Modulators of atp-binding cassette transporters

Abstract

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         each R 1  is an optionally substituted C 1-6  aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3-10  cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R 1  is an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 5- or 6-position of the pyridyl ring; 
         each R 2  is hydrogen, an optionally substituted C 1-6  aliphatic, an optionally substituted C 3-6  cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; 
         each R 3  and R′ 3  together with the carbon atom to which they are attached form an optionally substituted C 3-7  cycloaliphatic or an optionally substituted heterocycloaliphatic; 
         each R 4  is an optionally substituted aryl or an optionally substituted heteroaryl; and 
         each n is 1, 2, 3 or 4. 
       
     
     
         2 . The compound according to  claim 1 , wherein one R 1  that is attached to 5- or 6-position of the pyridyl ring is aryl or heteroaryl, each optionally substituted with 1, 2, or 3 of R D ; wherein R D  is —Z D R 9 ; wherein each Z D  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z D  are optionally and independently replaced by —CO—, —CS—, —CONR E —, —CONR E NR E —, —CO 2 —, —OCO—, —NR E CO 2 —, —O—, —NR E CONR E —, —OCONR E —, —NR E NR E —, —NR E CO—, —S—, —SO—, —SO 2 —, —NR E —, —SO 2 NR E —, —NR E SO 2 —, or —NR E SO 2 NR E —; each R 9  is independently R E , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; and each R E  is independently hydrogen, an optionally substituted C 1-8  aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 
     
     
         3 - 7 . (canceled) 
     
     
         8 . The compound according to  claim 2 , wherein one R 1  attached to the 5- or 6-position of the pyridyl ring is a 5 or 6 membered heteroaryl having 1, 2, or 3 heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the heteroaryl is substituted with 1 of R D , wherein R D  is —Z D R 9 ; each Z D  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z D  are optionally and independently replaced by —O—, —NHC(O)—, —C(O)NR E —, —SO 2 —, —NHSO 2 —, —NHC(O)—, —NR E SO 2 —, —SO 2 NH—, —SO 2 NR E —, —NH—, or —C(O)O—. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The compound according to  claim 1 , wherein one R 1  that is attached to the 5- or 6-position of the pyridyl ring is: 
       
         
           
           
               
               
           
         
         wherein 
         W 1  is —C(O)—, —SO 2 —, or —CH 2 —; 
         D is H, hydroxyl, or an optionally substituted group selected from aliphatic, cycloaliphatic, alkoxy, and amino; and 
         R D  is as defined in  claim 2 . 
       
     
     
         12 - 13 . (canceled) 
     
     
         14 . The compound according to  claim 1 , wherein one R 1  that is attached to the 5- or 6-position of the pyridyl ring is: 
       
         
           
           
               
               
           
         
         wherein: 
         W 1  is —C(O)—, —SO 2 —, or —CH 2 —; 
         each of A and B is independently H, an optionally substituted C 1-6  aliphatic, an optionally substituted C 3 -C 8  cycloaliphatic; or 
         A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic ring. 
       
     
     
         15 - 18 . (canceled) 
     
     
         19 . The compound according to  claim 1 , wherein one R 1  that is attached to the 5- or 6-position of the pyridyl ring is cycloaliphatic or heterocycloaliphatic, each optionally substituted with 1, 2, or 3 of R D ; wherein R D  is —Z D R 9 ; wherein each Z D  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z D  are optionally and independently replaced by —CO—, —CS—, —CONR E —, —CONR E NR E —, —CO 2 —, —OCO—, —NR E CO 2 —, —O—, —NR E CONR E —, —OCONR E —, —NR E NR E —, —NR E CO—, —SO—, —SO 2 —, —NR E —, —SO 2 NR E —, —NR E SO 2 —, or —NR E SO 2 NR E —; each R 9  is independently R E , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; and each R E  is independently hydrogen, an optionally substituted C 1-8  aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . The compound according to  claim 1 , wherein the one R 1  attached to the 5- or 6-position of the pyridyl ring is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         23 . (canceled) 
     
     
         24 . The compound according to  claim 1 , wherein R 2  is hydrogen and R 3  and R′ 3  together with the carbon atom to which they are attached form an unsubstituted C 3-7  cycloaliphatic or an unsubstituted heterocycloaliphatic. 
     
