Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity

Abstract

The present invention provides compositions and formulations of compounds having formula (I) and pharmaceutically acceptable derivatives thereof, wherein p, 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 injuries, conditions or diseases in which HGF/SF or the activities thereof, or agonists or antagonists thereof have a therapeutically useful role. In addition, methods are provided for treating such diseases or diseases starting at a time after the onset of the injury, condition or disease.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a compound having the structure of Formula (A): 
       
         
           
           
               
               
           
         
         tautomer thereof; or pharmaceutically acceptable derivative thereof; 
         wherein m is an integer from 1-3 and [C═C] m  for each occurrence is independently cis or trans; 
         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; 
         q is one or two; and 
         each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO 2 , —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety; —OR R , —S(═O) n R d , —NR b R c , and —C(═O)R a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety; 
         R a , for each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl; 
         R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl; 
         R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; optionally substituted aliphatic, aryl and heteroaryl; and 
       
       R e , for each occurrence, is independently hydrogen or optionally substituted aliphatic;
 in a buffer containing about 40% to about 60% (v/v) polyethylene glycol 300, about 5% to about 15% polysorbate 80, or combination thereof. 
 
     
     
         2 . The composition of  claim 1  wherein the polyethylene glycol 300 is present at about 50% (v/v). 
     
     
         3 . The composition of  claim 1  wherein the polysorbate 80 is present at about 10% (v/v). 
     
     
         4 . The composition of  claim 1  wherein the buffer is phosphate-buffered saline. 
     
     
         5 . The composition of  claim 1  wherein the pH is about 7.4. 
     
     
         6 . The composition of  claim 1  wherein the compound of Formula (A) is present at about 0.8 to about 10 milligrams per milliliter. 
     
     
         7 . The composition of  claim 1  wherein the polyethylene glycol 300 is present at about 50% (v/v), the polysorbate 80 is present at about 10% (v/v), the buffer is phosphate-buffered saline, pH 7.4, and the compound of Formula (A) is present at about 0.8 to about 10 milligrams per milliliter. 
     
     
         8 . The composition of  claim 1  wherein each R is independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a ; —NR b R c ; —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; and C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, each independently optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ;
 wherein each occurrence of R a  is independently selected from the group consisting of hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6  alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
 each occurrence of R b  and R c  is independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
 each occurrence of R d  is independently selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and 
 each occurrence of R e  is independently hydrogen or C 1-6  alkyl. 
 
     
     
         9 . The composition of  claim 1  wherein m is 1 and the compound has the structure: 
       
         
           
           
               
               
           
         
         wherein AR 1  is an optionally substituted moiety. 
       
     
     
         10 . The composition of  claim 10  wherein AR 1  is phenyl or naphthyl. 
     
     
         11 . The composition of  claim 10  wherein AR 1  is phenyl and the compound has the structure: 
       
         
           
           
               
               
           
         
         tautomer thereof; or a prodrug, salt, hydrate, or ester thereof; 
         wherein each R is independently selected from the group consisting of halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a ; —NR b R c ; —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; and C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, each independently optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         wherein each occurrence of R a  is independently selected from the group consisting of hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6  alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         each occurrence of R b  and R c  is independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         each occurrence of R d  is independently selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and 
       
       each occurrence of R e  is independently hydrogen or C 1-6  alkyl. 
     
     
         12 . The composition of  claim 1  wherein m is 1 and the compound has the structure: 
       
         
           
           
               
               
           
         
         wherein Cy is a heterocyclic moiety. 
       
     
     
         13 . The composition of  claim 12  wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         tautomer thereof; or a prodrug, salt, hydrate, or ester thereof; 
         wherein X is O, S or NR N  wherein R N  is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl or a nitrogen protecting group; and 
         each R is independently selected from the group consisting of hydrogen, halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a ; —NR b R c ; —S(O) n R d  where n=0-2; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; and C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, each independently optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         wherein each occurrence of R a  is independently selected from the group consisting of hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6  alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         each occurrence of R b  and R c  is independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         each occurrence of R d  is independently selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and 
       
       each occurrence of R e  is independently hydrogen or C 1-6 alkyl. 
     
     
         14 . The composition of  claim 13  wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         tautomer thereof; or a prodrug, salt, hydrate, or ester thereof. 
       
     
     
         15 . The composition of  claim 13  wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         tautomer thereof; or a prodrug, salt, hydrate, or ester thereof. 
       
