Modulators of atp-binding cassette transporters

Abstract

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

1 - 218 . (canceled) 
     
     
         219 . A method of treating cystic fibrosis in a mammal, comprising the step of administering to said mammal a compound of formula (II) or (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 X 1  is a bond, O, S, CF 2 , CH 2 , or NR; 
 R is H or R 2    
 A 1  is aryl or heteroaryl; 
 each B 1  is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or O; 
 wherein each A 1  or B 1  is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; 
 R 1  is 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 , 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 , 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 , or C(O)N(R 5 R 6 ); 
 R 5  is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1  substituents; and 
 R 6  is H or aliphatic; 
 
         provided that for compounds of formula (II):
 i) when both B 1  are simultaneously phenyl and X 1  is CH 2 , then A 1  is not 4-fluoro-phenyl, 4-phenyl-piperidyl, phenyl, 2,4-dichloro-phenyl, 4-methoxy-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 4-nitro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 2-chloro-phenyl, 1-naphthyl, 3-trifluoromethyl-phenyl, 2,3-dichlorophenyl, N-morpholinyl, 4-chloro-phenyl, 3-chloro-phenyl, or 3-nitro-phenyl; and 
 (ii) when X 1  is a bond, then A 1  is not an optionally substituted 6-membered heteroaryl ring with 1-3 nitrogen ring atoms; and 
 
         provided that for compounds of formula (III):
 (i) when X 1  is a bond, one B 1  is phenyl and the other B 1  is N-piperidyl, then A 1  is not; 
 
       
       
         
           
           
               
               
           
         
         
            and 
           (ii) when X 1  is a bond, then A 1  is not an optionally substituted 6-membered heteroaryl ring with 1-3 nitrogen ring atoms. 
         
       
     
     
         220 - 230 . (canceled) 
     
     
         231 . The method according to  claim 219 , wherein X 1  is CH 2 , CF 2 , or O. 
     
     
         232 . The method according to  claim 219 , wherein X 1  is CH 2 . 
     
     
         233 . The method according to  claim 219 , wherein A 1  is selected from phenyl, triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzo[b]thienyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indenyl, naphthyl, azulinyl, or anthracenyl. 
     
     
         234 . The method according to  claim 219 , wherein each B 1  is independently selected from optionally substituted C6-C10 aryl. 
     
     
         235 . The method according to  claim 219 , wherein each B 1  is independently an optionally substituted phenyl or naphthyl. 
     
     
         236 . The method according to  claim 219 , wherein each B 1  is an unsubstituted phenyl. 
     
     
         237 . The method according to  claim 219 , wherein each B 1  is independently selected from optionally substituted C5-C12 heteroaryl. 
     
     
         238 . The method according to  claim 219 , wherein each B 1  is independently and optionally substituted C5-C7 heteroaryl. 
     
     
         239 . The method according to  claim 238 , wherein each B 1  is independently selected from optionally substituted pyrazolyl or imidazolyl. 
     
     
         240 . The method according to  claim 219 , wherein B 1  is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl. 
     
     
         241 . The method according to  claim 219 , wherein A 1  is optionally substituted C6-C10 aryl ring. 
     
     
         242 . The method according to  claim 241 , wherein A 1  is optionally substituted phenyl or naphthyl. 
     
     
         243 . The method according to  claim 219 , wherein A 1  is optionally substituted C5-C12 heteroaryl ring. 
     
     
         244 . The method according to  claim 243 , wherein A is pyridinyl. 
     
     
         245 . The method according to  claim 219 , wherein each B 1  is independently an optionally substituted 3-12 membered heterocyclic ring having up to 4 heteroatoms selected from O, S, or NR. 
     
     
         246 . The method according to  claim 245 , wherein each B 1  is independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl.