Heterocyclic compounds useful in the treatment of disease

Abstract

Heterocyclic compounds are described that are lysophosphatidic acid receptor ligands that are useful in the treatment of lysophosphatidic acid receptor-dependent diseases and conditions.

1 . A compound having the structure of Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein R A  is —CO 2 H, tetrazolyl, —C(═O)NH 2 , —C(═O)NHR B , —CONHCN, —C(═O)NHSO 2 R B  or —C(═O)NHCH 2 CH 2 SO 3 H; 
 R B  is a substituted or unsubstituted C 1 -C 4  alkyl; 
 L 1  is a substituted or unsubstituted saturated C 1 -C 6  alkylene, or L 1  is —CH 2 —, 
 
       
         
           
           
               
               
           
         
       
       or dimethylmethane;
 A 1  is N or C; 
 Ring A has the structure of one of: 
 
       
         
           
           
               
               
           
         
         R C  is —CN, —F, —Cl, or C 1 -C 4  fluoroalkyl; 
         R D  is —N(R F )—C(═O)XCH(R G )—CY, wherein X is O and CY is unsubstituted phenyl or Phenyl substituted with one R H : 
       
       
         
           
           
               
               
           
         
         R E , R F  and R G  independently are —H or saturated C 1 -C 4  alkyl or R E  and R F  independently are —H or saturated C 1 -C 4  alkyl and one R G  is saturated —C 1 -C 4  alkyl and is taken together with the R H  phenyl moiety of the Ring A R D  substituent and the carbon atom to which R G  and said phenyl moiety is attached to define a substituted or unsubstituted carbocycle, and the other R G , if present, is as defined for R E ; and 
         each R H  is independently absent, a halogen, or substituted or unsubstituted saturated C 1 -C 4  alkyl. 
       
     
     
         2 . The compound according to  claim 1 , wherein:
 R A  is tetrazolyl   
       
         
           
           
               
               
           
         
       
       —C(═O)NH 2 , —CONHCN or —C(═O)NHSO 2 R B ;
 L 1  is —CH 2 —, 
 
       
         
           
           
               
               
           
         
       
       or dimethylmethane;
 in the ring 
 
       
         
           
           
               
               
           
         
       
       R H  is absent, a halogen, or —CH 3 ;
 in the ring 
 
       
         
           
           
               
               
           
         
       
       A 1  is C or N and R H  is —H;
 Ring A has the structure of 
 
       
         
           
           
               
               
           
         
         R C  is —F, —Cl, or —CN; 
         R F  is —H; 
         R G  is —CH 3  in an R configuration; and 
         in the CY ring 
       
       
         
           
           
               
               
           
         
       
       R H  is absent or a halogen. 
     
     
         3 . The compound according to  claim 2 , wherein:
 R A  is —C(═O)NHSO 2 R B ;   L 1  is   
       
         
           
           
               
               
           
         
         in the ring 
       
       
         
           
           
               
               
           
         
       
       R H  is absent;
 in the ring 
 
       
         
           
           
               
               
           
         
       
       A 1  is N and R H  is absent;
 R C  is —F or —Cl; and 
 in the CY ring 
 
       
         
           
           
               
               
           
         
       
       R H  is —Cl. 
     
     
         4 . (canceled) 
     
     
         5 . The compound according to  claim 2 , wherein
 R A  is —C(═O)NHSO 2 R B      L 1  is   
       
         
           
           
               
               
           
         
       
       or dimethylmethane 
       
         
           
           
               
               
           
         
         R C  is —F or —CN and 
         in the ring 
       
       
         
           
           
               
               
           
         
       
       A 1  is C and R H  is absent. 
     
     
         6 . (canceled) 
     
     
         7 . The compound according to  claim 2 , wherein R A  is —C(═O)NHSO 2 R B , wherein R B  is CH 3 ; and
 L 1  is 
 
       
         
           
           
               
               
           
         
       
       and
 R C  is —Cl; and 
 in the ring 
 
       
         
           
           
               
               
           
         
       
       A 1  is C and R H  is absent. 
     
     
         8 . (canceled) 
     
     
         9 . The compound according to  claim 2 , wherein:
 R A  is —C(═O)NH 2 ;   L 1  is   
       
         
           
           
               
               
           
         
         R C  is —F; and 
         in the ring 
       
       
         
           
           
               
               
           
         
       
       A 1  is C and R H  is absent. 
     
     
         10 . The compound according to  claim 9 , wherein the compound is (R)-1-(2-chlorophenyl)ethyl (1-(4′-(1-carbamoylcyclopropyl)-[1,1′-biphenyl]-4-yl)-4-fluoro-1H-pyrazol-5-yl)carbamate. 
     
