Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

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), 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, said method comprising the step of administering to said patient an effective amount of a compound of Formula I

• or pharmaceutically acceptable salts thereof, wherein:
• ring A is selected from:
• wherein:
• R1 is —CH3, —CF3 or —CN;
• R2 is hydrogen, —CH3, —CF3, —OH, or —CH2OH;
• R3 is hydrogen, —CH3, —OCH3, or —CN;
• Ra 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);
• provided that both R2 and R3 are not simultaneously hydrogen;
• and
• one of X and Y is nitrogen and the other is carbon.

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 of Formula I

• or pharmaceutically acceptable salts thereof, wherein:
• ring A is selected from:
• wherein:
• R1 is —CH3, —CF3 or —CN;
• R2 is hydrogen, —CH3, —CF3, —OH, or —CH2OH;
• R3 is hydrogen, —CH3, —OCH3, or CN;
• Ra 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);
• provided that both R2 and R3 are not simultaneously hydrogen;
• and
• one of X and Y is nitrogen and the other is carbon.

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 of Formula I

• or pharmaceutically acceptable salts thereof, wherein:
• ring A is selected from:
• wherein:
• R1 is —CH3—, —CF3 or —CN;
• R2 is hydrogen, —CH3, —CF3, —OH, or —CH2OH;
• R3 is hydrogen, —CH3, —OCH3, or —CN;
• Ra is hydrogen or a silyl protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyidiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM);
• provided that both R2 and R3 are not simultaneously hydrogen;
• and
• one of X and Y is nitrogen and the other is carbon.