Arylsulfonyl(hydroxy)piperidines as CCR6 inhibitors

Abstract

Compounds of formula (A) are provided that are useful for the treatment of diseases or conditions that are at least partially regulated by CCR6. TIFF2024534781000166.tif34170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 234,271, filed August 18, 2021, and U.S. Provisional Patent Application No. 63 / 354,906, filed June 23, 2022, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] STATEMENT REGARDING RIGHTS TO INVETIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT N / A

[0003] REFERENCE TO A "SEQUENCE LISTING," TABLE, OR COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISC N / A [Background technology]

[0004] Chemokines are chemotactic cytokines released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils, and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3:165-183 (1991); Schall, et al., Curr Opin. Immunol. 6:865-873 (1994); and Murphy, Rev. Immun., 12:593-633 (1994)). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responding cells, including changes in cell shape, transient increases in intracellular free calcium ion ([Ca2+]) concentrations, granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes), and the respiratory burst associated with leukocyte activation. Thus, chemokines are early triggers of the inflammatory response, causing the release, chemotaxis, and extravasation of inflammatory mediators to sites of infection or inflammation.

[0005] They are divided into two major classes of chemokines, CXC (alpha) and CC (beta), depending on whether the first two cysteines are separated by a single amino acid (CXC) or adjacent (CC). Alpha-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulating activity protein (MGSA), are primarily chemotactic for neutrophils, whereas beta-chemokines, such as RANTES, MIP-la, MIP-lb, monocyte chemoattractant protein-l (MCP-l), MCP-2, MCP-3 and eotaxin, are chemotactic for macrophages, T cells, eosinophils and basophils (Deng, et al., Nature, 381:661-666 (1996)). Chemokines bind to specific cell surface receptors, termed "chemokine receptors," which belong to a family of G protein-coupled seven transmembrane domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15:159-165 (1994)).

[0006] Upon binding to their cognate ligands, chemokine receptors transmit intracellular signals through associated trimeric G proteins, resulting in a rapid increase in intracellular calcium concentration. There are at least 11 human chemokine receptors that bind or respond to beta-chemokines, and at least seven that bind alpha-chemokines. In addition, CX3CR1 (fractalkine receptor) can bind fractalkine chemokines that are differentiated by a series of three amino acids between the first two cysteines. Chemokine receptors have been implicated as important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

[0007] CCR6 is known to be expressed primarily in B cells, IL17-secreting T cells, regulatory T cells and dendritic cells, and shows strong binding to its cognate ligand CCL20 (MIP-3α). It is expressed on approximately 30-60% of adult peripheral blood effector / memory CD4+ T cells. CCR6 is involved in leukocyte homing to inflamed tissues, especially the skin and lungs, and is co-expressed on almost all T cells with a skin-homing phenotype, including CD4+ T cells. Thus, CCR6 may play an important role in skin pathologies involving leukocytes.

[0008] CCR6 expression is associated with psoriasis in the following ways: In humans, the majority of skin-homing CD4 T cells in peripheral blood express CCR6, and a greater degree of CCL20-mediated chemotaxis occurs in T cells isolated from psoriasis patients (Homey, et.al., JI, 2000). IL17-secreting cells are central actors in several inflammatory diseases. T cells, such as γδ T cells and TH17 T cells, produce IL17 after activation. The pathogenic effects of IL17 are associated with human diseases such as rheumatoid arthritis (Patel DD et.al., Ann Rheum Dis 2013), multiple sclerosis (Zepp J, Wu L, and X Li Trends Immunol 2011), and psoriasis (Martin DA et.al., J Invest Dermatol 2012). Evidence strongly linking IL17 to psoriasis includes strong associations between psoriasis and genes upstream (IL-23) or downstream (NFκb) of the IL17 signaling pathway, as well as gene-wide association studies showing efficacy in targeting IL17 in clinical settings (Martin DA et.al., J. Invest Dermat. 2012; Papp et.al., NEJM, 2012). In addition to enhanced CCL20-mediated chemotaxis, CCR6+ T cells isolated from psoriasis patients can secrete IL-17A, IL22, and TNFα when compared to healthy controls (Kagami, et.al., J. Invest. Dermatol., 2010). Finally, ccl20 mRNA was upregulated in lesional psoriatic skin samples (Homey, et.al., JI, 2000; Dieu-Nosjean, et.al., JEM, 2000). In mice, CCR6 knockout mice were protected from psoriasis caused by IL-23. Thus, a large body of evidence in both mice and humans suggests a protective role for CCR6 blockade in psoriasis and psoriasis-like models.

[0009] Recent work on the discovery of CCR6 inhibitor compounds is described in Tawaraishi, et al., Bioorg. Med. Chem. Lett. 28:3067-3072 (2018). [Prior art documents]

Non-licensed literature

[0010] [Non-licensed document 1] Schall,Cytokine,3:165-183(1991)

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[0011] Given the clinical importance of CCR6, the identification of compounds that modulate CCR6 function represents an attractive avenue toward the development of new therapeutic agents. Such compounds and methods for their use are provided herein. [Means for solving the problem]

[0012] Described herein are compounds having the formula (A): [ka] In the formula, Ar 1 , Ar 2 , R 3 , R 4 , Z, and m have the meanings provided in the detailed description below.The compounds are useful for treating diseases or conditions that are at least partially regulated by CCR6.

[0013] Described herein are compounds having the formula (I): [ka] In the formula, Ar 1 , Ar 2 , R 3 , R 4 and m have the meanings provided in the detailed description below.The compounds are useful for treating diseases or conditions that are at least partially regulated by CCR6.

[0014] Pharmaceutical compositions of the compounds of formula (I) are also provided.

[0015] Further provided in this disclosure are preparative methods for synthesizing compounds of formula (I), as well as selected intermediates useful in the preparation.

[0016] BRIEF DESCRIPTION OF THE DRAWINGS Not applicable. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] I. Abbreviations and Definitions Unless otherwise stated, the term "alkyl," by itself or as part of another substituent, means a straight or branched chain hydrocarbon group having the specified number of carbon atoms (i.e., C1-8 means 1 to 8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. The term "cycloalkyl" refers to an unsaturated alkyl group having the indicated number of ring atoms (e.g., C 3-6Cycloalkyl) refers to a hydrocarbon ring that is fully saturated or has only one double bond between the ring vertices. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. The term "heterocycloalkane" or "heterocycloalkyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heterocycloalkane can be a monocyclic, bicyclic, or polycyclic ring system. Non-limiting examples of heterocycloalkane groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. Heterocycloalkane groups can be attached to the remainder of the molecule through a ring carbon or heteroatom.

[0018] The term "alkylene" by itself or as part of another substituent means a divalent group derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having four or fewer carbon atoms. Similarly, "alkenylene" and "alkynylene" refer to the unsaturated forms of "alkylene" having a double or triple bond, respectively.

[0019] As used herein, a wavy line crossing a single bond, double bond, or triple bond in any chemical structure shown herein. [ka] represents a point attachment of a single, double or triple bond to the remainder of the molecule.

[0020] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to an alkyl group attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl portions may be the same or different and may also form a 3- to 7-membered ring in combination with the nitrogen atom to which each is attached. Thus, dialkylamino, i.e., -NR a R b A group represented as: is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

[0021] The term "hydroxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms are replaced with a hydroxy (-OH) group. In some embodiments, a hydroxyalkyl has one to two hydroxy groups. In some embodiments, a hydroxyalkyl has one hydroxy group. With respect to the alkyl moiety, a hydroxyalkyl group is a C 1-6 Hydroxyalkyl groups can have any suitable number of carbon atoms and can be straight chained or branched, etc. Hydroxyalkyl groups include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropan-2-yl, and the like.

[0022] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-4 haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0023] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon group that may be a single ring or multiple rings (up to three rings) fused or covalently bonded to each other. The term "heteroaryl" ring refers to an aryl group (or aryl ring) containing 1 to 5 heteroatoms selected from N, O and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, Examples include indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, etc. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0024] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0025] The term "heterocyclic" or "heterocyclyl" refers to a non-aromatic ring having the indicated number of ring member vertices, at least one of which is a heteroatom selected from N, O, and S. For example, the phrase "a 4-7 membered heterocyclic ring having one or two heteroatoms as ring vertices selected from N, O, and S" refers to a single ring having 4 to 7 ring vertices, one or two of which are heteroatoms (N, O, or S). Examples of such rings include morpholine, pyrrolidine, tetrahydrofuran, thiomorpholine, piperidine, piperazine, and the like. The ring may have zero or one double bond between the ring vertices.

[0026] The phrase "bicyclic 9- or 10-membered fused aromatic or heteroaromatic ring having 0-4 heteroatoms as ring vertices selected from N, O, and S" refers to a ring system in which two adjacent ring vertices of a first ring are also adjacent ring vertices of a second ring (i.e., a fused ring system), and at least one of the two rings is aromatic. In some embodiments, both rings have aromaticity (e.g., naphthalene, quinolone, quinazoline, benzimidazole, benzothiophene, benzopyrazole). In some embodiments, only one ring is aromatic (e.g., indane, 1,2,3,4-tetrahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline).

[0027] The phrase "monocyclic 5- or 6-membered aromatic or heteroaromatic ring having 0-3 heteroatoms as ring vertices selected from N, O, and S" refers to a single ring that is aromatic (phenyl) or heteroaromatic (e.g., pyridine, thiophene, furan, pyrimidine, pyrazine).

[0028] A "3- to 6-membered spiro ring" refers to a group having two points of attachment at the vertices of the ring or at carbon atoms that are part of an alkylene group. For example, the group: [ka] is a bicyclic 9- or 10-membered fused aromatic or heteroaromatic ring having one heteroatom as a ring vertex, and the oxo substituent and two other substituents taken together form a 3-membered spiro ring and an oxo.

[0029] The term "spiroheterocycle", "spiroheterocyclyl" or "spiroheterocycloalkyl" refers to a saturated or partially unsaturated bicyclic ring having 6-12 ring atoms, with two rings connected through a single carbon atom (also known as a spiro atom). Spiroheterocyclyl groups have 1-5 heteroatoms selected from N, O and S as ring vertices, with the nitrogen atom optionally being quaternized. Partially unsaturated spiroheterocycloalkyl groups have a double bond in one of the rings. Representative examples include, but are not limited to, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]-nonane, 2,7-diazaspiro[4.4]nonane, and the like.

[0030] The term "substituent" refers to an atom or group of atoms substituted in place of a hydrogen atom of a parent molecule. Non-limiting examples of substituents in the present disclosure include R 1 and R 2 These substituents can be monovalent or divalent. Monovalent substituents are attached to the parent moiety by replacing one hydrogen atom of the parent moiety through a single bond. The hydrogen atom that the monovalent substituent replaces can be an available hydrogen atom from a carbon or nitrogen atom of the parent moiety. Divalent substituents are attached to the parent moiety by replacing two available hydrogen atoms of the parent moiety through a double bond. It is understood that the substituents described in this disclosure cannot be attached to the parent moiety in a way that results in an unstable molecule.

[0031] The term "pharmaceutical acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents contained in the compounds described herein. When the compounds of the present invention contain relatively highly acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutical acceptable salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Salts derived from pharma- ceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted, cyclic, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When a compound of the present invention contains a relatively highly basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids, such as the hydrochloride, hydrobromide, nitrate, carbonate, monohydrogencarbonate, phosphate, monohydrogenphosphate, dihydrogenphosphate, sulfate, monohydrogensulfate, hydroiodide or phosphite salts, and the like, as well as salts derived from relatively non-toxic organic acids, such as acetate, propionate, isobutyrate, malonate, benzoate, succinate, suberate, fumarate, mandelate, phthalate, benzenesulfonate, p-tolylsulfonate, citrate, tartrate and methanesulfonate salts.Also included are salts of amino acids, such as arginates, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).Certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0032] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise is equivalent to the parent form of the compound for purposes of the present invention.

[0033] In addition to salt forms, the present invention provides compounds that are in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to become the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0034] Certain compounds of the present invention can exist in solvated forms, including unsolvated forms and hydrated forms.In general, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention.Certain compounds of the present invention can exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present invention and are intended to be within the scope of the present invention.

[0035] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, positional isomers and individual isomers (e.g., separated enantiomers) are all intended to be embraced within the scope of the present invention. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of isotopes may be defined as ranging from the amount found in nature of the atom in question to the amount consisting of 100%. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 Radioisotopes such as C or deuterium ( 2 H) or carbon-13 ( 13 Non-radioactive isotopes such as C) may be incorporated. Such isotopic variations may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the invention may find additional utility, including but not limited to, as diagnostic and / or imaging reagents or cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the invention may have altered pharmacokinetic and pharmacodynamic properties that may contribute to increased safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0036] The term "acid isostere", unless otherwise specified, refers to a group that can replace a carboxylic acid, having an acidic functionality and steric and electronic properties that provide a similar activity level (or other compound property, such as solubility) as the carboxylic acid. Representative acid isosteres include hydroxamic acids, sulfonic acids, sulfinic acids, sulfonamides, acylsulfonamides, phosphonic acids, phosphinic acids, phosphoric acids, tetrazoles, and oxo-oxadiazoles.

[0037] The compounds of the present invention having formula I can exist in different isomeric forms. As used herein, the terms cis or trans are used in their conventional sense in the chemical art, i.e., referring to the relative positions of the substituents relative to a reference plane, for example a double bond, or a ring system, such as a decalin-type ring system or a hydroquinolone ring system. In cis isomers, the substituents are on the same side of the reference plane, and in trans isomers, the substituents are on opposite sides. Furthermore, various conformers are contemplated by the present invention, as are various rotamers. Conformers are stereoisomers that may differ in rotation around one or more σ-bonds. Rotamers are conformers that differ in rotation around only a single σ-bond.

[0038] II. Overview The present invention originates from the discovery that the compound of formula I acts as a strong antagonist of CCR6 receptor.This compound has in vivo anti-inflammatory activity and has excellent pharmacokinetic properties.Therefore, the compound provided herein is useful as a pharmaceutical composition, a method for treating CCR6-mediated disease, and a control in the assay for identifying competitive CCR6 antagonist.

[0039] III.Compound In one aspect, the present invention provides a compound of formula A: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form or rotamer thereof, During the ceremony, Ar 1 is halogen, CN, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -OR a and -NR a R b 0 to 5 R independently selected from the group consisting of 1a monocyclic 5- or 6-membered aromatic or heteroaromatic ring having 0-3 heteroatoms as ring vertices selected from N, O and S, substituted with a substituent; Each R a and R b are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 3-6 cycloalkyl; Ar 2 is the group consisting of: i) having 0 to 3 heteroatoms selected from N, O, and S as ring vertices, and 0 to 5 R 2 a monocyclic 5- or 6-membered aromatic or heteroaromatic ring substituted with; ii) having 0 to 4 heteroatoms selected from N, O, and S as ring vertices, and 0 to 5 R 2 Bicyclic 9- or 10-membered fused aromatic or heteroaromatic rings substituted with Selected from; Each R 2 is halogen, CN, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -OR c , -SR c , -COR c , -CO2R c , -NR c R d , -CONR c R d , -CO(NR c )2COR d , -SO2R c , -SO2NR c R d , -X 2 -CONR c R d , -X 2 -NR c SO2R d , -X 2 -NR c CO2Rd , -X 2 -P(=O)(OR d )2, -X 2 -OP(=O)(OR d )2, -NR c R d -X 2 -NR c R d , oxo, 4- to 6-membered heterocyclyl, 7- to 10-membered spiroheterocyclyl, and 5- or 6-membered heteroaryl; R 2 The heterocyclyl, spiroheterocyclyl and heteroaryl rings have 1 to 3 heteroatoms selected from N, O and S, each of which is unsubstituted or substituted with halogen, hydroxyl, oxo, C 1-4 Alkyl, Amino, C 1-4 Alkylamino, Di-C 1-4 Alkylamino, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and C 1-4 haloalkyl; and two R 2 groups optionally combined to form a 3- to 6-membered spiro ring or a 3- to 6-membered spiro heterocycle having 1 to 3 heteroatoms selected from N, O and S; R c are independently hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 hydroxyalkyl; R d are independently hydrogen, hydroxyl, halogen, Cyano, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 R is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; d C 3-6Cycloalkyl, 4- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl rings have 1 to 3 heteroatoms selected from N, O and S, each of which is unsubstituted or substituted with halogen, hydroxyl, oxo, C 1-4 Alkyl, Amino, C 1-4 Alkylamino, Di-C 1-4 Alkylamino, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and C 1-4 substituted with 1 or 2 members independently selected from the group consisting of haloalkyl; Or R c and R d are attached to the same nitrogen atom, together form a 4- to 7-membered heterocycle, including O, S, S(O), S(O)2, NH, and N(C 1-4 alkyl) as ring vertices; X 2 is C 1-4 is alkylene; Z is -O- or -N(R e )-, wherein R e is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 3-6 cycloalkyl; The subscript m is 0, 1 or 2; Each R 3 is halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy and C 2-4 is a member selected from the group consisting of hydroxyalkyl; R 4 , H, C 1-4 Alkyl, C 3-8 Cycloalkyl and C 1-4 haloalkyl.

[0040] In one aspect, the present invention provides a compound of formula A: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form or rotamer thereof, During the ceremony, Ar 1 is halogen, CN, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -OR a and -NR a R b 0 to 5 R independently selected from the group consisting of 1 a 5- or 6-membered aromatic or heteroaromatic ring substituted with a substituent; Each R a and R b are independently hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 3-6 cycloalkyl; Ar 2 is the group consisting of: i) having 0 to 3 heteroatoms selected from N, O, and S as ring vertices, and 0 to 5 R 2 a monocyclic 5- or 6-membered aromatic or heteroaromatic ring substituted with; ii) having 0 to 4 heteroatoms selected from N, O, and S as ring vertices, and 0 to 5 R 2 Bicyclic 9- or 10-membered fused aromatic or heteroaromatic rings substituted with Selected from; Each R 2 is halogen, CN, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8Haloalkyl, C 1-8 Hydroxyalkyl, -OR c , -SR c , -COR c , -CO2R c , -NR c R d , -CONR c R d , -CO(NR c )2COR d , -SO2R c , -SO2NR c R d , -X 2 -CONR c R d , -X 2 -NR c SO2R d , -X 2 -NR c CO2R d , -X 2 -P(=O)(OR d )2, -X 2 -OP(=O)(OR d )2, -NR c R d -X 2 -NR c R d , oxo, 4- to 6-membered heterocyclyl, 7- to 10-membered spiroheterocyclyl, and 5- or 6-membered heteroaryl; R 2 The heterocyclyl, spiroheterocyclyl and heteroaryl rings are each unsubstituted or substituted with halogen, hydroxyl, oxo, C 1-4 Alkyl, Amino, C 1-4 Alkylamino, Di-C 1-4 Alkylamino, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and C 1-4 haloalkyl; and two R 2 groups optionally combined to form a 3- to 6-membered spiro ring; R c are independently hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl, C1-4 Haloalkyl and C 1-4 hydroxyalkyl; R d are independently hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 R is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; d C 3-6 The cycloalkyl, 4- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl rings are each unsubstituted or substituted with halogen, hydroxyl, oxo, C 1-4 Alkyl, Amino, C 1-4 Alkylamino, Di-C 1-4 Alkylamino, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl and C 1-4 substituted with 1 or 2 members independently selected from the group consisting of haloalkyl; Or R c and R d are attached to the same nitrogen atom, together form a 4- to 7-membered heterocycle, including O, S, S(O), S(O)2, NH, and N(C 1-4 alkyl) as ring vertices; X 2 is C 1-4 is alkylene; Z is -O- or -N(R e )-, wherein R e is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 3-6 cycloalkyl; The subscript m is 0, 1 or 2; Each R 3 is halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy and C 2-4 is a member selected from the group consisting of hydroxyalkyl; R 4 , H, C 1-4 Alkyl, C 3-8 Cycloalkyl and C 1-4 haloalkyl.

[0041] In one aspect, the present invention provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form or rotamer thereof, During the ceremony, Ar 1 is halogen, CN, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -OR a and -NR a R b 0 to 5 R independently selected from the group consisting of 1 a 5- or 6-membered aromatic or heteroaromatic ring substituted with a substituent; Each R a and R b are independently hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 3-6 cycloalkyl; Ar 2 is the group consisting of: i) having 0 to 3 heteroatoms selected from N, O, and S as ring vertices, and 0 to 5 R 2 a monocyclic 5- or 6-membered aromatic or heteroaromatic ring substituted with; ii) having 0 to 4 heteroatoms selected from N, O, and S as ring vertices, and 0 to 5 R 2 Bicyclic 9- or 10-membered fused aromatic or heteroaromatic rings substituted with Selected from; Each R 2 is halogen, CN, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -OR c , -SR c , -COR c , -CO2R c , -NR c R d , -CONR c R d , -CO(NR c )2COR d , -SO2R c , -SO2NR c R d , -X 2 -CONR c R d , -X 2 -NR c SO2R d , -X 2 -NR c CO2R d , -NR c R d -X 2 -NR c R d , oxo, 4- to 6-membered heterocyclyl, 7- to 10-membered spiroheterocyclyl, and 5- or 6-membered heteroaryl; R 2 The heterocyclyl, spiroheterocyclyl and heteroaryl rings are each unsubstituted or substituted with halogen, hydroxyl, oxo, C 1-4 Alkyl, Amino, C 1-4 Alkylamino, Di-C 1-4 Alkylamino, C 1-4 Alkoxy and C 1-4haloalkyl; and two R 2 groups optionally combined to form a 3- to 6-membered spiro ring; Each R c and R d are independently hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 3-6 cycloalkyl; or R c and R d are attached to the same nitrogen atom, together they form O, S, S(O), S(O)2, NH and N(C 1-4 alkyl) as ring vertices; X 2 is C 1-4 is alkylene; The subscript m is 0, 1 or 2; Each R 3 is halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy and C 2-4 is a member selected from the group consisting of hydroxyalkyl; R 4 , H, C 1-4 Alkyl, C 3-8 Cycloalkyl and C 1-4 haloalkyl.

[0042] In one group of selected embodiments of the compounds of formula (I), Ar 2 is 0 to 5 R 2 In another group of selected embodiments of the compounds of formula (I), Ar is a bicyclic 9- or 10-membered aromatic or heteroaromatic ring substituted with 2 is 0 to 5 R 2is a monocyclic 5- or 6-membered aromatic or heteroaromatic ring substituted with

[0043] For compounds of formula (I), and in selected embodiments for each of the above embodiments, Ar 1 1 to 3 R 1 In still other embodiments selected for the compounds of formula (I) and for each of the above embodiments, Ar 1 1 to 3 R 1 It is a pyridyl substituted with a substituent.

[0044] In some embodiments, Z is O. In some embodiments, Z is -N(R e )-, wherein R e is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 3-6 cycloalkyl;

[0045] In yet other selected embodiments, Ar 2 Provided herein is a compound of formula (I), wherein is selected from the group consisting of: [ka] Each of them has 0 to 3 R 2 has been replaced with.

[0046] In yet other selected embodiments, Ar 2 Provided herein is a compound of formula (I), wherein is selected from the group consisting of: [ka] Each of them has 0 to 3 R 2 In some embodiments, R 2a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Hydroxyalkyl, -C(O)NH2, -C(O)N(H)C 1-4 Alkyl, -C(O)N(C 1-4 alkyl)2, -S(O)2C 1-4 Alkyl, -S(O)2N(H)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, and -C(O)C 1-4 alkyl.

[0047] In some embodiments, Ar 2 is selected from the group consisting of phenyl, pyridyl, thiazolyl, oxadiazolyl, imidazolyl, pyridazinyl, and oxazolyl, each of which is selected from the group consisting of 0 to 3 R 2 Provided herein are compounds of formula (I) substituted with Ar 2 is selected from the group consisting of phenyl, pyridyl, thiazolyl, and oxazolyl, each of which is selected from 0 to 3 R 2 Provided herein are compounds of formula (I) substituted with:

[0048] In yet other selected embodiments, Ar 2 0 to 3 R 2 Provided herein are compounds of formula (I) that are pyridyl substituted with Ar 2 0 to 2 R 2 Provided herein are compounds of formula (I) that are thiazolyl substituted with Ar 2 is 1,3,4-oxadiazolyl, and 0 to 2 R 2 Provided herein are compounds of formula (I) substituted with Ar 2 0 to 2 R 2 Provided herein are compounds of formula (I) which are imidazolyl substituted with

[0049] In other embodiments, the compound of formula (Ia): [ka] There is provided a compound of formula (I) having the formula:

[0050] In some selected embodiments, the compound of formula (Ia) is R 1 is a compound independently selected from the group consisting of CH3, CF3, Cl, and CN.

[0051] In some selected embodiments, the compound of formula (Ia) is Ar 2 However, 0 to 5 R 2 and n is a substituted bicyclic 9- or 10-membered aromatic or heteroaromatic ring.

[0052] In some selected embodiments, the compound of formula (Ia) is Ar 2 However, 0 to 5 R 2 and n is a substituted monocyclic 5- or 6-membered aromatic or heteroaromatic ring.

[0053] In other embodiments, the formula (Ia1): [ka] A compound of formula (I) having the formula 1 is -CN or -CF3.

[0054] In a related embodiment, a compound of formula (Ia1) is provided, wherein R 1 is -CN or -CF; Ar 2 is selected from the group consisting of: [ka] Each of them has 0 to 3 R 2 has been replaced with.

[0055] In a related embodiment, a compound of formula (Ia1) is provided, wherein R 1 is -CN or -CF; Ar 2 is the group consisting of: [ka] each of which is selected from 0 to 3 R 2 In some embodiments, R 2a is selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -C(O)NH2, -C(O)N(H)C 1-4 Alkyl, -C(O)N(C 1-4 alkyl)2, -S(O)2C 1-4 Alkyl, -S(O)2N(H)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, and -C(O)C 1-4 In some embodiments, R 2a is selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -C(O)NH2, -C(O)N(H)C 1-4 Alkyl, -C(O)N(C 1-4 alkyl)2, and -C(O)C 1-4 Alkyl.

[0056] In some embodiments, a compound of formula (Ia1) is provided, wherein R 1 is -CN or -CF; Ar 2 is selected from the group consisting of phenyl, pyridyl, thiazolyl, oxadiazolyl, imidazolyl, pyridazinyl, and oxazolyl, each of which is 0 to 2 R 2 In a related embodiment, R 1 is -CN or -CF3; Ar 2 is selected from the group consisting of phenyl, pyridyl, thiazolyl, and oxazolyl, each of which is 0 to 3 R 2 The compound of formula (Ia1) is provided, wherein

[0057] In some embodiments, Ar 2 Compounds of formula (Ia1) are provided, in which is selected from the group consisting of: [ka] Each of them has 0 to 2 R 2 wherein R 2b is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 hydroxyalkyl.

[0058] In some embodiments, Ar 2 Compounds of formula (Ia1) are provided, in which is selected from the group consisting of: [ka] Each of them has 0 to 2 R 2 wherein R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 hydroxyalkyl.

