HIF-1 Inhibitors

Abstract

HIF-1 inhibitors and methods of their use are provided. In particular, 2,2-dimethylbenzopyran based compounds and methods of their use, for example in the treatment or prevention of hypoxia-related pathologies are provided.

1 - 76 . (canceled) 
   
   
       77 . A pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, in an amount sufficient to inhibit intracellular HIF-1 activity, wherein formula I comprises a 2,2 dimethylbenzopyran moiety, wherein R 1  is O, and R 2  and R 6  are each H, and is: 
     
       
         
         
             
             
         
       
     
     wherein
 R 3  is selected from the group consisting of: an imidazole; a benzimidazole, a substituted benzimidazole, a pyridinoimidazole, a biphenylcarboxylate, and Z, wherein Z is selected from the group consisting of: —N(C(O)NH 2 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 NH 2 ; —N(CH 2 )NH 2 )(C(O)CH 2 CH 3 ), —N(CH 3 )(C(O)CH 2 NH 2 , and —N(C(O)NH 2 )pyridine; 
 R 4 , is selected from the group consisting of: H, a branched C 1-4  alkyl, an unbranched C 1-4  alkyl, alkenyl, alkoxy, aryl, a heterocycle, an alkyl substituted aryl, and a halo-substituted aryl; and 
 R 5  is H, methoxy (MeO), or an alkyl or alkenyl group linked to R 4 , thereby forming an aryl group. 
 
   
   
       78 . The pharmaceutical composition of  claim 77 , wherein R 5  is H or methoxy (MeO). 
   
   
       79 . The pharmaceutical composition of  claim 78 , wherein in the compound of formula I, R 3  is further selected from the group consisting of: imidazole, N-ethylurea, N-methylethane-1,2-diamine; N-acetamide, N 1 -methylglycinamide, pyridinoimidazole, N-pyridinylurea, 4-chloro-1-benzimidazole, benzimidazole, 2-methyl-1H-benzimidazole, and biphenyl-4-carboxylate. 
   
   
       80 . The pharmaceutical composition of  claim 78 , wherein in the compound of formula I, R 4  is selected from the group consisting of: 4-methylphenyl, 3-methoxyphenyl, 4-fluoro-3-methylphenyl, 4-chlorophenyl, phenyl)methyl, methyl, 3-methylbutyl, cyclohexyl, prop-2-en-1-yl, 3-hydroxyphenyl, 4-tert-butylphenyl, and phenyl. 
   
   
       81 . The pharmaceutical composition of  claim 78 , wherein the compound of formula I is selected from the group consisting of:
 1-[(2,2-dimethyl-2H-chromen-6-yl)(phenyl)methyl]-1H-imidazole;   1-[(2,2-dimethyl-4a,8a-dihydro-2H-chromen-6-yl)(4-methylphenyl)methyl]-1H-imidazole;   1-[(2,2-dimethyl-2H-chromen-6-yl)(3-methoxyphenyl)methyl]-1H-imidazole;   1-[(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)(4-methylphenyl)methyl]-1H-imidazole;   1-[(2,2-dimethyl-2H-chromen-6-yl)(4-fluoro-3-methylphenyl)methyl]-1H-imidazole;   1-[(4-chlorophenyl)(2,2-dimethyl-2H-chromen-6-yl)methyl]-1H-imidazole;   1-[(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)(phenyl)methyl]-1H-imidazole;   1-[1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methylbutyl]-1H-imidazole;   1-[1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethyl]-1H-imidazo[4,5-b]pyridine;   1-[1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methylbutyl]-1H-imidazo[4,5-b]pyridine;   4-chloro-1-[cyclohexyl(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-1H-benzimidazole;   1-[cyclohexyl(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-1H-benzimidazole;   1-[1-(2,2-dimethyl-2H-chromen-6-yl)prop-2-en-1-yl]-2-methyl-1H-benzimidazole;   (2,2-dimethyl-2H-chromen-6-yl)(3-hydroxyphenyl)methyl biphenyl-4-carboxylate;   1-[(4-tert-butylphenyl)(2,2-dimethyl-4a,8a-dihydro-2H-chromen-6-yl)methyl]-1H-imidazole;   N-[(2,2-dimethyl-4a,8a-dihydro-2H-chromen-6-yl)(phenyl)methyl]-N-ethylurea;   N-[(2,2-dimethyl-4a,8a-dihydro-2H-chromen-6-yl)(phenyl)methyl]-N-methylethane-1,2-diamine;   N-(aminomethyl)-N-[(2,2-dimethyl-4a,8a-dihydro-2H-chromen-6-yl)(phenyl)methyl]acetamide; and   N 1 -[(2,2-dimethyl-4a,8a-dihydro-2H-chromen-6-yl)(phenyl)methyl]-a-methylglycinamide.   
   