     
         25 . The compound according to  claim 24 , wherein R 3  and R′ 3  together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, an unsubstituted cyclopentyl, or an unsubstituted cyclohexyl. 
     
     
         26 . The compound according to  claim 1 , wherein R 4  is an aryl or heteroaryl optionally substituted with 1, 2, or 3 of —Z C R 8 , wherein each Z C  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z C  are optionally and independently replaced by —CO—, —CS—, —CONR C —, —CONR C NR C —, —CO 2 —, —OCO—, —NR C CO 2 —, —O—, —NR C CONR C —, —OCONR C —, —NR C NR C —, —NR C CO—, —S—, —SO—, —SO 2 —, —NR C —, —SO 2 NR C —, —NR C SO 2 —, or —NR C SO 2 NR C —; each R 8  is independently R C , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and each R C  is independently an optionally substituted C 1-8  aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 
     
     
         27 - 29 . (canceled) 
     
     
         30 . The compound according to  claim 26 , wherein R 4  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         31 . The compound according to  claim 1 , wherein said compound has formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R D  is —Z D R 9 , wherein each Z D  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z D  are optionally and independently replaced by —CO—, —CS—, —CONR E —, —CONR E NR E —, —CO 2 —, —OCO—, —NR E CO 2 —, —O—, —NR E CONR E —, —OCONR E —, —NR E NR E —, —NR E CO—, —S—, —SO—, —SO 2 —, —NR E —, —SO 2 NR E —, 
       
       —NR E SO 2 —, or —NR E SO 2 NR E —;
 R 9  is independently R E , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; 
 each R E  is independently hydrogen, an optionally substituted C 1-8  aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; 
 R 2  is C 1-4  aliphatic, C 3-6  cycloaliphatic, phenyl, or heteroaryl, each of which is optionally substituted, or R 2  is hydrogen; 
 R 3  and R′ 3  together with the carbon atom to which they are attached form a C 3-7  cycloaliphatic or a C 3-7  heterocycloaliphatic, each of which is optionally substituted with 1, 2, or 3 of —Z B R 7 , wherein each Z B  is independently a bond, or an optionally substituted branched or straight C 1-4  aliphatic chain wherein up to two carbon units of Z B  are optionally and independently replaced by —CO—, —CS—, —CONR B —, —CONR B NR B —, —CO 2 —, —OCO—, —NR B CO 2 —, —O—, —NR B CONR B —, —OCONR B —, —NR B NR B —, —NR B CO, —S—, —SO—, —SO 2 —, —NR B —, —SO 2 NR B —, —NR B SO 2 —, or —NR B SO 2 NR B —; 
 each R 7  is independently R B , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; 
 each R B  is independently hydrogen, an optionally substituted C 1-8  aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; 
 each R 4  is an aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 of —Z C R 8 , wherein each Z C  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z C  are optionally and independently replaced by —CO—, —CS—, —CONR C —, —CONR C NR C —, —CO 2 —, —OCO—, —NR C CO 2 —, —O—, —NR C CONR C —, —OCONR C —, —NR C NR C —, —NR C CO—, —S—, —SO—, —SO 2 —, —NR C —, —SO 2 NR C —, —NR C SO 2 —, or —NR C SO 2 NR C —; and 
 each R C  is independently an optionally substituted C 1-8  aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 
 
     
     
         32 . The compound according to  claim 31 , wherein Z D  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein one carbon unit of Z D  is optionally replaced by —SO 2 —, —CONR E —, —NR E SO 2 —, or —SO 2 NR E —. 
     
     
         33 . (canceled) 
     
     
         34 . The compound according to  claim 31 , wherein R 9  is an optionally substituted heteroaryl or an optionally substituted heterocycloaliphatic. 
     
