Modulators of cystic fibrosis transmembrane conductance regulator

Abstract

This invention relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is COOH or CH 2 OH.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R is COOH or CH 2 OH. 
       
     
     
         2 . A compound according to  claim 1 , wherein R is CH 2 OH. 
     
     
         3 . A compound according to  claim 1 , wherein R is COOH. 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . A pharmaceutical composition comprising:
 i. a compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt thereof; and   ii. a pharmaceutically acceptable carrier or adjuvant.   
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The pharmaceutical composition according to  claim 6 , wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The pharmaceutical composition according to  claim 6 , further comprising an additional agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-invective agent, an anti-inflammatory agent, a CFTR modulator, or a nutritional agent. 
     
     
         10 . A method of modulating CFTR activity in a biological sample comprising the step of contacting said biological sample with a compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of modulating CFTR activity in a biological sample according to  claim 10 , wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of modulating CFTR activity in a biological sample according to  claim 10 , wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A method of treating or lessening the severity of a disease in a patient comprising administering to said patient an effective amount of a compound of Formula I according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein said disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, 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 such 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. 
     
     
         14 . The method of  claim 13 , wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 13 , wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method according to  claim 13 , wherein said disease is cystic fibrosis. 
     
     
         17 . A kit for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo, comprising:
 i. a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof according to  claim 1 ;   ii. and instructions for:
 a. contacting the composition with the biological sample; and 
 b. measuring the activity of said CFTR or a fragment thereof. 
   
     
     
         18 . The kit of  claim 17 , further comprising instructions for:
 i. contacting an additional compound with the biological sample;   ii. measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound; and   iii. comparing the activity of the CFTR or a fragment thereof in the presence of the additional compound with the activity of the CFTR or a fragment thereof in the presence of a composition of Formula I.   
     
     
         19 . The kit according to  claim 18 , wherein the step of comparing the activity of said CFTR or a fragment thereof provides a measure of the density of said CFTR or a fragment thereof. 
     
     
         20 . The kit of  claim 17 , wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The kit of  claim 17 , wherein the compound of Formula I has the structure: