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, independently for each occurrence: 
         R 1  and R 2  are —Z A R 4 , wherein 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 A —, —CONR A NR A —, —CO 2 —, —OCO—, —NR A CO 2 —, —O—, —NR A CONR A —, —OCONR A —, —NR A NR A —, —NR A CO—, —S—, —SO—, —SO 2 —, —NR A —, —SO 2 NR A —, —NR A SO 2 —, or —NR A SO 2 NR A —; 
         R 4  is independently R A , halo, —OH, —NH 2 , —NO 2 , —CN, or —OCF 3 ; 
         R A  is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; 
         ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, O, and S; 
         n is an integer from 1 to 3 inclusive; 
         ring B is 
       
       
         
           
           
               
               
           
         
         
           wherein: 
           p is 1, 2, or 3; and 
           R 3  is C 1 -C 6  aliphatic or halo, and wherein R′ 3  and an adjacent R 3 , together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle. 
         
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is H or C 1 -C 6  aliphatic. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is H. 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein ring A is selected from 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein 1 R 3  is halo. 
     
     
         12 . The compound of  claim 1 , wherein 1 R 3  is F. 
     
     
         13 . The compound of  claim 1 , wherein R′ 3  and an adjacent R 3  together with the atoms to which they are attached form an optionally substituted heterocycle. 
     
     
         14 . The compound of  claim 1 , wherein R′ 3  and an adjacent R 3  together with the atoms to which they are attached form an optionally substituted 3 to 7 membered heterocycle in which one or more of the ring atoms is N, O, S, or a combination thereof. 
     
     
         15 . The compound of  claim 1 , wherein R′ 3  and an adjacent R 3  together with the atoms to which they are attached form an optionally substituted 7 membered heterocycle in which one or more of the ring atoms is N, O, S, or a combination thereof. 
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier or adjuvant. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the pharmaceutical composition comprises an additional agent selected from a mucolytic agent, a bronchodilator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, and a nutritional agent. 
     
     
         18 . (canceled) 
     
     
         19 . A method of treating or lessening the severity of a disease in a patient, wherein the disease is selected from cystic fibrosis, emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, 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, Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease, comprising administering to the patient a compound of  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein the disease is cystic fibrosis, emphysema, or COPD. 
     
     
         21 . The method of  claim 19 , wherein the disease is cystic fibrosis. 
     
     
         22 . The method of  claim 21 , wherein the patient is homozygous for a ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation. 
     
     
         23 . The method of  claim 21 , wherein the patient is homozygous for a G551D cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation. 
     
     
         24 . The method of  claim 21 , wherein the patient is heterozygous for a ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation. 
     
     
         25 . The method of  claim 21 , wherein the patient is heterozygous for a G551D cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled)