Dihydropyridinone mgat2 inhibitors

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 monoacylglycerol acyltransferase type 2 (MGAT2) inhibitors which may be used as medicaments.

1 - 10 . (canceled) 
     
     
         11 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of Formula 1, in combination simultaneously, separately or sequentially with one or more additional therapeutic agents, wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 ring A is independently phenyl; wherein said phenyl is substituted with 0-1 R 6  and 0-2 R 7 ; 
 R 1  is independently selected from: —(CH 2 ) m —(C 3-6  carbocycle substituted with 0-2 R b  and 0-2 R g ), wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated; 
 R 2  is independently selected from: C 1-4  alkyl, C 3-4  cycloalkyl, and C 1-4  haloalkyl; 
 R 3  is independently selected from: H, F, C 1-4  alkyl and CN; 
 R 4  is independently selected from: H, F, and C 1-4  alkyl; 
 R 3  and R 4  may be combined with the carbon atom to which they are attached to form a 3- to 6-membered carbocycle; 
 R 5  is independently selected from: C 1-4  alkyl, C 1-4  haloalkyl, N(C 1-4  alkyl) 2 , —(CH 2 ) m —C 3-6  carbocycle; 
 R 6  is, at each occurrence, independently selected from: halogen, C 1-5  alkyl substituted with 0-2 R h , C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, 
 
       —(CH 2 ) m —C 3-6  carbocycle, —(CH 2 ) m —NR f R i , CN, OR i , SR i ,
 R 7  is, at each occurrence, independently selected from: halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy; 
 alternatively, R 6  and R 7 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic ring; 
 R a  is, at each occurrence, independently selected from: halogen, OH, C 1-5  alkoxy, C 1-5  haloalkyl, C 1-6  haloalkoxy, N(C 1-4  alkyl) 2 , COOH, and —(CH 2 ) n —R c ; 
 R b  is, at each occurrence, independently selected from: halogen, OH, C 1-10  alkyl, C 1-10  alkoxy, C 1-10  haloalkyl, C 1-10  haloalkoxy, C 1-10  alkylthio, C 1-10  haloalkylthio, N(C 1-4  alkyl) 2 , —CONH(C 4-20  alkyl), —CONH(C 4-20  haloalkyl), 
 
       —O(CH 2 ) s O(C 1-6  alkyl), —O(CH 2 ) s O(C 1-6  haloalkyl), R c , and —(CH 2 ) n (O) t —(CH 2 ) m R c ;
 R c  is, at each occurrence, independently selected from: C 3-6  cycloalkyl substituted with 0-2 R d  C 3-6  cycloalkenyl substituted with 0-2 Rd, —(CH 2 ) n -(phenyl substituted with 0-3 Rd); 
 R d  is, at each occurrence, independently selected from: halogen, OH, CN, NO 2 , C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, tetrazolyl, OBn and phenyl; 
 R e  is, at each occurrence, independently selected from: H, C 1-8  haloalkyl, —(CH 2 ) n —C 3-6  carbocycle, CO(C 1-4  alkyl), COBn, and a C 1-12  hydrocarbon chain substituted with 0-1 C 1-4  haloalkyl; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated; 
 R f  is, at each occurrence, independently selected from: H and C 1-4  alkyl; 
 R g  and R h  are, at each occurrence, independently selected from: halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy; 
 R i  is, at each occurrence, independently selected from: C 1-4  alkyl, C 3-4  cycloalkyl and phenyl; 
 n, at each occurrence, is independently 0, 1 or 2; 
 m, at each occurrence, is independently 0, 1, 2, 3, or 4; 
 s, at each occurrence, is independently 1, 2, or 3; and 
 t, at each occurrence, is independently 0 or 1. 
 
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein the additional therapeutic agents are selected from: 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-restenotic agents, lipid lowering agents, anorectic agents, and appetite suppressants. 
     
     
         13 . The pharmaceutical composition according to  claim 11 , further comprising one or more additional therapeutic agents selected from: a dipeptidyl peptidase-IV inhibitor, a sodium-glucose transporter-2 inhibitor and a 11b-HSD-1 inhibitor. 
     
