Heteroaryl-substituted pyridines and methods of use

Abstract

The present invention relates to heteroaryl substituted pyridines and methods of use. The present invention discloses compounds having formula (I), wherein X 1 , X 2 , R 1 and R 2 As defined herein. The present invention relates to compounds and their use for the treatment of cystic fibrosis, processes for their production, pharmaceutical compositions comprising the same and methods of treating cystic fibrosis by administering the compounds of the invention.

Description

[0001] This application is a divisional application of an invention patent application with an application date of May 24, 2017, application number 201780033214.0, and invention name “Heteroaryl-substituted pyridine and method of use”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 345,315, filed on June 3, 2016, which is incorporated herein in its entirety for all purposes. Background of the Invention Technical Field

[0004] The present invention relates to substituted pyridine compounds, which are modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) protein and can be used to treat diseases and conditions mediated and regulated by CFTR. The present invention also relates to compositions containing the compounds of the present invention, methods for their preparation, and methods of treatment using the same. Background Art

[0006] ABC transporters are a family of homologous membrane transporters that regulate the transport of a wide variety of pharmacological substances (e.g., drugs, xenobiotics, anions, etc.), which bind and use cellular adenosine triphosphate (ATP) for specific activities. Some of these transporters were found to antagonize malignant cancer cells to chemotherapeutic drugs, acting as multidrug resistance proteins (e.g., MDR1-P glycoprotein or multidrug resistance protein MRP 1). So far, 48 ABC transporters have been identified, divided into 7 families based on their sequence identity and function.

[0007] ABC transporters provide protection against harmful environmental compounds by regulating a variety of important physiological roles in the body and therefore represent important potential drug targets for the treatment of diseases associated with transporter defects, outward cellular drug transport, and other diseases in which modulation of ABC transporter activity may be beneficial.

[0008] The cAMP / ATP-mediated anion channel CFTR is a member of the ABC transporter family that is often associated with disease and is expressed in various cell types, including absorptive and secretory epithelial cells, where it regulates anion transmembrane flux and the activity of other ion channels and proteins. CFTR activity in epithelial cells is essential for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues (Quinton, PM, 1990. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 4, 2709-2717).

[0009] The gene encoding CFTR has been identified and sequenced (Kerem, B., Rommens, JM, Buchanan, JA, Markiewicz, D., Cox, TK, Chakravarti, A., Buchwald, M., Tsui, LC, 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080). CFTR contains approximately 1480 amino acids encoding a protein consisting of tandem repeats of transmembrane domains, each of which contains six transmembrane helices and a nucleotide binding domain. The pair of transmembrane domains is connected by a large polar regulatory (R)-domain that has multiple phosphorylation sites that regulate channel activity and cellular trafficking.

[0010] Cystic fibrosis (CF) is caused by a defect in this gene that induces mutations in CFTR. Cystic fibrosis is the most common fatal genetic disease in humans and affects approximately 0.04% of white people (Bobadilla, JL, Macek, M., Jr, Fine, JP, Farrell, PM, 2002. Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening. Hum. Mutat. [Human mutation] 19, 575-606. doi: 10.1002 / humu.10041). For example, in the United States, approximately one in 2500 infants is affected, and as many as 10 million people carry a single copy of the defective gene without obvious disease effects; in addition, subjects with a single copy of the gene exhibit increased resistance to cholera and dehydration from diarrhea. This effect may explain the higher frequency of the CF gene in the human population.

[0011] In contrast, individuals with two copies of the CF-associated gene suffer from the debilitating and lethal effects of CF, including chronic lung infections.

[0012] In patients with cystic fibrosis, mutations in endogenous respiratory epithelial CFTR fail to confer chloride and bicarbonate permeability to epithelial cells in the lung and other tissues, resulting in reduced apical anion secretion and disruption of ion and fluid transport. This decline in anion transport leads to increased mucus and pathogen accumulation in the lung, triggering microbial infections that ultimately lead to death in CF patients.

[0013] In addition to respiratory problems, CF patients also suffer from gastrointestinal problems and pancreatic insufficiency, which can lead to death if left untreated. In addition, female subjects with cystic fibrosis have reduced fertility, and males with cystic fibrosis are infertile.

[0014] A variety of disease-causing mutations have been identified by sequence analysis of the CFTR gene of the CF chromosome (Kerem, B., Rommens, JM, Buchanan, JA, Markiewicz, D., Cox, TK, Chakravarti, A., Buchwald, M., Tsui, LC, 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080). The most common CF mutation and occurring in approximately 70% of cystic fibrosis cases, ΔF508-CFTR (present in at least 1 allele in approximately 90% of CF patients) contains a single amino acid deletion of phenylalanine 508. This deletion prevents the nascent protein from folding correctly, which in turn cannot leave the endoplasmic reticulum (ER) and be transported to the plasma membrane, and is then rapidly degraded. As a result, the number of channels present in the membrane is much lower than in cells expressing wild-type CFTR. In addition to impaired transport, the mutation results in a defect in channel gating. In fact, even though ΔF508-CFTR reaches the plasma membrane of cells (where it can function as a cAMP-activated chloride channel) by low temperature (27°C) rescue, its activity is significantly reduced compared to WT-CFTR (Pasyk, EA, Foskett, JK, 1995. Mutant (ΔF508) Cystic Fibrosis Transmembrane Conductance Regulator Cl-Channel Is Functional When Retained in Endoplasmic Reticulum of Mammalian Cells. [Mutant (ΔF508) When retained in the endoplasmic reticulum of mammalian cells, the cystic fibrosis transmembrane conductance regulator Cl-channel is functional] J. Biol. Chem. [Journal of Biological Chemistry] 270, 12347-12350).

[0015] Other mutations with lower incidence that change channel regulation or channel conduction are also identified. In the case of channel regulation mutants, the protein of mutation is suitably transported and positioned at plasma membrane but can not be activated or can not play a role as chloride channel (for example, missense mutations positioned in nucleotide binding domain), and the examples of these mutations are G551D, G178R and G1349D. The mutation that affects chloride conduction has the CFTR albumen (for example, missense mutations positioned in membrane spanning domain) that is correctly transported to cell membrane but produces the chloride flow of minimization, and the examples of these mutations are R117H and R334W.

[0016] In addition to cystic fibrosis, modulation of CFTR activity may be beneficial in other diseases that are not directly caused by CFTR mutations, such as chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjögren's syndrome.

[0017] COPD is characterized by the progressive and irreversible airflow limitation caused by excessive mucus secretion, bronchiolitis and emphysema. The potential treatment of common excessive mucus secretion and impaired mucociliary clearance in COPD can be to use an activator of mutant or wild-type CFTR. Specifically, the anion secretion increase across CFTR can promote fluid transport to the airway surface liquid to hydrate mucus and optimize the viscosity of the fiber perifluid. The resulting enhanced mucociliary clearance will help alleviate the symptoms relevant to COPD.

[0018] Dry eye disease is characterized by reduced tear production and abnormal tear film lipid, protein and mucin profiles. Many factors can cause dry eye disease, some of which include age, arthritis, Lasik eye surgery, chemical / thermal damage, medications, allergies, and diseases such as cystic fibrosis and Sjögren's syndrome. Increasing anion secretion via CFTR can enhance fluid transport from corneal endothelial cells and secretory glands around the eye, and ultimately improve corneal hydration, thereby helping to alleviate the symptoms associated with dry eye disease. Sjögren's syndrome is an autoimmune disease in which the immune system causes damage to glands that produce moisture inside the human body, including the eyes, mouth, skin, respiratory tissues, liver, vagina, and intestines. The resulting symptoms include dry eyes, oral and vaginal diseases, as well as lung disease. Sjögren's syndrome is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and polymyositis / dermatomyositis. The cause of the disease is believed to be in defective protein transport, and its treatment options are limited. Therefore, regulating CFTR activity can help moisturize different organs and help improve related symptoms.

[0019] In addition to CF, defective protein trafficking induced by ΔF508-CFTR has been shown to be a potential basis for various other diseases, particularly those in which functional defects in the endoplasmic reticulum (ER) prevent the CFTR protein from leaving the ER and / or degrade misfolded proteins (Morello, J.-P., Bouvier, M., Petaja-Repo, UE, Bichet, DG, 2000. Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol. Sci. 21, 466-469. doi: 10.1016 / S0165-6147(00)01575-3; Shastry, BS, 2003. Neurodegenerative disorders of protein aggregation. [Neurodegenerative disorders caused by protein aggregation] Neurochem. Int. [International Neurochemistry] 43, 1-7. doi: 10.1016 / S0197-0186(02)00196-1; Zhang, W., Fujii, N., Naren, AP, 2012. Recent advances and new perspectives in targeting CFTR for therapy of cystic fibrosis and enterotoxin-induced secretory diarrheas. [The latest developments and new perspectives in targeting CFTR for the treatment of cystic fibrosis and enterotoxin-induced secretory diarrhea] Future Med. Chem. [Future Medicinal Chemistry] 4, 329-345. doi: 10.4155 / fmc.12.1).

[0020] A number of inherited diseases are associated with defective ER processing equivalent to the defects observed with CFTR in CF, such as type 1 glycanosis CDG, hereditary emphysema (alpha-1-antitrypsin (PiZ variant)), congenital hyperthyroidism, osteogenesis imperfecta (type I, II, or IV procollagen), hereditary hypofibrinogenemia (fibrinogen), ACT deficiency (alpha-1-antichymotrypsin), diabetes insipidus (DI), neurohypophyseal DI (vasopressin N2-receptor), nephrogenic DI (aquaporin II), Charcot-Marie Tooth syndrome (peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease ( disease) (APP and presenilin), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders (e.g., Huntington's disease), spinocerebellar ataxia type I, spinobulbar muscular atrophy, dentatoruballi muscular atrophy, and myotonic dystrophy, as well as spongiform encephalopathies (e.g., hereditary Creutzfeldt-Jakob disease) (prion protein processing defects), Fabry disease (lysosomal alpha-galactosidase A), Gerstmann-Straussler syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome.

[0021] In addition to upregulating CFTR activity, a reduction in anion secretion by CFTR modulators would be beneficial in the treatment of secretory diarrhea, in which epithelial water transport is significantly increased due to secretagogue-activated chloride transport. This mechanism involves elevation of cAMP and stimulation of CFTR.

[0022] Excess chloride transport is seen in all diarrhea, regardless of etiology, and can cause dehydration, acidosis, impaired growth, and death. Acute and chronic diarrhea remain a major medical problem worldwide and are an important factor in malnutrition, causing death in children under 5 years of age (5 million deaths / year). In addition, diarrhea is a dangerous condition in patients with chronic inflammatory bowel disease (IBD) and / or acquired immunodeficiency syndrome (AIDS).

[0023] Therefore, there is a need for novel compounds that can modulate CFTR. Specifically, the present invention discloses compounds that can act as CFTR modulators for the treatment of cystic fibrosis. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for treating cystic fibrosis by administering the compounds of the present invention. Summary of the invention

[0024] In one aspect, the present invention provides compounds having Formula I and pharmaceutically acceptable salts thereof,

[0025]

[0026] in

[0027] X 1 and X 2 are independently selected

[0028] H;

[0029] Halogen;

[0030] C 1-4 Alkyl, optionally substituted with one or more independently selected halo;

[0031] C 1-4 Alkoxy, optionally substituted with one or more independently selected

[0032] -OH;

[0033] C 1-4 alkoxy; or

[0034] -NR 8A R 8B ;

[0035] -NR 9A R 9B ;

[0036] Cyclopropyl, optionally substituted with one or more independently selected R 5 Group substitution;

[0037] Phenoxy, optionally substituted with one or more independently selected R 5 group substitution; or

[0038] Phenyl, optionally substituted with one or more independently selected R 5 Group substitution;

[0039] R 1 yes

[0040] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0041] -OH;

[0042] C 1-4 alkoxy; or

[0043] a 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N;

[0044] Phenyl, optionally substituted with one or more independently selected R 4 Group substitution;

[0045] An N-linked 4- to 6-membered monocyclic heterocycle comprising 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R 5 Group substitution;

[0046] An N-linked 4- to 6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused to a phenyl group, wherein the monocyclic heterocycle and the phenyl group are optionally substituted by one or more independently selected R 5 Group substitution;

[0047] C 3-7 Cycloalkyl, optionally substituted with one or more independently selected R 5 Group substitution;

[0048] or

[0049] -NR 6 R 7 ;

[0050] R 2 is a 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 Group substitution;

[0051] Each R 3 Independently selected from the group consisting of:

[0052] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0053] C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A Group substitution;

[0054] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution;

[0055] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A Group substitution;

[0056] C 1-4 Alkoxy, optionally substituted with one or more independently selected C 3-7 Cycloalkyl, halo, or -OCH3 substitution;

[0057] -OR 11 ;

[0058] -OH;

[0059] Halogen;

[0060] -CN;

[0061] -OC(O)R 10 ;

[0062] -OS(O)2OH;

[0063] -NHC(=S)R 11 ;or

[0064] -OP(O)(OH)(OH);

[0065] -C(O)NH2;

[0066] Phenyl, wherein the phenyl is optionally substituted with one or more independently selected R A Group substitution;

[0067] A 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R A Group substitution;

[0068] C 3-7 Cycloalkyl, wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A Group substitution; and

[0069] A 4- to 6-membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution;

[0070] Each R 4Independently selected from the group consisting of:

[0071] Halogen;

[0072] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; and

[0073] C 1-4 alkoxy, optionally substituted with one or more independently selected halo; each R 5 Independently selected from the group consisting of:

[0074] -OH;

[0075] Halogen;

[0076] C 1-4 Alkyl, optionally substituted with one or more independently selected C 1-4 Alkoxy, halo or -OH substitution; and

[0077] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo;

[0078] R 6 It is H, C 1-4 Alkyl, or C 3-7 Cycloalkyl, wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R 5 Group substitution;

[0079] R 7 yes

[0080] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0081] Halogen;

[0082] Phenyl, optionally substituted with one or more independently selected groups below:

[0083] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; or

[0084] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo;

[0085] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo; or

[0086] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R 5 Group substitution;

[0087] Each R 8a and R 8b Independently selected from the group consisting of

[0088] H; and

[0089] C 1-4 alkyl;

[0090] R 9a and R 9b Independently selected from the group consisting of

[0091] H;

[0092] C 1-4 Alkyl; and

[0093] C 3-7 cycloalkyl; and

[0094] Each R 10 Independently selected from the group consisting of

[0095] C 1-6 Alkyl; and

[0096] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A Group substitution; each R 11 Independently selected from the group consisting of

[0097] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution;

[0098] A 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R A Group substitution;

[0099] C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A Group substitution; and

[0100] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A group substitution; and

[0101] Each R A Independently selected from the group consisting of

[0102] -CN,

[0103] Halogen;

[0104] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; and

[0105] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo.

[0106] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutical carrier. Such compositions can be administered according to the methods of the invention, typically as part of a treatment regimen, for the treatment or prevention of conditions and disorders associated with cystic fibrosis transmembrane conductance regulator protein activity. In a specific aspect, the pharmaceutical composition may additionally comprise other therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more specific aspect, the additional therapeutically active ingredient is an agent for the treatment of cystic fibrosis.

[0107] Additionally, the compounds of the invention useful in the pharmaceutical compositions and methods of treatment disclosed herein are pharmaceutically acceptable at the time of preparation and use.

[0108] Yet another aspect of the invention relates to methods for treating or preventing conditions and disorders associated with cystic fibrosis transmembrane conductance regulator protein activity in mammals. More specifically, the methods can be used to treat or prevent conditions and disorders associated with cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive pulmonary disease, or chronic obstructive airway disease. Thus, the compounds and compositions of the invention can be used as medicaments for treating or preventing diseases regulated by cystic fibrosis transmembrane conductance regulator.

[0109] Further described herein are compounds, compositions comprising these compounds, methods of making these compounds, and methods of treating or preventing conditions and disorders by administering these compounds.

[0110] In a specific aspect, compounds of the invention are provided for use in treating cystic fibrosis. In a specific aspect, compounds of the invention are provided for use in treating cystic fibrosis caused by class I, II, III, IV, V and / or VI mutations.

[0111] The present invention also provides a pharmaceutical composition comprising a compound of the present invention and a suitable pharmaceutical carrier for use in medicine. In a specific aspect, the pharmaceutical composition is for use in the treatment of cystic fibrosis.

[0112] The following paragraphs describe these and other objects of the present invention. These objects should not be considered to narrow the scope of the present invention. DETAILED DESCRIPTION

[0113] Described herein are compounds having formula I,

[0114]

[0115] Where X 1 , X 2 , R 1 , and R 2 Definitions are provided above in the Summary of the Invention and below in the Examples. Additionally, compositions containing such compounds and methods of using such compounds and compositions to treat conditions and disorders are also included.

[0116] Compounds included herein may contain one or more variables that occur more than once in any substituent or in a formula herein. The definition of the variable at each occurrence is independent of its definition at another occurrence. In addition, combinations of substituents are permitted only if such combinations result in stable compounds. A stable compound is a compound that can be isolated from a reaction mixture.

[0117] definition

[0118] Note that, as used in this specification and the intended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound as well as one or more of the same or different compounds, reference to "a pharmaceutically acceptable carrier" means a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, etc.

[0119] Unless specified to the contrary, the following terms used in the description and appended claims have the meanings presented below:

[0120] The term "alkoxy" as used herein means an alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy groups are, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy. In some cases, the number of carbon atoms in the alkoxy moiety is indicated by the prefix "C x-y ” indicates that x is the minimum number of carbon atoms in the substituent and y is the maximum number. Thus, for example, “C 1-6 "Alkoxy" means an alkoxy substituent containing 1 to 6 carbon atoms, and "C 1-4 "Alkoxy" means an alkoxy substituent containing from 1 to 4 carbon atoms.

[0121] The term "alkyl" as used herein means a saturated straight or branched hydrocarbon chain group. In some cases, the number of carbon atoms in the alkyl portion is indicated by the prefix "C x-y ” indicates that x is the minimum number of carbon atoms in the substituent and y is the maximum number. Thus, for example, “C 1-6 "Alkyl" means an alkyl substituent containing 1 to 6 carbon atoms, and "C 1-4 The term "alkyl" refers to an alkyl substituent containing from 1 to 4 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, and 1,2,2-trimethylpropyl.

[0122] Unless otherwise indicated, the term “ 3-7 "Cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted.

[0123] Unless otherwise indicated, the term “ 3-6 "Cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted.

[0124] Unless otherwise indicated, the term “ 4-6 "Cycloalkyl" means cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted.

[0125]

[0046] The term "halo" or "halogen" as used herein refers to chlorine (Cl), bromine (Br), iodine (I) and fluorine (F).

[0126] As used herein, the term "monocyclic heterocycle" or "monocyclicheterocycli" means a three-, four-, five-, six-, seven-, or eight-membered fully saturated monocyclic carbocyclic ring in which one or more carbon ring atoms are replaced by heteroatoms independently selected from the group consisting of O, N, and S. One carbon ring atom in the 3- and 4-membered monocyclic heterocycles is replaced by a heteroatom selected from the group consisting of O, N, and S. One, two, or three carbon ring atoms in the 5-, 6-, 7-, and 8-membered monocyclic heterocycles may be replaced by heteroatoms selected from the group consisting of O, N, and S. Examples of five-membered monocyclic heterocycles include those containing the following in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S and 2 N; 1 O and 1 N; or 1 O and 2 N. Non-limiting examples of 5-membered monocyclic heterocyclic groups include 1,3-dioxolanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl and thiazolidinyl. Examples of six-membered monocyclic heterocyclic rings include those containing the following in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. Examples of 6-membered monocyclic heterocyclic groups include tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, 1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl and trithianyl. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolpyridinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiadiazolinyl, thiadiazopyridinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl.

[0127] The term "4-6 membered monocyclic heterocycle or 4-6 membered monocyclic heterocyclic" as used herein means a 4-, 5- or 6-membered monocyclic heterocycle as defined above. Non-limiting examples of 4- to 6-membered monocyclic heterocycles include azetidinyl, oxetanyl, 1,3-dioxolanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, piperazinyl, piperidinyl, thiomorpholinyl and morpholinyl.

[0128] The term "3-6 membered monocyclic heterocycle or 3-6 membered monocyclic heterocyclic" as used herein means a 3-, 4-, 5- or 6-membered monocyclic heterocycle as defined above. Non-limiting examples of 3- to 6-membered monocyclic heterocycles include aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl, thiomorpholinyl and morpholinyl.

[0129] The term "5- to 11-membered spiro heterocycle" as used herein refers to a 3- to 6-membered monocyclic heterocycle in which two substituents on the same carbon atom of the 3- to 6-membered monocyclic heterocycle are taken together with the carbon atom to form a second ring system; wherein the second ring system is C 3-6 Cycloalkyl or 3- to 6-membered monocyclic heterocycle. Examples of 5- to 11-membered spiroheterocycles include, but are not limited to, 1-oxaspiro[4.4]nonan-3-yl and 1-oxaspiro[4.5]decan-3-yl.

[0130] The term "7- to 11-membered spiro heterocycle" as used herein refers to a 4- to 6-membered monocyclic heterocycle in which two substituents on the same carbon atom of the 4- to 6-membered monocyclic heterocycle are taken together with the carbon atom to form a second ring system; wherein the second ring system is C 4-6 Cycloalkyl or 4- to 6-membered monocyclic heterocycle. Specific examples of 7- to 11-membered spiroheterocycles are 6-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.4]octyl and 2-oxa-6-azaspiro[3.3]heptyl.

[0131] Unless otherwise indicated, monocyclic heterocycles and spiro heterocycles (including the exemplary rings) are optionally substituted and are attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring system. The nitrogen atom within the heterocycle may be optionally oxidized or may be optionally quaternized.

[0132] The term "5- to 6-membered monocyclic heteroaryl" as used herein means a 5- or 6-membered monocyclic aromatic ring structure in which one or more ring carbon atoms are replaced by heteroatoms independently selected from the group consisting of O, N and S. The 5-membered ring contains two double bonds. The 5-membered ring may also contain one heteroatom selected from the group consisting of O and S; or may contain one, two, three or four nitrogen atoms and optionally one oxygen atom or one sulfur atom. The 6-membered ring contains three double bonds and one, two, three or four nitrogen atoms. Representative examples of 5- to 6-membered monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridyl, pyridazinyl, pyrimpyridinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, such as 1,3-thiazolyl, thienyl, triazolyl and triazinyl. Unless otherwise indicated, the 5- to 6-membered monocyclic heteroaryl (including the exemplary rings) is optionally substituted and is attached to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the ring system. The nitrogen atom in the heteroaryl ring can be optionally oxidized or can be optionally quaternized.

[0133] The term "phenoxy" as used herein refers to a phenyl group attached to the parent molecular moiety through an oxygen atom.

[0134] The term "heteroatom" as used herein means nitrogen (N), oxygen (O) or sulfur (S).

[0135] The term "radiolabeled" means that at least one atom in the compound of the present invention is a radioactive atom or a radioisotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles (such as alpha particles or beta particles) or positrons. Examples of such radioactive atoms include, but are not limited to, 3 H (tritium), 14 C. 11 C. 15 O. 18 F. 35 S. 123 I and 125 I.

[0136] If a moiety is described as "substituted," a non-hydrogen group is in the place of a hydrogen group on any substitutable atom of the moiety. Thus, for example, a substituted heterocyclic moiety is a heterocyclic moiety in which at least one non-hydrogen group is in the place of a hydrogen group on the heterocyclic ring. It should be recognized that if there are one or more substitutions on a moiety, each non-hydrogen group may be the same or different (unless otherwise specified).

[0137] If a moiety is described as "optionally substituted," the moiety may be (1) unsubstituted, or (2) substituted. If a moiety is described as optionally substituted with up to a specified number of non-hydrogen groups, the moiety may be (1) unsubstituted; or (2) substituted with up to that specified number of non-hydrogen groups or substituted up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as being optionally substituted with up to 3 non-hydrogen groups, then any heteroaryl group having fewer than 3 substitutable positions would be optionally substituted with up to as many non-hydrogen groups as there are substitutable positions. For illustration, a tetrazolyl group (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen group. For further illustration, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen groups, then a primary amino nitrogen would be optionally substituted with up to 2 non-hydrogen groups, while a secondary amino nitrogen would be optionally substituted with up to only 1 non-hydrogen group.

[0138] The term "substituted with one or more" refers to one to four substituents. In one embodiment, it refers to one to three substituents. In other embodiments, it refers to one or two substituents. In yet another embodiment, it refers to one substituent.

[0139] The terms "treat, treating and treatment" refer to methods of alleviating or eliminating a disease and / or its associated symptoms. In certain embodiments, "treat, treating and treatment" refers to improving at least one physical parameter that may not be discerned by the subject. In yet another embodiment, "treat, treating and treatment" refers to regulating a disease or disorder physically (e.g., stabilizing perceptible symptoms), regulating a disease or disorder physiologically (e.g., stabilizing physical parameters), or both. In another embodiment, "treat, treating and treatment" refers to slowing the progression of a disease or disorder.

[0140] The term "prevent" ("prevent", "preventing" and "prevention") refers to a method of preventing the onset of a disease and / or its associated symptoms or preventing a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and / or its associated symptoms and reducing the risk of a subject acquiring or developing a disease or disorder.

[0141] The phrase "therapeutically effective amount" means an amount of a compound or a pharmaceutically acceptable salt thereof that is sufficient to prevent the occurrence of the condition or disorder being treated or to alleviate one or more symptoms thereof to some extent when administered alone or in combination with another therapeutic agent or treatment in a specific subject or subject population. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject to be treated. For example, in humans or other mammals, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting, or may be the amount required for a specific disease and subject to be treated according to the guidelines of the United States Food and Drug Administration or an equivalent foreign agency.

[0142] The term "subject" is defined herein to refer to an animal such as a mammal, including, but not limited to, primates (e.g., humans), cattle, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice, etc. In a preferred embodiment, the subject is a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0143] As used herein, "one or more class I mutations" refers to mutations that interfere with protein synthesis. They result in the introduction of premature termination signals (stop codons) of translation in the mRNA. Truncated CFTR proteins are unstable and rapidly degraded, so the net effect is that there is no protein at the apical membrane. Specifically, one or more class I mutations refers to p.Gly542X (G542X), W1282X, c.489+1G>T (621+1G>T), or c.579+1G>T (711+1G>T) mutations. More specifically, one or more class I mutations refers to G542X; or W1282X mutations.

[0144] As used herein, "one or more class II mutations" refers to mutations that affect protein maturation. This results in the production of CFTR proteins that cannot be properly folded and / or transported to the site on the apical membrane where they function. Specifically, one or more class II mutations refers to p.Phe508del (F508del), p.Ile507del, or p.Asn1303Lys (N1303K) mutations. More specifically, one or more class II mutations refers to F508del or N1303K mutations.

[0145] As used herein, "one or more class III mutations" refers to mutations that alter the regulation of the CFTR channel. The mutated CFTR protein is properly transported and localized to the plasma membrane but cannot be activated, or it cannot function as a chloride channel. Specifically, one or more class III mutations refer to p.Gly551Asp (G551D), G551S, R553G; G1349D; S1251N, G178R, S549N mutations. More specifically, one or more class III mutations refer to G551D, R553G, G1349D, S1251N, G178R, or S549N mutations.

[0146] As used herein, "one or more class IV mutations" refers to mutations that affect chloride ion conduction. The CFTR protein is correctly transported to the cell membrane, but produces reduced chloride flow or "gating defects" (mostly missense mutations located in the transmembrane domain). Specifically, one or more class IV mutations refers to p.Arg117His (R117H), R347P, or p.Arg334Trp (R334W) mutations.

[0147] As used herein, "one or more class V mutations" refers to mutations that reduce the level of normally functioning CFTR at the apical membrane or cause "conduction defects" (e.g., partial abnormal splicing mutations or inefficient transport missense mutations). Specifically, one or more class V mutations refer to c.1210-12T[5] (5T allele), c.S3140-26A>G (3272-26A>G), c.3850-2477C>T (3849+10kbC>T) mutations.

[0148] As used herein, "one or more class VI mutations" refers to mutations that reduce the stability of existing CFTR or mutations that affect the regulation of other channels and thus cause the inherent instability of the CFTR protein. In fact, despite its function, the CFTR protein is unstable on the cell surface and is rapidly removed and degraded by the cellular machinery. Specifically, one or more class VI mutations refer to rescued F508del, 120del23, N287Y, 4326delTC, or 4279insA mutations. More specifically, one or more class VI mutations refer to rescued F508del mutations.

[0149] Compound

[0150] The compounds of the present invention have the general formula I as described above.

[0151] Specific values ​​for the variable groups are described below. Such values ​​may be used with any of the other values, definitions, claims or examples defined above or below, as appropriate.

[0152] Certain embodiments relate to compounds having Formula I,

[0153]

[0154] in

[0155] X 1 and X 2 Independently selected from

[0156] H;

[0157] Halogen;

[0158] C 1-4 Alkyl, optionally substituted with one or more independently selected halo;

[0159] C 1-4 Alkoxy, optionally substituted with one or more independently selected

[0160] -OH;

[0161] C 1-4 alkoxy; or

[0162] -NR 8A R 8B ;

[0163] -NR 9A R 9B :

[0164] Cyclopropyl, optionally substituted with one or more independently selected R 5 Group substitution;

[0165] Phenoxy, optionally substituted with one or more independently selected R 5 group substitution; or

[0166] Phenyl, optionally substituted with one or more independently selected R 5 Group substitution;

[0167] R 1 yes

[0168] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0169] -OH;

[0170] C 1-4 alkoxy; or

[0171] a 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N;

[0172] Phenyl, optionally substituted with one or more independently selected R 4 Group substitution;

[0173] An N-linked 4- to 6-membered monocyclic heterocycle comprising 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R 5 Group substitution;

[0174] An N-linked 4- to 6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused to a phenyl group, wherein the monocyclic heterocycle and the phenyl group are optionally substituted by one or more independently selected R 5 Group substitution;

[0175] C 3-7 Cycloalkyl, optionally substituted with one or more independently selected R 5 group substitution; or

[0176] -NR 6 R 7 ;

[0177] R 2 is a 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 Group substitution;

[0178] Each R 3 Independently selected from the group consisting of:

[0179] C 1-4 Alkyl, optionally substituted with one or more independently selected groups:

[0180] C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A Group substitution;

[0181] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution;

[0182] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A Group substitution;

[0183] C 1-4 Alkoxy, optionally substituted with one or more independently selected C 3-7Cycloalkyl, halo, or -OCH3 substitution;

[0184] -OR 11 ;

[0185] -OH;

[0186] Halogen;

[0187] -CN;

[0188] -OC(O)R 10 ;

[0189] -OS(O)2OH;

[0190] -NHC(=S)R 11 ;or

[0191] -OP(O)(OH)(OH);

[0192] -C(O)NH2;

[0193] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A Group substitution;

[0194] A 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R A Group substitution;

[0195] C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A Group substitution; and

[0196] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution;

[0197] Each R 4 Independently selected from the group consisting of:

[0198] Halogen;

[0199] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; and

[0200] C 1-4 alkoxy, optionally substituted with one or more independently selected halo; each R 5 Independently selected from the group consisting of:

[0201] -OH;

[0202] Halogen;

[0203] C 1-4 Alkyl, optionally substituted with one or more independently selected C 1-4 Alkoxy, halo or -OH substitution; and

[0204] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo; R 6 It is H, C 1-4 Alkyl, or C 3-7 Cycloalkyl, wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R 5 Group substitution;

[0205] R 7 yes

[0206] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0207] Halogen;

[0208] Phenyl, optionally substituted with one or more independently selected groups below:

[0209] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; or

[0210] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo;

[0211] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo; or

[0212] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R 5 Group substitution;

[0213] Each R 8a and R 8b Independently selected from the group consisting of

[0214] H; and

[0215] C 1-4 alkyl;

[0216] R 9a and R 9bIndependently selected from the group consisting of

[0217] H;

[0218] C 1-4 Alkyl; and

[0219] C 3-7 cycloalkyl; and

[0220] Each R 10 Independently selected from the group consisting of

[0221] C 1-6 Alkyl; and

[0222] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A Group substitution; each R 11 Independently selected from the group consisting of

[0223] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution;

[0224] A 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R A Group substitution;

[0225] C 3-7 Cycloalkyl; wherein the C 3-7 Cycloalkyl is optionally substituted with one or more independently selected RA groups; and

[0226] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A group substitution; and

[0227] Each R A Independently selected from the group consisting of

[0228] -CN,

[0229] Halogen;

[0230] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; and

[0231] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo.

[0232] Certain embodiments relate to compounds having Formula I,

[0233]

[0234] in

[0235] X 1 and X 2 is an independently selected H;

[0236] Halogen;

[0237] C 1-4 Alkyl, optionally substituted with one or more independently selected halo;

[0238] C 1-4 Alkoxy, optionally substituted with one or more independently selected

[0239] -OH;

[0240] C 1-4 alkoxy; or

[0241] -NR 8A R 8B ;

[0242] -NR 9A R 9B ;

[0243] Cyclopropyl, optionally substituted with one or more independently selected R 5 Group substitution;

[0244] Phenoxy, optionally substituted with one or more independently selected R 5 group substitution; or

[0245] Phenyl, optionally substituted with one or more independently selected R 5 Group substitution;

[0246] R 1 yes

[0247] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0248] -OH;

[0249] C 1-4 alkoxy; or

[0250] a 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N;

[0251] Phenyl, optionally substituted with one or more independently selected R 4 Group substitution;

[0252] An N-linked 4- to 6-membered monocyclic heterocycle comprising 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R 5 Group substitution;

[0253] An N-linked 4- to 6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused to a phenyl group, wherein the monocyclic heterocycle and the phenyl group are optionally substituted by one or more independently selected R 5 Group substitution;

[0254] C 3-7 Cycloalkyl, optionally substituted with one or more independently selected R 5 group substitution; or

[0255] -NR 6 R 7 ;

[0256] R 2 is a 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 Group substitution;

[0257] Each R 3 Independently selected from the group consisting of:

[0258] C 1-4 Alkyl, optionally substituted with one or more independently selected cyclopropyl groups;

[0259] a 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N;

[0260] Phenyl;

[0261] C 1-4 Alkoxy, optionally substituted with one or more independently selected cyclopropyl, halo, or -OCH3;

[0262] -OR 11 ;

[0263] -OH;

[0264] Halogen;

[0265] -CN;

[0266] -OC(O)R 10 ;

[0267] -OS(O)2OH;

[0268] -NHC(=S)R 11 ;or

[0269] -OP(O)(OH)(OH);

[0270] -C(O)NH2;

[0271] C 3-7 Cycloalkyl; and

[0272] a 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N;

[0273] Each R 4 Independently selected from the group consisting of:

[0274] Halogen;

[0275] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; and

[0276] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo;

[0277] Each R 5 Independently selected from the group consisting of:

[0278] -OH;

[0279] Halogen;

[0280] C 1-4 Alkyl, optionally substituted with one or more independently selected C 1-4 Alkoxy, halo or -OH substitution; and

[0281] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo;

[0282] R 6 It is H, C 1-4 Alkyl, or C 3-7 Cycloalkyl, wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R 5 Group substitution;

[0283] R 7 yes

[0284] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0285] Halogen;

[0286] Phenyl, optionally substituted with one or more independently selected groups below:

[0287] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; or

[0288] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo;

[0289] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo; or

[0290] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R 5 Group substitution;

[0291] Each R 8a and R 8b Independently selected from the group consisting of

[0292] H; and

[0293] C 1-4 alkyl;

[0294] R 9a and R 9b Independently selected from the group consisting of

[0295] H;

[0296] C 1-4 Alkyl; and

[0297] C 3-7 cycloalkyl; and

[0298] Each R 10 Independently selected from the group consisting of

[0299] C 1-6 Alkyl; and

[0300] phenyl; and

[0301] Each R 11 Independently selected from the group consisting of

[0302] a 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N;

[0303] a 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S and N;

[0304] C3-7 Cycloalkyl; and

[0305] Phenyl, optionally substituted with one or more independently selected groups:

[0306] Halogen.

[0307] In certain embodiments of Formula I, R 1 is optionally selected from one or more independently selected R 4 A phenyl group substituted with a group.

[0308] In certain embodiments of Formula I, R 1 is optionally one, two or three independently selected R 4 A phenyl group substituted with a group.

[0309] In certain embodiments of Formula I, R 1 It is an unsubstituted phenyl group.

[0310] In certain embodiments of Formula I, R 1 is one or two independently selected R 4 A phenyl group substituted with a group.

[0311] In certain embodiments of Formula I, R 1 is an independently selected R 4 A phenyl group substituted with a group.

[0312] In certain embodiments of Formula I, each R 4 Independently selected from the group consisting of: fluorine; C 1-4 alkyl, which is optionally substituted with 1, 2 or 3 fluorines; and C 1-4 Alkoxy, which is optionally substituted with 1, 2 or 3 fluorines.

[0313] In certain embodiments of Formula I, each R 4 are independently selected from the group consisting of: C optionally substituted with 1, 2 or 3 fluorine 1-4 Alkyl; and C 1-4 Alkoxy, which is optionally substituted with 1, 2 or 3 fluorines.

[0314] In certain embodiments of Formula I, each R 4 is selected from the group consisting of: F, -CH3, -CH(CH3)2, t-Bu, -CF3, -OCH3, -OCH(CH3)2, and -OCF3. In some embodiments of Formula I, R 4 is selected from the group consisting of: F, -CF3, and -OCF3. In some embodiments of Formula I, R 4 is -CH(CH3)2. In some embodiments of Formula I, R 4is F. In some embodiments of Formula I, R 4 is -CF3. In some embodiments of Formula I, R 4 Yes - OCF3.

[0315] In certain embodiments of Formula I, R 1 It is a phenyl group substituted with one -OCF3.

[0316] In certain embodiments of Formula I, R 1 is an N-linked 4- to 6-membered monocyclic heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocyclic ring is optionally substituted by 1, 2 or 3 independently selected R 5 Group substitution.

[0317] In certain embodiments of Formula I, R 1 is an N-linked 4- to 6-membered monocyclic heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein the monocyclic heterocyclic ring is optionally substituted by 1, 2 or 3 independently selected R 5 In some such embodiments of Formula I, each R 5 is independently selected from the group consisting of: F, -CH3, -CH(CH3)2, t-Bu, -CF3, -OCH3, and -OCF3. In some such embodiments of Formula I, each R 5 Independently selected from the group consisting of: F, -CH3, t-Bu, -CF3, -OCH3, -CH2OH, and -OCF3.

[0318] In certain embodiments of Formula I, R 1 is azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl, each of which is optionally substituted with 1 or 2 independently selected R 5 In some such embodiments of Formula I, each R 5 Independently selected from the group consisting of F, -CH3, -CH(CH3)2, t-Bu, -CF3, -OCH3, and -OCF3.

[0319] In certain embodiments of Formula I, R 1 is piperidinyl, optionally substituted with 1 or 2 independently selected R 5 In some such embodiments of Formula I, each R 5 is independently selected from the group consisting of: F, -CH3, t-Bu, -CF3, -OCH3, and -OCF3. In some such embodiments, R 1 is piperidinyl substituted with two fluoro groups. In some such embodiments of Formula I, R 1is piperidinyl substituted with one fluoro group. In some such embodiments of Formula I, R 1 is piperidinyl substituted with one methyl group. In some such embodiments of Formula I, R 1 is piperidinyl substituted with two methyl groups. In some such embodiments of Formula I, R 1 is piperidinyl substituted with one -CF3. In some such embodiments of Formula I, R 1 is piperidinyl substituted with one OCH3. In some such embodiments of Formula I, R 1 is piperidinyl substituted with one OCF3. In some such embodiments of Formula I, R 1 It is a piperidinyl substituted with one t-Bu.

[0320] In certain embodiments of Formula I, R 1 is an N-linked 4- to 6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused to a phenyl group, wherein the monocyclic heterocycle and the phenyl group are optionally separated by 1, 2 or 3 independently selected R 5 In some such embodiments of Formula I, R 1 is 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, optionally substituted with 1, 2 or 3 independently selected R 5 In some such embodiments of Formula I, R 1 It is unsubstituted 3,4-dihydro-2H-benzo[b][1,4]oxazinyl.

[0321] In certain embodiments of Formula I, R 1 is optionally substituted with one or more independently selected -OH, C 1-4 Alkoxy substituted C 1-4 alkyl or a 4- to 6-membered monocyclic heterocyclic ring including 1 or 2 heteroatoms independently selected from the group consisting of O, S and N. In some such embodiments of Formula I, R1 is an unsubstituted C 1-4 In some such embodiments of Formula I, R 1 is C substituted with -OH 1-4 In some such embodiments of Formula I, R 1 It is C 1-4 Alkoxy substituted C 1-4 In some such embodiments of Formula I, R 1 It is C 1-4 alkyl, which is substituted with a 4- to 6-membered monocyclic heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N. In some such embodiments of Formula I, R 1 is -CH2CH3. In some such embodiments of Formula I, R 1is -CH2CH2OH. In some such embodiments of Formula I, R 1 is -CH(CH3)2. In some such embodiments, R 1 is -CH2CH2OCH3. In some such embodiments of Formula I, R 1 It is a C1 alkyl substituted by tetrahydrofuran.

[0322] In certain embodiments of Formula I, R 1 is optionally selected from one or more independently selected R 5 C 3-7 In some such embodiments of Formula I, R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some such embodiments of Formula I, R 1 It is cyclopentyl.

[0323] In certain embodiments of Formula I, R 1 Yes - NR 6 R 7 .

[0324] In certain embodiments of Formula I, R 1 Yes - NR 6 R 7 ;in

[0325] R 6 is H, -CH3, or cyclopropyl; wherein the cyclopropyl is optionally substituted by 1 or 2 independently selected R 5 Group substitution; and

[0326] R 7 yes

[0327] C 1-4 alkyl;

[0328] C 1-4 Alkyl, which is substituted by 1, 2 or 3 fluorine groups;

[0329] C 1-4 Alkyl substituted with one phenyl group, wherein the phenyl group is optionally substituted with 1, 2 or 3 independently selected groups

[0330] fluorine;

[0331] C 1-4 Alkyl, which is optionally substituted with 1, 2 or 3 fluorines; or

[0332] C 1-4 Alkoxy, optionally substituted with 1, 2 or 3 fluorine;

[0333] C 2-4 Alkyl, which has a C 1-4 Alkoxy substitution; or

[0334] C 1-4 alkyl, which is substituted with a 4- to 6-membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted with 1, 2 or 3 independently selected R 5 Group substitution.

[0335] In certain embodiments of Formula I, R1 is -NR 6 R 7 ;in

[0336] R 6 is H, -CH3, cyclobutyl or cyclopropyl; wherein the cyclobutyl and cyclopropyl are optionally substituted by 1 or 2 independently selected R 5 Group substitution; and

[0337] R 7 yes

[0338] C 1-4 alkyl;

[0339] C substituted with 1, 2 or 3 fluorine groups 1-4 alkyl;

[0340] C 1-4 Alkyl substituted with one phenyl group, wherein the phenyl group is optionally substituted with 1, 2 or 3 independently selected groups

[0341] fluorine;

[0342] C 1-4 Alkyl, which is optionally substituted with 1, 2 or 3 fluorines; or

[0343] C 1-4 Alkoxy, optionally substituted with 1, 2 or 3 fluorine;

[0344] C 2-4 Alkyl, which has a C 1-4 Alkoxy substitution; or

[0345] C 1-4 alkyl, which is substituted with a 4- to 6-membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted with 1, 2 or 3 independently selected R 5 Group substitution.

[0346] In certain embodiments of Formula I, R 7 is C substituted with a phenyl group 1-4 Alkyl, wherein the phenyl group is optionally substituted with 1, 2 or 3 independently selected CF3, fluorine or C 1-4 In some such embodiments, R7 is C substituted with a phenyl group 1-4 Alkyl, wherein the phenyl is substituted.

[0347] In certain embodiments of Formula I, X 1 is H; halogen; C 1-4 Alkyl, optionally substituted with one or more independently selected halo; C 1-4 Alkoxy, which is optionally substituted with one or more independently selected -OH, C 1-4 Alkoxy, or -NR 11A R 11B Replacement; -NR 12A R 12B ; optionally substituted cyclopropyl; optionally substituted phenoxy; or optionally substituted phenyl.

[0348] In certain embodiments of Formula I, R 1 Yes - NR 6 R 7 ;in

[0349] R6 is -CH3; and

[0350] R 7 yes

[0351] C 1-4 Alkyl substituted with one phenyl group, wherein the phenyl group is optionally substituted with 1, 2 or 3 independently selected groups

[0352] fluorine;

[0353] C 1-4 Alkyl, which is optionally substituted with 1, 2 or 3 fluorines; or

[0354] C 1-4 Alkoxy, optionally substituted with 1, 2 or 3 fluorine;

[0355] C 2-4 Alkyl, which has a C 1-4 Alkoxy substitution; or

[0356] C 1-4 alkyl, which is substituted with a 4- to 6-membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted with 1, 2 or 3 independently selected R 5 Group substitution.

[0357] In certain embodiments of Formula I, R 1 Yes - NR 6 R 7 ;in

[0358] R 6is -CH3; and

[0359] R 7 is C substituted with a phenyl group 1-4 In some such embodiments, R 1 Yes - NR 6 R 7 ; wherein R6 is -CH3; and R 7 is C substituted with a phenyl group 1-4 alkyl.

[0360] In certain embodiments of Formula I, X 1 and X 2 is independently selected H, halo, optionally substituted cyclopropyl, or optionally substituted phenyl.

[0361] In certain embodiments of Formula I, X 1 and X 2 is independently selected H, halo, or substituted cyclopropyl.

[0362] In certain embodiments of Formula I, X 1 and X 2 Each is H.

[0363] In certain embodiments of Formula I, X 1 is H; and X 2 In certain embodiments of Formula I, X 1 is H; and X 2 It's Br.

[0364] In certain embodiments of Formula I, X 1 is Cl; and X 2 is H. In certain embodiments of Formula I, X 1 is Br; and X 2 It's H.

[0365] In certain embodiments of Formula I, X 1 and X 2 are each independently selected H, bromine, -NR 12A R 12B , C 1-4 wherein cyclopropyl, phenoxy and phenyl are optionally substituted by 1, 2 or 3 independently selected R 5 group substituted, and C 1-4 The alkoxy group is optionally substituted with one or more independently selected -OH, C 1-4 Alkoxy or -NR 11A R 11BIn some such embodiments of Formula I, the cyclopropyl is unsubstituted. In some such embodiments of Formula I, the phenyl and phenoxy are substituted with F.

[0366] In certain embodiments of Formula I, X 1 and X 2 Each is H, bromine, cyclopropyl, or phenyl; wherein the cyclopropyl and phenyl are optionally substituted by 1, 2, or 3 independently selected R 5 In some such embodiments of Formula I, the cyclopropyl group is unsubstituted.

[0367] In certain embodiments of Formula I, X 1 It's bromine.

[0368] In certain embodiments of Formula I, X 2 It's bromine.

[0369] In certain embodiments of Formula I, X 1 is cyclopropyl, or phenyl; wherein the cyclopropyl and phenyl are optionally substituted by 1, 2, or 3 independently selected R 5 The group is substituted, and X 2 is H. In some such embodiments of Formula I, the cyclopropyl is unsubstituted.

[0370] In certain embodiments of Formula I, X 1 is cyclopropyl, phenoxy, or phenyl; wherein the cyclopropyl, phenoxy, and phenyl are optionally substituted by 1, 2, or 3 independently selected R 5 The group is substituted, and X 2 is H. In some such embodiments of Formula I, the cyclopropyl group is unsubstituted.

[0371] In certain embodiments of Formula I, X 1 is unsubstituted cyclopropyl or phenyl substituted with one fluorine; and X 2 It's H.

[0372] In certain embodiments of Formula I, X 1 is unsubstituted cyclopropyl, phenyl substituted with one fluorine, or phenoxy substituted with one fluorine; and X 2 It's H.

[0373] In certain embodiments of Formula I, X 1 is a substituted cyclopropyl; and X 2 It's H.

[0374] In certain embodiments of Formula I, X 1 is phenyl substituted with one fluorine; and X 2 It's H.

[0375] In certain embodiments of Formula I, X 1 is a phenoxy group substituted with one fluorine; and X 2 It's H.

[0376] In certain embodiments of Formula I, X 1 is optionally substituted with one or more independently selected -OH, C 1-4 Alkoxy, or -NR 11A R 11B Substituted C 1-4 Alkoxy; and X 2 is H. In some such embodiments of Formula I, R 11A and R 11B Is H or C 1-4 In some such embodiments of Formula I, R 11A and R 11B All are CH3.

[0377] In certain embodiments of Formula I, X 1 is unsubstituted C 1-4 Alkoxy; and X 2 is H. In some such embodiments, X 1 It is -OCH3.

[0378] In certain embodiments of Formula I, X 1 It is C 1-4 Alkoxy substituted C 1-4 Alkoxy; and X 2 is H. In some such embodiments of Formula I, X 1 It is -OCH2CH2OCH3.

[0379] In certain embodiments of Formula I, X 1 It is NR 11A R 11B Substituted C 1-4 Alkoxy; and X 2 is H. In some such embodiments of Formula I, R 11A and R 11B Is H or C 1-4 In some such embodiments of Formula I, R 11A and R 11B All are CH3.

[0380] In certain embodiments of Formula I, X 1 Yes - NR 12A R 12B ; and X 2 is H. In some such embodiments of Formula I, R 12A and R 12B It is H, C 1-4 Alkyl, or C3-7 In some such embodiments of Formula I, R 12A and R 12B In some such embodiments of Formula I, R 12A is H and R 12B It is cyclopropyl.

[0381] In certain embodiments of Formula I, R 2 is a 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 Group substitution;

[0382] Each R 3 Independently selected from the group consisting of:

[0383] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0384] C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A Group substitution;

[0385] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution;

[0386] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A Group substitution;

[0387] C 1-4 Alkoxy, optionally substituted with one or more independently selected C 3-7 Cycloalkyl, halo, or -OCH3 substitution;

[0388] -OR 11 ;

[0389] -OH;

[0390] Halogen;

[0391] -CN;

[0392] -OC(O)R 10 ;

[0393] -OS(O)2OH;

[0394] -NHC(=S)R 11 ;or

[0395] -OP(O)(OH)(OH);

[0396] -C(O)NH2;

[0397] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A Group substitution;

[0398] A 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R A Group substitution;

[0399] C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A Group substitution; and

[0400] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution.

[0401] In certain embodiments of Formula I, R 2 is a 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 In some such embodiments of Formula I, the monocyclic heteroaryl is unsubstituted. In some such embodiments of Formula I, the monocyclic heteroaryl is optionally substituted with an independently selected R 3 In some such embodiments of Formula I, the monocyclic heteroaryl is substituted by an independently selected R 3 replace.

[0402] In certain embodiments of Formula I, R 2 is a 5-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 In some such embodiments of Formula I, R 2 is imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, or thiazolyl; wherein the imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, and thiazolyl are optionally substituted by one or more independently selected R 3In some such embodiments of Formula I, the imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, and thiazolyl are unsubstituted. In some such embodiments of Formula I, the imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, and thiazolyl are optionally substituted with one or two independently selected R 3 In some such embodiments of Formula I, the imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, and thiazolyl groups are substituted with one or two independently selected R 3 In some such embodiments of Formula I, R 2 is oxadiazolyl or thiazolyl; wherein the oxadiazolyl or thiazolyl is substituted by an independently selected R 3 In some such embodiments of Formula I, R 2 is a substituted oxadiazolyl. In some such embodiments of Formula I, R 2 is a substituted thiazolyl. In some such embodiments of Formula I, R 2 is 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, or thiazolyl; wherein the 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, and thiazolyl are optionally substituted by one or more independently selected R 3 In some such embodiments of Formula I, the R 2 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, and thiazolyl are optionally substituted with one or two independently selected R 3 In some such embodiments of Formula I, the R 2 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, and thiazolyl are substituted with one or two independently selected R 3 In some such embodiments of Formula I, the R 2 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, and thiazolyl are optionally substituted with an independently selected R 3 In some such embodiments of Formula I, R 2 is a substituted 1,3,4-oxadiazolyl. In some such embodiments of Formula I, R 2 is a substituted 1,2,4-oxadiazolyl. In some such embodiments of Formula I, R 2 is a substituted 1,3,4-thiadiazolyl. In some such embodiments of Formula I, R 2 is a substituted thiazolyl group.

[0403] In certain embodiments of Formula I, R2 is a 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 In some such embodiments of Formula I, R 2 is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. Wherein the pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl are optionally substituted by one or more independently selected R 3 In some such embodiments of Formula I, the pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl are unsubstituted. In some such embodiments of Formula I, the pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl are optionally substituted with one or two independently selected R 3 In some such embodiments of Formula I, the pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl groups are substituted with one or two independently selected R 3 replace.

[0404] In certain embodiments of Formula I, each R 3 Independently selected from the group consisting of:

[0405] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0406] C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A Group substitution;

[0407] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution;

[0408] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A Group substitution;

[0409] C 1-4 Alkoxy, optionally substituted with one or more independently selected C 3-7 Cycloalkyl, halo, or -OCH3 substitution;

[0410] -OR 11 ;

[0411] -OH;

[0412] Halogen;

[0413] -CN;

[0414] -OC(O)R 10 ;

[0415] -OS(O)2OH;

[0416] -NHC(=S)R 11 ;or

[0417] -OP(O)(OH)(OH);

[0418] -C(O)NH2;

[0419] Phenyl; wherein the phenyl group is optionally substituted with one or more independently selected R A Group substitution:

[0420] A 5- to 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R A Group substitution;

[0421] C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A Group substitution; and

[0422] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R A Group substitution.

[0423] In certain embodiments of Formula I, each R 3 Independently selected from the group consisting of:

[0424] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0425] C 3-7 Cycloalkyl;

[0426] a 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N;

[0427] Phenyl;

[0428] C 1-4 Alkoxy, optionally substituted with one or more independently selected C 3-7 Cycloalkyl, halo, or -OCH3 substitution;

[0429] -OR 11 ;

[0430] -OH;

[0431] Halogen;

[0432] -NHC(=S)R 11 ;or

[0433] -OP(O)(OH)(OH);

[0434] -C(O)NH2;

[0435] C 3-7 Cycloalkyl; and

[0436] A 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N.

[0437] In certain embodiments of Formula I, each R 3 is independently -C(O)NH2.

[0438] In some embodiments of Formula I, each R 3 Independently C 3-7 In some embodiments of Formula I, each R 3 are independently C6 cycloalkyl.

[0439] In certain embodiments of Formula I, R 3 is independently a 4- to 6-membered monocyclic heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocyclic ring is optionally substituted by one or more independently selected R A In some such embodiments of Formula I, R 3 In some such embodiments of Formula I, R 3 is independently tetrahydropyranyl.

[0440] In certain embodiments of Formula I, each R 3 yes

[0441] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0442] C 3-7 Cycloalkyl;

[0443] a 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N;

[0444] Phenyl;

[0445] C 1-4 Alkoxy, optionally substituted with one or more independently selected C 3-7 Cycloalkyl, halo, or -OCH3 substitution;

[0446] -OR 11 ;

[0447] -OH;

[0448] Halogen;

[0449] -NHC(=S)R 11 ;or

[0450] -OP(O)(OH)(OH).

[0451] In certain embodiments of Formula I, each R3 is independently C 1-4 alkyl; optionally substituted with one or more independently selected -OH, halo, or -OP(O)(OH)(OH). In some such embodiments of Formula I, R 3 is independently unsubstituted C 1-4 In some such embodiments of Formula I, R 3 is independently -C(CH3)3. In some such embodiments of Formula I, R 3 is independently C substituted with one -OH 1-4 In some such embodiments of Formula I, R 3 is independently -CH2OH. In some such embodiments of Formula I, R 3 is independently -CH2CH2OH. In some such embodiments of Formula I, R 3 is independently -CH(OH)CH3. In some such embodiments of Formula I, R 3 is independently -C(OH)(CH3)2. In some such embodiments of Formula I, R 3 is independently -CH(OH)CF3. In some such embodiments of Formula I, R 3 is independently C substituted with one -OP(O)(OH)(OH) 1-4 In some such embodiments of Formula I, R 3 is independently a C1 alkyl substituted with one -OP(O)(OH)(OH). In some such embodiments of Formula I, R 3 is independently C substituted with one -OH and three F 1-4 In some such embodiments of Formula I, R 3 is independently a C2 alkyl substituted with one -OH and three F. In some such embodiments of Formula I, R 3 is independently a C3 alkyl substituted with one -OH and three Fs.

[0452] In certain embodiments of Formula I, each R 3 is independently optionally substituted C 1-4In some such embodiments of Formula I, R 3 Independently through a C 1-4 Alkoxy and a phenyl substituted C 1-4 In some such embodiments of Formula I, R 3 is independently -CH(OCH3)-phenyl. In some such embodiments of Formula I, R 3 Independently through a C 1-4 Alkoxy substituted C 1-4 Alkyl, wherein the C 1-4 The alkoxy group is optionally substituted with one or more independently selected C 3-7 In some such embodiments of Formula I, R 3 is -CH(OCH3)CH3. In some such embodiments, R 3 is independently -C(OCH3)(CH3)2. In some such embodiments of Formula I, R 3 is -CH2OCH3. In some such embodiments of Formula I, R 3 is -CH2CH2OCH3. In some such embodiments of Formula I, R 3 is -CH2OCH2CH3. In some such embodiments of Formula I, R 3 is -CH2OCF3. In some such embodiments of Formula I, R 3 is -CH2OCHF2. In some such embodiments of Formula I, R 3 is -CH2OCH2CH2OCH3. In some such embodiments of Formula I, R 3 Independently through a C 1-4 Alkoxy substituted C 1-4 Alkyl; wherein the C 1-4 The alkoxy group is optionally substituted with one or more independently selected C 3-7 In some such embodiments of Formula I, R 3 Independently

[0453] In certain embodiments of Formula I, R 3 Independently through a -OR 11 Substituted C 1-4 alkyl; and each R 11 independently selected from the group consisting of 4- to 6-membered monocyclic heterocyclic rings containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; 5- to 6-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S and N; C 3-7 Cycloalkyl; and phenyl; wherein the phenyl is optionally substituted with one or more independently selected RA In some such embodiments of Formula I, R 3 Independently through a -OR 11 Substituted C 1-4 Alkyl; each R 11 is independently phenyl; wherein the phenyl is optionally substituted with one or more independently selected R A In some such embodiments of Formula I, R 3 Independently In some such embodiments of Formula I, R 3 Independently In some such embodiments of Formula I, R 3 Independently through a -OR 11 Substituted C 1-4 Alkyl, and R 11 Independently C 3-7 In some such embodiments of Formula I, R 3 is independently -CH2O-C5cycloalkyl. In some such embodiments of Formula I, R 3 Independently C 1-4 Alkyl, which is substituted by a -OR 11 Replace, and R 11 is independently a 4- to 6-membered monocyclic heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N. In some such embodiments of Formula I, R 3 Independently

[0454] In certain embodiments of Formula I, R 3 Independently through a C 3-7 Cycloalkyl substituted C 1-4 Alkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R A In some such embodiments of Formula I, R 3 Independently through a C 3-7 Cycloalkyl substituted C 1-4 Alkyl; wherein the C 3-7 The cycloalkyl group is unsubstituted. In some such embodiments of Formula I, R 3 is independently a C1 alkyl substituted with a C3 cycloalkyl; wherein the C3 cycloalkyl is unsubstituted.

[0455] In certain embodiments of Formula I, R 3 Independently C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R AIn some such embodiments of Formula I, R3 is independently C 3-7 Cycloalkyl; wherein the C 3-7 The cycloalkyl group is unsubstituted. In some such embodiments of Formula I, R 3 is independently cyclopropyl.

[0456] In certain embodiments of Formula I, R 3 independently through a -NHC(=S)R 11 Substituted C 1-4 alkyl; and each R 11 independently selected from the group consisting of 4- to 6-membered monocyclic heterocyclic rings containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; 5- to 6-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S and N; C 3-7 Cycloalkyl; and phenyl; wherein the phenyl is optionally substituted with one or more independently selected R A and each R A are independently selected halo. In some such embodiments of Formula I, R 3 independently through a -NHC(=S)R 11 Substituted C 1-4 alkyl; and each R 11 Independently C 3-7 In some such embodiments of Formula I, R 3 independently through a -NHC(=S)R 11 substituted C1 alkyl; and each R 11 is independently cyclopropyl.

[0457] In certain embodiments of Formula I, R 3 is independently substituted with a 4- to 6-membered monocyclic heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N 1-4 wherein the monocyclic heterocyclic ring is optionally substituted by one or more independently selected R A In some such embodiments of Formula I, R 3 is independently C1 alkyl substituted with one tetrahydrofuranyl.

[0458] In certain embodiments of Formula I, R 2 is a 5-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl group is optionally substituted by one independently selected R 3 Substitution; wherein R 3 is independently C optionally substituted with one or more independently selected -OH, halo, or -OP(O)(OH)(OH)1-4 In some such embodiments of Formula I, R 2 is oxadiazolyl or thiazolyl, wherein the oxadiazolyl or thiazolyl is substituted by an independently selected R 3 Substitution; wherein R 3 is C optionally substituted with one or more independently selected -OH, halo, or -OP(O)(OH)(OH) 1-4 alkyl.

[0459] Included herein are compounds having Formula Ia or pharmaceutically acceptable salts thereof:

[0460]

[0461] Where n is 0, 1 or 2, R 4A is H, F, CH3, -CH(CH3)2, t-Bu, CF3, -OCH3, -O-CH(CH3)2, or -OCF3, each R 4B are independently F or -OCF3, and X 1 and R 2 is as defined in the Summary of the Invention and in the Examples of Formulas I and Ib herein.

[0462] In certain embodiments of Formula Ia, X 1 It's H.

[0463] In certain embodiments of Formula Ia, n is 0 or 1. In certain embodiments of Formula Ia, n is 0. In certain embodiments of Formula Ia, n is 1.

[0464] In certain embodiments of Formula Ia, R 4A is H, -CH(CH3)2, -O-CH(CH3)2, t-Bu, -CH3, -OCH3, F, CF3, or -OCF3.

[0465] In certain embodiments of Formula Ia, R 4A It is H, F, CF3 or -OCF3.

[0466] In certain embodiments of Formula Ia, R 4A It is F, CF3 or -OCF3.

[0467] In certain embodiments of Formula Ia, n is 0 or 1, R 4A is F, CF3 or -OCF3, and R 4B It's F.

[0468] In certain embodiments of Formula Ia, R 4A It's F.

[0469] In certain embodiments of Formula Ia, n is 0 and R 4A It's F.

[0470] In certain embodiments of Formula Ia, n is 0 and R 4A Yes - OCF3.

[0471] In certain embodiments of Formula Ia, n is 0 and R 4A It's H.

[0472] In certain embodiments of Formula Ia, X 1 is H; n is 0; R 4A Yes - OCF3; R 2 It is through an R 3 substituted 1,3,4-oxadiazolyl or thiazolyl; and R 3 is C optionally substituted with one or more independently selected -OH, halo, or -OP(O)(OH)(OH) 1-4 alkyl.

[0473] Included herein are compounds having Formula Ib or pharmaceutically acceptable salts thereof:

[0474]

[0475] And X 1 , R 1 , and R 2 is defined below and in the Summary of the Invention and in the Examples of Formula I herein.

[0476] Certain embodiments relate to compounds having Formula Ib,

[0477]

[0478] in

[0479] X 1 yes

[0480] H;

[0481] Halogen;

[0482] C 1-4 Alkyl, optionally substituted with one or more independently selected halo;

[0483] C 1-4 Alkoxy, optionally substituted with one or more independently selected groups: -OH;

[0484] C 1-4 alkoxy; or

[0485] -NR 8A R 8B ;

[0486] -NR 9A R 9B ;

[0487] Cyclopropyl, optionally substituted with one or more independently selected R 5 Group substitution;

[0488] Phenoxy, optionally substituted with one or more independently selected R 5 group substitution; or

[0489] Phenyl, optionally substituted with one or more independently selected R 5 Group substitution;

[0490] R 1 yes

[0491] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0492] -OH;

[0493] C 1-4 alkoxy; or

[0494] a 4- to 6-membered monocyclic heterocyclic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N;

[0495] Phenyl, optionally substituted with one or more independently selected R 4 Group substitution;

[0496] An N-linked 4- to 6-membered monocyclic heterocycle comprising 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R 5 Group substitution;

[0497] An N-linked 4- to 6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused to a phenyl group, wherein the monocyclic heterocycle and the phenyl group are optionally substituted by one or more independently selected R 5 Group substitution;

[0498] C 3-7 Cycloalkyl, optionally substituted with one or more independently selected R 5 group substitution; or

[0499] -NR 6 R 7 ;

[0500] R 2is a 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 Group substitution;

[0501] Each R 3 Independently are:

[0502] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0503] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo;

[0504] -OH;

[0505] Halogen;

[0506] -CN;

[0507] -OC(O)R 10 ;

[0508] -OS(O)2OH; or

[0509] -OP(O)(OH)(OH) substitution;

[0510] Each R 4 Independently selected from the group consisting of:

[0511] Halogen;

[0512] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; and

[0513] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo;

[0514] Each R 5 Independently selected from the group consisting of:

[0515] -OH;

[0516] Halogen;

[0517] C 1-4 Alkyl, optionally substituted with one or more independently selected C 1-4 Alkoxy, halo or -OH substitution; and

[0518] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo; R 6 It is H, C 1-4 Alkyl, or C3-7 Cycloalkyl, wherein the C 3-7 The cycloalkyl group is optionally substituted with one or more independently selected R 5 Group substitution;

[0519] R 7 yes

[0520] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0521] Halogen;

[0522] Phenyl, optionally substituted with one or more independently selected groups below:

[0523] C 1-4 Alkyl, optionally substituted with one or more independently selected halo; or

[0524] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo;

[0525] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo; or

[0526] A 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heterocycle is optionally substituted by one or more independently selected R 5 Group substitution;

[0527] Each R 8a and R 8b Independently selected from the group consisting of

[0528] H; and

[0529] C 1-4 alkyl;

[0530] R 9a and R 9b Independently selected from the group consisting of

[0531] H;

[0532] C 1-4 Alkyl; and

[0533] C 3-7 cycloalkyl; and

[0534] Each R 10 Independently selected from the group consisting of

[0535] C 1-6 Alkyl; and

[0536]

[00143] In certain embodiments of Formula Ib, X 1 is H, halo, optionally substituted cyclopropyl, or optionally substituted phenyl.

[0537] In certain embodiments of Formula Ib, X 1 is H, halo, or unsubstituted cyclopropyl.

[0538] In certain embodiments of Formula Ib, X 1 It's H.

[0539] In certain embodiments of Formula Ib, X 1 It is bromine, -NR 12A R 12B , alkoxy, cyclopropyl, phenoxy, or phenyl; wherein cyclopropyl, phenoxy and phenyl are optionally substituted by 1, 2 or 3 independently selected R 5 group substituted, and C 1-4 The alkoxy group is optionally substituted with one or more independently selected -OH, C 1-4 Alkoxy, or -NR 11A R 11B In some such embodiments of Formula Ib, the cyclopropyl is unsubstituted. In some such embodiments of Formula Ib, the phenyl and phenoxy are substituted with F.

[0540] In certain embodiments of Formula Ib, X 1 is bromine, cyclopropyl, or phenyl; wherein the cyclopropyl and phenyl are optionally substituted by 1, 2, or 3 independently selected R 5 In some such embodiments of Formula Ib, the cyclopropyl group is unsubstituted.

[0541] In certain embodiments of Formula Ib, X 1 It's bromine.

[0542] In certain embodiments of Formula Ib, X 1 is cyclopropyl, or phenyl; wherein the cyclopropyl and phenyl are optionally substituted by 1, 2, or 3 independently selected R 5 In some such embodiments of Formula Ib, the cyclopropyl group is unsubstituted.

[0543] In certain embodiments of Formula Ib, X 1 is cyclopropyl, phenoxy, or phenyl; wherein the cyclopropyl, phenoxy, and phenyl are optionally substituted by 1, 2, or 3 independently selected R 5 In some such embodiments of Formula Ib, the cyclopropyl group is unsubstituted.

[0544] In certain embodiments of Formula Ib, X 1 is unsubstituted cyclopropyl or phenyl substituted with one fluorine.

[0545] In certain embodiments of Formula Ib, X 1 is unsubstituted cyclopropyl, or phenyl substituted by one fluorine, or phenoxy substituted by one fluorine.

[0546] In certain embodiments of Formula Ib, X 1 is a substituted cyclopropyl.

[0547] In certain embodiments of Formula Ib, X 1 It is a phenyl group substituted with one fluorine.

[0548] In certain embodiments of Formula Ib, X 1 It is a phenoxy group substituted with one fluorine.

[0549] In certain embodiments of Formula Ib, X 1 is optionally substituted with one or more independently selected -OH, C 1-4 Alkoxy, or -NR 11A R 11B Substituted C 1-4 In some such embodiments of Formula Ib, R 11A and R 11B Is H or C 1-4 In some such embodiments of Formula Ib, R 11A and R 11B All are CH3.

[0550] In certain embodiments of Formula Ib, X 1 is unsubstituted C 1-4 In some such embodiments of Formula Ib, X 1 It is -OCH3.

[0551] In certain embodiments of Formula Ib, X 1 It is C 1-4 Alkoxy substituted C 1-4 In some such embodiments of Formula Ib, X 1 It is -OCH2CH2OCH3.

[0552] In certain embodiments of Formula Ib, X 1 It is NR 11A R 11B Substituted C 1-4 In some such embodiments of Formula Ib, R 11A and R 11B Is H or C 1-4In some such embodiments of Formula Ib, R 11A and R 11B All are CH3.

[0553] In certain embodiments of Formula Ib, X 1 Yes - NR 12A R 12B In some such embodiments of Formula Ib, R 12A and R 12B It is H, C 1-4 Alkyl, or C 3-7 In some such embodiments of Formula Ib, R 12A and R 12B In some such embodiments of Formula Ib, R 12A is H and R 12B It is cyclopropyl.

[0554] In one embodiment, the present invention is directed to a compound having Formula Ib, wherein

[0555] X 1 yes

[0556] H;

[0557] R 1 yes

[0558] Phenyl, optionally substituted with one or more independently selected R 4 Group substitution;

[0559] R 2 is a 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 Group substitution;

[0560] Each R 3 Independently

[0561] C 1-4 Alkyl, optionally substituted with one or more independently selected -OH;

[0562] halogen; or

[0563] -OP(O)(OH)(OH); and

[0564] Each R 4 Independently

[0565] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo.

[0566] In one embodiment, the present invention is directed to a compound having Formula Ib, wherein

[0567] X 1 yes

[0568] H;

[0569] R 1 yes

[0570] Phenyl, optionally substituted with one or more independently selected R 4 Group substitution;

[0571] R 2 is a 5-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl group is optionally substituted by one or more independently selected R 3 Group substitution;

[0572] Each R 3 Independently

[0573] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0574] -OH;

[0575] halogen; or

[0576] -OP(O)(OH)(OH); and

[0577] Each R 4 Independently

[0578] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo.

[0579] In one embodiment, the present invention is directed to a compound having Formula Ib, wherein

[0580] X 1 yes

[0581] H;

[0582] R 1 yes

[0583] Phenyl, optionally substituted with one or more independently selected R 4 Group substitution;

[0584] R 2 is an oxadiazolyl or thiazolyl group containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the oxadiazolyl or thiazolyl group is optionally substituted by one or more independently selected R 3 Group substitution;

[0585] Each R 3 Independently

[0586] C 1-4 Alkyl, optionally substituted with one or more independently selected

[0587] -OH;

[0588] halogen; or

[0589] -OP(O)(OH)(OH); and

[0590] Each R 4 Independently

[0591] C 1-4 Alkoxy, optionally substituted with one or more independently selected halo.

[0592] Substituent X 1 , X 2 , R 1 , and R 2 Various embodiments of have been discussed above. These substituent embodiments can be combined to form various embodiments of the present invention. All embodiments of the compounds of the present invention formed by combining the above substituent embodiments are within the scope of the applicant's invention.

[0593] Compounds having formula I include but are not limited to:

[0594] (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol;

[0595] (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl dihydrogen phosphate;

[0596] 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol;

[0597] 1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-2,2,2-trifluoroethan-1-ol;

[0598] (2-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazol-5-yl)methanol;

[0599] 2-(1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0600] (5-{3-amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol;

[0601] 5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazole-2-carboxamide;

[0602] {5-[3-amino-5-(4-fluorobenzene-1-sulfonyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methanol;

[0603] 2-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0604] 2-{5-[(S)-methoxy(phenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0605] 2-{5-[(cyclopropylmethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0606] 2-[5-(Phenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0607] 2-{5-[(cyclopentyloxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0608] 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-{5-[(trifluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}pyridin-3-amine;

[0609] 2-(5-{[(oxolan-3-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0610] 2-{5-[(2-methoxyethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0611] N-[(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)methyl]cyclopropanecarbothioamide;

[0612] 2-{5-[(S)-methoxy(phenyl)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0613] (2S)-2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)-1,1,1-trifluoropropan-2-ol;

[0614] 2-{5-[(1R)-1-methoxyethyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0615] 2-[5-(1-methoxyethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0616] 2-{5-[(1S)-1-methoxyethyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0617] 2-{5-[(cyclopropylmethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0618] 2-[5-(Ethoxymethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0619] 2-[5-(Methoxymethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0620] 2-(5-{[(pyridin-3-yl)oxy]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0621] 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-{5-[(trifluoromethoxy)methyl]-1,3,4-thiadiazol-2-yl}pyridin-3-amine;

[0622] 2-(5-{[(oxolan-3-yl)oxy]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0623] 2-{5-[(difluoromethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0624] 2-(5-{[(2S)-oxolan-2-yl]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0625] 2-(5-{[(2R)-oxolan-2-yl]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0626] 2-{5-[(2-methoxyethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0627] 2-{5-[(1R)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0628] 2-{5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0629] 2-[5-(Ethoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0630] 2-[5-(Methoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0631] 2-(5-{[(pyridin-3-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0632] 2-{5-[(difluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0633] 2-(5-{[(2S)-oxolan-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0634] 2-(5-{[(2R)-oxolan-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0635] 1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)ethan-1-ol;

[0636] 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)propan-2-ol;

[0637] (1S)-1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-2-phenylethan-1-ol;

[0638] (S)-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)(phenyl)methanol;

[0639] 2-[3-(2-methoxypropan-2-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0640] 2-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0641] 2-[3-(Oxan-4-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0642] 2-{3-[(4-fluorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0643] 2-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0644] 2-{3-[(Oxolan-2-yl)methyl]-1,2,4-oxadiazol-5-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0645] 2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0646] 2-[3-(Oxolan-3-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0647] 2-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0648] 2-[3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0649] 2-[3-(Methoxymethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;

[0650] (5-{3-amino-4-chloro-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol;

[0651] (5-{3-amino-5-[3-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol;

[0652] (5-{3-amino-5-[2-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol;

[0653] 5-amino-N-benzyl-6-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-N-methylpyridine-3-sulfonamide;

[0654] {5-[3-amino-5-(phenylsulfonyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methanol;

[0655] (5-{3-amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)methanol;

[0656] (5-{3-amino-6-bromo-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol;

[0657] (5-{3-amino-6-chloro-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol;

[0658] (5-{3-amino-5-[2-(propan-2-yl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol;

[0659] (5-{3-amino-4-bromo-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol;

[0660] 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,2,4-oxadiazol-3-yl)ethan-1-ol; and pharmaceutically acceptable salts thereof.

[0661] By using the Name 2015 naming algorithm (Advanced Chemical Development) or the Struct = Name naming algorithm (as Professional Edition 15.0.0.106) to name the compounds of the invention.

[0662] The compounds of the present invention may exist as stereoisomers, where asymmetric or chiral centers are present. These stereoisomers are "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" as used herein are configurations defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in: Pure Appl. Chem. 1976, 45: 13-30. The present invention encompasses various stereoisomers and mixtures thereof, and these are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing a racemic mixture followed by synthetic preparation by resolution methods well known to those of ordinary skill in the art. Examples of these resolution methods are: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optionally liberation of the optically pure product from the auxiliary, as described in Furnis, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on a chiral chromatographic column or (3) fractional recrystallization methods.

[0663] The compounds of the present invention may exist as cis or trans isomers, wherein the substituents on the ring may be attached in such a manner that they are on the same side of the ring relative to each other (cis) or on opposite sides of the ring relative to each other (trans). For example, cyclobutane may exist in a cis or trans configuration and may exist as a single isomer or a mixture of cis and trans isomers. Individual cis or trans isomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials using selective organic transformations, or prepared in single isomeric form by purifying a mixture of cis and trans isomers. These methods are well known to those of ordinary skill in the art and may include separation of isomers by recrystallization or chromatography.

[0664] It will be appreciated that the compounds of the invention may have tautomeric forms as well as geometric isomers and that these also form an aspect of the invention.

[0665] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of Formula I and Ia wherein one or more atoms are replaced by atoms having the same atomic number but having an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present disclosure include isotopes of: hydrogen such as 2 H and 3 H, carbon e.g. 11 C. 13 C and 14 C, chlorine, for example 36 Cl, fluorine such as 18 F, iodine e.g. 123 I and 125 I, nitrogen such as 13 N and 15 N, oxygen such as 15 O. 17 O and 18 O, phosphorus such as 32 P, and sulfur e.g. 35 S. Certain isotopically-labeled compounds of Formula I, Ia, and Ib (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose due to their ease of incorporation and ready detectability. Substitution with heavier isotopes such as deuterium (i.e., 2H) may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life and reduced dosage requirements, and hence may be preferred in some circumstances. Use of positron emitting isotopes (e.g., 11 C. 18 F. 15 O and 13 N) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula I, Ia, and Ib can generally be prepared by conventional techniques well known to those of ordinary skill in the art, or can be prepared by methods analogous to those described in the accompanying Examples using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[0666] Therefore, the formula diagram in this specification can only represent one of possible tautomeric forms, geometric isomer forms, or stereoisomeric forms.Should be understood that the present invention encompasses any tautomeric forms, geometric isomer forms, or stereoisomeric forms, and mixtures thereof, and is not limited to any tautomeric forms, geometric isomers, or stereoisomeric forms utilized in the formula diagram.

[0667] The compounds of Formula I, Ia, and Ib can be used in the form of pharmaceutically acceptable salts. The phrase "pharmaceutically acceptable salts" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio.

[0668] Pharmaceutically acceptable salts have been described in SM Berge et al., J. Pharmaceutical Sciences, 1977, 66: 1-19.

[0669] Compounds of Formula I, Ia, and Ib may contain basic or acidic functions or both and may be converted into pharmaceutically acceptable salts when desired by using appropriate acids or bases. These salts may be prepared in situ during the final isolation and purification of the compounds of the invention.

[0670] Examples of acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothioate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. In addition, basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides, such as but not limited to methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as but not limited to decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aryl alkyl halides such as benzyl and phenethyl bromides, etc. Water-soluble or oil-soluble or dispersible products are thus obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include the following inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and the following organic acids, such as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.

[0671] Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention by reacting the carboxylic acid-containing moiety with a suitable base (such as, but not limited to, a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate), or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal based cations, such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts, and non-toxic quaternary ammonium and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other examples of organic amines useful in forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0672] The compounds described herein may exist in unsolvated as well as solvated forms, including hydrated forms such as hemihydrates. In general, the solvated forms with pharmaceutically acceptable solvents (especially such as water and ethanol) are equivalent to the unsolvated forms for the purposes of the present invention.

[0673] Pharmaceutical composition

[0674] When used as a medicament, the compounds of the invention are typically administered in the form of a pharmaceutical composition. In one embodiment, such compositions can be prepared in a manner well known in the pharmaceutical art and include a therapeutically effective amount of a compound of Formula I, Ia, Ib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The phrase "pharmaceutical composition" refers to a composition suitable for administration for medical or veterinary use.

[0675] Pharmaceutical compositions comprising a compound of Formula I, Ia, or Ib (alone or in combination with another therapeutically active ingredient) can be administered to a subject orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (e.g., by powder, ointment, or drop form), buccally, or in the form of an oral or nasal spray. The term "parenteral" as used herein refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intraarticular injection and infusion.

[0676] As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials that can be used as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose, and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffers such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition according to the judgment of the formulator.

[0677] The pharmaceutical composition for parenteral injection comprises pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion and sterile powder, so as to be reconstituted into sterile injectable solution or dispersion just before use.The example of suitable aqueous and non-aqueous diluent, solvent or vehicle comprises water, ethanol, polyol (such as glycerol, propylene glycol, polyethylene glycol etc.), vegetable oil (such as olive oil), injection organic ester (such as ethyl oleate) and its suitable mixture.Can for example by using coating material (such as lecithin), by maintaining required particle size and by using surfactant to maintain appropriate fluidity in the case of dispersion.

[0678] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. The action of microorganisms may be prevented by adding various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Extended absorption of injectable drug forms may be caused by adding agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0679] In some cases, in order to prolong the effect of the drug, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystal or amorphous material. The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0680] Injectable depot forms can be prepared by forming a microencapsulated matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the properties of the specific polymer used, the release rate of the drug can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with human tissue.

[0681] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0682] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, the solid dosage form may contain 1% to 95% (w / w) of a compound of Formula I, Ia, or Ib. In certain embodiments, a compound of Formula I, Ia, or Ib, or a pharmaceutically acceptable salt thereof, may be present in the solid dosage form in a range of 5% to 70% (w / w). In such solid dosage forms, the active compound may be mixed with at least one pharmaceutically acceptable inert carrier (e.g., sodium citrate or dicalcium phosphate), and / or the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrators such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0683] The pharmaceutical composition may be in unit dosage form. In this dosage form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation containing discrete amounts of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form itself may be a capsule, tablet, cachet, or lozenge, or it may be an appropriate number of any of these dosage forms in packaged form. Depending on the specific application and the potency of the active ingredient, the amount of active ingredient in the unit dosage preparation may vary or be adjusted to a unit dose of from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to 95% (w / w). If desired, the composition may also contain other compatible therapeutic agents.

[0684] The dosage to be administered to a subject can be determined by the efficacy of the specific compound used and the condition of the subject, as well as the body weight or body surface area of ​​the subject to be treated. The size of the dosage is also determined by the presence, nature, and extent of any adverse side effects that accompany the administration of a specific compound in a specific subject. In determining the effective amount of a compound to be administered for the treatment or prevention of the disorder being treated, the physician can assess factors such as circulating plasma levels of the compound, compound toxicity, and / or disease progression.

[0685] For administration, the compound may be administered at a rate determined by factors such as the weight and general health of the subject, which factors may include, but are not limited to, the LD50 of the compound. 50 , the pharmacokinetic properties of the compound, contraindications to drugs, and side effects of the compound at different concentrations. Administration can be achieved via single or multiple doses.

[0686] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0687] Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifiers and may also be a composition that releases one or more active ingredients only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of useful embedding compositions include polymeric substances and waxes.

[0688] The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.

[0689] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may also contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0690] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0691] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0692] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound with a suitable non-irritating carrier or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0693] The compound can also be administered in the form of liposomes. Liposomes can generally be derived from phospholipids or other lipid substances. Liposomes can be formed by single- or multi-layer hydrated liquid crystals dispersed in an aqueous medium. Any physiologically acceptable and metabolizable non-toxic lipid that can form liposomes can be used. In addition to the compounds of the present invention, the compositions of the present invention in the form of liposomes may contain stabilizers, preservatives, excipients, etc. Examples of lipids include, but are not limited to, natural and synthetic phospholipids and phosphatidylcholines (lecithins) used alone or in combination.

[0694] Methods for forming liposomes have been described; see, for example, Prescott, ed., Methods in Cell Biology, Vol. XIV, Academic Press, New York (1976), pp. 33 et seq.

[0695] Dosage forms for topical administration of the compounds described herein include powders, sprays, ointments, and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants that may be needed. Ophthalmic preparations, eye ointments, powders, and solutions are also contemplated within the scope of the present invention.

[0696] The compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system.

[0697] How to use

[0698] The compounds and compositions can be administered to a subject using any amount and any route of administration for the treatment or prevention of cystic fibrosis, pancreatic insufficiency, Sjögren's syndrome (SS), chronic obstructive pulmonary disease (COLD), or chronic obstructive airways disease (COAD).

[0699] The term "administering" refers to a method of contacting a compound with a subject. Therefore, the compound can be administered by injection (i.e., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, parenteral or intraperitoneal). In addition, the compound described herein can be administered by inhalation (e.g., nasal). In addition, the compound can be administered transdermally, topically, via implantation, transdermally, topically and via implantation. In certain embodiments, the compound and its composition can be delivered orally. The compound can also be delivered rectal, buccal, intravaginal, ocular or by insufflation. Depending on the nature of the disorder or illness, the disorder and illness of CFTR-regulation can be treated prophylactically, acutely and chronically using the compound and its composition. Typically, the host or subject in each of these methods is human, although as described above, other mammals can also benefit from administering the compound and its composition.

[0700] The compounds of the present invention can be used as modulators of CFTR. Therefore, these compounds and compositions are particularly useful for treating diseases, disorders or conditions involving hyperactivity or inactivity of CFTR or for alleviating its severity or progression. Therefore, the present invention provides methods for treating cystic fibrosis, pancreatic insufficiency, Sjögren's syndrome (SS), chronic obstructive pulmonary disease (COLD) or chronic obstructive airway disease (COAD) of a subject, wherein the method comprises the following steps: administering to the subject a therapeutically effective amount of a compound with formula I, Ia or Ib or its preferred embodiments as stated above and administering or not administering a pharmaceutically acceptable carrier. In particular, the method is used to treat or prevent cystic fibrosis. In a more specific embodiment, cystic fibrosis is caused by I, II, III, IV, V and / or VI type mutations.

[0701] In another embodiment, the present invention provides a compound of the present invention for use in medicine or a pharmaceutical composition comprising the compound of the present invention. In a specific embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of the present invention for use in medicine. In a specific embodiment, the present invention provides a compound of the present invention for use in the treatment of cystic fibrosis, pancreatic insufficiency, Sjögren's syndrome (SS), chronic obstructive pulmonary disease (COLD) or chronic obstructive airway disease (COAD) or a pharmaceutical composition comprising the compound of the present invention. In a more specific embodiment, the present invention provides a compound of the present invention for use in the treatment of cystic fibrosis or a pharmaceutical composition comprising the compound of the present invention. In a more specific embodiment, cystic fibrosis is caused by type I, II, III, IV, V and / or VI mutations.

[0702] One embodiment is directed to the use of a compound of Formula I, Ia or Ib or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament. The medicament may optionally contain one or more additional therapeutic agents. In some embodiments, the medicament is used in the treatment of cystic fibrosis, pancreatic insufficiency, Sjögren's syndrome (SS), chronic obstructive pulmonary disease (COLD) or chronic obstructive airway disease (COAD). In a specific embodiment, the medicament is used in the treatment of cystic fibrosis. In a more specific embodiment, cystic fibrosis is caused by type I, II, III, IV, V and / or VI mutations.

[0703] The present invention is also directed to the use of a compound of Formula I, Ia or Ib or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive pulmonary disease and chronic obstructive airway disease. The medicament may optionally contain one or more additional therapeutic agents. In a specific embodiment, the present invention is directed to the use of a compound according to Formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cystic fibrosis. In a more specific embodiment, cystic fibrosis is caused by type I, II, III, IV, V and / or VI mutations.

[0704] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, wherein the other therapeutic agent is selected from the group consisting of a CFTR modulator and a CFTR amplifier. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, wherein the other therapeutic agent is a CFTR modulator.

[0705] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more corrective agents. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, another therapeutic agent is a cystic fibrosis therapeutic agent. In one embodiment, the present invention provides a method for treating cystic fibrosis in a subject, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention provides a method for treating cystic fibrosis in a subject, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents. In another embodiment, the present invention provides a method for treating cystic fibrosis in a subject, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, wherein the other therapeutic agent is selected from the group consisting of a CFTR modulator and a CFTR amplifier. In one embodiment, the present invention provides a method for treating cystic fibrosis in a subject, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, wherein the other therapeutic agent is a CFTR modulator. In one embodiment, the present invention provides a method for treating cystic fibrosis in a subject, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a cystic fibrosis therapeutic agent. In a specific embodiment, the one or more additional therapeutic agents are selected from the group consisting of: CFTR modulators and CFTR amplifiers. In a specific embodiment, the other therapeutic agent is one or more corrective agents. In another embodiment, the other therapeutic agent is a CFTR modulator. In a more specific embodiment, cystic fibrosis is caused by type I, II, III, IV, V and / or VI mutations.

[0706] The compounds of the present invention or their pharmaceutically acceptable salts can be administered as the sole active agent, or can be co-administered with other therapeutic agents (including other compounds or their pharmaceutically acceptable salts), which show the same or similar therapeutic activity and are measured to be safe and effective for the combination. The compounds of the present invention can be co-administered to the subject. The term "co-administered" refers to administering two or more different therapeutic agents to the subject in a single pharmaceutical composition or in separate pharmaceutical compositions. Therefore, co-administration involves the simultaneous administration of a single pharmaceutical composition comprising two or more therapeutic agents or the administration of two or more different compositions to the same subject at the same or different times.

[0707] The compounds of the present invention or pharmaceutically acceptable salts thereof can be co-administered with a therapeutically effective amount of one or more additional therapeutic agents to treat CFTR-mediated diseases, wherein examples of therapeutic agents include, but are not limited to, antibiotics (e.g., aminoglycosides, colistin, aztreonam, ciprofloxacin, and azithromycin), expectorants (e.g., hypertonic saline, acetylcysteine, dornase alfa and denufosol), pancreatic enzyme supplements (e.g., pancreatin, and pancreatic lipase), epithelial sodium channel blocker (ENaC) inhibitors, CFTR modulators (e.g., CFTR potentiators, CFTR correctors), and CFTR amplifiers. In one embodiment, the CFTR-mediated disease is cystic fibrosis, chronic obstructive pulmonary disease (COPD), dry eye disease, pancreatic insufficiency, or Sjogren's syndrome. In one embodiment, the CFTR-mediated disease is cystic fibrosis.

[0708] In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with one or two CFTR modulators and one CFTR amplifier. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with one synergist, one or more correctors, and one CFTR amplifier. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with one or more CFTR modulators. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with one CFTR modulator. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with two CFTR modulators. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with three CFTR modulators. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with one synergist and one or more correctors. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with one synergist and two correctors. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with one synergist. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with one or more correctors. In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts may be co-administered with one corrector. In one embodiment, the compounds of the present invention or a pharmaceutically acceptable salt thereof can be co-administered with two corrective agents. In one embodiment, the compounds of the present invention or a pharmaceutically acceptable salt thereof can be co-administered with one or more corrective agents and an amplifying agent. In one embodiment, the compounds of the present invention or a pharmaceutically acceptable salt thereof can be co-administered with one corrective agent and an amplifying agent. In one embodiment, the compounds of the present invention or a pharmaceutically acceptable salt thereof can be co-administered with two corrective agents and an amplifying agent. In one embodiment, the compounds of the present invention or a pharmaceutically acceptable salt thereof can be co-administered with one corrective agent. In one embodiment, the compounds of the present invention or a pharmaceutically acceptable salt thereof can be co-administered with two corrective agents.

[0709] Examples of CFTR potentiators include, but are not limited to, ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, PTI-808, N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide, and 3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide. Examples of synergists are also disclosed in WO 2005120497, WO 2008147952, WO 2009076593, WO 2010048573, WO 2006002421, WO 2008147952, WO 2011072241, WO2011113894, WO 2013038373, WO 2013038378, WO 2013038381, WO 2013038386, and WO2013038390; and U.S. Applications 14 / 271,080, 14 / 451,619, and 15 / 164,317.

[0710] In one embodiment, the synergist may be selected from the group consisting of:

[0711] Ivacaftor (VX-770, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide);

[0712] CTP-656;

[0713] NVS-QBW251;

[0714] FD1860293;

[0715] PTI-808;

[0716] 2-(2-Fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

[0717] N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide;

[0718] 2-(2-Hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

[0719] 2-(1-Hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

[0720] 5,5,7,7-Tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

[0721] 2-(2-Hydroxy-2-methylpropionylamino)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

[0722] 2-(1-(Hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

[0723] 2-(3-Hydroxy-2,2-dimethylpropionylamino)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

[0724] N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-1H-pyrazole-3-carboxamide;

[0725] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxamide;

[0726] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-isopropyl-1H-pyrazole-3-carboxamide;

[0727] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide;

[0728] 5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-1-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;

[0729] N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-ethyl-1H-pyrazole-3-carboxamide;

[0730] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide;

[0731] 2-(2-Hydroxypropionylamino)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

[0732] N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-1H-pyrazole-3-carboxamide;

[0733] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;

[0734] 4-bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;

[0735] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide;

[0736] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-1H-pyrazole-3-carboxamide;

[0737] 2-(2-Hydroxy-3,3-dimethylbutyrylamino)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

[0738] 2-[(2-Hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

[0739] 5-(2-Methoxy-ethoxy)-1H-pyrazole-3-carboxylic acid (3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide;

[0740] N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3-methoxypropyl)-1H-pyrazole-3-carboxamide;

[0741] N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethoxyethyl)-1H-pyrazole-3-carboxamide;

[0742] 2-[[(2S)-2-Hydroxy-3,3-dimethyl-butyryl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

[0743] 2-[[(2R)-2-Hydroxy-3,3-dimethyl-butyryl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

[0744] 2-[(2-Hydroxy-2,3,3-trimethyl-butyryl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

[0745] [5-[(3-Carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl dihydrogen phosphate;

[0746] [3-[(3-Carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl dihydrogen phosphate;

[0747] N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,4-dioxan-2-yl)-1H-pyrazole-3-carboxamide;

[0748] 5,5,7,7-Tetramethyl-2-[[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl]amino]-4H-thieno[2,3-c]pyran-3-carboxamide;

[0749] 2-[[(2S)-2-Hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

[0750] 3-amino-N-(2-hydroxy-2-methylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

[0751] 3-amino-N-[(4-hydroxy-1-methylpiperidin-4-yl)methyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

[0752] 3-amino-N-(3-hydroxy-2,2-dimethylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

[0753] 3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]pyridine-2-carboxamide;

[0754] 3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]pyridine-2-carboxamide;

[0755] 3-amino-5-[(3-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide;

[0756] 3-amino-N-[2-(cyclopropylamino)-2-oxoethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

[0757] (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(azetidin-1-yl)methanone;

[0758] (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-(hydroxymethyl)azepin-1-yl]methanone;

[0759] (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-fluoroazetidin-1-yl)methanone;

[0760] 3-amino-N-[(2R)-2-hydroxy-3-methoxypropyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;

[0761] (3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone;

[0762] (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone;

[0763] Racemic 3-amino-N-[(3R,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

[0764] 3-amino-5-[(4,4-difluoropiperidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;

[0765] (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

[0766] 3-amino-N-(2-hydroxy-4-methylpentyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

[0767] (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone;

[0768] 3-amino-N-(3,3,3-trifluoro-2-hydroxypropyl)-5-{[4-(trifluoromethyl)piperidin-1-yl]sulfonyl}pyridine-2-carboxamide;

[0769] 3-amino-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

[0770] 3-amino-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;

[0771] 3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2S)-2-hydroxypropyl]pyridine-2-carboxamide;

[0772] 3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2R)-2-hydroxy-3-methoxypropyl]pyridine-2-carboxamide;

[0773] 3-amino-N-[2-oxo-2-(propan-2-ylamino)ethyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;

[0774] (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

[0775] 3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3R)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;

[0776] (3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

[0777] 3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;

[0778] 3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;

[0779] 3-amino-N-[2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;

[0780] 3-amino-N-(3-tert-butoxy-2-hydroxypropyl)-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;

[0781] [3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

[0782] {3-amino-5-[(3-fluorophenyl)sulfonyl]pyridin-2-yl}[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone; and

[0783] 3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide.

[0784] Non-limiting examples of corrective agents include Lumacaft or (VX-809), 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (VX-661), VX-983, GL,PG2222, GLPG2665, GLPG2737, GLPG2851, GLPG3221, PTI-801, VX-152, VX-440, VX-659, VX-445, FDL169, FDL304, FD2052160 and FD2035659. Examples of corrective agents are also disclosed in U.S. Application Nos. 14 / 925,649, 14 / 926,727, 15 / 205,512, 15 / 496,094, 15 / 287,922, and 15 / 287,911.

[0785] In one embodiment, the one or more correctors may be selected from the group consisting of:

[0786] Lumacato (VX-809);

[0787] 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (VX-661);

[0788] VX-983;

[0789] GLPG2665;

[0790] GLPG2737;

[0791] GLPG3221;

[0792] PTI-801;

[0793] VX-152;

[0794] VX-440;

[0795] VX-659;

[0796] VX-445

[0797] FDL169

[0798] FDL304;

[0799] FD2052160;

[0800] FD2035659;

[0801] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0802] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0803] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0804] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0805] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0806] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;

[0807] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0808] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;

[0809] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0810] 3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcyclopentanecarboxylic acid;

[0811] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxypropyl]benzamide;

[0812] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0813] 3-[(2R,4R)-7-(Benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0814] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0815] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-benzopyran-2-yl]benzoic acid;

[0816] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;

[0817] 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0818] 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0819] 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0820] 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[0821] rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

[0822] rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

[0823] 3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

[0824] 3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

[0825] Racemic 3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

[0826] 3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

[0827] 3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

[0828] 4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

[0829] 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0830] 3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0831] 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0832] N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0833] 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[2-(morpholin-4-yl)ethanesulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0834] 3-cyclobutyl-N-[2-(dimethylamino)ethanesulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0835] 1-(4-Fluorophenyl)-N-(methylsulfonyl)-4-(1′-methyl[4,4′-bipiperidinyl]-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0836] 3-cyclobutyl-N-(methanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0837] 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(oxolane-3-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0838] 3-cyclobutyl-N-(dimethylsulfonyl)-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidinyl]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0839] 3-cyclobutyl-N-(morpholine-4-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0840] 3-cyclobutyl-N-(morpholine-4-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0841] 3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;

[0842] 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;

[0843] 3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;

[0844] 5-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]pyrazine-2-carboxylic acid;

[0845] 6-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic acid;

[0846] trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0847] 6-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic acid;

[0848] trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0849] Ethyl trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate;

[0850] cis-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0851] trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0852] 1-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclopropane-1-carboxylic acid;

[0853] trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0854] trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0855] trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0856] trans-4-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0857] trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0858] 4-{(2R,4R)-4-[2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-2-methylpropanamide]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;

[0859] 4-[(2R,4R)-4-{[1-(3,4-dichlorophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;

[0860] 4-[(2R,4R)-4-{[1-(4-bromophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;

[0861] 4-[(2R,4R)-7-methoxy-4-({1-[4-(trifluoromethyl)phenyl]cyclopropane-1-carbonyl}amino)-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;

[0862] 4-[(2R,4R)-7-methoxy-4-{[1-(4-methylphenyl)cyclopropane-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;

[0863] 4-{(2R,4R)-4-[(1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl)amino]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;

[0864] 3-[(2R,4R)-4-{[(1S)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;

[0865] 4-[(2R,4R)-4-{[(1S)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;

[0866] trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;

[0867] trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid; and

[0868] 4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid.

[0869] In one embodiment, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effects of known CFTR modulators (e.g., potentiators and correctors). Examples of CFTR amplifiers include PTI130 and PTI-428. Examples of amplifiers are also disclosed in International Patent Publication Nos.: WO 2015138909 and WO 2015138934.

[0870] In one embodiment, the additional therapeutic agent is a CFTR stabilizer. The CFTR stabilizer enhances the stability of the corrected CFTR that has been treated with a corrector, a corrector / potentiator, or other one or more CFTR modulator combinations. An example of a CFTR stabilizer is cavosonstat (N91115). Examples of stabilizers are also disclosed in International Patent Publication No.: WO2012048181.

[0871] In one embodiment, the additional therapeutic agent is an agent that reduces the activity of an epithelial sodium channel blocker (ENaC), the reduction being carried out directly by blocking the channel or indirectly by regulating a protease (e.g., serine protease, channel activating protease) that causes an increase in ENaC activity. Examples of such agents include camostat (trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, Aerolytic, amiloride, and VX-371. Additional agents that reduce the activity of an epithelial sodium channel blocker (ENaC) can be found in, for example, International Patent Publication Nos. WO 2009074575 and WO2013043720; and U.S. Patent No. US 8999976.

[0872] In one embodiment, the ENaC inhibitor is VX-371.

[0873] In one embodiment, the ENaC inhibitor is SPX-101 (S18).

[0874] The present invention is also directed to kits comprising one or more compounds and / or salts of the present invention and, optionally, one or more additional therapeutic agents.

[0875] The present invention is also directed to methods of using the compounds, salts, compositions and / or kits of the present invention, for example, to modulate the cystic fibrosis transmembrane conductance regulator (CFTR) protein and to treat diseases that can be treated by modulating the cystic fibrosis transmembrane conductance regulator (CFTR) protein, including cystic fibrosis, Gren's syndrome, pancreatic insufficiency, chronic obstructive pulmonary disease and chronic obstructive airway disease.

[0876] Universal synthesis

[0877] The compounds of the present disclosure may be better understood in conjunction with the following synthetic schemes and methods, which illustrate the means by which the compounds may be prepared.

[0878] The compounds disclosed herein can be prepared by various synthetic procedures. Representative procedures are shown in Schemes 1-3 but are not limited to Schemes 1-3. In Schemes 1-3, variable X 1 , X 2 , R 1 , and R 3 As described in the Summary of the Invention, or they represent chemical transformations known to those skilled in the art, can be converted into a moiety of one of the groups described.

[0879] Solution 1

[0880]

[0881] As shown in Scheme 1, compounds of formula (1-6) can be prepared from compounds of formula (1-1). Compounds of formula (1-1), wherein Hal is a halogen, can first be reacted with a thiol (R1-SH) in a solvent such as, but not limited to, N,N-dimethylacetamide, in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium carbonate, with conventional heating or heating with microwave radiation to give an intermediate thioether. In a second step, the intermediate thioether can be oxidized with hydrogen peroxide in a solvent such as cooled trifluoroacetic acid to give a compound of formula (1-2). Carboxylic acids of formula (1-2) can be coupled with hydrazides of formula (1-4) to give compounds of formula (1-5). Examples of conditions known to generate compounds of formula (1-5) from a mixture of carboxylic acid and hydrazide include, but are not limited to, the addition of a coupling agent such as, but not limited to: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI) or the corresponding hydrochloride salts, 1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphonyl chloride (BOPCI), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium hexafluorophosphate N-oxide or 2-( 7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HBTU), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine 2,4,6-trioxide The coupling agent can be added as a solid, a solution or as a reagent bound to a solid support resin. In addition to the coupling agent, an auxiliary coupling agent can promote the coupling reaction. Auxiliary coupling agents commonly used in coupling reactions include, but are not limited to, 4-(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole (HOBT). The reaction can be optionally carried out in the presence of a base such as, but not limited to, triethylamine, N, N-diisopropylethylamine or pyridine. The coupling reaction can be carried out in a solvent such as, but not limited to, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, and ethyl acetate. The reaction can be carried out at ambient temperature or heated. Heating can be performed conventionally or by microwave irradiation. Hydrazides of formula (1-4) are commercially available or prepared from esters of formula (1-3). Esters of formula (1-3) can be treated with hydrazine hydrate in a solvent such as, but not limited to, heated tetrahydrofuran. Compounds of formula (1-5) can be dehydrated by treatment with p-toluenesulfonyl chloride and a base such as triethylamine in a solvent such as, but not limited to, dichloromethane to give compounds of formula (1-6). R can be further manipulated under reaction conditions known to those skilled in the art. 3 Substituents to give R as described in the Summary of the Invention 3 Substituents. Compounds of formula (1-6) are representative of compounds of formula (I).

[0882] Solution 2

[0883]

[0884] As shown in Scheme 2, compounds of formula (1-6) can be prepared from compounds of formula (1-2) by substitution in the order shown in Scheme 1. In the case of a two-step process, compounds of formula (1-2) can be converted into compounds of formula (2-1). In the first step, the compound of formula (1-2) can be esterified by combining the compound of formula (1-2) with methanol or ethanol in the presence of an acid catalyst, such as, but not limited to, sulfuric acid. Heating the mixture provides an intermediate ester. In the second step, the intermediate ester can be treated with hydrazine hydrate in a heated solvent, such as tetrahydrofuran, to give a compound of formula (2-1). The conditions described in Scheme 1 can be used to couple the compound of formula (2-1) to the compound of formula (2-2) to couple the carboxylic acid to the hydrazide, thereby giving a compound of formula (1-5). The compound of formula (1-5) can be dehydrated as described in Scheme 1 to give a compound of formula (1-6). Compounds of formula (1-6) are representative of compounds of formula (I).

[0885] Solution 3

[0886]

[0887] As shown in Scheme 3, compounds of formula (3-3) can be prepared from compounds of formula (1-2). In the case of a two-step method, compounds of formula (1-2) can be converted into compounds of formula (3-1). The coupling conditions described in Scheme 1 can be used to couple compounds of formula (1-2) with ammonia to couple carboxylic acids and hydrazides to give intermediate primary amides. In a heated mixture of a solvent such as, but not limited to, tetrahydrofuran and toluene, in the presence of an acid such as 1M hydrochloric acid, the primary amide can react with phosphorus pentasulfide to give a thioamide of formula (3-1). In a heated solvent such as, but not limited to, 2-methyltetrahydrofuran, in the presence of a base such as, but not limited to, pyridine, the thioamide of formula (3-1) can react with an α-bromoaldehyde of formula (3-2) to give a compound of formula (3-3). Compounds of formula (3-3) are representative of compounds of formula (I).

[0888] Solution 4

[0889]

[0890] As shown in Scheme 4, compounds of formula (4-1) can be prepared from compounds of formula (1-2) in a sequence similar to that shown in Scheme 2. In the case of a two-step process, compounds of formula (1-2) can be converted to compounds of formula (2-1). In the first step, compounds of formula (1-2) can be coupled to tert-butyl carbazate using standard peptide coupling conditions known to those skilled in the art and widely available in the literature. The Boc-protected substrate can be treated with an acid, such as but not limited to TFA (trifluoroacetic acid), to provide compounds of formula (2-1). Compounds of formula (2-1) can be coupled to compounds of formula (2-2) using the conditions described in Scheme 1 to couple the carboxylic acid to the hydrazide to give compounds of formula (1-5). Compounds of formula (1-5) can be treated with Lawson's reagent to give compounds of formula (4-1). Typically, the reaction is carried out in a solvent, such as but not limited to toluene, at elevated temperature. The compound having the formula (4-1) is representative of the compound having the formula (I).

[0891] Solution 5

[0892]

[0893] As shown in Scheme 5, compounds of formula (5-2) can be prepared from compounds of formula (1-2). Coupling conditions can be used, for example, in the presence of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) and N-ethyl-N-isopropylpropan-2-amine, reacting a compound of formula (1-2) with a compound of formula (5-1), wherein R 3 As described herein. Typically, the reaction is carried out in a solvent such as, but not limited to, N,N-dimethylacetamide. The coupled intermediate can then be treated with tetrabutylammonium hydroxide to provide a compound of formula (5-2). Typically, the reaction is carried out at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran. Compounds of formula (5-2) are representative of compounds of formula (I).

[0894] Chemical synthesis procedures

[0895] List of abbreviations used in the Examples section: min stands for minute; DBU stands for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCI stands for desorption chemical ionization; DMSO stands for dimethyl sulfoxide; EDCI stands for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ESI stands for electrospray ionization; HATU stands for 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate; HPLC stands for high performance liquid chromatography; MS stands for mass spectrometry; NMR stands for nuclear magnetic resonance; wt stands for weight, and UPLC stands for ultra performance liquid chromatography.

[0896] The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It should be appreciated that where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise specified. The most suitable reaction conditions may vary with the specific reactants or solvents used, but these conditions may be determined by a person of ordinary skill in the art by conventional optimization procedures.

[0897] In addition, as will be appreciated by those of ordinary skill in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for particular functional groups as well as suitable conditions for protection and deprotection are well known in the art (Protective Groups in Organic Synthesis Third Edition; Greene, TW and Wuts, PGM, eds.; New York: Wiley-Interscience: New York, 1991).

[0898] The following methods are presented in detail to prepare the compounds of the present invention and comparative examples defined above. The compounds of the present invention can be prepared from starting materials and reactants known to those skilled in the art of organic synthesis or commercially available.

[0899] Unless otherwise specified, all reagents were of commercial grade and used as received without further purification. Commercially available anhydrous solvents were used for reactions performed under an inert atmosphere. Reagent grade solvents were used in all other cases unless otherwise specified. Column chromatography was performed on silica gel 60 (35-70 μm). Thin layer chromatography was performed using pre-coated silica gel F-254 plates (thickness 0.25 mm). Recordings were made on a Bruker Advance 300 NMR spectrometer (300 MHz), an Agilent 400 MHz NMR spectrometer or a 500 MHz NMR 1 H NMR spectroscopy. 1 Chemical shifts (δ) for H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) as an internal standard or to the appropriate residual solvent peak, i.e., CHCl3 (δ 7.27). Multiplicities are given as singlet (s), doublet (d), doublet of quartet (dq), triplet (t), quartet (q), quintet (quin), multiplet (m), and broad (br). Electrospray MS spectra were obtained on a Waters platform LC / MS spectrometer or using a Waters Acquity H-Class UPLC coupled to a Waters Mass Detector 3100 spectrometer. The following columns were used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID x 50 mm L; Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID x 30 mm L: or Waters MS 5 μm C18, 100 x 4.6 mm. These methods used a CH3CN / H2O gradient (H2O containing 0.1% CF3CO2H or 0.1% NH3) or a CH3OH / H2O gradient (H2O containing 0.05% CF3CO2H). Microwave heating was performed Initiator proceeds.

[0900] Reverse Phase Purification Method

[0901] Trifluoroacetic acid method

[0902] The samples were subjected to preparative HPLC C8(2) was purified on a 5 μm 100 AXIA column (30 mm×75 mm) using a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid (B) in water at a flow rate of 50 mL / min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A).

[0903] Preparative LC / MS Method TFA6

[0904] The samples were subjected to reverse phase preparative HPLC C8(2)5μm Purification was performed on an AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid (B) in water was used at a flow rate of 40 mL / min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15%-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100-15% A, 9.1-10 min 15% A). A custom-made purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 pressure module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D active separator; and Thermo MSQPlus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

[0905] Preparative LC / MS Method TFA8

[0906] The samples were subjected to reverse phase preparative HPLC C8(2)5μm Purification was performed on an AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid (B) in water was used at a flow rate of 40 mL / min (0-0.5 min 35% A, 0.5-8.0 min linear gradient 35%-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100%-35% A, 9.1-10 min 35% A). A custom-made purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 pressure module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D active separator; and ThermoMSQ Plus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft VisualBasic 6.0.

[0907] Preparative LC / MS Method TFA10

[0908] The samples were subjected to reverse phase preparative HPLC C8(2)5μm Purification was performed on an AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid (B) in water was used with a flow rate of 30 mL / min (0-0.2 min 5% A, 0.2-3.0 min linear gradient 5%-100% A, 4.1-4.5 min 100%-5% A, 4.5-5.0 min 5% A). A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 pressure module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D active separator; and Thermo MSQ Plus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

[0909] Preparative LC / MS Method AA6

[0910] The samples were subjected to reverse phase preparative HPLC C8(2)5μm Purification was performed on an AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate (B) in water was used at a flow rate of 40 mL / min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15%-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100%-15% A, 9.1-10 min 15% A). A custom-made purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 pressure module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D active separator; and ThermoMSQ Plus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft VisualBasic 6.0.

[0911] Preparative LC / MS Method AA7

[0912] The samples were subjected to reverse phase preparative HPLC C8(2)5μm Purification was performed on an AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate (B) in water was used at a flow rate of 40 mL / min (0-0.5 min 25% A, 0.5-8.0 min linear gradient 25%-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100%-25% A, 9.1-10 min 25% A). A custom-made purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 pressure module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D active separator; and ThermoMSQ Plus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft VisualBasic 6.0.

[0913] Example 1

[0914] (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[0915] Step 1: 3-Amino-5-(4-trifluoromethoxy-phenylsulfonyl)-pyridine-2-carboxylic acid

[0916] A solution of 3-amino-5-bromo-pyridine-2-carboxylic acid (CAS: 870997-85-6, 3.26 g, 15 mmol), 4-(trifluoromethoxy)benzene-1-thiol (CAS: 169685-29-4, 3.5 g, 18 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.22 mL, 15 mmol) was prepared in N,N-dimethylacetamide (15 mL). This mixture was heated at 140 °C in a microwave reactor for 45 minutes. Next, the mixture was diluted with a mixture of 1% acetic acid in water. A suspension was obtained, which was then filtered. The collected solid was washed with a 1% acetic acid / water mixture and then with petroleum ether. After drying in a vacuum oven, the title compound was obtained. 1 H NMR (400MHz, DMSO-d6) δppm 7.68 (d, J=2.0Hz, 1H), 7.64-7.60 (m, 2H), 7.48-7.44 (m, 2H), 6.99 (d, J=2.0Hz, 1H).

[0917] Step 2: 3-Amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid

[0918] 3-Amino-5-(4-trifluoromethoxy-phenylsulfonyl)-pyridine-2-carboxylic acid (12.5 g, 40 mmol, step 1) was dissolved in trifluoroacetic acid (80 mL), and the resulting mixture was cooled to 0° C. with an ice bath. Next, H 2O2 (14 mL, 160 mmol) and the mixture was stirred at 0°C until the reaction was complete. For workup, the mixture was diluted with a mixture of 1% acetic acid in water. A suspension was obtained which was then filtered. The collected solid was washed with a 1% acetic acid / water mixture followed by petroleum ether. After drying in a vacuum oven, the title compound was obtained. MS (ESI+) m / z 363 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δppm 8.26 (d, J=1.9Hz, 1H), 8.14 (d, J=8.8Hz, 2H), 7.79 (d, J=1.9Hz, 1H), 7.65 (d, J=8.4Hz, 2H).

