Pyrazole derivatives as modulators of hepatocyte growth factor (scatter factor) activity

Abstract

The present invention provides compounds having formula (I): and pharmaceutically acceptable derivatives thereof, wherein R 1 , R 2 and B are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases in which HGF/SF or the activities thereof, or agonists or antagonists thereof have a therapeutically useful role.

1 - 53 . (canceled) 
     
     
         54 . A method of preparing a pharmaceutical composition, the method comprising providing a compound: 
       
         
           
           
               
               
           
         
         or a tautomer thereof, 
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 m is 1; 
 A represents an optionally substituted aromatic or non-aromatic 5-6 membered monocyclic ring, optionally containing 1-4 heteroatoms selected from N, O or S; or an optionally substituted aromatic or non-aromatic 8-12 membered bicyclic ring, optionally containing 1-6 heteroatoms selected from N, O or S; 
 R is one or two substituents, and each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO 2 , —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , and —C(═O)R a ; 
 n is 0, 1, or 2; 
 each R R  is independently an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety; 
 R a , at each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, and an optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl; 
 R b  and R c , at each occurrence, are independently selected from the group consisting of hydrogen, hydroxy, SO 2 R d , and optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl; 
 R d , at each occurrence, is independently selected from the group consisting of hydrogen, —N(R e ) 2 , and optionally substituted aliphatic, aryl, or heteroaryl; and 
 R e , at each occurrence, is independently hydrogen or optionally substituted aliphatic; and 
 
         formulating the compound with at least one pharmaceutically acceptable excipient. 
       
     
     
         55 . The method of  claim 54 , wherein the pharmaceutical composition is an injectable pharmaceutical composition. 
     
     
         56 . The method of  claim 55 , wherein the pharmaceutical composition is disposed for parenteral administration. 
     
     
         57 . The method of  claim 56 , wherein the pharmaceutical composition comprises the compound in a concentration effective to deliver a dose within a range of from about 0.1 mg/kg to about 10 mg/kg. 
     
     
         58 . The method of  claim 55 , wherein the injectable pharmaceutical composition is sterile. 
     
     
         59 . The method of  claim 54 , wherein the compound is: 
       
         
           
           
               
               
           
         
         wherein R N  is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl, or a nitrogen protecting group. 
       
     
     
         60 . The method of  claim 54 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         61 . A method of administering a therapeutically effective amount of a compound: 
       
         
           
           
               
               
           
         
         or a tautomer thereof, 
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 m is 1; 
 A represents an optionally substituted aromatic or non-aromatic 5-6 membered monocyclic ring, optionally containing 1-4 heteroatoms selected from N, O or S; or an optionally substituted aromatic or non-aromatic 8-12 membered bicyclic ring, optionally containing 1-6 heteroatoms selected from N, O or S; 
 R is one or two substituents, and each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO 2 , —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , and —C(═O)R a ; 
 n is 0, 1, or 2; 
 each R R  is independently an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety; 
 R a , at each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, and an optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl; 
 R b  and R c , at each occurrence, are independently selected from the group consisting of hydrogen, hydroxy, SO 2 R d , and optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl; 
 R d , at each occurrence, is independently selected from the group consisting of hydrogen, —N(R e ) 2 , and optionally substituted aliphatic, aryl, or heteroaryl; and 
 R e , at each occurrence, is independently hydrogen or optionally substituted aliphatic, the method comprising administering a pharmaceutical composition comprising the compound. 
 
       
     
     
         62 . The method of  claim 61 , wherein the pharmaceutical composition is an injectable pharmaceutical composition. 
     
     
         63 . The method of  claim 62 , wherein the pharmaceutical composition is disposed for parenteral administration. 
     
     
         64 . The method of  claim 63 , wherein the pharmaceutical composition comprises the compound in a concentration effective to deliver a dose within a range of from about 0.1 mg/kg to about 10 mg/kg. 
     
     
         65 . The method of  claim 63 , wherein the injectable pharmaceutical composition is sterile. 
     
     
         66 . The method of  claim 61 , wherein the compound is: 
       
         
           
           
               
               
           
         
         wherein R N  is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl, or a nitrogen protecting group. 
       
     
     
         67 . The method of  claim 61 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         68 . The method of  claim 61 , comprising administering the pharmaceutical composition to a patient suffering from a disease, disorder, or condition selected from ischemic heart disease, damaged and/or ischemic organs, transplants or grafts, ischemia/reperfusion injury, myocardial ischemia, renal failure, renal fibrosis, idiopathic pulmonary fibrosis, vascularization of a damaged and/or ischemic organ, transplant or graft, amelioration of ischemia/reperfusion injury in the kidney, normalization of myocardial perfusion as a consequence of myocardial infarction, fibrosis secondary to renal obstruction, renal trauma and transplantation, and renal failure secondary to chronic diabetes or hypertension. 
     
     
         69 . A process for preparing a compound: 
       
         
           
           
               
               
           
         
         or a tautomer thereof, 
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 m is 1; 
 A represents an optionally substituted aromatic or non-aromatic 5-6 membered monocyclic ring, optionally containing 1-4 heteroatoms selected from N, O or S; or an optionally substituted aromatic or non-aromatic 8-12 membered bicyclic ring, optionally containing 1-6 heteroatoms selected from N, O or S; 
 R is one or two substituents, and each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO 2 , —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , and —C(═O)R a ; 
 n is 0, 1, or 2; 
 each R R  is independently an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety; 
 R a , at each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, and an optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl; 
 R b  and R c , at each occurrence, are independently selected from the group consisting of hydrogen, hydroxy, SO 2 R d , and optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl; 
 R d , at each occurrence, is independently selected from the group consisting of hydrogen, —N(Re) 2 , and optionally substituted aliphatic, aryl, or heteroaryl; and 
 R e , at each occurrence, is independently hydrogen or optionally substituted aliphatic, comprising a step of contacting a compound of formula: 
 
       
       
         
           
           
               
               
           
         
         with a compound: 
       
       
         
           
           
               
               
           
         
         under conditions suitable to afford the compound. 
       
     
     
         70 . The process of  claim 69 , comprising a step of contacting a compound of formula: 
       
         
           
           
               
               
           
         
         with a compound: 
       
       
         
           
           
               
               
           
         
         in the presence of ZnBr 2  to give the compound: 
       
       
         
           
           
               
               
           
         
       
     
     
         71 . The process of  claim 69 , wherein the compound is: 
       
         
           
           
               
               
           
         
         wherein R N  is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl, or a nitrogen protecting group. 
       
     
     
         72 . The process of  claim 69 , wherein the compound is selected from: