Heteroaryl-substituted pyridines and methods of application

Abstract

FIELD: pharmaceutical compositions.SUBSTANCE: compound of formula I, wherein X1 and X2 independently represent H; or halogen; R1 is phenyl optionally substituted with one or more independently selected R4 groups; or -NR6R7; R2 is a 5-6-membered monocyclic heteroaryl containing 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the 5-membered monocyclic heteroaryl is optionally substituted with one R3 group; each R3 is independently selected from the group consisting of: C1-4alkyl optionally substituted with one or more groups independently selected from: C3-7cycloalkyl; a 5-membered monocyclic heterocycle containing 1 heteroatom selected from the group consisting of O; phenyl; C1-4alkoxy optionally substituted with one or more groups independently selected from C3-7cycloalkyl, halogen, and OCH3; OR11; OH; halogen; NHC(=S)R11 and OP(O)(OH)(OH); C(O)NH2; C3-7cycloalkyl; and a 5-6-membered monocyclic heterocycle containing 1 heteroatom selected from the group consisting of O; each R4 is independently selected from the group consisting of: halogen; C1-4alkyl optionally substituted with one or more independently selected halogen atoms; and C1-4alkoxy optionally substituted with one or more independently selected halogen atoms; R6 is C1-4alkyl; R7 is C1-4alkyl optionally substituted with one phenyl; each R11 is independently selected from the group consisting of: 5-membered monocyclic heterocycle containing 1 O; 6-membered monocyclic heteroaryl containing 1 heteroatom selected from the group consisting of N; C3-7cycloalkyl; and phenyl; wherein phenyl is optionally substituted with one RA group; and each RA is independently selected from the group consisting of halogen and C1-4alkyl. The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier, for use in the treatment of diseases or disorders mediated by CFTR.EFFECT: compounds that are CFTR modulators for the treatment of CFTR-mediated diseases.14 cl, 7 tbl, 67 ex

Description

LINK TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 345,315, filed June 3, 2016, which is incorporated herein in its entirety for all purposes.BACKGROUND OF THE INVENTIONFIELD OF THE INVENTION

[0002] The present invention relates to substituted pyridine compounds that are modulators of the cystic fibrosis transmembrane conductance regulator protein (CFTR), useful in the treatment of diseases and conditions mediated and modulated 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 them. Description of the Prior Art

[0003] ABC transporters are a family of homologous membrane transporter proteins that regulate the transport of a wide range of pharmacological agents (e.g., drugs, xenobiotics, anions, etc.) by binding and utilizing cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters have been found to protect malignant cancer cells from chemotherapeutic agents by acting as multidrug resistance proteins (similar to the glycoprotein MDR1-P or the multidrug resistance protein MRP 1). To date, 48 ABC transporters have been identified, grouped into seven families based on their sequence identity and function.

[0004] ABC transporters provide protection against harmful compounds from the environment by regulating various important physiological roles in the body and thus represent important potential drug targets for the treatment of diseases associated with transporter disorders, extracellular drug transport, and other diseases in which modulation of ABC transporter activity may be beneficial.

[0005] The cAMP / ATP-mediated anion channel, CFTR, is a member of the ABC transporter family commonly associated with diseases and is expressed in a variety of cell types, including absorptive and secretory epithelial cells, where it regulates membrane anion flux, as well as the activity of other ion channels and proteins. CFTR activity in epithelial cells is critical for maintaining electrolyte transport throughout the body, including in pulmonary and intestinal tissues (Quinton, PM, 1990. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 4, 2709–2717).

[0006] The gene encoding CFTR has been identified and sequenced (Kerem, B., Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K., Chakravarti, A., Buchwald, M., Tsui, L. C., 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073–1080). CFTR contains approximately 1,480 amino acids that encode a protein composed of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide-binding domain. The pair of transmembrane domains are linked by a large polar regulatory (R) domain with multiple phosphorylation sites that regulate channel activity and cellular transport.

[0007] Cystic fibrosis (CF) is caused by a defect in this gene, which induces mutations in CFTR. Cystic fibrosis is the most common fatal genetic disorder in humans, affecting ~0.04% of white individuals (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. 19, 575-606. doi:10.1002 / humu.10041). In the United States, for example, approximately one in 2,500 children is affected, and up to 10 million people carry a unique copy of the defective gene without apparent adverse effects; Furthermore, individuals carrying a unique copy of the gene have increased resistance to cholera and dehydration due to diarrhea. This effect may explain the relatively high frequency of the CF gene in the population.

[0008] In contrast, individuals with two copies of the CF-associated gene suffer from the debilitating and fatal effects of CF, including chronic lung infections.

[0009] In patients with cystic fibrosis, CFTR mutations in the endogenous respiratory epithelium result in decreased chloride and bicarbonate permeability into lung epithelial cells and other tissues, leading to decreased apical anion secretion and impaired ion and fluid transport. This reduced anion transport leads to increased accumulation of mucus and pathogens in the lungs, causing microbial infections that ultimately lead to death in patients with CF.

[0010] In addition to respiratory disease, patients with CF also suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, can lead to death. Furthermore, female patients with CF suffer from reduced fertility, while male patients with CF are infertile.

[0011] Sequence analysis of the CFTR gene on chromosomes in CF has identified a number of disease-causing mutations (Kerem, B., Rommens, J.M., Buchanan, J.A., Markiewicz, D., Cox, T.K., Chakravarti, A., Buchwald, M., Tsui, L.C., 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080). ΔF508-CFTR, the most common mutation in CF (present in at least one allele in ~90% of CF patients) and affecting approximately 70% of cystic fibrosis cases, involves a single deletion of the amino acid phenylalanine 508. This deletion prevents the protein from folding correctly, preventing it from exiting the endoplasmic reticulum (ER) and entering the plasma membrane, and is therefore rapidly degraded. As a result, the number of channels present in the membrane is much smaller than in cells expressing wild-type CFTR.In addition to impaired transport, the mutation results in impaired gating of ion channels. Of course, even though ΔF508-CFTR can reach the cytoplasmic membrane upon low-temperature (27°C) release, where it can function as a cAMP-activated chloride channel, 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. J Biol. Chem. 270, 12347-12350).

[0012] Other mutations with lower frequency that alter channel regulation or channel conductance have also been identified. In the case of channel regulation mutants, the mutated protein is properly transported and localizes to the plasma membrane, but either fails to activate or fails to function as a chloride channel (e.g., as a result of missense mutations located in the nucleotide-binding domains); examples of such mutations are G551D, G178R, and G1349D. CFTR protein with mutations affecting chloride conductance is properly transported to the cell membrane but generates reduced chloride flux (e.g., as a result of missense mutations located in the transmembrane domain); examples of such mutations are R117H and R334W.

[0013] Besides cystic fibrosis, modulation of CFTR activity may be beneficial in other diseases not directly caused by CFTR mutations, such as chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome.

[0014] COPD is characterized by a progressive and irreversible reduction in airflow, resulting from increased mucus secretion, bronchiolitis, and emphysema. Potential treatment for increased mucus secretion and impaired mucociliary clearance, which are common in COPD, may involve the use of mutant or wild-type CFTR activators. Specifically, increased anion secretion via CFTR may facilitate fluid transport into airway surface fluid, moistening mucus and optimizing periciliary fluid viscosity. The resulting increased mucociliary clearance will contribute to the alleviation of COPD-related symptoms.

[0015] Dry eye disease is characterized by decreased tear production and abnormal lipid, protein, and mucin profiles in the tear film. Dry eye disease can be caused by a variety of factors, including age, arthritis, LASIK eye surgery, chemical / thermal burns, medications, allergies, and diseases such as cystic fibrosis and Sjogren's syndrome. Increased anion secretion via CFTR can enhance fluid transport from corneal epithelial cells and secretory glands surrounding the eye, ultimately improving corneal hydration, thereby helping to alleviate dry eye symptoms. Sjogren's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eyes, mouth, skin, lungs, liver, vagina, and intestines.Subsequent symptoms include dry eyes, mouth, and vagina, as well as lung disease. Sjögren's syndrome is also associated with rheumatoid arthritis, systemic lupus, scleroderma, and polymyositis / dermatomyositis. The cause of the disease is thought to be a defective protein transporter, for which treatment options are limited. Therefore, modulating CFTR activity may promote hydration of various organs and help alleviate associated symptoms.

[0016] Besides CF, defective protein transport induced by ΔF508-CFTR has been shown to cause a wide range of other diseases, particularly diseases where dysfunctional endoplasmic reticulum (ER) function can either impede the release of CFTR protein from the EP and / or cause the degradation of misfolded protein (Morello, J.-P., Bouvier, M., Petäjä-Repo, U.E., Bichet, D.G., 2000. Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol. Sci. 21, 466–469. doi:10.1016 / S0165-6147(00)01575-3; Shastry, B.S., 2003. Neurodegenerative disorders of protein aggregation. Neurochem. Int. 43, 1-7. doi:10.1016 / S0197-0186(02)00196-1; Zhang, W., Fujii, N., Naren, A.P., 2012. Recent advances and new perspectives in targeting CFTR for therapy of cystic fibrosis and enterotoxin-induced secretory diarrheas. Future Med. Chem. 4, 329-345. doi:10.4155 / fmc.12.1).

[0017] A number of genetic diseases are associated with defective processing in the ER, equivalent to the defect seen in CFTR in CF, such as CDG glycanosis type 1, hereditary emphysema (α-l-antitrypsin (PiZ variant)), congenital hyperthyroidism, osteogenesis imperfecta (procollagen type I, II, or IV), hereditary hypofibrinogenemia (fibrinogen), ACT deficiency (α-l-antichymotrypsin), diabetes insipidus (DI), neurohypophyseal DI (N2 vasopressin hormone receptor), nephrogenic DI (aquaporin II), Charcot-Marie-Tooth syndrome (peripheral myelin protein 22), Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (APP and presenilins), Parkinson's disease, lateral amyotrophic sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neurological disorders such as Huntington's disease, spinocerebellar ataxia type I, spinal bulbar muscular atrophy,dentato-rubro-pallido-Lewis atrophy and myotonic dystrophy, as well as spongiform encephalopathies such as hereditary Creutzfeldt-Jakob disease (a defect in prion protein processing), Fabry disease (lysosomal α-galactosidase A), Straussler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome.

[0018] In addition to enhancing CFTR activity, reducing anion secretion with CFTR modulators may be beneficial for the treatment of types of secretory diarrhea in which epithelial water transport is significantly increased as a result of chloride transport activation by the secretagogue. The mechanism involves increased cAMP levels and stimulation of CFTR.

[0019] Regardless of the cause, excessive chloride transport is present in all types of diarrhea and leads to dehydration, acidosis, impaired growth, and death. Acute and chronic diarrhea remain a serious health problem worldwide and are a significant contributor to malnutrition, leading to death in children under five (5,000,000 deaths / year). Furthermore, for patients with chronic inflammatory bowel disease (IBD) and / or acquired immunodeficiency syndrome (AIDS), diarrhea is a dangerous condition.

[0020] Therefore, there is a need for new compounds capable of modulating CFTR. In particular, 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 such compounds, pharmaceutical compositions containing such compounds, and methods for treating cystic fibrosis by administering the compounds of the present invention. SUMMARY OF THE INVENTION

[0021] In one aspect, the present invention provides compounds of formula I and pharmaceutically acceptable salts thereof, Where is X? 1 and X 2 independently selected from H; halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms;C 1-4 alkoxy optionally substituted with one or more substituents independently selected from OH;C 1-4 alkoxy or NR 8A R8B ;-NR 9A R 9B ;cyclopropyl, optionally substituted with one or more independently selected R groups 5 ;phenoxy, optionally substituted with one or more independently selected R groups 5 ; or phenyl, optionally substituted with one or more independently selected R groups 5 ;R 1 representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from OH;C 1-4 alkoxy or a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; phenyl optionally substituted with one or more independently selected R groups 4;an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R groups 5 ;an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused with phenyl, wherein the monocyclic heterocycle and phenyl are optionally substituted with one or more independently selected R groups 5 ;C 3-7 cycloalkyl optionally substituted by one or more independently selected R groups 5 ; or-NR 6 R 7 ;R 2is a 5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 ;each R 3 independently selected from the group consisting of:C 1-4 alkyl optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl; where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A ;a 4-6 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 with one or more independently selected R groups A ;phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ;C 1-4alkoxy optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl, halogen or OCH3;OR 11 ;OH;halogen;CN;OC(O)R 10 ;OS(O)2OH;NHC(=S)R 11 or OP(O)(OH)(OH);C(O)NH2;phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ;5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups A ;C 3-7 cycloalkyl; where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A; and 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 with one or more independently selected R groups A ;each R 4 independently selected from the group consisting of: halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; andC 1-4 alkoxy, optionally substituted with one or more independently selected halogen atoms; each R 5 independently selected from the group consisting of: OH; halogen; C 1-4 alkyl optionally substituted with one or more substituents independently selected from C 1-4 alkoxy, halogen or OH; andC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms;R 6 represents H, C 1-4 alkyl or C 3-7 cycloalkyl, where C 3-7cycloalkyl is optionally substituted with one or more independently selected R groups 5 ;R 7 representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from halogen; phenyl optionally substituted with one or more substituents independently selected from halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; orC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms;C 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms; or 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 with one or more independently selected R groups 5 ;each of R 8a and R 8bindependently selected from the group consisting of H and C 1-4 alkyl;R 9a and R 9b independently selected from the group consisting of H;C 1-4 alkyl and C 3-7 cycloalkyl; and each R 10 independently selected from the group consisting ofC 1-6 alkyl and phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ;each R 11 independently selected from the group consisting of 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 with one or more independently selected R groups A ;5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups A ;C 3-7 cycloalkyl; where C3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A ; and phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ; and each R A independently selected from the group consisting of CN, halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; andC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms.

[0022] Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutical carrier. Such compositions can be administered in accordance with the method of the present invention, typically as part of a treatment regimen for the treatment or prevention of conditions and disorders associated with transmembrane conductance regulator activity in cystic fibrosis. In a particular aspect, the pharmaceutical compositions may also contain additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention. In a more particular aspect, the additional therapeutically active ingredient is an agent for the treatment of cystic fibrosis.

[0023] Furthermore, the compounds of the present invention useful in the pharmaceutical compositions and methods of treatment disclosed herein are pharmaceutically acceptable as prepared and administered.

[0024] Another aspect of the present invention relates to a method for treating or preventing conditions and disorders associated with the activity of the cystic fibrosis transmembrane conductance regulator in mammals. More specifically, the method is suitable for treating or preventing conditions and disorders associated with cystic fibrosis, Sjogren's syndrome, pancreatic insufficiency, chronic obstructive pulmonary disease, or chronic airway obstruction. Therefore, the compounds and compositions of the present invention are useful as a medicament for treating or preventing a disease modulated by the cystic fibrosis transmembrane conductance regulator.

[0025] Compounds, compositions containing such compounds, methods for preparing the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are also described herein.

[0026] In a particular aspect, compounds of the present invention are provided for use in the treatment of cystic fibrosis. In a particular aspect, compounds of the present invention are provided for use in the treatment of cystic fibrosis caused by class I, II, III, IV, V and / or VI mutations.

[0027] The present invention also provides pharmaceutical compositions comprising a compound of the present invention and a suitable pharmaceutical carrier for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the treatment of cystic fibrosis.

[0028] These and other objects of the present invention are described in the following sections. These objects should not be construed as narrowing the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0029] This document describes compounds of formula I, Where X 1 , X 2 , R 1 and R 2defined above in the summary description and below in the detailed description. In addition, compositions containing such compounds and methods of treating conditions and disorders using such compounds and compositions are also included.

[0030] The compounds included in this document may contain one or more variables that occur more than once in any substituent or in the formulas in this document. The definition of a variable in each instance is independent of its definition in another instance. Furthermore, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds that can be isolated from the reaction mixture. Definitions

[0031] It should be noted that, as used in this specification and the appended claims, the singular form "a" or "the" includes plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a single compound as well as one or more identical or different compounds; a reference to "a pharmaceutically acceptable carrier" means a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers; and so on.

[0032] As used in this specification and the appended claims, unless otherwise specified, the following terms have the meaning given after them.

[0033] 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 include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. In some cases, the number of carbon atoms in the alkoxy moiety is indicated by the subscript "C" x - y ", where x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-6alkoxy" means an alkoxy substituent containing 1-6 carbon atoms, and "C1-4alkoxy" means an alkoxy substituent containing 1-4 carbon atoms.

[0034] The term "alkyl" as used herein means a saturated hydrocarbon radical with a straight or branched chain. In some cases, the number of carbon atoms in the alkyl moiety is indicated by the subscript "C x - y", where x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-6 alkyl" means an alkyl substituent containing from 1 to 6 carbon atoms, and "C1-4 alkyl" means 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.

[0035] Term "C 3-7 "Cycloalkyl" as used herein means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each optionally substituted, unless otherwise indicated.

[0036] Term "C 3-6"cycloalkyl" as used herein means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted, unless otherwise indicated.

[0037] Term "C 4-6 "cycloalkyl" as used herein means cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted, unless otherwise indicated.

[0038] The term "halo" or "halogen" as used in this document means chlorine (Cl), bromine (Br), iodine (I) and fluorine (F).

[0039] The term "monocyclic heterocycle" or "monocyclic heterocyclic" as used herein means a three-, four-, five-, six-, seven-, or eight-membered fully saturated monocyclic carbocyclic ring wherein one or more carbon atoms in the ring are substituted with a heteroatom independently selected from the group consisting of O, N, and S. 3 and 4 membered monocyclic heterocycles contain one carbon atom in the ring that is substituted with a heteroatom selected from the group consisting of O, N, and S. 5, 6, 7, and 8 membered monocyclic heterocycles may contain one, two, or three carbon atoms in the ring that are substituted with heteroatoms selected from the group consisting of O, N, and S. Examples of five-membered monocyclic heterocycles include heterocycles containing 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 a six-membered monocyclic heterocycle include heterocycles that contain 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, isothiazolinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranil and trithianyl.

[0040] The term "4-6-membered monocyclic heterocycle" or "4-6-membered monocyclic heterocyclic" used herein means a 4-, 5-, or 6-membered monocyclic heterocycle as defined above herein. Non-limiting examples of the 4-6-membered monocyclic heterocycle include azetidinyl, oxetanyl, 1,3-dioxolanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, piperazinyl, piperidinyl, thiomorpholinyl, and morpholinyl.

[0041] 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 herein. Non-limiting examples of 3-6-membered monocyclic heterocycle include aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl, thiomorpholinyl, and morpholinyl.

[0042] The term "5-11 membered spiroheterocycle" as used herein means a 3-6 membered monocyclic heterocycle, wherein two substituents on the same carbon atom of the 3-6 membered monocyclic heterocyclic ring together with said carbon atom form a second ring system; wherein the second ring system is C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocycle. Examples of 5- to 11-membered spiroheterocycle include, but are not limited to, 1-oxaspiro[4.4]non-3-yl and 1-oxaspiro[4.5]decan-3-yl.

[0043] The term "7-11 membered spiroheterocycle" as used herein means a 4-6 membered monocyclic heterocycle, wherein two substituents on the same carbon atom of the 4-6 membered monocyclic heterocyclic ring together with said carbon atom form a second ring system; wherein the second ring system is C 4-6cycloalkyl or 4-6 membered monocyclic heterocycle. Specific examples of 7-11 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.

[0044] Monocyclic heterocycles and spiroheterocycles, including typical rings, are optionally substituted and are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the ring systems, unless otherwise specified. Nitrogen atoms in heterocyclic rings may be optionally oxidized or may be optionally quaternized.

[0045] The term "5-6 membered monocyclic heteroaryl" as used herein means a five- or six-membered monocyclic aromatic ring structure, wherein one or more carbon atoms in the ring are replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. The five-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 5-6-membered monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl.5-6-membered monocyclic heteroaryls, including typical rings, are optionally substituted unless otherwise noted and are linked to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained in the ring systems. The nitrogen atom in heteroaryl rings may be optionally oxidized and may be optionally quaternized.

[0046] The term "phenoxy" as used herein means a phenyl attached to the parent molecular moiety through an oxygen atom.

[0047] The term "heteroatom" as used in this document means nitrogen (N), oxygen (O), or sulfur (S).

[0048] The term "radioactively labeled" refers to a compound of the present invention in which at least one of the atoms is a radioactive atom or a radioactive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, such as alpha particles, beta particles, or positrons. Examples of such radioactive atoms include, but are not limited to 3 H (tritium), 14 C, 11 C, 15 Oh, 18 F, 35 S, 123 I and 125 I.

[0049] When a moiety is described as "substituted," the non-hydrogen radical is located at the site of a hydrogen radical 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 radical is located at the site of a hydrogen radical on the heterocycle. It should be noted that if there is more than one substitution on a moiety, each non-hydrogen radical may be the same or different (unless otherwise specified).

[0050] If a moiety is described as "optionally substituted," the moiety may be either (1) unsubstituted or (2) substituted. If a moiety is described as optionally substituted by up to a specified number of non-hydrogen radicals, the moiety may be either (1) unsubstituted or (2) substituted by up to such specified number of non-hydrogen radicals or the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heteroaryl optionally substituted by up to 3 non-hydrogen radicals, any heteroaryl with fewer than 3 substitutable positions will be optionally substituted by a number of non-hydrogen radicals not exceeding the maximum number of substitutable positions that the heteroaryl has.As an example, tetrazolyl (which has only one substitutable position) will be optionally substituted by no more than one non-hydrogen radical. As a further example, if the amino nitrogen is described as optionally substituted by no more than two non-hydrogen radicals, then the primary amino nitrogen will be optionally substituted by no more than two non-hydrogen radicals, while the secondary amino nitrogen will be optionally substituted by only no more than one non-hydrogen radical.

[0051] The term "substituted by one or more" refers to one to four substituents. In one embodiment, it refers to one to three substituents. In further embodiments, it refers to one or two substituents. In yet another embodiment, it refers to one substituent.

[0052] The terms "treat," "treating," and "treatment" refer to a method of alleviating or eliminating a disease and / or its associated symptoms. In certain embodiments, "treat," "treating," and "treatment" refer to alleviating at least one physical parameter that may not be apparent to the subject. In another embodiment, "treat," "treating," and "treatment" refer to modulating a disease or disorder, either physically (e.g., stabilizing an overt symptom), physiologically (e.g., stabilizing a physical parameter), or both. In a further embodiment, "treat," "treating," and "treatment" refer to slowing the progression of a disease or disorder.

[0053] The terms "prevent," "implementing preventive measures," and "prevention" refer to the method of implementing preventive measures against the occurrence of a disease and / or its associated symptoms or eliminating the possibility of a subject acquiring a disease. As used herein, the terms "prevent," "implementing preventive measures," 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.

[0054] The phrase "therapeutically effective amount" means an amount of a compound or a pharmaceutically acceptable salt thereof sufficient to prevent the development of, or to alleviate to some extent, one or more symptoms of, the condition or disorder being treated, when administered alone or in combination with another therapeutic agent for the treatment of a particular subject or group of subjects. "Therapeutically effective amount" may vary depending on the compound, the disease and its severity, as well as the age, weight, health condition, etc. of the subject being treated.For example, for humans or other mammals, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting, or it may be an amount prescribed by the U.S. Food and Drug Administration or an equivalent foreign agency for the particular disease and subject being treated.

[0055] The term "subject" is defined herein to refer to animals such as mammals, including but not limited to primates (e.g., humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice, etc. In preferred embodiments, the subject is a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0056] The term "class I mutation(s)" used in this document refers to mutations that interfere with protein synthesis. They result in the formation of a premature translation termination signal (stop codon) in mRNA. Truncated CFTR proteins are unstable and rapidly degraded, so the net effect is that the protein is absent from the apical membrane. Specifically, class I mutation(s) refers to p.Gly542X (G542X), W1282X, c.489+1G>T (621+1G>T), or c.579+1G>T (711+1G>T). More specifically, class I mutation(s) refers to G542X or W1282X.

[0057] The term "Class II mutation(s)" as used in this document refers to mutations that affect protein maturation. They result in the production of CFTR protein that cannot fold properly and / or be transported to its site of action on the apical membrane. Specifically, Class II mutation(s) refers to the mutations p.Phe508del (F508del), p.Ile507del, or p.Asn1303Lys (N1303K). More specifically, Class II mutation(s) refers to the mutations F508del or N1303K.

[0058] The term "class III mutation(s)" as used herein 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 cannot function as a chloride channel. Specifically, the term "class III mutation(s)" refers to mutations p.Gly551Asp (G551D), G551S, R553G; G1349D; S1251N, G178R, S549N. More specifically, the class III mutation(s) refers to mutations G551D, R553G, G1349D, S1251N, G178R, or S549N.

[0059] The term "class IV mutation(s)" used in this document refers to mutations that affect chloride conductance. CFTR protein is properly transported into the cell membrane but generates a reduced chloride flux or "gating defect" (most are missense mutations located in the transmembrane domain). Specifically, class IV mutation(s) refers to mutations p.Arg117His (R117H), R347P, or p.Arg334Trp (R334W).

[0060]

[0005] (5T allele), c.S3140-26A>G (3272-26A>G), c.3850-2477C>T (3849+10kbC>T).

[0061] The term "class VI mutation(s)" as used herein refers to mutations that reduce the stability of existing CFTR or that affect the regulation of other channels, leading to intrinsic instability of the CFTR protein. Essentially, while still functional, the CFTR protein is unstable on the cell surface and is rapidly removed and degraded by cellular machinery. Specifically, class VI mutation(s) refers to the Rescued F508del, 120del23, N287Y, 4326dellTC, or 4279insA mutations. More specifically, class VI mutation(s) refers to the Rescued F508del mutations. Compounds

[0062] The compounds of the present invention are characterized by the general formula I described above.

[0063] Specific meanings of the variable groups are given below. Such meanings may be used, if necessary, in relation to any of the other meanings, definitions, claims, or embodiments defined above or below.

[0064] Certain embodiments relate to compounds of formula I, Where is X? 1 and X 2 independently selected from H; halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms;C 1-4 alkoxy optionally substituted with one or more substituents independently selected from OH;C 1-4 alkoxy or NR 8A R 8B ;-NR 9A R 9B ;cyclopropyl, optionally substituted with one or more independently selected R groups 5 ;phenoxy, optionally substituted with one or more independently selected R groups 5 ; or phenyl, optionally substituted with one or more independently selected R groups 5 ;R 1 representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from OH;C 1-4alkoxy or a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; phenyl optionally substituted with one or more independently selected R groups 4 ;an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R groups 5 ;an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused with phenyl, wherein the monocyclic heterocycle and phenyl are optionally substituted with one or more independently selected R groups 5 ;C 3-7 cycloalkyl optionally substituted by one or more independently selected R groups 5 ; or-NR 6 R 7 ;R 2is a 5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 ;each R 3 independently selected from the group consisting of:C 1-4 alkyl optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl; where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A ;a 4-6 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 with one or more independently selected R groups A ;phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ;C 1-4alkoxy optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl, halogen or OCH3;OR 11 ;OH;halogen;CN;OC(O)R 10 ;OS(O)2OH;NHC(=S)R 11 or OP(O)(OH)(OH);C(O)NH2;phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ;5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups A ;C 3-7 cycloalkyl; where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A; and 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 with one or more independently selected R groups A ;each R 4 independently selected from the group consisting of: halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; andC 1-4 alkoxy, optionally substituted with one or more independently selected halogen atoms; each R 5 independently selected from the group consisting of: OH; halogen; C 1-4 alkyl optionally substituted with one or more substituents independently selected from C 1-4 alkoxy, halogen or OH; andC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms;R 6 represents H, C 1-4 alkyl or C 3-7 cycloalkyl, where C 3-7cycloalkyl is optionally substituted with one or more independently selected R groups 5 ;R 7 representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from halogen; phenyl optionally substituted with one or more substituents independently selected from halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; orC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms;C 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms; or 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 with one or more independently selected R groups 5 ;each of R 8a and R 8bindependently selected from the group consisting of H and C 1-4 alkyl;R 9a and R 9b independently selected from the group consisting of H;C 1-4 alkyl and C 3-7 cycloalkyl; and each R 10 independently selected from the group consisting ofC 1-6 alkyl and phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ;each R 11 independently selected from the group consisting of 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 with one or more independently selected R groups A ;5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups A ;C 3-7 cycloalkyl; where C3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A ; and phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ; and each R A independently selected from the group consisting of CN, halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; andC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms.

[0065] Certain embodiments relate to compounds of formula I, Where is X? 1 and X 2 independently selected from H; halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms;C 1-4 alkoxy optionally substituted with one or more substituents independently selected from OH;C 1-4 alkoxy or NR 8A R 8B ;-NR9A R 9B ;cyclopropyl, optionally substituted with one or more independently selected R groups 5 ;phenoxy, optionally substituted with one or more independently selected R groups 5 ; or phenyl, optionally substituted with one or more independently selected R groups 5 ;R 1 representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from OH;C 1-4 alkoxy or a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; phenyl optionally substituted with one or more independently selected R groups 4 ;an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R groups5 ;an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused with phenyl, wherein the monocyclic heterocycle and phenyl are optionally substituted with one or more independently selected R groups 5 ;C 3-7 cycloalkyl optionally substituted by one or more independently selected R groups 5 ; or-NR 6 R 7 ;R 2 is a 5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 ;each R 3 independently selected from the group consisting of:C 1-4alkyl optionally substituted with one or more substituents independently selected from cyclopropyl; a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; phenyl; C 1-4 alkoxy optionally substituted with one or more substituents independently selected from cyclopropyl, halogen or OCH3;OR 11 ;OH;halogen;CN;OC(O)R 10 ;OS(O)2OH;NHC(=S)R 11 orOP(O)(OH)(OH);C(O)NH2;C 3-7 cycloalkyl; and a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; each R 4 independently selected from the group consisting of: halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; andC 1-4 alkoxy, optionally substituted with one or more independently selected halogen atoms; each R 5independently selected from the group consisting of: OH; halogen; C 1-4 alkyl optionally substituted with one or more substituents independently selected from C 1-4 alkoxy, halogen or OH; andC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms;R 6 represents H, C 1-4 alkyl or C 3-7 cycloalkyl, where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups 5 ;R 7 representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from halogen; phenyl optionally substituted with one or more substituents independently selected from halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; orC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms;C1-4 alkoxy optionally substituted with one or more independently selected halogen atoms; or 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 with one or more independently selected R groups 5 ;each of R 8a and R 8b independently selected from the group consisting of H and C 1-4 alkyl;R 9a and R 9b independently selected from the group consisting of H;C 1-4 alkyl and C 3-7 cycloalkyl; and each R 10 independently selected from the group consisting ofC 1-6 alkyl and phenyl; and each R 11independently selected from the group consisting of a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; a 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 optionally substituted with one or more substituents independently selected from halogen.

[0066] In certain embodiments of the IR formula 1 is phenyl optionally substituted by one or more independently selected R groups 4 .

[0067] In certain embodiments of the IR formula 1 is phenyl optionally substituted with one, two or three independently selected R groups 4 .

[0068] In certain embodiments of the IR formula 1 is a phenyl which is unsubstituted.

[0069] In certain embodiments of the IR formula 1 is phenyl substituted by one or two independently selected R groups 4 .

[0070] In certain embodiments of the IR formula 1 is phenyl substituted by one independently selected R group 4 .

[0071] In certain embodiments of Formula I, each R 4 independently selected from the group consisting of fluorine; C 1-4 alkyl optionally substituted with 1, 2 or 3 fluorine atoms; and C 1-4 alkoxy optionally substituted with 1, 2 or 3 fluorine atoms.

[0072] In certain embodiments of Formula I, each R 4 independently selected from the group consisting of C 1-4 alkyl optionally substituted with 1, 2 or 3 fluorine atoms; and C 1-4 alkoxy optionally substituted with 1, 2 or 3 fluorine atoms.

[0073] In certain embodiments of Formula I, each R 4is 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 IR 4 is selected from the group consisting of F, -CF3, and -OCF3. In some embodiments of formula IR 4 is CH(CH3)2. In some embodiments of formula IR 4 represents F. In some embodiments of formula IR 4 is CF3. In some embodiments of formula IR 4 represents -OCF3.

[0074] In certain embodiments of the IR formula 1 is a phenyl substituted with one -OCF3.

[0075] In certain embodiments of the IR formula 1is an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocycle is optionally substituted with 1, 2 or 3 independently selected R groups 5 .

[0076] In certain embodiments of the IR formula 1 is an N-linked 4-6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein the monocyclic heterocycle is optionally substituted with 1, 2 or 3 independently selected R groups 5 In some of these 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 of these embodiments of Formula I, each R 5 independently selected from the group consisting of F, -CH3, t-Bu, -CF3, -OCH3, CH2OH and -OCF3.

[0077] In certain embodiments of the IR formula 1 represents azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl, each optionally substituted with 1 or 2 independently selected R groups 5 In some of these 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.

[0078] In certain embodiments of the IR formula 1 represents piperidinyl, which is optionally substituted with 1 or 2 independently selected R groups 5 In some of these 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 of these embodiments, R 1 is piperidinyl substituted with two groups representing fluorine. In some of these embodiments of Formula IR 1is piperidinyl substituted with one group that is fluorine. In some of these embodiments of Formula IR 1 is piperidinyl substituted with one methyl group. In some of these embodiments of Formula IR 1 is piperidinyl substituted with two methyl groups. In some of these embodiments of Formula IR 1 is piperidinyl substituted with one CF3 group. In some of these embodiments of Formula IR 1 is piperidinyl substituted with one OCH3 group. In some of these embodiments of Formula IR 1 is piperidinyl substituted with one OCF3 group. In some of these embodiments of Formula IR 1 is a piperidinyl group substituted with one tBu group.

[0079] In certain embodiments of the IR formula 1is an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused with phenyl, wherein the monocyclic heterocycle and phenyl are optionally substituted with 1, 2 or 3 independently selected R groups 5 In some of these embodiments of formula IR 1 is 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, optionally substituted with 1, 2 or 3 independently selected R groups 5 In some of these embodiments of formula IR 1 is an unsubstituted 3,4-dihydro-2H-benzo[b][1,4]oxazinyl.

[0080] In certain embodiments of the IR formula 1 represents C 1-4 alkyl optionally substituted with one or more substituents independently selected from OH, C 1-4alkoxy or a 4-6 membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N. In some of these embodiments of formula IR 1 represents C 1-4 alkyl that is unsubstituted. In some of these embodiments of formula IR 1 represents C 1-4 alkyl that is substituted with OH. In some of these embodiments of formula IR 1 represents C 1-4 alkyl that is substituted by C 1-4 alkoxy. In some of these embodiments of formula IR 1 represents C 1-4 alkyl that is substituted with a 4-6 membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N. In some of these embodiments of formula IR 1 is CH2CH3. In some of these embodiments of formula IR 1is CH2CH2OH. In some of these embodiments of formula IR 1 is CH(CH3)2. In some of these embodiments, R 1 is CH2CH2OCH3. In some of these embodiments of formula IR 1 is a C1 alkyl substituted with tetrahydrofuran.

[0081] In certain embodiments of the IR formula 1 represents C 3-7 cycloalkyl optionally substituted by one or more independently selected R groups 5 In some of these embodiments of formula IR 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some of these embodiments of Formula IR 1 is cyclopentyl.

[0082] In certain embodiments of the IR formula 1 represents -NR 6 R 7 .

[0083] In certain embodiments of the IR formula1 represents -NR 6 R 7 ; where R 6 represents H, CH3, or cyclopropyl; wherein cyclopropyl is optionally substituted with 1 or 2 independently selected R groups 5 ; andR 7 representsC 1-4 alkyl;C 1-4 alkyl substituted by 1, 2 or 3 fluorine atoms;C 1-4 alkyl substituted with one phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro;C 1-4 alkyl optionally substituted with 1, 2 or 3 fluorine atoms; orC 1-4 alkoxy optionally substituted with 1, 2 or 3 fluorine atoms;C 2-4 alkyl substituted by one C 1-4 alkoxy; orC 1-4 alkyl substituted with one 4-6-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 with 1, 2 or 3 independently selected R groups 5 .

[0084] In certain embodiments of the IR formula 1 represents -NR 6 R 7 ; where R 6 represents H, CH3, cyclobutyl or cyclopropyl; wherein cyclobutyl and cyclopropyl are optionally substituted with 1 or 2 independently selected R groups 5 ; andR 7 representsC 1-4 alkyl;C 1-4 alkyl substituted by 1, 2 or 3 fluorine atoms;C 1-4 alkyl substituted with one phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro;C 1-4 alkyl optionally substituted with 1, 2 or 3 fluorine atoms; orC 1-4 alkoxy optionally substituted with 1, 2 or 3 fluorine atoms;C 2-4 alkyl substituted by one C 1-4 alkoxy; orC 1-4alkyl substituted with one 4-6-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 with 1, 2 or 3 independently selected R groups 5 .

[0085] In certain embodiments of the IR formula 7 represents C 1-4 alkyl substituted with one phenyl, wherein phenyl is optionally substituted with 1, 2 or 3 substituents independently selected from CF3, fluoro or C 1-4 alkoxy. In some of these embodiments, R 7 represents C 1-4 alkyl substituted by one phenyl, where phenyl is unsubstituted.

[0086] In certain embodiments of Formula IX 1 represents H; halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; C 1-4alkoxy optionally substituted with one or more substituents independently selected from OH, C 1-4 alkoxy or NR 11A R 11B ; NR 12A R 12B ; optionally substituted cyclopropyl; optionally substituted phenoxy or optionally substituted phenyl.

[0087] In certain embodiments of the IR formula 1 represents -NR 6 R 7 ; where R 6 is CH3; and R 7 representsC 1-4 alkyl substituted with one phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro;C 1-4 alkyl optionally substituted with 1, 2 or 3 fluorine atoms; orC 1-4 alkoxy optionally substituted with 1, 2 or 3 fluorine atoms;C 2-4 alkyl substituted by one C 1-4 alkoxy; orC 1-4alkyl substituted with one 4-6-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 with 1, 2 or 3 independently selected R groups 5 .

[0088] In certain embodiments of the IR formula 1 represents -NR 6 R 7 ; where R 6 is CH3; and R 7 represents C 1-4 alkyl substituted with one phenyl. In some of these embodiments, R 1 represents -NR 6 R 7 ; where R 6 is CH3; and R 7 represents C 1-4 alkyl substituted by one phenyl.

[0089] In certain embodiments of Formula IX 1 and X 2 independently selected from H, halogen, optionally substituted cyclopropyl or optionally substituted phenyl.

[0090] In certain embodiments of Formula IX 1 and X 2 independently selected from H, halogen, or unsubstituted cyclopropyl.

[0091] In certain embodiments of Formula I, each of X 1 and X 2 represents H.

[0092] In certain embodiments of Formula IX 1 represents H; and X 2 is Cl. In certain embodiments of Formula IX 1 represents H; and X 2 represents Br.

[0093] In certain embodiments of Formula IX 1 represents Cl; and X 2 represents H. In certain embodiments of formula IX 1 represents Br; and X 2 represents H.

[0094] In certain embodiments of Formula I, each of X 1 and X 2 independently selected from H, bromine, NR 12A R 12B , C 1-4alkoxy, cyclopropyl, phenoxy or phenyl; wherein cyclopropyl, phenoxy and phenyl are optionally substituted with 1, 2 or 3 independently selected R groups 5 , and at the same time C 1-4 alkoxy is optionally substituted with one or more substituents independently selected from OH, C 1-4 alkoxy or NR 11A R 11B In some of these embodiments of Formula I, cyclopropyl is unsubstituted. In some of these embodiments of Formula I, phenyl and phenoxy are substituted with F.

[0095] In certain embodiments of Formula I, each of X 1 and X 2 represents H, bromo, cyclopropyl or phenyl; wherein cyclopropyl and phenyl are optionally substituted with 1, 2 or 3 independently selected R groups 5 In some of these embodiments of Formula I, cyclopropyl is unsubstituted.

[0096] In certain embodiments of Formula IX 1 is bromine.

[0097] In certain embodiments of Formula IX 2 is bromine.

[0098] In certain embodiments of Formula IX 1 represents cyclopropyl or phenyl; wherein cyclopropyl and phenyl are optionally substituted with 1, 2 or 3 independently selected R groups 5 , and X 2 is H. In some of these embodiments of Formula I, cyclopropyl is unsubstituted.

[0099] In certain embodiments of Formula IX 1 represents cyclopropyl, phenoxy or phenyl; wherein cyclopropyl, phenoxy and phenyl are optionally substituted with 1, 2 or 3 independently selected R groups 5 , and X 2 is H. In some of these embodiments of Formula I, cyclopropyl is unsubstituted.

[00100] In certain embodiments of Formula IX 1 is unsubstituted cyclopropyl or phenyl substituted by one fluorine atom; and X 2represents H.

[00101] In certain embodiments of formula IX 1 represents unsubstituted cyclopropyl, phenyl substituted by one fluorine atom, or phenoxy substituted by one fluorine atom; and X 2 represents H.

[00102] In certain embodiments of formula IX 1 is unsubstituted cyclopropyl; and X 2 represents H.

[00103] In certain embodiments of formula IX 1 is phenyl substituted by one fluorine atom; and X 2 represents H.

[00104] In certain embodiments of formula IX 1 is phenoxy substituted by one fluorine atom; and X 2 represents H.

[00105] In certain embodiments of formula IX 1 represents C 1-4 alkoxy optionally substituted with one or more substituents independently selected from OH, C 1-4 alkoxy or NR 11A R 11B; and X 2 represents H. In some of these embodiments of formula IR 11A and R 11B represent H or C 1-4 alkyl. In some of these embodiments of formula I, R 11A , and R 11B is CH3.

[00106] In certain embodiments of Formula IX 1 represents C 1-4 alkoxy, which is unsubstituted; and X 2 represents H. In some of these embodiments, X 1 is OCH3.

[00107] In certain embodiments of Formula IX 1 represents C 1-4 alkoxy that is substituted with C 1-4 alkoxy; and X 2 represents H. In some of these embodiments of formula IX 1 is OCH2CH2OCH3.

[00108] In certain embodiments of Formula IX 1 represents C 1-4 alkoxy that is substituted with NR 11A R 11B ; and X2 represents H. In some of these embodiments of formula IR 11A and R 11B represent H or C 1-4 alkyl. In some of these embodiments of formula I, R 11A , and R 11B is CH3.

[00109] In certain embodiments of Formula IX 1 represents -NR 12A R 12B ; and X 2 represents H. In some of these embodiments of formula IR 12A and R 12B represent H, C 1-4 alkyl or C 3-7 cycloalkyl. In some of these embodiments of formula I, R 12A , and R 12B is CH3. In some of these embodiments of formula IR 12A represents H, and R 12B is cyclopropyl.