[0919] Step 3: 3-amino-N′-(hydroxyacetyl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbohydrazide (A-1654077.0)

[0920] To a 40 mL vial was added 3-amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid (0.50 g, 1.311 mmol, step 2) and N,N-dimethylformamide (3 mL). Then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU, 0.548 g, 1.442 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes. This solution was then transferred via cannula to another 20 mL vial containing 2-hydroxyacetohydrazide (0.154 g, 1.704 mmol) in N,N-dimethylformamide (3 mL). N,N-dimethylformamide (1 mL) was added as a rinse. Then Hunig's base (0.458 mL, 2.62 mmol) was added dropwise and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (20 mL) and 5% NaHCO (20 mL) were added, and the resulting two-phase mixture was stirred for 5 minutes, and the layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed with water (2 × 20 mL) and brine (20 mL), dried over Na SO, filtered, and then worked in vacuo to give the title compound, which was used without further purification (470 mg). 1 H NMR (501MHz, DMSO-d6) δppm 3.93 (d, J=5.9Hz, 2H), 5.48 (t, J=6.0Hz, 1H), 7.12-7.24 (m, 2H), 7.64 (dq, J=7.8, 1.1Hz, 2H), 7.75 ( d, J=2.0Hz, 1H), 8.09-8.16 (m, 2H), 8.21 (d, J=2.1Hz, 1H), 9.70 (s, 1H), 10.23 (s, 1H); MS (ESI-) m / z 433.1[MH] - .

[0921] Step 4: 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N′-({[tri(propan-2-yl)silyl]oxy}acetyl)pyridine-2-carbohydrazide

[0922] 3-Amino-N'-(hydroxyacetyl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbohydrazide (0.5315 g, 1.224 mmol, step 3) was suspended in 10 mL of dichloromethane in a 50-mL round bottom flask, and the flask was cooled to 0°C with an ice bath. Triethylamine (0.341 mL, 2.447 mmol) was added, followed by dropwise addition of triisopropylsilyl trifluoromethanesulfonate (0.660 mL, 2.447 mmol). The reaction mixture was stirred at 0°C for 15 minutes, at which time the flask was warmed to room temperature and stirred for an additional 2.5 hours. The reaction mixture was quenched by the addition of water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via flash chromatography, eluting with a gradient of 0-2.5% CHOH in CH2Cl2 on a 40 g silica gel column to provide 720 mg of the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 1.01(d, J=7.1Hz, 18H), 1.08-1.19(m, 3H), 5.03(s, 2H), 7.26(s, 2H), 7.60-7.68(m, 2H), 7.90 (d, J=2.0Hz, 1H), 8.11-8.20 (m, 2H), 8.41 (d, J=2.0Hz, 1H); MS (ESI+) m / z591.1[M+H] + .

[0923] Step 5: 5-[4-(Trifluoromethoxy)benzene-1-sulfonyl]-2-[5-({[tri(propyl-2-yl)silyl]oxy}methyl)-1,3,4-oxadiazol-2-yl]pyridin-3-amine

[0924] To a solution of 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N′-({[tri(propan-2-yl)silyl]oxy}acetyl)pyridine-2-carbohydrazide (0.4638 g, 0.785 mmol, step 4) and triethylamine (0.219 mL, 1.570 mmol) in dichloromethane (1.8 mL) was added p-toluenesulfonyl chloride (0.299 g, 1.570 mmol) and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then washed with saturated aqueous NaHCO3. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by precipitation from 3 mL of dimethyl sulfoxide and 3 mL of methanol to give 268 mg of the title compound. 1H NMR (400MHz, DMSO-d6) δppm 1.01(d, J=7.1Hz, 18H), 1.08-1.19(m, 3H), 5.03(s, 2H), 7.26(s, 2H), 7.60-7.68(m, 2H), 7.90 (d, J=2.0Hz, 1H), 8.11-8.20 (m, 2H), 8.41 (d, J=2.0Hz, 1H); MS (ESI+) m / z573.1[M+H] + .

[0925] Step 6: (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[0926] To a solution of 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-[5-({[tri(propyl-2-yl)silyl]oxy}methyl)-1,3,4-oxadiazol-2-yl]pyridin-3-amine (0.2664 g, 0.465 mmol, step 5) in tetrahydrofuran (3 mL) was added a solution of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.465 mL, 0.465 mmol) dropwise, and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was then partitioned between ethyl acetate and water. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then sonicated in dichloromethane to give a white solid, which was isolated via filtration and dried to constant weight to give 168 mg of the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 4.71 (s, 2H), 5.98 (s, 1H), 7.23 (s, 2H), 7.63 (dq, J=8.9, 1.1Hz, 2H), 7.87 (d, J=2.0Hz, 1H), 8.07-8.20 (m, 2H), 8.39 (d, J=2.0Hz, 1H); MS (ESI-) m / z 414.9[MH] - .

[0927] Alternative preparation of 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N′-({[tri(propan-2-yl)silyl]oxy}acetyl)pyridine-2-carbohydrazide

[0928] Step 1: Methyl {[tri(propan-2-yl)silyl]oxy} acetate

[0929] In dry N, N-dimethylformamide (1L), methyl 2-hydroxyacetate (CAS: 96-35-5, 80g, 888.9mmol) is mixed with imidazole (CAS: 288-32-4, 182g, 2.7mol). In this solution, triisopropylsilyl chloride (CAS: 13154-24-0, 228mL, 1.1mol) is added. Under nitrogen atmosphere, the resulting mixture is stirred at ambient temperature. After stirring overnight, the mixture is quenched with saturated NaHCO (1.5L), and then extracted with diethyl ether. The combined organic fractions are washed with 2MHCl (1.4L, 2.8mol), water (0.5L) and brine (1L). The organic layer is then dried over NaSO, filtered and concentrated to dryness, to provide 199g of the title compound used as is.

[0930] Step 2: 2-{[tri(propan-2-yl)silyl]oxy}acetohydrazide

[0931] Methyl { [tri (propyl-2-yl) silyl] oxy} acetate (199g, 808.4mmol) is dissolved in tetrahydrofuran (1L). Add aqueous hydrazine solution (35% w / w, 200mL, 2.2mol), and the mixture is refluxed overnight. Next, the mixture is quenched with NaHCO (1.5L), then extracted with ether (4×500mL). The combined organic fractions are dried over Na SO, filtered and concentrated to dryness, to provide 191g of raw material. Raw material is precipitated overnight from ethyl acetate / heptane (500mL, 5 / 95), to provide 122g of title compound.

[0932] Step 3: 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N′-({[tri(propan-2-yl)silyl]oxy}acetyl)pyridine-2-carbohydrazide

[0933] In dichloromethane (2L), 3-amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid (107.3g, 296.4mmol) is mixed with 2-{[tri(propyl-2-yl)silyl]oxy}acetohydrazide (87.5g, 355.7mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, CAS: 1892-57-5, 68.3g, 355.7mmol) and 4-dimethylaminopyridine (CAS: 1122-58-3, 43.4g, 355.7mmol). The resulting mixture is stirred at ambient temperature overnight. Next, the reaction is quenched with 1N HCl solution (1L, 1mol) and extracted with dichloromethane. The organic layer was then washed with brine and H2O, dried over Na2SO4, filtered and concentrated to dryness to provide 186.5 g of the title compound which was used as is.

[0934] Example 2

[0935] (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl dihydrogen phosphate

[0936] Step 1: (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl di-tert-butyl phosphate

[0937] 1H-tetrazole (0.45M in CH3CN, 42.7mL, 19.22mmol) was diluted with N,N-dimethylacetamide (19.22mL) and CH3CN was removed in vacuo at a bath temperature of 60°C. After the flask was cooled to room temperature, (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol (4g, 9.61mmol, Example 1) was added neat as a solid in one portion, followed by dropwise addition of di-tert-butyl N,N-diethylphosphoramidite (4.01mL, 14.41mmol). The reaction mixture was stirred at room temperature for 1 hour, at which time the reaction vessel was placed in a room temperature water bath and dropwise addition of hydrogen peroxide (30% aqueous solution, 2.94mL, 96mmol) was performed. A delayed exotherm to a temperature of 40°C was noted. After the flask had cooled to room temperature, the reaction mixture was stirred for 15 minutes, and the product began to precipitate out from the solution. The reaction mixture was diluted with ethyl acetate, washed with water and salt water, then dried over sodium sulfate, filtered, and concentrated in a vacuum. The solid residue was precipitated out from ethyl acetate / heptane to give 5.255 g of the title compound. 1HNMR(400MHz, CDCl3)δppm 8.49 (d, J=1.9Hz, 1H), 8.05 (d, J=8.8Hz, 2H), 7.75 (d, J=2.0Hz, 1H), 7.45-7.33 ( m, 2H), 6.39 (s, 2H), 5.27 (d, J=8.8Hz, 2H), 1.53 (s, 18H); MS (ESI-) m / z607.0[MH] - .

[0938] Step 2: (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl dihydrogen phosphate

[0939] (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazole-2-yl)methyl di-tert-butyl phosphate (5.0 g, 8.22 mmol, step 1) was dissolved in acetic acid (20.0 mL). HCl (1 M in acetic acid, 41.1 mL, 41.1 mmol) was added via a syringe, and the resulting solution was vigorously stirred at room temperature. After about 1 minute, solids began to precipitate from the solution. After the resulting suspension was stirred at room temperature for 30 minutes, the solids were collected with a sintering funnel. The filter cake was washed with 5 mL of acetic acid and 2×10 mL of heptane, and then dried in a vacuum oven at 35° C. for 16 hours to constant weight to give the title compound (3.7 g) as a solid. 1 H NMR (400MHz, methanol-d4) δppm 8.37 (d, J=2.0Hz, 1H), 8.14 (d, J=8.9Hz, 2H), 7.88 (d, J=2.0Hz, 1H), 7.58-7.49 (m, 2H), 5.28 (d, J=9.1Hz, 2H); MS (ESI-) m / z 495.0[MH] - .

[0940] Example 3

[0941] 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol

[0942] Step 1: Methyl 3-amino-5-[4-(trifluoromethoxy)phenyl]sulfonyl-pyridine-2-carboxylate

[0943] To a suspension of 3-amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid (1.08 g, 3 mmol, Example 1-Step 2) in CH3OH (20 mL), a few drops of H2SO4 were added. The resulting mixture was stirred at 70°C in a sealed vial for 72 hours. Next, the mixture was added to water and raised to pH=7 using 1M NaOH solution. The resulting precipitate was collected by filtration. The solid was washed with water and dried in a vacuum oven (50°C) to give the title compound (0.93 g), which was used without additional purification. MS (ESI+) m / z 377 [M+H] + .

[0944] Step 2: 3-Amino-5-[4-(trifluoromethoxy)phenyl]sulfonyl-pyridine-2-carbohydrazide

[0945] Hydrazine hydrate (CAS: 7803-57-8, 80% in water, 4 mL) was added to a solution of methyl 3-amino-5-[4-(trifluoromethoxy)phenyl]sulfonyl-pyridine-2-carboxylate (0.92 g, 2.44 mmol, step 1) in tetrahydrofuran (15 mL). The solution was heated at 55°C in a sealed vial. After stirring overnight, the mixture was diluted in water and the resulting suspension was filtered to give a solid, which was washed with water. After drying in a vacuum oven (50°C), the title compound (0.7 g) was given, which was used without additional purification. MS (ESI+) m / z 377 [M+H] + .

[0946] Step 3: 3-amino-N′-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbohydrazide

[0947] To a solution of 1-methyl-2-pyrrolidone (4 mL) containing 3-amino-5-[4-(trifluoromethoxy)phenyl]sulfonyl-pyridine-2-carbohydrazide (188 mg, 0.5 mmol, 1 eq., step 2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (190 mg, 0.5 mmol, HATU, 1 eq.) and triethylamine (139 μL, 1 mmol, 2 eq.) was added 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (72 mg, 0.5 mmol, [CAS No. 114715-77-4], 1 eq.). The resulting mixture was stirred at room temperature until the reaction was complete. After extraction with ethyl acetate and concentration of the combined organic fractions, the title compound was obtained. MS (ESI+) m / z 517 [M+H] + .

[0948] Step 4: 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N′-(3,3,3-trifluoro-2-methyl-2-{[tri(propan-2-yl)silyl]oxy}propanoyl)pyridine-2-carbohydrazide

[0949] To a suspension of 3-amino-N′-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbohydrazide (258 mg, 0.5 mmol, 1 eq, step 3) and triethylamine (28 μL, 1 mmol, 2 eq) in dichloromethane (15 mL) was added triisopropylsilyl trifluoromethanesulfonate (108 μL, 1 mmol CAS: 80522-42-5, 2 eq) dropwise at 0°C. The resulting mixture was stirred at 0°C for 15 minutes after which it was allowed to reach room temperature. After complete reaction, the mixture was added to water and extracted with ethyl acetate. The combined organic fractions were dried over Na2SO4 and concentrated to give the title compound which was used without further purification. MS (ESI+) m / z 629 [M-C3H7] + .

[0950] Step 5: 5-[4-(Trifluoromethoxy)benzene-1-sulfonyl]-2-[5-(1,1,1-trifluoro-2-{[tri(propyl-2-yl)silyl]oxy}propan-2-yl)-1,3,4-oxadiazol-2-yl]pyridin-3-amine

[0951] To a solution of 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N′-(3,3,3-trifluoro-2-methyl-2-{[tri(propan-2-yl)silyl]oxy}propanoyl)pyridine-2-carbohydrazide (336 mg, 0.5 mmol, 1 eq, step 4) and triethylamine (209 μL, 1.5 mmol, 3 eq) in dry dichloromethane (10 mL) was added p-toluenesulfonyl chloride (286 mg, 1.5 mmol, CAS: 98-59-9, 3 eq). The mixture was stirred at ambient temperature until completion. Next, the mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with aqueous NaHCO 3 solution, dried over Na 2 SO 4, and concentrated. The residue was purified by column chromatography using petroleum ether / ethyl acetate (9 / 1) as eluent to give the title compound. MS (ESI+) m / z 655 [M+H] + .

[0952] Step 6: 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol

[0953] To a solution of 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-[5-(1,1,1-trifluoro-2-{[tri(propyl-2-yl)silyl]oxy}propan-2-yl)-1,3,4-oxadiazol-2-yl]pyridin-3-amine (98 mg, 0.15 mmol, 1 eq, step 5) in tetrahydrofuran (5 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.15 mL, 0.15 mmol, 1 eq). The mixture was stirred at ambient temperature until completion. Next, the mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were dried and concentrated. The residue was purified by preparative chromatography using XSelect TM CSH Prep Guard column (C1819×10mm 5μm, Waters) and XSelect TM CSH Prep OBD column (C1819x100mm5μm, Waters) and a gradient of 0.1% formic acid (A) and acetonitrile (B) in water and a flow rate of 20mL / min were used. Alternatively, XBridge TM Prep Guard column (C1819x10mm5μm, Waters) with XBridge TM Prep OBD column (C18 19x100mm 5μm, Waters) and a gradient of 0.5% NH3 in water (A) and acetonitrile (B) at a flow rate of 20 mL / min. After elution, the solvent was removed under vacuum to give the title compound. MS (ESI+) m / z 499 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δppm 8.46 (d, J=2Hz, 1H), 8.16 (m, 2H), 7.93 (d, J=2Hz, 1H), 7.67 (m, 1H), 7.67 (m, 2H), 7.27 (br.s, 2H), 1.84 (s, 3H).

[0954] Example 4

[0955] 1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-2,2,2-trifluoroethane-1-ol

[0956] The title compound was prepared using the procedure described in the synthesis in Example 3, and 3,3,3-trifluoro-2-hydroxypropanoic acid was substituted for 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid in step 3, and the following sequence of intermediates was given: 3-amino-N′-(3,3,3-trifluoro-2-hydroxypropanoyl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbohydrazide (MS (ESI+) m / z 503 [M+H] + ), 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N′-(3,3,3-trifluoro-2-{[tri(propan-2-yl)silyl]oxy}propanoyl)pyridine-2-carbohydrazide (MS (ESI+) m / z 615 [M-C3H7] + , 643[M-CH3] + ), 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-[5-(2,2,2-trifluoro-1-{[tri(propyl-2-yl)silyl]oxy}ethyl)-1,3,4-oxadiazol-2-yl]pyridin-3-amine (MS (ESI+) m / z 641 [M+H] + )。MS(ESI+)m / z485[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δppm 8.43 (d, J=2Hz, 1H), 8.15 (m, 2H), 7.90 (d, J=2Hz, 1H), 7.67 (m, 2H), 7.29 (br s, 2H), 6.04 (t, J=6Hz, 1H), 4.74 (d, J=6Hz, 2H).

[0957] Example 5

[0958] (2-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazol-5-yl)methanol

[0959] Step 1: 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carboxamide

[0960] A solution of 3-amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid (140 mg, 0.386 mmol, Example 1-Step 2) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (294 mg, 0.773 mmol, HATU) in N,N-dimethylformamide (1.4 mL) was treated with triethylamine (108 μL, 0.773 mmol), stirred at room temperature for 20 minutes, treated with excess 37% aqueous ammonium hydroxide solution (407 μL, 3.86 mmol), and stirred overnight. The mixture was diluted with water (20 mL) and stirred for 15 minutes. The solid formed was collected by filtration, washed with water and dried under vacuum to provide the title compound (129 mg, 0.357 mmol, 92% yield). MS (DCI+) m / z 362 [M+H] + , 379[M+NH4] + ; 1 H NMR (400MHz, DMSO-d6) δppm8.17 (d, J=2.1Hz, 1H), 8.13-8.09 (m, 2H), 8.02 (br s, 1H), 7.69 (d, J=2.1Hz, 1H), 7.63 (d, J=8.1Hz, 2H), 7.58 (br s, 1H), 7.25 (bs, 2H).

[0961] Step 2: 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbothioamide

[0962] A mixture of 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carboxamide (80 mg, 0.221 mmol, step 1) and phosphorus pentasulfide (49.2 mg, 0.221 mmol) in tetrahydrofuran (2 mL) was stirred at 55 ° C for 45 minutes. The mixture was treated with 1M HCl (about 10 mL) and toluene (20 mL). The mixture was then stirred vigorously and heated to 95 ° C for 2 hours and then cooled to room temperature. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4), filtered, concentrated, redissolved in ethyl acetate / CH2Cl2, treated with silica gel (about 3 g), and concentrated to dryness. The silica gel suspension was transferred to the DASi 2 O column on top of a pre-equilibrated 25 g silica gel column. TM -12 cartridge. Chromatography eluting with a gradient of 20% to 50% ethyl acetate in heptane provided the title compound (36 mg, 0.095 mmol, 43.1% yield). 1HNMR (400MHz, DMSO-d6) δppm 9.93 (br s, 1H), 9.73 (br s, 1H), 8.20 (d, J = 2.1Hz, 1H), 8.16-8.11 (m, 2H), 7.81 (d, J = 2.1Hz, 1H), 7.71 (br s, 2H), 7.66 (d, J=8.1Hz, 2H).

[0963] Step 3: 2-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazole-5-carbaldehyde

[0964] A mixture of 3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-thiocarboxamide (30 mg, 0.079 mmol, step 2) and 2-bromomalonaldehyde (48.0 mg, 0.318 mmol) in 2-methyltetrahydrofuran was treated with pyridine (12.86 μL, 0.159 mmol) and the mixture was heated to 70° C. for 90 minutes. The mixture was cooled and partitioned between ethyl acetate (50 mL) and 0.1 M aqueous HCl (15 mL). The ethyl acetate layer was washed with brine, dried (MgSO ), filtered, concentrated, redissolved in CH Cl / ethyl acetate, treated with silica gel (about 1.5 g), and concentrated to dryness. The silica gel suspension was transferred to the DASi 2 O solution on top of a pre-equilibrated 12 g silica gel column. TM -12 cartridge. Elution with a gradient of 15% to 50% ethyl acetate in heptane provided the title compound (7 mg, 0.016 mmol, 20.51% yield). MS (ESI+) m / z 462 (M+CH3OH+H) + ; MS (ESI-) m / z 428 [MH] - ; 1 H NMR (400MHz, CDCl3) δppm 10.07 (s, 1H), 8.44 (s, 1H), 8.40 (d, J=1.9Hz, 1H), 8.06-8.01 (m, 2H), 7.62 (d, J=1.9Hz, 1H), 7.37 (d, J=8.1Hz, 2H).

[0965] Step 4: (2-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazol-5-yl)methanol

[0966] A solution of 2-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazole-5-carbaldehyde (7 mg, 0.016 mmol, Step 3) in methanol (1 mL) was treated with excess NaBH4 (5 mg), stirred at room temperature for 15 minutes, treated with 1M aqueous HCl (5 mL), and extracted with ethyl acetate (30 mL). The ethyl acetate layer was washed with brine, dried (MgSO4), filtered, and concentrated to dryness. The residue was dissolved in a mixture of CH2Cl2 and ethyl acetate, treated with silica gel (about 1.5 g), and concentrated to dryness. The silica gel suspension was transferred to a DASiO2 column on top of a pre-equilibrated 4 g silica gel column. TM -12 cartridge. Chromatography eluting with a gradient of 50% to 100% ethyl acetate in heptane provided the title compound (3 mg, 6.95 μmol, 42.7% yield). MS (ESI-) m / z 430 [MH] - ; 1 H NMR (400MHz, CDCl3) δppm 8.38 (d, J=1.7Hz, 1H), 8.04-8.00 (m, 2H), 7.77 (s, 1H), 7.54 (d, J=1.7Hz, 1H), 7 .35 (d, J=8.0Hz, 2H), 6.43 (s, 2H), 4.93 (d, J=5.9Hz, 2H), 1.90 (d, J=5.9Hz, 1H).

[0967] Example 6

[0968] 2-(1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[0969] A solution of iodobenzene (696 mg, 2.162 mmol), (2,2,6,6-tetramethyl-piperidin-1-yl)oxide (TEMPO, 45.0 mg, 0.288 mmol) and (5-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methanol (300 mg, 0.721 mmol, Example 1) in 1,4-dioxane (20 mL) and water (6.00 mL) was stirred at ambient temperature for 30 minutes. LC / MS analysis showed mainly the desired product. The mixture was extracted with 60 mL of ethyl acetate and 20 mL of water. The organic layer was separated and the solvent removed in vacuo. The material was stirred in 20 mL of ethyl acetate and filtered to give the title compound (177 mg, 0.458 mmol, 63.6% yield). 1H NMR (400MHz, DMSO-d6) δppm9.44 (s, 1H), 8.44 (d, J = 2.0Hz, 1H), 8.21-8.12 (m, 2H ), 7.93 (d, J=2.1Hz, 1H), 7.67 (dd, J=9.0, 1.2Hz, 2H), 7.30 (s, 2H); MS (ESI+) m / z 387(M+H + ).

[0970] Example 7

[0971] (5-{3-amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[0972] Step 1: 3-amino-5-((4-(trifluoromethyl)phenyl)thio)picolinic acid

[0973] A solution of 3-amino-5-bromopicolinic acid (15.00 g, 69.1 mmol) in N, N-dimethylformamide (150 mL) and 4-(trifluoromethyl)thiophenol (11.37 mL, 83 mmol) was bubbled with N2 for 20 minutes. N-ethyl-N-isopropylpropan-2-amine (24.14 mL, 138 mmol) was added to the reaction mixture. Under an atmosphere of N2, the reaction mixture was heated to 100 ° C for 4 hours. The reaction was slowly poured into a mixture of 150 mL of water and 20 mL of 1M HCl aqueous solution, which had been cooled to 0 ° C. The solid formed in the flask containing the reaction mixture was washed with water (100 mL) and petroleum (30 mL x 3), and dried under reduced pressure to give the title compound (19.5 g, 61.4 mmol, 89% yield). MS (ESI+) m / z 315.1 (M+H) + .

[0974] Step 2: 3-amino-5-((4-(trifluoromethyl)phenyl)sulfonyl)picolinic acid

[0975] 3-amino-5-((4-(trifluoromethyl)phenyl)thio)picolinic acid (2.000g, 6.36mmol) is dissolved in TFA (15mL), and the resulting mixture is cooled to 0°C with an ice bath. Next, H2O2 (2.60mL, 25.5mmol, 30% in water) is added at 0°C, and the mixture is stirred at 0°C for 1 hour. The mixture is allowed to warm to 20°C and stirred for 2 hours. The slurry is diluted with a mixture of 1% acetic acid in water. A suspension is obtained, and the mixture is then filtered. A 1% acetic acid / water mixture is used, and the collected solid is then washed with dichloromethane / methanol (10 / 1, 20mL). The solid is dried under reduced pressure to give the title compound (1.96g, 5.66mmol, 89% yield). 1 H NMR (400MHz, DMSO-d6) δppm8.28 (d, J=2.0Hz, 1H), 8.22 (d, J=8.3Hz, 2H), 8.06 (d, J=8.4Hz, 2H), 7.82 (d, J=2.0Hz, 1H), 7.12 (brs, 2H); MS (ESI+) m / z 347(M+H) + .

[0976] Step 3: 3-amino-N′-(2-hydroxyacetyl)-5-((4-(trifluoromethyl)phenyl)sulfonyl)picolinohydrazide

[0977] 3-Amino-5-((4-(trifluoromethyl)phenyl)sulfonyl)picolinic acid (3.00 g, 8.66 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.059 g, 0.433 mmol) and 2-hydroxyacetohydrazide (0.858 g, 9.53 mmol) were added to N,N-dimethylformamide (20 mL). The mixture was stirred at 25 °C for 10 minutes. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.491 g, 13.00 mmol) was added all at once. The mixture was stirred at 45 °C for 2 hours. Water (20 mL) was added. The mixture was filtered, washed with ethyl acetate (3 x 10 mL), and dried under reduced pressure to give the title compound (3.4 g, 7.96 mmol, 92% yield); MS (ESI+) m / z 419.7 (M+H) + .

[0978] Step 4: 3-amino-5-((4-(trifluoromethyl)phenyl)sulfonyl)-N′-(2-((triisopropylsilyl)oxy)acetyl)picolinohydrazide

[0979] To a mixture of 3-amino-N′-(2-hydroxyacetyl)-5-((4-(trifluoromethyl)phenyl)sulfonyl)picolinohydrazide (6.00 g, 14.34 mmol) in N,N-dimethylformamide (50 mL) was added triethylamine (5.00 mL, 35.9 mmol). The mixture was cooled to 0° C., and trifluoromethyltriisopropylsilanesulfonate (5.03 mL, 18.64 mmol) was added. The reaction mixture was stirred at 20° C. for 3 hours. Water (100 mL) was added. The solid was filtered, washed with water (50 mL x2), washed with ethyl acetate (2x15 mL), and dried under reduced pressure to give the title compound (7.2 g, 12.53 mmol, 87% yield). MS (ESI+) m / z 575.7 (M+H) + .

[0980] Step 5: 5-((4-(trifluoromethyl)phenyl)sulfonyl)-2-(5-(((triisopropylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-amine

[0981] A 250 mL three-necked round-bottom flask equipped with a stirring magnet was filled with 3-amino-5-((4-(trifluoromethyl)phenyl)sulfonyl)-N′-(2-((triisopropylsilyl)oxy)acetyl)picolinohydrazide (3.50 g, 6.09 mmol) and placed under an atmosphere of N2. N,N-dimethylpyridine-4-amine (0.074 g, 0.609 mmol), 4-methylbenzene-1-sulfonyl chloride (1.742 g, 9.14 mmol) and acetonitrile (35 mL) were added to generate a slurry. The reaction mixture was heated to 50°C. N-ethyl-N-isopropylpropane-2-amine (3.72 mL, 21.32 mmol) was slowly added via a syringe (internal temperature rose to 50°C during addition), causing the reaction mixture to become homogeneous. The reaction mixture was stirred at 50°C for 1 hour. The mixture was concentrated and water (15 mL) was added. The mixture was filtered and the solid was washed with water (15 mL x 2) and methanol (2 x 10 mL). The solid was dried under reduced pressure to provide the title compound (3.2 g, 5.12 mmol, 84% yield). MS (ESI+) m / z 557.2 (M+H) + .