   
       82 . The pharmaceutical composition of  claim 78 , wherein the compound is 1-[1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethyl]-1H-imidazo[4,5-b]pyridine; and has the formula II: 
     
       
         
         
             
             
         
       
     
   
   
       83 . The pharmaceutical composition of  claim 78 , comprising a hydrolysis, oxidation, or reduction reaction product of any of the compounds of claim  1 . 
   
   
       84 . The pharmaceutical composition of  claim 83 , wherein the hydrolysis, oxidation, or reduction reaction opens a nitrogen-containing ring of any of the compounds of claim  1 . 
   
   
       85 . The pharmaceutical composition of  claim 77 , comprising a compound of formula I wherein R 4  and R 5  are linked, thereby forming an aryl group, or a pharmaceutically acceptable salt or prodrug thereof, and in an amount sufficient to inhibit intracellular HIF-1 activity, wherein formula III comprises a 2,2 dimethylbenzopyran fused with a benzo group and is: 
     
       
         
         
             
             
         
       
       R 6  is selected from the group consisting of: an imidazole; a benzimidazole, a substituted benzimidazole, a pyridinoimidazole, a biphenylcarboxylate, and Z, wherein Z is selected from the group consisting of: —N(C(O)NH 2 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 NH 2 ; —N(CH 2 )NH 2 )(C(O)CH 2 CH 3 ), —N(CH 3 )(C(O)CH 2 NH 2 , and —N(C(O)NH 2 )pyridine; 
       R 7 , is selected from the group consisting of: H, a branched or unbranched C 1-4  alkyl, alkenyl, alkoxy, aryl, a heterocycle, an alkyl substituted aryl, and a halo substituted aryl. 
     
   
   
       86 . The pharmaceutical composition of  claim 85 , wherein the compound of formula II is selected from the group consisting of:
 1-[(3,3-dimethyl-7,10-dihydro-3H-benzo[f]chromen-8-yl)(4-fluoro-3-methylphenyl)methyl]-1H-imidazole;   1-[(3,3-dimethyl-7,10-dihydro-3H-benzo[f]chromen-8-yl)(3-methoxyphenyl)methyl]-1H-imidazole;   1-[(3,3-dimethyl-7,10-dihydro-3H-benzo[f]chromen-8-yl)(4-methylphenyl)methyl]-1H-imidazole; and   1-[1-(3,3-dimethyl-7,10-dihydro-3H-benzo[t]chromen-8-yl)-3-methylbutyl]-1H-imidazo[4,5-b]pyridine.   
   
   
       87 . A pharmaceutical composition comprising a compound selected from the group consisting of:
 1-[(8-methoxy-2,2-dimethyl-2H-chromen-7-yl)(phenyl)methyl]-1H-imidazo[4,5-b]pyridine;   N-isopropyl-3,4-dimethoxy-N-[(8-methoxy-2,2-dimethyl-2H-chromen-7-yl)methyl]benzenesulfonamide; and   1-[cyclohexyl(2,2,6-trimethyl-2H-chromen-8-yl)methyl]-1H-benzimidazole;   
     or a pharmaceutically acceptable salt or prodrug thereof, and in an amount sufficient to inhibit intracellular HIF-1 activity.