triazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-chloro-2-[4-((1R,2S)-2-{2-[4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine and 5-chloro-2-[4-((1S,2R)-2-{2-[4-(1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-chloro-2-[4-((1R,2S)-2-{2-[3-fluoro-4-(1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-chloro-2-[4-((1S,2R)-2-{2-
[3-fluoro-4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-fluoro-2-[4-((1R,2S)-2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-fluoro-2-[4-((1S,2R)-2-{2-
[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac-cis-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-
1-yl]-5-methylpyrimidine
Rac-cis-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
Rac-cis-5-fluoro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
Rac-cis-5-chloro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]-4-methylpyrimidine
Rac-cis-3,5-dichloro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyridine
Rac-cis-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]-5-(trifluoromethyl)pyridinium
trifluoroacetate
rac-trans-5-chloro-2-[4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac-trans-5-chloro-2-(4-{2-[2-(pyridin-4-yloxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
4-(2-{(1R,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-N-
cyclopropyl-2-fluorobenzamide
4-(2-{(1R,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
fluorobenzonitrile
5-chloro-2-[4-((1R,2R)-2-{2-[4-(1H-1,2,4-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-chloro-2-[4-((1R,2R)-2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-chloro-2-[4-((1R,2R)-2-{2-[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3-
fluorophenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac-trans-5-chloro-2-(4-{2-[2-(pyridin-4-yloxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
rac-trans-4-(2-{2-[1-(5-chloropyrimidin-2-yl) piperidin-4-yl]cyclopropyl} ethoxy)-6-
methylpyrimidine-2-carbonitrile
rac trans 6-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl] cyclopropyl} ethoxy)-2-
methylpyrimidine-4-carbonitrile
rac-trans-5-chloro-2-{4-[(2-{[4-(methylsulfonyl)phenoxy]methyl}cyclopropyl)methyl]piperidin-
1-yl}pyrimidine
5-chloro-2-[4-((1R,2R)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl} cyclopropyl)piperidin-1-
yl]pyrimidine
5-chloro-2-{4-[((1S,2S)-2-{[4-
(methylsulfonyl)phenoxy]methyl}cyclopropyl)methyl]piperidin-1-yl}pyrimidine
Rac-trans-4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-
yl]methyl}cyclopropyl)methoxy]-2-fluorobenzonitrile
4-[((1R,2R)-2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-
2-fluorobenzonitrile
Rac-trans 4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-
N-cyclopropyl-2-fluorobenzamide
4-[((1R,2R)-2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-
N-cyclopropyl-2-fluorobenzamide
4-[((1S,2S)-2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-
N-cyclopropyl-2-fluorobenzamide
5-chloro-2-{4-[((1R,2R)-2-{[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]methyl}cyclopropyl)methyl]piperidin-1-yl}pyrimidine
5-chloro-2-{4-[((1S,2S)-2-{[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]methyl}cyclopropyl)methyl]piperidin-1-yl}pyrimidine
rac-trans 5-chloro-2-{4-[(2-{[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3-
fluorophenoxy]methyl}cyclopropyl)methyl]piperidin-1-yl}pyrimidine
4-[((1S,2S)-2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-
yl]methyl}cyclopropyl)methoxy]benzenesulfonamide
rac-trans-6-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl] methyl} cyclopropyl)methoxy]-
2-methylpyrimidine-4-carbonitrile
rac-trans-4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-
6-methylpyrimidine-2-carbonitrile
rac-trans-4-[((1S,2S)-2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-
yl]methyl}cyclopropyl)methoxy]-3-fluorobenzonitrile
rac-cis-5-chloro-2-{4-[(2-{[4-(methylsulfonyl)phenoxy]methyl}cyclopropyl)methyl]piperidin-
1-yl}pyrimidine
rac-cis 4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-N-
cyclopropyl-2-fluorobenzamide
rac-cis-4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-6-
methylpyrimidine-2-carbonitrile
rac-cis 4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-2-
fluorobenzonitrile
or a pharmaceutically acceptable salt thereof.
