Compounds for use as GPR120 agonists

Patent metadata

Field	Value
Publication number	US-10227360-B2
Application number	US-201515117430-A
Country	US
Kind code	B2
Filing date	Feb 18, 2015
Priority date	Feb 19, 2014
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

The present invention relates to a compound of formula (I), or a tautomer, stereoisomer, geometrical isomer, prodrug, carboxylic acid isostere, solvate, polymorph, N-oxide, S-oxide or pharmaceutically acceptable salt thereof, which are GPR120 agonists. The present invention also relates to a pharmaceutical composition of a compound of formula (I) for the treatment of metabolic disorders, particularly Type 2 diabetes and associated diseases.

First claim

We claim:

1. A compound of formula (I):

or a stereoisomer, a tautomer, a geometrical isomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, an N-oxide, a S-oxide or a carboxylic acid isostere thereof;
wherein:
Ring A is a saturated or unsaturated optionally substituted 4- to 10-membered carbocycle; an optionally substituted 5- to 10-membered heteroaryl; or a saturated or partly saturated or unsaturated optionally substituted 5- to 10-membered heterocycle; wherein said heteroaryl or heterocycle contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;
Ring B and Ring C are independently selected from the group consisting of optionally substituted (C 6 -C 10 )aryl and optionally substituted 6- to 10-membered heteroaryl which contains 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S;
X is —(CR 8 R 9 ) p —O—, (CR 8 R 9 ) p —S—, —(CR 8 R 9 ) p —N(R 10 )—, —O—(CR 8 R 9 ) p —, —S—(CR 8 R 9 ) p — or —N(R 10 )—(CR 8 R 9 ) p ;
Y is —(CR 14 R 15 ) g —;
Q is —CO 2 M, —CONH 2 , —CONH[(C 1 -C 6 )alkyl], —CON[(C 1 -C 6 )alkyl] 2 or —CONHSO 2 (C 1 -C 6 )alkyl;
M is hydrogen, deuterium or (C 1 -C 6 )alkyl;
R 1 is

wherein
is point of attachment to Ring A;
J is —CH 2 —, —CHF—, —CF 2 —, —CH[(C 1 -C 6 )alkyl]—, or —C[(C 1 -C 6 )alkyl] 2 -;
“-----” represents an optional bond;
R a is hydrogen, (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, (C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, heteroaryl, heterocyclyl, (C 6 -C 10 )aryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl-, (C 6 -C 10 )aryloxy, heterocyclyl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heterocyclyl, heteroaryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heteroaryl, cyano, —NR 10 R 11 , —C(O)NR 10 R 11 , —C(S)NR 10 R 11 , —S(O) t R 12 and —C(O)R 13 ; or
R 1 and R 2 are combined together with one or two atoms of Ring A to form:

a 3- to 8-membered partly unsaturated or saturated carbocycle
wherein the said carbocycle or heterocycle can be unsubstituted or substituted with the one or more groups independently selected from the group consisting of (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, halogen, cyano, oxo, (C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, heteroaryl and heterocyclyl and
wherein Ring A together with R 1 and R 2 does not form an unsubstituted tetrahydronaphthyl group;
R 3 at each occurrence, is independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, (C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, heteroaryl, heterocyclyl, (C 6 -C 10 )aryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, heterocyclyl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heterocyclyl-, heteroaryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heteroaryl, cyano, —NR 10 R 11 , —C(O)NR 10 R 11 , —C(S)NR 10 R 11 , —S(O) t R 12 and —C(O)R 13 ;
R 4 at each occurrence, is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, halogen, cyano, (C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, heteroaryl, heterocyclyl, (C 6 -C 10 )aryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, heterocyclyl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heterocyclyl, heteroaryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heteroaryl, —NR 10 R 11 , —S(O) t R 12 and —C(O)R 13 ;
R 5 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, hydroxy, cyano, —COR 10 , —NR 10 R 11 , —CONR 10 R 11 , (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, —S(O) t R 12 and —C(O)R 13 ;
R 6 and R 7 are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and halogen;
R 8 and R 9 are independently selected from the group consisting of hydrogen, deuterium, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and halogen; or
R 8 and R 9 together with the carbon atom they are attached to form:

i) a 3- to 5-membered saturated carbocycle selected from the group consisting of cyclopropane, cyclobutane, cyclopentane and cyclohexane; or
ii) a 4- to 6-membered saturated heterocycle selected from the group consisting of oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrolidine and piperidine;
R 10 is hydrogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, heterocyclyl, heteroaryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl, heterocyclyl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heterocyclyl, heteroaryl-(C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl-heteroaryl or —S(O) t R 12 ;
R 11 is hydrogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, heterocyclyl, heteroaryl, (C 6 -C 10 )aryloxy, (C 6 -C 10 )aryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl, heterocyclyl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heterocyclyl, heteroaryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heteroaryl or —S(O) t R 12 ; or
R 10 and R 11 are combined together to form 3- to 8-membered saturated or unsaturated ring which contains 1, 2 or 3 heteroatoms independently selected from N, O and S;

R 12 and R 13 are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, heterocyclyl, heteroaryl, (C 6 -C 10 )aryl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl, heterocyclyl-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-heterocyclyl, heteroaryl-(C 1 -C 6 )alkyl and (C 1 -C 6 )alkyl-heteroaryl;
R 14 and R 15 are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and halogen; or
R 14 and R 15 are combined together to form a 3- to 5-membered saturated carbocycle or 4- to 6-membered saturated heterocycle which optionally contains 1 or 2 heteroatoms independently selected from the group consisting of N, O and S; wherein the said carbocycle or heterocycle can be unsubstituted or substituted;

g is 2, 3, 4, 5 or 6;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 1, 2 or 3;
r is 0, 1, 2, 3 or 4;
t is 0, 1 or 2;
wherein
(C 1 -C 6 )alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, heterocyclyl, heteroaryl, amino, cyano, nitro, —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —C(O)(C 1 -C 6 )alkyl, —C(O)O(C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N[(C 1 -C 6 )alkyl] 2 and —C(O)NHSO 2 (C 1 -C 6 )alkyl;
(C 3 -C 10 )cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, amino, cyano and nitro;
carbocycle is unsubstituted or substituted with one or more groups independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, (C 3 -C 10 )cycloalkyl, heteroaryl, heterocyclyl, amino, cyano, nitro, —C(O)O(C 1 -C 6 )alkyl, —C(O)NR 10 R 11 and —S(O) t R 12 ; where

Assignees

• Piramal Entpr Ltd

Inventors

• Kumar Sanjay
• Sharma Rajiv
• Halder Somnath
• Sawargave Sangameshwar Prabhakar
• Deore Vijaykumar Bhagwan

Classifications

• C07D285/12

  1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles · CPC title

• C07D333/16

  by oxygen atoms · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D213/57

  Nitriles · CPC title

• C07D221/04

  Ortho- or peri-condensed ring systems · CPC title