[0982] Step 6: (5-{3-amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[0983] At room temperature, a solution of 5-((4-(trifluoromethyl)phenyl)sulfonyl)-2-(5-(((triisopropylsilyl)oxy)methyl)-1,3,4-oxadiazole-2-yl)pyridine-3-amine (5.80g, 10.42mmol) in acetonitrile (50mL) was mixed for 5 minutes. Tetra-n-butylammonium fluoride (1.0M TBAF, 10.94mL, 10.94mmol) in tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction was concentrated to about 10mL. Water (30mL) was added. The solid was filtered and washed with water (2x30m) and methanol (15mL x 3). The solid was dried under vacuum to provide the title compound (3.57g, 8.92mmol, 86% yield). 1 H NMR (400MHz, DMSO-d6) δppm 8.46 (d, J=1.8Hz, 1H), 8.25 (d, J=8.2Hz, 2H), 8.07 (d, J=8.3Hz, 2H), 7.94 (d, J=1.8Hz, 1H), 7.30 (s, 2H), 6.04 (s, 1H), 4.76 (d, J=6.3Hz, 2H); MS (ESI+) m / z 401.0(M+H) + .

[0984] Example 8

[0985] 5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazole-2-carboxamide

[0986] Step 1: 2-(2-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinyl)hydrazine)-2-oxoacetamide

[0987] A 20 mL vial was filled with 3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinic acid (0.5 g, 1.380 mmol, Step 2 Example 1), 2-hydrazino-2-oxoacetamide (0.213 g, 2.070 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (9.39 mg, 0.069 mmol) and N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for 15 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.397 g, 2.070 mmol) was added all at once, and the mixture was heated at 45 °C for one hour. Water (8 mL) was added. The mixture was stirred at room temperature for 30 minutes, and filtered to provide the title compound (0.431 g, 0.963 mmol, 69.8% yield). 1H NMR (400MHz, DMSO-d6) δppm 10.53(s, 1H), 10.46(s, 1H), 8.23(d, J=2.0Hz, 1H), 8.18-8.13(m, 3H), 7.87(s , 1H), 7.78 (d, J=2.1Hz, 1H), 7.66 (d, J=7.9Hz, 1H), 7.21 (s, 2H); MS (APCI+) m / z 448(M+H) + .

[0988] Step 2: 5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazole-2-carboxamide

[0989] A 20 mL vial was filled with 2-(2-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinyl)hydrazine)-2-oxoacetamide (390 mg, 0.872 mmol, step 1), 4-dimethylaminopyridine (10.65 mg, 0.087 mmol), p-toluenesulfonyl chloride (316 mg, 1.656 mmol), and acetonitrile (5.1 mL). The resulting slurry was heated at 45°C. Hunig's base (N,N-diisopropylethylamine, 0.533 mL, 3.05 mmol) was added slowly dropwise, and heating at 45°C was continued for two hours. Water (8 mL) was added, and the slurry was stirred at room temperature for 30 minutes. The solid was filtered with filter paper using gravity. The solid was dissolved in 5 mL of DMSO with heating at 60°C, cooled, and filtered. The resulting solid was dried under vacuum for 16 h to provide the pure title compound (180 mg, 0.420 mmol, 48.1 % yield). 1 H NMR (400MHz, DMSO-d6) δppm8.68 (s, 1H), 8.46 (d, J=2.1Hz, 1H), 8.29 (s, 1H), 8.22-8.13 (m, 2H), 7.95 (d, J=2.1Hz, 1H), 7.67 (dt, J=7.9, 1.1Hz, 2H), 7.32 (s, 2H); MS (APCI+) m / z 430(M+H) + .

[0990] Example 9

[0991] {5-[3-Amino-5-(4-fluorobenzene-1-sulfonyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methanol

[0992] Step 1: 3-amino-5-((4-fluorophenyl)thio)picolinic acid

[0993] 3-Amino-5-bromopicolinic acid (5 g, 23.04 mmol) was stirred in N,N-dimethylformamide (50 mL). 4-Fluorothiophenol (3.54 g, 27.6 mmol) and N,N-diisopropylethylamine (8.05 mL, 46.1 mmol) were added. The reaction mixture was heated at 100 ° C for 5 hours. The mixture was cooled to room temperature. The reaction mixture was slowly poured into ice water, and the pH was adjusted to 5 with 1N HCl aqueous solution. The solid was filtered and washed with cold water, followed by petroleum ether to give the title compound (5.6 g, 20.77 mmol, 90% yield); MS (ESI+) m / z 265.7 (M+H) + .

[0994] Step 2: 3-amino-5-((4-fluorophenyl)sulfonyl)picolinic acid

[0995] 3-amino-5-((4-fluorophenyl)thio)picolinic acid (3g, 11.35mmol) is dissolved in trifluoroacetic acid (21mL), and the resulting mixture is cooled to 0°C with an ice bath. Next, hydrogen peroxide (4.64mL, 45.4mmol, 30% in water) is added at 0°C, and the mixture is stirred at 0°C for 1 hour. The mixture is allowed to warm to 20°C and stirred for 1 hour. The reaction mixture is diluted with a mixture of 1% acetic acid in water (150mL). Suspension is obtained, which is subsequently filtered. The collected solid is washed with ice water (200mL), and dried under reduced pressure to provide the title compound (3.0g, 10.02mmol, 88% yield). 1 H NMR (400MHz, DMSO-d6) δppm 8.25 (s, 1H), 8.11-8.07 (m, 2H), 8.06 (d, J=8.4Hz, 2H), 7.78 (s, 1H), 7.53 (t, J=8.8Hz, 2H), 7.12 (brs, 2H); MS (ESI+) m / z 297.7(M+H) + .

[0996] Step 3: 3-amino-5-((4-fluorophenyl)sulfonyl)-N′-(2-hydroxyacetyl)picolinohydrazide

[0997] 3-Amino-5-((4-fluorophenyl)sulfonyl)picolinic acid (5 g, 16.88 mmol), 1-hydroxy-7-azabenzotriazole (0.115 g, 0.844 mmol) and 2-hydroxyacetohydrazide (1.672 g, 18.56 mmol) in dimethylformamide (30 mL) were stirred at 25 °C for 10 minutes. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.85 g, 25.3 mmol) was added all at once at an internal temperature of 25 °C. The solution was stirred at 25 °C for 10 minutes and heated to 45 °C for 1 hour. The reaction mixture was added to ice water and stirred for 3 hours. The solid was collected by filtration and washed with ice water to provide the title compound (5.7 g, 14.70 mmol, 87% yield). MS (ESI+) m / z 369.7 (M+H) + .

[0998] Step 4: 3-amino-5-((4-fluorophenyl)sulfonyl)-N′-(2((triisopropylsilyl)oxy)acetyl)picolinohydrazide

[0999] A solution of 3-amino-5-((4-fluorophenyl)sulfonyl)-N′-(2-hydroxyacetyl)picolinohydrazide (6.2 g, 16.83 mmol) was stirred in N,N-dimethylformamide (45 mL) at 0°C. Triethylamine (7.04 mL, 50.5 mmol) was added, and triisopropylsilyl trifluoromethanesulfonate (8.77 g, 28.6 mmol) was added slowly. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was added to ice water and stirred for 2 hours. The solid was collected by filtration and washed with ice water to provide the title compound (8.5 g, 15.39 mmol, 91% yield). MS (ESI+) m / z 525.7 (M+H) + .

[1000] Step 5: 5-((4-fluorophenyl)sulfonyl)-2-(5-(((triisopropylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-amine

[1001] In acetonitrile (40 mL), a solution of 3-amino-5-((4-fluorophenyl)sulfonyl)-N′-(2-((triisopropylsilyl)oxy)acetyl)picolinohydrazide (4 g, 7.62 mmol), N,N-dimethylpyridin-4-amine (0.931 g, 7.62 mmol) and 4-methylbenzene-1-sulfonyl chloride (1.453 g, 7.62 mmol) was stirred. The reaction mixture was heated to 45° C. N-ethyl-N-isopropylpropan-2-amine (0.985 g, 7.62 mmol) was slowly added. The reaction mixture was heated at 45° C. for 2 hours and then cooled to room temperature. Water was added and the mixture was stirred for 1 hour. The mixture was filtered and washed with water to provide the title compound (3.8 g, 7.13 mmol, 93% yield). MS (ESI+) m / z 507.7 (M+H) + .

[1002] Step 6: (5-(3-amino-5-((4-fluorophenyl)sulfonyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methanol

[1003] In acetonitrile (120mL), a mixture of 5-((4-fluorophenyl)sulfonyl)-2-(5-(((triisopropylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-amine (8g, 15.79mmol) was stirred for 5 minutes. Tetra-n-butylammonium fluoride (18.95mL, 18.95mmol) was added. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was cooled to room temperature. 0.53mL of a solution of 85% H3PO4 in 75mL of water was slowly added to the reaction mixture. The resulting slurry was stirred at 20°C for 3 hours. The solid was filtered and washed with 35mL of a 1:5 (v / v) solution of CH3CN / water, washed with 15mL of water, and dried under vacuum to provide the title compound (5.06g, 14.15mmol, 90% yield). 1 H NMR (400MHz, DMSO-d6) δppm8.42 (d, J=2.0Hz, 1H), 8.13-8.08 (m, 2H), 7.90 (d, J=2.0Hz, 1H), 7.53 (t, J=10.4Hz, 2H), 7.27 (s, 2H), 6. (t, J=6.2Hz, 1H), 4.75 (d, J=6.4Hz, 2H); MS (ESI+) m / z 351.7(M+H) + .

[1004] Example 10

[1005] 2-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1006] Step 1: tert-Butyl 2-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinoyl)carbazate

[1007] 3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinic acid (100 mg, 0.276 mmol) in N,N-dimethylacetamide (4 mL) was added to a 20 mL vial. 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (115 mg, 0.304 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.145 mL, 0.828 mmol) were added followed by tert-butyl carbazate (43.8 mg, 0.331 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under a stream of nitrogen. The residue was diluted with 4 mL of ethyl acetate and washed with water (1 x 5 mL). The organic layer was concentrated and purified using silica gel chromatography (using ethyl acetate in heptane as a gradient, 5%-100%, 4 g column) to provide the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 10.16 (s, 1H), 8.82 (s, 1H), 8.18 (d, J=2.1Hz, 1H), 8.17-8.04 (m, 2H), 7.74 (d, J=2.1Hz, 1H), 7.68-7.56 (m, 2H), 7.18 (s, 2H), 1.39 (s, 9H).

[1008] Step 2: 3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide

[1009] Trifluoroacetic acid (1 mL, 12.98 mmol) was added to tert-butyl 2-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinyl)hydrazinecarboxylate, and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under a stream of nitrogen. The raw material was suspended in 1 mL of heptane and stirred overnight. The resulting solid was collected via filtration to give the title compound. 1 H NMR (501MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.25 (d, J=2.1Hz, 1H), 8.17-8.10 (m, 2H), 7.82 (d, J=2.0Hz, 1H), 7.65 (dq, J=7.9, 1.1Hz, 2H).

[1010] Step 3: 3-amino-N′-(cyclohexanecarbonyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide

[1011] Cyclohexanecarboxylic acid (25.7 mg, 0.201 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (70.0 mg, 0.184 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.088 mL, 0.502 mmol) in N,N-dimethylacetamide (1 mL) were added to a 4 mL vial. 3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide (63 mg, 0.167 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified using a reverse phase TFA6 purification procedure to provide the title compound (20 mg, 24.6% yield). 1 HNMR(501MHz, DMSO-d6:D2O=9:1(v / v))δppm 8.24 (d, J=2.0Hz, 1H), 8.20-8.12 (m, 2H), 7.76 (d, J=2.0Hz, 1H), 7.69-7.63 (m, 2H) , 2.28-2.18(m, 1H), 1.77-1.68(m, 3H), 1.62(d, J=12.6Hz, 1H), 1.43-1.12(m, 6H).

[1012] Step 4: 2-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1013] In a 4mL vial, 3-amino-N'-(cyclohexanecarbonyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide (20mg, 0.041mmol) was added to acetonitrile (1mL). p-Toluenesulfonyl chloride (15.68mg, 0.082mmol) and N-ethyl-N-isopropylpropan-2-amine (0.022mL, 0.123mmol) were added and the reaction mixture was stirred at room temperature overnight. By HPLC, the reaction mixture was only 50% complete, so the reaction mixture was heated to 65°C over the weekend. The mixture was directly purified using preparative HPLC / MS method TFA6 to provide the title compound (5.2mg, 27% yield). 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.43 (d, J=2.0Hz, 1H), 8.17 (d, J=8.9Hz, 2H), 7.89 (d, J=2.1Hz, 1H), 7.66 (dd, J=8.8, 1 .2Hz, 2H), 3.17-2.99 (m, 1H), 2.05 (d, J=12.0Hz, 2H), 1.83-1.20 (m, 8H); MS (APCI+) m / z 469.0(M+H) + .

[1014] Example 11

[1015] 2-{5-[(S)-methoxy(phenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1016] The title compound was prepared according to the procedure described in Example 10, substituting (S)-2-methoxy-2-phenylacetic acid for cyclohexanecarboxylic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.42 (d, J=2.0Hz, 1H), 8.16 (d, J=8.9Hz, 2H), 7.90 (d, J=2.1Hz, 1H), 7.70-7.61 (m, 2H), 7.52-7.36 (m, 5H), 5.89 (s, 1H), 3.41 (s, 3H); MS (APCI+) m / z 506.9(M+H) + .

[1017] Example 12

[1018] 2-{5-[(Cyclopropylmethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1019] The title compound was prepared according to the procedure described in Example 10, substituting 2-(cyclopropylmethoxy)acetic acid for cyclohexanecarboxylic acid. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.45 (d, J=2.1Hz, 1H), 8.19 (d, J=8.9Hz, 2H), 7.92 (d, J=2.0Hz, 1H), 7.70-7.64 (m, 2H), 4.82 (s, 2 H), 3.39 (d, J=7.0Hz, 2H), 1.09-0.94 (m, 1H), 0.56-0.40 (m, 2H), 0.24-0.15 (m, 2H); MS (APCI+) m / z 471.0(M+H) + .

[1020] Example 13

[1021] 2-[5-(Phenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1022] The title compound was prepared according to the procedure described in Example 10, substituting 2-phenoxyacetic acid for cyclohexanecarboxylic acid. 1 HNMR (500MHz, DMSO-d6:D2O=9:1 (v / v)) δppm8.44 (d, J=2.0Hz, 1H), 8.18 (d, J=9.0Hz, 2H), 7.92 (d, J=2.0Hz, 1H), 7.66 (d, J=8 .4Hz, 2H), 7.34 (dd, J=8.8, 7.3Hz, 2H), 7.09 (d, J=1.1Hz, 2H), 7.03 (t, J=7.4Hz, 1H), 5.51 (s, 2H); MS (APCI+) m / z492.9 (M+H) + .

[1023] Example 14

[1024] 2-{5-[(Cyclopentyloxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1025] The title compound was prepared according to the procedure described in Example 10, substituting 2-(cyclopentyloxy)acetic acid for cyclohexanecarboxylic acid. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.45 (d, J=2.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.92 (d, J=2.0Hz, 1H), 7.71-7. 62(m, 2H), 4.75(s, 2H), 4.13-4.03(m, 1H), 1.83-1.39(m, 8H); MS(APCI+)m / z 485.0(M+H) + .

[1026] Example 15

[1027] 5-[4-(Trifluoromethoxy)benzene-1-sulfonyl]-2-{5-[(trifluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}pyridin-3-amine

[1028] The title compound was prepared according to the procedure described in Example 10, substituting 2-(trifluoromethoxy)acetic acid for cyclohexanecarboxylic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm8.46 (d, J=2.0Hz, 1H), 8.19 (d, J=8. 9Hz, 2H), 7.94 (d, J=2.0Hz, 1H), 7.77-7.62 (m, 2H), 5.62 (s, 2H); MS (APCI+) m / z 484.9(M+H) + .

[1029] Example 16

[1030] 2-(5-{[(oxolan-3-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1031] The title compound was prepared according to the procedure described in Example 10, substituting 2-((tetrahydrofuran-3-yl)oxy) for cyclohexanecarboxylic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm8.45 (d, J=2.1Hz, 1H), 8.19 (d, J=9.0Hz, 2H), 7.92 (d, J=2.0Hz, 1 H), 7.72-7.56 (m, 2H), 4.83 (s, 2H), 4.39-4.30 (m, 1H), 3.79-3.59 (m, 4H), 2.14-1.76 (m, 2H); MS (APCI+) m / z 486.9(M+H) + .

[1032] Example 17

[1033] 2-{5-[(2-methoxyethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1034] Step 1: 3-amino-N′(2-(2-methoxyethoxy)acetyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide

[1035] To a 4 mL vial was added 2-(2-methoxyethoxy)acetic acid (0.4 M in N,N-dimethylacetamide, 199 μL, 0.08 mmol, 1.5 equiv) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.12 M in N,N-dimethylacetamide, 500 μL, 0.063 mmol, 1.2 equiv). 3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide (0.10 M in N,N-dimethylacetamide, 500 μL, 0.053 mmol, 1.0 equiv) from Step 2 in Example 10 was added followed by N-ethyl-N-isopropylpropan-2-amine (27 μL, 0.16 mmol, 3.0 equiv) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified using reverse phase procedure TFA6 to provide the title compound.

[1036] Step 2: 2-{5-[(2-methoxyethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1037] The compound from step 1 was transferred to a 4 mL vial and toluene (500 μL) was added. Only Lawson's reagent (32 mg, 0.08 mmol, 1.5 equiv) was added to the vial and the reaction was heated to 110 °C for 1 hour. The solvent was removed under a stream of nitrogen. Water and dichloromethane were added and the mixture was vortexed. The organic phase was removed, dried under a stream of nitrogen, and reconstituted in DMSO / CH3OH. The raw material was purified using reverse phase HPLC / MS method AA7 to provide the title compound (6.4 mg, 25% yield). 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.40 (d, J=2.0Hz, 1H), 8.19 (d, J=8.9Hz, 2H), 7.91 (d, J=2.0Hz, 1H), 7.72-7.62 (m, 2H), 4 .96(s, 2H), 3.74-3.68(m, 2H), 3.55-3.48(m, 2H), 3.27(s, 3H); MS(APCI+)m / z490.9(M+H) + .

[1038] Example 18

[1039] N-[(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)methyl]cyclopropanecarbothioamide

[1040] The title compound was prepared according to the procedure described in Example 17, substituting 2-(cyclopropylcarboxamido)acetic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.38 (d, J=2.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.89 (d, J=2.0Hz, 1H), 7.75-7.60 (m, 2H) , 5.22(s, 2H), 2.21-2.04(m, 1H), 1.12-0.99(m, 2H), 0.99-0.84(m, 2H); MS(APCI+)m / z 515.8(M+H) + .

[1041] Example 19

[1042] 2-{5-[(S)-methoxy(phenyl)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1043] The title compound was prepared according to the procedure described in Example 17, substituting (S)-methoxy-phenyl-acetic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.38 (d, J=2.0Hz, 1H), 8.17 (d, J=8.9Hz, 2H), 7.88 (d, J=2.0Hz, 1H), 7.70-7.62 (m, 2H), 7.52-7.31 (m, 5H), 5.89 (s, 1H), 3.41 (s, 3H); MS (APCI+) m / z 522.8(M+H)+ .

[1044] Example 20

[1045] (2S)-2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)-1,1,1-trifluoropropan-2-ol

[1046] The title compound was prepared according to the procedure described in Example 17, substituting (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.40 (d, J=2.0Hz, 1H), 8.19 (d, J=8.9Hz, 2H), 7.92 (d, J=2.0Hz, 1H), 7.70-7.64 (m, 3H), 1.86 (s, 3H); MS (APCI+) m / z 514.7 (M+H) + .

[1047] Example 21

[1048] 2-{5-[(1R)-1-methoxyethyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1049] The title compound was prepared according to the procedure described in Example 17, substituting (R)-2-methoxypropionic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.40 (d, J=2.0Hz, 1H), 8.26-8.14 (m, 2H), 7.90 (d, J=2.0Hz, 1H), 7.73-7.60 (m , 2H), 4.88 (q, J=6.5Hz, 1H), 3.35 (s, 3H), 1.55 (d, J=6.5Hz, 3H); MS (APCI+) m / z 460.9(M+H) + .

[1050] Example 22

[1051] 2-[5-(1-methoxyethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1052] The title compound was prepared according to the procedure described in Example 17, substituting 2-methoxypropionic acid for 2-(2-methoxyethoxy)acetic acid. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.40 (d, J=2.0Hz, 1H), 8.19 (d, J=8.9Hz, 2H), 7.90 (d, J=2.0Hz, 1H), 7.75-7.62 ( m, 2H), 4.88 (q, J=6.5Hz, 1H), 3.35 (s, 3H), 1.56 (d, J=6.5Hz, 3H); MS (APCI+) m / z 460.9(M+H) + .

[1053] Example 23

[1054] 2-{5-[(1S)-1-methoxyethyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1055] The title compound was prepared according to the procedure described in Example 17, substituting (S)-2-methoxypropionic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.40 (d, J=2.0Hz, 1H), 8.19 (d, J=8.9Hz, 2H), 7.90 (d, J=2.0Hz, 1H), 7.75-7.62 ( m, 2H), 4.88 (q, J=6.5Hz, 1H), 3.35 (s, 3H), 1.56 (d, J=6.5Hz, 3H); MS (APCI+) m / z 460.9(M+H) + .

[1056] Example 24

[1057] 2-{5-[(Cyclopropylmethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1058] The title compound was prepared according to the procedure described in Example 17, substituting 2-(cyclopropylmethoxy)acetic acid for 2-(2-methoxyethoxy)acetic acid. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.40 (d, J=2.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.90 (d, J=2.0Hz, 1H), 7.78-7.55 (m, 2H), 4.95 (s, 2H), 3. 42(d, J=6.9Hz, 2H), 1.13-0.86(m, 1H), 0.58-0.43(m, 2H), 0.29-0.11(m, 2H); MS(APCI+)m / z486.9(M+H) + .

[1059] Example 25

[1060] 2-[5-(Ethoxymethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1061] The title compound was prepared according to the procedure described in Example 17, substituting 2-ethoxyacetic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.40 (d, J=2.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.90 (d, J=2.0Hz, 1H), 7.71-7.63 ( m, 2H), 4.92 (s, 2H), 3.62 (q, J=7.0Hz, 2H), 1.18 (t, J=7.0Hz, 3H); MS (APCI+) m / z 460.9(M+H) + .

[1062] Example 26

[1063] 2-[5-(Methoxymethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1064] The title compound was prepared according to the procedure described in Example 17, substituting 2-methoxyacetic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.40 (d, J=2.0Hz, 1H), 8.19 (d, J=8.9Hz, 2H), 7.91 (d, J=2.0Hz, 1H), 7.73-7.57 (m, 2H), 4.89 (s, 2H), 3.42 (s, 3H); MS (APCI+) m / z 446.8 (M+H) + .

[1065] Example 27

[1066] 2-(5-{[(pyridin-3-yl)oxy]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1067] The title compound was prepared according to the procedure described in Example 17, substituting 2-(pyridin-3-yloxy)acetic acid hydrochloride for 2-(2-methoxyethoxy)acetic acid. 1 H NMIR(400MHz, DMSO-d6:D2O=9:1(v / v))δppm 8.61-8.54 (m, 1H), 8.40 (d, J=2.0Hz, 1H), 8.37 (d, J=5.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.92 (d, J= 2.0Hz, 1H), 7.87 (dd, J=8.6, 2.9Hz, 1H), 7.72-7.56 (m, 3H), 5.79 (s, 2H); MS (APCI+) m / z509.8 (M+H) + .

[1068] Example 28

[1069] 5-[4-(Trifluoromethoxy)benzene-1-sulfonyl]-2-{5-[(trifluoromethoxy)methyl]-1,3,4-thiadiazol-2-yl}pyridin-3-amine

[1070] The title compound was prepared according to the procedure described in Example 17, substituting 2-(trifluoromethoxy)acetic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.41 (d, J=2.0Hz, 1H), 8.19 (d, J=8.9Hz, 2H), 7.93 (d, J=2.0Hz, 1H), 7.73-7.61 (m, 2H), 5.70 (s, 2H); MS (APCI+) m / z 500.8 (M+H) + .

[1071] Example 29

[1072] 2-(5-{[(Oxolan-3-yl)oxy]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1073] The title compound was prepared according to the procedure described in Example 17, substituting 2-((tetrahydrofuran-3-yl)oxy)acetic acid for 2-(2-methoxyethoxy)acetic acid. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.40 (d, J=2.0Hz, 1H), 8.23-8.13 (m, 2H), 7.90 (d, J=2.0Hz, 1H), 7.70-7.65 (m, 2H), 4.95 (s, 2H), 4. 40-4.33(m, 1H), 3.84-3.76(m, 2H), 3.72-3.63(m, 2H), 2.04-1.93(m, 2H); MS(APCI+)m / z502.9(M+H) + .

[1074] Example 30

[1075] 2-{5-[(difluoromethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1076] The title compound was prepared according to the procedure described in Example 17, substituting 2-(difluoromethoxy)acetic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.41 (d, J=2.0Hz, 1H), 8.19 (d, J=8.9Hz, 2H), 7.92 (d, J=2.0Hz, 1H), 7.67 (dd, J=8.9, 1.1Hz, 2H), 6.88 (t, J=74.2Hz, 1H), 5.43 (s, 2H); MS (APCI+) m / z 482.8(M+H) + .

[1077] Example 31

[1078] 2-(5-{[(2S)-oxolan-2-yl]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1079] The title compound was prepared according to the procedure described in Example 17, substituting (S)-2-(tetrahydrofuran-2-yl)acetic acid for 2-(2-methoxyethoxy)acetic acid. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.39 (d, J=2.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.88 (d, J=2.1Hz, 1H), 7.71-7.62 (m, 2H), 4.21-4.13 (m, 1H), 3.86-3.61 (m, 2H) , 3.44-3.18 (m, 2H), 2.03 (dd, J=12.7, 6.3Hz, 1H), 1.89-1.78 (m, 2H), 1.54 (dd, J=12.2, 7.6Hz, 1H); MS (APCI+) m / z486.9 (M+H) + .

[1080] Example 32

[1081] 2-(5-{[(2R)-oxolan-2-yl]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1082] The title compound was prepared according to the procedure described in Example 17, substituting (R)-2-(tetrahydrofuran-2-yl)acetic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.39 (d, J=2.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.88 (d, J=2.0Hz, 1H), 7.70-7.58 (m, 2H), 4.24-4.11 (m, 1H), 3.85-3 .58 (m, 2H), 3.42-3.18 (m, 2H), 2.03 (dq, J=13.1, 6.8Hz, 1H), 1.90-1.75 (m, 2H), 1.62-1.45 (m, 1H); MS (APCI+) m / z 486.9(M+H) + .

[1083] Example 33

[1084] 2-{5-[(2-methoxyethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1085] The title compound was prepared according to the procedure described in Example 10, substituting 2-(2-methoxyethoxy)acetic acid for cyclohexanecarboxylic acid. 1H NMR (500MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.44 (d, J=2.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.92 (d, J=2.1Hz, 1H), 7.70-7.62 (m, 2H), 4.84(s, 2H), 3.70-3.66(m, 2H), 3.50-3.47(m, 2H), 3.23(s, 3H); MS(APCI+)m / z 474.8(M+H) + .

[1086] Example 34

[1087] 2-{5-[(1R)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1088] The title compound was prepared according to the procedure described in Example 10, substituting (R)-2-methoxypropionic acid for cyclohexanecarboxylic acid. 1 H NMR (500MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.45 (d, J=2.0Hz, 1H), 8.18 (d, J=9.0Hz, 2H), 7.91 (d, J=2.0Hz, 1H), 7.72-7.60 ( m, 2H), 4.82 (q, J=6.6Hz, 1H), 3.31 (s, 3H), 1.55 (d, J=6.6Hz, 3H); MS (APCI+) m / z 444.8(M+H) + .

[1089] Example 35

[1090] 2-{5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1091] The title compound was prepared according to the procedure described in Example 10, substituting (S)-2-methoxypropionic acid for cyclohexanecarboxylic acid. 1 H NMR (500MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.45 (d, J=2.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.91 (d, J=2.1Hz, 1H), 7.67 (d, J=8. 4Hz, 3H), 4.81 (q, J=6.7Hz, 1H), 3.31 (s, 3H), 1.55 (d, J=6.6Hz, 3H); MS (APCI+) m / z 444.8(M+H) + .

[1092] Example 36

[1093] 2-[5-(Ethoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1094] The title compound was prepared according to the procedure described in Example 10, substituting 2-ethoxyacetic acid for cyclohexanecarboxylic acid. 1 HNMR(500MHz, DMSO-d6:D2O=9:1(v / v))δppm 8.44 (d, J=2.0Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.92 (d, J=2.1Hz, 1H), 7.75-7.62 ( m, 2H), 4.79 (s, 2H), 3.59 (q, J=7.0Hz, 2H), 1.15 (t, J=7.0Hz, 3H); MS (APCI+) m / z 444.9(M+H) + .

[1095] Example 37

[1096] 2-[5-(Methoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1097] The title compound was prepared according to the procedure described in Example 10, substituting 2-methoxyacetic acid for cyclohexanecarboxylic acid. 1 HNMR(500MHz, DMSO-d6:D2O=9:1(v / v))δppm 8.44 (d, J=2.1Hz, 1H), 8.18 (d, J=8.9Hz, 2H), 7.92 (d, J=2.1Hz, 1H), 7.74-7.64 (m, 2H), 4.77 (s, 2H), 3.38 (s, 3H); MS (APCI+) m / z430.9 (M+H) + .

[1098] Example 38

[1099] 2-(5-{[(pyridin-3-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1100] The title compound was prepared according to the procedure described in Example 10, substituting 2-(pyridin-3-yloxy)acetic acid hydrochloride for cyclohexanecarboxylic acid. 1H NMR (500MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.52-8.38 (m, 3H), 8.31-8.24 (m, 1H), 8.18 (d, J=8.9Hz, 2H), 7.92 (d, J=2.0Hz, 1H), 7 .72-7.57(m, 3H), 7.46(dd, J=8.5, 4.7Hz, 2H), 5.64(s, 2H); MS(APCI+)m / z493.8(M+H) + .

[1101] Example 39

[1102] 2-{5-[(difluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1103] The title compound was prepared according to the procedure described in Example 10, substituting 2-(difluoromethoxy)acetic acid for cyclohexanecarboxylic acid. 1 H NMR (500MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.45 (d, J=2.0Hz, 1H), 8.25-8.13 (m, 2H), 7.93 (d, J=2.0Hz, 1H), 7.73-7.60 (m, 2H), 6.87 (t, J=73.9Hz, 1H), 5.31 (s, 2H); MS (APCI+) m / z 466.9(M+H) + .

[1104] Example 40

[1105] 2-(5-{[(2S)-oxolan-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1106] The title compound was prepared according to the procedure described in Example 10, substituting (S)-2-(tetrahydrofuran-2-yl)acetic acid for cyclohexanecarboxylic acid. 1H NMR (500MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.43 (d, J=2.0Hz, 1H), 8.25-8.11 (m, 2H), 7.90 (d, J=2.1Hz, 1H), 7.70-7.60 (m, 2H), 4.31-4.20 (m, 1H), 3.6 5-3.57(m, 2H), 3.28-3.02(m, 2H), 2.13-1.99(m, 1H), 1.93-1.76(m, 2H), 1.74-1.57(m, 1H); MS(APCI+)m / z 470.9(M+H) + .

[1107] Example 41

[1108] 2-(5-{[(2R)-oxolan-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1109] The title compound was prepared according to the procedure described in Example 10, substituting (R)-2-(tetrahydrofuran-2-yl)acetic acid for cyclohexanecarboxylic acid. 1 H NMR (500MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.43 (d, J=2.1Hz, 1H), 8.21-8.14 (m, 2H), 7.90 (d, J=2.1Hz, 1H), 7.70-7.64 (m, 2H), 4.29-4.22 (m, 1H), 3.64 ( s, 2H), 3.24-3.08 (m, 2H), 2.12-2.03 (m, 1H), 1.90-1.81 (m, 2H), 1.71-1.61 (m, 1H); MS (APCI+) m / z470.9 (M+H) + .

[1110] Example 42

[1111] 1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)ethan-1-ol

[1112] Step 1: (S)-3-amino-N′-(2-hydroxypropionyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide

[1113] To a 4 mL vial was added (S)-2-hydroxypropionic acid (10.8 mg, 0.12 mmol, 1.5 equiv) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (36.4 mg, 0.10 mmol, 1.2 equiv) in N,N-dimethylacetamide (1.0 mL). 3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide (30.0 mg, 0.08 mmol, 1.0 equiv) from Example 10, Step 2 was added, followed by N-ethyl-N-isopropylpropan-2-amine (42 μL, 0.24 mmol, 3.0 equiv). The reaction was stirred at room temperature for 1 hour. The reaction was purified using reverse phase method TFA10 to provide the title compound.

[1114] Step 2: (S)-3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)-N′-(2-((triisopropylsilyl)oxy)propanoyl)picolinohydrazide

[1115] The purified material from step 1 was suspended in 500 μL dichloromethane. Triethylamine (30 μL, 0.21mmol, 2.5 equivalents) was added, followed by TIPS trifluoromethanesulfonate (triisopropylsilyl trifluoromethanesulfonate, 50 μL, 0.21mmol, 2.5 equivalents). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water twice. The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated to provide the title compound.

[1116] Step 3: (S)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)-2-(5-(1-((triisopropylsilyl)oxy)ethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-amine

[1117] The residue from step 2 was dissolved in 500 μL CH3CN. 4-(Dimethylamino)pyridine (0.007 M, 1 mL, 0.007 mmol, 0.1 eq) and p-toluenesulfonyl chloride (0.14 M, 1 mL, 0.14 mmol, 1.9 eq) stock solutions were added, followed by diisopropylethylamine (50 μL, 0.29 mmol, 4.0 eq). The reaction mixture was heated at 45°C for 1 hour and then directly purified via reverse phase using method TFA8.

[1118] Step 4: 1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)ethan-1-ol

[1119] The compound from step 3 was dissolved in tetrahydrofuran (500 μL). Tetrabutylammonium fluoride (1M in tetrahydrofuran, 70 μL, 0.07mmol, 1.0 equivalent) was added at room temperature, and the reaction mixture was stirred until the reaction was completed by LC. The reaction mixture was purified via preparative reverse phase HPLC / MS method TFA8. After purification, the sample still contained traces of tetrabutylammonium salt and was re-purified using the same method to provide the title compound. 1 H NMR (501MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.44 (d, J=2.1Hz, 1H), 8.21-8.14 (m, 2H), 7.91 (d, J=2.1Hz, 1H), 7.70-7.64 (m, 2H), 5.05 (q, J=6.6Hz, 1H), 1.54 (d, J=6.7Hz, 3H); MS (APCI+) m / z 430.9(M+H) + .

[1120] Example 43

[1121] 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)propan-2-ol

[1122] The title compound was prepared according to the procedure described in Example 42, substituting 2-hydroxy-2-methylpropionic acid for (S)-2-hydroxypropionic acid. 1 H NMR (501MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.45 (d, J=2.0Hz, 1H), 8.21-8.14 (m, 2H), 7.91 (d, J=2.0Hz, 1H), 7.70-7.64 (m, 2H), 1.61 (s, 6H); MS (APCI+) m / z 444.9 (M+H) + .

[1123] Example 44

[1124] (1S)-1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-2-phenylethan-1-ol

[1125] The title compound was prepared according to the procedure described in Example 42 using (S)-2-

[1126] Hydroxy-3-phenylpropionic acid replaces (S)-2-hydroxypropionic acid. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.46 (d, J=2.0Hz, 1H), 8.23-8.14 (m, 2H), 7.91 (d, J=2.0Hz, 1H), 7.68 (d, J=8.4Hz, 2H), 7.31 -7.17 (m, 5H), 5.12 (t, J=7.2Hz, 1H), 3.20 (dd, J=7.1, 4.7Hz, 2H); MS (APCI+) m / z506.9 (M+H) + .

[1127] Example 45

[1128] (S)-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)(phenyl)methanol

[1129] The title compound was prepared according to the procedure described in Example 42, substituting (S)-2-hydroxy-2-phenylacetic acid for (S)-2-hydroxypropionic acid. 1 H NMIR(400MHz, DMSO-d6:D2O=9:1(v / v))δppm 8.40 (d, J=2.0Hz, 1H), 8.19-8.10 (m, 2H), 7.88 (d, J=2.0Hz, 1H), 7.68-7.6 0(m, 2H), 7.51-7.44(m, 2H), 7.44-7.29(m, 3H), 6.11(s, 1H); MS(APCI+)m / z 492.9(M+H) + .

[1130] Example 46

[1131] 2-[3-(2-methoxypropan-2-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1132] To a 4 mL vial was added 3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinic acid (60.4 mg, 0.167 mmol, 1.0 equiv) in N,N-dimethylacetamide (1 mL). 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (69.7 mg, 0.183 mmol, 1.1 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.087 mL, 0.500 mmol, 3.0 equiv) were added followed by (Z)-N′-hydroxy-2-methoxy-2-methylpropanamide (26.4 mg, 2 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 1 hour, at which time LC / MS showed the reaction was complete. The solvent was removed under a stream of nitrogen. The residue is diluted with 2mL dichloromethane and washed with water (1x5mL).The residue from the first step is diluted with 1mL tetrahydrofuran.Add tetrabutylammonium hydroxide (40%wt in water, 108mg, 0.167mmol), and the reaction mixture is stirred at room temperature for 3 hours.Under nitrogen stream, remove solvent.The residue is dissolved in 0.5mLCH3CN, and is added into the water of 4mL stirring, continues 30 minutes.Remove water via pipette, and solid is dissolved in DMSO, and uses TFA8, purifies on reversed-phase HPLC / MS. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.47 (d, J=2.1Hz, 1H), 8.26-8.15 (m, 2H), 7.99 (d, J=2.1Hz, 1H), 7.74-7.67 (m, 2H), 3.12 (s, 3H), 1.63 (s, 6H); MS (APCI+) m / z 458.8 (M+H) + .

[1133] Example 47

[1134] 2-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1135] The title compound was prepared according to the procedure described in Example 46, substituting N'-hydroxy-2-methoxy-propionamide for (Z)-N'-hydroxy-2-methoxy-2-methylpropionamide and by purifying the sample after the first and second steps. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.44 (d, J=2.0Hz, 1H), 8.23-8.14 (m, 2H), 7.96 (d, J=2.1Hz, 1H), 7.72-7.63 (m , 2H), 4.69 (q, J=6.6Hz, 1H), 3.28 (s, 3H), 1.53 (d, J=6.6Hz, 3H); MS (APCI+) m / z 444.9(M+H) + .

[1136] Example 48

[1137] 2-[3-(oxan-4-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1138] The title compound was prepared according to the procedure described in Example 46, substituting N'-hydroxytetrahydropyran-4-carboximidamide for (Z)-N'-hydroxy-2-methoxy-2-methylpropanamide and by purifying the sample after the first and second steps. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.43 (d, J=2.0Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d, J=2.1Hz, 1H), 7.71-7.63 (m, 2H), 3.96-3.88 (m, 2H) , 3.50 (td, J=11.5, 2.3Hz, 2H), 3.27-3.14 (m, 1H), 2.01-1.93 (m, 2H), 1.87-1.72 (m, 2H); MS (APCI+) m / z 470.8(M+H) + .

[1139] Example 49

[1140] 2-{3-[(4-fluorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1141] The title compound was prepared according to the procedure described in Example 46, substituting 2-(4-fluorophenoxy)-N'-hydroxy-acetamidine for (Z)-N'-hydroxy-2-methoxy-2-methylpropanamide and by purifying the sample after the first and second steps. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.44 (d, J=2.0Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 7.71-7.63 (m, 2H), 7.20-7.06 (m, 4H), 5.38 (s, 2H); MS (APCI+) m / z 510.8 (M+H) + .

[1142] Example 50

[1143] 2-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1144] The title compound was prepared according to the procedure described in Example 46, substituting 2-cyclopropyl-N'-hydroxy-acetamidine for (Z)-N'-hydroxy-2-methoxy-2-methylpropanamide and by purifying the sample after the first and second steps. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.43 (d, J=2.0Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 7.71-7.63 (m, 2H), 2.75 (d, J=7.0Hz, 2H), 1.19-1.14 (m, 1H), 0.58-0.49 (m, 2H), 0.32-0.24 (m, 2H); MS (APCI+) m / z 440.9(M+H) + .

[1145] Example 51

[1146] 2-{3-[(Oxolan-2-yl)methyl]-1,2,4-oxadiazol-5-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1147] The title compound was prepared according to the procedure described in Example 46, substituting N'-hydroxy-2-tetrahydrofuran-2-yl-acetamidine for (Z)-N'-hydroxy-2-methoxy-2-methylpropanamide and by purifying the sample after the first and second steps. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.43 (d, J=2.0Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 7.71-7.63 (m, 2H), 4.29 (p, J=6.6Hz, 1H), 3.80-3.74 (m , 1H), 3.65-3.56 (m, 1H), 3.00 (d, J=6.5Hz, 2H), 2.11-1.98 (m, 1H), 1.94-1.77 (m, 2H), 1.71-1.57 (m, 1H); MS (APCI+) m / z 470.8(M+H) + .

[1148] Example 52

[1149] 2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1150] The title compound was prepared according to the procedure described in Example 46, substituting N'-hydroxycyclopropanecarboximidamide for (Z)-N'-hydroxy-2-methoxy-2-methylpropanamide and by purifying the sample after the first and second steps. 1 H NMIR(400MHz, DMSO-d6:D2O=9:1(v / v))δppm 8.41 (d, J=2.1Hz, 1H), 8.22-8.13 (m, 2H), 7.93 (d, J=2.0Hz, 1H), 7.71-7.63 (m , 2H), 2.28-2.17(m, 1H), 1.19-1.09(m, 2H), 1.10-1.01(m, 2H); MS(APCI+)m / z 426.9(M+H) + .

[1151] Example 53

[1152] 2-[3-(Oxolan-3-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1153] The title compound was prepared according to the procedure described in Example 46, substituting N'-hydroxytetrahydrofuran-3-carboximidamide for (Z)-N'-hydroxy-2-methoxy-2-methylpropanamide and by purifying the sample after the first and second steps. 1H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.43 (d, J=2.1Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d, J=2.1Hz, 1H), 7.71-7.63 (m, 2H) , 4.07 (dd, J=8.5, 7.6Hz, 1H), 3.94-3.81 (m, 4H), 2.42-2.15 (m, 2H); MS (APCI+) m / z 456.9(M+H) + .

[1154] Example 54

[1155] 2-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1156] The title compound was prepared according to the procedure described in Example 46, substituting N'-hydroxy-2,2-dimethyl-propionamide for (Z)-N'-hydroxy-2-methoxy-2-methylpropionamide and by purifying the sample after the first and second steps. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.42 (d, J=2.1Hz, 1H), 8.22-8.14 (m, 2H), 7.95 (d, J=2.0Hz, 1H), 7.71-7.63 (m, 2H), 1.39 (s, 9H); MS (APCI+) m / z 442.9 (M+H) + .

[1157] Example 55

[1158] 2-[3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1159] The title compound was prepared according to the procedure described in Example 46, substituting N'-hydroxy-3-methoxy-propionamide for (Z)-N'-hydroxy-2-methoxy-2-methylpropionamide and by purifying the sample after the first and second steps. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.43 (d, J=2.1Hz, 1H), 8.22-8.14 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 7.71-7.63 (m , 2H), 3.78 (t, J=6.2Hz, 2H), 3.25 (s, 3H), 3.06 (t, J=6.3Hz, 2H); MS (APCI+) m / z 444.9(M+H)+ .

[1160] Example 56

[1161] 2-[3-(Methoxymethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[1162] The title compound was prepared according to the procedure described in Example 46, substituting N'-hydroxy-3-methoxy-acetamidine for (Z)-N'-hydroxy-2-methoxy-2-methylpropanamide and by purifying the sample after the first and second steps. 1 H NMR (400MHz, DMSO-d6:D2O=9:1 (v / v)) δppm 8.47 (d, J=2.0Hz, 1H), 8.27-8.18 (m, 2H), 7.98 (d, J=2.1Hz, 1H), 7.74-7.66 (m, 2H), 7.41-7.35 (m, 2H), 4.70 (s, 2H), 3.42 (s, 3H); MS (APCI+) m / z 430.9(M+H) + .

[1163] Example 57

[1164] (5-{3-amino-4-chloro-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[1165] {5-[3-amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyridin-2-yl]-[1,3,4]oxadiazol-2-yl}-methanol (200 mg, 0.48 mmol) was dissolved in acetic acid (5 mL). N-chlorosuccinimide (CAS: 128-09-6, 640 mg, 4.8 mmol) was added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, water was added, and the resulting suspension was filtered to provide 250 mg of raw material. The raw material was purified by reverse phase preparative HPLC (97% 10 mM NH4HCO3 / pH 10, 3% CH3CN) to provide two regioisomers, Example 57 and Example 64. Example 57: 1 H NMR (600MHz, DMSO-d6) δppm 8.34 (s, 1H), 8.09-8.14 (m, 2H), 7.64-7.68 (m, 2H), 7.45 (br.s., 2H), 6.03 (t, J=6.4Hz, 1H), 4.74 (d, J=6.4Hz, 2H), MS (ESI+) m / z 451 [M+H] + . Example 64: 1H NMR (600MHz, DMSO-d6) δppm 8.68 (s, 1H), 8.16-8.20 (m, 2H), 7.65 (m, 2H), 7.40 (s, 2H), 6.07 (t, J=6.3Hz, 1H), 4.78 (d, J=6.2Hz, 2H), MS (ESI+) m / z 451[M+H] + .

[1166] Example 58

[1167] (5-{3-amino-5-[3-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[1168] Step 1: Methyl 2-triisopropylsilyloxyacetate

[1169] Under N2 atmosphere, tri-isopropyl chloride (CAS: 13154-24-0, 228 mL, 1067 mmol) was added to a solution of methyl glycolate (CAS: 96-35-5, 80 g, 889 mmol) and imidazole (CAS: 288-32-4, 182 g, 1067 mmol) in N,N-dimethylformamide (1 L). The resulting solution was stirred at room temperature. After stirring overnight, thin layer chromatography (ethyl acetate / petroleum ether, 35: 65) showed complete consumption of the starting material. The reaction mixture was quenched with 1.5 L of saturated NaHCO3 aqueous solution. The resulting mixture was extracted with diethyl ether. The organic layer was sequentially washed with 1.4 L of 2N HCl aqueous solution (2.8 mol), 0.5 L of H2O, and 1 L of brine. The organic layer was then dried over Na2SO4, filtered and concentrated to dryness to give the crude title compound used as is in the next step.

[1170] Step 2: 2-Triisopropylsilyloxyacetohydrazide

[1171] Methyl 2-triisopropylsilyloxy acetate (199 g, 889 mmol) was dissolved in tetrahydrofuran (1 L). Hydrazine monohydrate (CAS: 7803-57-8, 35% w / w, 203 mL, 2.222 mol) was added, and the mixture was refluxed. After stirring overnight at reflux, thin layer chromatography (ethyl acetate / petroleum ether, 5: 95) showed complete consumption of the starting material. The reaction mixture was cooled and quenched with saturated NaHCO3 aqueous solution (1.5 L). The resulting solution was extracted with diethyl ether (4 x 500 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to provide 191 g of the raw material as a waxy solid. Purified from ethyl acetate / heptane (5%, 500 mL) to provide 122 g of the title compound. 1H NMR (400MHz, CDCl3) δppm7.76 (s, 1H), 7.26 (s, 1H), 4.28 (s, 2H), 3.87 (d, J = 4.3Hz, 2H), 1.19-1.05 (m, 21H).

[1172] Step 3: 3-Amino-5-(3-trifluoromethoxy-phenylsulfonyl)-pyridine-2-carboxylic acid

[1173] A solution of 3-amino-5-bromo-pyridine-2-carboxylic acid (CAS: 870997-85-6, 500 mg, 2.3 mmol), 3-(trifluoromethoxy)thiophenol (CAS: 220239-66-7, 534 mg, 2.76 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.344 mL, 2.3 mmol) was prepared in N,N-dimethylacetamide (2 mL). The mixture was heated at 150° C. for 45 minutes in a microwave reactor (Biotage, SW version 2.2). Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO aqueous solution, dried (Na2SO4), filtered, and concentrated to provide 783 mg of the title compound.

[1174] Step 4: 3-Amino-5-(3-trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid

[1175] 3-amino-5-(3-trifluoromethoxy-phenylsulfonyl)-pyridine-2-carboxylic acid (783mg, 2.37mmol) is dissolved in trifluoroacetic acid (5mL), and the resulting mixture is cooled to 0°C with an ice bath. Next, H2O2 (30% in water, 0.968mL, 9.48mmol) is added and the mixture is stirred at room temperature for 2 hours. The mixture is diluted with 1% acetic acid (10mL) in water. A suspension is obtained, which is then filtered. The collected solid is washed with 1% acetic acid, followed by petroleum ether, to provide 652mg of the title compound.

[1176] Step 5: 3-Amino-5-(3-trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid N′-(2-triisopropylsilanyloxy-acetyl)-hydrazide

[1177] To a dichloromethane solution (10 mL) containing 3-amino-5-(3-trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid (336 mg, 0.93 mmol) was added diisopropylethylamine (0.323 mL, 1.86 mmol), N-[(dimethylamino)-1H-1,2,3-triazole-[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium hexafluorophosphate N-oxide (354 mg, 0.93 mmol) and 2-triisopropylsilyloxyacetohydrazide (231 mg, 0.93 mmol). The resulting mixture was stirred at room temperature until the reaction was complete. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with NaHCO, dried (NaSO), filtered, and concentrated to provide 540 mg of the title compound.

[1178] Step 6: 5-(3-Trifluoromethoxy-benzenesulfonyl)-2-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-2-yl)-pyridin-3-ylamine

[1179] Under argon atmosphere, in dichloromethane, 3-amino-5-(3-trifluoromethoxy-benzenesulfonyl)-pyridine-2-carboxylic acid N '-(2-triisopropylsilyloxy-acetyl)-hydrazide (540mg, 0.91mmol) is mixed with p-toluenesulfonyl chloride (522mg, 2.74mmol) and triethylamine (381 μ L, 2.74mmol). The reaction mixture is stirred at ambient temperature for 18 hours. The reaction mixture is quenched with 1N NaOH aqueous solution and then extracted with dichloromethane. The organic layer is washed with water, dried over Na2SO4, filtered and concentrated to dryness, to provide 670mg of raw material. Raw material is purified by column chromatography (using dichloromethane as eluent), to provide 68mg of title compound.

[1180] Step 7: {5-[3-Amino-5-(3-trifluoromethoxy-benzenesulfonyl)-pyridin-2-yl]-[1,3,4]oxadiazol-2-yl}-methanol

[1181] 5-(3-trifluoromethoxy-benzenesulfonyl)-2-(5-triisopropylsilyloxymethyl-[1,3,4]oxadiazole-2-yl)-pyridin-3-ylamine (68mg, 0.12mmol) was dissolved in tetrahydrofuran (2mL). A solution of tetrabutylammonium fluoride (CAS: 429-41-4, 1M in tetrahydrofuran, 0.12mL, 0.12mmol) was added, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was concentrated. The raw material was quenched with H2O, dried (Na2SO4), filtered, and concentrated to provide 56mg of the title compound. After grinding in dichloromethane, 14mg of the title compound was obtained. 1H NMR (500MHz, DMSO-d6) δppm 8.47 (d, J=2.1Hz, 1H), 8.06 (m, 1H), 8.00 (s, 1H), 7.93 (d, J=1.8Hz, 1H), 7.82-7.87 (m, 1H), 7.78-7.82(m, 1H), 7.27(s, 2H), 6.02(t, J=6.4Hz, 1H), 4.75(d, J=6.4Hz, 2H), MS(ESI+)m / z 417[M+H] + .

[1182] Example 59

[1183] (5-{3-amino-5-[2-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[1184] The title compound was prepared as described in Example 58, substituting 2-(trifluoromethoxy)-thiophenol (CAS: 175278-01-0) for 3-(trifluoromethoxy)thiophenol. 1 H NMR (500MHz, DMSO-d6) δppm 8.31 (d, J=2.1Hz, 1H), 8.27 (m, 1H), 7.90-7.95 (m, 1H), 7.87 (d, J=1.8Hz, 1H), 7.73 (m, 1H), 7 .61 (d, J=8.2Hz, 1H), 7.32 (s, 2H), 6.02 (t, J=6.4Hz, 1H), 4.75 (d, J=6.4Hz, 2H), MS (ESI+) m / z 417[M+H] + .

[1185] Example 60

[1186] 5-amino-N-benzyl-6-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-N-methylpyridine-3-sulfonamide

[1187] Step 1: 3-Amino-5-bromo-pyridine-2-carboxylic acid N′-(2-triisopropylsilanyloxy-acetyl)-hydrazide

[1188] To a dichloromethane solution (200 mL) containing 3-amino-5-bromo-pyridine-2-carboxylic acid (CAS: 870997-85-6, 10 g, 46 mmol) was added diisopropylethylamine (16 mL, 92 mmol), N-[(dimethylamino)-1H-1,2,3-triazole-[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium hexafluorophosphate N-oxide (17.49 g, 46 mmol) and 2-triisopropylsilyloxyacetohydrazide (11.35 g, 46 mmol). The resulting solution was stirred at room temperature for 18 hours. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, and concentrated to provide 25.37 g of the title compound.

[1189] Step 2: 3-Amino-5-(4-methoxy-benzylsulfonyl)-pyridine-2-carboxylic acid N′-(2-triisopropylsilanyloxyacetyl)-hydrazide

[1190] A container filled with 3-amino-5-bromo-pyridine-2-carboxylic acid, N′-(2-triisopropylsilyloxy-acetyl)-hydrazide (1 g, 2.2 mmol), diisopropylethylamine (0.768 mL, 4.4 mmol) and toluene (10 mL) was dispatched, and the reaction vessel was filled with argon. Next, tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (68 mg, 007 mmol), Xantphos(4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (76 mg, 0.13 mmol) and (4-methoxy-phenyl)-methyl mercaptan (432 mg, 2.8 mmol) were added. The reaction vessel was once again filled with argon, and the reaction mixture was stirred at 110° C. for 18 hours. The reaction mixture was filtered through a silica plug (using ethyl acetate as eluent), and concentrated to provide 759 mg of the title compound.

[1191] Step 3: 5-(4-Methoxy-benzylsulfonyl)-2-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-2-yl)-pyridin-3-ylamine

[1192] Under argon atmosphere, in dichloromethane (10mL), 3-amino-5-(4-methoxy-benzylsulfonyl)-pyridine-2-carboxylic acid N '-(2-triisopropylsilyloxyacetyl)-hydrazide (160mg, 0.29mmol) is mixed with p-toluenesulfonyl chloride (166mg, 0.87mmol) and triethylamine (0.121mL, 0.87mmol). The reaction mixture is stirred at ambient temperature for 2 days. The mixture is quenched with 1N NaOH aqueous solution and then extracted with dichloromethane. The organic layer is washed with water, dried over Na2SO4, filtered and concentrated to dryness, to provide 360mg of raw material. The raw material is further purified by flash chromatography (SiO2, 5g column, eluted with dichloromethane), to provide 69mg of title compound.

[1193] Step 4: 5-amino-6-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-2-yl)-pyridine-3-sulfonyl chloride

[1194] A mixture of 5-(4-methoxy-benzylsulfonyl)-2-(5-triisopropylsilyloxymethyl[1,3,4]oxadiazole-2-yl)-pyridin-3-ylamine (69 mg, 0.14 mmol) in 2 mL of a mixture of CHCN / acetic acid / H0=7:0.37:0.18 was cooled in an ice bath and treated in batches with 1,3-dichloro-5,5-dimethylhydantoin (CAS: 118-52-5, 54 mg, 0.28 mmol). When the addition was complete, the resulting suspension was stirred at 0°C for 90 minutes and then at room temperature for 6 hours. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over NaSO, filtered and concentrated to give 98 mg of the title compound.

[1195] Step 5: 5-Amino-6-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-2-yl)-pyridine-3-sulfonic acid benzyl-methyl-amide

[1196] A suspension of 5-amino-6-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazole-2-yl)-pyridine-3-sulfonyl chloride (98 mg, 0.21 mmol) in dichloromethane (2 mL) was treated with pyridine (0.051 mL, 0.63 mmol) and N-methyl-benzylamine (CAS: 103-67-3, 0.037 mL, 0.28 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by column chromatography (SiO2, 2 g column, dichloromethane as eluent) to provide 36 mg of the title compound.

[1197] Step 6: 5-amino-N-benzyl-6-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-N-methyl-pyridine-3-sulfonamide

[1198] 5-amino-6-(5-triisopropylsilyloxymethyl-[1,3,4]oxadiazole-2-yl)-pyridine-3-sulfonic acid benzyl-methyl-amide (36 mg, 0.07 mmol) was dissolved in tetrahydrofuran (1 mL). A solution of tetrabutylammonium fluoride (TBAF, CAS: 429-41-4, 1M in tetrahydrofuran, 0.02 mL, 0.02 mmol) was added, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was concentrated to remove most of the tetrahydrofuran. The reaction mixture was quenched with H2O, extracted with ethyl acetate, dried (with Na2SO4), filtered, and concentrated to provide 18 mg of crude product. The resulting raw material was ground with dichloromethane to provide 3 mg of the title compound. 1 H NMR (500MHz, DMSO-d6) δ8.31 (d, J=1.8Hz, 1H),), 7.82 (d, J=1.8Hz, 1H), 7.36-7.42 (m, 3H), 7.33 (d, J=7.3 Hz, 2H), 7.23 (s, 2H), 6.04 (t, J=6.1Hz, 1H), 4.77 (d, J=5.5Hz, 2H), 4.23 (s, 2H), 2.63 (s, 3H), MS (ESI+) m / z 376[M+H] + .

