Substituted thioacetamides

Abstract

The present invention is directed to chemical compositions of substituted thioacetamides, processes for the preparation thereof and uses of the compositions in the treatment of diseases.

1 . A method of preparing a compound of formula eee  
     
       
         
         
             
             
         
       
     
     comprising converting a compound of formula ddd  
     
       
         
         
             
             
         
       
     
     to an ester, then reacting the ester with ammonia to give the compound of formula eee;  
     wherein 
 Ar 1  and Ar 2  are each independently selected from C 6 -C 10  aryl or heteroaryl; 
 wherein each of Ar 1  or Ar 2  may be independently optionally substituted with 1-3 substituents independently selected from:  
 a) H, C 6 -C 10  aryl, heteroaryl, F, Cl, Br, I, —CN, —CF 3 , —NO 2 , —OH, —OR 7 , —O(CH 2 ) p NR 9 R 10 , —OC(═O)R 7 , —OC(═O)NR 9 R 10 , —O(CH 2 ) p OR 8 , —CH 2 OR 8 , —NR 9 R 10 , —NR 8 S(═O) 2 R 7 , —NR 8 C(═O)R 7 , or —NR 8 C(═S)R 7 ;  
 b) —CH 2 OR 11 ;  
 c) —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═S)NR 9 R 10 , —CO 2 R 12 , —C(═O)R 13 , —C(═O)NR 9 R 10 , —C(═S)NR 9 R 10 , —CH═NOR 12 , —CH═NR 7 , —(CH 2 ) p NR 9 R 10 , —(CH 2 ) p NHR 11 , —CH═NNR 12 R 12A , —C(═NR 8 )NR 8A R 8B —NR 8 C(═NH)R 8A , —NR 8 C(═NH)NR 8A R 8B ,  
                     
 d) —S(O) y R 7 , —(CH 2 ) p S(O) y R 7 , —CH 2 S(O) y R 7 ; and  
 e) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, or C 2 -C 8  alkynyl, where: 
 1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or  
 2) each alkyl, alkenyl or alkynyl group is independently substituted with 1 to 3 groups independently selected from C 6 -C 10  aryl, heteroaryl, F, Cl, Br, I, CF 3 , —CN, —NO 2 , —OH, —OR 7 , —CH 2 OR 8 , —NR 9 R 10 , —O—(CH 2 ) p —OH, —S—(CH 2 ) p —OH, —X 1 (CH 2 ) p OR 7 , X 1 (CH 2 ) p NR 9 R 10 , —X 1  (CH 2 ) p C(═O)NR 9 R 10 , —X 1  (CH 2 ) p C(═S)NR 9 R 10 , —X 1 (CH 2 ) p OC(═O)NR 9 R 10 , —X 1  (CH 2 ) p CO 2 R 8 , —X 1 (CH 2 ) p S(O) y R 7 , —X 1 (CH 2 ) p NR 8 C(═O)NR 9 R 10 , —C(═O)R 13 , —CO 2 R 12 , —OC(═O)R 7 , —C(═O)NR 9 R 10 , —OC(═O)NR 12 R 12A , O-tetrahydropyranyl, —C(═S)NR 9 R 10 , —CH═NNR 12 R 12A , —CH═NOR 12 , —CH═NR 7 , —CH═NNHCH(N═NH)NH 2 , —NR 8 CO 2 R 7 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═S)NR 9 R 10 , —NHC(═NH)NH 2 , —NR 8 C(═O)R 7 , —NR 8 C(═S)R 7 , —NR 8 S(═O) 2 R 7 , —S(O) y R 7 , —S(═O) 2 NR 12 R 12A , —P(═O)(OR 8 ) 2 , —OR 11 , and a C 5 -C 7  monosaccharide where each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, or —O—C(═O)R 7 ;  
 
 
 X 1  is —O—, —S—, —N(R 8 )—;  
 R 7  is C 1 -C 6  alkyl, C 6 -C 10  aryl, or heteroaryl;  
 R 8 , R 8A  and R 8B  are each independently H, C 1 -C 4  alkyl, or C 6 -C 10  aryl;  
 R 9  and R 10  are independently selected from H, C 1 -C 4  alkyl, and C 6 -C 10  aryl; or R 9  and R 10  together with the nitrogen to which they are attached, form a 3-7 member heterocyclic ring;  
 R 11  is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;  
 R 12  and R 12A  are each independently selected from H, C 1 -C 6  alkyl, cycloalkyl, C 6 -C 10  aryl, and heteroaryl; or R 12  and R 12A , together with the nitrogen to which they are attached, form a 5-7 member heterocyclic ring;  
 R 13  is H, C 1 -C 6  alkyl, cycloalkyl, C 6 -C 10  aryl, heteroaryl, —C(═O)R 7 , —C(═O)NR 9 R 10 , or —C(═S)NR 9 R 10 ;  
 m is 0, 1, 2 or 3;  
 p is 1, 2, 3, or 4;  
 t is 2, 3, or 4;  
 y is 0, 1 or 2;  
 or the stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt or ester forms thereof.  
 
   
   
       2 . The method of  claim 1 , wherein m is 1.  
   
   
       3 . The method of  claim 1 , wherein Ar 1  and Ar 2  are each independently selected from a five or six membered heteroaryl comprising 1-3 atoms of —N—, —O—, or —S—.  
   
   
       4 . The method of  claim 3 , wherein Ar 1  and Ar 2  are 3-thienyl.  
   
   
       5 . The method of  claim 1 , wherein Ar 1  is phenyl and Ar 2  is a five or six membered heteroaryl comprising 1-3 atoms of —N—, —O—, or —S—.  
   
   
       6 . The method of  claim 1 , wherein Ar 1  and Ar 2  are each independently selected from phenyl, thienyl, isothiazolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, and imidazolyl.  
   
   
       7 . The method of  claim 6 , wherein Ar 1  and Ar 2  are phenyl.  
   
   
       8 . The method of  claim 7 , wherein m is 1.