Modulators of cystic fibrosis transmembrane conductance regulator

Abstract

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein: 
         ring A is selected from: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 ; 
         R 2  is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH; 
         R 3  is hydrogen, —CH 3 , —OCH 3 , or —CN;
 provided that both R 2  and R 3  are not simultaneously hydrogen. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound according to any one of  claims 2 - 5 , wherein R 1  is —CF 3 . 
     
     
         7 . The compound according to any one of  claims 2 - 5 , wherein R 1  is —CN. 
     
     
         8 . The compound according to any one of  claims 2 - 5 , wherein R 1  is —C≡CCH 2 N(CH 3 ) 2 . 
     
     
         9 . The compound according to any one of  claims 6 - 8 , wherein R 2  is hydrogen. 
     
     
         10 . The compound according to any one of  claims 6 - 8 , wherein R 2  is —CH 3 . 
     
     
         11 . The compound according to any one of  claims 6 - 8 , wherein R 2  is —CF 3 . 
     
     
         12 . The compound according to any one of  claims 6 - 8 , R 2  is —OH. 
     
     
         13 . The compound according to any one of  claims 6 - 8 , wherein R 2  is —CH 2 OH. 
     
     
         14 . The compound according to any one of  claims 10 - 13 , wherein R 3  is hydrogen. 
     
     
         15 . The compound according to any one of  claims 9 - 13 , wherein R 3  is —CH 3 . 
     
     
         16 . The compound according to any one of  claims 9 - 13 , wherein R 3  is —OCH 3 . 
     
     
         17 . The compound according to any one of  claims 9 - 13 , wherein R 3  is —CN. 
     
     
         18 . A compound selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . A pharmaceutical composition comprising a compound according to any one of  claims 1 - 18  and a pharmaceutically acceptable carrier or adjuvant. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , further comprising an additional agent selected from a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of Formula (I), or a nutritional agent. 
     
     
         21 . The pharmaceutical composition according to  claim 20 , wherein said additional agent is a CFTR modulator other than a compound of Formula (I). 
     
     
         22 . A method of treating or lessening the severity of a disease in a patient, 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 palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, 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, pancreatic insufficiency, osteoporosis, osteopenia, Gorham's Syndrome, chloride channelopathies, myotonia congenita (Thomson and Becker forms), Butter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia, or Sjogren's disease, said method comprising the step of administering to said patient an effective amount of a compound according to any one of  claims 1 - 18 . 
     
     
         23 . The method according to  claim 22 , wherein said disease is cystic fibrosis. 
     
     
         24 . A method of treating or lessening the severity of a disease in a patient, wherein said disease is associated with reduced CFTR function due to mutations in the gene encoding CFTR or environmental factors, said method comprising the step of administering to said patient an effective amount of a compound according to any one of  claims 1 - 18 . 
     
     
         25 . The method of  claim 24 , wherein disease is cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), female infertility caused by congenital absence of the uterus and vagina (CAUV), idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic rhinosinusitis, primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, diabetes, dry eye, constipation, allergic bronchopulmonary aspergillosis (ABPA), bone diseases, and asthma. 
     
     
         26 . A method of treating or lessening the severity of a disease in a patient, wherein said disease is associated with normal CFTR function, said method comprising the step of administering to said patient an effective amount of a compound according to any one of  claims 1 - 18 . 
     
     
         27 . The method of  claim 26 , wherein disease is chronic obstructive pulmonary disease (COPD), chronic bronchitis, recurrent bronchitis, acute bronchitis, rhinosinusitis, constipation, chronic pancreatitis, recurrent pancreatitis, and acute pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, liver disease, hereditary emphysema, gallstones, gasgtro-esophageal reflux disease, gastrointestinal malignancies, inflammatory bowel disease, constipation, diabetes, arthritis, osteoporosis, and osteopenia. 
     
     
         28 . The method of  claim 26 , wherein the disease is 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 palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, 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, Gorham's Syndrome, chloride channelopathies, myotonia congenita (Thomson and Becker forms), Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia, or Sjogren's disease. 
     
