Modulators of ATP-Binding Cassette Transporters

Abstract

The present invention provides compounds of Formula I useful as modulators of ABC transporter activity, or a pharmaceutically acceptable salt thereof, wherein R B , n, B, R C , R D , R E , A, and Z are described generally and in classes and subclasses below. The present invention also provides pharmaceutical compositions, methods and kits associated with Formula I, useful for as modulators, and for the treatments of disease and disease conditions associated with ABC transporter proteins.

1 - 44 . (canceled) 
   
   
       45 . A method of modulating ABC transporter activity comprising the step of contacting said transporter with a compound of formula I or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 A is C(O), or SO 2 ; 
 R C  and R D  are independently selected from H, (C1-C4)alkyl, and aryl, or may be taken together to form a (C3-C8)cycloalkyl or heterocyclic; 
 R E  is H, (C1-C4)alkyl optionally substituted with a substituent selected from CN, NO 2 , CF 3 , OCF 3 , OH, SR 6 , S(O)R 6 , SO 2 R 6 , COOH, COOR 6 , OR 6  or phenyl optionally substituted with R Z ; 
 B is aryl or heterocyclic; 
 Z is 
 
     
       
         
         
             
             
         
       
       
         wherein,
 L is (C1-C6)alkylidene, —O—((C1-C6)alkylidene), ((C1-6)alkylidene)-O—, or a bond, wherein up to two carbon atoms in said alkylidene in L are independently replaced with O, S, or N; 
 W is aryl, heterocyclic, or (C5-C7)cycloalkyl; 
 
       
       m and n are independently 0 to 5; and 
       R B  and R Z  are independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 , wherein:
 R 1  is oxo, R 6  or ((C1-C4)aliphatic) n Y; 
 n is 0 or 1; 
 Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, SR 6 , S(O)R 6 , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , N(R 8 ) 2 , COOH, COOR 6  or OR 6 ; or two R 1  on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy; 
 R 2  is aliphatic, wherein each R 2  optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ; 
 R 3  is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4  or R 5 ; 
 R 4  is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), SR 6 , SR 5 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , SO 3 R 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 5 C(O)R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 5 , NR 5 SO 2 R 6 , NR 6 SO 2 N(R 6 ) 2 , NR 5 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ; 
 R 5  is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1  substituents; 
 R 6  is H or aliphatic, wherein R 6  optionally comprises a R 7  substituent; 
 R 7  is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7  optionally comprises up to 2 substituents independently chosen from H, (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 ) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n -Q; 
 Q is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 -aliphatic, NH 2 , NH(aliphatic), N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , N(R 8 ) 2 , COOH, C(O)O-(aliphatic), or O-aliphatic; and 
 R 8  is an amino protecting group 
 provided that when L is a bond, R E  is hydrogen and A is C(O), then the following compound is excluded: 
 
     
     
       
         
               
               
               
             
                   
               
                   
                 ring W together with R Z   
                   
               
                 R C  & R D  together 
                 and m 
                 ring B with R B  & n 
               
                   
               
                 cyclopentyl 
                 benzofuran-2-yl 
                 3,4-dimethoxyphenyl 
               
                   
               
           
              
              
              
              
             
             
              
              
             
          
         
       
     
   
   
       46 . (canceled) 
   
   
       47 . The method according to  claim 45 , wherein said disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-cibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, secretory diarrhea or polycystic kidney disease, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease (due to Prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's disease. 
   
   
       48 . The method according to  claim 45 , wherein said disease is cystic fibrosis. 
   
   
       49 . A method of modulating activity of an anion channel in vitro or in vivo, comprising the step of contacting said channel with a compound according to  claim 45 . 
   
   
       50 . The method according to  claim 49 , wherein said anion channel is a chloride channel or a bicarbonate channel. 
   
   
       51 . The method according to  claim 50 , wherein said anion channel is a chloride channel. 
   
   
       52 . A method of treating an anion channel mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound according to  claim 45 . 
   
   
       53 . The method according to  claim 52 , wherein said disease is cystic fibrosis. 
   
   
       54 . (canceled) 
   
   
       55 . A kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo, comprising:
 (i) a composition comprising a compound according to  claim 45 ; and   (ii) instructions for:
 a) contacting the composition with the biological sample; 
 b) measuring activity of said ABC transporter or a fragment thereof. 
   
   
   
       56 . The kit according to  claim 55 , wherein said ABC transporter is CFTR.