Substituted spiropiperidinyl compounds useful as GPR120 agonists
View Patent ↗The present invention relates to a compound represented by formula (I): and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing diabetes, hyperlipidemia, obesity, inflammation related disorders, and related diseases and conditions. The compounds are useful as agonists of the G-protein coupled receptor GPR120. Pharmaceutical compositions and methods of treatment are also included.
1. A compound according to the formula:
or a pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl;
ring B is a cyclohexyl ring, wherein the cyclohexyl ring forms a spiro ring system with the adjoining piperidinyl ring;
each R 1 is
(1) halo,
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) hydroxy(C 1-6 )alkyl,
(5) (C 1-6 )alkoxy,
(6) halo(C 1-6 )alkoxy,
(7) (C 1-2 )alkoxy-(C 1-6 )alkoxy,
(8) (C 1-6 )alkyl-S—,
(9) halo(C 1-6 )alkyl-S—,
(10) nitro,
(11) (C 3-7 )cycloalkyl-O—,
(12) cyano,
(13) hydroxy,
(14) (C 1-6 )alkylC(O)—,
(15) ((C 1-6 )alkyl) 2 N—,
(16) phenyl, or
(17) 5- or 6-membered heteroaryloxy ring, containing 1-3 O, N, and S ring atoms,
wherein the phenyl and heteroaryloxy, groups are optionally substituted by 1-3 (C 1-6 )alkyl, halo(C 1-6 )alkyl, or halo groups; or alternatively two R 1 groups are linked together with the carbon to which they are both attached to form
each R 2 and R 3 are independently
(1) (C 1-6 )alkyl,
(2) halo(C 1-6 )alkyl,
(3) (C 1-6 )alkoxy,
(4) halo(C 1-6 )alkoxy,
(5) hydroxyl, or
(6) halo;
R 4 and R 5 are independently
(1) hydrogen,
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl, or
(4) halo;
R 6 is
(1) COOH,
(2) tetrazolyl,
(3) —(C 1-3 )alkylCOOH,
(4) (C 1-4 alkylNH 2 , or
(5) (C 1-4 )alkylOH;
q is 0, 1, or 2;
k is 0, 1, 2, or 3;
m is 0, 1, 2, or 3; and
n is 1, 2, or 3.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is chloro, fluoro, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, cyano, methoxy, methyl-S—, difluoromethoxy, trifluoromethoxy, trifluoromethyl-S—, methyl-O-ethoxy-, hydroxymethyl, isoproproxy, cyclobutoxy, cyclopropxy, cyclopentyloxy, ethylC(O)—, dimethylamine, hydroxy, nitro, 3-methyl-pyridinyl-O—, 6-methyl-pyridinyl-O—, 5-methyl-pyridinyl-O—,or phenyl, or two R 1 groups are linked together with the carbon to which they are both attached to form
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
4. A compound according to the formula:
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is
(1) halo,
(2) (C 1-6 )alkyl,
(3) halo(C 1-6 )alkyl,
(4) hydroxy(C 1-6 )alkyl,
(5) (C 1-6 )alkoxy,
(6) halo(C 1-6 )alkoxy,
(7) (C 1-2 )alkoxy-(C 1-6 )alkoxy,
(8) (C 1-6 )alkyl-S—,
(9) halo(C 1-6 )alkyl-S—,
(10) nitro,
(11) (C 3-7 )cycloalkyl-O—,
(12) cyano,
(13) hydroxy,
(14) (C 1-6 )alkylC(O)—,
(15) ((C 1-6 )alkyl) 2 N—,
(16) phenyl, or
(17) 5- or 6-membered heteroaryloxy ring, containing 1-3 O, N, and S ring atoms, wherein the phenyl and heteroaryloxy, groups are optionally substituted by 1-3 (C 1-6 )alkyl, halo(C 1-6 )alkyl, or halo groups; or alternatively two R 1 groups are linked together with the carbon to which they are both attached to form
R 5 is hydrogen or (C 1-6 )alkyl; and
n is 1, 2, or 3.
5. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is chloro, fluoro, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, cyano, methoxy, methyl-S—, difluoromethoxy, trifluoromethoxy, trifluoromethyl-S—, methyl-O-ethoxy-, hydroxymethyl, isoproproxy, cyclobutoxy, cyclopropxy, cyclopentyloxy, ethylC(O)—, dimethylamine, hydroxy, nitro, 3-methyl-pyridinyl-O—, 6-methyl-pyridinyl-O—, 5-methyl-pyridinyl-O—,or phenyl, or two R 1 groups are linked together with the carbon to which they are both attached to form
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is chloro, fluoro, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, cyano, methoxy, methyl-S—, difluoromethoxy, trifluoromethoxy, trifluoromethyl-S—, methyl-O-ethoxy-, hydroxymethyl, isoproproxy, cyclobutoxy, cyclopropxy, cyclopentyloxy, ethylC(O)—, dimethylamine, hydroxy, nitro, 3-methyl-pyridinyl-O—, 6-methyl-pyridinyl-O—, 5-methyl-pyridinyl-O—,or phenyl, or two R 1 groups are linked together with the carbon to which they are both attached to form
10. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is chloro, fluoro, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, cyano, methoxy, methyl-S—, difluoromethoxy, trifluoromethoxy, trifluoromethyl-S—, methyl-O-ethoxy-, hydroxymethyl, isoproproxy, cyclobutoxy, cyclopropxy, cyclopentyloxy, ethylC(O)—, dimethylamine, hydroxy, nitro, 3-methyl-pyridinyl-O—, 6-methyl-pyridinyl-O—, 5-methyl-pyridinyl-O—,or phenyl, or two R 1 groups are linked together with the carbon to which they are both attached to form