[0059] In some embodiments, Ar 2 is selected from the group consisting of: [ka] Each of them is 0 to 1 R 2 wherein R 2b is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 hydroxyalkyl.

[0060] In some embodiments, including those described above, R 1 is CF3; R 2is CN, -CH3, -OH, -NH2, -N(CH3)2, -C(O)NH2, -C(O)N(H)(CH3), -C(O)N(CH3)2, -C(O)CH3, -C(O)OCH3, -S(O)2NH2, Cl, F, -N(CH3)2, -OCH3, -CH2OH, -N(H)R d , piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, or azetidinyl, and the piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, and azetidinyl groups may be optionally substituted by one or two substituents selected from the group consisting of -CH3, C(CH3)2OH, OH, -OCH3, -NH2, and -N(CH3)2.

[0061] In some embodiments, including those described above, R 2 is CN, -CH3, -OH, -NH2, -N(CH3)2, -C(O)NH2, -C(O)N(H)(CH3), -C(O)N(CH3)2, -C(O)CH3, -C(O)OCH3, -S(O)2NH2, Cl, F, -N(CH3)2, -OCH3, or -CH2OH.

[0062] In some embodiments, including those described above, R 2 is piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, or azetidinyl, and the piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, and azetidinyl groups are -CH3, C(CH3)2OH, OH, -OCH3, -NH2, and -N(CH3) 2. and optionally substituted with 1 or 2 substituents selected from the group consisting of:

[0063] In some embodiments, including those described above, each R a and R b are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C3-6 In some embodiments, including those described above, each R a and R b is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 In some embodiments, including those described above, each R a and R b is hydrogen, C 1-4 Alkyl, and C 1-4 haloalkyl.

[0064] In some embodiments, including those described above, each R c and R d are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 3-6 In some embodiments, including those described above, each R c and R d is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 In some embodiments, including those described above, each R c and R d is hydrogen, C 1-4 Alkyl, and C 1-4 haloalkyl.

[0065] In some embodiments, including those described above, the subscript m is 0 (R 3 is not present). In other embodiments, including the above embodiment, subscript m is 1. In yet other embodiments, including the above embodiment, subscript m is 2.

[0066] In some selected embodiments, provided herein are compounds of Formula (I) selected from the following examples and / or provided in Tables 1-3.

[0067] A. Compound Preparation The example schemes below provide specific synthetic routes that can be followed to obtain certain compounds of the invention. Other routes or variations of the routes presented below will be readily apparent to one of skill in the art and are within the scope of the invention.

[0068] B. General synthesis method [ka] Suitably, the 1-N protected 4-amino-3-hydroxypiperidine (I) is reacted with S N The amine can be reacted with 2-halo-5-substituted pyridines (II) (X=F, Br or Cl) and base in an Ar substitution reaction to form 4-aminopyridyl-3-hydroxypiperidines (III). The protecting group can be removed under appropriate conditions to give 1-NH piperidine (IV) as the free base or as a protonated species with a counterion. This amine can be further treated with base and optionally substituted 4-bromosulfonyl chloride (V) in a sulfonamidation reaction to give 4-aminopyridyl-3-hydroxy-1-N-sulfonamides (VI). [ka]

[0069] 4-Aminopyridyl-3-hydroxy-1-N-piperidinyl-sulfonamides (VI) can be further elaborated by direct Suzuki cross-coupling reaction (A=boron species; aryl / heteroaryl boronic acid or ester) or by Miyura bromide / boronic acid ester exchange on the bromide (VI) followed by Suzuki coupling with Aryl / heteroaryl bromides (A=Br) to give the final compounds (X).

[0070] IV. Pharmaceutical Compositions In addition to the compounds provided above, compositions for modulating CCR6 activity in humans and animals will usually contain a pharmaceutical carrier or diluent.

[0071] The term "composition," as used herein, is intended to encompass any product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from the combination of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0072] The pharmaceutical composition for administering the compound of the present invention can be conveniently provided in unit dosage form and can be prepared by any method known in the art of pharmacy and drug delivery.All methods include the step of associating the active ingredient with the carrier that constitutes one or more auxiliary ingredients.In general, the pharmaceutical composition can be prepared by homogenizing and comminuted the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into desired formulation.In this pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect depending on the process or condition of the disease.

[0073] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying formulations as described in U.S. Pat. No. 6,451,339, hard or soft capsules, syrups, elixirs, liquids, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders and effervescent tablets. Compositions intended for oral use may be prepared by any method known in the art for producing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants and preservatives to provide pharma-ceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharma-ceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or enteric or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by the techniques described in U.S. Pat. Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0074] Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.Furthermore, emulsions may be prepared with non-water-miscible ingredients, such as oils, and stabilized with surfactants, such as mono- or diglycerides, PEG esters, etc.

[0075] Aqueous suspensions contain the active substance mixed with excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing agents or wetting agents can be natural phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0076] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents, such as those described above, can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0077] Dispersible powders or granules suitable for preparing aqueous suspension by adding water are provided in the mixture of active ingredient mixed with dispersing or wetting agent, suspending agent and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.Additional excipients, such as sweeteners, flavoring agents and coloring agents, may also be present.

[0078] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be natural gums, such as gum acacia or gum tragacanth, natural phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0079] Syrups and elixirs can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also contain demulcents, preservatives, flavoring agents and coloring agents. Oral liquid preparations can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.

[0080] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated by known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. As acceptable vehicles and solvents that may be used, water, Ringer's solution and isotonic sodium chloride solution may be used. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any sterile, fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0081] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. In addition, the compounds can be administered by intraocular delivery by using solutions or ointments. In addition, the compounds of interest can be delivered transdermally by using iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present invention are used. As used herein, topical application is also intended to include the use of mouthwashes and gargles.

[0082] The compounds of the present invention can be formulated for deposition on medical devices, which can include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets, or other devices that can be deployed or permanently implanted in a body lumen. As a specific example, it would be desirable to have devices and methods that can deliver the compounds of the present invention to areas of the body that have been treated by interventional techniques.

[0083] In an exemplary embodiment, the inhibitors of the present invention may be deposited within a medical device, such as a stent, and delivered to a treatment site for treatment of a part of the body.

[0084] Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are generally permanently implanted in the coronary arteries or peripheral vessels. Stent designs include those in U.S. Pat. Nos. 4,733,655 (Palmaz), 4,800,882 (Gianturco), or 4,886,062 (Wiktor). Such designs include both metallic and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents can also be used to deliver drugs to sites in contact with the vascular system, as disclosed in U.S. Patent No. 5,102,417 (Palmaz), as well as WO 91 / 12779 (Medtronic, Inc.) and WO 90 / 13332 (Cedars-Sanai Medical Center), U.S. Patent No. 5,419,760 (Narciso, Jr.) and U.S. Patent No. 5,429,634 (Narciso, Jr.), etc. Stents have also been used to deliver viruses to the lumen wall for gene delivery, as disclosed in U.S. Patent Application No. 5,833,651 (Donovan et al.).

[0085] The term "deposited" means that the inhibitor is coated, adsorbed, placed, or otherwise incorporated into the device by methods known in the art. For example, the inhibitor may be embedded in and released from a polymeric material that coats or spans the medical device ("matrix type"), or may be surrounded by and released through a polymeric material ("reservoir type"). In the latter example, the inhibitor may be encapsulated within or bound to the polymeric material using one or more techniques for producing such materials known in the art. In other formulations, the inhibitor may be linked to the surface of the medical device without the need for a coating by a removable bond and release over time, may be removed by active mechanical or chemical processes, or is in a permanently immobilized form that presents the inhibitor at the implantation site.

[0086] In one embodiment, the inhibitor may be incorporated with the polymer composition during the formation of a biocompatible coating for a medical device such as a stent. The coatings produced from these components are typically homogeneous and are useful for coating multiple devices designed for implantation.

[0087] The polymer can be either a biostable or a bioabsorbable polymer depending on the desired release rate or the degree of polymer stability desired, although bioabsorbable polymers are preferred for this embodiment because, unlike biostable polymers, bioabsorbable polymers do not persist for extended periods of time after implantation to cause adverse chronic local responses. Bioabsorbable polymers that can be used include poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoesters, poly These include, but are not limited to, polyphosphoester urethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonates), copoly(ether-esters) (e.g., PEO / PLA), polyalkylene oxalates, polyphosphazenes, and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, crosslinked or amphiphilic block copolymers of hydrogels, and other suitable bioabsorbable polymers known in the art.Also, biostable polymers with relatively low chronic tissue response such as polyurethanes, silicones, and polyesters can be used, as well as polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride, polyvinylidene chloride; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; vinyl compounds, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers. Other polymers may also be used if they can be dissolved and cured or polymerized on the medical device, such as copolymers of olefins with alkyl monomers; pyran copolymers; polyhydroxypropyl-methacrylamide-phenol; polyhydroxyethyl-aspartamide-phenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

[0088] The polymers and semipermeable polymer matrices can be formed into shaped articles such as valves, stents, tubes, prostheses, and the like.

[0089] In one embodiment of the invention, the inhibitors of the invention are bound to a polymer or semi-permeable polymer matrix formed as a stent or stent-graft device.

[0090] Typically, the polymer is applied to the surface of the implantable device by spin coating, dipping or spraying. Additional methods known in the art can also be utilized for this purpose. Spraying methods include conventional methods as well as microdeposition techniques with inkjet type dispensers. Additionally, photopatterning can be used to deposit the polymer on the implantable device to place the polymer only in specific parts of the device. This coating of the device provides a uniform layer around the device, allowing for improved diffusion of various analytes through the device coating.

[0091] In other embodiments of the invention, the inhibitor is formulated for release from the polymer coating into the environment in which the medical device is placed. The inhibitor may be released in a controlled manner over an extended period of time (e.g., months) using at least one of several well-known techniques, including polymeric carriers or layers to control elution. Some of these techniques have been previously described in U.S. Patent Application Publication No. 20040243225A1.

[0092] Furthermore, as described, for example, in U.S. Pat. No. 6,770,729, the reagents and reaction conditions of the polymer composition can be manipulated to control the release of the inhibitor from the polymer coating. For example, the diffusion coefficient of one or more polymer coatings can be adjusted to control the release of the inhibitor from the polymer coating. In a variation on this theme, the diffusion coefficient of one or more polymer coatings can be controlled to control the ability of an analyte present in the environment in which the medical device is placed (e.g., an analyte that promotes the degradation or hydrolysis of a portion of the polymer) to access one or more components within the polymer composition (e.g., thereby controlling the release of the inhibitor from the polymer coating). Yet another embodiment of the invention includes a device having multiple polymer coatings, each having multiple diffusion coefficients. In such an embodiment of the invention, the release of the inhibitor from the polymer coating can be controlled by the multiple polymer coatings.

[0093] In yet another embodiment of the present invention, the release of the inhibitor from the polymer coating is controlled by adjusting one or more properties of the polymer composition, such as the presence of one or more endogenous or exogenous compounds, or the pH of the polymer composition. For example, a particular polymer composition can be designed to release the inhibitor in response to a decrease in the pH of the polymer composition. Alternatively, a particular polymer composition can be designed to release the inhibitor in response to the presence of hydrogen peroxide.

[0094] V. Methods of Treating Diseases Modulated by CCR6 In one aspect, the present invention provides a method for treating or preventing a CCR6-mediated condition or disease by administering to a subject having such a condition or disease a therapeutically effective amount of any of the compounds of the present invention. Exemplary compounds for use in the method are those provided above, as well as those specifically exemplified in the Examples below and whose specific structures are provided herein. A "subject" is defined herein to include animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In other embodiments, the subject is a human.

[0095] As used herein, the phrase "CCR6-mediated condition or disease" and related phrases and terms refer to a condition or disease characterized by inappropriate, e.g., subnormal or supranormal, CCR6 functional activity. Inappropriate CCR6 functional activity may result from expression of CCR6 in cells that do not normally express CCR6, increased CCR6 expression (e.g., resulting in inflammatory and immunoregulatory disorders and diseases), or decreased CCR6 expression. Inappropriate CCR6 functional activity may also result from secretion of CCL 20 by cells that do not normally secrete CCL20, increased CCL20 expression (e.g., resulting in inflammatory and immunoregulatory disorders and diseases), or decreased CCL20 expression. A CCR6-mediated condition or disease may be fully or partially mediated by inappropriate CCR6 functional activity. However, a CCR6-mediated condition or disease is one in which modulation of CCR6 has some effect on the underlying condition or disease (e.g., a CCR6 antagonist brings about some improvement in the health of at least some patients).

[0096] The term "therapeutically effective amount" refers to that amount of the subject compound that elicits the biological or medical response in a tissue, system, animal or human that is desired by a researcher, veterinarian, physician or other clinician.

[0097] Diseases and conditions associated with inflammation, infection and cancer can be treated or prevented with the compounds and compositions of the present invention. In one group of embodiments, diseases or conditions, including chronic diseases of humans or other species, can be treated with inhibitors of CCR6 function. Such diseases or conditions include: (1) allergic diseases, such as systemic anaphylaxis or hypersensitivity reactions, drug allergies, insect bite allergies and food allergies; (2) inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis; (3) vaginitis; (4) psoriasis and inflammatory skin diseases, such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria and pruritus, vitiligo; (5) vasculitis; (6) spondyloarthropathy; (7) scleroderma; (8) asthma and respiratory allergic diseases, such as allergic asthma, allergic rhinitis, hypersensitivity pulmonary disease. (9) arthritis (including rheumatoid and psoriatic) and autoimmune diseases such as, for example, Hashimoto's thyroiditis and Grave's disease, multiple sclerosis, systemic lupus erythematosus, type I diabetes, glomerulonephritis, (10) transplant rejection (including allograft rejection and graft versus host disease), (11) other diseases in which it is necessary to inhibit undesirable inflammatory responses, such as atherosclerosis, myositis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome, and gout.

[0098] In another embodiment, the method relates to the treatment of a disease or condition selected from an allergic disease, psoriasis, skin conditions such as atopic dermatitis and asthma, and scleroderma.

[0099] In another group of embodiments, regulation of CCR6-dependent regulatory T cell trafficking can be modulated to treat diseases or conditions including cancer, infectious diseases (viral infections, e.g., HIV infections and bacterial infections), and immunosuppressive diseases, e.g., organ transplant conditions and skin transplant conditions. The term "organ transplant conditions" is meant to include bone marrow transplant conditions and solid organ (e.g., kidney, liver, lung, heart, pancreas, or combinations thereof) transplant conditions.

[0100] Depending on the disease to be treated and the condition of the subject, the compounds of the present invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical administration routes, and can be formulated, alone or together, into suitable dosage unit formulations containing conventional non-toxic pharma- ceutically acceptable carriers, adjuvants, and vehicles appropriate for each administration route. The present invention also contemplates administration of the compounds of the present invention in a depot formulation.

[0101] Those skilled in the art will understand that the agent that modulates CCR6 activity can be combined with other therapeutic agents and / or chemotherapeutic agents or radiation in a treatment regimen. In some cases, the amount of chemotherapeutic agent or radiation is an amount that would be sub-therapeutic if provided without combination with the composition of the present invention. Those skilled in the art will understand that "combination" can include combination in treatment (i.e., two or more drugs are administered as a mixture or at least simultaneously, or at least introduced into the subject at different times, but both are introduced so that they are simultaneously present in the subject's bloodstream). Furthermore, the composition of the present invention can be administered before or after a second treatment regimen, such as before or after administration of chemotherapy or radiation therapy.

[0102] The compounds of the present invention are therefore useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases.

[0103] In the treatment or prevention of conditions requiring chemokine receptor modulation, suitable dosage levels are generally about 0.001 to 100 mg per kg of patient body weight per day, which may be administered in single or multiple doses. In another embodiment, the dosage level is about 0.01 to about 25 mg / kg / day. In another embodiment, the dosage level is about 0.05 to about 10 mg / kg / day. Suitable dosage levels may be about 0.01 to 25 mg / kg per day, about 0.05 to 10 mg / kg per day, or about 0.1 to 5 mg / kg per day. Within this range, dosages may be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0 mg / kg per day. For oral administration, the composition may be provided in the form of a tablet containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of active ingredient for symptomatic adjustment of dosage to the patient being treated. The compound may be administered on a regimen of 1 to 4 times daily, or in other embodiments, once or twice daily.

[0104] It will be understood, however, that the specific dosage level and frequency of administration for any particular patient may vary, and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and length of action of that compound, the age, weight, genetic characteristics, general health, sex and diet of the subject, as well as the mode and time of administration, rate of excretion, drug combination, and the severity of the particular condition of the subject being treated.

[0105] Diseases and conditions associated with inflammation, immune disorders, infection and cancer can be treated or prevented with the compounds, compositions and methods of the invention.

[0106] The compounds and compositions of the present invention may be combined with other compounds and compositions having related utility to prevent and treat the condition or disease of interest, such as inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, polyarticular arthritis, multiple sclerosis, allergic diseases, psoriasis, atopic dermatitis and asthma, as well as inflammatory or autoimmune disorders, conditions and diseases including those conditions listed above.

[0107] For example, in the treatment or prevention of inflammation or autoimmunity or osteopenia associated with, for example, arthritis, the compounds and compositions may be used in combination with compounds such as anti-inflammatory or analgesic agents, such as opiate agonists, lipoxygenase inhibitors, such as inhibitors of 5-lipoxygenase, cyclooxygenase inhibitors, such as cyclooxygenase-2 inhibitors, interleukin inhibitors, such as interleukin-1 inhibitors, NMDA antagonists, inhibitors of nitric oxide or inhibitors of nitric oxide synthesis, nonsteroidal anti-inflammatory agents or cytokine suppressive anti-inflammatory agents, such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, steroidal analgesics, sufentanil, sulindac, tenidap, and the like. Similarly, the compounds and compositions may be administered with analgesics as listed above; enhancers such as caffeine, H2 antagonists (e.g., ranitidine), simethicone, aluminum hydroxide or magnesium hydroxide; decongestants such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine or levodesoxyephedrine; cough suppressants such as codeine, hydrocodone, caramiphen, carbetapentane or dextromethorphan; diuretics; and sedating or non-sedating antihistamines.

[0108] Similarly, the compounds and compositions of the present invention can be used in combination with other drugs that are used to treat, prevent, suppress or improve the disease or symptoms for which the compounds and compositions of the present invention are useful. Such other drugs can be administered simultaneously or sequentially with the compounds or compositions of the present invention, by a route and in an amount generally used therefor. When the compounds or compositions of the present invention are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds or compositions of the present invention can also be used. Thus, pharmaceutical compositions of the present invention include those that contain one or more other active ingredients or therapeutic agents in addition to the compounds or compositions of the present invention. Examples of other therapeutic agents that may be combined with the compounds or compositions of the invention, administered separately, or in the same pharmaceutical composition include: (a) VLA-4 antagonists; (b) corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone, salmeterol, salbutamol, formoterol; (c) cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®), and the like. (d) immunosuppressants such as brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine;(e) nonsteroidal antiasthmatics (e.g., terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (e.g., zafirlukast, montelukast, pranlukast, iralukast, povilkast, and SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) prolactins, propionic acid derivatives (e.g., aluminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, niloprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam, sud ... (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h) inhibitors of phosphodiesterase type IV (PDE IV); (i) gold compounds such as auranofin and aurothioglucose; (j) etanercept (Enbrel®);(k) antibody therapeutics such as Orthoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®) and infliximab (Remicade®, adalimumab (Humira®), golimumab (Simponi®), rituximab (Rituxan®), tocilizumab (Actemra®); (l) other antagonists of chemokine receptors, particularly CCR5, CXCR2, CXCR3, CCR2, CCR3, CCR4, CCR7, CX3CR1 and CXCR6; (m) lubricants or emollients such as petrolatum and lanolin; (n) keratolytic agents (e.g. tazarotene), (o) vitamin D3 derivatives, such as calcipotriene or calcipotriol (Dovonex®), ));(p) PUVA;(q) anthralin (Drithrocreme®), (r) etretinate (Tegison®) and isotretinoin;(s) multiple sclerosis treatments such as interferon beta-1β (Betaseron®), interferon (beta-1α (Avonex®), azathioprine (Imurek®, Imuran®), glatiramer acetate (Capoxone®), glucocorticoids (e.g. prednisolone) and cyclophosphamide, (t) DMARDS such as methotrexate and leflunomide;(u) antimetabolites such as 5-aminosalicylic acid and its prodrugs, hydroxychloroquine, D-penicillamine, azathioprine, 6-mercaptopurine and methotrexate;These include, but are not limited to, DNA synthesis inhibitors such as hydroxyurea, and microtubule disrupting agents such as colchicine, and other compounds such as proteasome inhibitors such as bortezomib (Velcade®). The weight ratio of the compound of the present invention to the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when the compound of the present invention is combined with an NSAID, the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, and in other embodiments, from about 200:1 to about 1:200. Combinations of the compound of the present invention with other active ingredients will also generally be within the above ranges, but in each case an effective dose of each active ingredient will be used.; EXAMPLES

[0109] VI. Working Examples The following examples are offered to illustrate, but not to limit, the claimed invention.

[0110] Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1H-NMR was recorded on a Varian Mercury 400 MHz NMR spectrometer. Important peaks are provided relative to TMS and are listed in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and proton number. Mass spectrometry results are reported as the ratio of mass to charge followed by the relative abundance of each ion (in parentheses). In tables, a single m / e value is reported for the M+H (or MH where noted) ion containing the most common atomic isotopes. The isotopic pattern corresponds to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry was performed on a Hewlett-Packard MSD electrospray mass spectrometer using an HP1100 HPLC equipped with an Agilent Zorbax SB-C18, 2.1×50 mm, 5μ column for sample delivery. Typically, the analytes were dissolved in methanol at 0.1 mg / mL and 1 microliter was infused into the mass spectrometer with the delivery solvent, scanning from 100 to 1500 daltons. All of the compounds could be analyzed in positive ESI mode using acetonitrile / water with 1% formic acid as the delivery solvent. The compounds provided below could also be analyzed in negative ESI mode using acetonitrile / water with 2 mM NHOAc as the delivery system.

[0111] The following abbreviations are used in the examples and throughout the description of the invention: HPLC, high pressure liquid chromatography; DMF, dimethylformamide; TFA, trifluoroacetic acid; THF, tetrahydrofuran; EtOAc, ethyl acetate; BOC2O, di-tertbutyl dicarbonate or BOC anhydride; HPLC, high pressure liquid chromatography; DIPEA, diisopropylethylamine; HBTU, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; dppf, 1,1'-bis(diphenylphosphino)ferrocene; Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0); DIPEA, diisopropylethylamine; DMP, dimethyl phthalate; Me, methyl; Et, ethyl; DCM, dichloromethane.

[0112] Compounds within the scope of the present invention can be synthesized using a variety of reactions known to those skilled in the art, as described below. Those skilled in the art will also recognize that alternative methods may be employed to synthesize the target compounds of the present invention, and that the approaches described in the main body of this specification, while not exhaustive, provide widely applicable and practical routes to compounds of interest.

[0113] Certain molecules claimed in this patent can exist in different enantiomeric and diastereomeric forms, and all such variants of these compounds are claimed.

[0114] The detailed description of the experimental procedures used to synthesize compounds of interest herein results in molecules that are illustrated by physical data that identifies the compounds and structural diagrams that relate to the compounds.

[0115] Those skilled in the art will also recognize that acids and bases are frequently used during standard workup procedures in organic chemistry. Salts of parent compounds may also be prepared during the laboratory procedures described within this patent, where they have the required inherent acidity or basicity.

[0116] Example A: Preparation of the bromine intermediate (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To a round bottom flask was added tert-butyl (3S,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (8.65 g, 40 mmol), 2-bromo-5-(trifluoromethyl)pyridine (18.08 g, 80 mmol), NMP (40 mL), and N,N-diisopropylethylamine (21 mL, 120 mmol). The reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was cooled to room temperature and diluted with 2 M HCl (100 mL, 200 mmol). The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature and washed with 2-methyltetrahydrofuran (2 x 100 mL). The organic layer was discarded and the aqueous layer was basified to pH 13-14 by addition of 50% aqueous sodium hydroxide and extracted with 2-methyltetrahydrofuran (5 x 100 mL). The combined organic layers were stirred and a solution of sodium bicarbonate (5.04 g, 60 mmol) in water (100 mL) was added followed by 4-bromobenzenesulfonyl chloride (10.22 g, 40 mmol). The reaction mixture was stirred at room temperature for 45 min. The layers were separated and the organic layer was washed with water (100 mL) and concentrated. The solvent was exchanged to toluene and a white solid appeared. The solid was filtered, washed with toluene and dried to give (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 17 H 18 F3N3O3S [M+H] + The calculated value was 480.0 and the actual value was 480.1.

[0117] Example B: (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To tert-butyl N-[(3S,4R)-3-hydroxy-4-piperidyl]carbamate (10.0 g, 0.046 mol) in 100 mL of CHCl is added 100 mL of saturated NaHCO and 4-bromobenzenesulfonyl chloride (12.32 g, 0.048 mol). The heterogeneous mixture is stirred with an overhead stirrer for 16 h. The solid is collected by filtration and the precipitate is rinsed with CHCl. ​​The material is dried under vacuum to give tert-butyl N-[(3S,4R)-1-(4-bromophenyl)sulfonyl-3-hydroxy-4-piperidyl]carbamate.

[0118] To tert-butyl N-[(3S,4R)-1-(4-bromophenyl)sulfonyl-3-hydroxy-4-piperidyl]carbamate (17.28 g, 0.040 mol) in a 200 mL round bottom flask is added 4 M HCl / dioxane (84.4 mL, 0.336 mol). The heterogeneous mixture is heated to 70 °C for 2 h. The mixture is poured into 500 mL of Et2O. The solid is filtered off and air dried to give (3S,4R)-4-amino-1-(4-bromophenyl)sulfonyl-piperidin-3-ol hydrochloride.

[0119] To (3S,4R)-4-amino-1-(4-bromophenyl)sulfonyl-piperidin-3-ol hydrochloride (250 mg, 0.67 mmol) in 1 mL of NMP, add 2-chloro-3-methyl-5-(trifluoromethyl)pyridine (275 mg, 1.40 mmol) and N,N-diisopropylethylamine (337 uL, 1.93 mmol). The mixture is heated at 100° C. for 16 h, then at 120° C. o Heat at RT for 24 h. The mixture is diluted with EtOAc (30 mL) and washed with HO (4 x 15 mL) and brine (30 mL). The organic phase is partitioned, dried over MgSO, filtered, and concentrated. The crude material is purified by SiO chromatography (hexanes / ethyl acetate) to give (3S,4R)-1-(4-bromophenyl)sulfonyl-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]piperidin-3-ol. MS: (ES) m / z C 18 H19 BrF3N3O3S [M+H] + Calculated value: 494.0 / 496.0, actual value: 493.9 / 495.9.

[0120] Example C: 2-(((3S,4R)-1-((4-bromophenyl)sulfonyl)-3-hydroxypiperidin-4-yl)amino)-5-(trifluoromethyl)nicotinonitrile [ka] A mixture of 2-chloro-5-(trifluoromethyl)nicotinonitrile (103 mg, 0.50 mmol), (3S,4R)-4-amino-1-((4-bromophenyl)sulfonyl)piperidin-3-ol hydrochloride (279 mg, 0.75 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) in NMP (1 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water. The resulting solid was filtered, washed with water and purified by SiO2 gel chromatography (hexane / ethyl acetate) to give 2-(((3S,4R)-1-((4-bromophenyl)sulfonyl)-3-hydroxypiperidin-4-yl)amino)-5-(trifluoromethyl)nicotinonitrile. MS: (ES) m / z C 18 H 19 BrF3N3O3S [M+H] + The calculated value was 505.0, and the actual value was 504.9.

[0121] Example D: 6-(((3S,4R)-1-((4-bromophenyl)sulfonyl)-3-hydroxypiperidin-4-yl)amino)nicotinonitrile [ka] 6-(((3S,4R)-1-((4-bromophenyl)sulfonyl)-3-hydroxypiperidin-4-yl)amino)nicotinonitrile was synthesized by the procedure described in Example C starting from (3S,4R)-4-amino-1-((4-bromophenyl)sulfonyl)piperidin-3-ol hydrochloride and 6-fluoronicotinonitrile.

[0122] Example 1: (3S,4R)-1-((4-(3-amino-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] In a septum-capped vial, (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (70 mg, 0.14 mmol) was added 2M K2CO3 (0.23 mL, 0.46 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (42 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and allowed to cool when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give (3S,4R)-1-((4-(3-amino-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 24 H 23 F3N6O3S [M+H] + Calculated value: 533.1, measured value: 533.2. 1H NMR (400MHz, methanol-d4)δ 8.26(s,1H),8.18(s,1H),7.97(dd,J=8.6,0.8Hz,1H),7.96 - 7.88(m,4H),7.71- 7.65(m,1H),7.57(dd,J=8.6,1.5Hz,1H),6.80(d,J=9.2Hz,1H),4.02(s,1H),3.94 - 3.86(m,1H),3.75 - 3.65(m,2H),2.80(d,J=11.8Hz,1H),2.69(t,J=11.0Hz,1H),2.10 - 2.01(m,1H),1.88 - 1.80(m,1H).

[0123] Example 2: 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,4-dihydroquinolin-2(1H)-one [ka] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (70 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (36 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and then cooled when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,4-dihydroquinolin-2(1H)-one. MS: (ES) m / z C 26 H 25 F3N4O4S [M+H] +Calculated value: 547.2, measured value: 547.2. 1 H NMR (400MHz, methanol-d4)δ 8.19(s,1H),7.94 - 7.84(m,4H),7.76(d,J=9.3Hz,1H),7.60 - 7.50(m,2H),6.99(d,J=8.2Hz,1H),6.88(d,J=9.4Hz,1H),4.01(s,1H),3.91 - 3.85(m,1H),3.68 - 3.59(m,2H),3.05(t,J=7.6Hz,2H),2.82(d,J=11.9Hz,1H),2.75 - 2.66(m,1H),2.62(t,J=7.6Hz,2H),2.12 - 2.01(m,1H),1.91 - 1.83(m,1H).

[0124] Example 3: 7-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one [ka] Step 1: Preparation of the boronic ester intermediate: (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka]

[0125] (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (460 mg, 0.96 mmol), bis(pinacolato)diboron (300 mg, 1.2 mmol), KOAc (200 mg, 2.0 mmol) and Pd(dppf)Cl2·DCM (14 mg, 0.017 mmol) in a septum-capped vial. To this was added 5 mL of dioxane and the mixture was flushed with nitrogen for 20 min. The vial was sealed and the mixture was stirred at 90 °C for 2.5 h and the reaction proceeded to completion when it was cooled. The mixture was diluted with ethyl acetate (10 mL) and filtered to remove inorganic solids. The filtrate was concentrated and the resulting residue was purified by silica gel flash chromatography (10-54% EtOAc, hexanes) to give the title pinacol boronic ester.

[0126] Step 2: To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 7-bromo-3,4-dihydroisoquinolin-1(2H)-one (36 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and the reaction proceeded to completion upon which it was cooled. The mixture was purified by preparative reverse phase HPLC to give 7-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one. MS: (ES) m / z C 26 H 25 F3N4O4S [M+H] + Calculated value: 547.2, measured value: 547.2. 1H NMR(400MHz,methanol-d4)δ 8.49 - 8.41(m,2H),8.29 - 8.16(m,3H),8.06(d,J=8.1Hz,2H),7.98(d,J=8.3Hz,2H),7.76(d,J=9.2Hz,1H),6.88(d,J=9.3Hz,1H),4.02(s,1H),3.93 - 3.86(m,1H),3.70 - 3.63(m,2H),3.35 - 3.25(m,4H),2.88 - 2.80(m,1H),2.73(t,J=11.0Hz,1H),2.12 - 2.01(m,1H),1.91 - 1.83(m,1H).

[0127] Example 4: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)isoindoline-2-carboxamide [ka] Step 1: To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 5-bromoisoindoline (32 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and the reaction proceeded to completion upon which it was cooled. The mixture was purified by preparative reverse phase HPLC to give the intermediate (3S,4R)-1-((4-(isoindolin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol.

[0128] Step 2: To (3S,4R)-1-((4-(isoindolin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (9 mg, 0.017 mmol) in a vial was added acetonitrile (1 mL), isocyanatotrimethylsilane (4 mg, 0.035 mmol) and DIPEA (8.8 mg, 0.068 mmol). The mixture was stirred at room temperature for 1 h and then purified via preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)isoindoline-2-carboxamide. MS: (ES) m / z C 26 H 26 F3N5O4S [M+H] + Calculated value: 562.2, actual value: 562.2. 1 H NMR(400MHz,methanol-d4)δ 8.19(s,1H),7.92 - 7.86(m,4H),7.78(d,J=9.2Hz,1H),7.65(d,J=8.4Hz,2H),7.45(d,J=7.9Hz,1H),6.91(d,J=9.2Hz,1H),4.75(d,J=9.0Hz,4H),4.01(s,1H),3 .88(d,J=10.1Hz,1H),3.64(d,J=11.9Hz,2H),2.83(d,J=12.4Hz,1H),2.70(d,J=11.7Hz,1H),2.04(t,J=11.3Hz,1H),1.88(d,J=5.2Hz,1H).

[0129] Example 5: 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)phthalazin-1(2H)-one [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 6-bromophthalazin-1(2H)-one (36 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and allowed to cool when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)phthalazin-1(2H)-one. MS: (ES) m / z C 25 H 22 F3N5O4S [M+H] + Calculated value: 546.1, measured value: 546.2. 1 H NMR (400MHz, methanol-d4)δ 8.46(d,J=8.5Hz,1H),8.44(s,1H),8.26(d,J=1.6Hz,1H),8.23 - 8.19(m,1H),8.17(d,J=2.2Hz,1H),8.08 - 8.04(m,2H),7.98(d,J=8.2Hz,2H),7.70 - 7.61(m,1H),6.79 - 6.74(m,1H),4.02(s,1H),3.95 - 3.87(m,1H),3.70(dt,J=9.4,4.6Hz,2H),2.83(d,J=12.3Hz,1H),2.72(t,J=11.1Hz,1H),2.12 - 1.95(m,1H),1.89 - 1.78(m,1H).

[0130] Example 6: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3-methylpicolinamide [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (70 mg, 0.13 mmol) in a septum-capped vial was added K2CO3 (56 mg, 0.41 mmol), 4-bromo-3-methylpicolinamide (28 mg, 0.13 mmol), Pd(dppf)Cl2·DCM (13 mg, 0.016 mmol). To this was added 3 mL of dioxane and 0.7 mL of water. The mixture was flushed with nitrogen for 6 minutes. The vial was sealed and the mixture was stirred at 100 °C for 4 hours and then cooled down after the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3-methylpicolinamide. MS: (ES) m / z C 24 H 25 F3N5O4S [M+H] + Calculated value: 536.2, measured value: 536.1. 1 H NMR(400MHz, methanol-d4)δ 8.50(d,1H),8.22(s,1H),7.95(d,J=8.0Hz,2H),7.87(d,J=9.4Hz,1H),7.64(d ,J=8.1Hz,2H),7.41(d,J=4.8Hz,1H),7.01(d,J=9.4Hz,1H),4.03(s,1H),3.93 - 3.86(m,1H),3.74 - 3.65(m,2H),2.85(d,J=12.3Hz,1H),2.80 - 2.71(m,1H),2.43(s,3H),2.14 - 2.04(m,1H),1.88(d,J=13.0Hz,1H).

[0131] Example 7: 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (73 mg, 0.14 mmol) in a septum-capped vial was added K2CO3 (68 mg, 0.49 mmol), 6-bromopicolinamide (29 mg, 0.14 mmol), Pd(dppf)Cl2·DCM (10 mg, 0.012 mmol). To this was added 3 mL of dioxane and 0.7 mL of water. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 2.4 h and then cooled when the reaction had proceeded to completion. The mixture was purified by silica gel chromatography to give 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide. MS: (ES) m / z C 23 H 23 F3N5O4S [M+H] + Calculated value: 522.1, measured value: 522.2. 1 H NMR(400MHz, methanol-d4)δ 8.45(d,J=8.1Hz,2H),8.24 - 8.05(m,4H),7.94(d,J=8.5Hz,2H),7.55(d,J=9.2Hz,1H),6.64(d,J=9.0Hz,1H),4.01(s,1H),3.95 - 3.86(m,1H),3.76 - 3.65(m,2H),2.78(d,J=12.3Hz,1H),2.67(t,J=11.2Hz,1H),2.08 - 1.95(m,1H),1.82(d,J=6.9Hz,1H).

[0132] Example 8: 7-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1,4-dihydroisoquinolin-3(2H)-one [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 7-bromo-1,4-dihydroisoquinolin-3(2H)-one (36 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and then cooled down until the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 7-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1,4-dihydroisoquinolin-3(2H)-one. MS: (ES) m / z C 26 H 25 F3N4O4S [M+H] + Calculated value: 547.2, measured value: 547.2. 1 H NMR (400MHz, methanol-d4)δ 8.20(s,1H),7.94 - 7.84(m,4H),7.82(d,J=9.2Hz,1H),7.65 - 7.60(m,2H),7.36(d,J=8.2Hz,1H),6.95(d,J=9.3Hz,1H),4.56(d,J=2.3Hz,2H),4.01(s,1H),3.91 - 3.84(m,1H),3.67 - 3.58(m,4H),2.84(d,J=12.1Hz,1H),2.78 - 2.68(m,1H),2.12 - 2.01(m,1H),1.91 - 1.83(m,1H).

[0133] Example 9: 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)indolin-2-one [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 6-bromoindolin-2-one (34 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and then cooled down until the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)indolin-2-one. MS: (ES) m / z C 25 H 23 F3N4O4S [M+H] + Calculated value: 533.1, actual value: 533.1. 1 H NMR (400MHz, methanol-d4)δ 8.20(s,1H),7.94 - 7.84(m,4H),7.82(d,J=9.2Hz,1H),7.65 - 7.60(m,2H),7.36(s,1H),6.95(d,J=9.3Hz,1H),4.01(s,1H),3.91 - 3.84(m,1H),3.72 - 3.65(m,2H),3.61(s,2H),2.92 - 2.74(m,2H),2.12 - 2.01(m,1H),1.91 - 1.83(m,1H).

[0134] Example 10: (3S,4R)-1-((4-(2-((hydroxymethyl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (71 mg, 0.13 mmol) in a septum-capped vial was added K2CO3 (66 mg, 0.48 mmol), (4-bromopyridin-2-yl)methanol (33 mg, 0.17 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 3 mL of dioxane and 0.7 mL of water. The mixture was flushed with nitrogen for 9 minutes. The vial was sealed and the mixture was stirred at 100 °C for 1.4 hours and then cooled when the reaction had proceeded to completion. The mixture was purified by silica gel chromatography to give (3S,4R)-1-((4-(2-((hydroxymethyl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 23 H 24 F3N4O4S [M+H] + Calculated value: 509.1, measured value: 509.1. 1 H NMR(400MHz, methanol-d4)δ 8.64(d,J=5.5Hz,1H),8.17 - 8.13(m,1H),8.10 - 7.94(m,5H),7.85(dd,J=5.7,1.8Hz,1H),7.56(dd,J=9.6,2.4Hz,1H),6.64( d,J=9.0Hz,1H),4.87(s,2H),4.00(s,1H),3.91(dt,J=10.9,3.5Hz,1H),3.77 - 3.66(m,2H),2.79(dd,J=12.4,2.1Hz,1H),2.73 - 2.62(m,1H),2.08 - 1.93(m,1H),1.80(dd,J=13.2,3.8Hz,1H).

[0135] Example 11: (3S,4R)-1-((4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] A mixture of 4-bromopyridine-2-carboxylate (432 mg, 2.0 mmol) and hydrazine monohydrate (0.39 mL, 8.0 mmol) in ethanol (5 mL) was stirred at 70° C. for 1.5 h. The reaction mixture was cooled to room temperature. The resulting solid was filtered, washed with ethanol, and dried to give 4-bromopicolinohydrazide.

[0136] A mixture of 4-bromopicolinohydrazide (108 mg, 0.50 mmol), trimethyl orthoacetate (1.3 mL, 10.0 mmol) and one drop of concentrated hydrochloride was stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL, 2.5 mmol) was added and stirring was continued at 110 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated. Purification by SiO2 gel chromatography (hexanes / ethyl acetate) gave 2-(4-bromopyridin-2-yl)-5-methyl-1,3,4-oxadiazole.

[0137] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (79 mg, 0.15 mmol) in a septum-capped vial was added K2CO3 (62 mg, 0.45 mmol), 2-(4-bromopyridin-2-yl)-5-methyl-1,3,4-oxadiazole (43 mg, 0.18 mmol), dioxane (1.5 mL) and water (0.5 mmol). The mixture was flushed with nitrogen for 20 min. Pd(dppf)Cl2·DCM (12 mg, 0.015 mmol) was added and the mixture was flushed with nitrogen for an additional 5 min. The vial was sealed and the mixture was stirred at 100° C. for 16 h, at which point the reaction proceeded to completion and was then cooled. The mixture was purified by SiO2 gel chromatography (hexanes / ethyl acetate, then ethyl acetate / methanol) followed by preparative reverse phase HPLC to give ((3S,4R)-1-((4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 24 F3N6O4S [M + H] + Calculated value: 561.2, actual value: 561.2. 1 H NMR(400MHz,DMSO-d6)δ 8.89(dd,J=5.2,0.8Hz,1H),8.46(dt,J=1.7,0.8Hz,1H),8.19(s,1H),8.17(d,J=8.6Hz,2H),8.04(dd,J=5.2,1.9Hz,1H),7.92(d,J= 8.5Hz,2H),7.58(dd,J=9.0,2.6Hz,1H),7.12(d,J=7.9Hz,1H),6.69(d,J=8.9Hz,1H),5.26(d,J=4.0Hz,1H),3.97-3.85(m,2H),3.60 - 3.45(m,2H),2.74(d,J=12.1Hz,1H),2.68-2.58(m,4H),1.97 - 1.82(m,1H),1.70-1.61(m,1H).

[0138] Example 12: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)isoindolin-1-one [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 5-bromoisoindolin-1-one (34 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and allowed to cool when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)isoindolin-1-one. MS: (ES) m / z C 25 H 23 F3N4O4S [M+H] + Calculated value: 533.1, actual value: 533.1. 1 H NMR (400MHz, methanol-d4)δ 8.20(s,1H),7.94 - 7.84(m,4H),7.82(d,J=9.2Hz,1H),7.65 - 7.60(m,2H),7.36(s,1H),6.95(d,J=9.3Hz,1H),4.56(d,J=2.3Hz,2H),4.01(s,1H),3.91 - 3.84(m,1H),3.72 - 3.65(m,2H),2.92 - 2.74(m,2H),2.12 - 2.01(m,1H),1.91 - 1.83(m,1H).

[0139] Example 13: (3S,4R)-1-((4-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-amine (34 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and then cooled down when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give (3S,4R)-1-((4-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 23 H 22 F3N7O3S [M+H] + Calculated value: 534.1, measured value: 534.1. 1 H NMR(400MHz, methanol-d4)δ 8.77(s,1H),8.20 - 8.10(m,2H),7.99(s,3H),7.82(d,J=9.2Hz,1H),7.68 - 7.61(m,2H),6.74(d,J=9.3Hz,1H),4.01(s,1H),3.95 - 3.85(m,1H),3.78 - 3.68(m,2H),2.82 - 2.76(m,1H),2.73 - 2.58(m,1H),2.10 - 1.95(m,1H),1.88 - 1.78(m,1H).

[0140] Example 14: 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,4-dihydroquinazolin-2(1H)-one [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 6-bromo-3,4-dihydroquinazolin-2(1H)-one (36 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and then cooled down until the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,4-dihydroquinazolin-2(1H)-one. MS: (ES) m / z C 25 H 24 F3N5O4S [M+H] + Calculated value: 548.2, actual value: 548.2. 1 H NMR (400MHz, methanol-d4)δ 8.18(s,1H),7.90 - 7.82(m,4H),7.72(d,J=9.2Hz,1H),7.56 - 7.46(m,2H),6.92(d,J=9.3Hz,1H),6.84(d,J=9.3Hz,1H),4.55(s,2H),4.01(s,1H),3.93 - 3.85(m,1H),3.70 - 3.60(m,2H),2.85 - 2.76(m,1H),2.74 - 2.65(m,1H),2.10 - 2.00(m,1H),1.90 - 1.80(m,1H).

[0141] Example 15: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-7-methoxyindolin-2-one [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added 2M K2CO3 (0.23 mL, 0.46 mmol), 5-bromo-7-methoxyindolin-2-one (39 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and then cooled down when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-7-methoxyindolin-2-one. MS: (ES) m / z C 26 H 25 F3N4O5S [M+H] + Calculated value: 563.2, actual value: 563.2. 1 H NMR (400MHz, methanol-d4)δ 8.19(s,1H),7.90 - 7.84(m,4H),7.76(d,J=9.2Hz,1H),7.26 - 7.20(m,2H),6.90(d,J=9.3Hz,1H),4.03 - 3.99(m,1H),3.97(s,3H),3.91 - 3.84(m,1H),3.70 - 3.58(m,4H),2.81(d,J=12.1Hz,1H),2.75 - 2.66(m,1H),2.11 - 2.00(m,1H),1.90 - 1.83(m,1H).

[0142] Example 16: (3S,4R)-1-((4-(7-methyl-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added K2CO3 (0.65 mg, 0.47 mmol), 5-bromo-7-methyl-1H-indazole (33 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (0.12 mg, 0.015 mmol). To this was added 1 mL of dioxane and 0.5 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 4 h and the reaction proceeded to completion before being cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(7-methyl-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 25 F3N5O3S [M+H] + Calculated value: 532.2, actual value: 532.2. 1H NMR(400MHz,CD3OD)δ 8.19(bs,1H),8.13(s,1H),7.95 - 7.91(m,3H),7.90 - 7.86(m,2H),7.79(dd,J=9.6,2Hz,1H),7.54 - 7.53(m,1H),6.93(d,J=9.2Hz,1H),4.03 - 4.00(m,1H),3.88(ddd,J=9.3,4.0,4.0Hz,1H),3.71 - 3.56(m,2H),2.85(d,J=12.3Hz,1H),2.74(dd,J=11.3,11.3Hz,1H),2.65(s,3H),2.19 - 1.97(m,1H),1.91 - 1.83(m,1H).

[0143] Example 17: (3S,4R)-1-((4-(6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added K2CO3 (65 mg, 0.47 mmol), 5-bromo-6-methyl-1H-pyrrolo[2,3-b]pyridine (33 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.014 mmol). To this was added 1 mL of dioxane and 0.3 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and then cooled down until the reaction had proceeded to completion. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C25 H 25 F3N5O3S [M+H] + Calculated value: 532.2, actual value: 532.0. 1 H NMR(400MHz,CD3OD)δ 8.41(s,1H),8.24 - 8.17(m,1H),8.00 - 7.92(m,2H),7.76 - 7.73(m,2H),7.73 - 7.71(m,1H),7.61(d,J=3.5Hz,1H),6.85(d,J=9.1Hz,1H),6.80(d,J=3.5Hz,1H),4.05 - 4.01(m,1H),3.92(ddd,J=10.4,4.4,4.4Hz,1H),3.78 - 3.70(m,2H),2.83(d,J=13.0Hz,1H),2.76 - 2.68(m,1H),2.68(s,3H),2.16 - 1.98(m,1H),1.94 - 1.77(m,1H).

[0144] Example 18: 2-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)isonicotinamide [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (70 mg, 0.13 mmol) in a septum-capped vial was added K2CO3 (59 mg, 0.43 mmol), 2-bromoisonicotinamide (28 mg, 0.14 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.015 mmol). To this was added 3 mL of dioxane and 0.7 mL of water. The mixture was flushed with nitrogen for 14 minutes. The vial was sealed and the mixture was stirred at 100 °C for 2.3 hours and then cooled when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 2-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)isonicotinamide. MS: (ES) m / z C 23 H 23 F3N5O4S [M+H] + Calculated value: 522.1, measured value: 522.2. 1 H NMR (400MHz, methanol-d4)δ 8.84(dd,J=5.1,0.8Hz,1H),8.38 - 8.36(m,1H),8.35 - 8.31(m,2H),8.20(s,1H),8.00 - 7.92(m,2H),7.87 - 7.79(m,2H),6.97(d,J=9.3Hz,1H),4.05 - 3.99(m,1H),3.91 - 3.84(m,1H),3.65(d,J=11.6Hz,2H),2.87(d,J=11.9Hz,1H),2.76(t,J=11.6Hz,1H),2.05(t,J=9.8Hz,1H),1.92 - 1.83(m,1H).

[0145] Example 19: 3-amino-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (80 mg, 0.15 mmol) in a septum-capped vial was added K2CO3 (65 mg, 0.47 mmol), 3-amino-5-bromopicolinamide (37 mg, 0.17 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.015 mmol). To this was added 3 mL of dioxane and 0.7 mL of water. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 2.3 h and then cooled when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 3-amino-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide. MS: (ES) m / z C 23 H 24 F3N6O4S [M+H] + Calculated value: 537.2, measured value: 537.2. 1 H NMR(400MHz, methanol-d4)δ 8.20(d,J=2.3Hz,1H),8.15(d,J=2.0Hz,1H),7.95 - 7.88(m,4H),7.83(dd,J=9.6,2.4Hz,1H),7.43(d,J=2.0Hz,1H),6.97(d,J=9.3Hz,1H),4.05 - 3.99(m,1H),3.88(dt,J=10.3,3.9Hz,1H),3.65(d,J=12.3Hz,2H),2.85(d,J=12.3Hz,1H),2.74(t,J=10.8Hz,1H),2.13 - 2.00(m,1H),1.91 - 1.82(m,1H).

[0146] Example 20: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-5-methylpicolinamide [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (80 mg, 0.15 mmol) in a septum-capped vial was added K2CO3 (65 mg, 0.47 mmol), 4-bromo-5-methylpicolinamide (33 mg, 0.15 mmol), Pd(dppf)Cl2·DCM (15 mg, 0.018 mmol). To this was added 3 mL of dioxane and 0.7 mL of water. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 4 h and the reaction proceeded to completion before being cooled. The mixture was purified by preparative reverse phase HPLC to give 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-5-methylpicolinamide. MS: (ES) m / z C 24 H 25 F3N5O4S [M+H] + Calculated value: 536.2, measured value: 536.1. 1 H NMR(400MHz, methanol-d4)δ 8.51(d,J=5.0Hz,1H),8.25(t,J=1.8Hz,1H),7.99 - 7.87(m,3H),7.68 - 7.60(m,2H),7.41(d,J=5.0Hz,1H),7.07(d,J=9.4Hz,1H),4.03(d,J=2.7Hz,1H),3.90(dt,J=10.4,3.9Hz,1H),3.71(d,J=12.4Hz,2H),2.90 - 2.79(m,1H),2.80 - 2.69(m,1H),2.43(d,J=0.5Hz,3H),2.17 - 2.00(m,1H),1.93 - 1.84(m,1H).

[0147] Example 21: (3S,4R)-1-((4-(7-methoxy-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added K2CO3 (65 mg, 0.47 mmol), 5-bromo-6-methyl-1H-pyrrolo[2,3-b]pyridine (37 mg, 0.157 mmol), Pd(dppf)Cl2·DCM (0.012 mg, 0.015 mmol). To this was added 1 mL of dioxane and 0.35 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 2 h and then cooled down after the reaction had proceeded to completion. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(7-methoxy-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 25 F3N5O4S [M+H] + Calculated value: 548.2, measured value: 548.1. 1 H NMR(400MHz,CD3OD)δ 8.18 - 8.15(m,1H),8.06(s,1H),7.96 - 7.90(m,2H),7.87 - 7.83(m,2H),7.78(d,J=9.0Hz,1H),7.64(d,J=1.3Hz,1H),7.10(d,J=1.2Hz,1H),6.92(d,J=9.3Hz,1H),4.07(s,3H),4.01 - 3.98(m,1H),3.85(ddd,J=10.0,3.2,3.2Hz,1H),3.68 - 3.53(m,2H),2.82(d,J=11.7Hz,1H),2.72(dd,J=10.0,10.0Hz,1H),2.10 - 1.98(m,1H),1.88 - 1.80(m,1H).

[0148] Example 22: (3S,4R)-1-((4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added K2CO3 (65 mg, 0.47 mmol), 5-bromo-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (41 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.015 mmol). To this was added 1 mL of dioxane and 0.35 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and then cooled down until the reaction had proceeded to completion. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 22 F6N5O3S [M+H] + Calculated value: 586.1, actual value: 586.0. 1H NMR(400MHz,CD3OD)δ 8.17(bs,1H),8.15(s,1H),7.86(d,J=8.4Hz,2H),7.80(d,J=9.3Hz,1H),7.64(d,J=3.6Hz,1H),7.60(d,J=8.4Hz,2H),6.95(d,J=9.3Hz,1H),6.70 - 6.66(m,1H),4.00 - 3.96(m,1H),3.84(ddd,J=10.4,4.0,4.0Hz,1H),3.67(dd,J=12.8,5.2Hz,2H),2.78(d,J=12.1Hz,1H),2.67(dd,J=10.8,10.8Hz,1H),2.15 - 1.99(m,1H),1.89 - 1.74(m,1H).

[0149] Example 23: (3S,4R)-1-((4-(1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added K2CO3 (75 mg, 0.142 mmol), 5-bromo-1H-indazole (31 mg, 0.158 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.015 mmol). To this was added 1 mL of dioxane and 0.35 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 110 °C for 16 h and the reaction proceeded to completion before being cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 24 H 23F3N5O3S [M+H] + Calculated value: 518.1, measured value: 517.9. 1 H NMR(400MHz,CD3OD)δ 8.15(bs,1H),8.11(d,J=1.0Hz,1H),8.09(dd,J=1.7,0.9Hz,1H),7.90(d,J=8.8Hz,2H),7.85(d,J=8.8Hz,2H),7.76 - 7.71(m,2H),7.63(ddd,J=8.8,1.0,1.0Hz,1H),6.87(d,J=9.2Hz,1H),4.00 - 3.96(m,1H),3.84(d,J=10.2,4.0,4.0Hz,1H),3.60(dd,J=12.3,3.6Hz,2H),2.80(d,J=12.1Hz,1H),2.70(dd,J=11.6,11.6Hz,1H),2.18 - 1.91(m,1H),1.84(s,1H).

[0150] Example 24: (3S,4R)-1-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added K2CO3 (65 mg, 0.47 mmol), 5-bromo-1H-pyrrolo[2,3-b]pyridine (31 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.015 mmol). To this was added 1 mL of dioxane and 0.35 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and then cooled down after the reaction had proceeded to completion. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 24 H 23 F3N5O3S [M+H] + Calculated value: 518.1, measured value: 517.9. 1 H NMR(400MHz,CD3OD)δ 8.54(dd,J=10.0,2.0Hz,2H),8.17 - 8.14(m,1H),7.91(d,J=8.8Hz,2H),7.87(d,J=8.8Hz,2H),7.79(dd,J=9.4,2.4H z,1H),7.53(d,J=3.5Hz,1H),6.94(d,J=9.3Hz,1H),6.68(d,J=3.5Hz,1H),3.99 - 3.95(m,1H),3.82(ddd,J=10.3,3.8,3.8Hz,1H),3.60(d,J=12.2Hz,2H),2.79(dd,J=12.4,2.0Hz,1H),2.67(ddd,J=8.0,8.0,3.2Hz,1H),2.07 - 1.96(m,1H),1.85 - 1.77(m,1H).

[0151] Example 25: (3S,4R)-1-((4-(6-methyl-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added K2CO3 (65 mg, 0.47 mmol), 5-bromo-6-methyl-1H-indazole (33 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.015 mmol). To this was added 1 mL of dioxane and 0.35 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion upon which it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(6-methyl-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 25 F3N5O3S [M+H] + The calculated value was 531.2, and the measured value was 531.9. 1H NMR(400MHz,CD3OD)δ 8.19(bs,1H),8.01(d,J=1.0Hz,1H),7.86(d,J=8.8Hz,2H),7.79(d,J=9.1,2.0Hz,1H),7.62-7.59(m,3H),7.46 - 7.45(m,1H),6.92(d,J=9.3Hz,1H),4.02 - 3.99(m,1H),3.88(ddd,J=9.7,3.6,3.6Hz,1H),3.67(dd,J=12.3,4.8Hz,2H ),2.82(d,J=12.3Hz,1H),2.70(dd,J=11.5,11.5Hz,1H),2.35(s,3H),2.12 - 2.00(m,1H),1.90 - 1.81(m,1H).

[0152] Example 26: (3S,4R)-1-((4-(4-methyl-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.14 mmol) in a septum-capped vial was added K2CO3 (65 mg, 0.47 mmol), 5-bromo-4-methyl-1H-indazole (33 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (12 mg, 0.015 mmol). To this was added 1 mL of dioxane and 0.35 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion upon which it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(4-methyl-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H25 F3N5O3S [M+H] + The calculated value was 531.2, and the measured value was 531.9. 1 H NMR(400MHz,CD3OD)δ 8.16(bs,1H),8.15(d,J=1.0Hz,1H),7.85(d,J=8.4Hz,2H),7.76(d,J=9.1,2.0Hz,1H),7.6 0(d,J=8.8Hz,2H),7.43(d,J=8.6Hz,1H),7.28(d,J=8.6Hz,1H),6.89(d,J=9.3Hz,1H),4.01 - 3.98(m,1H),3.86(ddd,J=10.5,3.2,3.2Hz,1H),3.65(d,J=11.8,3.2Hz,2H ),2.81(d,J=12.3Hz,1H),2.68(dd,J=11.5,11.5Hz,1H),2.52(s,3H),2.10 - 1.96(m,1H),1.88 - 1.80(m,1H).

[0153] Example 27: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)nicotinamide [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (60 mg, 0.11 mmol) in a septum-capped vial was added K2CO3 (49 mg, 0.36 mmol), 5-bromonicotinamide (23 mg, 0.11 mmol), Pd(dppf)Cl2·DCM (9.4 mg, 0.012 mmol). To this was added 3 mL of dioxane and 0.7 mL of water. The mixture was flushed with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 2 hours and allowed to cool when the reaction had proceeded to completion. The mixture was purified by silica gel chromatography to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)nicotinamide. MS: (ES) m / z C 23 H 23 F3N5O4S [M+H] + Calculated value: 522.1, measured value: 521.9. 1 H NMR(400MHz, methanol-d4)δ 9.05(dd,J=8.6,2.1Hz,2H),8.60(t,J=2.1Hz,1H),8.15(t,J=1.7Hz,1H),8.02(d,J=8.6Hz,2H) ,7.97(d,J=8.6Hz,2H),7.68(d,J=7.3Hz,1H),6.79(d,J=9.2Hz,1H),3.99(d,J=3.7Hz,1H),3.91 - 3.83(m,1H),3.70 - 3.61(m,2H),2.81(d,J=11.7Hz,1H),2.69(t,J=11.1Hz,1H),2.07 - 1.96(m,1H),1.86 - 1.76(m,1H).

[0154] Example 28: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (60 mg, 0.11 mmol) in a septum-capped vial was added K2CO3 (45 mg, 0.33 mmol), 2-bromo-4-pyridinecarboxamide (25 mg, 0.12 mmol), Pd(dppf)Cl2·DCM (9.4 mg, 0.012 mmol). To this was added 3 mL of dioxane and 0.7 mL of water. The mixture was flushed with nitrogen for 15 min. The vial was sealed and the mixture was stirred at 100 °C for 1.3 h and then cooled down after the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide. MS: (ES) m / z C 23 H 23 F3N5O4S [M+H] + Calculated value: 522.1, measured value: 521.9. 1 H NMR(400MHz,DMSO-d6)δ 9.03(dd,J=2.3,0.9Hz,1H),8.37(dd,J=8.2,2.3Hz,1H),8.25 - 8.20(m,2H),8.16(d,J=8.0Hz,1H),8.11 - 8.06(m,2H),7.93 - 7.86(m,2H),7.75(s,1H),7.63(dd,J=9.0,2.5Hz,1H),7.30(s,1H),6.75(d,J=9.0Hz,1H),3.90(d,J=12.4Hz,2H),3.59 - 3.46(m,2H),2.71(d,J=11.8Hz,1H),2.63 - 2.55(m,1H),1.95 - 1.82(m,1H),1.73 - 1.62(m,1H).

[0155] Example 29: tert-butyl (2-(3-cyano-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)carbamate [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (144 mg, 0.27 mmol) in a septum-capped vial was added K2CO3 (104 mg, 0.75 mmol), tert-butyl (2-(5-bromo-3-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)carbamate (100 mg, 0.27 mmol), Pd(dppf)Cl2·DCM (23 mg, 0.028 mmol). To this was added 6 mL of dioxane and 1.5 mL of water. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100° C. for 16 hours and cooled when the reaction had proceeded to completion. The mixture was purified by silica gel chromatography to give tert-butyl (2-(3-cyano-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)carbamate. MS: (ES) m / z C 32 H 35 F3N7O5S [M+H] + Calculated value: 686.2, measured value: 685.9. 1H NMR(400MHz,DMSO-d6)δ 8.82(d,J=2.0Hz,1H),8.48(d,J=2.9Hz,2H),8.18(s,1H),8.08(d,J=8.1Hz,2H),7.84(d,J=8.1Hz,2H),7.56(dd,J=9.4,2 .5Hz,1H),7.10(s,1H),6.96(d,J=6.0Hz,1H),6.68(d,J=8.9Hz,1H),5.23(s,1H),4.38(t,J=5.8Hz,2H),3.88(s,2H),3.58 - 3.44(m,2H),3.43 - 3.35(m,2H),2.71(d,J=11.5Hz,1H),2.66 - 2.53(m,1H),1.93 - 1.81(m,1H),1.70 - 1.62(m,1H),1.27(s,9H).

[0156] Example 30: 2-amino-6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)quinazolin-4(3H)-one [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (70 mg, 0.13 mmol) in a septum-capped vial was added K2CO3 (53 mg, 0.38 mmol), 2-amino-6-bromoquinazolin-4-ol (32 mg, 0.13 mmol) Pd(dppf)Cl2·DCM (13 mg, 0.016 mmol). To this was added 3 mL of dioxane and 1 mL of water. The mixture was flushed with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 2 hours and allowed to cool when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 2-amino-6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)quinazolin-4(3H)-one. MS: (ES) m / z C25 H 24 F3N6O4S [M+H] + The calculated value was 561.2, and the measured value was 561.3. 1 H NMR (400MHz, methanol-d4)δ 8.44(d,J=2.2Hz,1H),8.21 - 8.12(m,2H),8.00 - 7.89(m,4H),7.62 - 7.51(m,2H),6.66(d,J=9.0Hz,1H),4.01(q,J=4.1,3.2Hz,1H),3.91(dt,J=10.8,3.7Hz,1H),3.76 - 3.64(m,2H),2.82 - 2.74(m,1H),2.67(td,J=11.5,3.0Hz,1H),2.03 - 1.95(m,1H),1.82(dt,J=13.6,3.9Hz,1H).

[0157] Example 31: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide [ka] To (3S,4R)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (50 mg, 0.095 mmol) in a septum-capped vial was added K2CO3 (41 mg, 0.30 mmol), 4-bromopicolinamide (19 mg, 0.095 mmol), Pd(dppf)Cl2·DCM (7.3 mg, 0.089 mmol). To this was added 3.0 mL of dioxane and 0.7 mL of water. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1.9 h and the reaction proceeded to completion before being cooled. The reaction mixture was diluted with 0.1% aqueous trifluoroacetic acid (1 mL), acetic acid (0.5 mL), and 1-methyl-2-pyrrolidone (1 mL). This solution was injected through a syringe filter into a preparative HPLC (27-50% ACN, 0.1% TFA) and the product was eluted with 33% ACN. The clean fractions were lyophilized to give the title compound. MS: (ES) m / z C 23 H 23 F3N5O4S [M+H] + Calculated value: 522.1, measured value: 522.3. 1 H NMR(400MHz,DMSO-d6)δ 8.75(dd,J=5.1,0.8Hz,1H),8.35(dd,J=2.0,0.8Hz,1H),8.26 - 8.18(m,2H),8.15 - 8.07(m,2H),8.00(dd,J=5.1,1.9Hz,1H),7.93 - 7.85(m,2H),7.77(d,J=3.1Hz,1H),7.65 - 7.58(m,1H),7.29(s,1H),6.73(d,J=9.0Hz,1H),3.94 - 3.83(m,2H),3.56 - 3.45(m,2H),2.71(d,11.7Hz,1H),2.64 - 2.53(m,1H),1.91 - 1.80(m,1H),1.68 - 1.61(m,1H).

[0158] Example 32: 5-(4-(((3R,4S)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ka] To (3R,4S)-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (58 mg, 0.11 mmol) in a septum-capped vial was added K2CO3 (42 mg, 0.30 mmol), 5-bromo-3-cyano-1H-pyrrolo[2,3-b]pyridine (32 mg, 0.14 mmol), Pd(dppf)Cl2·DCM (15 mg, 0.018 mmol). To this was added 4 mL of dioxane and 1 mL of water. The mixture was flushed with nitrogen for 12 min. The vial was sealed and the mixture was stirred at 100 °C for 3.8 h and then cooled when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 5-(4-(((3R,4S)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. MS: (ES) m / z C 25 H 22 F3N6O3S [M+H] + Calculated value: 543.1, measured value: 543.3. 1H NMR(400MHz,DMSO-d6)δ 13.02(d,J=3.1Hz,1H),8.82(d,J=2.1Hz,1H),8.52(dd,J=21.2,2.6Hz,2H),8.20(d,J=2.4Hz,1H),8.14 - 8.06(m,2H),7.89 - 7.81(m,2H),7.58(dd,J=9.0,2.6Hz,1H),7.12(s,1H),6.70(d,J=9.0Hz,1H), 5.25(s,1H),3.89(s,2H),3.52(t,J=13.5Hz,2H),2.72(d,J=11.8Hz,1H),2.66 - 2.52(m,1H),1.88(dd,J=12.1,8.5Hz,1H),1.67(d,J=12.8Hz,1H).

[0159] Example 33: 6-[[(3S,4R)-3-hydroxy-1-[4-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]sulfonyl-4-piperidyl]amino]pyridine-3-carbonitrile [ka] 6-(((3S,4R)-1-((4-bromophenyl)sulfonyl)-3-hydroxypiperidin-4-yl)amino)nicotinonitrile (80.0 mg, 0.18 mmol), bis(pinacolato)diboron (69.7 mg, 0.27 mmol), KOAc (53.9 mg, 0.55 mmol) and Pd(dppf)Cl2·DCM (1.34 mg, 0.002 mmol) were placed in a septum-capped vial. To this was added 2 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 2 h and cooled upon completion of the reaction. To the mixture was added 5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridine (52.3 mg, 0.25 mmol), Pd(dppf)Cl2·DCM (12.1 mg, 0.02 mmol) and 0.5 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by preparative reverse phase HPLC to give 6-[[(3S,4R)-3-hydroxy-1-[4-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]sulfonyl-4-piperidyl]amino]pyridine-3-carbonitrile. MS: (ES) m / z C 25 H 24 N6O3S [M+H] + The calculated value was 489.1, and the measured value was 489.2. 1 H NMR(400MHz,DMSO-d6)δ 11.83(s,1H),8.33(d,J=2.2Hz,1H),8.15(s,1H),7.84(d,J=8.0Hz,2H),7.70(d,J=8.0Hz,2H),7.65(d,J=8.9H z,1H),7.54(m,1H),7.46(bs,1H),6.70(d,J=8.9Hz,1H),3.91(m,3H),3.65(d,J=7.4Hz,1H),3.54(m,1H),2.77 - 2.69(m,1H),2.61(t,J=11.2Hz,1H),1.96 - 1.88(m,1H),1.73 - 1.63(m, 1H).(Me is occluded in the solvent).

[0160] Example 34: 5-[4-[[(3S,4R)-4-[(5-cyano-2-pyridyl)amino]-3-hydroxy-1-piperidyl]sulfonyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ka] 6-(((3S,4R)-1-((4-bromophenyl)sulfonyl)-3-hydroxypiperidin-4-yl)amino)nicotinonitrile (80.0 mg, 0.18 mmol), bis(pinacolato)diboron (69.7 mg, 0.27 mmol), KOAc (53.9 mg, 0.55 mmol) and Pd(dppf)Cl2·DCM (1.34 mg, 0.002 mmol) were placed in a septum-capped vial. To this was added 2 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 2 h and cooled upon completion of the reaction. To the mixture was added 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (55.0 mg, 0.25 mmol), Pd(dppf)Cl2·DCM (12.1 mg, 0.02 mmol) and 0.5 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by preparative reverse phase HPLC to give 5-[4-[[(3S,4R)-4-[(5-cyano-2-pyridyl)amino]-3-hydroxy-1-piperidyl]sulfonyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. MS: (ES) m / z C 25 H 21 N7O3S [M+H] + The calculated value was 500.1, and the actual value was 500.1. 1H NMR(400MHz,DMSO-d6)δ 13.03(d,J=3.0Hz,1H),8.82(s,1H),8.55(d,J=2.0Hz,1H),8.50(s,1H),8.32(s,1H) ),8.11(d,J=8.1Hz,2H),7.85(d,J=8.0Hz,2H),7.63(dd,J=8.7,2.3Hz,1H),7.43(bs ,1H),6.68(d,J=8.9Hz,1H),3.91(m,3H),3.67(d,J=7.4Hz,1H),3.53(t,J=8.8Hz,1H ),2.72(d,J=11.8Hz,1H),2.61(t,J=11.3Hz,1H),1.88(dd,J=13.4,9.6Hz,1H),1.71 - 1.62(m,1H).

[0161] Example 35: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4-methyl-1H-indazole-3-carbonitrile [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (50 mg, 0.10 mmol), bis(pinacolato)diboron (32 mg, 0.13 mmol), KOAc (30 mg, 0.31 mmol) and Pd(dppf)Cl2·DCM (1 mg, 0.001 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 110 °C for 30 min and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (81 mg, 0.59 mmol), 5-bromo-4-methyl-1H-indazole-3-carbonitrile (16 mg, 0.07 mmol), Pd(dppf)Cl2·DCM (10 mg, 0.021 mmol) and 0.25 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 110 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4-methyl-1H-indazole-3-carbonitrile. MS: (ES) m / z C 26 H 24 F3N6O3S [M+H] + Calculated value: 557.2, measured value: 557.1. 1 H NMR(400MHz,CD3OD)δ 8.22(s,1H),7.92(d,J=8.4Hz,2H),7.83(d,J=9.1Hz,1H),7.64(d,J=8.4Hz,2H),7.60(d,J=8.7Hz,1H),7.41(d,J=8 .7Hz,1H),6.97(d,J=9.2Hz,1H),4.04(s,1H),3.91(ddd,J=10.5,3.9,3.9Hz,1H),3.71(dd,J=11.3,4.5Hz,2H),2.94 - 2.81(m,1H),2.79 - 2.70(m,1H),2.70(s,3H),2.26 - 1.96(m,1H),1.96 - 1.71(m,1H).

[0162] Example 36: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-6-methyl-1H-indazole-3-carbonitrile [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (50 mg, 0.10 mmol), bis(pinacolato)diboron (32 mg, 0.13 mmol), KOAc (30 mg, 0.31 mmol) and Pd(dppf)Cl2·DCM (1 mg, 0.001 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 110 °C for 30 min and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (81 mg, 0.59 mmol), 5-bromo-4-methyl-1H-indazole-3-carbonitrile (23 mg, 0.1 mmol), Pd(dppf)Cl2·DCM (10 mg, 0.021 mmol) and 0.25 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 110 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-7-methyl-1H-indazole-3-carbonitrile. MS: (ES) m / z C 26 H 24 F3N6O3S [M+H] + Calculated value: 557.2, measured value: 557.1. 1H NMR(400MHz,CD3OD)δ 8.20(s,1H),8.03 - 7.87(m,5H),7.81(dd,J=9.3,2.4Hz,1H),7.67(dd,J=2.0,1.0Hz,1H),6.94(d,J=9.3Hz,1H),4.04 - 4.01(m,1H),3.89(ddd,J=10.3,3.8,3.8Hz,1H),3.68 - 3.63(m,2H),2.86(d,J=11.9Hz,1H),2.79 - 2.71(m,1H),2.70(s,3H),2.16 - 1.95(m,1H),1.95 - 1.75(m,1H).

[0163] Example 37: 4-(4-(((3S,4R)-4-((5-cyanopyridin-2-yl)amino)-3-hydroxypiperidin-1-yl)sulfonyl)phenyl)picolinamide [ka] 6-(((3S,4R)-1-((4-bromophenyl)sulfonyl)-3-hydroxypiperidin-4-yl)amino)nicotinonitrile (80.0 mg, 0.18 mmol), bis(pinacolato)diboron (69.7 mg, 0.27 mmol), KOAc (53.9 mg, 0.55 mmol) and Pd(dppf)Cl2·DCM (1.34 mg, 0.002 mmol) were placed in a septum-capped vial. To this was added 2 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 2 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (45.6 mg, 0.33 mmol), 4-bromopyridine-2-carboxamide (49.8 mg, 0.25 mmol), Pd(dppf)Cl2·DCM (12.1 mg, 0.02 mmol) and 0.5 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography and then triturated from CHCl2 to give 4-(4-(((3S,4R)-4-((5-cyanopyridin-2-yl)amino)-3-hydroxypiperidin-1-yl)sulfonyl)phenyl)picolinamide. MS: (ES) m / z C 23 H 22 N6O4S [M+H] + The calculated value was 479.1 and the actual value was 479.0. 1 H NMR(400MHz,DMSO-d6)δ 8.78(d,J=5.1Hz,1H),8.37(s,1H),8.32(s,1H),8.24(s,1H),8.12(d,J=8.0Hz,2H),8.01(dd,J=5.1,2.0Hz,1H),7.91(d,J=8 .1Hz,2H),7.78(d,J=2.9Hz,1H),7.63(dd,J=8.7,2.3Hz,1H),7.41(bs,1H),6.67(d,J=8.9Hz,1H),5.28(d,J=4.6Hz,1H),3.99 - 3.85(m,2H),3.59 - 3.47(m,2H),2.74(d,J=11.9Hz,1H),2.68 - 2.58(m,1H),1.95 - 1.81(m,1H),1.70 - 1.60(m,1H).

[0164] Example 38: (3S,4R)-1-((4-(3-amino-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol), bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (62 mg, 0.63 mmol) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol) in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was purged with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 3 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added 2M K2CO3 (0.53 mL, 1.06 mmol), 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine (45 mg, 0.21 mmol), and Pd(dppf)Cl2·DCM (17 mg, 0.21 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(3-amino-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 23 H 22 F3N7O3S [M+H] + Calculated value: 534.1, measured value: 534.2. 1H NMR(400MHz, methanol-d4)δ 8.84(d,J=2.2Hz,1H),8.62(d,J=2.2Hz,1H),8.19(s,1H),7.95(d,J=0.7Hz ,4H),7.77(dd,J=9.2,2.4Hz,1H),6.90(d,J=9.2Hz,1H),4.02(s,1H),3.93 - 3.86(m,1H),3.70 - 3.63(m,2H),2.88 - 2.80(m,1H),2.73(t,J=11.0Hz,1H),2.12 - 2.01(m,1H),1.91 - 1.83(m,1H).

[0165] Example 39: Methyl 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinate [ka] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (80 mg, 0.17 mmol) was added bis(pinacolato)diboron (52 mg, 0.20 mmol), KOAc (54 mg, 0.55 mmol) and Pd(dppf)Cl2·DCM (1.3 mg, 0.0016 mmol) in a 4 mL vial. To this was added 2 mL of dioxane and the mixture was flushed with nitrogen for 7 min. The vial was sealed with a Teflon-lined cap and the mixture was stirred at 100 °C for 1.5 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (120 mg, 0.87 mmol), 4-bromopyridine-2-carboxylic acid methyl ester (36 mg, 0.17 mmol), Pd(dppf)Cl2·DCM (13 mg, 0.016 mmol) and 0.5 mL of water. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and the reaction proceeded to completion when it was cooled. The mixture was purified by silica gel chromatography to give methyl 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinate. MS: (ES) m / z C 24 H 24 F3N4O5S [M+H] + Calculated value: 537.1, measured value: 537.2. 1 H NMR (400MHz, methanol-d4)δ 8.79(d,J=5.0Hz,1H),8.49(s,1H),8.15(s,1H),8.10 - 7.92(m,5H),7.54(d,J=9.1Hz,1H),6.62(d,J=9.0Hz,1H),4.05 - 3.97(m,4H),3.94 - 3.88(m,1H),3.77 - 3.66(m,2H),2.79(d,J=12.4Hz,1H),2.71 - 2.62(m,1H),2.06 - 1.95(m,1H),1.80(d,J=12.9Hz,1H).

[0166] Example 40: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-N,N-dimethylpicolinamide [ka] In a 40 mL vial, methyl 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinate (50 mg, 0.093 mmol) was dissolved in acetonitrile (1 mL). To this solution was added 40% aqueous dimethylamine (1 mL, 12 mmol). The vial was sealed and heated at 60° C. for 2 h, after which the reaction was concentrated in vacuo and the residue was purified by preparative reverse phase chromatography to give 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-N,N-dimethylpicolinamide. MS: (ES) m / z C 25 H 27 F3N5O4S [M+H] + The calculated value was 550.2, and the measured value was 550.1. 1 H NMR(400MHz,DMSO-d6)δ 8.72(s,1H),8.22(s,1H),8.12(d,J=8.1Hz,2H),8.04 - 7.83(m,4H),7.74 - 7.56(m,1H),7.27(s,1H),6.74(d,J=9.0Hz,1H),3.88(s,2H),3.60- 3.45(m,2H),3.05(s,3H),2.97(s,3H),2.72(d,J=12.0Hz,1H),2.66 - 2.56(m,1H),1.94 - 1.82(m,1H),1.70 - 1.62(m,1H).

[0167] Example 41: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-N-(2-hydroxyethyl)picolinamide [ka] In a 40 mL vial, methyl 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinate (52 mg, 0.097 mmol) was dissolved in acetonitrile (1 mL). To this was added ethanolamine (90 mg, 1.5 mmol) and the solution was heated for 3.7 h, after which the reaction was concentrated and purified by preparative reverse phase chromatography to give 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-N-(2-hydroxyethyl)picolinamide. MS: (ES) m / z C 25 H 27 F3N5O5S [M+H] + Calculated value: 566.2, actual value: 566.2. 1 H NMR(400MHz, methanol-d4)δ 8.75(dd,J=5.1,0.8Hz,1H),8.42(dd,J=1.9,0.8Hz,1H),8.19(d,J=2.3Hz,1H),8.13 - 8.03(m,2H),8.02 - 7.95(m,2H),7.91(dd,J=5.1,1.9Hz,1H),7.76(dd,J=9.2,2.4Hz,1H),6.88(d,J=9.2Hz,1H),4.01(s,1H),3.93 - 3.84(m,1H),3.75(t,J=5.6Hz,2H),3.72 - 3.63(m,2H),3.59(t,J=5.6Hz,2H),2.85(d,J=12.1Hz,1H),2.74(t,J=10.2Hz,1H),2.10 - 1.99(m,1H),1.89-1.81(m,1H).

[0168] Example 42: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)thiazole-2-carboxamide [ka] (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (80 mg, 0.17 mmol), bis(pinacolato)diboron (52 mg, 0.20 mmol), KOAc (53 mg, 0.54 mmol) and Pd(dppf)Cl2·DCM (2.6 mg, 0.0032 mmol) in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 3.5 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (122 mg, 0.88 mmol), 5-bromothiazole-2-carboxamide (38 mg, 0.18 mmol), Pd(dppf)Cl2·DCM (13 mg, 0.015 mmol) and 0.5 mL of water. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 3 h and the reaction proceeded to completion when it was cooled. The mixture was purified by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)thiazole-2-carboxamide. MS: (ES) m / z C 21 H 21 F3N5O4S2[M+H] + Calculated value: 528.1, measured value: 528.1. 1 H NMR(400MHz,DMSO-d6)δ 8.56(s,1H),8.28(s,1H),8.23 - 8.17(m,1H),8.06 - 7.98(m,2H),7.98 - 7.92(m,1H),7.85 - 7.77(m,2H),7.60(dd,J=9.1,2.5Hz,1H),7.25(s,1H),6.71(d,J=9.0Hz,1H),3.94 - 3.83(m,2H),3.53 - 3.42(m,2H),2.70(d,J=12.0Hz,1H),2.65 - 2.54(m,1H),1.83(dd,J=12.1,8.8Hz,1H),1.68 - 1.59(m,1H).