[00110] In certain embodiments of formula IR 2is a 5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 ;each R 3 independently selected from the group consisting of:C 1-4 alkyl optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl; where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A ;a 4-6 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 with one or more independently selected R groups A ;phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ;C 1-4alkoxy optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl, halogen or OCH3;OR 11 ;OH;halogen;CN;OC(O)R 10 ;OS(O)2OH;NHC(=S)R 11 orOP(O)(OH)(OH);C(O)NH 2; phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ;5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups A ;C 3-7 cycloalkyl; where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A; and 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 with one or more independently selected R groups A .

[00111] In certain embodiments of the IR formula 2 is a 5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 In some of these embodiments of Formula I, the monocyclic heteroaryl is unsubstituted. In some of these embodiments of Formula I, the monocyclic heteroaryl is optionally substituted with one independently selected R 3 In some of these embodiments of Formula I, the monocyclic heteroaryl is substituted with one independently selected R 3.

[00112] In certain embodiments of the IR formula 2 is a 5-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 In some of these embodiments of formula IR 2 represents imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl or thiazolyl; wherein imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl and thiazolyl are optionally substituted with one or more independently selected R groups 3In some of these embodiments of Formula I, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, and thiazolyl are unsubstituted. In some of these embodiments of Formula I, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl, and thiazolyl are optionally substituted with one or two independently selected R 3 In some of these embodiments of Formula I, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, thiadiazolyl and thiazolyl are substituted with one or two independently selected R 3 In some of these embodiments of formula IR 2 is oxadiazolyl or thiazolyl; wherein the oxadiazolyl or thiazolyl is substituted with one independently selected R 3 In some of these embodiments of formula IR 2 is a substituted oxadiazolyl. In some of these embodiments of Formula IR 2is a substituted thiazolyl. In some of these embodiments of Formula IR 2 represents 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl or thiazolyl; wherein 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl and thiazolyl are optionally substituted with one or more independently selected R groups 3 In some of these embodiments of formula IR 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 of these embodiments of formula IR 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 of these embodiments of formula IR 2 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl and thiazolyl are substituted with one independently selected R 3In some of these embodiments of formula IR 2 is a substituted 1,3,4-oxadiazolyl. In some of these embodiments of Formula IR 2 is a substituted 1,2,4-oxadiazolyl. In some of these embodiments of Formula IR 2 is a substituted 1,3,4-thiadiazolyl. In some of these embodiments of Formula IR 2 is a substituted thiazolyl.

[00113] In certain embodiments of formula IR 2 is a 6-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 In some of these embodiments of formula IR 2represents pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; wherein pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl are optionally substituted with one or more independently selected R groups 3 In some of these embodiments of Formula I, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl are unsubstituted. In some of these embodiments of Formula I, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl are optionally substituted with one or two independently selected R 3 In some of these embodiments of Formula I, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl are substituted with one or two independently selected R 3 .

[00114] In certain embodiments of Formula I, each R 3 independently selected from the group consisting of:C 1-4 alkyl optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl; where C 3-7cycloalkyl is optionally substituted with one or more independently selected R groups A ;a 4-6 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 with one or more independently selected R groups A ;phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A ;C 1-4 alkoxy optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl, halogen or OCH3;OR 11 ;OH;halogen;CN;OC(O)R 10 ;OS(O)2OH;NHC(=S)R 11 or OP(O)(OH)(OH);C(O)NH2;phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A;5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups A ;C 3-7 cycloalkyl; where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A ; and 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 with one or more independently selected R groups A .

[00115] In certain embodiments of Formula I, each R 3 independently selected from the group consisting of:C 1-4 alkyl optionally substituted with one or more substituents independently selected from C 3-7cycloalkyl; a 4-6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; phenyl; C 1-4 alkoxy optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl, halogen or OCH3;OR 11 ;OH;halogen;NHC(=S)R 11 orOP(O)(OH)(OH);C(O)NH2;C 3-7 cycloalkyl; and a 4-6 membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N.

[00116] In certain embodiments of Formula I, each R 3 independently represents C(O)NH2.

[00117] In some embodiments of Formula I, each R 3 independently represents C 3-7 cycloalkyl. In some embodiments of Formula I, each R 3 independently represents C6 cycloalkyl.

[00118] In certain embodiments of formula IR 3independently represents 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 with one or more independently selected R groups A In some of these embodiments of formula IR 3 independently represents tetrahydrofuranyl. In some of these embodiments of Formula IR 3 independently represents tetrahydropyranyl.

[00119] In certain embodiments of Formula I, each R 3 representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from C 3-7 cycloalkyl; a 4-6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; phenyl; C 1-4 alkoxy optionally substituted with one or more substituents independently selected from C3-7 cycloalkyl, halogen or OCH3;OR 11 ;OH;halogen;NHC(=S)R 11 or OP(O)(OH)(OH).

[00120] In certain embodiments of Formula I, each R 3 independently represents C 1-4 alkyl optionally substituted with one or more substituents independently selected from OH, halogen, or OP(O)(OH)(OH). In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl that is unsubstituted. In some of these embodiments of formula IR 3 independently represents C(CH3)3. In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted with one OH. In some of these embodiments, the IR formula 3 independently represents CH2OH. In some of these embodiments of formula IR 3independently represents CH2CH2OH. In some of these embodiments of formula IR 3 independently represents CH(OH)CH3. In some of these embodiments of formula IR 3 independently represents C(OH)(CH3)2. In some of these embodiments of formula IR 3 independently represents CH(OH)CF3. In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted with one OP(O)(OH)(OH). In some of these embodiments, the IR formula 3 independently represents C1 alkyl substituted with one OP(O)(OH)(OH). In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted with one OH and three F. In some of these embodiments, the formula IR 3independently represents C2 alkyl substituted with one OH and three F. In some of these embodiments of formula IR 3 independently represents C3 alkyl substituted with one OH and three F.

[00121] In certain embodiments of Formula I, each R 3 independently represents optionally substituted C 1-4 alkyl. In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted by one C 1-4 alkoxy and one phenyl. In some of these embodiments of formula IR 3 independently represents CH(OCH3)phenyl. In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted by one C 1-4 alkoxy, where C 1-4 alkoxy is optionally substituted with one or more substituents independently selected from C 3-7cycloalkyl, halogen, or OCH3. In some of these embodiments of formula IR 3 is CH(OCH3)CH3. In some of these embodiments, R 3 independently represents C(OCH3)(CH3)2. In some of these embodiments of formula IR 3 is CH2OCH3. In some of these embodiments of formula IR 3 is CH2CH2OCH3. In some of these embodiments of formula IR 3 is CH2OCH2CH3. In some of these embodiments of formula IR 3 is CH2OCF3. In some of these embodiments of formula IR 3 is CH2OCHF2. In some of these embodiments of formula IR 3 is CH2OCH2CH2OCH3. In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted by one C 1-4 alkoxy; where C 1-4alkoxy is optionally substituted with one or more independently selected C 3-7 cycloalkyls. In some of these embodiments of formula IR 3 independently represents .

[00122] In certain embodiments of the IR formula 3 independently represents C 1-4 alkyl substituted with one OR 11 ; and each R 11 independently selected from the group consisting of a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; a 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 phenyl is optionally substituted with one or more independently selected R groups A In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted with one OR 11 ; and R11 independently represents phenyl; wherein phenyl is optionally substituted with one or more independently selected R groups A In some of these embodiments of formula IR 3 independently represents In some of these embodiments of formula IR 3 independently represents In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted with one OR 11 , and R 11 independently represents C 3-7 cycloalkyl. In some of these embodiments of formula IR 3 independently represents CH2O-C5cycloalkyl. In some of these embodiments of Formula IR 3 independently represents C 1-4 alkyl substituted with one OR 11 , and R 11independently represents a 4-6 membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N. In some of these embodiments of formula IR 3 independently represents .

[00123] In certain embodiments of the IR formula 3 independently represents C 1-4 alkyl substituted by one C 3-7 cycloalkyl; where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted by one C 3-7 cycloalkyl; where C 3-7 cycloalkyl is unsubstituted. In some of these embodiments of formula IR 3independently represents C1 alkyl substituted with one C3 cycloalkyl; wherein the C3 cycloalkyl is unsubstituted.

[00124] In certain embodiments of formula IR 3 independently represents C 3-7 cycloalkyl; where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups A In some of these embodiments of formula IR 3 independently represents C 3-7 cycloalkyl; where C 3-7 cycloalkyl is unsubstituted. In some of these embodiments of formula IR 3 independently represents cyclopropyl.

[00125] In certain embodiments of formula IR 3 independently represents C 1-4 alkyl substituted with one NHC(=S)R 11 ; and each R 11independently selected from the group consisting of a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; a 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 phenyl is optionally substituted with one or more independently selected R groups A ; and each R A is an independently selected halogen. In some of these embodiments of formula IR 3 independently represents C 1-4 alkyl substituted with one NHC(=S)R 11 ; and each R 11 independently represents C 3-7 cycloalkyl. In some of these embodiments of formula IR 3 independently represents C1 alkyl substituted with one NHC(=S)R 11 ; and each R 11independently represents cyclopropyl.

[00126] In certain embodiments of formula IR 3 independently represents C 1-4 alkyl substituted with one 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 with one or more independently selected R groups A In some of these embodiments of formula IR 3 independently represents C1 alkyl substituted with tetrahydrofuranyl.

[00127] In certain embodiments of formula IR 2 is a 5-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one independently selected R 3 ; where R 3 independently represents C 1-4alkyl optionally substituted with one or more substituents independently selected from OH, halogen, or OP(O)(OH)(OH). In some of these embodiments of formula IR 2 is oxadiazolyl or thiazolyl, wherein the oxadiazolyl or thiazolyl is substituted with one independently selected R 3 ; where R 3 independently represents C 1-4 alkyl, optionally substituted with one or more substituents independently selected from OH, halogen, or OP(O)(OH)(OH).

[00128] Compounds of formula Ia or pharmaceutically acceptable salts thereof are included herein, I-where n is 0, 1, or 2, R 4A represents H, F, CH3, -CH(CH3)2, t-Bu, CF3, -OCH3, -O-CH(CH3)2, or -OCF3, each R 4B independently represents F or -OCF3, and X 1 and R 2are defined herein in the summary and embodiments for Formulas I and Ib.

[00129] In certain embodiments, Formulas Ia X 1 is H.

[00130] 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.

[00131] 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.

[00132] In certain embodiments of Formula Ia, R 4A is H, F, CF3, or -OCF3.

[00133] In certain embodiments of Formula Ia, R 4A is F, CF3, or -OCF3.

[00134] In certain embodiments of Formula Ia, n is 0 or 1, R 4A represents F, CF3, or -OCF3, and R 4B represents F.

[00135] In certain embodiments of formula Ia R4A represents F.

[00136] In certain embodiments of formula Ia, n is 0, and R 4A represents F.

[00137] In certain embodiments of formula Ia, n is 0, and R 4A is -OCF3.

[00138] In certain embodiments of Formula Ia, n is 0 and R 4A represents H.

[00139] In certain embodiments of formula Ia X 1 represents H; n is 0; R 4A is OCF3; R 2 is 1,3,4-oxadiazolyl or thiazolyl substituted with one R 3 ; and R 3 represents C 1-4 alkyl optionally substituted with one or more substituents independently selected from OH; halogen or OP(O)(OH)(OH).

[00140] Compounds of formula Ib or pharmaceutically acceptable salts thereof are included herein, I-bwhere X 1 , R 1 and R 2are defined herein below and in the summary and embodiments for Formula I.

[00141] Certain embodiments relate to compounds of Formula Ib, I-bwhere X 1 is H;halogen;C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms;C 1-4 alkoxy optionally substituted with one or more substituents independently selected from OH;C 1-4 alkoxy or NR 8A R 8B ;NR 9A R 9B ;cyclopropyl, optionally substituted with one or more independently selected R groups 5 ;phenoxy, optionally substituted with one or more independently selected R groups 5 ; or phenyl, optionally substituted with one or more independently selected R groups 5 ;R 1 representsC 1-4alkyl optionally substituted with one or more substituents independently selected from OH;C 1-4 alkoxy or a 4- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; phenyl optionally substituted with one or more independently selected R groups 4 ;an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R groups 5 ;an N-linked 4-6-membered monocyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S, fused with phenyl, wherein the monocyclic heterocycle and phenyl are optionally substituted with one or more independently selected R groups 5 ;C 3-7cycloalkyl optionally substituted by one or more independently selected R groups 5 ; orNR 6 R 7 ;R 2 is a 5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 ;each R 3 independently representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from C 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms;OH;halogen;CN;OC(O)R 10 ;OS(O)2OH or OP(O)(OH)(OH);each R 4 independently selected from the group consisting of: halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; andC 1-4alkoxy, optionally substituted with one or more independently selected halogen atoms; each R 5 independently selected from the group consisting of: OH; halogen; C 1-4 alkyl optionally substituted with one or more substituents independently selected from C 1-4 alkoxy, halogen or -OH; andC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms;R 6 represents H, C 1-4 alkyl or C 3-7 cycloalkyl, where C 3-7 cycloalkyl is optionally substituted with one or more independently selected R groups 5 ;R 7 representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from halogen; phenyl optionally substituted with one or more substituents independently selected from halogen; C 1-4alkyl optionally substituted with one or more independently selected halogen atoms; orC 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms;C 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms; or 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 with one or more independently selected R groups 5 ;each of R 8a and R 8b independently selected from the group consisting of H and C 1-4 alkyl;R 9a and R 9b independently selected from the group consisting of H;C 1-4 alkyl and C 3-7 cycloalkyl; and each R 10 independently selected from the group consisting ofC 1-6 alkyl phenyl.

[00142] In certain embodiments of Formula Ib X 1is H, halogen, optionally substituted cyclopropyl, or optionally substituted phenyl.

[00143] In certain embodiments of Formula Ib X 1 represents H, halogen, or unsubstituted cyclopropyl.

[00144] In certain embodiments of Formula Ib, X 1 is H.

[00145] In certain embodiments of Formula Ib X 1 is bromine, NR 12A R 12B , alkoxy, cyclopropyl, phenoxy or phenyl; wherein cyclopropyl, phenoxy and phenyl are optionally substituted with 1, 2 or 3 independently selected R groups 5 , and at the same time C 1-4 alkoxy is optionally substituted with one or more substituents independently selected from OH, C 1-4 alkoxy or NR 11A R 11B. In some of these embodiments of Formula Ib, cyclopropyl is unsubstituted. In certain embodiments of Formula Ib, phenyl and phenoxy are substituted with F.

[00146] In certain embodiments of Formula Ib, X 1 represents bromo, cyclopropyl or phenyl; wherein cyclopropyl and phenyl are optionally substituted with 1, 2 or 3 independently selected R groups 5 . In certain embodiments of Formula Ib, cyclopropyl is unsubstituted.

[00147] In certain embodiments of Formula Ib, X 1 is bromine.

[00148] In certain embodiments of Formula Ib, X 1 represents cyclopropyl or phenyl; wherein cyclopropyl and phenyl are optionally substituted with 1, 2 or 3 independently selected R groups 5 . In certain embodiments of Formula Ib, cyclopropyl is unsubstituted.

[00149] In certain embodiments of Formula Ib, X 1represents cyclopropyl, phenoxy or phenyl; wherein cyclopropyl, phenoxy and phenyl are optionally substituted with 1, 2 or 3 independently selected R groups 5 . In certain embodiments of Formula Ib, cyclopropyl is unsubstituted.

[00150] In certain embodiments of Formula Ib, X 1 is unsubstituted cyclopropyl or phenyl substituted with one fluorine atom.

[00151] In certain embodiments of Formula Ib X 1 is unsubstituted cyclopropyl or phenyl substituted with one fluorine atom, or phenoxy substituted with one fluorine atom.

[00152] In certain embodiments of Formula Ib X 1 is unsubstituted cyclopropyl.

[00153] In certain embodiments of Formula Ib, X 1 is phenyl substituted with one fluorine atom.

[00154] In certain embodiments of Formula Ib X 1is phenoxy substituted with one fluorine atom.

[00155] In certain embodiments of Formula Ib X 1 represents C 1-4 alkoxy optionally substituted with one or more substituents independently selected from OH, C 1-4 alkoxy or NR 11A R 11B . In some of these embodiments, formula Ib R 11A and R 11B represent H or C 1-4 alkyl In some of these embodiments, formula Ib as R 11A , and R 11B represents CH3.

[00156] In certain embodiments of Formula Ib, X 1 represents C 1-4 alkoxy that is unsubstituted. In some of these embodiments of Formula Ib, X 1 is OCH3.

[00157] In certain embodiments of Formula Ib, X 1 represents C 1-4 alkoxy that is substituted with C 1-4alkoxy. In some of these embodiments, formula Ib X 1 is OCH2CH2OCH3.

[00158] In certain embodiments of Formula Ib, X 1 represents C 1-4 alkoxy that is substituted with NR 11A R 11B . In some of these embodiments, formula Ib R 11A and R 11B represent H or C 1-4 alkyl In some of these embodiments, formula Ib as R 11A , and R 11B represents CH3.

[00159] In certain embodiments of Formula Ib, X 1 represents NR 12A R 12B . In some of these embodiments, formula Ib R 12A and R 12B represent H, C 1-4 alkyl or C 3-7 cycloalkyl. In some of these embodiments, formula Ib as R 12A , and R 12B is CH3. In some of these embodiments of Formula Ib, R 12Arepresents H, and R 12B is cyclopropyl.

[00160] In one embodiment, the present invention relates to compounds of formula Ib, wherein X 1 represents H;R 1 is phenyl optionally substituted with one or more independently selected R groups 4 ;R 2 is a 5-6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 ;each R 3 independently representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from OH; halogen or OP(O)(OH)(OH); and each R 4 independently representsC 1-4alkoxy, optionally substituted with one or more independently selected halogen atoms.

[00161] In one embodiment, the present invention relates to compounds of formula Ib, wherein X 1 represents H;R 1 is phenyl optionally substituted with one or more independently selected R groups 4 ;R 2 is a 5-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R groups 3 ;each R 3 independently representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from OH; halogen or OP(O)(OH)(OH); and each R 4 independently representsC 1-4alkoxy, optionally substituted with one or more independently selected halogen atoms.

[00162] In one embodiment, the present invention relates to compounds of formula Ib, where X 1 represents H;R 1 is phenyl optionally substituted with one or more independently selected R groups 4 ;R 2 is oxadiazolyl or thiazolyl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein oxadiazolyl and thiazolyl are optionally substituted with one or more independently selected R groups 3 ;each R 3 independently representsC 1-4 alkyl optionally substituted with one or more substituents independently selected from OH; halogen or OP(O)(OH)(OH); and each R 4 independently representsC 1-4alkoxy optionally substituted with one or more independently selected halogen atoms.

[00163] Various embodiments of substituents X 1 , X 2 , R 1 and R 2have been discussed above. Such embodiments of the substituents can be combined to obtain various embodiments of the present invention. All embodiments of the compounds of the present invention obtained by combining the embodiments of the substituents discussed above are within the scope of the invention of the applicant.

[00164] Representative compounds of formula I include, but are not limited to: (5-{3-amino-5-[4-(trifluoromethoxy)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-oxadiazol-2-yl)methyl dihydrogen phosphate; 2-(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl] (ridin-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 l]-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-(trift ormethoxy)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 n-3-amine;(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;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-methoxyeth yl]-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)benzo l-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}pyridine -3-amino;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-amino;2-(5-{[(2S)-oc solan-2-yl]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amino;2-(5-{[(2R)-oxolan-2-yl ]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amino;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-(trifluoromethox i)benzene-1-sulfonyl]pyridin-3-amine;2-[5-(ethoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyride in-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-oxadia (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 l-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine;2-[3-(oxan-4-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethox i)benzene-1-sulfonyl]pyridin-3-amine;2-{3-[(4-fluorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfo nyl]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-sulfo nyl]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-(trifluoro methoxy)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 l-2-yl)methanol;5-amino-N-benzyl-6-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-N-methylpyridine-3-sulfonamide;{5-[3-amino-5-(benzenesulfonyl)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)be nzole-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;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.

[00165] The compounds of the present invention are named using the Name 2015 naming algorithm from Advanced Chemical Development or the Struct=Name naming algorithm, which is part of CHEMDRAW® Professional version 15.0.0.106.

[00166] 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 about the chiral carbon atom. The terms "R" and "S" as used herein represent the configurations defined in the 1974 IUPAC recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. Various stereoisomers and mixtures thereof are contemplated by the present invention and are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers, or by preparing racemic mixtures followed by the use of resolution methods,well known to those skilled in the art. Examples of such separation 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 isolation 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 a mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods.

[00167] 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 can be in the cis or trans configuration and can be present as a single isomer or a mixture of cis- and trans-isomers. Individual cis- or trans-isomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials using selective organic transformations or obtained in single isomer form by purifying mixtures of cis- and trans-isomers. Such methods are well known to those skilled in the art and may involve separation of the isomers by recrystallization or chromatography.

[00168] It is to be understood that the compounds of the present invention can be characterized by tautomeric forms as well as geometric isomers,and that they also form an aspect of the present invention.

[00169] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula I and Ia wherein one or more atoms are replaced by atoms of the same atomic number but with an atomic mass or mass number different from the atomic mass or mass number that predominate in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen isotopes such as, 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 Oh, 17 O and 18 O, phosphorus, such as 32 P, and sulfurs such as 35S. Certain isotopically labeled compounds of formulas I, Ia, and Ib, e.g., containing a radioactive isotope, are useful in tissue distribution studies of drugs and / or substrates. Radioactive isotopes of tritium, i.e., 3 H, and carbon-14, vol. e. 14 C, are particularly suitable for this purpose due to their ease of incorporation and ease of detection. Substitution with heavier isotopes, such as deuterium, i.e. 2 H, may provide certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dose requirements, and may therefore be preferable in some cases. Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O and 13N, can be useful in positron emission tomography (PET) studies to determine the degree of receptor occupancy by the substrate. Isotopically labeled compounds of formulas I, Ia and Ib can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples using suitable isotopically labeled reagents in place of the unlabeled reagents previously used.

[00170] Thus, the formula depictions in this specification may represent only one of the possible tautomeric, geometric or stereoisomeric forms. It is to be understood that the present invention encompasses any tautomeric, geometric or stereoisomeric form and mixtures thereof and is not limited to only one tautomeric, geometric or stereoisomeric form used in the formula depictions.

[00171] Compounds of formulas I,Ia and Ib can be used in the form of pharmaceutically acceptable salts. The phrase "pharmaceutically acceptable salt" means those salts which, under careful medical evaluation, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions and the like and which meet a reasonable benefit / risk ratio.

[00172] Pharmaceutically acceptable salts are described in SM Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.

[00173] The compounds of formulas I, Ia and Ib may contain either basic or acidic functional groups, or both, and can be converted into a pharmaceutically acceptable salt, if necessary, using a suitable acid or base. Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention.

[00174] 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 (Isothionate), 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. Also, the basic nitrogen-containing groups can be quaternized with such agents as 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; arylalkyl halides such as benzyl and phenethyl bromides, etc. This gives products that are soluble or dispersible in water or oil. Examples of acids,which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.

[00175] Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the present invention by reacting the carboxylic acid-containing moiety with a suitable base, such as, but not limited to, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, 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 cations such as, but not limited to, lithium, sodium, potassium, calcium,magnesium and aluminum, etc., and non-toxic quaternary ammonium and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, etc. Other examples of organic amines suitable for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, etc.

[00176] The compounds described herein may exist in unsolvated forms as well as solvated forms, including hydrated forms such as hemihydrates. In general, solvated forms with pharmaceutically acceptable solvents such as water and ethanol, among others,equivalent to the unsolvated forms for the purposes of the present invention. Pharmaceutical Compositions

[00177] When a compound of the present invention is used as a pharmaceutical, it is 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 comprise a therapeutically effective amount of a compound of Formulas I, Ia, Ib, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. The phrase "pharmaceutical composition" refers to a composition suitable for administration in human or veterinary use.

[00178] Pharmaceutical compositions that contain a compound of Formulas I, Ia, or Ib, alone or in combination with an additional therapeutically active ingredient, can be administered to subjects orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments, or drops),buccally or as an oral or nasal spray. The term "parenterally" as used herein refers to routes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injections and infusions.

[00179] The term "pharmaceutically acceptable carrier" as used herein means a non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material or excipient for any type of formulation. Some examples of substances that can serve 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; auxiliary means,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; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, and in addition, colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives, and antioxidants may also be present in the composition,depending on the judgment of the preparer.

[00180] Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of coating agents such as lecithin, by maintaining the required particle size in the case of dispersions and by the use of surfactants.

[00181] These compositions may also contain auxiliary substances such as preservatives, wetting agents,emulsifiers and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, such as paraben, chlorobutanol, phenolsorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[00182] In some cases, in order to prolong the action of a drug, it may be desirable to slow the absorption of the drug upon subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance characterized by poor solubility in water. In such a case, the rate of absorption of the drug depends on its dissolution rate, which, in turn,may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered dosage form can be achieved by dissolving or suspending the drug in an oil carrier medium.

[00183] Depot injectable formulations are created by preparing microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by incorporating the drug into liposomes or microemulsions that are compatible with body tissues.

[00184] Injectable formulations can be sterilized, for example,by filtration through a bacteria-retaining filter or by incorporating sterilizing agents as sterile solid compositions that can be dissolved or dispersed in sterile water or another sterile injectable medium immediately before use.

[00185] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, the solid dosage forms may contain from 1% to 95% (w / w) of a compound of Formulas I, Ia, or Ib. In certain embodiments, a compound of Formulas I, Ia, or Ib, or pharmaceutically acceptable salts thereof, may be present in a solid dosage form in a range of from 5% to 70% (w / w). In such solid dosage forms, the active compound may be mixed with at least one inert pharmaceutically acceptable carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or dry diluents, such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binding agents such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) tablet disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules,The dosage form of tablets and pills may also contain buffering agents.

[00186] The pharmaceutical composition may be a unit dosage form. In this form, the drug is divided into single doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged drug, wherein the package contains discrete quantities of the drug, for example, packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, sachet, or lozenge itself, or it may be represented by the appropriate number of any of these in packaged form. The amount of active ingredient in a unit dose of the drug can be varied or adjusted from 0.1 mg to 1000 mg,from 1 mg to 100 mg or from 1% to 95% (w / w) of a single dose according to the particular application and strength of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[00187] The dose to be administered to a subject may be determined based on the potency of the particular compound being used and the condition of the subject, as well as the body weight or surface area of ​​the subject being treated. The amount of the dose will also be determined by the presence, nature, and extent of any adverse effects that accompany the administration of the particular compound to the particular subject. In determining the effective amount of a compound to be administered in the treatment or prevention of the disorder being treated, the physician may evaluate factors such as circulating plasma levels of the compound, toxicity of the compound, and / or disease progression, etc.

[00188] With respect to administration, the compounds may be administered at a rate determined by factors such aswhich may include, without limitation, LD, 501 , X 2 , R 1 and R 3 are as described in the summary, or they represent a fragment that can be converted into one of the indicated groups using chemical transformations known to a person skilled in the art. Scheme 1

[00224] As shown in Scheme 1, compounds of formula (1-6) can be prepared from compounds of formula (1-1). Compounds of formula (1-1), where Hal is a halogen, can first be reacted with thiols (R 1-SH) in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium carbonate in a solvent such as, but not limited to, N,N-dimethylacetamide with heating either conventionally or by microwave irradiation to produce intermediate thioethers. In a second step, the intermediate thioethers can be oxidized with hydrogen peroxide in a solvent such as cooled trifluoroacetic acid to produce compounds of formula (1-2). Carboxylic acids of formula (1-2) can be coupled with acylhydrazines of formula (1-4) to produce compounds of formula (1-5).Examples of conditions known to provide the formation of compounds of formula (1-5) from a mixture of a carboxylic acid and an acylhydrazine include, but are not limited to, the addition of a coupling reagent 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 salt, 1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphine chloride (BOPCl), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium N-oxide hexafluorophosphate or hexafluorophosphate 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 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-trioxatriphosphinane-2,4,6-trioxide (T3P®).The coupling reagents can be added as a solid, a solution, or as a reagent bound to a solid polymer support. In addition to the coupling reagents, coupling auxiliary reagents can facilitate the coupling reaction. Coupling auxiliary reagents that are frequently 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 optionally be 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 solvents such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, and ethyl acetate. The reactions can be carried out at ambient temperature or with heating. Heating can be achieved either conventionally or by microwave radiation.Acylhydrazines of formula (1-4) are either commercially available or are 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). A substituent representing R. 3 , can be further manipulated under reaction conditions known to those skilled in the art to yield substituents representing R 3 , described in the brief description. Compounds of formula (1-6) are typical examples of compounds of formula (I). Scheme 2

[00225] As shown in Scheme 2, compounds of formula (1-6) can be prepared from compounds of formula (1-2) using a method alternative to the sequence shown in Scheme 1. Compounds of formula (1-2) can be converted to compounds of formula (2-1) using a two-step process. In the first step, compounds of formula (1-2) can be esterified by combining compounds 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 the formation of intermediate esters. These intermediate esters can be treated in a second step with hydrazine hydrate in a heated solvent, such as tetrahydrofuran, to provide compounds of formula (2-1). Compounds of formula (2-1) can be coupled with compounds of formula (2-2) using the conditions described in Scheme 1, coupling a carboxylic acid and an acylhydrazine to provide compounds of formula (1-5).Compounds of formula (1-5) can be dehydrated as described in Scheme 1 to yield compounds of formula (1-6). Compounds of formula (1-6) are typical examples of compounds of formula (I). Scheme 3.

[00226] As shown in Scheme 3, compounds of formula (3-3) can be prepared from compounds of formula (1-2). Compounds of formula (1-2) can be converted to compounds of formula (3-1) via a two-step process. Compounds of formula (1-2) can also be coupled with ammonia using the coupling conditions described in Scheme 1 to couple a carboxylic acid and an acylhydrazine to produce intermediate primary amides. These primary amides can be reacted with phosphorus pentasulfide in the presence of an acid, such as 1 M hydrochloric acid, in a heated mixture of solvents, such as, but not limited to, tetrahydrofuran and toluene, to produce thioamides of formula (3-1). Thioamides of formula (3-1) can be reacted with α-bromaldehydes of formula (3-2) in the presence of a base, such as, but not limited to, pyridine, in a heated solvent, such as, but not limited to, 2-methyltetrahydrofuran, to yield compounds of formula (3-3).Compounds of formula (3-3) are typical examples of compounds of formula (I). Scheme 4.

[00227] As shown in Scheme 4, compounds of formula (4-1) can be prepared from compounds of formula (1-2) via a sequence similar to that shown in Scheme 2. Compounds of formula (1-2) can be converted to compounds of formula (2-1) via a two-step process. In the first step, compounds of formula (1-2) are coupled with stret-butylhydrazine carboxylate using standard peptide bond formation 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 with compounds of formula (2-2) using the conditions described in Scheme 1, coupling a carboxylic acid and an acylhydrazine to provide compounds of formula (1-5). Compounds of formula (1-5) can be treated with Lawesson's reagent to give compounds of formula (4-1).The reaction is typically carried out at elevated temperature in a solvent such as, but not limited to, toluene. Compounds of formula (4-1) are typical examples of compounds of formula (I). Scheme 5.

[00228] As shown in Scheme 5, compounds of formula (5-2) can be prepared from compounds of formula (1-2). Compounds of formula (1-2) can be reacted with compounds of formula (5-1), where R 3described herein, using coupling conditions such as 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. Typically, the reaction is carried out in a solvent such as, but not limited to, N,N-dimethylacetamide. The resulting coupling intermediate can then be treated with tetrabutylammonium hydroxide to provide compounds 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 examples of compounds of formula (I). Chemical Synthesis Procedures

[00229] List of abbreviations used in the examples section: min means minute; DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene; DCI means desorption chemical ionization; DMSO means dimethyl sulfoxide; EDCI means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ESI means electrospray ionization; HATU means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC means high performance liquid chromatography; MS means mass spectrometry; NMR means nuclear magnetic resonance; wt. means gravimetric, and UPLC means ultra high performance liquid chromatography.

[00230] The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that where typical or preferred process conditions (i.e., reaction temperatures, reaction times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise indicated.Optimum reaction conditions may vary depending on the particular reagents or solvent used, but such conditions can be determined by one skilled in the art through routine optimization procedures.

[00231] Furthermore, as will be apparent to those skilled in the art, typical protecting groups may be necessary to prevent undesired reactions involving certain functional groups. The selection of an appropriate protecting group for a particular functional group, 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.; Wiley-Interscience: New York, 1991).

[00232] The following methods are presented in detail for the preparation of a compound of the present invention, as defined herein above and in the comparative examples.The compound of the present invention can be prepared by one skilled in the art of organic synthesis from known or commercially available starting materials and reagents.

[00233] All reagents were of commercial grade and were used as is without further purification unless otherwise indicated. Commercially available anhydrous solvents were used for reactions carried out under an inert atmosphere. Chemically pure solvents were used in all other cases unless otherwise indicated. Column chromatography was performed on silica gel 60 (35-70 μm). Thin layer chromatography was performed using pre-coated silica gel F-254 plates (0.25 mm thick). Spectra. 1 H NMR was recorded on a Bruker Advance 300 NMR spectrometer (300 MHz), an Agilent NMR spectrometer at 400 MHz, or at 500 MHz. Chemical shifts (δ) for the spectra 1H NMR spectra were recorded in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the corresponding peak of the residual solvent, i.e., CHCl3 (δ 7.27), as an internal standard. Multiplicities are reported as singlet (s), doublet (d), doublet quartets (dq), triplet (t), quartet (q), quintuplet (quin), multiplet (m), and broad (br) signals. Electrospray MS spectra were acquired on a Waters platform LC / MS spectrometer or a Waters Acquity H-Class UPLC coupled to a Waters spectrometer with a 3100 mass detector. Columns used were Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm id x 50 mm long, Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm id x 30 mm long, or Waters Xterra® MS 5 μm C18, 100 x 4.6 mm. Methods utilized either CH3CN / H2O gradients (H2O contains either 0.1% CF3CO2H or 0.1% NH3) or CH3OH / H2O gradients (H2O contains 0.05% CF3CO2H).Microwave heating was performed using a Biotage® Initiator. Reverse Phase Cleanup Methods Trifluoroacetic Acid Method

[00234] Samples were purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm, 100E AXIA column (30 mm × 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used 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).Preparative LC / MS, method TFA6

[00235] Samples were purified by reversed-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm, 100E AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) 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 purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 manometric module; Gilson 155 UV / VIS detector; Gilson 506C interface unit; Gilson FC204 fraction collector; Agilent G1968D active flow splitter; and a Thermo MSQ Plus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom application developed in-house using Microsoft Visual Basic 6.0. Preparative LC / MS, TFA8

[00236] method Samples were purified by reversed-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm, 100E AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) 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 purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 manometric module; Gilson 155 UV / VIS detector; Gilson 506C interface unit; Gilson FC204 fraction collector; Agilent G1968D active flow splitter; and a Thermo MSQ Plus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom application developed in-house using Microsoft Visual Basic 6.0. Preparative LC / MS, method TFA10

[00237] Samples were purified by reversed-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm, 100E AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used at 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 manometric module; Gilson 155 UV / VIS detector; Gilson 506C interface unit; Gilson FC204 fraction collector; Agilent G1968D active flow splitter; and a Thermo MSQ Plus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom application developed in-house using Microsoft Visual Basic 6.0. Preparative LC / MS, Method AA6

[00238] Samples were purified by reversed-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm, 100E AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) 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 purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 manometric module; Gilson 155 UV / VIS detector; Gilson 506C interface unit; Gilson FC204 fraction collector; Agilent G1968D active flow splitter; and a Thermo MSQ Plus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom application developed in-house using Microsoft Visual Basic 6.0. Preparative LC / MS, Method AA7

[00239] Samples were purified by reversed-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm, 100E AXIA column (50 mm × 21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) 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 dedicated purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 pressure module; Gilson 155 UV / VIS detector; Gilson 506C interface unit; Gilson FC204 fraction collector; Agilent G1968D active flow splitter; and Thermo MSQ Plus mass spectrometer. The system was controlled by a combination of Thermo Xcalibur 2.0.7 software and a custom-developed application using Microsoft Visual Basic 6.0. Example 1 (5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol Step 1. 3-Amino-5-(4-trifluoromethoxyphenylsulfanyl)pyridine-2-carboxylic acid

[00240] A solution of 3-amino-5-bromopyridine-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 for 45 minutes in a microwave reactor. The mixture was then 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 mixture of 1% acetic acid / water, followed by petroleum ether. Drying in a vacuum oven yielded the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (d, J = 2.0 Hz, 1H), 7.64-7.60 (m, 2H), 7.48-7.44 (m, 2H), 6.99 (d, J = 2.0 Hz, 1H). Step 2. 3-Amino-5-(4-trifluoromethoxybenzenesulfonyl)pyridine-2-carboxylic acid

[00241] 3-Amino-5-(4-trifluoromethoxyphenylsulfanyl)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 in an ice bath. H2O2 (14 mL, 160 mmol) was then added, and the mixture was stirred at 0°C until the reaction was complete. For work-up, the mixture was diluted with 1% acetic acid in water. A suspension was obtained, which was then filtered. The collected solid was washed with 1% acetic acid / water, followed by petroleum ether. After drying in a vacuum oven, the title compound was obtained. MS (ESI+) m / z 363 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d,J=1.9 Hz, 1H), 8.14 (d,J=8.8 Hz, 2H), 7.79 (d,J=1.9 Hz, 1H), 7.65 (d,J=8.4 Hz, 2H). Step 3. 3-Amino-N'-(hydroxyacetyl)-5-[4-(trifluoromethoxy)benzenesulfonyl]pyridine-2-carbohydrazide (A-1654077.0)

[00242] To a 40 mL vial was added 3-amino-5-(4-trifluoromethoxybenzenesulfonyl)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]pyridinium 3-oxide hexafluorophosphate (HATU, 0.548 g, 1.442 mmol) was added and the resulting solution was stirred for 30 min at room temperature. 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 washing solution.Hunig's base (0.458 mL, 2.62 mmol) was then added dropwise, and the mixture was stirred for 30 min at room temperature. Ethyl acetate (20 mL) and 5% NaHCO3 (20 mL) were added, the resulting biphasic mixture was stirred for 5 min, 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 Na2SO4, filtered, and then concentrated in vacuo to give the title compound, which was used without further purification (470 mg). 1 H NMR (501 MHz, DMSO-d6) δ ppm 3.93 (d, J=5.9 Hz, 2H), 5.48 (t, J=6.0 Hz, 1H), 7.12-7.24 (m, 2H), 7.64 (dq, J=7.8, 1.1 Hz, 2H), 7.75 (d, J=2.0 Hz, 1H), 8.09-8.16 (m, 2H), 8.21 (d, J=2.1 Hz, 1H), 9.70 (s, 1H), 10.23 (s, 1H); MS (ESI-)mass / charge433.1 [MH] -.Step 4. 3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N'-({[tri(propan-2-yl)silyl]oxy}acetyl)pyridine-2-carbohydrazide

[00243] 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-bottomed flask, and the flask was cooled to 0°C in an ice bath. Triethylamine (0.341 mL, 2.447 mmol) was added, followed by the dropwise addition of triisopropylsilyl trifluoromethanesulfonate (0.660 mL, 2.447 mmol). The reaction mixture was stirred at 0°C for 15 min, after which the flask was warmed to room temperature and stirred for an additional 2.5 h. 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 by flash chromatography, eluting with a gradient of 0-2.5% CH3OH in CH2Cl2 on a 40 g silica gel column to give 720 mg of the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (d, J=7.1 Hz, 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=2.0 Hz, 1H), 8.11-8.20 (m, 2H), 8.41 (d, J=2.0 Hz, 1H); MS (ESI+)mass / charge591.1 [M+H] +.Step 5. 5-[4-(Trifluoromethoxy)benzene-1-sulfonyl]-2-[5-({[tri(propan-2-yl)silyl]oxy}methyl)-1,3,4-oxadiazol-2-yl]pyridin-3-amine

[00244] 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 lipo-toluenesulfonyl chloride (0.299 g, 1.570 mmol), and the reaction mixture was stirred at The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then washed with a saturated aqueous solution of NaHCO3. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by precipitation from 3 mL of dimethyl sulfoxide and 3 mL of methanol to yield 268 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (d, J=7.1 Hz, 18H), 1.08-1.19 (m, 3H), 5.03 (s, 2H), 7.26 (s, 2H), 7.0 (d) (J=7.68 Hz, 1H), 8.11–8.20 (m, 2H), 8.41 (d, J=2.0 Hz, 1H); MS (ESI+)mass / charge573.1 [M+H] +.Step 6. (5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[00245] To a solution of 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-[5-({[tri(propan-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 dropwise a solution of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.465 mL, 0.465 mmol), and the reaction mixture was stirred at room temperature for 1.5 h. 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 yield a white solid, which was isolated by filtration and dried to constant weight to yield 168 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.71 (s, 2H), 5.98 (s, 1H), 7.23 (s, 2H), 7.63 (dq, J=8.9, 1.1 Hz, 2H), 7.87 (d, J=2.0 Hz, 1H), 8.07-8.20 (m, 2H), 8.39 (d, J=2.0 Hz, 1H); MS (ESI-)mass / charge414.9 [MH] -.Alternative Method for the Preparation of 3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N'-({[tri(propan-2-yl)silyl]oxy}acetyl)pyridine-2-carbohydrazideStep 1. Methyl {[tri(propan-2-yl)silyl]oxy}acetate

[00246] Methyl 2-hydroxyacetate (CAS: 96-35-5, 80 g, 888.9 mmol) was mixed with imidazole (CAS: 288-32-4, 182 g, 2.7 mol) in dry N,N-dimethylformamide (1 L). To this solution was added triisopropylsilyl chloride (CAS: 13154-24-0, 228 mL, 1.1 mol). The resulting mixture was stirred at ambient temperature under a nitrogen atmosphere. After stirring overnight, the mixture was quenched with saturated NaHCO3 (1.5 L) and extracted successively with diethyl ether. The combined organic fractions were washed with 2 M HCl (1.4 L, 2.8 mol), water (0.5 L), and brine (1 L). The organic layer was then dried over Na2SO4, filtered, and concentrated to dryness to yield 199 g of the title compound, which was used without purification. Step 2.2-{[Tri(propan-2-yl)silyl]oxy}acetohydrazide

[00247] Methyl {[tri(propan-2-yl)silyl]oxy}acetate (199 g, 808.4 mmol) was dissolved in tetrahydrofuran (1 L). Aqueous hydrazine solution (35% w / w, 200 mL, 2.2 mol) was added and the mixture was heated at reflux overnight. The mixture was then quenched with NaHCO3 (1.5 L) followed by extraction with ether (4 × 500 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated to dryness to yield 191 g of crude material. The crude material was precipitated overnight from ethyl acetate / heptane (500 mL, 5 / 95) to give 122 g of the title compound.Step 3.3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-N'-({[tri(propan-2-yl)silyl]oxy}acetyl)pyridine-2-carbohydrazide

