Substituted spiropiperidinyl compounds useful as GPR120 agonists

Patent metadata

Field	Value
Publication number	US-9708270-B2
Application number	US-201314434524-A
Country	US
Kind code	B2
Filing date	Oct 11, 2013
Priority date	Oct 11, 2012
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

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.

First claim

What is claimed is:

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

Assignees

• Merck Sharp & Dohme

Inventors

• Chelliah Mariappan
• Chu Hong Dong
• Cox Jason M
• Debenham John S
• Eagen Keith
• Lan Ping
• London Clare
• Plotkin Michael A
• Shah Unmesh
• Sinz Christopher Joseph
• Sun Zhongxiang
• Vaccaro Henry M
• Venkatraman Srikanth

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title