Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonists

Abstract

The present invention provides compounds of Formula (I):or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.

What is claimed is: 
     
         1 . A compound according to Formula (I): 
       
         
           
           
               
               
           
         
         or stereoisomers, tautomers, a pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein 
         R 2  is independently selected from H and C 1-4  alkyl substituted with 1-5 R 9 ; 
         R 13  is independently selected from H, D, and C 1-4  alkyl substituted with 1-3 R 9 ; 
         R 3  and R 4  are independently selected from H, C 1-7  alkyl substituted with 1-3 R 9 , —(CR 7 R 7 ) r —C 3-8  cycloalkyl substituted with 1-3 R 8 , —(CR 7 R 7 ) r -aryl substituted with 1-3 R 8 , C 2-7 alkenyl substituted with 1-3 R 9 , —(CR 7 R 7 ) r -5-6 membered heterocyclic ring substituted with 1-3 R 8 , —(CR 7 R 7 ) r -5-6 membered heteroaryl ring substituted with 1-3 R 8 , or R 3  and R 4  combine with the N to which they are attached to form a 4-9 membered heterocyclic ring substituted with 1-3 R 8 ; 
         X 1 , X 2 , X 3 , and X 4  are independently selected from CR 5  and N; provided no more than two of X 1 , X 2 , X 3 , or X 4  are N; 
         R 5  is independently selected from H, F, Cl, OR 7 , CN, N(R 7 ) 2 , C 1-4  alkyl substituted with 1-5 R 9 , C 1-4  alkoxy substituted with 1-5 R 9 , and C 1-4  heteroalkyl substituted with 1-5 R 9 ; 
         R 6  is C 3-8  cycloalkyl which is substituted with R 10  and (—CH 2 ) 0-1 R 11 ; 
         R 7  is independently selected from H, C 1-4  alkyl, and C 3-6  cycloalkyl; or R 7  and R 7 , together with the carbon atom to which they both attach, form a C 3-6  cycloalkyl ring; 
         R 8  is independently selected from H, D, C 1-6  alkyl substituted with 1-5 R 9 , C 2-6  alkenyl, C 2-6  alkynyl, phenyl, —(CH 2 ) r —C 3-6  cycloalkyl, F, Cl, Br, CN, COOH, and C 1-4  alkoxy; 
         R 9  is independently selected from H, D, F, Cl, NH 2 , OH, OC 1-5 alkyl, C 1-5 alkyl, C 1-5  heteroalkyl C 3-6  cycloalkyl, and phenyl, wherein when R 9  is Cl, NH 2  or OH it is not substituted on C 1  of the the alkyl to which it is attached; 
         R 10  is independently selected from H, D, C 1-4  alkyl, F, Cl, Br, OR 7 , NHC(═O)OR 7 , and NHC(═O)OR 7 ; 
         R 11  is independently selected from H, CN, —C(═O)R 12 , tetrazolyl, 
       
       
         
           
           
               
               
           
         
         R 12  is independently selected from OH, OC 1-4  alkyl, NH 2 , NHCH 2 CH 2 SO 3 H, and NHSO 2 C 1-4 alky; 
         r is independently selected from zero, 1, 2, 3, and 4, 
         and n is slected from 1, 2, 3, or 4. 
       
     
     
         2 . The compound of  claim 1 , wherein
 R 3  and R 4  are independently selected from H, C 1-7  alkyl substituted with 1-3 R 9 , —(CR 7 R 7 ) r —C 3-8  cycloalkyl substituted with 1-3 R 8 , —(CR 7 R 7 ) r -aryl substituted with 1-3 R 8 , C 2-7 alkenyl substituted with 1-3 R 9 , —(CR 7 R 7 ) r -5-6 membered heterocyclic ring substituted with 1-3 R 8 , —(CR 7 R 7 ) r -5-6 membered heteroaryl ring substituted with 1-3 R 8 , and R 3  and R 4  combine with the N to which they are attached to form the following:   
       
         
           
           
               
               
           
         
       
       each of which may be substituted with 1-3 R 8 , and
 n equals 1 or 2. 
 
     
     
         3 . The compound according to  claim 1  wherein,
 R 3  and R 4  are independently selected from H, C 1-7  alkyl substituted with 1-3 R 9 , —(CR 7 R 7 ) r —C 3-8  cycloalkyl substituted with 1-3 R 8 , —(CR 7 R 7 ) r -aryl substituted with 1-3 R 8 , C 2-7 alkenyl substituted with 1-3 R 9 , 
 
       
         
           
           
               
               
           
         
         each of which can be substituted with 1-3 R 8 , and R 3  and R 4  combine with the N to which they are attached to form a 4-9 membered heterocyclic ring substituted with 1-3 R 8 ; and 
         n equals 1 or 2. 
       
     
     
         4 . A compound according to Formula (II): 
       
         
           
           
               
               
           
         
         or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein 
         R 2  is independently selected from H and C 1-4  alkyl substituted with 1-5 R 9 ; 
         R 13  is independently selected from H, D, and C 1-4  alkyl substituted with 1-3 R 9 ; 
         R 3  and R 4  are independently selected from H, C 1-7  alkyl substituted with 1-3 R 9 , —(CR 7 R 7 ) r —C 3-6  cycloalkyl substituted with 1-3 R 8 , and —(CR 7 R 7 ) r -aryl substituted with 1-3 R 8 ; 
         X 1 , X 2 , X 3 , and X 4  are independently selected from CR 5  and N; provided no more than two of X 1 , X 2 , X 3 , or X 4  are N; 
         R 5  is independently selected from H, F, Cl, OR 7 , CN, N(R 7 ) 2 , C 1-4  alkyl substituted with 1-5 R 9 , C 1-4  alkoxy substituted with 1-5 R 9 , and C 1-4  heteroalkyl substituted with 1-5 R 9 ; 
         R 6  is 
       
       
         
           
           
               
               
           
         
         R 7  is independently selected from H, C 1-4  alkyl, and C 3-6  cycloalkyl; or R 7  and R 7 , together with the carbon atom to which they both attach, form a C 3-6  cycloalkyl ring; 
         R 8  is independently selected from H, C 1-6  alkyl substituted with 1-5 R 9 , C 2-6  alkenyl, C 2-6  alkynyl, —(CH 2 ) r —C 3-6  cycloalkyl, F, Cl, Br, CN, and COOH; 
         R 9  is independently selected from H, F, Cl, NH 2 , OH, OC 1-5 alkyl, C 1-5 alkyl, C 1-5  heteroalkyl C 3-6  cycloalkyl, and phenyl wherein when R 9  is Cl, NH 2  or OH it is not substituted on C 1  of the the alkyl to which it is attached; 
         R 10  is independently selected from H, D, C 1-4  alkyl, F, Cl, Br, ORS, NHC(═O)OR 7 , and NHC(═O)OR 7 ; 
         R 11  is independently selected from CN, —C(═O)R 12 , tetrazolyl, 
       
       
         
           
           
               
               
           
         
         R 12  is independently selected from OH, OC 1-4  alkyl, NH 2 , NHCH 2 CH 2 SO 3 H, and NHSO 2 C 1-4 alky; 
         r is independently selected from zero, 1, 2, 3, and 4. 
       
     
     
         5 . The compound of  claim 4  having Formula (VII): 
       
         
           
           
               
               
           
         
         or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein 
         R 2  is independently selected from CH 3  and CD 3 ; 
         R 13  is independently selected from H and C 1-4  alkyl; 
         R 3  is independently selected from H and C 1-4  alkyl; 
         R 4  is independently selected from C 1-6  alkyl substituted with 1-3 R 9 , (CR 7 R 7 ) r —C 3-6  cycloalkyl substituted with 1-3 R 8 , and —(CR 7 R 7 ) r -aryl substituted with 1-3 R 8 ; 
         R 5  is independently selected from H, F, Cl, CN, and C 1-4  alkyl; 
         R 6  is 
       
       
         
           
           
               
               
           
         
         R 7  is independently selected from H, C 1-4  alkyl, and C 3-6  cycloalkyl; or R 7  and R 7 , together with the carbon atom to which they both attach, form a C 3-6  cycloalkyl ring; 
         R 8  is independently selected from H, C 1-6  alkyl substituted with 1-5 R 9 , C 3-6  cycloalkyl, F, Cl, Br, CN, ═O, and COOH; 
         R 9  is independently selected from H, F, Cl, NH 2 , OH, OC 1-5 alkyl, C 1-5 alkyl, C 3-6  cycloalkyl, and phenyl, wherein when R 9  is Cl, NH 2  or OH it is not substituted on C 1  of the the alkyl to which it is attached; 
         R 10  is independently selected from H, C 1-4  alkyl, and F; 
         R 11  independently selected from —C(═O)R 12  and tetrazolyl; 
         R 12  is independently selected from OH and NHSO 2 C 1-4 alky; and 
         r is independently selected from zero, 1, 2, 3, and 4. 
       
     
     
         6 . The compound of  claim 5 , or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein
 R 2  is independently selected from CH 3  and CD 3 ;   R 13  is independently selected from H and CH 3 ;   R 3  is independently selected from H and CH 3 ;   R 4  is independently selected from C 1-6  alkyl,   
       
         
           
           
               
               
           
         
         R 5  is independently selected from H, F, Cl, and C 1-4  alkyl; 
         R 6  is 
       
       
         
           
           
               
               
           
         
         R 7  is independently selected from H, C 1-4  alkyl, and C 1-6  cycloalkyl; and 
         R 8  is independently selected from H, F, Cl, Br, CN, and C 1-4  alkyl. 
       
     
     
         7 . The compound of  claim 5  having Formula (VIII): 
       
         
           
           
               
               
           
         
         or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein 
         R 2  is independently selected from CH 3  and CD 3 ; 
         R 13  is independently selected from H and CH 3 ; 
         R 3  is independently selected from H and CH 3 ; 
         R 4  is independently selected from 
       
       
         
           
           
               
               
           
         
         R 5  is independently selected from H, F, and CH 3 ; and 
         R 8  is independently selected from H, F, Cl, Br, CN, and C 1-4  alkyl. 
       
     
     
         8 . The compound of  claim 4  having Formula (IX): 
       
         
           
           
               
               
           
         
         or an enantiomer, a diastereomer, a stereoisomer, a pharmaceutically acceptable salt thereof, wherein 
         R 2  is independently selected from CH 3  and CD 3 ; 
         R 13  is independently selected from H and C 1-4  alkyl; 
         R 13  is independently selected from H and C 1-4  alkyl; 
         R 4  is independently selected from C 1-6  alkyl substituted with 1-3 R 9 , (CR 7 R 7 ) r —C 3-6  cycloalkyl substituted with 1-3 R 8 , and —(CR 7 R 7 ) r -aryl substituted with 1-3 R 8 ; 
         R 5  is independently selected from H, F, Cl, CN, and C 1-4  alkyl; 
         R 6  is 
       
       
         
           
           
               
               
           
         
         R 7  is independently selected from H, C 1-4  alkyl, and C 3-6  cycloalkyl; or R 7  and R 7 , together with the carbon atom to which they both attach, form a C 3-6  cycloalkyl ring; 
         R 8  is independently selected from H, C 1-6  alkyl substituted with 1-5 R 9 , C 3-6  cycloalkyl, F, Cl, Br, CN, ═O, and COOH; 
         R 9  is independently selected from H, F, Cl, NH 2 , OH, OC 1-5 alkyl, C 1-5 alkyl, C 3-6  cycloalkyl, and phenyl, wherein when R 9  is Cl, NH 2  or OH it is not substituted on C 1  of the the alkyl to which it is attached; 
         R 10  is independently selected from H and F; 
         R 11  is independently selected from —C(═O)R 12  and tetrazolyl; 
         R 12  is independently selected from OH and —C(═O)NHSO 2 Me; and 
         r is independently selected from zero, 1, 2, 3, and 4. 
       
     
     
         9 . A pharmaceutical composition comprising one or more compounds according to  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         10 . A method of treating fibrosis in a mammal comprising administering a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to the mammal in need thereof. 
     
     
         11 . A method of treating a disease, disorder, or condition in a mammal comprising administering a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, to the mammal in need thereof; wherein the disease, disorder or condition is selected from pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), hepatic fibrosis, renal fibrosis, arterial fibrosis, systemic sclerosis, liver fibrosis, skin fibrosis, fibrosis of the gut, and ocular fibrosis. 
     
     
         12 . The method of  claim 11 , wherein the disease, disorder, or condition is pulmonary fibrosis, hepatic fibrosis, renal fibrosis, arterial fibrosis, or systemic sclerosis. 
     
     
         13 . The method of  claim 11 , wherein the disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF). 
     
     
         14 . The method of  claim 11 , wherein the disease, disorder, or condition is non-alcoholic steatohepatitis (NASH).