     
         14 . A method for the treatment of a disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula 1, where said disorder is selected from: diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH), retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), non-cardiac ischemia, lipid disorders, or glaucoma, wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 ring A is independently phenyl; wherein said phenyl is substituted with 0-1 R 6  and 0-2 R 7 ; 
 R 1  is independently selected from: —(CH 2 ) m —(C 3-6  carbocycle substituted with 0-2 R h  and 0-2 R g ), wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated; 
 R 2  is independently selected from: C 1-4  alkyl, C 3-4  cycloalkyl, and C 1-4  haloalkyl; 
 R 3  is independently selected from: H, F, C 1-4  alkyl and CN; 
 R 4  is independently selected from: H, F, and C 1-4  alkyl; 
 R 3  and R 4  may be combined with the carbon atom to which they are attached to form a 3- to 6-membered carbocycle; 
 R 5  is independently selected from: C 1-4  alkyl, C 1-4  haloalkyl, N(C 1-4  alkyl) 2 , —(CH 2 ) m —C 3-6  carbocycle; 
 R 6  is, at each occurrence, independently selected from: halogen, C 1-5  alkyl substituted with 0-2 R h  C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, 
 
       —(CH 2 ) m —C 3-6  carbocycle, —(CH 2 ) m —NR f R i , CN, OR i , SR i ,
 R 7  is, at each occurrence, independently selected from: halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy; 
 alternatively, R 6  and R 7 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic ring; 
 R a  is, at each occurrence, independently selected from: halogen, OH, C 1-5  alkoxy, C 1-5  haloalkyl, C 1-6  haloalkoxy, N(C 1-4  alkyl) 2 , COOH, and —(CH 2 ) n —R c ; 
 R b  is, at each occurrence, independently selected from: halogen, OH, C 1-10  alkyl, C 1-10  alkoxy, C 1-10  haloalkyl, C 1-10  haloalkoxy, C 1-10  alkylthio, C 1-10  haloalkylthio, N(C 1-4  alkyl) 2 , —CONH(C 4-20  alkyl), —CONH(C 4-20  haloalkyl), 
 
       —O(CH 2 ) s O(C 1-6  alkyl), —O(CH 2 ) s O(C 1-6  haloalkyl), R c , and —(CH 2 ) n (O) t —(CH 2 ) m R c ;
 R c  is, at each occurrence, independently selected from: C 3-6  cycloalkyl substituted with 0-2 R d  C 3-6  cycloalkenyl substituted with 0-2 Rd, —(CH 2 ) m -(phenyl substituted with 0-3 R d ); 
 R d  is, at each occurrence, independently selected from: halogen, OH, CN, NO 2 , C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, tetrazolyl, OBn and phenyl; 
 R e  is, at each occurrence, independently selected from: H, C 1-8  haloalkyl, —(CH 2 ) n —C 3-6  carbocycle, CO(C 1-4  alkyl), COBn, and a C 1-12  hydrocarbon chain substituted with 0-1 C 1-4  haloalkyl; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated; 
 R f  is, at each occurrence, independently selected from: H and C 1-4  alkyl; 
 R g  and R h  are, at each occurrence, independently selected from: halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4  haloalkoxy; 
 R i  is, at each occurrence, independently selected from: C 1-4  alkyl, C 3-4  cycloalkyl and phenyl; 
 n, at each occurrence, is independently 0, 1 or 2; 
 m, at each occurrence, is independently 0, 1, 2, 3, or 4; 
 s, at each occurrence, is independently 1, 2, or 3; and 
 t, at each occurrence, is independently 0 or 1. 
 
     
     
         15 . The method of  claim 14 , wherein the compound of Formula 1 is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 14 , wherein the compound of Formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 14 , wherein the compound of Formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 14 , wherein the compound of Formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 14 , wherein the compound of Formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 14 , wherein the compound of Formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 14 , wherein the compound of Formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 14 , wherein the compound of Formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The method of  claim 14 , wherein the compound of Formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of  claim 14 , wherein the compound of Formula 1 is: