Inhibitors of beta-hydroxylase for treatment of cancer

Abstract

The present invention relates to compounds which modulate (e.g., inhibit) the activity of beta-hydrolase (e.g., ASPH), including novel 2-aryl-5-amino-3(2H)-furanone and 2-heteroaryl-5-amino-3(2H)-furanone compounds, pharmaceutical compositions thereof, methods for their synthesis, and methods of using these compounds to modulate the activity of ASPH in an a cell-free sample, a cell-based assay, and in a subject. Other aspects of the invention relate to use of the compounds disclosed herein to ameliorate or treat cell proliferation disorders.

1 - 39 . (canceled) 
     
     
         40 . A method for treating a cancer in which asparatyl (asparaginyl) beta-hydroxylase (ASPH) is overexpressed, comprising administering to a subject in need thereof a therapeutically efficient amount of a compound of Formula Ia or Ib: 
       
         
           
           
               
               
           
         
       
       or a salt, ester, metabolite, prodrug, or solvate thereof, wherein
 Ar 1  is substituted or unsubstituted C 6 -C 20  aryl or 5 to 20-membered heteroaryl; 
 X is C(O), C(S), or S(O) 2 ; 
 W 1  is a single bond, O, CR 50 R 51 , or NR 52  when X is CO and W 1  is a single bond, CR 50 R 51 , or NR 52  when X is SO 2 ; and 
 each of R 50 , R 51 , R 52 , and R 53  independently is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 2 -C 6  alkenyl, substituted or unsubstituted C 2 -C 6  alkynyl, substituted or unsubstituted C 6 -C 20  aryl, substituted or unsubstituted C 7 -C 26  arylalkyl, substituted or unsubstituted 5 to 20-membered heteroaryl, and substituted or unsubstituted 6-26 membered heteroarylalkyl, 
 wherein said compound inhibits ASPH enzyme activity. 
 
     
     
         41 . The method of  claim 40 , wherein the compound is of Formula IIa: 
       
         
           
           
               
               
           
         
       
       or a salt, ester, metabolite, prodrug, or solvate thereof, wherein
 each of Ar 1  and Ar 2  independently is unsubstituted C 6 -C 14  aryl, unsubstituted 5 to 14-membered heteroaryl, or C 6 -C 14  aryl or 5 to 14-membered heteroaryl each substituted with one or more substituents selected from the group consisting of halo, CN, NO 2 , NO, N 3 , OR a , NR a R b , C(O)R a , C(O)OR a , C(O)NR a R b , NRbC(O)R a , —S(O) b R a , —S(O) b NR a R b , or R S1 , in which R S1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 5- or 6-membered heteroaryl, or 4 to 12-membered heterocycloalkyl, b is 0, 1, or 2, each of R a  and R b , independently is H or R S2 , and R S2  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; and each of R S1  and R S2 , is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C(O)OH, C(O)O—C 1 -C 6  alkyl, CN, C 1 -C 6  alkyl, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         42 . (canceled) 
     
     
         43 . The method of  claim 40 , wherein R 53  is unsubstituted C 1 -C 6  alkyl or C 1 -C 6  alkyl substituted with one or more substituents selected from halo, OH, CN, and amino. 
     
     
         44 - 49 . (canceled) 
     
     
         50 . The method of  claim 40 , wherein R 53  is unsubstituted C 1 -C 6  alkyl or C 1 -C 6  alkyl substituted with one or more substituents selected from halo, OH, CN, and amino. 
     
     
         51 . The method of  claim 40 , wherein:
 X is S(O) 2  and W 1  is CR 50 R 51  or a single bond;   X is C(O) and W 1  is O; or   X is C(S) and W 1  is NR 52 .   
     
     
         52 . The method of  claim 40 , wherein each of R 50 , R 51 , and R 52  independently is H, unsubstituted C 1 -C 6  alkyl, or C 1 -C 6  alkyl substituted with one or more substituents selected from halo, OH, CN, and amino. 
     
     
         53 . The method of  claim 41 , wherein each of Ar 1  and Ar 2  independently is phenyl, naphthyl, or 5 to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, CN, NO 2 , NO, N 3 , OR a , NR a R b , C(O)R a , C(O)OR a , C(O)NR a R b , NRbC(O)R a , —S(O) b R a , —S(O) b NR a R b , or R S1 , in which R S1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 5- or 6-membered heteroaryl, or 4 to 12-membered heterocycloalkyl, b is 0, 1, or 2, each of R a  and R b , independently is H or R S2 , and R S2  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; and each of R S1  and R S2 , is optionally substituted with one or more substituents selected from the group consisting of halo, OH, oxo, C(O)OH, C(O)O—C 1 -C 6  alkyl, CN, C 1 -C 6  alkyl, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
     
     
         54 . The method of  claim 53 , wherein each of Ar 1  and Ar 2  independently is selected from phenyl, 1-naphthyl, 2-naphthyl, 2-furanyl, 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxymethylphenyl, 4-carboxymethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 4-chloro-2-fluorophenyl, and 5-chloro-2-fluorophenyl. 
     
     
         55 . The method of  claim 54 , wherein Ar 1  is selected from phenyl, 1-naphthyl, 2-naphthyl, 2-furanyl, 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxymethylphenyl, 4-carboxymethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 4-chloro-2-fluorophenyl, and 5-chloro-2-fluorophenyl. 
     
     
         56 . The method of  claim 40 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         57 . The method of  claim 40 , wherein the cancer comprises a solid tumor. 
     
     
         58 . The method of  claim 57 , wherein said ASPH is overexpressed on the surface of solid tumor. 
     
     
         59 . The method of  claim 40 , wherein the cancer comprises a hematologic tumor. 
     
     
         60 . The method of  claim 58 , wherein the solid tumor is a cancer of liver, pancreas, stomach, colon, breast, prostate, lung, or brain. 
     
     
         61 . The method of  claim 59 , wherein said solid tumor is a pancreatic cancer, hepatocellular cancer, cholangiocarcinoma, colon cancer, breast cancer, prostate cancer, lung cancer, and glioblastoma. 
     
     
         62 . The method of  claim 40 , wherein said compound is administered orally, intranasally, intravenously, intrathecally, intramuscularly, intrabronchially, intrarectally, intraocularly, intravaginally, or systemically. 
     
     
         63 . The method of  claim 60 , wherein said compound is delivered through blood-brain barrier. 
     
     
         64 . The method of  claim 40 , wherein said compound is administered at a dose of 0.01 to 50 milligrams/kilogram of body weight. 
     
     
         65 . The method of  claim 40 , wherein the subject is a human.