[0169] Example 43: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-7-methyl-1H-indazole-3-carbonitrile [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (50 mg, 0.10 mmol), bis(pinacolato)diboron (32 mg, 0.13 mmol), KOAc (30 mg, 0.31 mmol) and Pd(dppf)Cl2·DCM (1 mg, 0.001 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 110 °C for 30 min and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (81 mg, 0.59 mmol), 5-bromo-7-methyl-1H-indazole-3-carbonitrile (23 mg, 0.1 mmol), Pd(dppf)Cl2·DCM (10 mg, 0.021 mmol) and 0.25 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 110 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-7-methyl-1H-indazole-3-carbonitrile. MS: (ES) m / z C 26 H 24 F3N6O3S [M+H] + Calculated value: 557.2, measured value: 557.1. 1H NMR(400MHz,CD3OD)δ 8.20(s,1H),8.03 - 7.87(m,5H),7.81(dd,J=9.3,2.4Hz,1H),7.67(dd,J=2.0,1.0Hz,1H),6.94(d,J=9.3Hz,1H),4.04 - 4.01(m,1H),3.89(ddd,J=10.3,3.8,3.8Hz,1H),3.68 - 3.63(m,2H),2.86(d,J=11.9Hz,1H),2.79 - 2.71(m,1H),2.70(s,3H),2.16 - 1.95(m,1H),1.95 - 1.75(m,1H).

[0170] Example 44: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-6-methoxypicolinamide [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (80 mg, 0.17 mmol), bis(pinacolato)diboron (52 mg, 0.20 mmol), KOAc (49 mg, 0.50 mmol) and Pd(dppf)Cl2·DCM (1.6 mg, 0.0020 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 2.5 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (125 mg, 0.91 mmol), 4-bromo-6-methoxypicolinamide (41 mg, 0.18 mmol), Pd(dppf)Cl2·DCM (14 mg, 0.017 mmol) and 0.5 mL of water. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1.2 h and the reaction proceeded to completion when it was cooled. The mixture was purified by preparative reverse phase HPLC to give 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-6-methoxypicolinamide. MS: (ES) m / z C 24 H 25 F3N5O5S [M+H] + Calculated value: 552.2, measured value: 552.2. 1 H NMR(400MHz,DMSO-d6)δ 8.23(s,1H),8.15 - 8.05(m,3H),7.96(d,J=1.4Hz,1H),7.87(d,J=8.1Hz,2H),7.77(s,1H),7.69 - 7.61(m,1H),7.44 - 7.34(m,2H),6.77(d,J=9.0Hz,1H),4.03(s,3H),3.96 - 3.85(m,2H),3.57 - 3.46(m,2H),2.71(d,J=11.9Hz,1H),2.67 - 2.54(m,1H),1.95 - 1.80(m,1H),1.66(d,J=12.4Hz,1H).

[0171] Example 45: (3S,4R)-1-((4-(4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (98 mg, 0.204 mmol), bis(pinacolato)diboron (62 mg, 0.245 mmol, 1.2 equiv), potassium acetate (60 mg, 0.612 mmol, 3 equiv) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (3 mg, 0.004 mmol, 0.02 equiv) were added to 1 mL of dioxane in a 20 mL septum-capped vial and the mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 125 °C for 15 min, then cooled under a nitrogen atmosphere to reveal complete conversion to the boronate ester intermediate. To the mixture was added: potassium carbonate (141 mg, 1.02 mmol, 5 equiv), 5-bromo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (46 mg, 0.204 mmol, 1 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (20 mg, 0.025 mmol, 0.12 equiv) and 0.5 mL of water. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 105° C. for 16 h and then cooled under a nitrogen atmosphere to reveal complete conversion of the boronate ester intermediate. The mixture was diluted with 3 mL of EtOAc and 2 mL of water. The aqueous layer was discarded. The organic layer was concentrated under a stream of nitrogen and dissolved in 4 mL of DMSO. The solution was injected through a syringe filter into a preparative HPLC (20-50% ACN, 0.1% TFA) to give the title compound. MS: (ES) m / z C 26 H 26 F3N5O3S [M+H] + Calculated value: 546.2, actual value: 546.2. 1H NMR(400MHz,DMSO-d6)δ 11.48(s,1H),8.21(s,1H),7.81(d,J=7.9Hz,2H),7.58(dd,J=8.8,2.5Hz,1H),7.49(d,J =7.9Hz,2H),7.39-7.32(m,1H),7.20-7.05(m,1H),6.70(d,J=8.9Hz,1H),6.49-6.43(m,1 H),5.26(d,J=4.2Hz,1H),3.95-3.85(m,2H),3.60-3.46(m,2H),2.68(d,J=11.8Hz,1H),2 .56(t,J=12Hz,1H),2.20(s,3H),2.16(s,3H),1.90(q,J=11.6Hz,1H),1.73-1.63(m,1H).

[0172] Example 46: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol), bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (61 mg, 0.62 mmol) and Pd(dppf)Cl2·DCM (2 mg, 0.002 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (163 mg, 0.62 mmol), 5-bromo-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (54 mg, 0.23 mmol), Pd(dppf)Cl2·DCM (20 mg, 0.021 mmol) and 0.25 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. MS: (ES) m / z C 26 H 24 F3N6O3S [M+H] + Calculated value: 557.2, measured value: 557.2. 1H NMR(400MHz,DMSO-d6)δ 12.80(d,J=3.1Hz,1H),8.42(d,J=3.0Hz,1H),8.20(ddd,J=2.3,1.0,1.0Hz,1H),7.94(s,1H),7.82(d,J =8.4Hz,2H),7.72(d,J=8.4Hz,2H),7.59(dd,J=9.1,2.6Hz,1H),7.18(s,1H),6.71(d,J=9.0Hz,1H),3.95 - 3.85(m,1H),3.57 - 3.46(m,2H),2.69(d,J=12Hz,2H),2.62 - 2.52(m,1H),2.51(s,3H),1.95 - 1.84(m,1H),1.70 - 1.63(m,1H).

[0173] Example 47: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] In a septum-capped vial, (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol was added 2M K2CO3 (0.26 mL, 0.53 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (41 mg, 0.16 mmol), Pd(dppf)Cl2·DCM (13 mg, 0.016 mmol). To this was added 1 mL of dioxane. The mixture was purged with nitrogen for 5 minutes. The vial was sealed and the mixture was stirred at 100 °C for 16 hours and then cooled down when the reaction had proceeded to completion. The mixture was purified by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. MS: (ES) m / z C 24H 22 F3N5O4S [M+H] + Calculated value: 534.1, measured value: 534.2. 1 H NMR (400MHz, methanol-d4)δ 8.19(s,1H),7.85(s,4H),7.80 - 7.75(m,1H),7.44 - 7.33(m,2H),7.16(d,J=8.1Hz,1H),6.90(d,J=9.3Hz,1H),4.05 - 3.98(m,1H),3.92 - 3.84(m,1H),3.68 - 3.60(m,2H),2.88 - 2.78(m,1H),2.76 - 2.67(m,1H),2.11 - 2.01(q,J=10.1Hz,1H),1.91 - 1.82(m,1H).

[0174] Example 48: 3-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol), bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (62 mg, 0.63 mmol) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was purged with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 3 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added 2M K2CO3 (0.53 mL, 1.06 mmol), 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (45 mg, 0.21 mmol), and Pd(dppf)Cl2·DCM (17 mg, 0.21 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 3-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. MS: (ES) m / z C 24 H 22 F3N5O4S [M+H] + Calculated value: 534.1, measured value: 534.2. 1 H NMR(400MHz, methanol-d4)δ 9.10(s,1H),8.46(s,1H),8.21(s,1H),8.05 - 7.94(m,4H),7.87(d,J=9.3Hz,1H),7.01(d,J=9.4Hz,1H),4.59(s,2H),4.02(s,1H),3.94 - 3.78(m,1H),3.70 - 3.60(m,2H),2.92 - 2.74(m,2H),2.13 - 1.85(m,2H).

[0175] Example 49: (3S,4R)-1-((4-(3-amino-1-methyl-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol), bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (62 mg, 0.63 mmol) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was purged with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 3 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added 2M K2CO3 (0.53 mL, 1.06 mmol), 5-bromo-1-methyl-1H-indazol-3-amine (47 mg, 0.21 mmol), and Pd(dppf)Cl2·DCM (17 mg, 0.21 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(3-amino-1-methyl-1H-indazol-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 25 F3N6O3S [M+H] + Calculated value: 547.2, measured value: 547.2. 1H NMR(400MHz, methanol-d4)δ 8.19(s,1H),8.12(s,1H),7.95 - 7.83(m,5H),7.77(dd,J=9.2,2.4Hz,1H),7.55(s,1H),6.90(d,J=9.1Hz,1H),4.02(s,1H),3.95 - 4.80(m,4H),3.71 - 3.62(m,2H),2.82(d,J=12.2Hz,1H),2.71(t,J=11.2Hz,1H),2.11 - 2.03(m,1H),1.90 - 1.82(m,1H).

[0176] Example 50: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-N-methylpicolinamide [ka] In a 40 mL vial, methyl 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinate (34 mg, 0.063 mmol) was dissolved in a 33% solution of methylamine in ethanol (4 mL, 34 mmol). The vial was sealed and heated at 50° C. for 2 h, after which the reaction was concentrated in vacuo and the residue purified by preparative reverse phase chromatography to give 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-N-methylpicolinamide. MS: (ES) m / z C 24 H 25 F3N5O4S [M+H] + Calculated value: 536.2, measured value: 536.1. 1H NMR (400MHz, methanol-d4)δ 8.74(dd,J=5.0,0.8Hz,1H),8.41(dd,J=1.9,0.8Hz,1H),8.17 - 8.13(m,1H),8.10 - 8.02(m,2H),8.02 - 7.93(m,2H),7.90(dd,J=5.1,1.9Hz,1H),7.55(dd,J=9.0,2.5Hz,1H),6.63(d,J=8.9Hz,1H),4.01(s,1H),3.92(d,J=10.9Hz,1H),3.76 - 3.65(m,2H),3.01(s,3H),2.79(d,J=12.3Hz,1H),2.68(t,J=10.8Hz,1H),2.09 - 1.92(m,1H),1.85 - 1.77(m,1H).

[0177] Example 51: 2-Hydroxy-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)nicotinamide [ka] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (80 mg, 0.17 mmol) was added bis(pinacolato)diboron (52 mg, 0.20 mmol), KOAc (51 mg, 0.52 mmol) and Pd(dppf)Cl2·DCM (1.4 mg, 0.0017 mmol) in a 4 mL vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed with a Teflon-lined cap and the mixture was stirred at 100 °C for 2.7 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (121 mg, 0.88 mmol), 5-bromo-2-hydroxynicotinamide (37 mg, 0.17 mmol), Pd(dppf)Cl2·DCM (13 mg, 0.016 mmol) and 0.5 mL of water. The mixture was flushed with nitrogen for 8 min, the vial was sealed and the mixture was stirred at 100 °C for 1.3 h and the reaction proceeded to completion upon which it was cooled. The mixture was purified by preparative reverse phase HPLC to give 2-hydroxy-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)nicotinamide. MS: (ES) m / z C 23 H 23 F3N5O5S [M+H] + Calculated value: 538.1, actual value: 538.0. 1 H NMR(400MHz, methanol-d4)δ 8.85(d,J=2.9Hz,1H),8.19(s,1H),8.12(d,J=2.9Hz,1H),7.93 - 7.82(m,4H),7.79(d,J=8.0Hz,1H),6.92(d,J=9.3Hz,1H),4.01(s,1H),3.91 - 3.84(m,1H),3.68 - 3.59(m,2H),2.82(d,J=12.4Hz,1H),2.72(t,J=11.3Hz,1H),2.10 - 2.00(m,1H),1.85(d,J=12.6Hz,1H).

[0178] Example 52: (3S,4R)-1-((4-(2-(1H-imidazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] Step a: To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (190 mg, 0.40 mmol) in a septum-capped vial was added bis(pinacolato)diboron (122 mg, 0.48 mmol), KOAc (118 mg, 1.2 mmol), dioxane (2 mL) and Pd(dppf)Cl2·DCM (3 mg, 0.0040 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1.5 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (276 mg, 2.0 mmol), 4-bromopicolinaldehyde (89 mg, 0.48 mmol), water (1 mL), and Pd(dppf)Cl2·DCM (33 mg, 0.040 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1.5 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography to give 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinaldehyde.

[0179] Step b: A mixture of (3S,4R)-1-((4-(2-(1H-imidazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (130 mg, 0.26 mmol), glyoxal (40 wt% in water, 60 μL, 0.52 mmol) and ammonium acetate (100 mg, 1.3 mmol) in methanol (2 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL). The resulting solid was filtered and purified by preparative reverse phase HPLC followed by SiO2 gel chromatography to give (3S,4R)-1-((4-(2-(1H-imidazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 24 F3N6O3S [M + H] + Calculated value: 545.2, measured value: 545.1. 1 H NMR(400MHz,DMSO-d6)δ 12.99(s,1H),8.73(d,J=5.2Hz,1H),8.37(s,1H),8.19(s,1H),8.12(d,J=8.0Hz,2H),7.91(d,J=7.9Hz,2H),7.81 - 7.73(m,1H),7.62 - 7.54(m,1H),7.22(s,2H),7.12(s,1H),6.69(d,J=9.0Hz,1H),5.25(d,J=4.4Hz,1H),3.98-3.84(m, 2H),3.58-3.44(m,2H),2.78-2.70(m,1H),2.68-2.58(m,1H),1.95-1.79(m,1H),1.70-1.61(m,1H).

[0180] Example 53: 2-amino-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)nicotinamide [ka] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (82 mg, 0.17 mmol) was added bis(pinacolato)diboron (54 mg, 0.21 mmol), KOAc (51 mg, 0.52 mmol) and Pd(dppf)Cl2·DCM (2.4 mg, 0.0029 mmol) in a 4 mL vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 8 min. The vial was sealed with a Teflon-lined cap and the mixture was stirred at 100 °C for 3.6 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (117 mg, 0.85 mmol), 2-amino-5-bromonicotinamide (37 mg, 0.17 mmol), Pd(dppf)Cl2·DCM (13 mg, 0.016 mmol) and 0.5 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 1.3 h and the reaction proceeded to completion when it was cooled. The mixture was purified by preparative reverse phase HPLC to give 2-amino-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)nicotinamide. MS: (ES) m / z C 23 H 24 F3N6O4S [M+H] + Calculated value: 537.2, measured value: 537.2. 1 H NMR(400MHz, methanol-d4)δ 8.78(d,J=2.0Hz,1H),8.49 - 8.43(m,1H),8.17(s,1H),7.94(d,J=2.1Hz,4H),7.65(d,J=8.9Hz,1H),6.75(d,J=9.1Hz,1H),4.01(s,1H),3.89(d,J=10.4Hz,1H),3.77 - 3.64(m,2H),2.76(d,J=12.2Hz,1H),2.64(t,J=11.5Hz,1H),2.02(dd,J=13.3,9.5Hz,1H),1.82(d,J=15.1Hz,1H).

[0181] Example 54: 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol), bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (62 mg, 0.63 mmol) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 3 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added 2M K2CO3 (0.53 mL, 1.06 mmol), 6-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (37 mg, 0.21 mmol), and Pd(dppf)Cl2·DCM (17 mg, 0.21 mmol). The mixture was purged with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. MS: (ES) m / z C 23 H 21 F3N6O4S [M+H] + Calculated value: 535.1, measured value: 535.2. 1H NMR (400MHz, methanol-d4)δ 8.27(s,1H),8.19(s,1H),7.92 - 7.87(m,4H),7.78 - 7.74(m,1H),7.683(s,1H),6.90(d,J=9.3Hz,1H),4.05 - 3.98(m,1H),3.92 - 3.84(m,1H),3.68 - 3.60(m,2H),2.88 - 2.78(m,1H),2.76 - 2.67(m,1H),2.11 - 2.01(q,J=10.1Hz,1H),1.91 - 1.82(m,1H).

[0182] Example 55: (3S,4R)-1-((4-(3-amino-1H-indazol-6-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol), bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (62 mg, 0.63 mmol) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 3 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added 2M K2CO3 (0.53 mL, 1.06 mmol), 6-bromo-1H-indazol-3-amine (45 mg, 0.21 mmol), and Pd(dppf)Cl2·DCM (17 mg, 0.21 mmol). The mixture was purged with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion upon which it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(3-amino-1H-indazol-6-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 24 H 23 F3N6O3S [M+H] + Calculated value: 533.1, actual value: 533.1. 1 H NMR (400MHz, methanol-d4)δ 8.18(s,1H),8.04(dd,J=8.6,0.8Hz,1H),7.98 - 7.90(m,4H),7.74 - 7.65(m,2H),7.57(dd,J=8.6,1.5Hz,1H),6.80(d,J=9.2Hz,1H),4.02(s,1H),3.94 - 3.86(m,1H),3.75 - 3.65(m,2H),2.80(d,J=11.8Hz,1H),2.69(t,J=11.0Hz,1H),2.10 - 2.01(m,1H),1.88 - 1.80(m,1H).MS:(ES)m / z C 24 H 23 F3N6O3S [M+H] +Calculated value: 533.1, actual value: 533.1.

[0183] Example 56: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ka] A mixture of 5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridine (422 mg, 2.0 mmol), paraformaldehyde (66 mg, 2.2 mmol) and dimethylamine hydrochloride (179 mg, 2.2 mmol) in 1-butanol (10 mL) was stirred at 100° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated. The residue was suspended in 1 M HCl (20 mL) and washed with diethyl ether (3×10 mL). The ether extracts were discarded and the aqueous layer was basified to pH 12 by addition of solid potassium carbonate and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated to give 1-(5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethanamine, which was used directly without purification.

[0184] A mixture of 1-(5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethanamine (300 mg, 1.1 mmol) and hexamethylenetetramine (154 mg, 1.1 mmol) in propionic acid (1 mL) and water (0.5 mL) was stirred at 120° C. for 3.5 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The resulting solid was filtered, washed with water and acetonitrile, and dried to give 5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde, which was used directly without purification.

[0185] A mixture of 5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (120 mg, 0.50 mmol) and hydroxylamine hydrochloride (42 mg, 0.60 mmol) in pyridine (1 mL) was stirred at room temperature for 1 h. Acetic anhydride (2.5 mL) was added and stirring was continued at 100° C. for 1.5 h. The reaction mixture was allowed to cool to room temperature and diluted with water (10 mL). The resulting solid was filtered, washed with water and purified by SiO2 gel chromatography (hexane / ethyl acetate) to give 1-acetyl-5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.

[0186] 1-Acetyl-5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (100 mg, 0.36 mmol) was dissolved in methanol (2 mL) and 1M NaOH (2 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give 5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, which was used directly without purification.

[0187] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (96 mg, 0.20 mmol) in a septum-capped vial was added bis(pinacolato)diboron (61 mg, 0.24 mmol), KOAc (59 mg, 0.60 mmol), dioxane (1 mL) and Pd(dppf)Cl2·DCM (2 mg, 0.0020 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and then cooled when the reaction had proceeded to completion. To the mixture was added K2CO3 (83 mg, 0.60 mmol), 5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (57 mg, 0.24 mmol), dioxane (2 mL), water (1 mL) and Pd(dppf)Cl2·DCM (16 mg, 0.020 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. MS: (ES) m / z C 26 H 24 F3N6O3S [M + H] + Calculated value: 557.2, measured value: 557.1. 1H NMR (400MHz, DMSO-d6) δ 12.93(s,1H),8.51(d,J=1.6Hz,1H),8.28(s,1H),8.22(d,J=2.5Hz,1H),7.86( d,J=7.7Hz,2H),7.72(d,J=7.7Hz,2H),7.60(d,J=8.7Hz,1H),7.15(s,1H),6.72 (d,J=8.9Hz,1H),5.27(d,J=4.4Hz,1H),3.99-3.86(m,2H),3.61-3.48(m,2H),2 .74(d,J=11.8Hz,1H),2.68-2.58(m,4H),1.97-1.84(m,1H),1.73-1.64(m,1H).

[0188] Example 57: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinonitrile [ka] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (190 mg, 0.40 mmol) was added K2CO3 (166 mg, 1.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (110 mg, 0.48 mmol), dioxane (2 mL), water (1 mL) and Pd(dppf)Cl2·DCM (33 mg, 0.040 mmol) in a septum-capped vial. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 17 h and then cooled when the reaction had proceeded to completion. The mixture was purified by SiO2 gel chromatography (0-100% EtOAc / Hexanes) to give 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinonitrile. MS: (ES) m / z C 23 H 21 F3N5O3S [M + H] +The calculated value was 504.1, and the actual value was 504.0. 1 H NMR(400MHz,DMSO-d6)δ 8.88(d,J=5.2Hz,1H),8.54(d,J=1.8Hz,1H),8.21-8.14(m,4H),7.92(d,J=8.2Hz,2H),7.58(d,J=9.1Hz,1H),7.12(s,1H),6.69(d,J=8.9Hz,1H) ),5.25(d,J=4.3Hz,1H),3.96-3.84(m,2H),3.60-3.46(m,2H),2.73(d, J=11.8Hz,1H),2.68-2.57(m,1H),1.93-1.80(m,1H),1.70-1.60(m,1H).

[0189] Example 58: (3S,4R)-1-((4-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (65 mg, 0.135 mmol), bis(pinacolato)diboron (48 mg, 0.162 mmol), KOAc (46 mg, 0.46 mmol) and Pd(dppf)Cl2·DCM (1 mg, 0.01 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (112 mg, 0.81 mmol), 5-bromo-4-methoxy-1H-pyrrolo[2,3-b]pyridine (34 mg, 0.15 mmol), Pd(dppf)Cl2·DCM (10 mg, 0.010 mmol) and 0.5 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 25 F3N5O4S [M+H] + Calculated value: 548.2, measured value: 548.1. 1 H NMR(400MHz,CD3OD)δ 8.27(s,1H),8.20(s,1H),7.91(d,J=7.6Hz,2H),7.80(d,J=8.1Hz,2H),7.72(d,J=9.1Hz,1H),7.57(d,J=3.2 Hz,1H),7.25(d,J=3.6Hz,1H),6.84(d,J=8.9Hz,1H),4.54(s,3H),4.03(s,1H),3.91(d,J=10.3Hz,1H),3.75 - 3.66(m,2H),2.81(d,J=12.2Hz,1H),2.70(dd,J=11.3,11.3Hz,1H),2.19 - 1.98(m,1H),1.89 - 1.81(m,1H).

[0190] Example 59: 3-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)pyrido[2,3-d]pyridazin-5(6H)-one [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol), bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (62 mg, 0.63 mmol) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol) were placed in a septum-capped vial. To this was added 1 mL of dioxane and the mixture was purged with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 3 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added 2M K2CO3 (0.53 mL, 1.06 mmol), 3-bromopyrido[2,3-d]pyridazin-5(6H)-one (48 mg, 0.21 mmol), and Pd(dppf)Cl2·DCM (17 mg, 0.21 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 3-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)pyrido[2,3-d]pyridazin-5(6H)-one. MS: (ES) m / z C 24 H 21 F3N6O4S [M+H] + Calculated value: 547.1, measured value: 547.2. 1H NMR(400MHz,DMSO-d6)δ 9.32(d,J=2.8Hz,1H),8.75 - 8.69(m,1H),8.32(s,1H),8.16 - 8.05(m,3H),7.82(d,J=8.1Hz,2H),7.51(dd,J=8.9,2.5Hz,1H),7.05(d,J=7.3Hz,1H),6.63(d,J=8.9Hz,1H),5.18(d,J=4.4Hz,1H),3.90 - 3.80(m,2H),3.52 - 3.40(m,2H),2.67(d,J=11.7Hz,1H),2.62 - 2.50(m,1H),1.88 - 1.75(m,1H),1.64 - 1.55(m,1H).

[0191] Example 60: (3S,4R)-1-((4-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (800 mg, 1.7 mmol) in a septum-capped vial was added bis(pinacolato)diboron (510 mg, 2.0 mmol), KOAc (530 mg, 5.4 mmol) and Pd(dppf)Cl2·DCM (14 mg, 0.017 mmol). To this was added 13 mL of dioxane and the mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 1.3 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (1.2 g, 8.3 mmol), 5-bromo-4-methyl-1H-pyrrolo[2,3-b]pyridine (390 mg, 1.8 mmol), Pd(dppf)Cl2·DCM (140 mg, 0.17 mmol) and 7 mL of water. The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 2.5 h and the reaction proceeded to completion before cooling. After the mixture was cooled to room temperature and left overnight, a significant amount of precipitate was observed. To the mixture was added 5 mL of water and the dark brown precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo leaving 820 mg of a brown powder. The residue was purified by SiO2 gel chromatography (20-100% EtOAc, dichloromethane). The clean fractions were concentrated to dryness and triturated with dichloromethane to give the title compound as an off-white powder. MS: (ES) m / z C 25 H 25 F3N5O3S [M+H] + Calculated value: 532.2, measured value: 532.3. 1H NMR (400MHz, methanol-d4)δ 8.19 - 8.14(m,1H),8.08(s,1H),7.95 - 7.87(m,2H),7.67(d,J=8.0Hz,2H),7.60 - 7.52(m,1H),7.43(d,J=3.1Hz,1H),6.68 - 6.60(m,2H),4.05 - 3.90(m,2H),3.79 - 3.67(m,2H),2.79(d,J=11.8Hz,1H),2.68(td,J=11.5,3.0Hz,1H),2.54(d,J=1.0Hz,3H),2.07 - 1.96(m,1H),1.89 - 1.79(m,1H).

[0192] Example 61: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ka] (3S,4R)-1-((4-Bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (800 mg, 1.7 mmol), bis(pinacolato)diboron (510 mg, 2.0 mmol), KOAc (490 mg, 5.0 mmol) and Pd(dppf)Cl2·DCM (14 mg, 0.017 mmol) were placed in a septum-capped vial. To this was added 3 mL of dioxane and the mixture was flushed with nitrogen for 20 min. The vial was sealed and the mixture was stirred at 100 °C for 45 min and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (1.2 g, 8.7 mmol), 5-bromo-3-cyano-1H-pyrrolo[2,3-b]pyridine (370 mg, 1.7 mmol), Pd(dppf)Cl2·DCM (136 mg, 0.17 mmol) and 2 mL of water. The mixture was flushed with nitrogen for 20 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by silica gel chromatography (50-100% EtOAc / DCM) to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. MS: (ES) m / z C 25 H 22 F3N6O3S [M+H] + Calculated value: 543.1, measured value: 543.3. 1H NMR(400MHz,DMSO-d6)δ 13.02(d,J=3.1Hz,1H),8.85 - 8.80(m,1H),8.58 - 8.47(m,2H),8.24 - 8.18(m,1H),8.11(d,J=8.1Hz,2H),7.86(d,J=8.1Hz,2H),7.59(dd,J=9.0,2.5Hz,1H),7.16 - 7.09(m,1H),6.71(d,J=9.0Hz,1H),5.29 - 5.23(m,1H),3.96 - 3.88(m,2H),3.60 - 3.47(m,2H),2.73(d,J=11.8Hz,1H),2.62(t,J=11.0Hz,1H),2.02 - 1.83(m,1H),1.72 - 1.63(m,1H).

[0193] Example 62: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide [ka] ((3S,4R)-1-((4-(4,6-Dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 5-bromo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine by the one-pot Miyaura / Suzuki procedure described in Example 33.

[0194] ((3S,4R)-1-((4-(4,6-Dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (94 mg, 0.17 mmol) was dissolved in acetic acid (4 mL) in a septum-capped vial. Peracetic acid (32%, 54 μL, 1.5 equiv.) was added and the solution was stirred at room temperature for 24 h. Additional peracetic acid (32%, 18 μL, 0.5 equiv.) was added. ) was added and the solution was stirred at 30° C. overnight, then a third portion of peracetic acid (32%, 18 μL, 0.5 equiv.) was added and the solution was stirred at 35° C. for 6 h. The mixture was injected directly into a preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide. MS: (ES) m / z C 26 H 26 F3N5O4S [M + H] + Calculated value 562.2, actual value 562.2. 1H NMR(400MHz,DMSO-d6)δ 12.35(s,1H),8.30 - 8.17(m,1H),7.95 - 7.79(m,2H),7.61(dd,J=9.0,2.5Hz,1H),7.58 - 7.52(m,2H),7.40(dd,J=3.4,1.9Hz,1H),7.13(d,J=7.5Hz,1H),6.73(d,J=8.9Hz,1H),6.66(dd,J=3.4,1.7Hz,1H),5.26(d,J=4.5Hz,1H),4.00 - 3.89(m,2H),3.63 - 3.49(m,2H),2.82 - 2.70(m,1H),2.70 - 2.56(m,1H),2.25(s,3H),2.18(s,3H),1.98 - 1.84(m,1H),1.77 - 1.61(m,1H).

[0195] Example 63: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ka] To 5-bromo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (337 mg, 1.50 mmol) dissolved in NMP (5 mL) was added 60% NaH (72 mg, 1.80 mmol, 1.2 equiv.) and iodine (404 mg, 1.59 mmol, 1.06 equiv.) in a septum-capped vial. After stirring at room temperature for 1 h, 30 mL of water and 0.1 mL of acetic acid were added. The solid was filtered off, washed on a funnel with 30 mL of water, dried, then washed with 5 mL of cyclohexane, and dried again to give 5-bromo-3-iodo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine. This material was used in the next step without further purification. A 172 mg sample (0.49 mmol) of the solid thus obtained was placed in a septum-capped vial, 1 mL of THF was added, and the slurry was cooled to 0° C. under nitrogen. To the slurry was added 0.16 mL of a 3 M solution of methylmagnesium bromide in diethyl ether (0.48 mmol, 0.98 equiv.), followed by 0.25 mL of 2 M isopropylmagnesium chloride in THF (1.02 equiv.). The temperature was raised to 20° C. and 0.4 mL of 1.3 M isopropylmagnesium chloride lithium chloride complex (turbo Grignard, 1.06 equiv.) in THF was added, followed by raising the temperature to 30° C. An additional 0.2 mL of the turbo Grignard solution (0.53 equiv.) was added and the solution was stirred at 30° C. for an additional 2 h. The solution was cooled to 20° C. and dimethylmalononitrile (141 mg, 1.50 mmol, 3.06 equiv.) dissolved in THF (1 mL) was added. After 15 min, the mixture was quenched by the addition of 10% aqueous acetic acid and extracted with DCM. The evaporated extract was purified on silica gel using a 10-50% gradient of ethyl acetate in hexanes as eluent. The concentrated product-containing fractions gave a residue which was triturated with 1 mL of diethyl ether to give pure 5-bromo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile as a white powder. MS: (ES) m / z C 10 H8BrN3[M + H] +The calculated value was 250.0 and the measured value was 250.2.

[0196] 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 5-bromo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile by the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 27 H 26 F3N6O3S [M + H] + Calculated value: 571.2, measured value: 571.2. 1 H NMR(400MHz,DMSO-d6)δ 12.70(d,J=3.1Hz,1H),8.38(d,J=3.0Hz,1H),8.24 - 8.21(m,1H),7.86(d,J=8.2Hz,2H),7.60(dd,J=9.0,2.5Hz,1H),7.54(d,J=8.2H z,2H),7.12(d,J=7.4Hz,1H),6.72(d,J=8.9Hz,1H),5.25(d,J=4.5Hz,1H),3.98 - 3.88(m,2H),3.63 - 3.48(m,2H),2.76 - 2.70(m,1H),2.61(t,J=10.6Hz,1H),2.36(s,3H),2.24(s,3H),1.98 - 1.86(m,1H),1.73 - 1.64(m,1H).

[0197] Example 64: (3S,4R)-1-((4-(2-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] A mixture of methyl 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinate (134 mg, 0.25 mmol) and hydrazine monohydrate (48 μL, 1.0 mmol) in ethanol (1 mL) was stirred at 70° C. for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to provide 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinohydrazide, which was used directly without purification.

[0198] A mixture of 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinohydrazide (47 mg, 0.088 mmol), acetamidine hydrochloride (17 mg, 0.18 mmol) and potassium carbonate (36 mg, 0.26 mmol) in 1-butanol (1 mL) was stirred at 100° C. for 17 h. The reaction mixture was cooled to room temperature and purified by preparative reverse phase HPLC to give (3S,4R)-1-((4-(2-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 25 F3N7O3S [M+H] + The calculated value was 560.2, and the measured value was 560.1. 1H NMR(400MHz,DMSO-d6)δ 8.79(s,1H),8.35(d,J=1.8Hz,1H),8.20(d,J=2.4Hz,1H),8.13(d,J=7.4Hz,2H),7.91(d,J=8.3Hz,2H),7.87(br s,1H),7.58(dd,J=9.0,2.5Hz,1H),7.11(d,J=7.6Hz,1H),6.69(d,J=8.9Hz,1H),5.25(d,J=4.5Hz,1H),3.99 - 3.83(m,2H),3.52(t,J=13.0Hz,2H),2.77 - 2.71(m,1H),2.68 - 2.58(m,1H),2.40(s,3H),1.97 - 1.80(m,1H),1.70 - 1.62(m,1H).

[0199] Example 65: (3S,4R)-1-((4-(2-(1-methyl-1H-imidazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] A mixture of 4-bromopyridine-2-carboxaldehyde (186 mg, 1.0 mmol), glyoxal (40 wt% in water, 0.23 mL, 2.0 mmol) and ammonium acetate (385 mg, 5.0 mmol) in methanol (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Purification by SiO2 gel chromatography (hexanes / ethyl acetate) gave 4-bromo-2-(1H-imidazol-2-yl)pyridine.

[0200] A mixture of 4-bromo-2-(1H-imidazol-2-yl)pyridine (90 mg, 0.40 mmol) and cesium carbonate (169 mg, 0.52 mmol) in tetrahydrofuran (2 mL) was stirred at 0° C. Iodomethane (62 μL, 1.0 mmol) was added and the reaction mixture was stirred overnight with gradual warming to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL), filtered, and concentrated. Purification by SiO2 gel chromatography (hexanes / ethyl acetate) gave 4-bromo-2-(1-methyl-1H-imidazol-2-yl)pyridine. MS: (ES) m / z C9H9BrN3[M+H] + Calculated value: 238.0, actual value: 238.0.

[0201] (3S,4R)-1-((4-(2-(1-methyl-1H-imidazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 4-bromo-2-(1-methyl-1H-imidazol-2-yl)pyridine by the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 26 H 26 F3N6O3S [M + H] + Calculated value: 559.2, measured value: 559.2. 1H NMR(400MHz,DMSO-d6)δ 8.75(d,J=5.2Hz,1H),8.43 - 8.39(m,1H),8.22 - 8.18(m,1H),8.10(d,J=8.1Hz,2H),7.91(d,J=8.1Hz,2H),7.79 - 7.74(m,1H),7.61 - 7.54(m,1H),7.37(s,1H),7.13 - 7.09(m,1H),7.07(s,1H),6.69(d,J=8.9Hz,1H),5.25(d,J=4.4Hz,1H),4.10(s,3H),3.98 - 3.84(m,2H),3.58 - 3.46(m,2H),2.79 - 2.72(m,1H),2.69 - 2.59(m,1H),1.94 - 1.80(m,1H),1.71 - 1.61(m,1H).

[0202] Example 66: (3S,4R)-1-((4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] A mixture of 4-bromopicolinic acid (202 mg, 1.0 mmol) and 1,1'-carbonyldiimidazole (178 mg, 1.1 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 3 h. N-Hydroxyacetamidine (148 mg, 2.0 mmol) was added and stirring was continued at 100° C. overnight. The reaction mixture was allowed to cool to room temperature and diluted with water (10 mL). The resulting solid was filtered, washed with water and purified by SiO2 gel chromatography (hexane / ethyl acetate) to give 5-(4-bromopyridin-2-yl)-3-methyl-1,2,4-oxadiazole.

[0203] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (82 mg, 0.17 mmol) in a septum-capped vial was added bis(pinacolato)diboron (52 mg, 0.20 mmol), KOAc (49 mg, 0.50 mmol), dioxane (1 mL) and Pd(dppf)Cl2·DCM (1 mg, 0.0017 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and then cooled when the reaction had proceeded to completion. To the mixture was added K2CO3 (70 mg, 0.51 mmol), 5-(4-bromopyridin-2-yl)-3-methyl-1,2,4-oxadiazole (48 mg, 0.20 mmol), water (0.5 mL) and Pd(dppf)Cl2·DCM (14 mg, 0.017 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 3 h and the reaction proceeded to completion when it was cooled. The reaction mixture was diluted with ethyl acetate (10 mL), filtered through celite and concentrated. The mixture was purified by SiO2 gel chromatography (dichloromethane / ethyl acetate) followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 24 F3N6O4S [M + H] + Calculated value: 561.2, actual value: 561.2. 1H NMR(400MHz,DMSO-d6)δ 8.95(d,J=5.1Hz,1H),8.54(s,1H),8.21 - 8.16(m,3H),8.13(dt,J=5.2,1.4Hz,1H),7.92(d,J=7.6Hz,2H),7.61 - 7.53(m,1H),7.11(d,J=7.5Hz,1H),6.69(d,J=9.0Hz,1H),5.25(d,J=4.4Hz,1H),3.97 - 3.85(m,2H),3.59 - 3.46(m,2H),2.74(d,J=11.5Hz,1H),2.63(dd,J=12.7,9.6Hz,1H),2.49(s,3H),1.94 - 1.77(m,1H),1.70 - 1.62(m,1H).

[0204] Example 67: (3S,4R)-1-((4-(2-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] A mixture of 4-bromopicolinonitrile (549 mg, 3.0 mmol), hydroxylamine hydrochloride (313 mg, 4.5 mmol) and N,N-diisopropylethylamine (0.84 mL, 4.8 mmol) in ethanol (3 mL) was stirred at 70° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated to give 4-bromo-N-hydroxypicolinamidine, which was used without purification.

[0205] A mixture of 4-bromo-N-hydroxypicolinamidine (216 mg, 1.0 mmol) and acetic anhydride (2 mL) was stirred at 110° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate (50 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. Purification by SiO2 gel chromatography (hexanes / ethyl acetate) gave 3-(4-bromopyridin-2-yl)-5-methyl-1,2,4-oxadiazole.

[0206] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (82 mg, 0.17 mmol) in a septum-capped vial was added bis(pinacolato)diboron (52 mg, 0.20 mmol), KOAc (49 mg, 0.50 mmol), dioxane (1 mL) and Pd(dppf)Cl2·DCM (1 mg, 0.0017 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and then cooled when the reaction had proceeded to completion. To the mixture was added K2CO3 (117 mg, 0.85 mmol), 3-(4-bromopyridin-2-yl)-5-methyl-1,2,4-oxadiazole (50 mg, 0.20 mmol), water (0.5 mL) and Pd(dppf)Cl2·DCM (14 mg, 0.017 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1.5 h and the reaction proceeded to completion when it was cooled. The reaction mixture was diluted with ethyl acetate (10 mL), filtered through celite and concentrated. The mixture was purified by SiO2 gel chromatography (hexane / ethyl acetate) followed by preparative reverse phase HPLC to give (3S,4R)-1-((4-(2-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 25 H 24 F3N6O4S [M + H] +Calculated value: 561.2, actual value: 561.2. 1 H NMR(400MHz,DMSO-d6)δ 8.89(dd,J=5.1,0.8Hz,1H),8.39 - 8.32(m,1H),8.21 - 8.19(m,1H),8.14(d,J=8.5Hz,2H),8.02(dd,J=5.1,1.9Hz,1H),7.92(d,J=8.4Hz,2H ),7.59(dd,J=9.0,2.5Hz,1H),7.13(s,1H),6.70(d,J=9.0Hz,1H),5.23(s,1H),3.99 - 3.82(m,2H),3.57 - 3.47(m,2H),2.78-2.70(m,4H),2.69 - 2.58(m,1H),1.95 - 1.81(m,1H),1.72 - 1.61(m,1H).

[0207] Example 68: (3S,4R)-1-((4-(2-(1,3,4-oxadiazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] A mixture of formic acid hydrazide (180 mg, 3.0 mmol) and 4-bromopicolinic acid (404 mg, 2.0 mmol) in DMF (4 mL) was stirred and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) was added followed by 1-hydroxybenzotriazole monohydrate (337 mg, 2.2 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was dissolved in tetrahydrofuran (20 mL) and trimethylamine (1.1 mL, 8.0 mmol) was added followed by benzenesulfonyl chloride (0.51 mL, 4.0 mmol). The reaction mixture was stirred at 60 °C for 17 h. The reaction mixture was cooled to room temperature. The solid was filtered and washed with tetrahydrofuran. The filtrate was concentrated and purified by SiO2 gel chromatography (hexanes / ethyl acetate) to give 2-(4-bromopyridin-2-yl)-1,3,4-oxadiazole. MS: (ES) m / z C7H5BrN3O [M+H] + Calculated value: 226.0, actual value: 226.0.

[0208] (3S,4R)-1-((4-(2-(1,3,4-oxadiazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 2-(4-bromopyridin-2-yl)-1,3,4-oxadiazole via the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 24 H 22 F3N6O4S [M + H] + Calculated value: 547.2, measured value: 547.2. 1H NMR(400MHz,DMSO-d6)δ 9.49(s,1H),8.92(dd,J=5.1,0.8Hz,1H),8.52(dd,J=1.7,0.8Hz,1H),8.22 - 8.15(m,3H),8.07(dd,J=5.2,1.8Hz,1H),7.93(d,J=8.5Hz,2H),7.58(dd,J=8.9,2.6Hz,1H),7.09(d,J=7.5Hz,1H),6.6 9(d,J=8.9Hz,1H),5.24(d,J=4.4Hz,1H),3.97-3.86(m,2H),3.54(dt,J=16.3,8.3Hz,2H),2.75(d,J=12.2Hz,1H),2.69 - 2.59(m,1H),1.94 - 1.82(m,1H),1.72 - 1.61(m,1H).

[0209] Example 69: (3S,4R)-1-((4-(2-(5-amino-1,3,4-oxadiazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] A mixture of semicarbazide hydrochloride (167 mg, 1.5 mmol) and sodium acetate (164 mg, 2.0 mmol) in ethanol (8 mL) and water (2 mL) was stirred and 4-bromopyridine-2-carboxaldehyde (186 mg, 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The resulting solid was filtered, washed with ethanol, and dried to give 2-((4-bromopyridin-2-yl)methylene)hydrazine-1-carboxamide.

[0210] A mixture of 2-((4-bromopyridin-2-yl)methylene)hydrazine-1-carboxamide (180 mg, 0.74 mmol) and potassium carbonate (152 mg, 1.1 mmol) in dioxane (8 mL) was stirred and iodine (226 mg, 0.89 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Additional potassium carbonate (152 mg, 1.1 mmol) and iodine (226 mg, 0.89 mmol) were added and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium sulfite (10 mL) and extracted with 2:1 chloroform:isopropanol (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated to give 5-(4-bromopyridin-2-yl)-1,3,4-oxadiazol-2-amine. MS: (ES) m / z C7H6BrNO [M+H] + Calculated value: 241.0, actual value: 241.0.

[0211] (3S,4R)-1-((4-(2-(5-amino-1,3,4-oxadiazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 5-(4-bromopyridin-2-yl)-1,3,4-oxadiazol-2-amine via the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 24 H 23 F3N7O4S [M + H] + The calculated value was 562.1, and the actual value was 562.0. 1H NMR(400MHz,DMSO-d6)δ 8.79(d,J=5.2Hz,1H),8.28(d,J=1.7Hz,1H),8.22 - 8.18(m,1H),8.12(d,J=8.2Hz,2H),7.94 - 7.88(m,3H),7.58(dd,J=9.0,2.5Hz,1H),7.46(s,2H),7.09(d,J=7.5Hz,1H),6.69( d,J=8.9Hz,1H),5.23(s,1H),3.97-3.85(m,2H),3.53(dt,J=16.0,8.2Hz,2H),2.80 - 2.72(m,1H),2.64(dd,J=11.8,9.1Hz,1H),1.95 - 1.82(m,1H),1.66(dq,J=12.3,3.7Hz,1H).

[0212] Example 70: (3S,4R)-1-((4-(2-(5-methyloxazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] A mixture of 4-bromopicolinic acid (404 mg, 2.0 mmol), propargylamine (0.26 mL, 4.0 mmol) and N,N-diisopropylethylamine (1.1 mL, 3.0 mmol) in DMF (4 mL) was stirred and HATU (1.14 g, 3.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL). The resulting solid was filtered, washed with water and dried to give 4-bromo-N-(prop-2-yn-1-yl)picolinamide.

[0213] 4-Bromo-N-(prop-2-yn-1-yl)picolinamide (120 mg, 0.50 mmol) was dissolved in 1,2-dichloroethane (2 mL) and trifluoromethanesulfonic acid (0.44 mL, 5.0 mmol) was added dropwise. The reaction mixture was stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature, poured into saturated sodium bicarbonate (50 mL) and extracted with 2:1 chloroform:isopropanol (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 2-(4-bromopyridin-2-yl)-5-methyloxazole. MS: (ES) m / z C9H8BrNO [M+H] + Calculated value 239.0, measured value 239.0.

[0214] (3S,4R)-1-((4-(2-(5-methyloxazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 2-(4-bromopyridin-2-yl)-5-methyloxazole via the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 26 H 25 F3N5O4S [M + H] + The calculated value was 560.2, and the measured value was 560.1. 1H NMR(400MHz,DMSO-d6)δ 8.80(dd,J=5.2,0.8Hz,1H),8.35(dd,J=1.8,0.8Hz,1H),8.20(dt,J=2.3,1.1Hz,1H),8.13(d,J=8.4Hz,2H),7.94 - 7.88(m,3H),7.58(dd,J=9.0,2.6Hz,1H),7.13(d,J=1.3Hz,1H),7.09(d,J=7.6Hz,1H),6.69(d,J=8.9Hz,1H),5.23(d,J=4.5Hz,1H),4.00 - 3.84(m,2H),3.53(dt,J=16.2,8.2Hz,2H),2.75(d,J=12.0Hz,1H),2.69 - 2.59(m,1H),2.44(d,J=1.2Hz,3H),1.94 - 1.81(m,1H),1.71 - 1.61(m,1H).

[0215] Example 71: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-1H-imidazole-2-carboxamide [ka] To a solution of 5-bromo-1-methyl-1H-imidazole-2-carboxaldehyde (200 mg, 1.06 mmol) in pyridine (1 mL) was added hydroxylamine hydrochloride (93 mg, 1.3 mmol). The mixture was stirred at room temperature for 2 h. Acetic anhydride (2.0 mL, 21 mmol) was then added to the mixture, and the mixture was stirred at 100° C. for 44 h. After cooling, the reaction mixture was added to a mixture of ethyl acetate and water, and the aqueous layer was discarded. The organic phase was concentrated, and the residue was purified via SiO2 gel chromatography (hexane / ethyl acetate) to give 5-bromo-1-methyl-1H-imidazole-2-carbonitrile.

[0216] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (96 mg, 0.20 mmol) in a septum-capped vial was added bis(pinacolato)diboron (77 mg, 0.16 mmol), KOAc (49 mg, 0.50 mmol), dioxane (1.5 mL) and Pd(dppf)Cl2·DCM (1.7 mg, 0.0021 mmol). The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and then cooled when the reaction had proceeded to completion. To the mixture was added K2CO3 (114 mg, 0.83 mmol), 5-bromo-1-methyl-1H-imidazole-2-carbonitrile (33 mg, 0.18 mmol), water (0.7 mL), and Pd(dppf)Cl2·DCM (11 mg, 0.013 mmol). The mixture was flushed with nitrogen for 10 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography (hexane / ethyl acetate followed by dichloromethane / ethyl acetate) to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-1H-imidazole-2-carbonitrile.

[0217] To a solution of 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-1H-imidazole-2-carbonitrile (60 mg, 0.12 mmol) in DMSO (1 mL) was added 30% hydrogen peroxide (33 mg, 0.29 mmol) followed immediately by 1 M sodium hydroxide (0.32 mL, 0.32 mmol). LCMS showed immediate formation of the desired product. The mixture was treated with acetic acid to obtain a slightly acidic pH and purified by reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-1H-imidazole-2-carboxamide. MS: (ES) m / z C 22 H 24 F3N6O4S [M + H] + Calculated value: 525.2, actual value: 525.2. 1 H NMR(400MHz,DMSO-d6)δ 8.24 - 8.17(m,1H),7.89 - 7.82(m,3H),7.79(d,J=8.4Hz,2H),7.59(dd,J=8.9,2.6Hz,1H),7.54(d,J=2.3Hz,1H),7.29( s,1H),7.10(d,J=7.5Hz,1H),6.70(d,J=8.9Hz,1H),5.23(d,J=4.5Hz,1H),3.99(s,3H),3.96 - 3.85(m,2H),3.58 - 3.45(m,2H),2.76 - 2.69(m,1H),2.61(td,J=10.7,10.2,2.5Hz,1H),1.88(qd,J=10.8,4.0Hz,1H),1.72 - 1.60(m,1H).

[0218] Example 72: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-1H-imidazole-2-carboxamide [ka] To a solution of 4-bromo-1-methyl-1H-imidazole (500 mg, 3.1 mmol) dissolved in tetrahydrofuran (2 mL) and cooled in an acetone / CO2 bath was added slowly via syringe a 0.8 M solution of lithium diisopropylamide (4.0 mL, 3.2 mmol) in THF / diethyl ether. After 20 min, the mixture was transferred to an ice bath and stirred for 30 min, after which N,N-dimethylformamide (0.50 mL, 6.5 mmol) was added. The mixture was cooled to 0°C for 30 min. o The mixture was stirred at RT for 1 h, quenched with 1M HCl, and the pH was adjusted to 7. The organic phase was separated and the aqueous phase was extracted twice with 3 mL of ethyl acetate. The combined organic phase was concentrated and purified by flash chromatography (ethyl acetate / hexanes) to give 4-bromo-1H-imidazole-2-carbaldehyde.

[0219] To a solution of 4-bromo-1H-imidazole-2-carbaldehyde (260 mg, 1.4 mmol) in pyridine (1 mL) was added hydroxylamine hydrochloride (140 mg, 2.0 mmol) and the mixture was stirred for 1 h. Acetic anhydride (2.0 mL, 21 mmol) was added and the resulting mixture was stirred at 100° C. for 17 h. The mixture was concentrated under high vacuum to remove most of the volatiles and the resulting residue was dissolved in ethyl acetate and water. The aqueous phase was separated and discarded, and the organic phase was concentrated and purified by SiO2 chromatography (ethyl acetate / dichloromethane) to give 4-bromo-1H-imidazole-2-carbonitrile.

[0220] 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-1H-imidazole-2-carbonitrile was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 4-bromo-1H-imidazole-2-carbonitrile by the one-pot Miyaura / Suzuki procedure described in Example 33. Nitrile hydrolysis with hydrogen peroxide according to the procedure described in Example 71 gave 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-1H-imidazole-2-carboxamide. MS: (ES) m / z C 22 H 24 F3N6O4S [M + H] + Calculated value: 525.2, actual value: 525.2. 1 H NMR(400MHz, methanol-d4)δ 8.15(d,J=2.3Hz,1H),8.05(d,J=8.4Hz,2H),7.82-7.78(m,3H),7.54(dd,J=8.9,2.5Hz,1H),6.62(d,J=9.0Hz,1H),4.07(s,3H),4.02 - 3.97(m,1H),3.91(dt,J=10.7,3.8Hz,1H),3.72 - 3.61(m,2H),2.75(dd,J=12.2,2.1Hz,1H),2.64(dt,J=11.6,6.1Hz,1H),2.00(qd,J=11.0,4.1Hz,1H),1.81(dt,J=13.5,3.7Hz,1H).

[0221] Example 73: 3-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrazole-5-carboxamide [ka] Methyl 3-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrazole-5-carboxylate was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and methyl 3-bromo-1H-pyrazole-5-carboxylate by the one-pot Miyaura / Suzuki procedure described in Example 33.

[0222] To a solution of methyl 3-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrazole-5-carboxylate (48 mg, 0.091 mmol) in methanol (0.50 mL) was added 28% ammonium hydroxide (0.45 g, 7.4 mmol). The mixture was stirred at 40° C. for 16 h and purified by reverse phase HPLC to give 3-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrazole-5-carboxamide. MS: (ES) m / z C 21 H 22 F3N6O4S [M + H] + The calculated value was 511.1, and the actual value was 511.0. 1 H NMR(400MHz, methanol-d4)δ 8.15(d,J=2.4Hz,1H),8.07 - 7.93(m,2H),7.88(d,J=8.1Hz,2H),7.54(dd,J=9.0,2.5Hz,1H),7.23(s,1H),6.62(d,J=9.0Hz,1H),4.02 - 3.98(m,1H),3.92(dt,J=10.9,3.7Hz,1H),3.73 - 3.63(m,2H),2.83 - 2.74(m,1H),2.70 - 2.61(m,1H),2.07 - 1.93(m,1H),1.84 - 1.76(m,1H).

[0223] Example 74: N-hydroxy-4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide [ka] To a stirred solution of methyl 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinate (53 mg, 0.099 mmol) in methanol (0.50 mL) and THF (0.50 mL) was added 50 wt % aqueous hydroxylamine (190 mg, 3.3 mmol). The mixture was stirred at room temperature for 2 days after which it was diluted with NMP, methanol and 0.1% trifluoroacetic acid and purified by reverse phase HPLC to give N-hydroxy-4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide. MS: (ES) m / z C 23 H 23 F3N5O5S [M + H] + Calculated value: 538.1, measured value: 538.2. 1 H NMR(400MHz, methanol-d4)δ 8.72(d,J=5.1Hz,1H),8.38(d,J=2.1Hz,1H),8.18(d,J=2.2Hz,1H),8.05(d,J=8.3Hz,2 H),7.98(d,J=8.5Hz,2H),7.89(dd,J=5.1,1.9Hz,1H),7.69(dd,J=9.2,2.4Hz,1H),6.82 - 6.78(m,1H),4.03 - 3.99(m,1H),3.91(dt,J=10.4,3.7Hz,1H),3.73 - 3.64(m,2H),2.88 - 2.81(m,1H),2.78 - 2.69(m,1H),2.03(ddt,J=14.3,10.4,5.3Hz,1H),1.88 - 1.79(m,1H).

