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, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

1 . 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 ; 
         W is a bond or is an optionally substituted C 1 -C 6  alkylidene chain wherein up to two methylene units of W 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 —, —NR′SO 2 NR′—; 
         R W  is independently R′, halo, NO 2 , CN, CF 3 , or OCF 3 ; 
         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 1-8  aliphatic group; 
         R 7  is hydrogen or a C 1-6  aliphatic group optionally substituted with —X—R X ; 
         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: 
         i) when R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are hydrogen, then Ar 1  is not phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-hydroxyphenyl, 2,4-dinitrophenyl, 3,5-dicarboxylic acid phenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-ethylphenyl, 3-nitro-4-methylphenyl, 3-carboxylic-acid phenyl, 2-fluorophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-ethoxyphenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-dimethylaminophenyl, 3,4-dimethylphenyl, 2-ethylphenyl, or 4-ethoxycarbonylphenyl; 
         ii) when R 1 , R 2 , R 3 , R 5 , R 6  and R 7  are hydrogen, and R 4  is methoxy, then Ar 1  is not 2-fluorophenyl or 3-fluorophenyl; 
         iii) when R 1 , R 3 , R 4 , R 5 , R 6  and R 7  are hydrogen, R 2  is 1,2,3,4-tetrahydroisoquinolin-1-yl-sulfonyl, then Ar 1  is not 3-trifluoromethylphenyl; 
         iv) when R 1 , R 2 , R 3 , R 4 , R 5  and R 7  are hydrogen, R 6  is methyl, then Ar 1  is not phenyl; 
         v) when R 1 , R 4 , R 5 , R 6  and R 7  are hydrogen, R 2  and R 3 , taken together, are methylenedioxy, then Ar 1  is not 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-carboethoxyphenyl, 6-ethoxy-benzothiazol-2-yl, 6-carboethoxy-benzothiazol-2-yl, 6-halo-benzothiazol-2-yl, 6-nitro-benzothiazol-2-yl, or 6-thiocyano-benzothiazol-2-yl. 
         vi) when R 1 , R 4 , R 5 , R 6  and R 7  are hydrogen, R 2  and R 3 , taken together, are methylenedioxy, then Ar 1  is not 4-substituted phenyl wherein said substituent is —SO 2 NHR xx , wherein R xx  is 2-pyridinyl, 4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl; 
         vii) when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are hydrogen, then Ar 1  is not thiazol-2-yl, 1H-1,2,4-triazol-3-yl, or 1H-1,3,4-triazol-2-yl; 
         viii) when R 1 , R 2 , R 3 , R 5 , R 6 , and R 7  are hydrogen, and R 4  is CF 3 , OMe, chloro, SCF 3 , or OCF 3 , then Ar 1  is not 5-methyl-1,2-oxazol-3-yl, thiazol-2-yl, 4-fluorophenyl, pyrimidin-2-yl, 1-methyl-1,2-(1H)-pyrazol-5-yl, pyridine-2-yl, phenyl, N-methyl-imidazol-2-yl, imidazol-2-yl, 5-methyl-imidazol-2-yl, 1,3-oxazol-2-yl, or 1,3,5-(1H)-triazol-2-yl; 
         ix) when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  each is hydrogen, then Ar 1  is not pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl, 4-methoxy-6-methyl-1,3,5-triazin-2-yl; 5-bromo-pyridin-2-yl, pyridin-2-yl, or 3,5-dichloro-pyridin-2-yl; 
         x) when R 1 , R 2 , R 3 , R 4 , R 5  and R 7  each is hydrogen, R 6  is hydroxy, then Ar 1  is not 2,6-dichloro-4-aminosulfonyl-phenyl; 
         xi) when R 2  or R 3  is an optionally substituted N-piperazyl, N-piperidyl, or N-morpholinyl, then Ar 1  is not an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-yl, or indazolyl; 
         xii) when R 2  is optionally substituted cyclohexylamino, then Ar 1  is not optionally substituted phenyl, pyridyl, or thiadiazolyl; 
         xiii) Ar 1  is not optionally substituted tetrazolyl; 
         xiv) when R 2 , R 4 , R 5 , R 6 , and R 7  each is hydrogen, and R 1  and R 3  both are simultaneously CF 3 , chloro, methyl, or methoxy, then Ar 1  is not 4,5-dihydro-1,3-thiazol-2-yl, thiazol-2-yl, or [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl; 
         xv) when R 1 , R 4 , R 5 , R 6 , and R 7  each is hydrogen, and Ar 1  is thiazol-2-yl, then neither R 2  nor R 3  is isopropyl, chloro, or CF 3 ; 
         xvi) when Ar 1  is 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, phenyl, or 3-chlorophenyl, then:
 a) when R 1 , R 2 , R 4 , R 5 , R 6 , and R 7  each is hydrogen, then R 3  is not methoxy; or 
 b) when R 1 , R 3 , R 4 , R 5 , R 6 , and R 7  each is hydrogen, then R 2  is not chloro; or 
 c) when R 1 , R 2 , R 3 , R 5 , R 6 , and R 7  each is hydrogen, then R 4  is not methoxy; or 
 d) when R 1 , R 3 , R 4 , R 6 , and R 7  each is hydrogen, and R 5  is ethyl, then R 2  is not chloro; 
 e) when R 1 , R 2 , R 4 , R 5 , R 6 , and R 7  each is hydrogen, then R 3  is not chloro; 
 