     
         29 . 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) according to  claim 1 ;   (ii) instructions for:
 a) contacting the composition with the biological sample; 
 b) measuring activity of said CFTR or a fragment thereof. 
   
     
     
         30 . The kit of  claim 29 , further comprising instructions for:
 a) contacting an additional composition with the biological sample;   b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and   c) comparing the activity of the CFTR in the presence of the additional compound with the density of CFTR in the presence of a composition of Formula (I).   
     
     
         31 . A method of modulating CFTR activity in a biological sample comprising the step of contacting said CFTR with a compound according to any one of  claims 1 - 18 . 
     
     
         32 . A process for preparing a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein the process comprises: 
         (a) reacting the acid of formula 1d with an amine of formula 2c to provide a compound of Formula (I) 
       
       
         
           
           
               
               
           
         
         
           wherein: 
         
         ring A is selected from: 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 ; 
         R 2  is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH; 
         R 3  is hydrogen, —CH 3 , —OCH 3 , or —CN;
 provided that both R 2  and R 3  are not simultaneously hydrogen, and 
 
         R a  is hydrogen or a silyl protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS) triisopropylsilyl (TIPS) and [2-(trimethylsilyl)ethoxy]methyl (SEM). 
       
     
     
         33 . The process of  claim 32 , wherein the reaction of the acid of formula 1d with the amine of formula 2c occurs in a solvent in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and triethylamine or in a solvent in the presence of propyl phosphonic acid cyclic anhydride (T3P®) and pyridine. 
     
     
         34 . The process of  claim 33 , wherein the solvent comprises N,N-dimethyl formamide, ethyl acetate, or 2-methyltetrahydrofuran. 
     
     
         35 . The process of  claim 32 , wherein R a  is hydrogen or TBDMS. 
     
     
         36 . The process of  claim 32 , wherein R a  is TBDMS. 
     
     
         37 . The process of  claim 32  further comprising a deprotection step to remove the silyl protecting group when ring A is 
       
         
           
           
               
               
           
         
       
       wherein R a  is a silyl protecting group, to generate a compound of Formula (I), wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         38 . The process of  claim 32 , wherein the amine of formula 2c is prepared from a compound of formula 2a comprising the steps of:
 (a) reacting the compound of formula 2a with an amine of formula 3 to provide the compound of formula 2b   
       
         
           
           
               
               
           
         
         wherein: 
         Hal is F, Cl, Br, or I; and 
         the amine of formula 3 is 
       
       
         
           
           
               
               
           
         
          and 
         (b) reducing the compound of formula 2b to the amine of formula 2c. 
       
       
         
           
           
               
               
           
         
       
     
     
         39 . The process of  claim 38 , wherein the amine of formula 3 in step (a) is generated in situ from the amine hydrochloride salt. 
     
     
         40 . The process of  claim 38 , wherein R a  is hydrogen or TBDMS. 
     
     
         41 . The process of  claim 38 , wherein R a  is TBDMS. 
     
     
         42 . The process of  claim 38 , wherein step (a) occurs in a polar aprotic solvent in the presence of a tertiary amine base. 
     
     
         43 . The process of  claim 42 , wherein step (a) occurs in acetonitrile in the presence of triethylamine. 
     
     
         44 . The process of  claim 38 , wherein the reaction temperature of step (a) is between approximately 75° C. and approximately 85° C. 
     
     
         45 . The process of  claim 38 , wherein the reaction time is between approximately 2 and approximately 30 hours. 
     
     
         46 . The process of  claim 38 , wherein step (b) occurs in a polar protic solvent in the presence of a palladium catalyst. 
     
     
         47 . The process of  claim 46 , wherein the solvent in step (b) comprises methanol or ethanol. 
     
     
         48 . The process of  claim 38 , wherein step (b) occurs in a polar protic solvent in the presence of Fe and FeSO 4  or Zn and AcOH. 
     
     
         49 . The process of  claim 48 , wherein the polar protic solvent is water. 
     
