Small molecule modulators of cytokine activity

Abstract

The present invention provides compounds having formula (I) or (II): and pharmaceutically acceptable derivatives thereof, wherein m, p, R 1 , R 2 , R 3 and R 4 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 diseases, disorders or conditions associated with HGF/SF or other cytokine activity.

1 - 71 . (canceled) 
   
   
       72 - 108 . (canceled) 
   
   
       109 . An isolated compound having the structure: 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt, ester, or salt of such an ester thereof; 
       wherein Cy is an N-linked 5- to 10-membered heterocyclic or heteroaryl group other than an optionally substituted homopiperidinyl group, wherein Cy is optionally substituted with p occurrences of R 4 ; 
       p is an integer from 1 to 6; 
       each occurrence of R 4  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, or acyl moiety; 
       m is an integer from 1 to 4; 
       each occurrence of R 4  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R a , for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety; 
       R b  and R c , for each occurrence, are independently hydrogen, hydroxy, SO 2 R d , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R d , for each occurrence, is independently hydrogen, —N(R e ) 2 , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; and 
       R e , for each occurrence, is independently hydrogen or aliphatic; 
       with the proviso that the compound does not have one of the following structures: 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         wherein p and R 4  are as defined above, 
       
     
     
       
         
         
             
             
         
       
       wherein R 4A  is hydrogen, methyl, methoxy, 
       chloro or —NO 2 , 
     
   
   
       110 . The compound of  claim 109 , wherein Cy is one of: 
     
       
         
         
             
             
         
       
     
     wherein:
 q is 1, 2 or 4; and 
 R 4A  is hydrogen, hydroxyl, SO 2 R d , or an alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl moiety. 
 
   
   
       111 . The compound of  claim 109 , wherein Cy is one of: 
     
       
         
         
             
             
         
       
     
     wherein:
 q is 1, 2 or 4; and 
 R 4A  is hydrogen, hydroxyl, SO 2 R d , or an alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl moiety. 
 
   
   
       112 . The compound of  claim 109 , wherein:
 each occurrence of R 4  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl moiety;   each occurrence of R 1  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl moiety;   wherein R a , for each occurrence, is independently hydrogen or an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety;   R b  and R c , for each occurrence, are independently hydrogen, hydroxy, SO 2 R d , or an alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl moiety;   R d , for each occurrence, is independently hydrogen, —N(R e ) 2 , alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; and   R e , for each occurrence, is independently hydrogen or alkyl.   
   
   
       113 . The compound of  claim 109 , having the structure: 
     
       
         
         
             
             
         
       
       wherein q is 1, 2, or 4. 
     
   
   
       114 . The compound of  claim 109 , having one of the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       115 . The compound of  claim 109 , wherein at least one occurrence of —R 1  is —NO 2 . 
   
   
       116 . The compound of  claim 109 , wherein at least one occurrence of R 1  is —NH 2 . 
   
   
       117 . The compound of  claim 109 , wherein at least one occurrence of R 1  is —COOH, —C(═O)OCH 3 , —COCH 3 , —CONH 2 , —SO 2 OH, —SO 2 CH 3 , —SO 2 CF 3 , —OPO 2 OH, —NHC(═O)CH 3 , —NHC(═O)CF 3 , —NHSO 2 CH 3  or —NHSO 2 CF 3 . 
   
   
       118 . The compound of  claim 109 , wherein at least one occurrence of R 1  is halogen. 
   
   
       119 . The compound of  claim 109 , wherein at least one occurrence of R 1  is an optionally substituted N-linked heterocyclic group. 
   
   
       120 . The compound of  claim 119 , wherein the N-linked heterocyclic group is an optionally substituted N-pyrrolyl. 
   
   
       121 . The compound of  claim 109 , wherein at least one occurrence of R 1  is an aliphatic moiety. 
   
   
       122 . The compound of  claim 109 , wherein at least one occurrence of R 1  is a lower alkyl moiety. 
   
   
       123 . The compound of  claim 109 , wherein at least one occurrence of R 4  is an aliphatic group. 
   
   
       124 . The compound of  claim 109 , wherein each occurrence of R 4  is independently an aliphatic group. 
   
   
       125 . The compound of  claim 124 , wherein the aliphatic group is an optionally substituted cyclic or acyclic C 6-12  alkyl, C 6-12  alkenyl, or C 6-12  alkynyl group. 
   
   
       126 . The compound of  claim 124 , wherein the aliphatic group is an optionally substituted -(alkyl)aryl group. 
   
   
       127 . The compound of  claim 109 , wherein at least one occurrence of R 4  is —NR b R c ; wherein R b  and R c  are independently hydrogen, hydroxy, SO 2 R d , or an alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl moiety; R d  is hydrogen, —N(R e ) 2 , alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; and R e  is hydrogen or alkyl. 
   
   
       128 . The compound of  claim 109 , wherein at least one occurrence of R 4  is —NH 2 . 
   
   
       129 . The compound of  claim 109 , wherein at least one occurrence of R 4  is —C(═O)OR a ; wherein R a  is hydrogen or an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety. 
   
   
       130 . The compound of  claim 109 , wherein at least one occurrence of R 4  is —CO 2 H. 
   
   
       131 . The compound of  claim 109 , wherein m is 0 or 1. 
   
   
       132 . The compound of  claim 109 , wherein p is 0 or 1. 
   
   
       133 . A pharmaceutical composition comprising:
 a pharmaceutically acceptable carrier, adjuvant or vehicle; and   a compound having the structure:   
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt, ester, or salt of such an ester thereof; 
       wherein Cy is an N-linked 5- to 10-membered heterocyclic or heteroaryl group other than an optionally substituted homopiperidinyl group, wherein Cy is optionally substituted with p occurrences of R 4 ; 
       p is an integer from 1 to 6; 
       each occurrence of R 4  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, or acyl moiety; 
       m is an integer from 1 to 4; 
       each occurrence of R 1  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R a , for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety; 
       R b  and R c , for each occurrence, are independently hydrogen, hydroxy, SO 2 R d , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R d , for each occurrence, is independently hydrogen, —N(R e ) 2 , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; and 
       R e , for each occurrence, is independently hydrogen or aliphatic; 
     
     with the proviso that the compound does not have one of the following structures: 
     
       
         
         
             
             
         
       
     
     wherein R 4A  is hydrogen, methyl, wherein p and R 4  are as defined above methoxy, chloro or —NO 2    
   
   
       134 . A method for:
 agonizing HGF/SF activity;   agonizing c-met;   stimulating cell proliferation;   promoting angiogenic activity,   promoting the formation of new blood vessels;   inducing proliferation of epithelial cells, neuronal cells, Schwann cells or oligodendrocyte cells;   promoting axonal growth;   inducing myelin production; and/or   reducing fibrosis;   in a subject comprising:   administering to a subject in need thereof, optionally with a pharmaceutically acceptable carrier, adjuvant or vehicle, a therapeutically effective amount of a compound having the structure:   
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt, ester, or salt of such an ester thereof; 
       wherein Cy is an N-linked 5- to 10-membered heterocyclic or heteroaryl group other than an optionally substituted homopiperidinyl group, wherein Cy is optionally substituted with p occurrences of R 4 ; 
       p is an integer from 1 to 6; 
       each occurrence of R 4  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, or acyl moiety; 
       m is an integer from 1 to 4; 
       each occurrence of R 1  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R a , for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety; 
       R b  and R c , for each occurrence, are independently hydrogen, hydroxy, SO 2 R d , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R d , for each occurrence, is independently hydrogen, —N(R e ) 2 , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; and 
       R e , for each occurrence, is independently hydrogen or aliphatic. 
     
   
   
       135 . A method for protecting from cell apoptosis in a subject comprising:
 administering to a subject in need thereof, optionally with a pharmaceutically acceptable carrier, adjuvant or vehicle, a therapeutically effective amount of a compound having the structure:   
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt, ester, or salt of such an ester thereof; 
       wherein Cy is an N-linked 5- to 10-membered heterocyclic or heteroaryl group other than an optionally substituted homopiperidinyl group, wherein Cy is optionally substituted with p occurrences of R 4 ; 
       p is an integer from 1 to 6; 
       each occurrence of R 4  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, or acyl moiety; 
       m is an integer from 1 to 4; 
       each occurrence of R 1  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R a , for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety; 
       R b  and R c , for each occurrence, are independently hydrogen, hydroxy, SO 2 R d , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R d , for each occurrence, is independently hydrogen, —N(R e ) 2 , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; and 
       R e , for each occurrence, is independently hydrogen or aliphatic; 
     
     with the proviso that the compound does not have the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       136 . A method for:
 agonizing HGF/SF activity;   agonizing c-met;   stimulating cell proliferation;   promoting angiogenic activity,   promoting the formation of new blood vessels;   inducing proliferation of epithelial cells, neuronal cells, Schwann cells or oligodendrocyte cells;   promoting axonal growth;   inducing myelin production; and/or   reducing fibrosis;   in a subject comprising:   administering to a subject in need thereof, optionally with a pharmaceutically acceptable carrier, adjuvant or vehicle, a therapeutically effective amount of a compound having the structure:   
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt, ester, or salt of such an ester thereof; 
       wherein m is an integer from 1 to 4; 
       each occurrence of R 1  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R 2  and R 3  are independently hydrogen, hydroxyl, —NH 2 , an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic or acyl moiety; 
       R a , for each occurrence, is independently selected from the group consisting of hydrogen and an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety; 
       R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic; and 
       R e , for each occurrence, is independently hydrogen or aliphatic. 
     
   
   
       137 . A method for protecting from cell apoptosis in a subject comprising:
 administering to a subject in need thereof a therapeutically effective amount of a compound having the structure:   
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt, ester, or salt of such an ester thereof; 
       wherein m is an integer from 1 to 4; 
       each occurrence of R 1  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R 2  and R 3  are independently hydrogen, hydroxyl, —NH 2 , an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R e , —C(═O)R a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic or acyl moiety; 
       R a , for each occurrence, is independently selected from the group consisting of hydrogen and an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety; 
       R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic; and 
       R e , for each occurrence, is independently hydrogen or aliphatic; 
       with the proviso that the compound does not have one of the following structures: 
     
     
       
         
         
             
             
         
       
     
   
   
       138 . A method for treating or lessening the severity of fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease or lung (pulmonary) fibrosis, multiple sclerosis or a neurodegenerative disease in a subject comprising administering to a subject in need thereof, optionally with a pharmaceutically acceptable carrier, adjuvant or vehicle, a therapeutically effective amount of a compound having the structure: 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt, ester, or salt of such an ester thereof; 
       wherein m is an integer from 1 to 4; 
       each occurrence of R 1  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R 2  and R 3  are independently hydrogen, hydroxyl, —NH 2 , an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic or acyl moiety; or R 2  and R 3  taken together with the nitrogen to which they are attached form an optionally substituted heteroaromatic or heterocyclic group other than an optionally substituted homopiperidinyl group comprising 4-10 ring members and 0-3 additional heteroatoms selected from the group consisting of O, N and S; the heteroaromatic or heterocyclic group optionally further substituted with one or more optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl groups; 
       R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic; and 
       R e , for each occurrence, is independently hydrogen or aliphatic; 
       with the proviso that the compound does not have one of the following structures: 
     
     
       
         
         
             
             
         
       
     
   
   
       139 . The method of  claim 138 , wherein the neurodegenerative disease is metachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus-Merzbacher disease or Alexander's disease. 
   
   
       140 . The method of  claim 138 , wherein the method is for treating or lessening the severity of a disease or condition selected from 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, traumatic head injury, spinal cord injury, and other cerebrovascular diseases; myocardial ischemia; atherosclerosis; peripheral vascular disease; cardiovascular diseases; diabetes; renal failure; renal fibrosis, lung fibrosis or idiopathic pulmonary fibrosis; and multiple sclerosis. 
   
   
       141 . The method of  claim 138 , wherein the method is for the treatment of wounds for acceleration of healing; promoting vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, or other tissues or 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; and/or diabetes mellitus. 
   
   
       142 . The method of  claim 138 , wherein the compound has the following structure: 
     
       
         
         
             
             
         
       
       wherein Cy is an N-linked 5- to 10-membered heterocyclic or heteroaryl group other than an optionally substituted homopiperidinyl group, wherein Cy is optionally substituted with p occurrences of R 4 . 
     
   
   
       143 . A method for treating or lessening the severity of liver disease, lung disease, fibrotic disease, renal fibrosis, renal fibrosis secondary to renal obstruction, renal trauma, liver fibrosis, lung fibrosis, idiopathic pulmonary fibrosis, radiocontrast nephropathy, promotion of vascularization of organs, peripheral vascular disease, 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, or inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiency), comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure: 
     
       
         
         
             
             
         
       
     
   
   
       144 . An isolated compound having the structure: 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt, ester, or salt of such an ester thereof; 
       wherein Cy is an N-linked pyrrolyl group optionally substituted with p occurrences of R 4 ; 
       p is 1, 3, or 4; 
       each occurrence of R 4  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       m is an integer from 1 to 4; 
       each occurrence of R 1  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R a , for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety; 
       R b  and R c , for each occurrence, are independently hydrogen, hydroxy, SO 2 R d , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R d , for each occurrence, is independently hydrogen, —N(R e ) 2 , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; and 
       R e , for each occurrence, is independently hydrogen or aliphatic. 
     
   
   
       145 . An isolated compound having the structure: 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt, ester, or salt of such an ester thereof; 
       wherein Cy is an N-linked pyrrolyl group optionally substituted with p occurrences of R 4 ; 
       p is 2; 
       each occurrence of R 4  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted C 2-20  aliphatic moiety, an optionally substituted alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       m is an integer from 1 to 4; 
       each occurrence of R 1  is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a  or —C(═O)OR a ; wherein n is 0-2, R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R a , for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety; 
       R b  and R c , for each occurrence, are independently hydrogen, hydroxy, SO 2 R d , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety; 
       R d , for each occurrence, is independently hydrogen, —N(R e ) 2 , or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; and 
       R e , for each occurrence, is independently hydrogen or aliphatic.