     
     
         16 . The composition of  claim 13  wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         tautomer thereof; or a prodrug, salt, hydrate, or ester thereof; 
         wherein R N  is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl or a nitrogen protecting group. 
       
     
     
         17 . The composition of  claim 16  wherein R N  is hydrogen. 
     
     
         18 . The composition of  claim 1  wherein the compound is (E)-3(5)-[2-(2,3-methylenedioxyphenyl)vinyl]-1H-pyrazole, (Z)-3(5)-[2-(2,3-methylenedioxyphenyl)vinyl]-1H-pyrazole, (E)-3(5)-[2-(2-chloro-5-trifluoromethylphenyl)vinyl]-1H-pyrazole, (Z)-3(5)-[2-(2-chloro-5-trifluoromethylphenyl)vinyl]-1H-pyrazole, (E)-3(5)-[2-(2-trifluoromethylphenyl)vinyl]-1H-pyrazole, (Z)-3 (5)-[2-(2-trifluoromethylphenyl)vinyl]-1H-pyrazole, (E)-3 (5)-[2-(2-furyl)vinyl]-1H-pyrazole, (Z)-3(5)-[2-(2-furyl)vinyl]-1H-pyrazole, (E)-3 (5)-[2-(2-thienyl)vinyl]-1H-pyrazole, (Z)-3(5)-[2-(2-thienyl)vinyl]-1H-pyrazole, (E)-3-(2-(5-nitro furan-2-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(5-nitrofuran-2-yl)vinyl)-1H-pyrazole, (E)-3-styryl-1H-pyrazole, (Z)-3-styryl-1H-pyrazole, (E)-2-(2-(1H-pyrazol-3-yl)vinyl)-1H-indole, (Z)-2-(2-(1H-pyrazol-3-yl)vinyl)-1H-indole, (E)-4-(2-(1H-pyrazol-3-yl)vinyl)-N,N-dimethylaniline, (Z)-4-(2-(1H-pyrazol-3-yl)vinyl)-N,N-dimethylaniline, (E)-3-(4-methoxystyryl)-1H-pyrazole, (Z)-3-(4-methoxystyryl)-1H-pyrazole, (E)-3-(2,6-dichlorostyryl)-1H-pyrazole, (Z)-3-(2,6-dichlorostyryl)-1H-pyrazole, (E)-3-(2-(naphthalen-2-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(naphthalen-2-yl)vinyl)-1H-pyrazole, (E)-3-(2-(1H-pyrrol-2-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(1H-pyrrol-2-yl)vinyl)-1H-pyrazole, (E)-3-(2-(thiophen-3-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(thiophen-3-yl)vinyl)-1H-pyrazole, (E)-3-(2-(1H-pyrrol-3-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(1H-pyrrol-3-yl)vinyl)-1H-pyrazole, (E)-3-(2-(furan-3-yl)vinyl)-1H-pyrazole, or (Z)-3-(2-(furan-3-yl)vinyl)-1H-pyrazole. 
     
     
         19 . A composition comprising a compound having the structure of Formula (B): 
       
         
           
           
               
               
           
         
         C(5)-positional isomer thereof; or a prodrug, salt, hydrate, or ester thereof; 
         wherein R 1  is SO 2 AL 2 , C(═O)(CH 2 ) m AL 2 , C(═O)OAL 2 , C(═O)NHAL 2 , SO 2 Aryl, C(═O)(CH 2 ) m Aryl, C(═O)OAryl, C(═O)Oheterocyclic, C(═O)(CH 2 ) m Heterocyclic, or C(═O)NHAryl; wherein m is an integer from 0-3; AL 2  is an aliphatic or alicyclic moiety; and AL 2 , the aryl and heterocyclic moiety are independently optionally substituted with one or more substituents independently selected from hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; or COCH 2 OC 2 H 5 OCH 3 ; and 
         R 3  is a cis or trans CHCHAryl, CHCHHeterocyclic, phenoxyphenyl, or a heterocyclic group, wherein the aryl, heterocyclic or phenoxyphenyl moiety may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; 
         wherein R a  is selected from the group consisting of hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6  alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         R b  and R c  are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         R d  is selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and 
         R e  is hydrogen or C 1-6  alkyl; 
         in a buffer containing about 40% to about 60% (v/v) polyethylene glycol 300, about 5% to about 15% polysorbate 80, or the combination thereof. 
       
     
     
         20 . The composition of  claim 19  wherein the polyethylene glycol 300 is present at about 50% (v/v). 
     
     
         21 . The composition of  claim 19  wherein the polysorbate 80 is present at about 10% (v/v). 
     
     
         22 . The composition of  claim 19  wherein the buffer is phosphate-buffered saline. 
     
     
         23 . The composition of  claim 22  wherein the pH is about 7.4. 
     
     
         24 . The composition of  claim 19  wherein the compound of Formula (B) is present at about 0.8 to about 10 milligrams per milliliter. 
     
     
         25 . The composition of  claim 19  wherein the polyethylene glycol 300 is present at about 50% (v/v), the polysorbate 80 is present at about 10% (v/v), the buffer is phosphate-buffered saline,
 pH 7.4, and the compound of Formula (B) is present at about 0.8 to about 10 milligrams per milliliter. 
 
     
     
         26 . The composition of  claim 19  wherein AL 2  is an alkyl or cycloalkyl moiety. 
     
     
         27 . The composition of  claim 19  wherein R 1  is C(═O)(CH 2 ) m AL 2 , C(═O)OAL 2 , C(═O)(CH 2 ) m Aryl, C(═O)OAryl, C(═O)OHeterocyclic, or C(═O)(CH 2 ) m Heterocyclic; where m is an integer from 1-3; AL 2  is an aliphatic or alicyclic moiety; and AL 2 , the aryl and heterocyclic moiety are independently optionally substituted with one or more substituents independently selected from hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6 alkoxy, aryl, heteroaryl and heterocyclyl; or COCH 2 OC 2 H 5 OCH 3 ;
 R 3  is a cis or trans CHCHAryl, CHCHHeterocyclic, phenoxyphenyl, or a heterocyclic group, wherein the aryl, heterocyclic or phenoxyphenyl moiety may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and 
 wherein each occurrence of R a  is independently selected from the group consisting of hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6  alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
 each occurrence of R b  and R c  is independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
 each occurrence of R d  is independently selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and 
 each occurrence of R e  is independently hydrogen or C 1-6  alkyl. 
 
     
     
         28 . The composition of  claim 19  wherein R 3  is a cis or trans CHCHAryl, optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl. 
     
     
         29 . The composition of  claim 19  wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         C(5)-positional isomer thereof; or a prodrug, salt, hydrate, or ester thereof; 
         wherein R 1  is SO 2 AL 2 , C(═O)(CH 2 ) m AL 2 , C(═O)OAL 2 , C(═O)NHAL 2 , SO 2 Aryl, C(═O)(CH 2 ) m Aryl, C(═O)OAryl, C(═O)Oheterocyclic, C(═O)(CH 2 ) m Heterocyclic, or C(═O)NHAryl; wherein m is an integer from 1-3; AL 2  is an aliphatic or alicyclic moiety; and AL 2 , the aryl and heterocyclic moiety are independently optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; or COCH 2 OC 2 H 5 OCH 3 ; and 
         CHCHAr is a cis or trans CH═CHAryl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; 
         wherein each occurrence of R a  is independently selected from the group consisting of hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         each occurrence of R b  and R c  is independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         each occurrence of R d  is independently selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and 
         each occurrence of R e  is independently hydrogen or C 1-6  alkyl. 
       
     
     
         30 . The composition of  claim 19  wherein R 1  is C(═O)(CH 2 ) m AL 2 , C(═O)OAL 2 , C(═O)(CH 2 ) m Aryl, C(═O)OAryl, C(═O)OHeterocyclic or C(═O)(CH 2 ) m Heterocyclic; wherein m is an integer from 1-3; AL 2  is an aliphatic or alicyclic moiety; and AL 2 , the aryl and heterocyclic moiety are independently optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6 alkoxy, aryl, heteroaryl and heterocyclyl; or COCH 2 OC 2 H 5 OCH 3 . 
     
     
         31 . The composition of  claim 19  wherein R 1  is SO 2 AL 2 , C(═O)AL 2 , C(═O)NHAL 2 , SO 2 Aryl, C(═O)Aryl, or C(═O)NHAryl; wherein AL 2  is an aliphatic or alicyclic moiety; and AL 2  and the aryl moiety are independently optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6 alkoxy, aryl, heteroaryl and heterocyclyl; or COCH 2 OC 2 H 5 OCH 3 . 
     
     
         32 . The composition of any one of  claims 29 - 31  wherein AL 2  is an alkyl or cycloalkyl moiety. 
     
     
         33 . The composition of  claim 19  wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         C(5)-positional isomer thereof; or a prodrug, salt, hydrate, or ester thereof; 
         wherein AR is an optionally fused 3-12 membered aromatic or alicyclic mono- or bicyclic-ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; heterocycle; carboxy ester; or —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; —NR f R g ; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; and 
         R 3  is a cis or trans CHCHheterocyclic, phenoxyphenyl, or a heterocyclic group, optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; 
         wherein R a  is selected from the group consisting of hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6  alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         R b  and R c  are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         R d  is selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; 
         R e  is hydrogen or C 1-6  alkyl; and 
         R f  and R g  are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 . 
       
     
     
         34 . The composition of  claim 19  wherein the compound is 3(5)-[2-(phenyl)vinyl]-1-(4-chlorobenzoyl)-1H-pyrazole, (E)-furan-2-yl(3-styryl-1H-pyrazol-1-yl)methanone, (E)-(3-(2,6-dichlorostyryl)-1H-pyrazol-1-yl)(thiophen-2-yl)methanone, (E)-2-(4-methoxyphenyl)-1-(3-styryl-1H-pyrazol-1-yl)ethanone, (E)-cyclopropyl(3-styryl-1H-pyrazol-1-yl)methanone, (E)-(6-morpholinopyridin-3-yl)(3-styryl-1H-pyrazol-1-yl)methanone, (E)-(3-(2-(furan-2-yl)vinyl)-1H-pyrazol-1-yl)(4-(trifluoromethoxy)phenyl)methanone, (E)-(3-(2-(furan-2-yl)vinyl)-1H-pyrazol-1-yl)(3-(trifluoromethoxy)phenyl)methanone, (E)-(3-(2-(furan-2-yl)vinyl)-1H-pyrazol-1-yl)(2-(trifluoromethoxy)phenyl)methanone, (E)-(3-(2-(furan-2-yl)vinyl)-1H-pyrazol-1-yl)(phenyl)methanone, (E)-benzo[d][1,3]dioxol-5-yl(3-(2-(furan-2-yl)vinyl)-1H-pyrazol-1-yl)methanone, (E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)(4-(trifluoromethoxy)phenyl)methanone, (E)-3-(3-(2-(furan-2-yl)vinyl)-1H-pyrazole-1-carbonyl)benzonitrile, (E)-methyl 4-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1-carbonyl)benzoate, (E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)(3-(trifluoromethoxy)phenyl)methanone, (E)-phenyl(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methanone, (E)-benzo[d][1,3]dioxol-5-yl(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methanone, (E)-3-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1-carbonyl)benzonitrile, (E)-4-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1-carbonyl)benzonitrile, (E)-4-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1-carbonyl)benzoic acid, (E)-cyclohexyl(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methanone, (E)-1-(4-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1-carbonyl)piperidin-1-yl)ethanone, (E)-(3-(2-(furan-2-yl)vinyl)-1H-pyrazol-1-yl)(1-methyl-1H-pyrrol-2-yl)methanone, (E)-2-cyclopentyl-1-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)ethanone, (E)-2-(4-chlorophenyl)-1-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)ethanone, (E)-(6-chloropyridin-3-yl)(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methanone, (E)-3-(3-(2-(1H-pyrrol-2-yl)vinyl)-1H-pyrazol-1-yl)benzonitrile, (E)-3-(3-(2-(furan-3-yl)vinyl)-1H-pyrazole-1-carbonyl)benzonitrile, (E)-3-(3-(2-(1H-pyrrol-3-yl)vinyl)-1H-pyrazole-1-carbonyl)benzonitrile, (E)-3-(3-(2-(thiophen-3-yl)vinyl)-1H-pyrazole-1-carbonyl)benzonitrile. 
     
     
         35 . An orally bioavailability solid dosage form comprising about 10-20% (w/w) of a compound having the structure of Formula (A): 
       
         
           
           
               
               
           
         
         tautomer thereof; or pharmaceutically acceptable derivative thereof; 
         wherein m is an integer from 1-3 and [C═C] m  for each occurrence is independently cis or trans; 
         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; 
         q is one or two; and 
         each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO 2 , —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety; —OR R , —S(═O) n R d , —NR b R c , and —C(═O)R a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety; 
         R a , for each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl; 
         R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl; 
         R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; optionally substituted aliphatic, aryl and heteroaryl; and 
         R e , for each occurrence, is independently hydrogen or optionally substituted aliphatic; 
         further comprising about 10-20% (w/w) GELUCIRE® 44/14, about 10-20% (w/w) vitamin E TPS, 0 to about 60% polyethylene glycol 400, 0 to about 40% Lubrizol, 0 to about 15% Cremophor RH 40 (w/w), and about 1% (w/w) BHT. 
       