[00248] 3-Amino-5-(4-trifluoromethoxybenzenesulfonyl)pyridine-2-carboxylic acid (107.3 g, 296.4 mmol) was mixed with 2-{[tri(propan-2-yl)silyl]oxy}acetohydrazide (87.5 g, 355.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, CAS: 1892-57-5, 68.3 g, 355.7 mmol) and 4-dimethylaminopyridine (CAS: 1122-58-3, 43.4 g, 355.7 mmol) in dichloromethane (2 L). The resulting mixture was stirred at ambient temperature overnight. The reaction was then quenched with 1 N HCl (1 L, 1 mol) and extracted with dichloromethane. The organic layer was washed with brine and H2O, dried over Na2SO4, filtered, and concentrated to dryness to give 186.5 g of the title compound, which was used without purification.Example 2(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl dihydrogen phosphate Step 1. (5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyldi-tert-butylphosphate

[00249] 1H-Tetrazole (0.45 M in CH3CN, 42.7 mL, 19.22 mmol) was diluted with Using N,N-dimethylacetamide (19.22 ml) and CH3CN was removed in vacuo at a bath temperature of 60°C. After cooling the flask to room temperature, (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol (4 g, 9.61 mmol, Example 1) was added in one portion as a neat solid, followed by the dropwise addition of di-tert-butyl N,N-diethylphosphoramidite (4.01 mL, 14.41 mmol). The reaction mixture was stirred for 1 h at room temperature, after which the reaction vessel was placed in a room temperature water bath and hydrogen peroxide (30% aqueous, 2.94 mL, 96 mmol) was added dropwise.A slow exotherm was observed up to 40°C. After cooling the flask to room temperature, the reaction mixture was stirred for 15 minutes, and the product began to precipitate from the solution. The reaction mixture was diluted with ethyl acetate, washed with water and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo. The solid residue was precipitated from ethyl acetate / heptanes to yield 5.255 g of the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.49 (d, J = 1.9 Hz, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.45-7.33 (m, 2H), 6.39 (s, 2H), 5.27 (d, J = 8.8 Hz, 2H), 7.75 (d, m / z 607.0 [MH] -.Step 2. (5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl dihydrogen phosphate

[00250] (5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-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 syringe, and the resulting solution was thoroughly stirred at room temperature. After approximately 1 minute, a solid began to precipitate out of solution. The resulting suspension was stirred for 30 min at room temperature, after which the solids were collected using a fritted funnel. The filter cake was washed with 5 mL of acetic acid and 2 × 10 mL of heptanes and then dried to constant weight in a vacuum oven for 16 h at 35°C to yield the title compound as a solid (3.7 g). 1H NMR (400 MHz, methanol-d4) δ ppm 8.37 (d,J=2.0 Hz, 1H), 8.14 (d,J=8.9 Hz, 2H), 7.88 (d,J=2.0 Hz, 1H), 8.14 (d,J=9.1 Hz, 2H); MS (ESI-)m / z 495.0 [MH] - .Example 32-(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-olStep 1. Methyl 3-amino-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carboxylate

[00251] To a suspension of 3-amino-5-(4-trifluoromethoxybenzenesulfonyl)pyridine-2-carboxylic acid (1.08 g, 3 mmol, Example 1 - Step 2) in CH3OH (20 mL) were added a few drops of H2SO4. The resulting mixture was stirred at 70°C in a closed vial for 72 h. The mixture was then added to water, which was adjusted to pH 7 with 1 M NaOH. 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 further purification. MS (ESI+) m / z 377 [M+H]+ Step 2. 3-Amino-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carbohydrazide

[00252] Hydrazine hydrate (CAS: 7803-57-8, 80% in water, 4 mL) was added to a solution of methyl 3-amino-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carboxylate (0.92 g, 2.44 mmol, step 1) in tetrahydrofuran (15 mL). The solution was heated at 55 °C in a closed vial. After stirring overnight, the mixture was diluted with water and the resulting suspension was filtered to give a solid, which was washed with water. Subsequent drying in a vacuum oven (50 °C) gave the title compound (0.7 g), which was used without further purification. MS (ESI+)mass / charge377 [M+H] +.Step 3. 3-Amino-N'-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbohydrazide

[00253] To a solution of 1-methyl-2-pyrrolidinone (4 mL) containing 3-amino-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carbohydrazide (188 mg, 0.5 mmol, 1 eq, step 2), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (190 mg, 0.5 mmol, HATU, 1 eq), and triethylamine (139 3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (72 mg, 0.5 mmol, [CAS No. 114715-77-4], 1 equiv) was added to a solution of 1 mL of ethyl acetate. The resulting mixture was stirred at room temperature until the reaction was complete. The title compound was obtained after extraction with ethyl acetate and concentration of the combined organic fractions. MS (ESI+) m / z 517 [M+H] +.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

[00254] 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) at 0°C was added dropwise Triisopropylsilyl trifluoromethanesulfonate (108 μL, 1 mmol CAS: 80522-42-5, 2 eq.) was added to the reaction mixture. The resulting mixture was stirred at 0°C for 15 min and then allowed to reach room temperature. After completion of the reaction, the mixture was added to water and extracted with ethyl acetate. The combined organic fractions were dried with Na2SO4 and concentrated to give the title compound, which was used without further purification. MS (ESI+)m / z 629 [M-C3H7] +.Step 5. 5-[4-(Trifluoromethoxy)benzene-1-sulfonyl]-2-[5-(1,1,1-trifluoro-2-{[tri(propan-2-yl)silyl]oxy}propan-2-yl)-1,3,4-oxadiazol-2-yl]pyridin-3-amine

[00255] 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 To dichloromethane (10 mL) was added lipotoluenesulfonyl chloride (286 mg, 1.5 mmol, CAS: 98-59-9, 3 eq.). The mixture was stirred at ambient temperature until complete. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic fraction was washed with aqueous NaHCO3, dried with Na2SO4, and concentrated. The residue was purified by column chromatography using petroleum ether / ethyl acetate (9 / 1) as eluent to afford the title compound. MS (ESI+) m / z 655 [M+H] +.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

[00256] To a solution of 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-[5-(1,1,1-trifluoro-2-{[tri(propan-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 1 M tetrabutylammonium fluoride in tetrahydrofuran (0.15 mL, 0.15 mmol, 1 eq). The mixture was stirred at ambient temperature until complete. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic fractions were dried and concentrated. The residue was purified by preparative chromatography (XSelect™ CSH Prep guard column, C18, 19 × 10 mm, 5 μm (Waters) with an XSelect™ CSH Prep OBD column, C18, 19 × 100 mm, 5 μm (Waters) and a gradient of 0.1% formic acid in water (A) and acetonitrile (B) at a flow rate of 20 mL / min.Alternatively, an XBridge™ Prep guard column, C18, 19 × 10 mm, 5 μm (Waters) with an XBridge™ Prep OBD column, C18, 19 × 100 mm, 5 μm (Waters) and a gradient of 0.5% NH3 in water (A) and acetonitrile (B) at a flow rate of 20 mL / min were used. After elution, the solvent was removed under vacuum to afford the title compound. MS (ESI+) m / z 499 [M+H]. + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (d, J=2 Hz, 1H), 8.16 (m, 2H), 7.93 (d, J=2 Hz, 1H), 7.67 (m, 1H), 7.67 (m, 2H), 7.27 (br. s, 2H), 1.84 (s, 3H). Example 41-(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-2,2,2-trifluoroethan-1-ol

[00257] The title compound was prepared using the procedures described in the synthesis of Example 3 and replacing 3,3,3-trifluoro-2-hydroxypropanoic acid to 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid in step 3, and obtaining the following sequence of intermediates: 3-amino-N'-(3,3,3-trifluoro-2-hydroxypropanoyl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbohydrazide (MS (ESI+)m / z503 [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+) mass / charge 615 [M-C3H7] + , 643 [M-CH3] +), 5-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2-[5-(2,2,2-trifluoro-1-{[tri(propan-2-yl)silyl]oxy}ethyl)-1,3,4-oxadiazol-2-yl]pyridin-3-amine (MS (ESI+) mass / charge 641 [M+H] + ). MS (ESI+) mass / charge 485 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J=2 Hz, 1H), 8.15 (m, 2H), 7.90 (d, J=2 Hz, 1H), 7.67 (m, 2H), 7.29 (br s, 2H), 6.04 (t, J=6 Hz, 1H), 4.74 (d, J =6 Hz, 2H). Example 5(2-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazol-5-yl)methanolStep 1. 3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carboxamide

[00258] Solution 3-Amino-5-(4-trifluoromethoxybenzenesulfonyl)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]pyridinium 3-oxide hexafluorophosphate (294 mg, 0.773 mmol, HATU) in N,N-dimethylformamide (1.4 mL) were treated with triethylamine (108 μL, 0.773 mmol), stirred at room temperature for 20 min, treated with excess 37% aqueous ammonium hydroxide (407 μL, 3.86 mmol), and stirred overnight. The mixture was diluted with water (20 mL) and stirred for 15 min.The solid that formed was collected by filtration, washed with water, and dried under vacuum to give the title compound (129 mg, 0.357 mmol, 92% yield). MS (DCI+) m / z 362 [M+H]. + , 379 [M+NH4] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d,J=2.1 Hz, 1H), 8.13-8.09 (m, 2H), 8.02 (br s, 1H), 7.69 (d,J=2.1 Hz, 1H), 8.13-8.09 (m, 2H), 8.02 (br s, 1H), 7.69 (d,J=8.1 Hz, 2H), 7.58 (br s, 1H), 7.25 (bs, 2H). Step 2. 3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbothioamide

[00259] Mixture 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) were stirred at 55°C for 45 min. The mixture was treated with 1 M HCl (~10 mL) and toluene (20 mL). The mixture was thoroughly stirred and heated to 95°C for 2 h 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 (~3 g), and concentrated to dryness.The silica gel-containing suspension was transferred to a DASi™-12 cartridge on a pre-equilibrated column with 25 g of silica gel. Chromatography eluting with a gradient of 20% to 50% ethyl acetate in heptanes afforded the title compound (36 mg, 0.095 mmol, 43.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.93 (br s, 1H), 9.73 (br s, 1H), 8.20 (d,J=2.1 Hz, 1H), 8.16-8.11 (m, 2H), 7.81 (d,J=2.1 Hz, 1H), 8.16-8.11 (m, 2H), 7.81 (d,J=8.1 Hz, 2H). Step 3. 2-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazol-5-carbaldehyde

[00260] Mixture 3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridine-2-carbothioamide (30 mg, 0.079 mmol, step 2) and 2-bromomalonaldehyde (48.0 mg, 0.318 mmol) in 2-methyltetrahydrofuran were treated with pyridine (12.86 μL, 0.159 mmol), and the mixture was heated to 70°C for 90 min. 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 (MgSO4), filtered, concentrated, redissolved in CH2Cl2 / ethyl acetate, treated with silica gel (~1.5 g), and concentrated to dryness.The silica gel-containing suspension was loaded onto a DASi™-12 cartridge, pre-equilibrated on a 12 g silica gel column. Elution with a gradient of 15% to 50% ethyl acetate in heptanes afforded the title compound (7 mg, 0.016 mmol, 20.51% yield). MS (ESI+) m / z 462 (M+CH3OH+H). + ; MS (ESI-)mass / charge428 [MH] - ; 1H NMR (400 MHz, CDCl3) δ ppm 10.07 (s, 1H), 8.44 (s, 1H), 8.40 (d,J=1.9 Hz, 1H), 8.06-8.01 (m, 2H), 7.62 (d,J=1.9 Hz, 1H), 7.37 (d,J=8.1 Hz, 2H).Step 4. (2-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazol-5-yl)methanol

[00261] Solution 2-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3-thiazol-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 min, treated with 1 M 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 (~1.5 g), and concentrated to dryness. The silica gel-containing suspension was loaded onto a DASi™-12 cartridge, on a pre-equilibrated column with 4 g of silica gel.Chromatography using a gradient elution of 50% to 100% ethyl acetate in heptanes afforded the title compound (3 mg, 6.95 μmol, 42.7% yield). MS (ESI-)m / z 430 [MH]. - ; 1H NMR (400 MHz, CDCl3) δ ppm 8.38 (d, J=1.7 Hz, 1H), 8.04-8.00 (m, 2H), 7.77 (s, 1H), 7.54 (d, J=1.7 Hz, 1H), 8.04-8.00 (m, 2H), 7.77 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 6.43 (s, 2H), 4.93 (d, J=5.9 Hz, 2H), 1.90 (d, J=5.9 Hz, 1H).Example 62-(1,3,4-Oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00262] A solution of iodobenzene (696 mg, 2.162 mmol), (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (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 min. LC / MS analysis showed primarily 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 was removed in vacuo.The crude material was stirred in 20 mL of ethyl acetate and filtered to give the title compound (177 mg, 0.458 mmol, 63.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.44 (s, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.21-8.12 (m, 2H), 7.93 (d, J=2.1 Hz, 1H), 7.67 (dd, J=9.0, 1.2 Hz, 2H), 7.30 (s, 2H); MS (ESI+)m / z387 (M+H +).Example 7(5-{3-Amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol Step 1. 3-Amino-5-((4-(trifluoromethyl)phenyl)thio)picolinic acid

[00263] A solution of 3-amino-5-bromopicolinic acid (15.00 g, 69.1 mmol) in N,N-dimethylformamide (150 mL) and 4-(trifluoromethyl)benzenethiol (11.37 mL, 83 mmol) was bubbled with N2 for 20 min. N-Ethyl-N-isopropylpropan-2-amine (24.14 mL, 138 mmol) was added to the reaction mixture. The reaction mixture was heated to 100°C under N2 for 4 h. The reaction mixture was slowly poured into a mixture of 150 mL of water and 20 mL of 1 M aqueous HCl solution, which was cooled to 0°C. The resulting solid was washed in the flask containing the reaction mixture with water (100 mL) and petroleum ether (30 mL x 3) and then 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) +.Step 2. 3-Amino-5-((4-(trifluoromethyl)phenyl)sulfonyl)picolinic acid

[00264] 3-Amino-5-((4-(trifluoromethyl)phenyl)thio)picolinic acid (2.000 g, 6.36 mmol) was dissolved in trifluoroacetic acid (TFA, 15 mL), and the resulting mixture was cooled to 0°C in an ice bath. Then, H2O2 (2.60 mL, 25.5 mmol, 30% in water) was added at 0°C, and the mixture was stirred at 0°C for 1 h. The mixture was allowed to warm to 20°C and stirred for 2 h. The slurry was diluted with a mixture of 1% acetic acid in water. A suspension was obtained, and the mixture was subsequently filtered. The collected solid was washed with 1% acetic acid / water and then with dichloromethane / methanol (10 / 1, 20 mL). The solid was dried under reduced pressure to give the title compound (1.96 g, 5.66 mmol, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 2.0 Hz, 1H), 7.12 (brs, 2H); MS (ESI+) m / z 347 (M+H) + .Step 3. 3-Amino-N'-(2-hydroxyacetyl)-5-((4-(trifluoromethyl)phenyl)sulfonyl)picolinohydrazide

[00265] 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 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.491 g, 13.00 mmol) was added in one portion. The mixture was stirred at 45°C for 2 h. 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) +.Step 4. 3-Amino-5-((4-(trifluoromethyl)phenyl)sulfonyl)-N'-(2-((triisopropylsilyl)oxy)acetyl)picolinohydrazide

[00266] 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 trifluoromethyl triisopropylsilanesulfonate (5.03 mL, 18.64 mmol) was added. The reaction mixture was stirred at 20 °C for 3 h. Water (100 mL) was added. The solid was filtered, washed with water (50 mL x 2), washed with ethyl acetate (2 x 15 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) +.Step 5. 5-((4-(Trifluoromethyl)phenyl)sulfonyl)-2-(5-(((triisopropylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-amine

[00267] To a 250 mL three-necked round-bottom flask equipped with a stir bar was charged 3-amino-5-((4-(trifluoromethyl)phenyl)sulfonyl)-N'-(2-((triisopropylsilyl)oxy)acetyl)picolinohydrazide (3.50 g, 6.09 mmol) and placed under N2. N,N-Dimethylpyridin-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, resulting in a slurry. The reaction mixture was heated to 50°C. Ethyl-N-isopropylpropan-2-amine (3.72 mL, 21.32 mmol) was slowly added via syringe (the internal temperature was increased to 50°C during the addition), resulting in a homogeneous reaction mixture. The reaction mixture was stirred at 50°C for 1 h. 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 give the title compound (3.2 g, 5.12 mmol, 84% yield). MS (ESI+) m / z 557.2 (M+H). +.Step 6. (5-{3-Amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[00268] A solution of 5-((4-(trifluoromethyl)phenyl)sulfonyl)-2-(5-(((triisopropylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-amine (5.80 g, 10.42 mmol) in acetonitrile (50 mL) was stirred at room temperature for 5 min. Tetra-N-butylammonium fluoride (1.0 M TBAF, 10.94 mL, 10.94 mmol) in tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was concentrated to approximately 10 mL. Water (30 mL) was added. The solid was filtered and washed with water (2 x 30 mL) and methanol (15 mL x 3). The solid was dried under vacuum to give the title compound (3.57 g, 8.92 mmol, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 1.8 Hz, 1H), 7.30 (s, 2H), 6.04 (s, 1H), 4.76 (d, J = 6.3 Hz, 2H); MS (ESI+) m / z 401.0 (M+H) +.Example 85-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazole-2-carboxamideStep 1. 2-(2-(3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinoyl)hydrazinyl)-2-oxoacetamide

[00269] A 20 mL vial was charged with 3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinic acid (0.5 g, 1.380 mmol, Step 2, Example 1), 2-hydrazinyl-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 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.397 g, 2.070 mmol) was added in one portion and the mixture was heated at 45°C for 1 h. Water (8 mL) was added. The mixture was stirred for 30 min at room temperature and filtered to give the title compound (0.431 g, 0.963 mmol, 69.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 10.46 (s, 1H), 8.23 ​​(d, J=2.0 Hz, 1H), 8.18-8.13 (m, 3H), 7.87 (s, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.21 (s, 2H); MS (APCI+)m / z 448 (M+H) +.Step 2. 5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazole-2-carboxamide

[00270] A 20 mL vial was charged with 2-(2-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinoyl)hydrazinyl)-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 slowly added dropwise, and heating was continued at 45°C for two hours. Water (8 mL) was added, and the slurry was stirred for 30 minutes at room temperature. The solid was filtered through 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 hours to afford the pure title compound (180 mg, 0.420 mmol, 48.1% yield).1 H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.29 (s, 1H), 8.22-8.13 (m, 2H), 7.95 (d, J=2.1 Hz, 1H), 7.67 (dt, J=7.9, 1.1 Hz, 2H), 7.32 (s, 2H); MS (APCI+)m / z 430 (M+H) +.Example 9 {5-[3-Amino-5-(4-fluorobenzene-1-sulfonyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methanol Step 1 3-Amino-5-((4-fluorophenyl)thio)picolinic acid

[00271] 3-Amino-5-bromopicolinic acid (5 g, 23.04 mmol) was stirred in N,N-dimethylformamide (50 mL). 4-Fluorobenzenethiol (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 h. The mixture was cooled to room temperature. The reaction mixture was slowly poured into ice water and the pH was adjusted to 5 with 1 N aqueous HCl. 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) +.Step 2. 3-Amino-5-((4-fluorophenyl)sulfonyl)picolinic acid

[00272] 3-Amino-5-((4-fluorophenyl)thio)picolinic acid (3 g, 11.35 mmol) was dissolved in trifluoroacetic acid (21 mL), and the resulting mixture was cooled to 0°C in an ice bath. Hydrogen peroxide (4.64 mL, 45.4 mmol, 30% in water) was added at 0°C, and the mixture was stirred at 0°C for 1 h. The mixture was allowed to warm to 20°C and stirred for 1 h. The reaction mixture was diluted with 1% acetic acid in water (150 mL). A suspension was obtained, which was then filtered. The collected solid was washed with ice water (200 mL) and dried under reduced pressure to give the title compound (3.0 g, 10.02 mmol, yield 88%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (s, 1H), 8.11-8.07 (m, 2H), 8.06 (d, J=8.4 Hz, 2H), 7.78 (s, 1H), 7.53 (t, J=8.8 Hz, 2H), 7.12 (brs, 2H); MS (ESI+)m / z 297.7 (M+H) +.Step 3. 3-Amino-5-((4-fluorophenyl)sulfonyl)-N'-(2-hydroxyacetyl)picolinohydrazide

[00273] 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 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.85 g, 25.3 mmol) was added in one portion at an internal temperature of 25 °C. The solution was stirred at 25°C for 10 min and heated to 45°C for 1 h. The reaction mixture was added to ice water and stirred for 3 h. The solid was collected by filtration and washed with ice water to give the title compound (5.7 g, 14.70 mmol, 87% yield). MS (ESI+) m / z 369.7 (M+H) +.Step 4. 3-Amino-5-((4-fluorophenyl)sulfonyl)-N'-(2((triisopropylsilyl)oxy)acetyl)picolinohydrazide

[00274] 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 o C. Triethylamine (7.04 mL, 50.5 mmol) was added, and triisopropylsilyl trifluoromethanesulfonate (8.77 g, 28.6 mmol) was slowly added. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was added to ice water and stirred for 2 h. The solid was collected by filtration and washed with ice water to give the title compound (8.5 g, 15.39 mmol, 91% yield). MS (ESI+) m / z 525.7 (M+H) +.Step 5. 5-((4-Fluorophenyl)sulfonyl)-2-(5-(((triisopropylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-amine

[00275] 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 in acetonitrile (40 mL). The reaction mixture was heated to 45°C. N-ethyl-N-isopropylpropan-2-amine (0.985 g, 7.62 mmol) was added slowly. The reaction mixture was heated at 45°C for 2 h and then cooled to room temperature. Water was added, and the mixture was stirred for 1 h. The mixture was filtered, and the solid was washed with water to give the title compound (3.8 g, 7.13 mmol, 93% yield). MS (ESI+) m / z 507.7 (M+H) +.Step 6. (5-(3-Amino-5-((4-fluorophenyl)sulfonyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methanol

[00276] A mixture of 5-((4-fluorophenyl)sulfonyl)-2-(5-(((triisopropylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-amine (8 g, 15.79 mmol) was stirred for 5 min in acetonitrile (120 mL). Tetra-N-butylammonium fluoride (18.95 mL, 18.95 mmol) was added. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was cooled to room temperature. A solution of 0.53 mL of 85% H3PO4 in 75 mL of water was slowly added to the reaction mixture. The resulting slurry was stirred at 20°C for 3 h. The solid was filtered and washed with 35 mL of a 1:5 (v / v) solution of CH3CN / water, washed with 15 mL of water, and dried under vacuum to afford the title compound (5.06 g, 14.15 mmol, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (d, J = 2.0 Hz, 1H), 8.13-8.08 (m, 2H), 7.90 (d, J = 2.0 Hz, 1H), 7.53 (t, J = 10.4 Hz, 2H), 7.27 (s, 2H), 6, (t, J = 6.2 Hz, 1H), 4.75 (d, J = 6.4 Hz, 2H); MS (ESI+) m / z 351.7 (M+H) +.Example 102-(5-Cyclohexyl-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine Tert-butyl 2-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinoyl)hydrazinecarboxylate Tert-butyl 2-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinoyl)hydrazinecarboxylate

[00277] To a 20 mL vial was added 3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinic acid (100 mg, 0.276 mmol) in N,N-dimethylacetamide (4 mL). 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 hydrazinecarboxylate (43.8 mg, 0.331 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under a stream of nitrogen. The residue was diluted with 4 mL of ethyl acetate and washed with water (1×5 mL).The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate in heptanes as a gradient, 5-100%, 4 g column) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (s, 1H), 8.82 (s, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.17-8.04 (m, 2H), 7.74 (d, J=2.1 Hz, 1H), 8.17-8.04 (m, 2H), 7.74 (d, Step 2. 3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide

[00278] Trifluoroacetic acid (1 mL, 12.98 mmol) was added to tert-butyl 2-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinoyl)hydrazinecarboxylate and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under a stream of nitrogen. The crude material was suspended in 1 mL of heptanes and stirred overnight. The resulting solid was collected by filtration to afford the title compound. 1H NMR (501 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.25 (d,J=2.1 Hz, 1H), 8.17-8.10 (m, 2H), 7.82 (d,J=2.0 Hz, 1H), 7.65 (dq,J=7.9, 1.1 Hz, 2H). Step 3. 3-Amino-N'-(cyclohexanecarbonyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide

[00279] Cyclohexanecarboxylic acid (25.7 mg, 0.201 mmol), hexafluorophosphate(V) 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium (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). 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 h. The reaction mixture was purified using the reverse-phase TFA6 procedure to give the title compound (20 mg, 24.6% yield). 1H NMR (501 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.24 (d,J=2.0 Hz, 1H), 8.20-8.12 (m, 2H), 7.76 (d,J=2.0 Hz, 1H), 8.20-8.12 (m, 2H), 7.76 (d,J=12.6 Hz, 1H), 1.43-1.12 (m, 6H). Step 4. 2-(5-Cyclohexyl-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00280] In a 4 mL vial, 3-amino-N'-(cyclohexanecarbonyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide (20 mg, 0.041 mmol) was added to acetonitrile (1 mL). N-toluenesulfonyl chloride (15.68 mg, 0.082 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.022 mL, 0.123 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was only 50% reacted, as determined by HPLC, so the reaction mixture was heated to 65°C over the weekend. The mixture was directly purified using the TFA6 preparative HPLC / MS method to give the title compound (5.2 mg, 27% yield). 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.43 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.9 Hz, 2H), 7.89 (d, J=2.1 Hz, 1H), 7.66 (dd, J=8.8, 1.2 Hz, 2H), 3.17-2.99 (m, 1H), 2.05 (d, J=12.0 Hz, 2H), 1.83-1.20 (m, 8H); MS (APCI+)m / z 469.0 (M+H) + .Example 112-{5-[(S)-Methoxy(phenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00281] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for (S)-2-methoxy-2-phenylacetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.42 (d,J=2.0 Hz, 1H), 8.16 (d,J=8.9 Hz, 2H), 7.90 (d,J=2.1 Hz, 1H), 7.70-7.61 (m, 2H), 7.52-7.36 (m, 5H), 5.89 (s, 1H), 3.41 (s, 3H); MS (APCI+) mass / charge506.9 (M+H) +.Example 122-{5-[(Cyclopropylmethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00282] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-(cyclopropylmethoxy)acetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.45 (d,J=2.1 Hz, 1H), 8.19 (d,J=8.9 Hz, 2H), 7.92 (d,J=2.0 Hz, 1H), 7.70-7.64 (m, 2H), 4.82 (s, 2H), 3.39 (d,J=7.0 Hz, 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) + .Example 132-[5-(Phenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00283] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-phenoxyacetic acid. 1H NMR (500 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.44 (d,J=2.0 Hz, 1H), 8.18 (d,J=9.0 Hz, 2H), 7.92 (d,J=2.0 Hz, 1H), 7.66 (d,J=8.4 Hz, 2H), 7.34 (dd,J=8.8, 7.3 Hz, 2H), 7.09 (d,J=1.1 Hz, 2H), 7.03 (t,J=7.4 Hz, 1H), 5.51 (s, 2H); MS (APCI+)m / z 492.9 (M+H) + .Example 142-{5-[(Cyclopentyloxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00284] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-(cyclopentyloxy)acetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.45 (d,J=2.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.92 (d,J=2.0 Hz, 1H), 8.18 (d, MS (APCI+)m / z 485.0 (M+H) +.Example 155-[4-(Trifluoromethoxy)benzene-1-sulfonyl]-2-{5-[(trifluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}pyridin-3-amine

[00285] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-(trifluoromethoxy)acetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.46 (d, J=2.0 Hz, 1H), 8.19 (d, J=8.9 Hz, 2H), 7.94 (d, J=2.0 Hz, 1H), 7.77-7.62 (m, 2H), 5.62 (s, 2H); MS (APCI+)m / z 484.9 (M+H) + .Example 162-(5-{[(Oxolan-3-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00286] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-((tetrahydrofuran-3-yl)oxy)acetic acid. 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (vol / v)) δ ppm 8.45 (d,J=2.1 Hz, 1H), 8.19 (d,J=9.0 Hz, 2H), 7.92 (d,J=72m (7,7,2,5), Hz 4.83 (s, 2H), 4.39–4.30 (m, 1H), 3.79–3.59 (m, 4H), 2.14–1.76 (m, 2H); MS (APCI+)mass / charge486.9 (M+H) +.Example 17 2-{5-[(2-Methoxyethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine Step 1. 3-Amino-N'-(2-(2-methoxyethoxy)acetyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide

[00287] To a 4 mL vial were added 2-(2-methoxyethoxy)acetic acid (0.4 M in N,N-dimethylacetamide, 199 μL, 0.08 mmol, 1.5 eq.) and hexafluorophosphate(V) 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium (0.12 M in N,N-dimethylacetamide, 500 µL, 0.063 mmol, 1.2 eq). 3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide from step 2 in Example 10 (0.10 M in N,N-dimethylacetamide, 500 µL, 0.053 mmol, 1.0 eq) was added followed by N-ethyl-N-isopropylpropan-2-amine (27 µL, 0.16 mmol, 3.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified using the reverse-phase TFA6 procedure to give the title compound.Step 2.2-{5-[(2-Methoxyethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00288] The compound from step 1 was transferred to a 4 mL vial and toluene (500 μL) was added. Neat Lawesson's reagent (32 mg, 0.08 mmol, 1.5 eq) was added to the vial and the reaction mixture was heated to 110 °C for 1 h. 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 crude material was purified using reverse-phase HPLC / MS method AA7 to give the title compound (6.4 mg, 25% yield). 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d, J=2.0 Hz, 1H), 8.19 (d, J=8.9 Hz, 2H), 7.91 (d, J=2.0 Hz, 1H), 8.19 (d, MS (APCI+)m / z 490.9 (M+H) +.Example 18N-[(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)methyl]cyclopropanecarbothioamide

[00289] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for 2-(cyclopropanecarboxamido)acetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.38 (d,J=2.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.89 (d,J=2.0 Hz, 1H), 8.18 (d, MS (APCI+) mass / charge515.8 (M+H) + .Example 192-{5-[(S)-Methoxy(phenyl)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00290] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for (S)-methoxyphenylacetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.38 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.9 Hz, 2H), 7.88 (d, J=2.0 Hz, 1H), 8.17 (d, MS (APCI+)m / z 522.8 (M+H) +.Example 20(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

[00291] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d,J=2.0 Hz, 1H), 8.19 (d,J=8.9 Hz, 2H), 7.92 (d,J=2.0 Hz, 1H), 7.70-7.64 (m, 3H), 1.86 (s, 3H); MS (APCI+)m / z 514.7 (M+H) + .Example 212-{5-[(1R)-1-Methoxyethyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00292] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for (R)-2-methoxypropanoic acid. 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d, J=2.0 Hz, 1H), 8.26-8.14 (m, 2H), 7.90 (d, J=2.0 Hz, 1H), 8.26-8.14 (m, 2H), 7.90 (d, J=6.5 Hz, 1H), 3.35 (s, 3H), 1.55 (d, J=6.5 Hz, 3H); MS (APCI+)m / z 460.9 (M+H) + .Example 222-[5-(1-Methoxyethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00293] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for 2-methoxypropanoic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d,J=2.0 Hz, 1H), 8.19 (d,J=8.9 Hz, 2H), 7.90 (d,J=2.0 Hz, 1H), 7.75-7.62 (m, 2H), 4.88 (q,J=6.5 Hz, 1H), 3.35 (s, 3H), 1.56 (d,J=6.5 Hz, 3H); MS (APCI+)m / z 460.9 (M+H) +.Example 232-{5-[(1S)-1-Methoxyethyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00294] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for (S)-2-methoxypropanoic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d,J=2.0 Hz, 1H), 8.19 (d,J=8.9 Hz, 2H), 7.90 (d,J=2.0 Hz, 1H), 7.75-7.62 (m, 2H), 4.88 (q,J=6.5 Hz, 1H), 3.35 (s, 3H), 1.56 (d,J=6.5 Hz, 3H); MS (APCI+)m / z 460.9 (M+H) + .Example 242-{5-[(Cyclopropylmethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00295] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for 2-(cyclopropylmethoxy)acetic acid. 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d,J=2.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.90 (d,J=2.0 Hz, 18H), 18.9 Hz (d,J=2.0 Hz, 16H), 2H), 1.13–0.86 (m, 1H), 0.58–0.43 (m, 2H), 0.29–0.11 (m, 2H); MS (APCI+)mass / charge486.9 (M+H) + .Example 252-[5-(Ethoxymethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00296] The compound indicated in the heading was obtained in accordance with the procedure described in Example 17, by replacing 2-ethoxyacetic acid with 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d,J=2.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.90 (d,J=2.0 Hz, 1H), 7.6 Hz, 7.6 Hz, 4.92 (s, 2H), 3.62 (q,J=7.0 Hz, 2H), 1.18 (t,J=7.0 Hz, 3H); MS (APCI+)mass / charge460.9 (M+H) +.Example 262-[5-(Methoxymethyl)-1,3,4-thiadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00297] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for 2-methoxyacetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d, J=2.0 Hz, 1H), 8.19 (d, J=8.9 Hz, 2H), 7.91 (d, J=2.0 Hz, 1H), 8.19 (d, MS (APCI+)m / z 446.8 (M+H) + .Example 272-(5-{[(Pyridin-3-yl)oxy]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00298] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for 2-(pyridin-3-yloxy)acetic acid hydrochloride. 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.61-8.54 (m, 1H), 8.40 (d,J=2.0 Hz, 1H), 8.37 (d,J=5.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.92 (d,J=2.0 Hz, 1H), 7.87 (dd,J=8.6, 2.9 Hz, 1H), 7.72-7.56 (m, 3H), 5.79 (s, 2H); MS (APCI+)m / z 509.8 (M+H) + .Example 285-[4-(Trifluoromethoxy)benzene-1-sulfonyl]-2-{5-[(trifluoromethoxy)methyl]-1,3,4-thiadiazol-2-yl}pyridin-3-amine

[00299] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for 2-(trifluoromethoxy)acetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.41 (d,J=2.0 Hz, 1H), 8.19 (d,J=8.9 Hz, 2H), 7.93 (d,J=2.0 Hz, 1H), 7.73-7.61 (m, 2H), 5.70 (s, 2H); MS (APCI+)m / z 500.8 (M+H) +.Example 29 2-(5-{[(Oxolan-3-yl)oxy]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00300] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for 2-((tetrahydrofuran-3-yl)oxy)acetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d,J=2.0 Hz, 1H), 8.23-8.13 (m, 2H), 7.90 (d,J=2.0 Hz, 1H), 8.23-8.13 (m, 2H), 7.90 (d, MS (APCI+) mass / charge 502.9 (M+H) + .Example 302-{5-[(Difluoromethoxy)methyl]-1,3,4-thiadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00301] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for 2-(difluoromethoxy)acetic acid. 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.41 (d,J=2.0 Hz, 1H), 8.19 (d,J=8.9 Hz, 2H), 7.92 (d,J=2.0 Hz, 6.1 Hz, 6.7 Hz), dd,J=17. Hz, 2H), 6.88 (t,J=74.2 Hz, 1H), 5.43 (s, 2H); MS (APCI+)mass / charge482.8 (M+H) + .Example 312-(5-{[(2S)-Oxolan-2-yl]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00302] Specified in the heading of the compound in accordance with the procedure received described in Example 17 by substituting (S)-2-(tetrahydrofuran-2-yl)acetic acid for 2-(2-methoxyethoxy)acetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.39 (d,J=2.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.88 (d,J=2.1 Hz, 1H), 7.6 Hz, 7.6 Hz, 4.21-4.13 (m, 1H), 3.86-3.61 (m, 2H), 3.44-3.18 (m, 2H), 2.03 (dd,J=12.7, 6.3 Hz, 1H), 1.89-1.78 (m, 2H), 1H); MS (APCI+)mass / charge486.9 (M+H) +.Example 322-(5-{[(2R)-Oxolan-2-yl]methyl}-1,3,4-thiadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00303] The title compound was prepared according to the procedure described in Example 17, substituting 2-(2-methoxyethoxy)acetic acid for (R)-2-(tetrahydrofuran-2-yl)acetic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.39 (d,J=2.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.88 (d,J=2.0 Hz, 1H), 8.18 (d,J=13.1, 6.8 Hz, 1H), 1.90-1.75 (m, 2H), 1.62-1.45 (m, 1H); MS (APCI+) mass / charge486.9 (M+H) + .Example 332-{5-[(2-Methoxyethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00304] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-(2-methoxyethoxy)acetic acid. 1H NMR (500 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.44 (d,J=2.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.92 (d,J=2.1 Hz, 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) + .Example 342-{5-[(1R)-1-Methoxyethyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00305] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for (R)-2-methoxypropanoic acid. 1 H NMR (500 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.45 (d,J=2.0 Hz, 1H), 8.18 (d,J=9.0 Hz, 2H), 7.91 (d,J=2.0 Hz, 1H), 7.72-7.60 (m, 2H), 4.82 (q,J=6.6 Hz, 1H), 3.31 (s, 3H), 1.55 (d,J=6.6 Hz, 3H); MS (APCI+)m / z 444.8 (M+H) +.Example 352-{5-[(1S)-1-Methoxyethyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00306] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for (S)-2-methoxypropanoic acid. 1 H NMR (500 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.45 (d,J=2.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.91 (d,J=2.1 Hz, 1H), 7.67 (d,J=8.4 Hz, 3H), 4.81 (q,J=6.7 Hz, 1H), 3.31 (s, 3H), 1.55 (d,J=6.6 Hz, 3H); MS (APCI+)m / z 444.8 (M+H) + .Example 362-[5-(Ethoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00307] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-ethoxyacetic acid. 1H NMR (500 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.44 (d,J=2.0 Hz, 1H), 8.18 (d,J=8.9 Hz, 2H), 7.92 (d,J=2.1 Hz, 1H), 7.75-7.62 (m, 2H), 4.79 (s, 2H), 3.59 (q,J=7.0 Hz, 2H), 1.15 (t,J=7.0 Hz, 3H); MS (APCI+)m / z 444.9 (M+H) + .Example 372-[5-(Methoxymethyl)-1,3,4-oxadiazol-2-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00308] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-methoxyacetic acid. 1 H NMR (500 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.44 (d, J=2.1 Hz, 1H), 8.18 (d, J=8.9 Hz, 2H), 7.92 (d, J=2.1 Hz, 1H), 8.18 (d, MS (APCI+)m / z 430.9 (M+H) +.Example 382-(5-{[(Pyridin-3-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00309] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-(pyridin-3-yloxy)acetic acid hydrochloride. 1 H NMR (500 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.52-8.38 (m, 3H), 8.31-8.24 (m, 1H), 8.18 (d, J=8.9 Hz, 2H), 7.92 (d, J=2.0 Hz, 1H), 7.72-7.57 (m, 3H), 7.46 (dd, J=8.5, 4.7 Hz, 2H), 5.64 (s, 2H); MS (APCI+)m / z 493.8 (M+H) + .Example 392-{5-[(Difluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00310] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for 2-(difluoromethoxy)acetic acid. 1H NMR (500 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.45 (d,J=2.0 Hz, 1H), 8.25-8.13 (m, 2H), 7.93 (d,J=2.0 Hz, 1H, 2H), 8-8.3, (H 7.93 (d,J=73.9 Hz, 1H), 5.31 (s, 2H); MS (APCI+)mass / charge466.9 (M+H) + .Example 402-(5-{[(2S)-Oxolan-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00311] Specified in the heading of the compound, in accordance with the compound described in Example 10 by substituting (S)-2-(tetrahydrofuran-2-yl)acetic acid for cyclohexanecarboxylic acid. 1 H NMR (500 MHz, DMSO-d6:D2O=9:1 (vol / vol)) δ ppm 8.43 (d,J=2.0 Hz, 1H), 8.25-8.11 (m, 2H), 7.90 (d,J=2.1 Hz, 1H, 70), 7.0-7,2H), 4.31-4.20 (m, 1H), 3.65-3.57 (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+)mass / charge470.9 (M+H) +.Example 412-(5-{[(2R)-Oxolan-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00312] The title compound was prepared according to the procedure described in Example 10, substituting cyclohexanecarboxylic acid for (R)-2-(tetrahydrofuran-2-yl)acetic acid. 1 H NMR (500 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.43 (d, J=2.1 Hz, 1H), 8.21-8.14 (m, 2H), 7.90 (d, J=2.1 Hz, 1H), 8.21-8.14 (m, 2H), 7.90 (d, MS (APCI+)m / z 470.9 (M+H) +.Example 421-(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)ethan-1-olStep 1. (S)-3-Amino-N'-(2-hydroxypropanoyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide

[00313] To a 4 mL vial were added (S)-2-hydroxypropanoic acid (10.8 mg, 0.12 mmol, 1.5 eq.) 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 eq) in N,N-dimethylacetamide (1.0 mL). 3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinohydrazide from Example 10, Step 2 (30.0 mg, 0.08 mmol, 1.0 eq) was added, followed by N-ethyl-N-isopropylpropan-2-amine (42 µL, 0.24 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified using reverse phase method TFA10 to give the title compound. Step 2.(S)-3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)-N'-(2-((triisopropylsilyl)oxy)propanoyl)picolinohydrazide

[00314] The purified material from step 1 was suspended in 500 μL of dichloromethane. Triethylamine (30 μL, 0.21 mmol, 2.5 eq) was added followed by TIPS triflate (triisopropylsilyl trifluoromethanesulfonate, 50 μL, 0.21 mmol, 2.5 eq). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was washed twice with water. The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated to give the title compound. Step 3. (S)-5-((4-(Trifluoromethoxy)phenyl)sulfonyl)-2-(5-(1-((triisopropylsilyl)oxy)ethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-amine

[00315] The residue from step 2 was dissolved in 500 µL of CH3CN. Stock solutions of 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) were added.) followed by the addition of diisopropylethylamine (50 µL, 0.29 mmol, 4.0 equiv). The reaction mixture was heated at 45 °C for 1 h and then directly purified by reverse-phase method TFA8. Step 4. 1-(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)ethan-1-ol

[00316] The compound from step 3 was dissolved in tetrahydrofuran (500 µL). Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 70 µL, 0.07 mmol, 1.0 equiv) was added at room temperature and the reaction mixture was stirred until complete, as determined by LC. The reaction mixture was purified using the TFA8 preparative reverse-phase HPLC / MS method. After purification, the sample still contained trace amounts of tetrabutylammonium salts and was repurified using the same method to yield the title compound. 1H NMR (501 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.44 (d, J=2.1 Hz, 1H), 8.21-8.14 (m, 2H), 7.91 (d, J=2.1 Hz, 1H), 7.70-7.64 (m, 2H), 5.05 (q, J=6.6 Hz, 1H), 1.54 (d, J=6.7 Hz, 3H); MS (APCI+)m / z 430.9 (M+H) + .Example 432-(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)propan-2-ol

[00317] The title compound was prepared according to the procedure described in Example 42, substituting (S)-2-hydroxypropanoic acid for 2-hydroxy-2-methylpropanoic acid. 1 H NMR (501 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.45 (d, J=2.0 Hz, 1H), 8.21-8.14 (m, 2H), 7.91 (d, J=2.0 Hz, 1H), 8.21-8.14 (m, 2H), 7.91 (d, MS (APCI+)m / z 44.9 (M+H) +.Example 44(1S)-1-(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-2-phenylethan-1-ol

[00318] The title compound was prepared according to the procedure described in Example 42, substituting (S)-2-hydroxy-3-phenylpropanoic acid for (S)-2-hydroxypropanoic acid. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.46 (d,J=2.0 Hz, 1H), 8.23-8.14 (m, 2H), 7.91 (d,J=2.0 Hz, 1H), 7.68 (d,J=8.4 Hz, 2H), 7.31-7.17 (m, 5H), 5.12 (t,J=7.2 Hz, 1H), 3.20 (dd,J=7.1, 4.7 Hz, 2H); MS (APCI+) mass / charge506.9 (M+H) + .Example 45(S)-(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)(phenyl)methanol

[00319] The title compound was prepared according to the procedure described in Example 42, substituting (S)-2-hydroxy-2-phenylacetic acid for (S)-2-hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.40 (d, J=2.0 Hz, 1H), 8.19-8.10 (m, 2H), 7.88 (d, J=2.0 Hz, 1H), 8.19-8.10 (m, 2H), 7.88 (d, MS (APCI+)m / z 492.9 (M+H) +.Example 462-[3-(2-Methoxypropan-2-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00320] 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 eq) and N-ethyl-N-isopropylpropan-2-amine (0.087 mL, 0.500 mmol, 3.0 eq) were added, followed by (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide (26.4 mg, 0.2 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 1 h, after which the completion of the reaction was confirmed by LC / MS. The solvent was removed under a stream of nitrogen. The residue was diluted with 2 mL of dichloromethane and washed with water (1×5 mL). The residue from the first step was diluted with 1 ml of tetrahydrofuran. Tetrabutylammonium hydroxide (40% by weight) was added.in water, 108 mg, 0.167 mmol) and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed under a stream of nitrogen. The residue was dissolved in 0.5 mL of CH3CN and added to 4 mL of stirred water over 30 min. Water was removed with a pipette and the solid was dissolved in DMSO and purified by reversed-phase HPLC / MS using the TFA8 method. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.47 (d, J=2.1 Hz, 1H), 8.26-8.15 (m, 2H), 7.99 (d, J=2.1 Hz, 1H), 8.26-8.15 (m, 2H), 7.99 (d, MS (APCI+)m / z 458.8 (M+H) + .Example 472-[3-(1-Methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00321] The title compound was prepared according to the procedure described in Example 46 substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for N'-hydroxy-2-methoxypropanamidine and purifying the sample after both the first and second steps. 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.44 (d,J=2.0 Hz, 1H), 8.23-8.14 (m, 2H), 7.96 (d,J=2.1 Hz, 1H, 7.7), 7.2-2H), 4.69 (q,J=6.6 Hz, 1H), 3.28 (s, 3H), 1.53 (d,J=6.6 Hz, 3H); MS (APCI+)mass / charge444.9 (M+H) + .Example 482-[3-(Oxan-4-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00322] The heading compound was obtained in accordance with the procedure described in Example 46 by replacingN'-hydroxytetrahydropyran-4-carboxamidine with (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide and by means of sample purification after both, first and second, steps. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (vol / vol)) δ ppm 8.43 (d,J=2.0 Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d,J=2.1 Hz, 1H, 7.7), 7.6-m, (2H), 3.96-3.88 (m, 2H), 3.50 (td,J=11.5, 2.3 Hz, 2H), 3.27-3.14 (m, 1H), 2.01-1.93 (m, 2H), 1.87-1.72 (m, 2H); MS (APCI+)mass / charge470.8 (M+H) +.Example 492-{3-[(4-Fluorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00323] The title compound was prepared according to the procedure described in Example 46, substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for 2-(4-fluorophenoxy)-N'-hydroxyacetamidine and purifying the sample after both the first and second steps. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.44 (d,J=2.0 Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d,J=2.0 Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d, MS (APCI+) mass / charge 510.8 (M+H) + .Example 50 2-[3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00324] The title compound was prepared according to the procedure described in Example 46, substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for 2-cyclopropyl-N'-hydroxyacetamidine and purifying the sample after both the first and second steps. 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.43 (d, J=2.0 Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d, J=2.0 Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d, J=7.0 Hz, 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) + .Example 512-{3-[(Oxolan-2-yl)methyl]-1,2,4-oxadiazol-5-yl}-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00325] The title compound was prepared according to the procedure described in Example 46 substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for N'-hydroxy-2-tetrahydrofuran-2-ylacetamidine and purifying the sample after both the first and second steps. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.43 (d,J=2.0 Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d,J=2.0 Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d,J=6.6 Hz, 1H), 3.80-3.74 (m, 1H), 3.65-3.56 (m, 1H), 3.00 (d,J=6.5 Hz, 2H), 2.11-1.98 (m, 1H), 1.94-1.77 (m, 2H), 1.71-1.57 (m, 1H); MS (APCI+) mass / charge 470.8 (M+H) +.Example 522-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00326] The title compound was prepared according to the procedure described in Example 46 substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for N'-hydroxycyclopropanecarboxamidine and purifying the sample after both the first and second steps. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.41 (d, J=2.1 Hz, 1H), 8.22-8.13 (m, 2H), 7.93 (d, J=2.0 Hz, 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) + .Example 532-[3-(Oxolan-3-yl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00327] The title compound was prepared according to the procedure described in Example 46 substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for N'-hydroxytetrahydrofuran-3-carboxamidine and purifying the sample after both the first and second steps.1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.43 (d,J=2.1 Hz, 1H), 8.23-8.14 (m, 2H), 7.94 (d,J=2.1 Hz, 1H), 7.71-7.63 (m, 2H), 4.07 (dd,J=8.5, 7.6 Hz, 1H), 3.94-3.81 (m, 4H), 2.42-2.15 (m, 2H); MS (APCI+) mass / charge456.9 (M+H) + .Example 54 2-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00328] The title compound was prepared according to the procedure described in Example 46 substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for N'-hydroxy-2,2-dimethylpropanamidine and purifying the sample after both the first and second steps. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.42 (d, J=2.1 Hz, 1H), 8.22-8.14 (m, 2H), 7.95 (d, J=2.0 Hz, 1H), 7.71-7.63 (m, 2H), 1.39 (s, 9H); MS (APCI+)m / z 442.9 (M+H) +.Example 55 2-[3-(2-Methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00329] The title compound was prepared according to the procedure described in Example 46 substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for N'-hydroxy-3-methoxypropanamidine and purifying the sample after both the first and second steps. 1 H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.43 (d, J=2.1 Hz, 1H), 8.22-8.14 (m, 2H), 7.94 (d, J=2.0 Hz, 1H), 7.71-7.63 (m, 2H), 3.78 (t, J=6.2 Hz, 2H), 3.25 (s, 3H), 3.06 (t, J=6.3 Hz, 2H); MS (APCI+)m / z 444.9 (M+H) + .Example 56 2-[3-(Methoxymethyl)-1,2,4-oxadiazol-5-yl]-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-3-amine

[00330] The title compound was prepared according to the procedure described in Example 46 substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for N'-hydroxy-3-methoxyacetamidine and purifying the sample after both the first and second steps. 1H NMR (400 MHz, DMSO-d6:D2O=9:1 (v / v)) δ ppm 8.47 (d, J=2.0 Hz, 1H), 8.27-8.18 (m, 2H), 7.98 (d, J=2.1 Hz, 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) + .Example 57(5-{3-Amino-4-chloro-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[00331] {5-[3-Amino-5-(4-trifluoromethoxybenzenesulfonyl)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 obtain 250 mg of crude material. The crude material was purified by reverse phase preparative HPLC (97% 10 mM NH4HCO3 / pH 10, 3% CH3CN) to give two regioisomers, Example 57 and Example 64. Example 57: 1H NMR (600 MHz, DMSO-d6) δ ppm 8.34 (s, 1H), 8.09-8.14 (m, 2H), 7.64-7.68 (m, 2H), 7.45 (br. s., 2H), 6.01.4 (t, J J=6.4 Hz, 2H), MS (ESI+)mass / charge451 [M+H] + . Example 64: 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 8.16-8.20 (m, 2H), 7.65 (m, 2H), 7.40 (s, 2H), 6.07 (t, J=6.2 (7.3 Hz), J=78, 1H 2H), MS (ESI+)mass / charge451 [M+H] +.Example 58(5-{3-Amino-5-[3-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanolStep 1: Methyl 2-triisopropylsilyloxyacetate

[00332] Triisopropyl 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 dry N,N-dimethylformamide (1 L) under N2. 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 aqueous NaHCO3. The resulting mixture was extracted with diethyl ether. The organic layer was washed successively with 1.4 L of 2 N aqueous HCl (2.8 mol), 0.5 L of H2O, and 1 L of brine.The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to give the crude title compound, which was used without purification in the next step. Step 2. 2-Triisopropylsilyloxyacetohydrazide

[00333] Methyl 2-triisopropylsilyloxyacetate (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 heated under reflux. After stirring overnight under 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 aqueous NaHCO3 (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 yield 191 g of crude material as a waxy solid.Precipitation from ethyl acetate / heptane (5%, 500 mL) afforded 122 g of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.76 (s, 1H), 7.26 (s, 1H), 4.28 (s, 2H), 3.87 (d, J=4.3 Hz, 2H), 1.19-1.05 (m, 21H). Step 3. 3-Amino-5-(3-trifluoromethoxyphenylsulfanyl)pyridine-2-carboxylic acid

[00334] A solution of 3-amino-5-bromopyridine-2-carboxylic acid (CAS: 870997-85-6, 500 mg, 2.3 mmol), 3-(trifluoromethoxy)benzenethiol (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 min 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 aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated to give 783 mg of the title compound. Step 4.3-Amino-5-(3-trifluoromethoxybenzenesulfonyl)pyridine-2-carboxylic acid

[00335] 3-Amino-5-(3-trifluoromethoxyphenylsulfanyl)pyridine-2-carboxylic acid (783 mg, 2.37 mmol) was dissolved in trifluoroacetic acid (5 mL), and the resulting mixture was cooled to 0°C in an ice bath. Then, H2O2 (30% in water, 0.968 mL, 9.48 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with 1% acetic acid in water (10 mL). A suspension was obtained, which was then filtered. The collected solid was washed with 1% acetic acid, followed by petroleum ether to give 652 mg of the title compound. Step 5.3-Amino-5-(3-trifluoromethoxybenzenesulfonyl)pyridine-2-carboxylic acid N'-(2-triisopropylsilanyloxyacetyl)hydrazide

[00336] To a solution of dichloromethane (10 ml) containing 3-amino-5-(3-trifluoromethoxybenzenesulfonyl)pyridine-2-carboxylic acid (336 mg, 0.93 mmol) were added diisopropylethylamine (0.323 ml, 1.86 mmol), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium N-oxide hexafluorophosphate (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 NaHCO3, dried (Na2SO4), filtered, and concentrated to yield 540 mg of the title compound. Step 6.5-(3-Trifluoromethoxybenzenesulfonyl)-2-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-2-yl)pyridin-3-ylamine

[00337] 3-Amino-5-(3-trifluoromethoxybenzenesulfonyl)pyridine-2-carboxylic acid N'-(2-triisopropylsilanyloxyacetyl)hydrazide (540 mg, 0.91 mmol) was mixed with tosyl chloride (522 mg, 2.74 mmol) and triethylamine (381 μL, 2.74 mmol) in dichloromethane under argon. The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 1 N aqueous NaOH and successively extracted with dichloromethane. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated to dryness to yield 670 mg of crude material. The crude material was purified by column chromatography (using dichloromethane as eluent) to yield 68 mg of the title compound. Step 7.{5-[3-Amino-5-(3-trifluoromethoxybenzenesulfonyl)pyridin-2-yl]-[1,3,4]oxadiazol-2-yl}methanol

[00338] 5-(3-Trifluoromethoxybenzenesulfonyl)-2-(5-triisopropylsilaneoxymethyl[1,3,4]oxadiazol-2-yl)pyridin-3-ylamine (68 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL). Tetrabutylammonium fluoride solution (CAS: 429-41-4, 1 M in tetrahydrofuran, 0.12 mL, 0.12 mmol) was added, and the resulting mixture was stirred at room temperature for 10 min. The mixture was concentrated. The crude material was quenched with H2O, extracted with ethyl acetate, dried (Na2SO4), filtered, and concentrated to yield 56 mg of crude material. Trituration with dichloromethane yielded 14 mg of the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.47 (d, J = 2.1 Hz, 1H), 8.06 (m, 1H), 8.00 (s, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.82-7.87 (m, 1H), 7.78-7.82 (m, 1H), 7.27 (s, 2H), 6.02 (t, J=6.4 Hz, 1H), 4.75 (d, J=6.4 Hz, 2H), MS (ESI+) mass / charge417 [M+H] +.Example 59(5-{3-Amino-5-[2-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[00339] The heading compound was obtained as described by substituting Example 58 2-(trifluoromethoxy)benzene thiol (CAS: 175278-01-0) on 3-(trifluoromethoxy)benzene thiol). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.31 (d, J=2.1 Hz, 1H), 8.27 (m, 1H), 7.90-7.95 (m, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.73 (d, 7.61 Hz). J=8.2 Hz, 1H), 7.32 (s, 2H), 6.02 (t, J=6.4 Hz, 1 H), 4.75 (d, J=6.4 Hz, 2H), MS (ESI+)mass / charge417 [M+H] +.Example 60 5-Amino-N-benzyl-6-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-N-methylpyridine-3-sulfonamide Step 1. 3-Amino-5-bromopyridine-2-carboxylic acid N'-(2-triisopropylsilanyloxyacetyl)hydrazide

[00340] To a solution of dichloromethane (200 mL) containing 3-amino-5-bromopyridine-2-carboxylic acid (CAS: 870997-85-6, 10 g, 46 mmol) was added diisopropylethylamine (16 mL, 92 mmol), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (17.49 g, 46 mmol) and 2-triisopropylsilyloxyacetohydrazide (11.35 g, 46 mmol) were added. The resulting solution was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated aqueous NaHCO3, dried with Na2SO4, filtered, and concentrated to give 25.37 g of the title compound. Step 2.3-Amino-5-(4-methoxybenzylsulfanyl)pyridine-2-carboxylic acid N'-(2-triisopropylsilanyloxyacetyl)hydrazide

[00341] A vessel filled with a mixture of 3-amino-5-bromopyridine-2-carboxylic acid N'-(2-triisopropylsilanyloxyacetyl)hydrazide (1 g, 2.2 mmol), diisopropylethylamine (0.768 ml, 4.4 mmol) and toluene (10 ml) was evacuated and the reaction vessel was filled with argon. Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (68 mg, 0.07 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 76 mg, 0.13 mmol), and (4-methoxyphenyl)methanethiol (432 mg, 2.8 mmol) were then added. The reaction vessel was refilled with argon, and the reaction mixture was stirred at 110°C for 18 h. The reaction mixture was filtered through a silica plug (using ethyl acetate as eluent) and concentrated to give 759 mg of the title compound. Step 3.5-(4-Methoxybenzylsulfanyl)-2-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-2-yl)pyridin-3-ylamine

[00342] 3-Amino-5-(4-methoxybenzylsulfanyl)pyridine-2-carboxylic acid N'-(2-triisopropylsilanyloxyacetyl)hydrazide (160 mg, 0.29 mmol) was mixed with tosyl chloride (166 mg, 0.87 mmol) and triethylamine (0.121 mL, 0.87 mmol) in dichloromethane (10 mL) under argon. The reaction mixture was stirred at ambient temperature for 2 days. The mixture was quenched with 1 N aqueous NaOH and successively extracted with dichloromethane. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated to dryness to yield 360 mg of crude material. The crude material was further purified by flash chromatography (SiO2, 5 g column, eluted with dichloromethane) to yield 69 mg of the title compound. Step 4.5-Amino-6-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-2-yl)-pyridine-3-sulfonyl chloride

[00343] A mixture of 5-(4-methoxybenzylsulfanyl)-2-(5-triisopropylsilanyloxymethyl[1,3,4]oxadiazol-2-yl)pyridin-3-ylamine (69 mg, 0.14 mmol) in 2 mL of CH3CN / acetic acid / H2O = 7: 0.37: 0.18 was cooled in an ice bath and treated portionwise with 1,3-dichloro-5,5-dimethylhydantoin (CAS: 118-52-5, 54 mg, 0.28 mmol). After complete addition, 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 Na2SO4, filtered, and concentrated to yield 98 mg of the title compound. Step 5.5-Amino-6-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-2-yl)pyridine-3-sulfonic acid benzylmethylamide

[00344] A suspension of 5-amino-6-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-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-methylbenzylamine (CAS: 103-67-3, 0.037 ml, 0.28 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was purified by column chromatography (SiO2, 2 g column, dichloromethane as eluent) to give 36 mg of the title compound. Step 6. 5-Amino-N-benzyl-6-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-N-methylpyridine-3-sulfonamide

[00345] 5-Amino-6-(5-triisopropylsilanyloxymethyl-[1,3,4]oxadiazol-2-yl)pyridine-3-sulfonic acid benzylmethylamide (36 mg, 0.07 mmol) was dissolved in tetrahydrofuran (1 mL).Tetrabutylammonium fluoride solution (TBAF, CAS: 429-41-4, 1 M in tetrahydrofuran, 0.02 mL, 0.02 mmol) was added and the resulting mixture was stirred at room temperature for 10 min. The mixture was concentrated to remove most of the tetrahydrofuran. The reaction mixture was quenched with H2O, extracted with ethyl acetate, dried (Na2SO4), filtered, and concentrated to yield 18 mg of crude product. The resulting crude material was triturated with dichloromethane to yield 3 mg of the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.31 (d,J=1.8 Hz, 1H), 7.82 (d,J=1.8 Hz, 1H), 7.36-7.42 (m,3H), 7.33 (d,J=7.3 Hz, 2H), 7.23 (s, 2H), 6.04 (t,J=6.1 Hz, 1H), 4.77 (d,J=5.5 Hz, 2H), 4.23 (s, 2H), 2.63 (s, 3H), MS (ESI+) mass / charge376 [M+H] +.Example 61{5-[3-Amino-5-(benzenesulfonyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methanol

[00346] The heading compound was obtained as described in Example 58 by substituting 3-benzol (CAS: 108-98-5) on 3-(trifluoromethoxy)benzene thiol. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.40 (d, J=1.8 Hz, 1H), 7.97-8.04 (m, 2H), 7.90 (d, J=2.1 Hz, 1H), 7.74-7.80 (m, 1H-7.6), 7.6 Hz, (2H), 7.26 (br. s, 2H), 6.01 (t, J=6.4 Hz, 1H), 4.74 (d, J=6.4 Hz, 2H), MS (ESI+)mass / charge333 [M+H] +.Example 62(5-{3-Amino-5-[4-(trifluoromethyl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-thiadiazol-2-yl)methanolStep 1. 5-[4-(Trifluoromethyl)phenyl]sulfonyl-2-[5-(triisopropylsilyloxymethyl)-1,3,4-thiadiazol-2-yl]pyridin-3-amine

[00347] 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 Lawesson's reagent (CAS No. 19172-47-5, 155 mg, 0.38 mmol) and the solution was heated under reflux for 1 h. Water was added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated to give 178 mg of crude material. The crude material was purified by column chromatography (SiO2, 2 g column, eluent dichloromethane) to give 107 mg of the title compound. Step 2.[5-[3-Amino-5-[4-(trifluoromethyl)phenyl]sulfonyl-2-pyridyl]-1,3,4-thiadiazol-2-yl]methanol

[00348] 5-[4-(Trifluoromethyl)phenyl]sulfonyl-2-[5-(triisopropylsilyloxymethyl)-1,3,4-thiadiazol-2-yl]pyridin-3-amine (107 mg, 0.18 mmol) was dissolved in tetrahydrofuran (3 mL). Tetrabutylammonium fluoride solution (TBAF, CAS: 429-41-4, 1 M in tetrahydrofuran, 0.18 mL, 0.18 mmol) was added, and the resulting mixture was stirred at room temperature for 10 min. 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 yield 140 mg of crude material. Trituration with dichloromethane yielded 36 mg of the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.42 (d, J=1.8 Hz, 1H), 8.24 (d, J=8.2 Hz, 2H), 8.05 (d, J=8.2 Hz, 2H), 7.91 (d, J=1.8 Hz, 1H), 7.49 (s, 2H), 6.29 (br. s., 1H), 4.89 (br. s., 2H), MS (ESI+)m / z 417 [M+H]+ , MS (ESI+)mass / charge417 [M+H] +.Example 63(5-{3-Amino-6-bromo-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[00349] 5-[3-Amino-5-(4-trifluoromethoxybenzenesulfonyl)pyridin-2-yl]-[1,3,4]oxadiazol-2-yl}methanol (200 mg, 0.48 mmol) was dissolved in acetic acid (5 mL). N-bromosuccinimide (NBS, 85 mg, 0.48 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. Additional NBS (170 mg, 0.41 mmol) was added, and the mixture was stirred at room temperature for another 24 h. An additional amount of NBS (340 mg, 0.82 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated, water was added, and the reaction mixture was extracted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic phases were combined, dried (with Na2SO4), filtered, and concentrated to yield 380 mg of crude material.The crude material was purified by preparative reverse-phase HPLC (using mixed eluents, 97% 10 mM NH4HCO3 / pH 10 3% CH3CN) to give the title compound (Example 63) and Example 66. Example 63: 1 H NMR (600 MHz, DMSO-d6) δ ppm 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=6.4 Hz, 1H), 4.74 (d, J=6.4 Hz, 2H), MS (ESI+)m / z496 [M+H] + Example 66: 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 8.16 (d, 2H), 7.64 (m, 2H), 6.07 (t, J=6.4 Hz, 1H), 7.36 (br. s., 2H), 4.78 (d, J=6.4 Hz, 2H), MS (ESI+)m / z 496 [M+H] +.Example 64(5-{3-Amino-6-chloro-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[00350] {5-[3-Amino-5-(4-trifluoromethoxybenzenesulfonyl)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 obtain 250 mg of a crude product. The crude material was purified by preparative reverse-phase HPLC (using 97% 10 mM NH4HCO3 / pH 10 3% CH3CN as eluent) to afford both regioisomers, Example 57 and the title compound. Example 64: 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 8.16-8.20 (m, 2H), 7.65 (m, 2H), 7.40 (s, 2H), 6.07 (t, J=6.3 Hz, 1H), 4.78 (d, J=6.2 Hz, 2H), MS (ESI+)mass / charge451 [M+H] +.Example 65(5-{3-Amino-5-[2-(propan-2-yl)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[00351] The heading compound was obtained as described by substituting Example 58 2-isopropylbenzene thiol (CAS: 6262-87-9) on 3-(trifluoromethoxy)benzene thiol. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.24 (d, J=2.1 Hz, 1H), 8.12 (m, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.76 (m, 1H), 7.66 (m, 1H), 7.7, 7.7 Hz, (s, 2H), 6.01 (t, J=6.4 Hz, 1H), 4.75 (d, J=6.1 Hz, 2H), 3.64 (m, 1H), 1.01 (d, J=6.7 Hz, 6H), MS (ESI+)mass / charge375 [M+H] +.Example 66(5-{3-Amino-4-bromo-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol

[00352] 5-[3-Amino-5-(4-trifluoromethoxybenzenesulfonyl)pyridin-2-yl]-[1,3,4]oxadiazol-2-yl}methanol (200 mg, 0.48 mmol) was dissolved in acetic acid (5 mL). N-bromosuccinimide (NBS, 85 mg, 0.48 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. Additional NBS (170 mg, 0.41 mmol) was added, and the mixture was stirred at room temperature for another 24 h. An additional amount of NBS (340 mg, 0.82 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated, water was added, and the reaction mixture was extracted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic phases were combined, dried (with Na2SO4), filtered, and concentrated to yield 380 mg of crude material.The crude material was purified by preparative reverse phase HPLC (using eluents 97% 10 mM NH4HCO3 / pH 10 3% CH3CN) to give the title compound and Example 63. Example 63: 1 H NMR (600 MHz, DMSO-d6) δ ppm 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=6.4 Hz, 1H), 4.74 (d, J=6.4 Hz, 2H), MS (ESI+)m / z496 [M+H] + Example 66: 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.68 (s, 1H, ), 8.16 (d, 2H,), 7.64 (m, 2H), 6.07 (t, J=6.4 Hz, 1H), 7.36 (br. s., 2H), 4.78 (d, J=6.4 Hz, 2H), MS (ESI+)m / z 496 [M+H] + .Example 67 2-(5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,2,4-oxadiazol-3-yl)ethan-1-ol

[00353] The title compound was prepared according to the procedure described in Example 46 substituting (Z)-N'-hydroxy-2-methoxy-2-methylpropanimidamide for N',3-dihydroxypropanimidamide and purifying the sample after both the first and second steps. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=2.1 Hz, 1H), 8.20-8.14 (m, 2H), 7.94 (d, J=2.1 Hz, 1H), 7.74-7.60 (m, 2H), 7.37 (s, 2H), 4.83 (t, J=5.5 Hz, 1H), 3.84 (q, J=6.2 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H). MS (APCI+) m / z 431.0 (M+H) +.Biological Examples

[00354] List of abbreviations used in the biological examples section: cAMP for cyclic adenosine monophosphate; DMSO for dimethyl sulfoxide; D-PBS for Dulbecco's phosphate-buffered saline; and PBS for phosphate-buffered saline.In vitro assaysYFP-halide uptake assay for the CFTR-ΔF508 mutation

[00355] The YFP-halide uptake assay was used to measure the functionality of cystic fibrosis transmembrane conductance regulator (CFTR) channels in the CFBE41o- cystic fibrosis bronchial epithelial cell line. The assay was used to evaluate the ability of compounds to increase the probability of opening existing CFTR channels in the membrane. It was carried out based on the observation that the fluorescence of the yellow fluorescent protein (YFP) variant YFP H148Q, I152L, F47L is significantly quenched by halide ions such as 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; Nagai, T., Ibata, K., Park, E.S., Kubota, M., Mikoshiba, K., Miyawaki, A., 2002. A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. Nat. 20, 87-90. doi:10.1038 / nbt0102-87). sown in 384-well plates (3000 CFBE cells / well). One day after seeding, CFBE cells were transduced with adenoviral vectors directing expression of the CFTR ΔF508 mutant and the YFP reporter. Cells were incubated at 27°C, 5% CO2 for 24 hours to ensure proper folding and migration to the membrane of the CFTR channel, or treated with a CFTR modulator for 24 hours at 37°C.

[00357] The following day, CFTR channels were activated by treatment with the cAMP-inducing factor forskolin (10.67 μM) and the test compound in 1xD-PBS with a total volume of 30 μl (from Gibco, catalog number 14090-041) for 10 min, after which 30 μl of the following iodine solution (375 mM NaI, 7.5 mM KI, 1.76 mM KH2PO4, 10.1 mM Na2HPO4, 13.75 mM glucose) were added. Iodine-induced fluorescence quenching was recorded immediately after iodide administration for 2 min on an 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 at 36 seconds (F) / fluorescence before injection (F0))) and the EC value. 50 were obtained from (1-F / F0) versus compound concentration plot. Table I. Illustrative EC values 50 , measured by the YFP-halide absorption assay for CFTR-ΔF508, of the compounds of the present invention. Connection number % activation EC 50 (nM) Connection number % activation EC 50 (nM) 1 113,82 5,57 34 102,19 21,34 3 120,51 2,36 35 98,52 20,83 4 103,69 1,8 36 102,93 12,27 5 58,29 >667 37 119,85 28,66 6 86,03 78,11 38 109,05 223,95 7 109,69 5,8 39 119,45 9,88 8 93,73 299,95 40 106,65 36,75 9 104,65 96,75 41 96,97 41,3 10 106,5 14,87 42 109,65 1,57 11 109,82 35,07 43 110,8 <0,77 12 100,38 8,52 44 105,25 1,63 13 100,57 327,1 45 109,25 1,13 14 116,8 67,87 46 82,3 >1660 15 113,65 6,94 47 59,4 >1660 16 110,75 78,12 48 6,28 >4990 17 117,3 11,39 49 29,2 >3325 18 106,2 9,09 50 45,59 >1660 19 97,54 349,8 51 23,23 >3325 20 97,45 8,12 52 3,42 >4990 21 109,42 8,54 53 15,28 >4990 22 112,9 15,17 54 12,02 >4990 23 100,92 37,09 55 2,76 >4990 24 100,82 13,75 57 93,64 2,41 25 104,42 4,4 58 104,91 3,51 26 101,69 3,33 59 106,56 4,25 27 96,45 150,75 60 122,9 15,31 28 50,3 1660 61 97,36 97,4 29 102,9 16,04 62 113 <0,44 30 94,98 3,61 63 109,95 <0,39 31 102,85 36,92 64 122 <0,46 32 105,02 36,55 65 106,55 <1,05 33 103,5 39,84 66 <1,18 100,47 YFP-halide uptake assay for the CFTR-G551D

[00358] mutation. The YFP-halide uptake assay was used to measure the functionality of cystic fibrosis transmembrane conductance regulator (CFTR) channels. The assay was used to evaluate the ability of compounds to increase the channel opening of existing mutant CFTR channels in the membrane. It was based on the observation that the fluorescence of the yellow fluorescent protein (YFP) variant YFP H148Q, I152L, F47L is significantly quenched by halide ions such as 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).

[00359] For this purpose, HEK293 cells were seeded in 96-well plates. Upon seeding, the cells were reverse transfected with plasmid vectors directing expression of the CFTR G551D mutant and the YFP reporter. Cells were incubated at 37°C, 5% CO2 for 24 hours to ensure sufficient CFTR protein expression.

[00360] The following day, CFTR channels were activated by treatment with the cAMP-inducing factor forskolin (10.67 μM) and test compound in D-PBS (Gibco) for 10 minutes before adding solution I - (137 mM NaI, 2.7 mM KI, 1.76 mM KH2PO4, 10.1 mM Na2HPO4, 5 mM glucose). Induced I - Fluorescence quenching was recorded immediately after the introduction of I -within 7 seconds. The ability of the compound to increase the channel opening was directly related to the decrease in fluorescence and was expressed as (1-(fluorescence after 7 seconds (F) / fluorescence before administration (F0))) and the EC value 50 were obtained from (1-F / F0) versus compound concentration plot.

[00361] Similar YHA assays were performed on other CFTR mutants with defective ion channel gating or channel conductance defects to determine the effect of the compound on channel activity. Examples of mutants are G178R, G1349D, S549N, R117H, R334W. This assay was also applied to additional CFTR class I mutants including G542X, W1282X; class II mutants including N1303K, and class III mutants including S1251N; or wild-type CFTR.Table II. Illustrative EC values 50 , measured by the YFP-halide absorption assay for CFTR-G551D, of the compounds of the present invention. Connection number % activation EC 50 (nM) 1 37,7 >10000 3 49,0 181 4 34,3 >6768,2 5 0,3 >10000 Table III. Illustrative EC values 50 , measured by the YFP-halide absorption assay for CFTR-G178R, of the compounds of the present invention. Connection number % activation EC 50 (nM) 1 67,2 196 3 57,4 1440 Table IV. Illustrative EC values 50 , measured by the YFP-halide absorption assay for CFTR-G1349D, of the compounds of the present invention. Connection number % activation EC 50 (nM) 1 72,8 137 3 58,6 44,9 Table V. Illustrative EC values 50 , measured by the YFP-halide absorption assay for CFTR-S549N, of the compounds of the present invention. Connection number % activation EC 50 (nM) 1 75,4 275 3 56,3 55,9 Table VI. Illustrative EC values 50 , measured by the YFP-halide absorption assay for CFTR-R117H, of the compounds of the present invention. Connection number % activation EC 50 (nM) 1 88,7 184 3 89,0 35,5 Cellular Assays

[00362] Electrophysiological measurements in primary human bronchial epithelial cell cultures are a useful preclinical surrogate for determining 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), thus compounds are evaluated in the Ussing chamber and / or TECC assay, which are electrophysiological measurement assays.Ussing Chamber AssayProtocol

[00363] The Ussing chamber assay measures the functionality of the cystic fibrosis transmembrane conductance regulator (CFTR) by measuring the short-circuit current (Isc) generated across the basolateral and apical membranes of lung epithelial cells.

[00364] To measure Isc, the epithelium is short-circuited by applying a current that is regulated by a feedback amplifier to maintain the transepithelial potential (Vt) at 0 mV. The required current is regulated by a feedback loop and is continuously measured. The voltage is periodically fixed at values ​​different from 0 mV, thus allowing the transepithelial resistance (Rt) to be estimated.

[00365] For this purpose, bronchial epithelial cells isolated from CF patients homozygous for the CFTR ΔF508 mutation (hAEC-CF, Epithelix) or heterozygous for the CFTR G551D and ΔF508 mutations (University of North Carolina, Chapel Hill) are plated on Snapwell collagen type IV-coated scaffolds. TM(Corning-Costar). Human airway epithelium is prepared by allowing the air-liquid interface to become exposed for 21 days to form well-differentiated polarized cultures that resemble in vivo pseudostratified ciliated epithelium (Fulcher, ML, Gabriel, S., Burns, KA, Yankaskas, JR, Randell, SH, 2005. Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 107, 183-206). For samples homozygous for ΔF508 CFTR, differentiated cells were treated with 3 μM VX809 (2626 South Loop West, Suite 225, Houston, TX 77054, USA, catalog number S1565) to ensure sufficient expression of properly folded CFTR protein on the membrane (48 hours of treatment for the basolateral membrane and 24 hours of treatment for the apical membrane), after which electrophysiological parameters were recorded. For heterozygous G551D / ΔF508, differentiated cells were used for recording as is.

[00366] To record electrophysiological parameters, human respiratory epithelium is placed in Ussing chambers to measure 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 K2HPO4, pH 7.4, 5 mM glucose) on the basolateral side and glutamate-Ringer's solution (120 mM monosodium glutamate, 25 mM NaHCO3, 1.2 mM CaCl2, 1.2 mM MgCl2, 0.8 mM KH2PO4, 0.8 mM K2HPO4, pH 7.4, 5 mM glucose) on the apical side to create a Cl gradient. -Both chambers are supplied with a gas containing 95% O2, 5% CO2 and maintained at 27°C. Amiloride is applied on the apical side to inhibit endogenous ENaC currents, while forskolin is applied on both the apical and basolateral sides to stimulate CFTR. After forskolin administration, compounds are added to both sides to test their effectiveness in enhancing CFTR release. The increase in Isc is used as a measure of the increase in CFTR activity, and EC values 50 can be obtained by measuring the effect of different concentrations of the compound on the short-circuit current in primary cells, for this purpose the same Snapwell was used TM to add increased amounts of the compound and increase the signal I scat each step were then converted into a dose-response curve. Inh-172, a CFTR-specific inhibitor, was used to test the specificity of the test compounds.TECC AssayProtocol for Primary Bronchial Epithelial Cells

[00367] The TECC (transepithelial clamping circuit, EP model) assay measures the functionality of the cystic fibrosis transmembrane conductance regulator (CFTR) by measuring the short-circuit current (Isc) generated across the basolateral and apical membranes of lung epithelial cells. In TECC, the transepithelial potential PD and transepithelial resistance (Rt) are measured in an open circuit and converted to Isc using Ohm's law. 24 wells can be measured simultaneously, providing high throughput compared to Ussing chambers.

[00368] For this purpose, bronchial epithelial cells isolated from CF patients homozygous for the CFTR ΔF508 mutation (hAEC-CF, McGill, UNC) are plated on collagen type IV-coated Transwell scaffolds ®(Costar). Human airway epithelium is prepared by allowing the air-liquid interface to develop for 21 days to form well-differentiated polarized cultures that resemble in vivo pseudostratified ciliated epithelium (Fulcher, ML, Gabriel, S., Burns, KA, Yankaskas, JR, Randell, SH, 2005. Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 107, 183-206). For ΔF508 CFTR homozygous samples, differentiated cells were treated with 3 μM VX809 (2626 South Loop West, Suite 225, Houston, TX 77054, USA, catalog number S1565) or 0.15 μM GLPG2222 to ensure sufficient expression of properly folded CFTR protein on the membrane (48 h of treatment for the basolateral membrane and 24 h of treatment for the apical membrane), and electrophysiological parameters were recorded.

[00369] Compound information can be obtained from ΔF508 CFTR homozygous samples by looking at increased CFTR activity when compounds are added acutely or chronically.

[00370] For acute electrophysiological recording, human airway epithelia are mounted in a TECC electrophysiological hotplate and maintained at 37°C. The epithelium is 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 K2HPO4, pH 7.4, 5 mM glucose) on both the basolateral and apical sides. Amiloride is administered apically to inhibit endogenous ENaC currents, while forskolin is administered to both the apical and basolateral sides to stimulate CFTR. After forskolin administration, the compounds are added to both sides to test their effectiveness in enhancing CFTR release. Measurements are taken for 20 minutes, with recordings every 2 minutes.The increase in Isc is used as a measure of the increase in CFTR activity, the EC value. 50can be obtained by measuring the effect of different concentrations of a compound on Isc in primary cells, for which purpose each transwell is treated with different concentrations of the compound. Inh-172, a CFTR-specific inhibitor, is used to test the specificity of the test compounds.

[00371] Similar TECC recordings are performed using primary cells for other CFTR mutants with defective ion channel gating or with defects in channel conductance to determine the effect of the compound on channel activity. Examples of mutants include R117H, G178R. Similar primary cells containing class I CFTR mutants, including G542X, W1282X; and additional class II mutants, including N1303K, can be used to record electrophysiological parameters.Results

[00372] Following this protocol, the following values ​​were obtained. The difference between ΔIsc measured as DMSO (baseline) and ΔIsc measured with the test compound.EC measurements 50in the TECC analysis for CFTR ΔF508Table VII. EC values 50 in the TECC assay for CFTR ΔF508 for exemplary compounds of the present invention. Connection number EC 50 (nM) 1 40 4 6

[00373] The data presented in this application show that the compounds of the present invention exhibit in vitro activity and may be useful in vivo in the treatment of cystic fibrosis.

[00374] Additional advantages of the present invention of the Applicant will be apparent to those skilled in the art upon review of this patent application.

[00375] It is understood that the foregoing detailed description and the appended examples are illustrative only and should not be construed as limitations on the scope of the present invention, which is defined solely by the appended claims and the equivalents of the claims. Various changes and modifications of the embodiments will be apparent to those skilled in the art.Such changes and modifications, including but not limited to those relating to chemical structures, substituents, derivatives, intermediates, methods of synthesis, compositions or methods, or any combination of such changes and modifications of the application of the present invention, may be made without departing from the spirit and scope thereof.

Claims

1. Compound of formula I I, where X 1 and X 2 independently represent H; or halogen; R 1 is phenyl optionally substituted by one or more independently selected R groups 4 ; or -NR 6 R 7 ; R 2 is a 5-6-membered monocyclic heteroaryl containing 2 or 3 heteroatoms independently selected from the group consisting of O, S and N, wherein the 5-membered monocyclic heteroaryl is optionally substituted with one R group 3 ; each R 3 independently selected from the group consisting of: C 1-4 alkyl optionally substituted with one or more groups independently selected from: C 3-7 cycloalkyl; a 5-membered monocyclic heterocycle containing 1 heteroatom selected from the group consisting of O; phenyl; C 1-4 alkoxy optionally substituted with one or more groups independently selected from C 3-7 cycloalkyl, halogen and -OCH3; -OR 11 ; -OH; halogen; -NHC(=S)R 11 And -OP(O)(OH)(OH); -C(O)NH2; C 3-7 cycloalkyl; and 5-6-membered monocyclic heterocycle containing 1 heteroatom selected from the group consisting of O; each R 4 independently selected from the group consisting of: halogen; C 1-4 alkyl optionally substituted with one or more independently selected halogen atoms; and C 1-4 alkoxy optionally substituted with one or more independently selected halogen atoms; R 6 represents C 1-4 alkyl; R 7 represents C 1-4alkyl optionally substituted with one phenyl; each R 11 independently selected from the group consisting of: 5-membered monocyclic heterocycle containing 1 O; 6-membered monocyclic heteroaryl containing 1 heteroatom selected from the group consisting of N; C 3-7 cycloalkyl; and phenyl; wherein phenyl is optionally substituted with one R group A ; And each R A independently selected from the group consisting of halogen and C 1-4 alkyl; and wherein the compound of formula I is not (5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol.

2. The compound according to item 1, where R 1 is phenyl optionally substituted with one independently selected R group 4 .

3. The compound according to item 1, where R 1 is a phenyl substituted with one -OCF3.

4. The compound according to item 1, where each of X 1 and X 2 represents H.

5. The compound according to item 1, where R 2 is 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl or thiazolyl, wherein 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl and thiazolyl are substituted with one independently selected R 3 .

6. The compound according to item 1, where R 3 represents C 1-4 alkyl optionally substituted with one or more groups independently selected from -OH; halogen or -OP(O)(OH)(OH).

7. The compound according to item 5, where R 3 represents C 1-4 alkyl optionally substituted with one or more groups independently selected from -OH; halogen or -OP(O)(OH)(OH).

8. The compound according to claim 1, wherein the compound has formula Ia Ia where n is 0, 1, or 2; R 4Ais H, F, -CH3, -CH(CH3)2, t-Bu, CF3, -OCH3, -OCH(CH3)2, or -OCF3; each R 4B independently represents F or -OCF3; and X 1 and R 2 defined in paragraph 1.

9. The connection according to item 8, where X 1 represents H.

10. The compound according to claim 8, where n is 0; and R 4A represents -OCF3.

11. The connection according to item 8, where X 1 represents H; n is equal to 0; R 4A represents -OCF3; R 2 is 1,3,4-oxadiazolyl or thiazolyl substituted with one R 3 ; And R 3 represents C 1-4 alkyl optionally substituted with one or more groups independently selected from -OH; halogen or OP(O)(OH)(OH).

12. The compound of claim 1, 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]pyridin-2-yl}-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-(benzenesulfonyl)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.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, for use in the treatment of diseases or disorders mediated by CFTR.

14. The compound according to claim 1 or the pharmaceutical composition according to claim 13 for use in the treatment of cystic fibrosis.

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