     
         50 . A process for preparing a compound of Formula (Ic), 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, comprising the steps of: 
         (a) reacting a compound of formula 2a with an amine of formula 3 to provide a compound of formula 2b 
       
       
         
           
           
               
               
           
         
         (b) converting the compound of formula 2b to the amine of formula 2c via reduction 
       
       
         
           
           
               
               
           
         
          and 
         (c) reacting the amine of formula 2c with an acid of formula 1d to provide a compound of Formula (Ic) 
       
       
         
           
           
               
               
           
         
         wherein Hal is F, Cl, Br, or I; 
         the amine of formula 3 is 
       
       
         
           
           
               
               
           
         
          and 
         ring A is selected from: 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 ; 
         R 2  is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH; 
         R 3  is hydrogen, —CH 3 , —OCH 3 , or —CN;
 provided that both R 2  and R 3  are not simultaneously hydrogen, and 
 
         R a  is hydrogen or a silyl protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM). 
       
     
     
         51 . The process of  claim 50 , wherein the amine of formula 3 in step (a) is generated in situ from the amine hydrochloride salt. 
     
     
         52 . The process of  claim 51 , wherein R a  is hydrogen or TBDMS. 
     
     
         53 . The process of  claim 52 , wherein R a  is TBDMS. 
     
     
         54 . The process of  claim 50 , wherein step (a) occurs in a polar aprotic solvent in the presence of a tertiary amine base. 
     
     
         55 . The process of  claim 54 , wherein step (a) occurs in acetonitrile in the presence of triethylamine. 
     
     
         56 . The process of  claim 50 , wherein the reaction temperature of step (a) is between approximately 75° C. and approximately 85° C. 
     
     
         57 . The process of  claim 50 , wherein the reaction time is between approximately 2 and approximately 30 hours. 
     
     
         58 . The process of  claim 50 , wherein step (b) occurs in a polar protic solvent in the presence of a palladium catalyst. 
     
     
         59 . The process of  claim 58 , wherein the solvent in step (b) comprises methanol or ethanol. 
     
     
         60 . The process of  claim 50 , wherein step (b) occurs in a polar protic solvent in the presence of Fe and FeSO 4  or Zn and AcOH. 
     
     
         61 . The process of  claim 50 , wherein the polar protic solvent is water. 
     
     
         62 . The process of  claim 50 , wherein step (c) occurs in a solvent in the presence of O-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and triethylamine or in a solvent in the presence of propyl phosphonic acid cyclic anhydride (T3P®) and pyridine. 
     
     
         63 . The process of  claim 62 , wherein the solvent in step (c) comprises N,N-dimethyl formamide (DMF), ethyl acetate, or 2-methyltetrahydrofuran. 
     
     
         64 . The process of  claim 62 , wherein R a  is hydrogen or TBDMS. 
     
     
         65 . The process of  claim 64 , wherein R a  is TBDMS. 
     
     
         66 . The process of  claim 50  further comprising a deprotection reaction when ring A is 
       
         
           
           
               
               
           
         
       
       wherein R a  is a silyl protecting group, to generate a compound of Formula (I), wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
         67 . A compound which is 
       
         
           
           
               
               
           
         
       
       wherein ring A is 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 , and 
         R a  is hydrogen or a silyl protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM). 
       
     
     
         68 . A compound which is 
       
         
           
           
               
               
           
         
       
       wherein ring A is 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 , and 
         R a  is hydrogen or a silyl protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS) triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM). 
       
     
     
         69 . A compound of Formula (IA): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein: 
         ring A is selected from 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 ; 
         R 2  is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH; 
         R 3  is hydrogen, —CH 3 , —OCH 3 , or —CN;
 provided that both R 2  and R 3  are not simultaneously hydrogen, and 
 
         R a  is a silyl protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM). 
       
     
     
         70 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein: 
         ring A is selected from: 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 ; 
         R 2  is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH; 
         R 3  is hydrogen, —CH 3 , —OCH 3 , or —CN;
 provided that both R 2  and R 3  are not simultaneously hydrogen; 
 
         made by the process of any of  claims 45 - 61 . 
       
     
     
         71 . A compound which is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         made by the process of any of  claims 50 - 66 .