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 independently an optionally substituted C 1-6  aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3-10  membered cycloaliphatic or an optionally substituted 4 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R 1  is an optionally substituted aryl attached to the 3-position of the phenyl ring; 
 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; 
 Ring A is an optionally substituted cycloaliphatic; 
 Each R 4  is an optionally substituted aryl or an optionally substituted heteroaryl, provided that R 4  is not a benzo[d][1,3]dioxolyl ring; and 
 n is 1, 2, 3, 4, or 5. 
 
     
     
         2 . The compound of claim Error! Reference source not found.  1 , wherein the one R 1  attached to the 3-position of the phenyl ring is an aryl optionally substituted with 1, 2, or 3 of R A , wherein R A  is —Z A R 5 ; in which each Z A  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z A  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 5  is independently R B , halo, —B(OH) 2 , —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; and 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. 
     
     
         3 . The compound of  claim 2 , wherein the one R 1  attached to the 3-position of the phenyl ring is a phenyl optionally substituted with 1, 2, or 3 of R A . 
     
     
         4 . The compound of  claim 3 , wherein the one R 1  attached to the 3-position of the phenyl ring is a phenyl substituted with one of R A , wherein R A  is —Z A R 5 ; each Z A  is independently a bond or an optionally substituted branched or straight C 1-6  aliphatic chain wherein up to two carbon units of Z A  are optionally and independently replaced by —O—, —NHC(O)—, —C(O)NR B —, —SO 2 —, —NHSO 2 —, —NHC(O)—, —SO—, —NR B SO 2 —, —SO 2 NH—, —SO 2 NR B —, —NH—, or —C(O)O—. 
     
     
         5 . The compound of  claim 4 , wherein one carbon unit of Z A  is replaced by —O—, —NHC(O)—, —C(O)NR B —, —SO 2 —, —NHSO 2 —, —NHC(O)—, —SO—, —NR B SO 2 —, —SO 2 NH—, —SO 2 NR B —, —NH—, or —C(O)O—. 
     
     
         6 . The compound of  claim 2 , wherein R 5  is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, or halo. 
     
     
         7 .- 10 . (canceled) 
     
     
         11 . The compound of  claim 2 , wherein R 1  is: 
       
         
           
           
               
               
           
         
         wherein 
         W 1  is —C(O)—, —SO 2 —, —NHC(O)—, or —CH 2 —; and 
         D is H, hydroxy, or an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted alkoxy, and amino. 
       
     
     
         12 . The compound of  claim 11 , wherein D is OH, an optionally substituted C 1-6  aliphatic, an optionally substituted C 3 -C 8  cycloaliphatic, an optionally substituted alkoxy, or an optionally substituted amino. 
     
     
         13 . The compound of claim Error! Reference source not found.  12 , wherein D is an optionally substituted amino of the formula 
       
         
           
           
               
               
           
         
       
       wherein each of A and B is independently H, an optionally substituted C 1-6  aliphatic, an optionally substituted C 3 -C 8  cycloaliphatic, an optionally substituted 3-8 membered heterocycloaliphatic, acyl, sulfonyl, or
 A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic ring. 
 
     
     
         14 . The compound of  claim 11 , wherein R 1  is: 
       
         
           
           
               
               
           
         
         wherein: 
         W 1  is —C(O)—, —SO 2 —, —NHC(O)—, or —CH 2 —; 
         Each of A and B is independently H or an optionally substituted C 1-6  aliphatic; or 
         A and B, taken together, form an optionally substituted 4-7 membered heterocycloaliphatic ring. 
       
     
     
         15 . The compound of  claim 13 , wherein A is H and B is C 1-6  aliphatic optionally substituted with 1, 2, or 3 of halo, oxo, CN, hydroxy, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted hydroxyalkyl, an optionally substituted alkoxy, an optionally substituted alkoxyalkyl, an optionally substituted cycloaliphatic, amino, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 
     
     
         16 . The compound of  claim 13 , wherein A and B, taken together with the nitrogen atom, form an optionally substituted 3-7 membered heterocycloaliphatic ring. 
     
     
         17 . The compound of  claim 15 , wherein A and B, taken together with the nitrogen atom, form an optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolidin-3-yl, and 1,4-diazepan-1-yl. 
     
     
         18 . The compound of  claim 15 , wherein the heterocycloaliphatic ring is optionally substituted with 1, 2, or 3 of halo, oxo, alkyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, or carboxy. 
     
     
         19 . The compound of claim Error! Reference source not found.  1 , wherein R 2  is hydrogen or methyl. 
     
     
         20 . The compound of  claim 1 , wherein ring A is an unsubstituted C 3-7  cycloaliphatic. 
     
     
         21 . The compound of  claim 20 , wherein ring A is an unsubstituted cyclopropyl, an unsubstituted cyclopentyl, or an unsubstituted cyclohexyl. 
     
     
         22 . The compound of  claim 21 , wherein ring A is an unsubstituted cyclopropyl. 
     
     
         23 . The compound of  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 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. 
     
     
         24 . The compound of  claim 23 , wherein R 4  is an aryl optionally substituted with 1, 2, or 3 of —Z C R 8 . 
     
     
         25 . The compound of  claim 24 , wherein R 4  is phenyl optionally substituted with 1, 2, or 3 of —Z C R 8 . 
     
     
         26 . The compound of  claim 23 , wherein R 4  is a heteroaryl optionally substituted with 1, 2, or 3 of —Z C R 8 . 
     
     
         27 . The compound of  claim 23 , wherein R 4  is one selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         28 .- 66 . (canceled) 
     
     
         67 . A compound having a structure selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         68 . A pharmaceutical composition comprising:
 (i) a compound according to  claim 1 ; and   (ii) a pharmaceutically acceptable carrier.   
     
     
         69 . The composition of  claim 68 , optionally further comprising a mucolytic agent, a bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a 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  claim 1 . 
     
     
         71 . The method of  claim 70  wherein the ABC transporter is CFTR. 
     
     
         72 . A method for treating or lessening the severity of a disease in a patient need thereof, wherein said disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis 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, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, 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; provided that R 4  is not a benzo[d][1,3]dioxolyl ring when the disease is cystic fibrosis 
     
     
         73 . A kit for use in measuring the activity of an 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 ; and   (ii) instructions for:
 a) contacting the composition with the biological sample; and 
 b) measuring activity of said ABC transporter or a fragment thereof. 
   
     
     
         74 . The kit of  claim 73 , 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 composition; and   c) comparing the activity of the ABC transporter in the presence of the additional composition with the density of the ABC transporter in the presence of a composition comprising a compound of formula (I).   
     
     
         75 . The kit of  claim 73  or  claim 74 , wherein the kit is used to measure the activity of CFTR.