17. A compound in accordance with claim 14 , selected from the group consisting of:
TABLE 1-a
rac cis-5-chloro-2-[4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl} cyclopropyl)piperidin-1-
yl]pyrimidine, 5-chloro-2-[4-((1S,2R)-2-{2-[4-
(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-chloro-2-
[4-((1R,2S)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl) piperidin-1-
yl]pyrimidine
rac-cis 5-chloro-2-{4-[2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-
1-yl}pyrimidine, 5-chloro-2-{4-[(1R,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-
yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine, 5-chloro-2-{4-[(1S,2R)-2-(2-{[5-
(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-(1H-1,2,4-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-(1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-N-
cyclopropyl-2-fluorobenzamide
rac cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
fluorobenzonitrile
rac cis-5-chloro-2-[4-(2-{2-[4-
(cyclopropylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1,2,4-oxadiazol-3-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1,2,4-oxadiazol-5-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1,3-oxazol-4-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-(4-{2-[2-(4-isoxazol-4-ylphenoxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
rac cis-5-chloro-2-(4-{2-[2-(4-isoxazol-5-ylphenoxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-pyrazol-3-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-pyrazol-4-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-pyrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-1,2,4-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(4H-1,2,4-triazol-4-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac-cis-5-fluoro-2-[4-(2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-methyl-2-[4-(2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(2H-1,2,3-triazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-1,2,3-triazol-5-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-fluoro-4-(1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-fluoro-2-[4-(2-{2-[3-fluoro-4-(1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-2-[4-(2-{2-[3-fluoro-4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]-5-methylpyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(2H-tetrazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(5-methyl-2H-tetrazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidine-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(5-methyl-1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-chloro-2-[4-(1S,2R)-(2-{2-[4-(methylsulfinyl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine, 5-chloro-2-[4-(1R,2S)-(2-{2-[4-
(methylsulfinyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
6-(1S,2R)-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile, 6-(1R,2S)-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-
4-yl]cyclopropyl}ethoxy)-2-methylpyrimidine-4-carbonitrile
Rac-cis-1-[4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)phenyl]ethanone
Rac-cis-2-methyl-6-(2-{2-[1-(5-methylpyrazin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile
Rac-cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine-2-carbonitrile
2-methyl-6-(1S,2R)-(2-{2-[1-(5-methylpyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile, 2-methyl-6-(1R,2S)-(2-{2-[1-(5-
methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile
Rac-cis-2-methyl-6-(2-{2-[1-(5-methylpyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine-4-carbonitrile
Rac-cis-2,4-dimethyl-6-(2-{2-[1-(5-methylpyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)pyrimidine
Rac-cis-6-(2-{2-[1-(5-chloro-4-methylpyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)-2-methylpyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(5-chloropyridin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(4,5-dimethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(5-chloro-4-methylpyridin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-6-(2-{2-[1-(5-fluoro-4-methylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-
2-methylpyrimidine-4-carbonitrile
Rac-cis-2-methyl-6-[2-(2-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-
yl}cyclopropyl)ethoxy]pyrimidine-4-carbonitrile
Rac-cis-5-chloro-2-(4-{2-[2-(pyridine-3-yloxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
Rac-cis-5-chloro-2-(4-{2-[2-(pyrimidin-4-yloxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
Rac-cis-5-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-
yl]cyclopropyl}ethoxy)nicotinonitrile
Rac-cis-6-(2-{2-[1-(5-chloropyrimidin-2-yl) piperidin-4-yl] cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-4-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl} ethoxy)-6-
methylpyrimidine-2-carbonitrile
Rac-cis-6-(2-{2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-
methylpyrimidine-4-carbonitrile
Rac-cis-5-(2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)pyridine-
2-carbonitrile
Rac-cis-5-chloro-2-(4-{2-[2-(pyridine-4-yloxy)ethyl]cyclopropyl}piperidin-1-
yl)pyrimidine
5-chloro-2-(1S,2R)-{4-[2-(2-{[5-(1H-1,2,3-triazol-1-yl)pyridin-2-
yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine, 5-chloro-2-(1R,2S)-{4-[2-(2-{[5-
(1H-1,2,3-triazol-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine
5-chloro-2-[4-((1R,2S)-2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-
1-yl]pyrimidine and 5-chloro-2-[4-((1S,2R)-2-{2-[3-fluoro-4-(5-
methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
rac cis-5-chloro-2-[4-(2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine, 5-chloro-2-[4-((1S,2R)-2-{2-
[4-(1H-1,2,3-triazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-
chloro-2-[4-((1R,2S)-2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-fluoro-2-[4-((1R,2S)-2-{2-[4-(1H-1,2,3-triazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-fluoro-2-[4-((1S,2R)-2-
{2-[4-(1H-1,2,3-triazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-chloro-2-[4-((1R,2S)-2-{2-[4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-
1-yl]pyrimidine and 5-chloro-2-[4-((1S,2R)-2-{2-[4-(1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-chloro-2-[4-((1R,2S)-2-{2-[3-fluoro-4-(1H-tetrazol-1-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-chloro-2-[4-((1S,2R)-2-
{2-[3-fluoro-4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
5-fluoro-2-[4-((1R,2S)-2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine and 5-fluoro-2-[4-((1S,2R)-2-
{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-
yl]pyrimidine
rac-cis-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-
1-yl]-5-methylpyrimidine
Rac-cis-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
Rac-cis-5-fluoro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine
Rac-cis-5-chloro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]-4-methylpyrimidine
Rac-cis-3,5-dichloro-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyridine
Rac-cis-2-[4-(2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-
yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]-5-(trifluoromethyl)pyridinium
trifluoroacetate
rac-cis-5-chloro-2-{4-[(2-{[4-(methylsulfonyl)phenoxy]methyl}cyclopropyl)methyl]piperidin-
1-yl}pyrimidine
rac-cis 4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-
N-cyclopropyl-2-fluorobenzamide
rac-cis-4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-
6-methylpyrimidine-2-carbonitrile
rac-cis 4-[(2-{[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl}cyclopropyl)methoxy]-
2-fluorobenzonitrile.
or a pharmaceutically acceptable salt thereof.
18. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprised of a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
20. A method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, in an amount that is effective to treat type 2 diabetes.