     
         35 . (canceled) 
     
     
         36 . The compound according to  claim 1 , wherein said compound has formula V-A or formula V-B: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         T is an optionally substituted C 1-2  aliphatic chain, wherein each of the carbon units is optionally and independently replaced by —CO—, —CS—, —COCO—, —SO 2 —, —B(OH)—, or —B(O(C 1-6  alkyl))-; 
         each of R 1 ′ and R 1 ″ is an optionally substituted C 1-6  aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy; 
         R D1  is attached to carbon number 3″ or 4″; 
         each R D1  and R D2  is —Z D R 9 , wherein each Z D  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z D  are optionally and independently replaced by —CO—, —CS—, —CONR E —, —CONR E NR E —, —CO 2 —, —OCO—, —NR E CO 2 —, —O—, —NR E CONR E —, —OCONR E —, —NR E NR E —, —NR E CO, —S—, —SO—, —SO 2 —, —NR E —, —SO 2 NR E —, —NR E SO 2 —, or —NR E SO 2 NR E —; 
         R 9  is independently R E , halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCF 3 ; 
         or R D1  and R D2 , taken together with atoms to which they are attached, form a 3-8 membered saturated, partially unsaturated, or aromatic ring with up to 3 ring members independently selected from the group consisting of O, NH, NR E , and S; and 
         each R E  is independently hydrogen, an optionally substituted C 1-8  aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 
       
     
     
         37 - 40 . (canceled) 
     
     
         41 . The compound according to  claim 36 , wherein T is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, —C(O)— 
       
         
           
           
               
               
           
         
       
       —C(Phenyl) 2 -, —B(OH)—, and —CH(OEt)-. 
     
     
         42 - 49 . (canceled) 
     
     
         50 . The compound according to  claim 36 , wherein R 9  is an optionally substituted 3-8 membered heterocyclic selected from 
       
         
           
           
               
               
           
         
       
     
     
         51 - 52 . (canceled) 
     
     
         53 . The compound according to  claim 36 , wherein R 9  is 
       
         
           
           
               
               
           
         
       
     
     
         54 - 55 . (canceled) 
     
     
         56 . The compound according to  claim 36 , wherein R D1  and R D2 , taken together with phenyl containing carbon atoms 3″ and 4″, is 
       
         
           
           
               
               
           
         
       
     
     
         57 - 58 . (canceled) 
     
     
         59 . A compound of formula (I′): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         one of G 1  and G 2  is N and the other of G 1  and G 2  is CH; 
         each R 1  is an optionally substituted C 1-6  aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R 1  is an optionally substituted aryl or an optionally substituted heteroaryl attached to the 5- or 6-position of the pyridyl ring; 
         each R 2  is hydrogen, an optionally substituted C 1-6  aliphatic, an optionally substituted C 3-6  cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; 
         each R 3  and R′ 3  together with the carbon atom to which they are attached form an optionally substituted C 3-7  cycloaliphatic or an optionally substituted heterocycloaliphatic; 
         each R 4  is an optionally substituted aryl or an optionally substituted heteroaryl; and 
         each n is 1, 2, 3, or 4. 
       
     
     
         60 . The compound according to  claim 59 , wherein the compound has formula (I′-A) or formula (I′-B), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 1 , R 2 , R 3 , R′ 3 , R 4 , and n are defined above. 
       
     
     
         61 . A compound according to  claim 1 , wherein the compound is selected from Table 1. 
     
     
         62 . A pharmaceutical composition comprising:
 (i) a compound according to  claim 1 ; and   (ii) a pharmaceutically acceptable carrier.   
     
     
         63 . The composition according to  claim 62 , optionally further comprising a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, or a nutritional agent. 
     
     
         64 . A method of modulating ABC transporter activity comprising the step of contacting said ABC transporter with a compound of formula (I) or formula (I′): 
       
         
           
           
               
               
           
         
         wherein: 
         one of G 1  and G 2  is a nitrogen, and the other is a carbon; 
         each R 1  is an optionally substituted C 1-6  aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3-10  cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R 1  is an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 5- or 6-position of the pyridyl ring; 
         each R 2  is hydrogen, an optionally substituted C 1-6  aliphatic, an optionally substituted C 3-6  cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; 
         each R 3  and R′ 3  together with the carbon atom to which they are attached form an optionally substituted C 3-7  cycloaliphatic or an optionally substituted heterocycloaliphatic; 
         each R 4  is an optionally substituted aryl or an optionally substituted heteroaryl; and 
         each n is 1-4. 
       
     
     
         65 . The method according to  claim 64 , wherein the ABC transporter is CFTR. 
     
     
         66 . A method of treating or lessening the severity of cystic fibrosis in a patient, said method comprising the step of administering to said patient an effective amount of a compound of formula I according to  claim 1  or formula I′ according to  claim 59 . 
     
     
         67 - 69 . (canceled)