     
         11 . The compound according to  claim 2 , wherein:
 R A  is —C(═O)NHSO 2 R B , wherein R B  is —CH 3 ; and   L 1  is   
       
         
           
           
               
               
           
         
         R C  is —F and 
         in the ring 
       
       
         
           
           
               
               
           
         
       
       A 1  is C and R H  is absent. 
     
     
         12 . The compound according to  claim 11 , wherein the compound is (R)-1-(2-chlorophenyl)ethyl (4-fluoro-1-(2′-fluoro-4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (4-fluoro-1-(2′-fluoro-4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(2′-fluoro-4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (4-chloro-1-(4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, or (R)-1-(2-chlorophenyl)ethyl (4-fluoro-1-(4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, 
     
     
         13 . The compound according to  claim 2 , wherein:
 R A  is tetrazolyl   
       
         
           
           
               
               
           
         
         L 1  is 
       
       
         
           
           
               
               
           
         
       
       and
 R C  is —F or —Cl; and 
 in the ring 
 
       
         
           
           
               
               
           
         
       
       A 1  is C and R H  is —H. 
     
     
         14 . The compound according to  claim 13 , wherein the compound is (R)-1-(2-chlorophenyl)ethyl (1-(4′-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-4-fluoro-1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (1-(4′-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-4-chloro-1H-pyrazol-5-yl)carbamate or (R)-1-(2-chlorophenyl)ethyl (1-(4′-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-4-chloro-1H-pyrazol-5-yl)carbamate. 
     
     
         15 . The compound according to  claim 2 , wherein:
 R A  is —CONHCN   L 1  is   
       
         
           
           
               
               
           
         
       
       and
 R C  is —F or —Cl; and 
 in the ring 
 
       
         
           
           
               
               
           
         
       
       A 1  is C and R H  is absent. 
     
     
         16 . The compound according to  claim 15  wherein the compound is (R)-1-phenylethyl (4-chloro-1-(4′-(1-(cyanocarbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(4′-(1-(cyanocarbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, or (R)-1-(2-chlorophenyl)ethyl (1-(4′-(1-(cyanocarbamoyl)cyclopropyl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-4-fluoro-1H-pyrazol-5-yl)carbamate. 
     
     
         17 . The compound according to  claim 2  wherein the compound is (R)-1-phenylethyl (4-chloro-1-(4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate. 
     
     
         18 . The compound according to  claim 1 , wherein R G  is in an R or S configuration. 
     
     
         19 . A pharmaceutical composition comprising:
 the compound according to  claim 1 ; and   at least one pharmaceutically acceptable excipient.   
     
     
         20 . A method for treating a lysophosphatidic acid-dependent disease or condition in a subject in need thereof, the method comprising:
 administering to the subject a therapeutically effective amount of the compound according to  claim 1 .   
     
     
         21 . The method according to  claim 20 , wherein the lysophosphatidic acid-dependent disease or condition is diabetic nephropathy or nonalcoholic steatohepatitis (NASH). 
     
     
         22 . A compound according to  claim 1 , selected from the group consisting of (R)-1-(2-chlorophenyl)ethyl (1-(4′-(1-carbamoylcyclopropyl)-[1,1′-biphenyl]-4-yl)-4-fluoro-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (4-fluoro-1-(2′-fluoro-4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (4-fluoro-1-(2′-fluoro-4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (4-chloro-1-(2′-fluoro-4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (4-chloro-1-(4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (4-fluoro-1-(4′-(1-((methylsulfonyl)carbamoyl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (1-(4′-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-4-fluoro-1H-pyrazol-5-yl)carbamate, (R)-1-phenylethyl (1-(4′-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-4-chloro-1H-pyrazol-5-yl)carbamate, (R)-1-(2-chlorophenyl)ethyl (1-(4′-(1-(1H-tetrazol-5-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)-4-chloro-1H-pyrazol-5-yl)carbamate, 3-[(R)-1-Phenylethoxycarbonylamino]-4-chloro-2-{4′-[1-(cyanoamino)carbonylcyclopropyl]-4-biphenylyl}-2H-pyrazole, 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-4-chloro-2-{4′-[1-(cyanoamino)carbonylcyclopropyl]-4-biphenylyl}-2H-pyrazole, and 3-[(R)-1-(o-Chlorophenyl)ethoxycarbonylamino]-2-{4′-[1-(cyanoamino)carbonylcyclopropyl]-2′-fluoro-4-biphenylyl}-4-fluoro-2H-pyrazole.