Phenyl-(aza)cycloalkyl carboxylic acid gpr120 modulators

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.

1 . The compound according to formula (I) 
       
         
           
           
               
               
           
         
         or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein: 
         L 1  is independently a hydrocarbon linker substituted with 0-2 R a , a hydrocarbon-heteroatom linker substituted with 0-2 R a , or 
       
       —(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;
 L 2  is independently selected from: a bond, O, S, CH 2 , and C(═O); 
 R 1  is independently selected from: C 3-8  cycloalkyl, C 5-8  cycloalkenyl, and 4- to 8-membered azacycloalkyl; wherein each moiety is substituted with 0-1 R 3  and 0-3 R 4 ; 
 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  is independently selected from: 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 5 ; 
 X is independently selected from: O, S and NH; 
 R 4 , at each occurrence, is independently selected from: halogen, and C 1-4  alkyl; 
 R 5  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, CO 2 (C 1-4  alkyl), and COPh; and 
 m is independently 0, 1, or 2. 
 
     
     
         2 . A compound according to  claim 1  of Formula (II): 
       
         
           
           
               
               
           
         
         or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof. 
       
     
     
         3 . A compound according to  claim 2   or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof,   wherein:   L 1  is independently a hydrocarbon linker substituted with 0-1 R a ,   
       a hydrocarbon-heteroatom linker substituted with 0-1 R a , or 
       —(O) 0-1 —(CH 2 ) 1-3 —(C 3-4  cycloalkyl substituted with 0-1 R a )—(CH 2 ) 0-1 —; 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 O;
 W is independently selected from: CH and N; 
 R 2 , at each occurrence, is independently selected from: halogen, C 1-4  alkyl, and C 1-4  alkoxy; 
 R 3  is independently selected from: C 1-4  alkoxy, C 1-4  haloalkoxy, Bn, and —(O) 0-1 —R 5 ; 
 R 4 , at each occurrence, is independently selected from: halogen, and C 1-4  alkyl; 
 R 5  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 a , at each occurrence, is independently selected from: halogen, OH, C 1-4  alkyl, and C 1-4  alkoxy; 
 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, CO 2 (C 1-4  alkyl), and COPh; and 
 m is independently 0, 1, or 2. 
 
     
     
         4 . A compound according to  claim 3  of Formula (III) 
       
         
           
           
               
               
           
         
         or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof. 
       
     
     
         5 . A compound according to  claim 4   or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof,   wherein:   L 1  is independently a hydrocarbon linker substituted with 0-1 OH,   
       a hydrocarbon-heteroatom linker or —(O) 0-1 —(CH 2 ) 1-3 -(cyclopropyl)-(CH 2 ) 0-1 —; wherein said hydrocarbon linker has one to five carbon atoms and may be straight or branched, saturated or unsaturated; and said hydrocarbon-heteroatom linker has one to five carbon atoms and may be straight or branched, and has one to three carbon atoms and O. 
     
     
         6 . A compound according to  claim 5   or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof,   wherein:   L 1  is independently selected from: (CH 2 ) 3-4 , (CH 2 ) 2-3 OCH 2 ,   
       
         
           
           
               
               
           
         
         R 3  is independently selected from: Bn, and —(O) 0-1 —R 5 ; 
         R 5  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, CN, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, and CO 2 (C 1-4  alkyl). 
       
     
     
         7 . A compound according to  claim 1  selected from the exemplified Examples 1 to 28 and 31 to 63,
 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof. 
 
     
     
         8 . 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. 
     
     
         9 . The pharmaceutical composition according to  claim 8 , further comprising one or more other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-pancreatitis agents, lipid lowering agents, anorectic agents and appetite suppressants. 
     
     
         10 . The pharmaceutical composition according to  claim 8 , 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 . The compound of  claim 1  for use in treating 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 such as NASH (Non-Alcoholic SteatoHepatitis), NAFLD (Non-Alcoholic Fatty Liver Disease) and liver cirrhosis. 
     
     
         12 . A compound for use according to  claim 11 , wherein the compound of  claim 1  is used simultaneously, separately or sequentially with one or more additional therapeutic agents.