Modulators of atp-binding cassette transporters

Abstract

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

What is claimed is: 
     
         1 - 58 . (canceled) 
     
     
         59 . 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 of formula I   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Ar 1  is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar 1  has m substituents, each independently selected from —WR W ; 
         wherein each occurrence of WR W  is selected from halo, cyano, CF 3 , CHF 2 , OCHF 2 , Me, Et, CH(Me) 2 , CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh, O-fluorophenyl, O-difluorophenyl, O-methoxyphenyl, O-tolyl, O-benzyl, SMe, SCF 3 , SCHF 2 , SEt, CH 2 CN, NH 2 , NHMe, N(Me) 2 , NHEt, N(Et) 2 , C(O)CH 3 , C(O)Ph, C(O)NH 2 , SPh, SO 2 -(amino-pyridyl), SO 2 NH 2 , SO 2 Ph, SO 2 NHPh, SO 2 —N-morpholino, SO 2 —N-pyrrolidyl, N-pyrrolyl, N-morpholino, 1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl, 4-Methyl-2,4-dihydro-pyrazol-3-one-2-yl, benzimidazol-2yl, furan-2-yl, 4-methyl-4H-[1,2,4]triazol-3-yl, 3-(4′-chlorophenyl)-[1,2,4]oxadiazol-5-yl, NHC(O)Me, NHC(O)Et, NHC(O)Ph, 2-indolyl, 5-indolyl, —CH 2 CH 2 OH, —OCF 3 , O-(2,3-dimethylphenyl), 5-methylfuryl, —SO 2 —N-piperidyl, 2-tolyl, 3-tolyl, 4-tolyl, O-butyl, NHCO 2 C(Me) 3 , CO 2 C(Me) 3 , isopropenyl, n-butyl, O-(2,4-dichlorophenyl), NHSO 2 PhMe, O-β-chloro-5-trifluoromethyl-2-pyridyl), phenylhydroxymethyl, 2,5-dimethylpyrrolyl, NHCOCH 2 C(Me) 3 , O-(2-tert-butyl)phenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 4-hydroxymethyl phenyl, 4-dimethylaminophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-cyanomethylphenyl, 4-isobutylphenyl, 3-pyridyl, 4-pyridyl, 4-isopropylphenyl, 3-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-methylthiophenyl, 4-methylthiophenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 5-chloro-2-methoxyphenyl, 2-OCF 3 -phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 4-phenoxyphenyl, 2-fluoro-3-methoxy-phenyl, 2,4-dimethoxy-5-pyrimidyl, 5-isopropyl-2-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluoro-phenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonyl phenyl, 3-isopropyloxycarbonylphenyl, 3-acetamidophenyl, 4-fluoro-3-methylphenyl, 4-methanesulfinyl-phenyl, 4-methanesulfonyl-phenyl, 4-N-(2-N,N-dimethylaminoethyl)carbamoylphenyl, 5-acetyl-2-thienyl, 2-benzothienyl, 3-benzothienyl, furan-3-yl, 4-methyl-2-thienyl, 5-cyano-2-thienyl, N′-phenylcarbonyl-N-piperazinyl, —NHCO 2 Et, —NHCO 2 Me, N-pyrrolidinyl, —NHSO 2 (CH 2 ) 2  N-piperidine, —NHSO 2 (CH 2 ) 2  N-morpholine, —NHSO 2 (CH 2 ) 2 N(Me) 2 , COCH 2 N(Me)COCH 2 NHMe, —CO 2 Et, O-propyl, —CH 2 CH 2 NHCO 2 C(Me) 3 , hydroxy, aminomethyl, pentyl, adamantyl, cyclopentyl, ethoxyethyl, C(Me) 2 CH 2 OH, C(Me) 2 CO 2 Et, —CHOHMe, CH 2 CO 2 Et, —C(Me) 2 CH 2 NHCO 2 C(Me) 3 , O(CH 2 ) 2 OEt, O(CH 2 ) 2 OH, CO 2 Me, hydroxymethyl, 1-methyl-1-cyclohexyl, 1-methyl-1-cyclooctyl, 1-methyl-1-cycloheptyl, C(Et) 2 C(Me) 3 , C(Et) 3 , CONHCH 2 CH(Me) 2 , 2-aminomethyl-phenyl, ethenyl, 1-piperidinylcarbonyl, ethynyl, cyclohexyl, 4-methylpiperidinyl, —OCO 2 Me, —C(Me) 2 CH 2 NHCO 2 CH 2 CH(Me) 2 , —C(Me) 2 CH 2 NHCO 2 CH 2 CH 2 CH 3 , —C(Me) 2 CH 2 NHCO 2 Et, —C(Me) 2 CH 2 NHCO 2 Me, —C(Me) 2 CH 2 NHCO 2 CH 2 C(Me) 3 , —CH 2 NHCOCF 3 , —CH 2 NHCO 2 C(Me) 3 , —C(Me) 2 CH 2 NHCO 2 (CH 2 ) 3 CH 3 , C(Me) 2 CH 2 NHCO 2 (CH 2 ) 2 OMe, C(OH) (CF 3 ) 2 , —C(Me) 2 CH 2 NHCO 2 CH 2 -tetrahydrofuran-3-yl, C(Me) 2 CH 2 O(CH 2 ) 2 OMe, or 3-ethyl-2,6-dioxopiperidin-3-yl; 
         m is 0-5; 
         each of R 1 , R 2 , R 3 , R 4 , and R 5  is independently —X—R X ; 
         X is a bond or is an optionally substituted C 1 -C 6  alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO 2 —, —OCO—, —NR′CO 2 —, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO 2 —, —NR′—, —SO 2 NR′—, NR′SO 2 —, or —NR′SO 2 NR′—; 
         R X  is independently R′, halo, NO 2 , CN, CF 3 , or OCF 3 ; 
         R 6  is hydrogen, CF 3 , —OR′, —SR′, or an optionally substituted C 1-6  aliphatic group; 
         R 7  is hydrogen; 
         R′ is independently selected from hydrogen or an optionally substituted group selected from a C 1 -C 8  aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         provided that the following compounds of  FIG. 1  are excluded: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
          and 
         (ii) instructions for:
 a) contacting the composition with the biological sample; and 
 b) measuring activity of said ABC transporter or a fragment thereof. 
 
       
     
     
         60 . The kit of  claim 59 , further comprising instructions for
 a) contacting an additional composition with the biological sample;   b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and   c) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of formula I.   
     
     
         61 . The kit of  claim 59 , wherein the kit is used to measure the density of CFTR.