         xvi) when R 1 , R 3 , R 4 , R 5 , R 6 , and R 7  each is hydrogen, and R 2  is CF 3  or OCF 3 , then Ar 1  is not [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl; 
         xvii) when R 1 , R 2 , R 4 , R 5 , R 6 , and R 7  each is hydrogen, and R 3  is hydrogen or CF 3 , then Ar 1  is not a phenyl substituted with —OCH 2 CH 2 Ph, —OCH 2 CH 2 (2-trifluoromethyl-phenyl), —OCH 2 CH 2 -(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl), or substituted 1H-pyrazol-3-yl; and 
         xviii) the following two compounds are excluded: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound according to  claim 1 , wherein Ar 1  is selected from: 
       
         
           
           
               
               
           
         
         wherein ring A 1  5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or 
         A 1  and A 2 , together, is an 8-14 aromatic, bicyclic or tricyclic aryl ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         3 - 13 . (canceled) 
     
     
         14 . The compound according to  claim 2 , wherein said compound has formula IIA or formula IIB: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound according to  claim 2 , wherein said compound has formula IIIA, formula IIIB, formula IIIC, formula IIID, or formula IIIE: 
       
         
           
           
               
               
           
         
         wherein:
 each of X 1 , X 2 , X 3 , X 4 , and X 5  is independently selected from CH or N; and X 6  is O, S, or NR′. 
 
       
     
     
         16 - 18 . (canceled) 
     
     
         19 . The compound according to  claim 15 , wherein said compound has formula IVA, formula IVB, or formula IVC: 
       
         
           
           
               
               
           
         
       
     
     
         20 . (canceled) 
     
     
         21 . The compound according to  claim 19 , wherein said compound has formula VA-1: 
       
         
           
           
               
               
           
         
         wherein each of WR W2  and WR W4  is independently selected from hydrogen, CN, CF 3 , halo, C1-C6 straight or branched alkyl, 3-12 membered cycloaliphatic, phenyl, C5-C10 heteroaryl or C3-C7 heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S, or N, wherein said WR W2  and WR W4  is independently and optionally substituted with up to three substituents selected from —OR′, —CF 3 , —OCF 3 , SR′, S(O)R′, SO 2 R′, —SCF 3 , halo, CN, —COOR′, —COR′, —O(CH 2 ) 2 N(R′)(R′), —O(CH 2 )N(R′)(R′), —CON(R′)(R′), —(CH 2 ) 2 OR′, —(CH 2 )OR′, CH 2 CN, optionally substituted phenyl or phenoxy, —N(R′)(R′), —NR′C(O)OR′, —NR′C(O)R′, —(CH 2 ) 2 N(R′)(R′), or —(CH 2 )N(R′)(R′); and 
         WR W5  is selected from hydrogen, —OH, NH 2 , CN, CHF 2 , NHR′, N(R′) 2 , —NHC(O)R′, —NHC(O)OR′, NHSO 2 R′, —OR′, CH 2 OH, CH 2 N(R′) 2 , C(O)OR′, SO 2 NHR′, SO 2 N(R′) 2 , or CH 2 NHC(O)OR′. Or, WR W4  and WR W5  taken together form a 5-7 membered ring containing 0-3 three heteroatoms selected from N, O, or S, wherein said ring is optionally substituted with up to three WR W  substituents. 
       
     
     
         22 - 31 . (canceled) 
     
     
         32 . The compound according to  claim 19 , wherein said compound has formula V-A-2: 
       
         
           
           
               
               
           
         
         wherein:
 Y is CH 2 , C(O)O, C(O), or S(O) 2 ; and 
 m is 0-4. 
 
       
     
     
         33 . The compound according to  claim 19 , wherein said compound has formula V-A-3: 
       
         
           
           
               
               
           
         
         wherein:
 Q is W; 
 R Q  is R W ; 
 m is 0-4; and 
 n is 0-4. 
 
       
     
     
         34 . The compound according to  claim 19 , wherein said compound has formula V-A-4: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound according to  claim 19 , wherein said compound has formula V-A-5: 
       
         
           
           
               
               
           
         
         wherein:
 m is 0-4. 
 
       
     
     
         36 . The compound according to  claim 19 , wherein said compound has formula V-A-6: 
       
         
           
           
               
               
           
         
         wherein:
 ring B is a 5-7 membered monocyclic or bicyclic, heterocyclic or heteroaryl ring optionally substituted with up to n occurrences of -Q-R Q ; 
 Q is W; 
 R e  is R W ; 
 m is 0-4; and 
 n is 0-4. 
 