[0224] Example 75: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,5-dimethylpicolinonitrile [ka] To a solution of (4-bromo-3,5-dimethylpyridin-2-yl)methanol (300 mg, 1.4 mmol) in dichloromethane (6 mL) was added manganese dioxide (300 mg, 3.5 mmol) and the mixture was stirred for 30 h. TLC indicated some remaining starting material was present. Additional manganese dioxide (300 mg, 3.5 mmol) was added and the mixture was stirred for an additional 21 h, at which point TLC indicated complete conversion. The dichloromethane was removed in vacuo and the residue was purified by SiO2 gel chromatography (ethyl acetate / hexanes) to give 4-bromo-3,5-dimethylpicolinaldehyde.

[0225] To a solution of 4-bromo-3.5-picolinaldehyde (217 mg, 1.0 mmol) in pyridine (1 mL) was added hydroxylamine hydrochloride (104 mg, 1.5 mmol). The mixture was stirred at room temperature for 50 minutes. Acetic anhydride (2.0 mL, 21 mmol) was then added to the mixture, and the mixture was stirred at 100° C. for 17 hours. After cooling, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (10 mL), and stirred with water (5 mL). The aqueous phase was discarded, and the organic layer was concentrated and purified by SiO2 gel chromatography to give 4-bromo-3.5-dimethylpicolinonitrile.

[0226] 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,5-dimethylpicolinonitrile was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 4-bromo-3,5-dimethylpicolinonitrile by the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 26 H 25 F3N5O4S [M + H] + Calculated value: 532.2, actual value: 532.2. 1 H NMR(400MHz,DMSO-d6)δ 8.60(s,1H),8.24 - 8.19(m,1H),7.90(d,J=8.3Hz,2H),7.59(dd,J=8.9,2.6Hz,1H),7.54(d,J=8.5H z,2H),7.11(d,J=7.3Hz,1H),6.71(d,J=8.9Hz,1H),5.25(d,J=4.4Hz,1H),3.98 - 3.86(m,2H),3.62 - 3.47(m,2H),2.77 - 2.69(m,1H),2.60(dd,J=11.8,9.0Hz,1H),2.20(s,3H),2.09(s,3H),1.97 - 1.84(m,1H),1.73 - 1.63(m,1H).

[0227] Example 76: (3S,4R)-1-((4-(5-(piperazin-1-yl)pyridin-3-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To a vial containing 3,5-dibromopyridine (1 g, 4.2 mmol) was added piperazine (730 mg, 8.5 mmol). The contents were heated at 130° C. for 16 hours and then purified by silica gel column chromatography to give 1-(5-bromopyridin-3-yl)piperazine.

[0228] (3S,4R)-1-((4-(5-(piperazin-1-yl)pyridin-3-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 1-(5-bromopyridin-3-yl)piperazine via the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 26 H 30 F3N6O3S [M + H] + Calculated value: 563.2, measured value: 563.1. 1 H NMR(400MHz, methanol-d4)δ 8.43(d,J=1.8Hz,1H),8.38(d,J=2.7Hz,1H),8.15(s,1H),7.93(s,4H),7.7 6(t,J=2.3Hz,1H),7.55(dd,J=9.1,2.5Hz,1H),6.63(d,J=8.9Hz,1H),4.02 - 3.99(m,1H),3.94 - 3.88(m,1H),3.76 - 3.66(m,2H),3.64 - 3.57(m,4H),3.46 - 3.41(m,4H),2.79 - 2.73(m,1H),2.68 - 2.60(m,1H),2.08 - 1.95(m,1H),1.84 - 1.76(m,1H).

[0229] Example 77: 7-Fluoro-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-indazole-3-carbonitrile [ka] To a vial containing 5-bromo-7-fluoro-1H-indazole (500 mg, 2.3 mmol) in DMF (6 mL) was added KOH (260 mg, 4.6 mmol) and I2 (1.2 g, 4.7 mmol). The reaction mixture was stirred at room temperature for 16 h and then purified by silica gel column chromatography to give 5-bromo-7-fluoro-3-iodo-1H-indazole.

[0230] To a vial containing 5-bromo-7-fluoro-3-iodo-1H-indazole (350 mg, 1.0 mmol) in DMA (3 mL) was added Zn (40 mg, 0.62 mmol), Zn(CN)2 (200 mg, 1.7 mmol), CuI (200 mg, 1.05 mmol) and Pd(dppf)Cl2-dichloromethane complex (117 mg, 0.14 mmol). The reaction mixture was heated at 140° C. for 16 h. The contents were filtered through Celite, concentrated and then purified by silica gel column chromatography to give 5-bromo-7-fluoro-1H-indazole-3-carbonitrile. MS: (ES) m / z C8H4BrFN3[M + H] + The calculated value was 240.0 and the measured value was 239.9.

[0231] 7-Fluoro-5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-indazole-3-carbonitrile was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol and 5-bromo-7-fluoro-3-iodo-1H-indazole by the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 25 H 31 F4N6O3S [M + H] + The calculated value was 561.1, and the measured value was 561.2. 1H NMR (400MHz, methanol-d4)δ 8.19(s,1H),8.02 - 7.97(m,3H),7.95 - 7.91(m,2H),7.78 - 7.73(m,1H),7.70(dd,J=12.0,1.3Hz,1H),6.88(d,J=9.2Hz,1H),4.04 - 4.00(m,1H),3.90(dt,J=10.3,3.7Hz,1H),3.71 - 3.62(m,2H),2.90 - 2.82(m,1H),2.80 - 2.71(m,1H),2.12 - 1.98(m,1H),1.90 - 1.82(m,1H).

[0232] Example 78: 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-7-methylisoindolin-1-one [ka] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol) in a septum-capped vial was added bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (62 mg, 0.63 mmol), dioxane (1 mL) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (83 mg, 0.60 mmol), 5-bromo-7-methylisoindolin-1-one (47 mg, 0.21 mmol), dioxane (2 mL), water (1 mL), and Pd(dppf)Cl2·DCM (17 mg, 0.021 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 5-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-7-methylisoindolin-1-one. MS: (ES) m / z C 26 H 26 F3N4O4S [M + H] + Calculated value: 547.2, measured value: 547.2. 1 H NMR(400MHz,methanol-d4)δ 8.19(s,1H),7.99 - 7.88(m,4H),7.77(d,J=9.2Hz,1H),7.69(s,1H),7.57(s,1H),6.90(d,J=9.2Hz,1H),4.47(s,2H),4.02(s,1H),3.93 - 3.86(m,1H),3.71-3.61(m,2H),2.89 - 2.81(m,1H),2.75(s,3H),2.79 - 2.69(m,1H),2.13 - 1.98(m,1H),1.91 - 1.82(m,1H).

[0233] Example 79: 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-8-methoxyphthalazin-1(2H)-one [ka] To a vial containing methyl 4-bromo-2-formyl-6-methoxybenzoate (270 mg, 0.99 mmol) was added hydrazine (1 mL). The mixture was stirred at room temperature and a white solid formed immediately. The solid was filtered, rinsed with TBME (1 mL) and air-dried to give 6-bromo-8-methoxyphthalazin-1(2H)-one.

[0234] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol) in a septum-capped vial was added bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (62 mg, 0.63 mmol), dioxane (1 mL) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (83 mg, 0.60 mmol), 6-bromo-8-methoxyphthalazin-1(2H)-one (54 mg, 0.21 mmol), dioxane (2 mL), water (1 mL), and Pd(dppf)Cl2·DCM (17 mg, 0.021 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-8-methoxyphthalazin-1(2H)-one. MS: (ES) m / z C 26 H 25F3N5O5S [M + H] + Calculated value: 576.2, actual value: 576.2. 1 H NMR (400MHz, methanol-d4)δ 8.70(s,1H),8.56(s,1H),8.22(s,1H),8.02 - 7.94(m,2H),7.87 - 7.81(m,1H),7.71 - 7.64(m,2H),6.98(d,J=9.2Hz,1H),4.03(s,2.4Hz,1H),3.95 - 3.88(m,1H),3.77 - 3.68(m,2H),2.90 - 2.82(m,1H),2.80 - 2.70(m,1H),2.45(s,3H).2.15 - 2.01(m,1H),1.92 - 1.82(m,1H).

[0235] Example 80: 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-N,N,4-trimethylisoindoline-2-carboxamide [ka] To a solution of 6-bromo-4-methylisoindoline (70 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.1 mL) in DCM (1 mL) was added dimethylcarbamic chloride (39 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 h and concentrated to dryness. Purification by SiO2 gel chromatography (hexane / ethyl acetate) gave 6-bromo-N,N,4-trimethylisoindoline-2-carboxamide.

[0236] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (100 mg, 0.21 mmol) in a septum-capped vial was added bis(pinacolato)diboron (64 mg, 0.25 mmol), KOAc (62 mg, 0.63 mmol), dioxane (1 mL) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and allowed to cool when the reaction had proceeded to completion. To the mixture was added K2CO3 (83 mg, 0.60 mmol), 6-bromo-N,N,4-trimethylisoindoline-2-carboxamide (60 mg, 0.21 mmol), dioxane (2 mL), water (1 mL) and Pd(dppf)Cl2·DCM (17 mg, 0.021 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and the reaction proceeded to completion when it was cooled. The mixture was purified by SiO2 gel chromatography followed by preparative reverse phase HPLC to give 6-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-N,N,4-trimethylisoindoline-2-carboxamide. MS: (ES) m / z C 29 H 33 F3N5O4S [M + H] + Calculated value: 604.2, measured value: 604.2. 1 H NMR(400MHz,methanol-d4)δ 8.19(s,1H),7.89 - 7.85(m,4H),7.77(dd,J=9.3,2.4Hz,1H),7.44(d,J=9.0Hz,2H),6.89(d,J=9.2Hz,1H),4.87(s,2H),4.80(s,2H),4.04-3.99(m,1H),3.93 - 3.85(m,1H),3.68 - 3.59(m,2H),2.98(s,6H),2.88 - 2.80(m,1H),2.77-2.68(m,1H),2.37(s,3H),2.10 - 2.01(m,1H),1.86(m,1H).

[0237] Example 81: 4-(4-(((3S,4R)-3-hydroxy-4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide [ka] A mixture of tert-butyl (3S,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (216 mg, 1.0 mmol) and cesium carbonate (652 mg 2.0 mmol) in DMSO (2 mL) and water (1 mL) was stirred and copper(I) iodide (19 mg, 0.10 mmol) was added followed by 4-iodobenzotrifluoride (0.15 mL, 1.0 mmol). The reaction mixture was stirred at 90° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with 28% aqueous NH3 (10 mL) and water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over magnesium sulfate, filtered and concentrated. Purification by SiO2 gel chromatography (hexanes / ethyl acetate) gave tert-butyl (3S,4R)-3-hydroxy-4-((4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate.

[0238] tert-Butyl (3S,4R)-3-hydroxy-4-((4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (85 mg, 0.24 mmol) was stirred in dioxane (2 mL) and HCl (4 M in dioxane, 2 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the crude residue was suspended in 2-methyltetrahydrofuran (5 mL). A solution of potassium carbonate (133 mg, 0.96 mmol) in water (1 mL) was added followed by 4-bromobenzenesulfonyl chloride (92 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 2 h. The aqueous layer was removed and the organic layer was concentrated. Purification by SiO2 gel chromatography (hexane / ethyl acetate) gave (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((4-(trifluoromethyl)phenyl)amino)piperidin-3-ol.

[0239] 4-(4-(((3S,4R)-3-hydroxy-4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((4-(trifluoromethyl)phenyl)amino)piperidin-3-ol and 4-bromopicolinamide by the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 24 H 24 F3N4O4S [M + H] + Calculated value: 521.1, measured value: 521.1. 1H NMR(400MHz,DMSO-d6)δ 8.77(d,J=5.1Hz,1H),8.36(d,J=1.9Hz,1H),8.22(d,J=2.6Hz,1H),8.14(d,J=8.3Hz,2H),8.01(dd,J=5.2,1.9Hz,1H),7.90( d,J=8.3Hz,2H),7.76(d,J=2.7Hz,1H),7.29(d,J=8.5Hz,2H),6.72(d,J=8.6Hz,2H),5.99(d,J=8.2Hz,1H),5.17(s,1H),3.88 - 3.83(m,1H),3.59 - 3.50(m,2H),3.50 - 3.41(m,1H),2.75 - 2.69(m,1H),2.65 - 2.57(m,1H),1.82(qd,J=11.7,10.8,3.7Hz,1H),1.66(dd,J=13.5,4.1Hz,1H).

[0240] Example 82: 4-[4-[[(3S,4R)-3-hydroxy-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]pyridine-2-carboxamide [ka] A solution of (3S,4R)-1-(4-bromophenyl)sulfonyl-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]piperidin-3-ol (200 mg; 0.40 mmol), bis-pinacordiboron (150 mg, 0.28 mml), KOAc (90 mg; 0.92 mmol) and Pd(dppf)Cl2 (6 mg, 0.007 mmol) in 6 mL of dioxane is degassed with N2 bubbling for 30 min. The mixture is heated at 100 °C for 1 h. The mixture is diluted with 1.4 mL of H2O and degassed for 10 min. To this was added K2CO3 (130 mg, 0.87 mmol), 4-bromopyridine-2-carboxamide (175 mg, 0.87 mmol) and Pd(dppf)Cl2·DCM (35 mg, 0.043 mmol). The mixture was diluted to 100 oC for 16 h. The reaction is cooled to room temperature, concentrated, and the residue is purified by column chromatography on silica gel (hexanes / ethyl acetate) to give 4-[4-[[(3S,4R)-3-hydroxy-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]pyridine-2-carboxamide. MS: (ES) m / z C 24 H 24 F3N5O4S [M+H] + Calculated value: 536.2, actual value: 536.1. 1 H NMR(400MHz,DMSO-d6)δ 8.78(dd,J=5.2,0.8Hz,1H),8.37(dd,J=2.1,0.9Hz,1H),8.27 - 8.18(m,1H),8.16 - 8.09(m,3H),8.01(dd,J=5.1,1.9Hz,1H),7.96 - 7.88(m,2H),7.77(d,J=2.7Hz,1H),7.57 - 7.52(m,1H),5.83 - 5.74(m,1H),5.28(d,J=4.5Hz,1H),4.01(ddt,J=11.5,7.4,3.7Hz,1H),3.93(s,1H),3.68(dd,J=15.5,12.0Hz,2H),2.69 - 2.61(m,1H),2.55(m,1H),2.11(s,3H),1.97(qd,J=12.5,4.5Hz,1H),1.71(dd,J=12.9,3.8Hz,1H).

[0241] Example 83: 5-[4-[[(3S,4R)-3-hydroxy-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1-methyl-imidazole-2-carboxamide [ka] A solution of (3S,4R)-1-(4-bromophenyl)sulfonyl-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]piperidin-3-ol (200 mg; 0.40 mmol), bis-pinacordiboron (150 mg, 0.28 mml), KOAc (90 mg; 0.92 mmol) and Pd(dppf)Cl2 (6 mg, 0.007 mmol) in 6 mL of dioxane is degassed with N2 bubbling for 30 min. The mixture is heated at 100 °C for 1 h. The mixture is diluted with 1.4 mL of H2O and degassed for 10 min. To this was added K2CO3 (130 mg, 0.87 mmol), 5-bromo-1-methyl-imidazole-2-carbonitrile (125 mg, 0.67 mmol) and Pd(dppf)Cl2·DCM (35 mg, 0.043 mmol). The mixture was diluted to 100 o Heat at C for 16 h. The reaction is cooled to rt, concentrated, and the residue is purified by column chromatography on silica gel (0-100% EtOAc / CHCl) to give 5-[4-[[(3S,4R)-3-hydroxy-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1-methyl-imidazole-2-carbonitrile.

[0242] To a solution of 5-[4-[[(3S,4R)-3-hydroxy-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1-methyl-imidazole-2-carbonitrile (165.4 mg; 0.32 mmol) in DMSO (1 mL) is added 1 M NaOH (1 mL) and 30% H2O2 (70 μL). The mixture is stirred for 30 min. The reaction is diluted with 30 mL of EtOAc. To this is added saturated NH4Cl and the phases are separated. The organic phase is separated, dried over MgSO4, filtered, concentrated, and the residue is purified by preparative HPLC to give 5-[4-[[(3S,4R)-3-hydroxy-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1-methyl-imidazole-2-carboxamide. MS: (ES) m / z C 23 H26 F3N6O4S [M+H] + Calculated value: 539.2, measured value: 539.1. 1 H NMR(400MHz,DMSO-d6)δ 8.14(d,J=2.5Hz,1H),7.98 - 7.71(m,5H),7.55(s,2H),7.30(s,1H),5.79(d,J=7.6Hz,1H),5.29(d,J=4.4Hz,1H),4.08 - 3.97(m,4H),3.93(s,1H),3.66(t,J=15.2Hz,2H),2.64(d,J=11.9Hz,1H),2.55(m,1H),2.12(s,3H),1.97(qd,J=12.6,4.4Hz,1H),1.79 - 1.65(m,1H).

[0243] Example 84: (3S,4R)-1-[4-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-pyridyl]phenyl]sulfonyl-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]piperidin-3-ol [ka] A solution of (3S,4R)-1-(4-bromophenyl)sulfonyl-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]piperidin-3-ol (200 mg; 0.40 mmol), bis-pinacordiboron (150 mg, 0.28 mml), KOAc (90 mg; 0.92 mmol) and Pd(dppf)Cl2·DCM (6 mg, 0.007 mmol) in 6 mL of dioxane is degassed with N2 bubbling for 30 min. The mixture is heated at 100 °C for 1 h. LC-MS shows the desired borylated product. The mixture is diluted with 1.4 mL of HO and degassed for 10 min. To this is added K2CO3 (130 mg, 0.87 mmol), 2-(4-bromo-2-pyridyl)-5-methyl-1,3,4-oxadiazole (175 mg, 0.87 mmol) and Pd(dppf)Cl2 (35 mg, 0.043 mmol). The mixture is diluted to 100 oHeat at 37°C for 16 h. The reaction is cooled to room temperature, concentrated, and the residue is purified by silica gel column chromatography (0-100% EtOAc / Hexanes) to give (3S,4R)-1-[4-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-pyridyl]phenyl]sulfonyl-4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]piperidin-3-ol. MS: (ES) m / z C 26 H 26 F3N6O4S [M+H] + Calculated value: 575.2, measured value: 575.1. 1 H NMR(400MHz,DMSO-d6)δ 8.90(d,J=5.1Hz,1H),8.47(s,1H),8.21 - 8.11(m,3H),8.05(d,J=5.2Hz,1H),7.93(d,J=8.1Hz,2H),7.55(d,J=2.5Hz,1H ),5.80(d,J=7.6Hz,1H),4.01(ddt,J=11.9,7.7,3.7Hz,1H),3.93(s,1H),3.75 - 3.62(m,2H),2.66(d,J=4.9Hz,5H),2.11(s,3H),1.97(dt,J=14.7,10.9Hz,1H),1.72(dd,J=13.1,4.3Hz,1H).

[0244] Example 85: 4-(4-(((3S,4R)-4-((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)-3-hydroxypiperidin-1-yl)sulfonyl)phenyl)picolinamide [ka] To 2-(((3S,4R)-1-((4-bromophenyl)sulfonyl)-3-hydroxypiperidin-4-yl)amino)-5-(trifluoromethyl)nicotinonitrile (190 mg, 0.38 mmol) was added bis(pinacolato)diboron (117 mg, 0.46 mmol), KOAc (118 mg, 1.2 mmol), dioxane (2 mL) and Pd(dppf)Cl2·DCM (3 mg, 0.0038 mmol) in a septum-capped vial. The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and then cooled when the reaction had proceeded to completion. To the mixture was added K2CO3 (263 mg, 0.85 mmol), 4-bromopicolinamide (92 mg, 0.46 mmol), water (1 mL), and Pd(dppf)Cl2·DCM (31 mg, 0.038 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 18 h and the reaction proceeded to completion upon which it was cooled. The reaction mixture was diluted with ethyl acetate (10 mL), filtered through Celite, and concentrated. The mixture was purified by SiO2 gel chromatography (hexane / ethyl acetate) followed by preparative reverse phase HPLC to give 4-(4-(((3S,4R)-4-((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)-3-hydroxypiperidin-1-yl)sulfonyl)phenyl)picolinamide. MS: (ES) m / z C 24 H 22 F3N6O4S [M + H] + Calculated value: 547.1, actual value: 547.0. 1H NMR(400MHz,DMSO-d6)δ 8.77(d,J=5.1Hz,1H),8.57 - 8.54(m,1H),8.43(d,J=2.4Hz,1H),8.36(d,J=1.8Hz,1H),8.22(d,J=2.8Hz,1H),8.12(d,J=8.1Hz,2H),8.03 - 7.99(m,1H),7.91(d,J=8.1Hz,2H),7.80 - 7.74(m,1H),6.74(d,J=7.5Hz,1H),4.05(ddt,J=11.4,7.3,3.6Hz,1H),3.92(d,J=3.0Hz,1H),3.74 - 3.61(m,2H),2.65(d,J=12.2Hz,1H),2.55-2.46(m,1H),1.96(qd,J=12.4,4.1Hz,1H),1.80 - 1.68(m,1H).

[0245] Example 86: 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide [ka] A mixture of 2-chloro-5-(trifluoromethyl)pyrimidine (110 mg, 0.60 mmol), (3S,4R)-4-amino-1-((4-bromophenyl)sulfonyl)piperidin-3-ol hydrochloride (446 mg, 1.2 mmol) and N,N-diisopropylethylamine (0.42 mL, 2.4 mmol) in NMP (1 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water. The resulting solid was filtered, washed with water and purified by SiO2 gel chromatography (hexane / ethyl acetate) to give (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 16 H 17 F3N4O3S [M+H] + The calculated value was 481.0 and the measured value was 480.9.

[0246] 4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)picolinamide was synthesized from (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-3-ol and 4-bromopicolinamide by the one-pot Miyaura / Suzuki procedure described in Example 33. MS: (ES) m / z C 22 H 22 F3N6O4S [M + H] + Calculated value: 523.1, actual value: 523.0. 1 H NMR(400MHz,DMSO-d6)δ 8.77(d,J=5.1Hz,1H),8.59(s,2H),8.36(d,J=1.9Hz,1H),8.21(d,J=2.6Hz,1H),8.12(d,J=8.2Hz,2H) ,8.00(dd,J=5.0,1.9Hz,1H),7.90(d,J=8.2Hz,2H),7.76(d,J=2.7Hz,1H),7.65(d,J=7.4Hz,1H),5.22 - 5.14(m,1H),3.95-3.87(m,2H),3.59 - 3.43(m,2H),2.82 - 2.74(m,1H),2.72 - 2.62(m,1H),1.93(dtd,J=13.7,10.2,3.9Hz,1H),1.68(dt,J=13.4,4.2Hz,1H).

[0247] Example 87: [(3S,4R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3-piperidyl]methanol [ka] To (3S,4R)-4-amino-1-(4-bromophenyl)sulfonyl-piperidin-3-ol; hydrochloride salt (250 mg, 0.67 mmol) in 1 mL of NMP, add 5-chloro-2-fluoropyridine (200 mg, 1.52 mmol) and DIPEA (270 uL, 1.54 mmol). The mixture is heated at 100° C. for 16 h and then at 120° C. o Heat at RT for 24 h. The mixture is diluted with EtOAc (30 mL) and washed with HO (4 x 15 mL) and brine (30 mL). The organic phase is partitioned, dried over MgSO, filtered, and concentrated. The crude material is purified by SiO chromatography (0-100% EtOAc / Hexanes) to give (3S,4R)-1-(4-bromophenyl)sulfonyl-4-[(5-chloro-2-pyridyl)amino]piperidin-3-ol.

[0248] A solution of [(3S,4R)-1-(4-bromophenyl)sulfonyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3-piperidyl]methanol, bis-pinacolatodiboron (90 mg; 0.35 mmol), KOAc (35 mg; 0.36 mmol) and Pd(dppf)Cl2 (3 mg, 0.004 mmol) in 2 mL of dioxane is degassed with N2 bubbling for 30 min. The mixture is heated at 100 °C for 1 h. The mixture is diluted with 0.5 mL of H2O and degassed for 10 min. To this is added K2CO3 (55 mg, 0.37 mmol), 4-bromopyridine-2-carboxamide (38 mg, 0.18 mmol) and Pd(dppf)Cl2·DCM (12 mg, 0.02 mmol). The mixture is heated at 100 °C for 1 h. o C for 16 h. The reaction is cooled to room temperature, concentrated, and the residue is purified by column chromatography on silica gel (0-100% EtOAc / Hexanes) to give impure material. This residue is purified by preparative thin layer chromatography on silica (1 mm, 5% MeOH / CHCl) to give [(3S,4R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3-piperidyl]methanol. MS: (ES) m / z C22 H 22 ClN5O4S [M+H] + The calculated value was 490.1 and the actual value was 490.0. 1 H NMR(400MHz,DMSO-d6)δ 8.77(d,J=5.2Hz,1H),8.37(d,J=1.9Hz,1H),8.22(d,J=2.6Hz,1H),8.12(d,J=8.1Hz,2H),8.01(dd,J=5.2,1.9Hz,1H),7.94 - 7.85(m,3H),7.77(d,J=2.6Hz,1H),7.38(dd,J=9.0,2.7Hz,1H),6.61(d,J=9.0Hz,1H),6.49(dd,J=8.9,2.9Hz,1H),5.18(d,J=5.4Hz,1H),3.90 - 3.74(m,2H),3.56 - 3.45(m,2H),2.78 - 2.68(m,1H),2.68 - 2.57(m,1H),1.94 - 1.77(m,1H),1.69 - 1.60(m,1H).

[0249] Example 88: 1-(4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)pyridin-2-yl)piperazin-2-one [ka] To (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (50 mg, 0.11 mmol) in a septum-capped vial was added bis(pinacolato)diboron (32 mg, 0.12 mmol), KOAc (33 mg, 0.33 mmol), dioxane (1 mL) and Pd(dppf)Cl2·DCM (2 mg, 0.0021 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 1 h and then cooled when the reaction had proceeded to completion. To the mixture was added K2CO3 (40 mg, 0.30 mmol), tert-butyl 4-(4-bromopyridin-2-yl)-3-oxopiperazine-1-carboxylate (39 mg, 0.11 mmol), dioxane (2 mL), water (1 mL), and Pd(dppf)Cl2·DCM (9.0 mg, 0.011 mmol). The mixture was flushed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 100 °C for 16 h and then cooled down when the reaction had proceeded to completion. The mixture was purified by SiO2 gel chromatography to give tert-butyl 4-(4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate (34 mg, yield: 29.6%). MS: (ES) m / z C 26 H 28 F3N6O4S [M-Boc] + Calculated value: 577.2, actual value: 577.2.

[0250] To a vial containing tert-butyl 4-(4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)pyridin-2-yl)-3-oxopiperazine-1-carboxylate (34 mg, 0.05 mmol) in CHCl (0.5 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 1 h until the reaction was complete. The reaction mixture was concentrated to dryness and purified by preparative reverse phase HPLC to give 1-(4-(4-(((3S,4R)-3-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)pyridin-2-yl)piperazin-2-one. MS: (ES) m / z C 26 H 28 F3N6O4S [M + H] + Calculated value 577.2, observed value 577.2. 1 H NMR (400MHz, methanol-d4)δ 8.60(d,J=4.0Hz,1H),8.25(s,1H),8.18(s,1H),8.02 - 7.94(m,4H),7.70 - 7.62(m,2H),6.78(d,J=9.2Hz,1H),4.33(dd,J=6.5,4.8Hz,2H),4.10(s,2H),3.95 - 3.87(m,2H),3.77 - 3.68(m,4H),2.85 - 2.65(m,2H),2.10 - 1.95(m,1H),1.88 - 1.78(m,1H).

[0251] Example 89: (3S,4R)-1-((4-(6-morpholinopyridin-3-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To a vial containing (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (1 g, 2.09 mmol) and (6-fluoropyridin-3-yl)boronic acid (360 mg, 2.56 mmol) in HO (3 mL) and dioxane (6 mL) was added potassium carbonate (860 mg, 6.23 mmol). The mixture was degassed with N for 10 min and Pd(dppf)Cl-dichloromethane complex (160 mg, 0.20 mmol) was added. The contents were heated at 105° C. for 2 h and then extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography to give (3S,4R)-1-((4-(6-fluoropyridin-3-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol.

[0252] To a vial containing (3S,4R)-1-((4-(6-fluoropyridin-3-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (75 mg, 0.15 mmol) in NMP (0.5 mL) was added morpholine (66 mg, 0.75 mmol). The contents were heated to 130° C. for 2 h and then purified by silica gel column chromatography followed by preparative HPLC to give (3S,4R)-1-((4-(6-morpholinopyridin-3-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 26 H 29 F3N5O4S [M + H] + Calculated value: 564.2, actual value: 564.2. 1H NMR(400MHz,CD3OD)δ 8.49(d,J=2.5Hz,1H),8.15(d,J=2.4Hz,1H),8.00 - 7.92(m,1H),7.88 - 7.81(m,4H),7.54(dd,J=9.0,2.5Hz,1H),6.94(d,J=8.9Hz,1H),6.62(d,J=8.9Hz,1H),3 .99(bs,1H),3.92(dd,J=10.5,3.9Hz,1H),3.81(dd,J=4.8,4.8Hz,4H),3.67(t,J=12.9H z,2H),3.57(dd,J=4.8,4.8Hz,4H),2.76(dd,J=12.4,2.1Hz,1H),2.64(ddd,J=12.0,12. 0,3.2Hz,1H),2.00(dddd,J=10.8,10.8,10.8,4.0Hz,1H),1.80(dd,J=13.3,4.1Hz,1H).

[0253] Example 90: (3S,4R)-1-((4-(2-(pyrrolidin-1-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol [ka] To a septum-capped vial equipped with a stir bar was added (3S,4R)-1-((4-bromophenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (0.50 g, 1.0 mmol), (2-fluoropyridin-4-yl)boronic acid (0.15 g, 1.0 mmol), K2CO3 (0.43 g, 3.1 mmol), and Pd(dppf)Cl2·DCM (0.085 g, 0.10 mmol), followed by 3.0 mL of 4:1 dioxane:H2O. The reaction mixture was flushed with N2 for 20 min and then heated to 100 °C for 1 h. Upon completion, the reaction was cooled, the contents were applied to Celite, and the product was isolated using SiO2 chromatography (hexanes / ethyl acetate) to give (3S,4R)-1-((4-(2-fluoropyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 22 H 21 F4N4O3S [M + H] + The calculated value was 497.1, and the actual value was 497.0.

[0254] To a septum-capped vial equipped with a stir bar was added (3S,4R)-1-((4-(2-fluoropyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol (0.050 g, 0.10 mmol), followed by 1.5 mL of NMP and pyrrolidine (0.072 g, 1.0 mmol). The reaction mixture was heated to 150° C. and stirred for 16 h. Upon completion, the reaction was cooled to room temperature, quenched with water, extracted with EtOAc, and purified via reverse phase HPLC to give (3S,4R)-1-((4-(2-(pyrrolidin-1-yl)pyridin-4-yl)phenyl)sulfonyl)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-3-ol. MS: (ES) m / z C 26 H 29 F3N5O3S [M + H] + Calculated value 548.2, measured value 548.0; 1H NMR(400MHz,DMSO-d6)δ 8.20(s,1H),8.16(d,J=5.5Hz,1H),8.02(d,J=8.1Hz,2H),7.86(d,J=8.2Hz,2H),7.58(dd,J=9.0,2.2Hz, 1H),7.10(d,J=7.1Hz,1H),6.95(d,J=3.3Hz,1H),6.82(bs,1H),6.69(d,J=9.0Hz,1H),5.22(bs,1H),3.95 - 3.83(m,2H),3.58 - 3.45(m,6H),2.72(d,J=11.5Hz,1H),2.60(t,J=11.5Hz,1H),2.03 - 1.94(m,4H),1.87(m,1H),1.66(m,1H).

[0255] Biological Example 1: Migration Assay Chemotaxis assays can be used to determine the effectiveness of potential receptor antagonists in blocking migration mediated through chemokine receptors such as CCR6. This assay is routinely performed using a ChemoTX® microchamber system with a polycarbonate membrane with a pore size of 5 μm. Chemokine receptor-expressing cells are required for such assays. In this case, Ba / F3 cells transfected with the gene for human CCR6 under the control of the CMV promoter (Palacios et al., Nature, 309:126, 1984) were used. To initiate such assays, hCCR6-transfected Ba / F3 cells are first grown for 24 hours in medium supplemented with sodium butyrate, which increases CCR6 transcription through the CMV promoter. The prepared Ba / F3 cells are harvested by centrifugation at 400×g at room temperature and then suspended at 4 million / ml in human serum. The compounds to be tested are serially diluted from a maximum final concentration of 10 μM (or an equivalent volume of its solvent, DMSO) and then added to the cell / serum mixture. 50A concentration (10 nM) of recombinant human CCL20 (MIP-3α / LARC) is placed in the lower well of a ChemoTX® plate. A 5 μm (pore size) polycarbonate membrane is placed on the plate and 20 μL of the cell / compound mixture is transferred onto each well of the membrane. The plate is incubated at 37° C. for 45 minutes, after which the polycarbonate membrane is removed and 5 μl of the DNA intercalating dye CyQUANT (Invitrogen, Carlsbad, CA) is added to the lower well. The amount of fluorescence, which corresponds to the number of cells that have migrated, is measured using a Spectrafluor Plus plate reader (TECAN, San Jose, CA).

[0256] IC in migration assay 50 Compounds in Tables 1-3 with values ​​less than 1 nM are designated (+++), those between 1 and 10 nM are designated (++), and those less than 1000 nM but greater than 10 nM are designated (+).

[0257] [Table 1]

[0258] [Table 2]

[0259] [Table 3]

[0260] [Table 4]

[0261] [Table 5]

[0262] [Table 6]

[0263]

Table 7

[0264]

Table 8

[0265]

Table 9

[0266]

Table 10

[0267]

Table 11

[0268]

Table 12

[0269]

Table 13

[0270]

Table 14

[0271]

Table 15

[0272]

Table 16

[0273]

Table 17

[0274]

Table 18

[0275]

Table 19

[0276]

Table 20

[0277]

Table 21

[0278]

Table 22

[0279]

Table 23

[0280]

Table 24

[0281]

Table 25

[0282]

Table 26

[0283]

Table 27

[0284] [Table 28]

[0285] [Table 29]

[0286] [Table 30]

[0287] [Table 31]

[0288] [Table 32]

[0289] Biological Example 2: Comparative Activity A comparison table is given below to illustrate the advantages of the OH group on the piperidine ring as shown.

[0290] [Table 33]

[0291] [Table 34]

[0292] [Table 35]

[0293] [Table 36]

[0294] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light of them will occur to those skilled in the art and are to be included within the spirit and scope of this application and the scope of the appended claims.

[0295] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form or rotamer thereof, During the ceremony, Ar １ is halogen, CN, C １－８ Alkyl, C ３－８ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, C １－８ Hydroxyalkyl, —OR ａ and -NR ａ R ｂ 0 to 5 R independently selected from the group consisting of １ a monocyclic 5- or 6-membered aromatic or heteroaromatic ring having 0 to 3 heteroatoms as ring vertices selected from N, O, and S, substituted with a substituent; Each R ａ and R ｂ are independently hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl and C ３－６ cycloalkyl; Ar ２ is the group consisting of: i) having 0 to 3 heteroatoms as ring vertices selected from N, O, and S, and 0 to 5 R ２ a monocyclic 5- or 6-membered aromatic or heteroaromatic ring substituted with ii) has 0 to 4 heteroatoms as ring vertices selected from N, O, and S, and 0 to 5 R ２ a bicyclic 9- or 10-membered fused aromatic or heteroaromatic ring substituted with Selected from: Each R ２ is halogen, CN, C １－８ Alkyl, C ３－８ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, C １－８ Hydroxyalkyl, —OR ｃ , -SR ｃ , -COR ｃ , -CO ２ R ｃ , -NR ｃ R ｄ , -CONR ｃ R ｄ , —CO(NR ｃ ) ２ COR ｄ , -SO ２ R ｃ , -SO ２ NR ｃ R ｄ , -X ２ -CONR ｃ R ｄ , -X ２ -NR ｃ SO ２ R ｄ , -X ２ -NR ｃ CO ２ R ｄ , -X ２ -P(=O)(OR ｄ ) ２ , -X ２ -OP(=O)(OR ｄ ) ２ , -N(R ｃ )-R ｄ -X ２ -NR ｃ R ｄ , oxo, 4- to 6-membered heterocyclyl, 7- to 10-membered spiroheterocyclyl, and 5- or 6-membered heteroaryl; R ２ The heterocyclyl ring, spiroheterocyclyl ring and heteroaryl ring of the formula (I) have 1 to 3 heteroatoms selected from N, O and S, each of which is unsubstituted or substituted with halogen, hydroxyl, oxo, C １－４ Alkyl, amino, C １－４ Alkylamino, di-C １－４ Alkylamino, C １－４ Alkoxy, C １－４ Hydroxyalkyl and C １－４ haloalkyl; and two R ２ groups optionally combined to form a 3- to 6-membered spirocyclic ring or a 3- to 6-membered spiroheterocyclic ring having 1 to 3 heteroatoms selected from N, O, and S; R ｃ are independently hydrogen, hydroxyl, C １－４ Alkyl, C １－４ Haloalkyl and C １－４ hydroxyalkyl; R ｄ are independently hydrogen, hydroxyl, halogen, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C ３－６ is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; R ｄ The above C ３－６ The cycloalkyl, 4- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl rings have 1 to 3 heteroatoms selected from N, O, and S, each of which is unsubstituted or substituted with halogen, hydroxyl, oxo, C １－４ Alkyl, amino, C １－４ Alkylamino, di-C １－４ Alkylamino, C １－４ Alkoxy, C １－４ Hydroxyalkyl and C １－４ substituted with 1 or 2 members independently selected from the group consisting of haloalkyl; Or, R ｃ and R ｄ When attached to the same nitrogen atom, they combine to form 4 A seven-membered heterocycle is one selected from the group consisting of O, S, S(O), S(O) ２ , NH and N(C １－４ forming a heterocycle having 0 to 2 additional heteroatoms as ring vertices selected from: X ２ is C １－４ alkylene; m is 0, 1 or 2; Each R ３ is halogen, CN, C １－４ Alkyl, C １－４ Alkoxy, C ３－８ Cycloalkyl, C １－４ Haloalkyl, C １－４ Haloalkoxy and C ２－４ hydroxyalkyl; R ４ is H, C １－４ Alkyl, C ３－８ Cycloalkyl and C １－４ haloalkyl, The compound or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form or rotamer thereof.

2. Formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form or rotamer thereof, During the ceremony, Ar １ is halogen, CN, C １－８ Alkyl, C ３－８ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, C １－８ Hydroxyalkyl, —OR ａ and -NR ａ R ｂ 0 to 5 R independently selected from the group consisting of １ a 5- or 6-membered aromatic or heteroaromatic ring substituted with a substituent; Each R ａ and R ｂ are independently hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl and C ３－６ cycloalkyl; Ar ２ is the group consisting of: i) having 0 to 3 heteroatoms as ring vertices selected from N, O, and S, and 0 to 5 R ２ a monocyclic 5- or 6-membered aromatic or heteroaromatic ring substituted with ii) has 0 to 4 heteroatoms as ring vertices selected from N, O, and S, and 0 to 5 R ２ a bicyclic 9- or 10-membered fused aromatic or heteroaromatic ring substituted with Selected from: Each R ２ is halogen, CN, C １－８ Alkyl, C ３－８ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, C １－８ Hydroxyalkyl, —OR ｃ , -SR ｃ , -COR ｃ , -CO ２ R ｃ , -NR ｃ R ｄ , -CONR ｃ R ｄ , —CO(NR ｃ ) ２ COR ｄ , -SO ２ R ｃ , -SO ２ NR ｃ R ｄ , -X ２ -CONR ｃ R ｄ , -X ２ -NR ｃ SO ２ R ｄ , -X ２ -NR ｃ CO ２ R ｄ , -X ２ -P(=O)(OR ｄ ) ２ , -X ２ -OP(=O)(OR ｄ ) ２ , -NR ｃ R ｄ -X ２ -NR ｃ R ｄ , oxo, 4- to 6-membered heterocyclyl, 7- to 10-membered spiroheterocyclyl, and 5- or 6-membered heteroaryl; R ２ The heterocyclyl ring, spiroheterocyclyl ring and heteroaryl ring of the formula (I) are each unsubstituted or substituted with halogen, hydroxyl, oxo, C １－４ Alkyl, amino, C １－４ Alkylamino, di-C １－４ Alkylamino, C １－４ Alkoxy, C １－４ Hydroxyalkyl and C １－４ haloalkyl; and two R ２ groups optionally combined to form a 3- to 6-membered spiro ring; R ｃ are independently hydrogen, hydroxyl, halogen, cyano, C １－４ Alkyl, C １－４ Haloalkyl and C １－４ hydroxyalkyl; R ｄ are independently hydrogen, hydroxyl, halogen, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C ３－６ is selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; R ｄ The above C ３－６ The cycloalkyl, 4- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl rings are each unsubstituted or substituted with halogen, hydroxyl, oxo, C １－４ Alkyl, amino, C １－４ Alkylamino, di-C １－４ Alkylamino, C １－４ Alkoxy, C １－４ Hydroxyalkyl and C １－４ substituted with 1 or 2 members independently selected from the group consisting of haloalkyl; Or, R ｃ and R ｄ when attached to the same nitrogen atom, are taken together to form a 4- to 7-membered heterocycle, including O, S, S(O), S(O) ２ , NH and N(C １－４ forming a heterocycle having 0 to 2 additional heteroatoms as ring vertices selected from: X ２ is C １－４ alkylene; m is 0, 1 or 2; Each R ３ is halogen, CN, C １－４ Alkyl, C １－４ Alkoxy, C ３－８ Cycloalkyl, C １－４ Haloalkyl, C １－４ Haloalkoxy and C ２－４ hydroxyalkyl; R ４ is H, C １－４ Alkyl, C ３－８ Cycloalkyl and C １－４ haloalkyl, The compound or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form or rotamer thereof.

3. Ar １ is halogen, CN, C １－８ Alkyl, C ３－８ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, C １－８ Hydroxyalkyl, —OR ａ and -NR ａ R ｂ 0 to 5 R independently selected from the group consisting of １ a 5- or 6-membered aromatic or heteroaromatic ring substituted with a substituent; Each R ａ and R ｂ are independently hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl and C ３－６ cycloalkyl; Ar ２ is the group consisting of: i) having 0 to 3 heteroatoms as ring vertices selected from N, O, and S, and 0 to 5 R ２ a monocyclic 5- or 6-membered aromatic or heteroaromatic ring substituted with ii) has 0 to 4 heteroatoms as ring vertices selected from N, O, and S, and 0 to 5 R ２ bicyclic 9- or 10-membered fused aromatic or heteroaromatic rings substituted with Each R ２ is halogen, CN, C １－８ Alkyl, C ３－８ Cycloalkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Haloalkyl, C １－８ Hydroxyalkyl, —OR ｃ , -SR ｃ , -COR ｃ , -CO ２ R ｃ , -NR ｃ R ｄ , -CONR ｃ R ｄ , —CO(NR ｃ ) ２ COR ｄ , -SO ２ R ｃ , -SO ２ NR ｃ R ｄ , -X ２ -CONR ｃ R ｄ , -X ２ -NR ｃ SO ２ R ｄ , -X ２ -NR ｃ CO ２ R ｄ , -NR ｃ R ｄ -X ２ -NR ｃ R ｄ , oxo, 4- to 6-membered heterocyclyl, 7- to 10-membered spiroheterocyclyl, and 5- or 6-membered heteroaryl; R ２ The heterocyclyl ring, spiroheterocyclyl ring and heteroaryl ring of the formula (I) are each unsubstituted or substituted with halogen, hydroxyl, oxo, C １－４ Alkyl, amino, C １－４ Alkylamino, di-C １－４ Alkylamino, C １－４ Alkoxy and C １－４ haloalkyl; and two R ２ groups optionally combined to form a 3- to 6-membered spiro ring; Each R ｃ and R ｄ are independently hydrogen, hydroxyl, halogen, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl and C ３－６ cycloalkyl; or R ｃ and R ｄ When attached to the same nitrogen atom, they together form O, S, S(O), S(O) ２ , NH and N(C １－４ forming a 4- to 7-membered heterocyclic ring having 0-2 additional heteroatoms as ring vertices selected from: X ２ is C １－４ alkylene; m is 0, 1 or 2; Each R ３ is halogen, CN, C １－４ Alkyl, C １－４ Alkoxy, C ３－８ Cycloalkyl, C １－４ Haloalkyl, C １－４ Haloalkoxy and C ２－４ hydroxyalkyl; R ４ is H, C １－４ Alkyl, C ３－８ Cycloalkyl and C １－４ haloalkyl, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form or rotamer thereof.

4. Ar ２ But 0 to 5 R ２ 4. The compound of any one of claims 1 to 3, wherein R is a bicyclic 9- or 10-membered fused aromatic or heteroaromatic ring substituted with R, or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof.

5. Ar ２ But 0 to 5 R ２ 4. The compound of any one of claims 1 to 3, wherein R is a monocyclic 5- or 6-membered aromatic or heteroaromatic ring substituted with R, or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof.

6. Ar １ is phenyl, and 1 to 3 R １ The compound according to any one of claims 1 to 5, which is substituted with a substituent.

7. Ar １ is pyridyl, and 1 to 3 R １ The compound according to any one of claims 1 to 5, which is substituted with a substituent.

8. 8. The compound of claim 1, 2, 4, 6, or 7, wherein Ar ２ is the group consisting of: 【Chemistry 3】 each of which is selected from 0 to 3 R ２ The compound is substituted with

9. 8. The compound of claim 1, 2, 4, 6, or 7, wherein Ar ２ is the group consisting of: 【Chemistry 4】 each of which is selected from 0 to 3 R ２ wherein R ２ａ is hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, —C(O)NH ２ , -C(O)N(H)C １－４ Alkyl, —C(O)N(C １－４ alkyl) ２ , -S(O) ２ C １－４ Alkyl, —S(O) ２ N(H)C １－４ Alkyl, —C(O)OC １－４ Alkyl, and —C(O)C １－４ A compound selected from the group consisting of alkyl.

10. Ar ２ is selected from the group consisting of phenyl, pyridyl, thiazolyl, oxadiazolyl, imidazolyl, pyridazinyl, and oxazolyl, each of which is selected from the group consisting of 0 to 3 R ２ 8. The compound of claim 1, 2, 4, 6, or 7, substituted with:

11. Ar ２ But 0 to 3 R ２ 8. The compound of claim 1, 2, 4, 6, or 7, which is pyridyl substituted with:

12. Ar ２ But 0 to 2 R ２ 8. The compound of claim 1, 2, 4, 6, or 7, which is thiazolyl substituted with:

13. Ar ２ But 0 to 2 R ２ 8. The compound of any one of claims 1, 2, 4, 6, or 7, which is 1,3,4-oxadiazolyl substituted with

14. Ar ２ But 0 to 2 R ２ 8. The compound of claim 1, 2, 4, 6, or 7, which is imidazolyl substituted with:

15. Formula (Ia): 【Chemistry 5】 The compound according to any one of claims 1 to 3, having the formula:

16. Each R １ But CH ３ , C.F. ３ 16. The compound of claim 15, wherein each of the groups is independently selected from the group consisting of Cl and CN.

17. Ar ２ But 0 to 5 R ２ 16. The compound of claim 15, wherein the bicyclic 9- or 10-membered fused aromatic or heteroaromatic ring is substituted with

18. Ar ２ But 0 to 5 R ２ 16. The compound of claim 15, wherein the ring is a monocyclic 5- or 6-membered aromatic or heteroaromatic ring substituted with

19. Ar ２ But 0 to 3 R ２ 16. The compound of claim 15, wherein the heteroaromatic ring is a 5- or 6-membered heteroaromatic ring substituted with

20. Formula (Ia1): 【Chemistry 6】 20. The compound of any one of claims 15 to 19, having the formula: １ is -CN or -CF ３ A compound.

21. Formula (Ia1): 【Chemistry 7】 16. The compound of claim 15 having the formula: １ is -CN or -CF ３ and Ar ２ is the group consisting of: 【Chemistry 8】 each of which is selected from 0 to 3 R ２ The compound is substituted with

22. Formula (Ia1): 【Chemistry 9】 16. The compound of claim 15 having the formula: １ is -CN or -CF ３ and Ar ２ is the group consisting of: 【Chemistry 10】 each of which is selected from 0 to 3 R ２ wherein R ２ａ is hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, —C(O)NH ２ , -C(O)N(H)C １－４ Alkyl, —C(O)N(C １－４ alkyl) ２ , -S(O) ２ C １－４ Alkyl, —S(O) ２ N(H)C １－４ Alkyl, —C(O)OC １－４ Alkyl, and —C(O)C １－４ A compound selected from the group consisting of alkyl.

23. Formula (Ia1): 【Chemistry 11】 16. The compound of claim 15 having the formula: １ is -CN or -CF ３ and Ar ２ is selected from the group consisting of phenyl, pyridyl, thiazolyl, oxadiazolyl, imidazolyl, pyridazinyl, and oxazolyl, each of which is selected from the group consisting of 0 to 2 R ２ The compound is substituted with

24. 24. The compound of claim 23, wherein Ar ２ is the group consisting of: 【Chemistry 12】 each of which is selected from 0 to 2 R ２ wherein R ２ｂ is hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, and C １－４ A compound selected from the group consisting of hydroxyalkyl.

25. 25. The compound of claim 24, wherein Ar ２ is the group consisting of: 【Chemistry 13】 each of which is selected from 0 to 2 R ２ wherein R ａ is hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, and C １－４ A compound selected from the group consisting of hydroxyalkyl.

26. 25. The compound of claim 24, wherein Ar ２ is the group consisting of: 【Chemistry 14】 each of which is selected from 0 to 1 R ２ wherein R ２ｂ is hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, and C １－４ A compound selected from the group consisting of hydroxyalkyl.

27. A compound according to any one of claims 1 to 26, R １ is CF ３ and R ２ is CN, -CH ３ , —OH, —NH ２ , -N(CH ３ ) ２ , —C(O)NH ２ , -C(O)N(H)(CH ３ ), -C(O)N(CH ３ ) ２ , —C(O)CH ３ , -C(O)OCH ３ , -S(O) ２ NH ２ , Cl, F, -N(CH ３ ) ２ , -OCH ３ , -CH ２ OH, —N(H)R ｄ , piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, or azetidinyl, wherein the piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, and azetidinyl groups are each independently selected from the group consisting of -CH ３ , C(CH ３ ) ２ OH, OH, -OCH ３ , -NH ２ , and -N(CH ３ ) ２ A compound optionally substituted with one or two substituents selected from the group consisting of:

28. R ２ CN, -CH ３ , —OH, —NH ２ , -N(CH ３ ) ２ , —C(O)NH ２ , -C(O)N(H)(CH ３ ), -C(O)N(CH ３ ) ２ , —C(O)CH ３ , —C(O)OCH ３ , -S(O) ２ NH ２ , Cl, F, -N(CH ３ ) ２ , -OCH ３ , or -CH ２ 28. The compound of claim 27, wherein:

29. R ２ is piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, or azetidinyl, and the piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, and azetidinyl groups are each independently selected from the group consisting of —CH ３ , C(CH ３ ) ２ OH, OH, -OCH ３ , -NH ２ , and -N(CH ３ ) ２ 28. The compound of claim 27, optionally substituted with one or two substituents selected from the group consisting of:

30. The following: 【Chemistry 15】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 3. The compound of claim 1 or 2, selected from the group consisting of compounds of the formula:

31. Formula: 【Chemistry 16】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

32. Formula: 【Chemistry 17】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

33. Formula: 【Chemistry 18】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

34. Formula: 【Chemistry 19】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

35. Formula: 【Chemistry 20】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

36. Formula: 【Chemical 21】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

37. Formula: 【Chemical 22】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

38. Formula: 【Chemical 23】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

39. Formula: 【Chemistry 24】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

40. Formula: 【Chemistry 25】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

41. Formula: 【Chemical 26】 31. The compound of claim 30, having the formula: or a pharmaceutically acceptable salt thereof.

42. 42. A pharmaceutical composition comprising a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof, and a pharmaceutically acceptable excipient.

43. 42. Use of a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof, in the manufacture of a medicament for treating a disease or condition that is at least partially modulated by CCR6.

44. 44. The use of claim 43, wherein the disease or condition is an inflammatory disease or condition.

45. 44. The use of claim 43, wherein the disease or condition is atopic dermatitis, scleroderma, lumbar disc disease, psoriasis, pustular psoriasis, rheumatoid arthritis, psoriatic arthritis, arthritis associated with systemic lupus erythematosus, endometriosis, or periodontitis.

46. 44. The use according to claim 43, wherein the disease or condition is psoriasis or pustular psoriasis.

47. 47. The use of any one of claims 43, 44, 45 or 46, wherein the compound is a compound of claim 15, 22, 23 or 30, or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof.

48. 48. The use of claim 47, wherein the compound is a compound of claim 43 or a pharmaceutically acceptable salt thereof.

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