[1199] Example 61

[1200] {5-[3-Amino-5-(phenylsulfonyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methanol

[1201] The title compound was prepared as described in Example 58, substituting 3-thiophenol (CAS: 108-98-5) for 3-(trifluoromethoxy)thiophenol. 1 H NMR (500MHz, DMSO-d6) δppm 8.40 (d, J=1.8Hz, 1H), 7.97-8.04 (m, 2H), 7.90 (d, J=2.1Hz, 1H), 7.74-7.80 (m, 1H), 7.66 -7.71 (m, 2H), 7.26 (br.s, 2H), 6.01 (t, J=6.4Hz, 1H), 4.74 (d, J=6.4Hz, 2H), MS (ESI+) m / z 333[M+H] + .

[1202] Example 62

[1203] (5-{3-amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)methanol

[1204] Step 1: 5-[4-(Trifluoromethyl)phenyl]sulfonyl-2-[5-(triisopropylsilyloxymethyl)-1,3,4-thiadiazol-2-yl]pyridin-3-amine

[1205] To a suspension of 3-amino-5-[4-(trifluoromethoxy)phenyl]sulfonyl-N′-(2-triisopropylsilyloxyacetyl)pyridine-2-carbohydrazide (200 mg, 0.35 mmol) in dry toluene (8 mL) was added Lawson's reagent (CAS No. 19172-47-5, 155 mg, 0.38 mmol), and the solution was refluxed for 1 hour. Water was added, and the mixture was extracted with ethyl acetate, dried (with Na2SO4), filtered, and concentrated to provide 178 mg of raw material. The raw material was purified by column chromatography (SiO2, 2 g column, eluent was dichloromethane) to provide 107 mg of the title compound.

[1206] Step 2: [5-[3-amino-5-[4-(trifluoromethyl)phenyl]sulfonyl-2-pyridinyl]-1,3,4-thiadiazol-2-yl]methanol

[1207] 5-[4-(trifluoromethyl)phenyl]sulfonyl-2-[5-(triisopropylsilyloxymethyl)-1,3,4-thiadiazol-2-yl]pyridine-3-amine (107mg, 0.18mmol) was dissolved in tetrahydrofuran (3mL). A solution of tetrabutylammonium fluoride (TBAF, CAS: 429-41-4, 1M in tetrahydrofuran, 0.18mL, 0.18mmol) was added, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was concentrated to remove most of the tetrahydrofuran. The reaction mixture was quenched with H2O, extracted with ethyl acetate, dried (with Na2SO4), filtered, and concentrated to provide 140mg of raw material. After grinding with dichloromethane, 36mg of the title compound was obtained. 1 H NMR (500MHz, DMSO-d6) δppm 8.42 (d, J=1.8Hz, 1H), 8.24 (d, J=8.2Hz, 2H), 8.05 (d, J=8.2Hz, 2H), 7.91 (d, J=1.8Hz, 1H), 7.49 (s, 2H), 6.29 (br.s., 1H), 4.89 (br.s., 2H), MS (ESI+) m / z 417[M+H] + ,MS(ESI+)m / z 417[M+H] + .

[1208] Example 63

[1209] (5-{3-amino-6-bromo-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[1210] 5-[3-amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyridin-2-yl]-[1,3,4]oxadiazole-2-yl}-methanol (200mg, 0.48mmol) was dissolved in acetic acid (5mL). N-bromosuccinimide (NBS, 85mg, 0.48mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. Additional NBS (170mg, 0.41mmol) was added, and the mixture was stirred at room temperature for another 24 hours. Once again, an additional amount of NBS (340mg, 0.82mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, water was added, and the reaction mixture was extracted with ethyl acetate, and washed with saturated NaHCO3 aqueous solution. The organic phases were combined, dried (with Na2SO4), filtered, and concentrated to provide 380mg of raw material. The material was purified by reverse phase preparative HPLC (using a mixture of eluents, 97% 10 mM NH4HCO3 / pH 103% CH3CN) to provide the title compound (Example 63) and Example 66. Example 63: 1 H NMR (600 MHz, DMSO-d6) δppm 8.34 (s, 1H), 8.09-8.14 (m, 2H), 7.64-7.68 (m, 2H), 7.45 (br.s., 2H), 6.03 (t, J=6.4Hz, 1H), 4.74 (d, J=6.4Hz, 2H), MS (ESI+) m / z 496 [M+H] + . Example 66: 1 H NMR (600MHz, DMSO-d6) δppm8.68 (s, 1H), 8.16 (d, 2H), 7.64 (m, 2H), 6.07 (t, J=6.4Hz, 1H), 7.36 (br.s., 2H), 4.78 (d, J=6.4Hz, 2H), MS (ESI+) m / z 496[M+H] + .

[1211] Example 64

[1212] (5-{3-amino-6-chloro-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[1213] {5-[3-amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyridin-2-yl]-[1,3,4]oxadiazol-2-yl}-methanol (200 mg, 0.48 mmol) was dissolved in acetic acid (5 mL). N-chlorosuccinimide (CAS: 128-09-6, 640 mg, 4.8 mmol) was added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, water was added, and the resulting suspension was filtered to provide 250 mg of crude product. The material was purified by reverse phase preparative HPLC (using a mixture of eluents, 97% 10 mM NH4HCO3 / pH 103% CH3CN) to provide two regioisomers, Example 57 and the title compound. Example 64: 1 HNMR (600MHz, DMSO-d6) δppm 8.68 (s, 1H), 8.16-8.20 (m, 2H), 7.65 (m, 2H), 7.40 (s, 2H), 6.07 (t, J=6.3Hz, 1H), 4.78 (d, J=6.2Hz, 2H), MS (ESI+) m / z 451[M+H] + .

[1214] Example 65

[1215] (5-{3-amino-5-[2-(propan-2-yl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[1216] The title compound was prepared as described in Example 58, substituting 2-isopropyl-thiophenol (CAS: 6262-87-9) for 3-(trifluoromethoxy)thiophenol. 1 H NMR (600MHz, DMSO-d6) δppm 8.24 (d, J=2.1Hz, 1H), 8.12 (m, 1H), 7.81 (d, J=2.1Hz, 1H), 7.76 (m, 1H), 7.66 (m, 1H), 7.55 (m, 1H), 7.27 (s, 2H), 6.01 (t, J=6.4Hz, 1H), 4.75 (d, J=6.1Hz, 2H), 3.64 (m, 1H), 1.01 (d, J=6.7Hz, 6H), MS (ESI+) m / z 375[M+H] + .

[1217] Example 66

[1218] (5-{3-amino-4-bromo-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[1219] 5-[3-amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyridin-2-yl]-[1,3,4]oxadiazole-2-yl}-methanol (200mg, 0.48mmol) was dissolved in acetic acid (5mL). N-bromosuccinimide (NBS, 85mg, 0.48mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. Additional NBS (170mg, 0.41mmol) was added, and the mixture was stirred at room temperature for another 24 hours. Additional amounts of NBS (340mg, 0.82mmol) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, water was added, and the reaction mixture was extracted with ethyl acetate, and washed with saturated NaHCO3 aqueous solution. The organic phases were combined, dried (with Na2SO4), filtered, and concentrated to provide 380mg of raw material. The material was purified by reverse phase preparative HPLC (using eluent, 97% 10 mM NH4HCO3 / pH 103% CH3CN) to provide the title compound and Example 63. Example 63: 1 H NMR (600MHz, DMSO-d6) δppm 8.34(s, 1H), 8.09-8.14(m, 2H), 7.64-7.68(m, 2H), 7.45(br.s., 2H), 6.03(t, J=6.4Hz, 1H), 4.74(d, J=6.4Hz, 2H), MB(EBI+)m / z 496[M+H] + . Example 66: 1 HNMR (600MHz, DMSO-d6) δppm 8.68 (s, 1H,), 8.16 (d, 2H,), 7.64 (m, 2H), 6.07 (t, J = 6.4Hz, 1H), 7.36 (br.s., 2H), 4.78 (d, J = 6.4Hz, 2H), MS (ESI+) m / z496 [M+H] + .

[1220] Example 67

[1221] 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,2,4-oxadiazol-3-yl)ethan-1-ol

[1222] The title compound was prepared according to the procedure described in Example 46, substituting N',3-dihydroxypropionamide for (Z)-N'-hydroxy-2-methoxy-2-methylpropionamide and by purifying the sample after the first and second steps. 1H NMR (400MHz, DMSO-d6) δppm 8.44 (d, J=2.1Hz, 1H), 8.20-8.14 (m, 2H), 7.94 (d, J=2.1Hz, 1H), 7.74-7.60 (m, 2H) , 7.37 (s, 2H), 4.83 (t, J=5.5Hz, 1H), 3.84 (q, J=6.2Hz, 2H), 2.95 (t, J=6.4Hz, 2H). MS(APCI+)m / z 431.0(M+H) + .

[1223] Biological Examples

[1224] List of abbreviations used in the Biological Examples section: cAMP stands for cyclic adenosine phosphate; DMSO stands for dimethyl sulfoxide; D-PBS stands for Dulbecco's phosphate-buffered saline; and PBS stands for phosphate-buffered saline.

[1225] In vitro analysis

[1226] YFP-halide influx assay for CFTR-ΔF508 mutation

[1227] The YFP halide influx assay measures the functionality of the cystic fibrosis transmembrane conductance regulator (CFTR) channel in cystic fibrosis bronchial epithelial cells CFBE41o-. This assay is used to assess the ability of compounds to increase the open probability of existing CFTR channels in the membrane. It exploits the observation that the fluorescence of the yellow fluorescent protein (YFP) variant YFP H148Q, I152L, F47L is substantially altered by halide ions (e.g., Cl - and I -) quenching (Galietta, LJV, Haggie, PM, Verkman, AS, 2001. Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett. 499, 220-224. doi: 10.1016 / S0014-5793(01)02561-3; Nagai, T., Ibata, K., Park, ES, Kubota, M., Mikoshiba, K., Miyawaki, A., 2002. A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. [Rapid and efficient maturation of yellow fluorescent protein variants for cell biology applications] Nat. Biotechnol. 20, 87-90. doi: 10.1038 / nbt0102-87).

[1228] For this purpose, CFBE41o- cells were seeded in 384-well plates (3000 CFBE cells / well). One day after seeding, CFBE cells were transduced with an adenoviral vector directing the expression of the CFTRΔF508 mutant and the YFP reporter gene. The cells were incubated at 27° C., 5% CO2 for 24 hours to allow proper folding and migration to the membrane of the CFTR channel or treated with CFTR modulators at 37° C. for 24 hours.

[1229] The next day, CFTR channels were activated by treating with cAMP inducer forskolin (10.67 μM) and test compounds in 1xD-PBS (total volume of 30 μL, from Gibco, catalog number: 14090-041) for 10 minutes, followed by the addition of 30 μL of the following iodide solution (375 mM NaI, 7.5 mM KI, 1.76 mM KH2PO4, 10.1 mM Na2HPO4, 13.75 mM glucose). I-induced quenching of fluorescence was recorded immediately after 2 minutes of iodide injection on FDSS / μCell (Hamamatsu). The ability of the compound to increase channel opening was directly related to the decrease in fluorescence, and was expressed as (1-(fluorescence after 36 seconds (F) / fluorescence before injection (F0))) and EC was derived from (1-F / F0) versus compound concentration plots. 50 .

[1230] Table I. Illustrative EC values ​​of compounds of the invention measured against CFTR-ΔF508 by YFP-halide influx assay 50 .

[1231]

[1232] YFP-halide influx assay with CFTR-G551D mutation

[1233] The YFP halide influx assay measures the functionality of the cystic fibrosis transmembrane conductance regulator (CFTR) channel. This assay is used to assess the ability of compounds to increase channel opening of existing mutant CFTR channels in the membrane. It exploits the observation that the fluorescence of the yellow fluorescent protein (YFP) variants YFP H148Q, I152L, F47L is substantially quenched by halide ions (e.g., Cl- and I-) (Galietta, LJV, Haggie, PM, Verkman, AS, 2001. Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett. 499, 220-224. doi: 10.1016 / S0014-5793(01)02561-3).

[1234] For this purpose, HEK293 cells were seeded in 96-well plates. During seeding, cells were reverse transfected with a plasmid vector directing the expression of the CFTRG551D mutant and the YFP reporter gene. Cells were incubated at 37° C., 5% CO 2 for 24 hours to allow sufficient expression of the CFTR protein.

[1235] The next day, CFTR channels were activated by treating with the cAMP inducer forskolin (10.67 μM) and the test compound in D-PBS (Gibco) for 10 min, followed by the addition of I-solution (137 mM NaI, 2.7 mM KI, 1.76 mM KH2PO4, 10.1 mM Na2HPO4, 5 mM glucose). - After 7 seconds, the I-induced quenching of fluorescence was recorded immediately. The ability of the compound to increase channel openness was directly related to the decrease in fluorescence and was expressed as (1-(fluorescence after 7 seconds (F) / fluorescence before injection (F0))) and the EC was derived from a plot of (1-F / F0) versus compound concentration. 50 .

[1236] Similar YHA assays were developed for other channel gating defective or channel conduction defective CFTR mutants to measure the effects of compounds on channel activity. Examples of mutants are G178R, G1349D, S549N, R117H, R334W. This assay was also used for other class I CFTR mutants, including G542X, W1282X; class II mutants, including N1303K; and class III mutants, including S1251N; or wild-type CFTR.

[1237] Table II. Illustrative ECs of compounds of the invention measured against CFTR-G551D by YFP-halide influx assay 50 .

[1238] Compound No. activation% <![CDATA[EC 50 (nM)]]> 1 37.7 ＞10000 3 49.0 181 4 34.3 ＞6768.2 5 0.3 ＞10000

[1239] Table III. Illustrative ECs of compounds of the invention measured against CFTR-G178R by YFP-halide influx assay 50 .

[1240] Compound No. activation% <![CDATA[EC 50 (nM)]]> 1 67.2 196 3 57.4 1440

[1241] Table IV. Illustrative EC of compounds of the invention measured against CFTR-G1349D by YFP-halide influx assay 50 .

[1242] Compound No. activation% <![CDATA[EC 50 (nM)]]> 1 72.8 137 3 58.6 44.9

[1243] Table V. Illustrative ECs of compounds of the invention measured against CFTR-S549N by YFP-halide influx assay 50 .

[1244] Compound No. activation% <![CDATA[EC 50 (nM)]]> 1 75.4 275 3 56.3 55.9

[1245] Table VI. Illustrative ECs of compounds of the invention measured against CFTR-R117H by YFP-halide influx assay 50 .

[1246] Compound No. activation% <![CDATA[EC 50 (nM)]]> 1 88.7 184 3 89.0 35.5

[1247] Cell analysis

[1248] Electrophysiological measurements in primary human bronchial epithelial cell cultures are useful preclinical surrogates for clinical efficacy (Rowe, SM, Verkman, AS, 2013. Cystic Fibrosis Transmembrane Regulator Correctors and Potentiators. Cold Spring Harb. Perspect. Med. 3, a009761. doi: 10.1101 / cshperspect.a009761), whereby compounds are evaluated in Ussing chambers and / or TECC assays, which are electrophysiological measurement assays.

[1249] Ussing Chamber Analysis

[1250] plan

[1251] The Ussing chamber assay measures the functionality of the cystic fibrosis transmembrane conductance regulator (CFTR) by measuring the short circuit current (Isc) generated in the basolateral and apical membranes of lung epithelial cells.

[1252] To measure Isc, the epithelium is short-circuited by injecting a current that is regulated by a feedback amplifier to maintain the transepithelial potential (Vt) at 0 mV. The amount of current required is regulated by the feedback circuit and measured simultaneously. The voltage is intermittently clamped to a value other than 0 mV, thereby enabling the transepithelial resistance (R t ).

[1253] For this purpose, bronchial epithelial cells isolated from CF patients homozygous for the CFTR ΔF508 mutation (hAEC-CF, Epitheliix) or heterozygous for the CFTR G551D and ΔF508 mutations (University of North Carolina, Chapel Hill) were plated on collagen IV-coated Snapwell TM Human airway epithelium was generated by providing an air-liquid interface for 21 days to form a well-differentiated polarized culture similar to the pseudostratified ciliated epithelium in vivo (Fulcher, ML, Gabriel, S., Burns, KA, Yankaskas, JR, Randell, SH, 2005. Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 107, 183-206). In the case of homotypic ΔF508 CFTR preparations, differentiated cells were treated with 3 μM VX809 (2626 South Loop West, Suite 225, Houston, TX 77054 USA, Catalog No.: S1565) to allow for full expression of properly folded CFTR protein on the membrane (48 hours basolateral treatment and 24 hours apical treatment) before electrophysiological recordings. For heterotypic G551D / ΔF508, differentiated cells were used as is for recordings.

[1254] For electrophysiological recordings, human airway epithelia were mounted in Ussing chambers for measuring short-circuit current (Isc). The epithelium was immersed in NaCl-Ringer's solution (120 mM NaCl, 25 mM NaHCO3, 1.2 mM CaCl2, 1.2 mM MgCl2, 0.8 mM KH2PO4, 0.8 mM pH 7.4 K2HPO4, 5 mM glucose) on the basolateral side and glutamate-Ringer's solution (120 mM sodium glutamate, 25 mM NaHCO3, 1.2 mM CaCl2, 1.2 mM MgCl2, 0.8 mM K2HPO4, 0.8 mM pH 7.4 K2HPO4, 5 mM glucose) on the apical side to generate a Cl- gradient. Both chambers were ventilated with 95% O2, 5% CO2 and maintained at 27°C. Endogenous ENaC currents were inhibited using apical amiloride, while forskolin was applied apically and basolaterally to stimulate CFTR. After forskolin triggering, compounds were added to both sides to test their potential to increase CFTR gating. ECs were generated by measuring the effects of different concentrations of compounds on short-circuit currents on primary cells, using the increase in Isc as a measure of increased CFTR activity. 50 value, for this purpose, use the same Snapwell TM can be used to add increasing amounts of compounds and then process each step sc The increase in signal was converted into a dose response curve.Inh-172, a specific inhibitor of CFTR, was used to test the specificity of the tested compounds.

[1255] TECC analysis

[1256] Primary bronchial epithelial cell protocol

[1257] The TECC (transepithelial clamp circuit, EP design) assay measures the short-circuit current (I sc ) to measure the functionality of the cystic fibrosis transmembrane conductance regulator (CFTR). In TECC, the transepithelial potential (PD) and transepithelial resistance (R) are measured in an open circuit. t ) and using Ohm's law, it is converted to I sc . 24 wells can be measured simultaneously, allowing for higher throughput compared to an Ussing chamber.

[1258] For this purpose, bronchial epithelial cells isolated from homozygous CF patients harboring the CFTRΔF 508 mutation (hAEC-CF, McGill, UNC) were plated on collagen IV-coated Human airway epithelium was generated by providing an air-liquid interface for 21 days to form a well-differentiated polarized culture that resembles the pseudostratified ciliated epithelium in vivo (Fulcher, ML, Gabriel, S., Burns, KA, Yankaskas, JR, Randell, SH, 2005. Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 107, 183-206). In the case of homozygous ΔF508 CFTR preparations, differentiated cells were treated with 3 μM VX809 (2626 South Loop West, Suite 225, Houston, TX 77054 USA, Catalog No.: S1565) or 0.15 μM GLPG2222 to allow for full expression of properly folded CFTR protein on the membrane (48 hours basolateral treatment and 24 hours apical treatment) prior to electrophysiological recordings.

[1259] Information on compounds can be captured on homozygous ΔF508 CFTR samples to observe increases in CFTR activity when compounds are added in either acute or chronic models.

[1260] For electrophysiological recordings in the acute mode, human airway epithelium was mounted in a TECC heating plate for electrophysiological measurements and maintained at 37°C. The epithelium was immersed in NaCl-Ringer's solution (120mM NaCl, 25mM NaHCO3, 1.2mM CaCl2, 1.2mM MgCl2, 0.8mM KH2PO4, 0.8mM K2HPO4, pH7.4, 5mM glucose) on the basolateral and apical sides. Endogenous ENaC currents were inhibited using apical amiloride, while forskolin was applied to the apical and basolateral sides to stimulate CFTR. After forskolin triggering, compounds were added to both sides to test their potential to increase CFTR gating. Measurements were performed over a 20-minute time frame and recorded every 2 minutes. Using I sc As a measure of increased CFTR activity, the effect of different concentrations of compound on I sc The influence of EC 50 To determine the specificity of the tested compounds, different concentrations of the compounds were used to treat each transwell.

[1261] Similar TECC recordings are performed using primary cells for other channel gating defective or channel conduction defective CFTR mutants to measure the effect of compounds on channel activity. Examples of mutants include R117H, G178R. Similarly, primary cells containing class I CFTR mutants (including G542X, W1282X) and other class II mutants (including N1303K) can be used for electrophysiological recordings.

[1262] result

[1263] When this protocol was implemented, the following values ​​were obtained. The difference between ΔIsc was measured with DMSO (baseline) and ΔIsc was measured with the test compound.

[1264] CFTR ΔF508 TECC analysis EC 50 Measurement

[1265] Table VII. CFTR ΔF508 EC of Illustrative Compounds of the Invention 50 TECC analysis.

[1266] Compound No. <![CDATA[EC 50 (nM)]]> 1 40 4 6

[1267] The data provided in this application show that the compounds of the invention exhibit in vitro activity and can be used in vivo in the treatment of cystic fibrosis.

[1268] Additional benefits of applicant's invention will be apparent to those skilled in the art from a reading of this patent application.

[1269] It should be understood that the foregoing detailed description and the accompanying examples are merely illustrative and are not to be construed as limiting the scope of the present invention, which is limited only by the appended claims and their equivalents. Various changes and modifications to the embodiments should be apparent to those of ordinary skill in the art. Without departing from the spirit and scope of the present invention, such changes and modifications of the present invention's use (including but not limited to those related to chemical structures, substituents, derivatives, intermediates, synthesis, formulation or methods), or any combination of such changes and modifications, may be made.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in X 1 and X 2 is an independently selected H; or halogen; R 1 yes Phenyl, optionally substituted with one or more independently selected R 4 group substitution; or -NR 6 R 7 ; R 2 is a 5-membered monocyclic heteroaryl selected from 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl and thiazolyl, wherein the monocyclic heteroaryl is optionally substituted by one or more independently selected R 3 Group substitution; Each R 3 Independently selected from the group consisting of: C 1-4 Alkyl, which is optionally substituted with one or more groups independently selected from the group consisting of: C 3-7 Cycloalkyl; a 4- to 6-membered monocyclic heterocycle containing 1 oxygen atom; Phenyl, wherein the phenyl is optionally substituted with one or more independently selected R A Group substitution; C 1-4 Alkoxy, which is optionally substituted by one or more independently selected from halogen or -OCH3 group substitution; -OR 11 ; -OH; halogen; -NHC(=S)R 11 ;and -OP(O)(OH)(OH); -C(O)NH2; A 5- to 6-membered monocyclic heteroaryl group containing 1 nitrogen atom; C 3-7 Cycloalkyl; and a 4- to 6-membered monocyclic heterocycle containing 1 oxygen atom; Each R 4 Independently selected from the group consisting of: halogen; C 1-4 alkyl, optionally substituted with one or more independently selected halogens; and C 1-4 Alkoxy, optionally substituted with one or more independently selected halogens; R 6 It is C 1-4 alkyl; R 7 yes C 1-4 Alkyl, which is substituted with phenyl; Each R 11 Independently selected from the group consisting of a 4- to 6-membered monocyclic heterocycle containing 1 oxygen atom; A 5- to 6-membered monocyclic heteroaryl group containing 1 nitrogen atom; C 3-7 Cycloalkyl; and Phenyl, wherein the phenyl group is optionally substituted with one or more independently selected R A group substitution; and Each R A Independently selected from the group consisting of Halogens; and C 1-4 Alkoxy.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally selected by an independently selected R 4 A phenyl group substituted with a group.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a phenyl group substituted with one -OCF3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is H.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, or thiazolyl, wherein the 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, and thiazolyl are substituted by one R 3 replace.

6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having formula Ia, in n is 0, 1, or 2; R 4A H、F、-CH3、-CH(CH3)2、t-Bu、CF3、-OCH3、-OCH(CH3)2 and-OCF3; Each R 4B are independently F or -OCF3; and X 1 and R 2 As described in claim 1.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein X 1 It's H.

8. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, in n is 0; and R 4A Yes - OCF3.

9. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, in X 1 It is H; n is 0; R 4A Yes - OCF3; R 2 It is through an R 3 substituted 1,3,4-oxadiazolyl or thiazolyl; and R 3 is optionally substituted with one or more independently selected -OH, halogen or -OP(O)(OH)(OH) substituted C 1-4 alkyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl dihydrogen phosphate; 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol; 1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-2,2,2-trifluoroethan-1-ol; (2-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazol-5-yl)methanol; 2-(1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; (5-{3-amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol; 5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazole-2-carboxamide; {5-[3-amino-5-(4-fluorobenzene-1-sulfonyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methanol; 2-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(S)-methoxy(phenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(cyclopropylmethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[5-(Phenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(cyclopentyloxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-{5-[(trifluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}pyridin-3-amine; 2-(5-{[(oxolan-3-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(2-methoxyethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; N-[(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)methyl]cyclopropanecarbothioamide; 2-{5-[(S)-methoxy(phenyl)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; (2S)-2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2- 1,3,4-thiadiazol-2-yl)-1,1,1-trifluoropropan-2-ol; 2-{5-[(1R)-1-methoxyethyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[5-(1-methoxyethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(1S)-1-methoxyethyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(cyclopropylmethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[5-(Ethoxymethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[5-(Methoxymethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-(5-{[(pyridin-3-yl)oxy]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-{5-[(trifluoromethoxy)methyl]-1,3,4-thiadiazol-2-yl}pyridin-3-amine; 2-(5-{[(oxolan-3-yl)oxy]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(difluoromethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-(5-{[(2S)-oxolan-2-yl]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-(5-{[(2R)-oxolan-2-yl]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(2-methoxyethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(1R)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(1S)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[5-(Ethoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[5-(Methoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-(5-{[(pyridin-3-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{5-[(difluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-(5-{[(2S)-oxolan-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-(5-{[(2R)-oxolan-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)ethan-1-ol; 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)propan-2-ol; (1S)-1-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-2-phenylethan-1-ol; (S)-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)(phenyl)methanol; 2-[3-(2-methoxypropan-2-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[3-(1-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[3-(oxan-4-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{3-[(4-fluorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-{3-[(Oxolan-2-yl)methyl]-1,2,4-oxadiazol-5-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[3-(Oxolan-3-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; 2-[3-(Methoxymethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine; (5-{3-amino-4-chloro-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol; (5-{3-amino-5-[3-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol; (5-{3-amino-5-[2-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol; 5-amino-N-benzyl-6-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-N-methylpyridine-3-sulfonamide; {5-[3-amino-5-(phenylsulfonyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methanol; (5-{3-amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)methanol; (5-{3-amino-6-bromo-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol; (5-{3-amino-6-chloro-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol; (5-{3-amino-5-[2-(propan-2-yl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol; (5-{3-amino-4-bromo-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol; and 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,2,4-oxadiazol-3-yl)ethan-1-ol.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

12. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, in the preparation of a medicament for treating cystic fibrosis.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and one or more corrective agents.

14. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and one or more corrective agents in the preparation of a medicament for treating cystic fibrosis in a subject.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

16. The pharmaceutical composition of claim 15, wherein the additional therapeutic agent is selected from the group consisting of: a CFTR modulator and a CFTR amplifier.

17. The pharmaceutical composition of claim 15, wherein the additional therapeutic agent is a CFTR modulator.

18. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, in the preparation of a medicament for treating cystic fibrosis in a subject.

19. The use of claim 18, wherein the additional therapeutic agent is selected from the group consisting of: a CFTR modulator and a CFTR amplifier.

20. The use of claim 18, wherein the additional therapeutic agent is a CFTR modulator.

21. The use of claim 18, wherein the additional therapeutic agent is a CFTR corrector.

22. The use of claim 18, wherein the compound or a pharmaceutically acceptable salt thereof is administered together with a CFTR corrector.

23. The use of claim 18, wherein the compound or a pharmaceutically acceptable salt thereof is administered together with two CFTR correctors.

Images