       
     
     
         37 - 39 . (canceled) 
     
     
         40 . The compound according to  claim 19 , wherein said compound has formula V-B-1: 
       
         
           
           
               
               
           
         
         wherein:
 one of Q 1  and Q 3  is N(WR W ) and the other of Q 1  and Q 3  is selected from O, S, or N(WR W ); 
 Q 2  is C(O), CH 2 —C(O), C(O)—CH 2 , CH 2 , CH 2 —CH 2 , CF 2 , or CF 2 —CF 2 ; and 
 m is 0-3. 
 
       
     
     
         41 - 42 . (canceled) 
     
     
         43 . The compound according to  claim 19 , wherein said compound has formula V-B-2: 
       
         
           
           
               
               
           
         
         wherein
 R W1  is hydrogen or C1-C6 aliphatic; 
 each of R W3  is hydrogen or C1-C6 aliphatic; or 
 both R W3  taken together form a C3-C6 cycloalkyl or heterocyclic ring having up to two heteroatoms selected from O, S, or NR′, wherein said ring is optionally substituted with up to two WR W  substituents; and 
 m is 0-4. 
 
       
     
     
         44 - 45 . (canceled) 
     
     
         46 . The compound according to  claim 19 , wherein said compound has formula V-B-3: 
       
         
           
           
               
               
           
         
         wherein:
 Q 4  is a bond, C(O), C(O)O, or S(O) 2 ; 
 R W1  is hydrogen or C1-C6 aliphatic; and 
 m is 0-4. 
 
       
     
     
         47 . The compound according to  claim 19 , wherein said compound has formula V-B-4: 
       
         
           
           
               
               
           
         
         wherein:
 m is 0-4. 
 
       
     
     
         48 . The compound according to  claim 19 , wherein said compound has formula V-B-5: 
       
         
           
           
               
               
           
         
         wherein:
 ring A 2  is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A 2  and the phenyl ring fused thereto together have up 4 substituents independently selected from WR W ; and 
 m is 0-4. 
 
       
     
     
         49 . (canceled) 
     
     
         50 . The compound according to  claim 19 , wherein said compound has formula V-B-5-a: 
       
         
           
           
               
               
           
         
         wherein:
 G 4  is hydrogen, halo, CN, CF 3 , CHF 2 , CH 2 F, optionally substituted C1-C6 aliphatic, aryl-C1-C6 alkyl, or a phenyl, wherein G 4  is optionally substituted with up to 4 WR W  substituents; wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with —CO—, —CONR′—, —CO 2 —, —OCO—, —NR′CO 2 —, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—, —SO 2 NR′—, NR′SO 2 —, or —NR′SO 2 NR′—.; 
 G 5  is hydrogen or an optionally substituted C1-C6 aliphatic; 
 
         wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WR W . 
       
     
     
         51 - 55 . (canceled) 
     
     
         56 . A compound having formula A-I: 
       
         
           
           
               
               
           
         
         or a salt thereof; 
         wherein:
 G 1  is hydrogen, R′, C(O)R′, C(S)R′, S(O)R′, S(O) 2 R′, Si(CH 3 ) 2 R′, P(O)(OR′) 3 , P(S)(OR′) 3 , or B(OR′) 2 ; 
 G 2  is halo, CN, CF 3 , isopropyl, or phenyl wherein said isopropyl or phenyl is optionally substituted with up to 3 substituents independently selected from WR W , wherein W and R W  are as defined above for formula I and embodiments thereof; 
 G 3  is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G 3  is optionally substituted with up to 3 substituents independently selected from WR W , wherein W and R W  are as defined above for formula I and embodiments thereof; provided that when G 1  is methoxy, G 3  is tert-butyl, then G 2  is not 2-amino-4-methoxy-5-tert-butyl-phenyl. 
 
       
     
     
         57 - 62 . (canceled) 
     
     
         63 . A compound having formula A-II: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 G 4  is hydrogen, halo, CN, CF 3 , CHF 2 , CH 2 F, optionally substituted C1-C6 aliphatic, aralkyl, or a phenyl ring optionally substituted with up to 4 WR W  substituents; 
 G 5  is hydrogen or an optionally substituted C1-C6 aliphatic; 
 
         provided that both, G 4  and G 5 , are not simultaneously hydrogen; 
         wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WR W . 
       
     
     
         64 - 67 . (canceled) 
     
     
         68 . A pharmaceutical composition comprising a compound of formula I according to  claim 1  and a pharmaceutically acceptable carrier or adjuvant. 
     
     
         69 . The composition according to  claim 68 , wherein said composition comprises an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CFTR modulator, or a nutritional agent. 
     
     
         70 . A method of modulating ABC transporter activity comprising the step of contacting said ABC transporter with a compound of formula I according to  claim 1 . 
     
     
         71 - 72 . (canceled) 
     
     
         73 . 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 according to  claim 1 ;   (ii) instructions for:
 a) contacting the composition with the biological sample; 
 b) measuring activity of said ABC transporter or a fragment thereof. 
   
     
     
         74 - 75 . (canceled)