     
     
         36 . An orally bioavailable solid dosage form comprising a compound having the structure of Formula (A): 
       
         
           
           
               
               
           
         
         tautomer thereof; or pharmaceutically acceptable derivative thereof; 
         wherein m is an integer from 1-3 and [C═C] m  for each occurrence is independently cis or trans; 
         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; 
         q is one or two; and 
         each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO 2 , —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety; —OR R , —S(═O) n R d , —NR b R c , and —C(═O)R a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety; 
         R a , for each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl; 
         R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl; 
         R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; optionally substituted aliphatic, aryl and heteroaryl; and 
         R e , for each occurrence, is independently hydrogen or optionally substituted aliphatic; 
         and mannitol, optionally in combination with lactobionic acid, gluconic acid, methanesulfonic acid, or any combination thereof. 
       
     
     
         37 . An orally bioavailable solid dosage form comprising a compound having the structure of Formula (A): 
       
         
           
           
               
               
           
         
         tautomer thereof; or pharmaceutically acceptable derivative thereof; 
         wherein m is an integer from 1-3 and [C═C] m  for each occurrence is independently cis or trans; 
         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; 
         q is one or two; and 
         each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO 2 , —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety; —OR R , —S(═O) n R d , —NR b R c , and —C(═O)R a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety; 
         R a , for each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl; 
         R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl; 
         R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; optionally substituted aliphatic, aryl and heteroaryl; and 
         R c , for each occurrence, is independently hydrogen or optionally substituted aliphatic; 
         and oleic acid, in combination with crystalline cellulose, pregelatinized starch, or any combination thereof. 
       
     
     
         38 . An orally bioavailable solid dosage form comprising about 10-20% (w/w) of a compound having the structure of Formula (B): 
       
         
           
           
               
               
           
         
         C(5)-positional isomer thereof; or a prodrug, salt, hydrate, or ester thereof; 
         wherein R 1  is SO 2 AL 2 , C(═O)(CH 2 ) m AL 2 , C(═O)OAL 2 , C(═O)NHAL 2 , SO 2 Aryl, C(═O)(CH 2 ) m Aryl, C(═O)OAryl, C(═O)Oheterocyclic, C(═O)(CH 2 ) m Heterocyclic, or C(═O)NHAryl; wherein m is an integer from 0-3; AL 2  is an aliphatic or alicyclic moiety; and AL 2 , the aryl and heterocyclic moiety are independently optionally substituted with one or more substituents independently selected from hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; or COCH 2 OC 2 H 5 OCH 3 ; and 
         R 3  is a cis or trans CHCHAryl, CHCHHeterocyclic, phenoxyphenyl, or a heterocyclic group, wherein the aryl, heterocyclic or phenoxyphenyl moiety may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; 
         wherein R a  is selected from the group consisting of hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6  alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         R b  and R c  are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         R d  is selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and 
         R e  is hydrogen or C 1-6  alkyl; 
         further comprising about 10-20% (w/w) GELUCIRE® 44/14, about 10-20% (w/w) vitamin E TPS, 0 to about 60% polyethylene glycol 400, 0 to about 40% Lubrizol, 0 to about 15% Cremophor RH 40 (w/w), and about 1% (w/w) BHT. 
       
     
     
         39 . An orally bioavailable solid dosage form comprising a compound having the structure of Formula (B): 
       
         
           
           
               
               
           
         
         C(5)-positional isomer thereof; or a prodrug, salt, hydrate, or ester thereof; 
       
       wherein R 1  is SO 2 AL 2 , C(═O)(CH 2 ) m AL 2 , C(═O)OAL 2 , C(═O)NHAL 2 , SO 2 Aryl, C(═O)(CH 2 ) m Aryl, C(═O)OAryl, C(═O)Oheterocyclic, C(═O)(CH 2 ) m Heterocyclic, or C(═O)NHAryl; wherein m is an integer from 0-3; AL 2  is an aliphatic or alicyclic moiety; and AL 2 , the aryl and heterocyclic moiety are independently optionally substituted with one or more substituents independently selected from hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; or COCH 2 OC 2 H 5 OCH 3 ; and
 R 3  is a cis or trans CHCHAryl, CHCHHeterocyclic, phenoxyphenyl, or a heterocyclic group, wherein the aryl, heterocyclic or phenoxyphenyl moiety may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6 alkoxy, aryl, heteroaryl and heterocyclyl; 
 wherein R a  is selected from the group consisting of hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6  alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
 R b  and R c  are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
 R d  is selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and 
 R e  is hydrogen or C 1-6  alkyl; 
 and mannitol, optionally in combination with lactobionic acid, gluconic acid, methanesulfonic acid, or any combination thereof. 
 
