Cyclobutane containing carboxylic acid GPR120 modulators

Patent metadata

Field	Value
Publication number	US-10023519-B2
Application number	US-201515509225-A
Country	US
Kind code	B2
Filing date	Sep 8, 2015
Priority date	Sep 9, 2014
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

Abstract

The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR120 G protein-coupled receptor modulators which may be used as medicaments.

First claim

What is claimed is:

1. A compound of formula (I)

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof, wherein:
designates a single or double bond;
x and y can be both a single bond; when x is a double bond, then y is a single bond and R 3 is absent; when y is a double bond, then x is a single bond and R 4 is absent;
X is independently selected from: a bond, O, CH 2 , —CH 2 CH 2 —, —OCH 2 —, and —CH 2 O—;
Y is independently a hydrocarbon linker substituted with 0-2 R a , a hydrocarbon-heteroatom linker substituted with 0-2 R a , or —(CH 2 ) 1-3 -(O) 0-1 -(CH 2 ) 1-3 —(C 3-4 cycloalkyl substituted with 0-2 R a )—(CH 2 ) 0-2 —; wherein said hydrocarbon linker has one to six carbon atoms and may be straight or branched, saturated or unsaturated; and said hydrocarbon-heteroatom linker has one to four carbon atoms and one group selected from O, CO, S, NH, CONH, and NHCO;
W is independently selected from: a bond and 0;
R 1 is —W—R 5 ;
R 2 , at each occurrence, is independently selected from: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-6 haloalkoxy, and C 1-4 haloalkylthio;
R 3 and R 4 , at each occurrence, are independently selected from: H, C 1-4 alkyl, and C 1-4 alkoxy;
R 3 may combine with X to form a 3- to 4 carbocycle;
R 4 may combine with Y to form a 3- to 4 carbocycle;
R 5 is independently selected from: C 3-10 carbocycle, pyridyl, thiazolyl and dihydrobenzofuranyl; wherein each moiety is substituted with 0-1 R 6 and 0-3 R 7 ;
R 6 is independently selected from: unsubstituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 haloalkylthio and —(X 1 ) 0-1 -(CH 2 ) 0-2 —R 8 ;
X 1 is independently selected from: O, S, NH and CO;
R 7 , at each occurrence, is independently selected from: halogen, unsubstituted C 1-4 alkyl and C 1-4 alkoxy;
R 8 is independently selected from: C 3-6 carbocycle and a 5- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR b , O, and S; wherein said carbocycle and heterocycle are substituted with 0-3 R c ;
R a , at each occurrence, is independently selected from: halogen, OH, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R b , at each occurrence, is independently selected from: H, C 1-4 alkyl, and —(CH 2 ) 0-2 -phenyl;
R c , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, and COPh; and
n is independently 0, 1, or 2.

2. A compound of Formula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof,
wherein:
X is independently selected from: a bond, O, CH 2 , —OCH 2 —, and —CH 2 O—;
Y is independently selected from: —(CH 2 ) 0-3 O(CH 2 ) 1-2 —, —(CH 2 ) 1-3 —,

W is independently selected from: a bond and O;
R 2 , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, and C 1-4 alkoxy;
R 3 and R 4 , at each occurrence, are independently selected from: H, C 1-4 alkyl, and C 1-4 alkoxy;
R 6 is independently selected from: C 1-4 alkoxy, C 1-4 haloalkoxy, Bn, and —(O) 0-1 —R 8 ;
R 7 , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, and C 1-4 alkoxy;
R 8 is independently selected from: C 3-6 cycloalkyl, phenyl, tetrahydropyranyl, oxadiazolyl, thiazolyl, pyridyl, and pyridazinyl; wherein each moiety is substituted with 0-2 R c ;
R c , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, and COPh; and
m and n, at each occurrence, are independently 0, 1, or 2.

3. A compound according to claim 2
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof,
wherein:
Y is independently selected from: —(CH 2 ) 0-3 O(CH 2 ) 1-2 —, and —(CH 2 ) 1-3 —;
W is O;
R 3 and R 4 are H; and
m and n, at each occurrence, are independently 0 or 1.

4. A compound according to claim 3
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof,
wherein:
R 6 is independently selected from: Bn and —(O) 0-1 —R 8 ;
R 8 is independently selected from: phenyl and pyridyl; wherein each moiety is substituted with 0-2 R c ; and
R c , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy.

5. A compound selected from the exemplified Examples 1 to 68, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6 , further comprising one or more other suitable therapeutic agents selected from: a dipeptidyl peptidase-IV inhibitor, a sodium-glucose transporter-2 inhibitor and a 11b-HSD-1 inhibitor.

8. A method for the treatment of diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetic kidney disease, acute kidney injury, cardiorenal syndrome, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, congestive heart failure, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, fatty liver disease, dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), lipid disorders and liver diseases, NASH (Non-Alcoholic SteatoHepatitis), NAFLD (Non-Alcoholic Fatty Liver Disease) or liver cirrhosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound according to claim 1 .

9. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 2 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9 , further comprising one or more other suitable therapeutic agents selected from: a dipeptidyl peptidase-IV inhibitor, a sodium-glucose transporter-2 inhibitor and a 11b-HSD-1 inhibitor.

11. A method for the treatment of diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetic kidney disease, acute kidney injury, cardiorenal syndrome, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, congestive heart failure, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, fatty liver disease, dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), lipid disorders and liver diseases, NASH (Non-Alcoholic SteatoHepatitis), NAFLD

Assignees

• Bristol Myers Squibb Co

Inventors

• Shi Yan
• Wang Ying
• Cheng Peter T W
• Wu Shung C

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61K31/50

  Pyridazines; Hydrogenated pyridazines · CPC title

• A61K31/351

  not condensed with another ring · CPC title