     
     
         40 . An orally bioavailable solid dosage form comprising a compound having the structure of Formula (B): 
       
         
           
           
               
               
           
         
         C(5)-positional isomer thereof; or a prodrug, salt, hydrate, or ester thereof; 
         wherein R 1  is SO 2 AL 2 , C(═O)(CH 2 ) m AL 2 , C(═O)OAL 2 , C(═O)NHAL 2 , SO 2 Aryl, C(═O)(CH 2 ) m Aryl, C(═O)OAryl, C(═O)Oheterocyclic, C(═O)(CH 2 ) m Heterocyclic, or C(═O)NHAryl; wherein m is an integer from 0-3; AL 2  is an aliphatic or alicyclic moiety; and AL 2 , the aryl and heterocyclic moiety are independently optionally substituted with one or more substituents independently selected from hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; or COCH 2 OC 2 H 5 OCH 3 ; and 
         R 3  is a cis or trans CHCHAryl, CHCHHeterocyclic, phenoxyphenyl, or a heterocyclic group, wherein the aryl, heterocyclic or phenoxyphenyl moiety may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen; halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)R a , —NR b R c , or —S(O) n R d  where n=0-2; C 1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen and C 1-6  alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring containing 0-3 heteroatoms selected from the group consisting of N, O, and S; C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, or C 3-6  cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and further optionally substituted with 1-3 substituents independently selected from the group consisting of —C(═O)R a , —NR b R c , —S(O) n R d  where n=0-2, hydroxy, C 1-6  alkoxy, haloC 1-6  alkoxy, aryl, heteroaryl and heterocyclyl; 
         wherein R a  is selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, C 1-6  alkoxy, aryl, heteroaryl, and NR b R c , wherein C 1-6  alkyl and C 1-6  alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         R b  and R c  are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; C 1-6  alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro and N(R e ) 2 ; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4  alkyl, C 1-5  alkoxy, nitro, and N(R e ) 2 ; 
         R d  is selected from the group consisting of hydrogen; N(R e ) 2 ; C 1-6  alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-5  alkoxy, nitro, and N(R e ) 2 ; aryl and heteroaryl; and 
         R e  is hydrogen or C 1-6  alkyl; 
         and oleic acid, in combination with crystalline cellulose, pregelatinized starch, or any combination thereof. 
       
     
     
         41 . The method for treating or lessening the severity of a disease or condition selected from fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease or lung (pulmonary) fibrosis; liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; renal failure; renal fibrosis; idiopathic pulmonary fibrosis; treatment of wounds for acceleration of healing; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; muscular dystrophy, amyotrophic lateral sclerosis, and/or diabetes mellitus; comprising administering a composition or solid dosage form of any one of  claims 1 - 40 . 
     
     
         42 . A method for treating or lessening the severity of a disease or condition selected from fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease or lung (pulmonary) fibrosis, liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; renal failure; renal fibrosis, idiopathic pulmonary fibrosis, acceleration of wound healing; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; muscular dystrophy, amyotrophic lateral sclerosis, and/or diabetes mellitus;
 which method comprises administering the composition or solid dosage form of any one of  claims 1 - 40 , a compound of Formula A of  claim 1  or a compound of Formula B of  claim 19 , said administering first provided at a time after the initial injury or onset of disease.   
     
     
         43 . The method of  claim 42  wherein the time is at least 3 hours after the initial injury or onset of said disease. 
     
     
         44 . The method of  claim 43  wherein the time is at least 24 hours after the initial injury or onset of said disease. 
     
     
         45 . The method of  claim 44  wherein the time is at least one week after the initial injury or onset of said disease. 
     
     
         46 . A method for treating muscular dystrophy in a subject in need thereof comprising administering to the subject an effective amount of the composition or solid dosage form of any one of  claims 1 - 40 , a compound of Formula A of  claim 1  or a compound of Formula B of  claim 19 . 
     
     
         47 . A method for treating amyotrophic lateral sclerosis in a subject in need thereof comprising administering to the subject an effective amount of the composition or solid dosage form of any one of  claims 1 - 40 , a compound of Formula A of  claim 1  or a compound of Formula B of  claim 19 .