Compounds as CCR6 inhibitors

Abstract

The present invention relates to a compound represented by general formula (I) (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 , X 3 , X 4 and X 5 is as defined herein), compositions comprising such compounds, processes for making such compounds, and methods of using such compounds. TIFF2026504498000367.tif63169

Description

[Background technology]

[0001] Immune surveillance, the migration of immune cells throughout the body, is a tightly regulated process involved in many aspects of health and disease. Chemokines and their corresponding receptors play a key role in these trafficking patterns, and they are involved in directing the appropriate cells to the appropriate tissues (Griffith, JW, Sokol, CL & Luster, AD (2014). Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity. Immunology, 32(1), 659-702 and Zlotnik, A. & Yoshie, O. (2012). The Chemokine Superfamily Revisited. Immunity, 36(5), 705-716).

[0002] Chemokines, or chemotactic cytokines, are a family of approximately 50 small signaling proteins secreted by various cell populations (David, BA & Kubes, P. (2019). Exploring the complex role of chemokines and chemoattractants in vivo on leukocyte dynamics. Immunological Reviews, 289(1), 9-30 and Griffith, JW, Sokol, CL & Luster, AD (2014). Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity. Immunology, 32(1), 659-702). Chemokines are divided into four major subfamilies, designated CC, CXC, CX3C, and C, based on the location of the canonical cysteine ​​residue in their N-terminal regions. The secretion and diffusion of chemokines creates a concentration gradient that directs the migration of cells expressing the corresponding receptor. Chemokine receptors are a family of approximately 20 seven-transmembrane proteins differentially expressed on the surface of immune cells. They can be divided into two major subfamilies: G protein-coupled chemokine receptors, which mediate immune cell trafficking; and atypical chemokine receptors, which are thought to be chemokine scavengers that affect chemokine gradients. They are also classified into four subfamilies according to the subfamily of their primary chemokine ligand. In some cases, a single chemokine can signal through multiple receptors, and often a single receptor can be stimulated by multiple chemokines. These promiscuous interactions complicate pharmacological intervention of signaling pathways.

[0003] CCR6, also known as CD196, is a chemokine receptor expressed on a variety of adaptive and innate immune cells, including B cells, T cells, dendritic cells, and neutrophils. For example, T17 cells, which play a key role in the pathogenesis of multiple autoimmune diseases, express CCR6, and this signal has been shown to recruit these cells to inflamed peripheral tissues (Esplugues, E., Huber, S., Gagliani, N., Hauser, A.E., Town, T., Wan, Y.Y., O'Connor, W., Rongvaux, A., Rooijen, N.V., Haberman, A.M., Iwakura, Y., Kuchroo, V.K., Kolls, J.K., Bluestone, J.A., Herold, K.C. & Flavell, R.A. (2011). Control of T17 cells occurs in the small intestine. Nature, 475(7357), 514-518 and Singh, S.P., Zhang, H.H., Foley, J.F., Hedrick, M.N. & Farber, J.M. (2008). Human T Cells That Are Able to Produce IL-17 Express The chemokine receptor CCR6. The Journal of Immunology, 180(1), 214-221). The ligand for CCR6 is CCL20, also known as macrophage inflammatory protein 3 alpha (MIP-3 alpha) and liver- and activation-regulated chemokine (LARC). The CCR6 / CCL20 pair is somewhat unique because it has only one binding partner and thus forms a pharmacologically selective receptor-ligand pair (Schutyser, E., Struyf, S. & Damme, JV (2003). The CC chemokine CCL20 and its receptor CCR6. Cytokine & Growth Factor Reviews, 14(5), 409-426).

[0004] CCL20 expression and secretion is increased in the presence of inflammatory stimuli. High levels of CCL20 can be found in inflamed tissues associated with several inflammatory autoimmune diseases, including psoriatic disease, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis (Richmond, JM, Strassner, JP, Essien, KI & Harris, JE (2019). T-cell positioning by chemokines in autoimmune skin diseases. Immunological Reviews, 289(1), 186-204, Lee, AY & Korner, H. (2014). CCR6 and CCL20: emerging players in the pathogenesis of rheumatoid arthritis. Immunology and Cell Biology, 92(4), 354-358, Raman, D., Sobolik-Delmaire, T. & Richmond, A. (2011). Chemokines in health and disease. Experimental Cell Research, 317(5), 575-589, Pene, J., Chevalier, S., Preisser, L., Venereau, E., Guilleux, M.-H., Ghanam, S., Moles, J.-P., Danger, Y., Ravon, E., Lesaux, S., Yssel, H. & Gascan, H. (2008). Chronically Inflamed Human Tissues Are Infiltrated by Highly Differentiated Th17 Lymphocytes. The Journal of Immunology, 180(11), 7423-7430 and Schutyser, E., Struyf, S. & Damme, JV (2003). The CC chemokine CCL20 and its receptor CCR6. Cytokine&Growth Factor Reviews, 14(5), 409-426).

[0005] Genetic linkage, clinical associations, and preclinical studies highlight the important role of CCR6 in these inflammatory diseases (Hamburg, JP van & Tas, SW (2018). Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis. Journal of Autoimmunity, 87, 69-81 and Kurko, J., Besenyei, T., Laki, J., Glant, TT, Mikecz, K. & Szekanecz, Z. (2013). Genetics of Rheumatoid Arthritis - A Comprehensive Review. Clinical Reviews in Allergy & Immunology, 45(2), 170-179). For example, CCR6 gene variants are associated with the highest risk of Crohn's disease (CD) among the chemokine receptor family (Lee, AYS, Eri, R., Lyons, AB, Grimm, MC & Korner, H. (2013). CC Chemokine Ligand 20 and Its Cognate Receptor CCR6 in Mucosal T Cell Immunology and Inflammatory Bowel Disease: Odd Couple or Axis of Evil Frontiers in Immunology, 4, 194).

[0006] This high selectivity makes CCR6 an attractive drug target: selective CCR6 inhibitors would result in on-target pharmacology alone. Summary of the Invention

[0007] A first object of the present invention is to provide a compound of formula (I) [ka] (In the formula, X 1 is CH or N, X 2 is CH or N, X 3 is CH or N, X 4 is O or NH, X 5 is CH or N, R 1 is aryl, heterocyclyl, or heteroaryl, and aryl, heterocyclyl, and heteroaryl are each independently selected from the group consisting of one or more R 1a may be substituted with R 1a is C 1~6 Alkyl, oxo, cyano, carbamoyl, C 1~6 Alkylcarbamoyl-, C 1~6 Alkoxy C 1~6 Alkyl-, C 3~6 cycloalkyl, or heterocyclyl; R 2 is hydrogen or halogen, R 3 is hydrogen or halogen, R 4 is hydrogen, halogen or C 1~6 is alkyl, R 5 is hydrogen, halogen or C 1-6 is alkyl, R 6 -OR 6a , -SR 6b or hydrogen, R 6a is C 1~6 is haloalkyl, R 6b is C 1~6 is haloalkyl, R 7 -OR 7a , -SR 7b or hydrogen, R 7a is C 1~6 is haloalkyl, R 7b is C 1~6 is haloalkyl, However, R 6and R 7 must be different, R 6 or R 7 is hydrogen), and pharmaceutically acceptable salts thereof.

[0008] A second object of the present invention is a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, comprising the steps of: 1 is N and X 4 is O, A compound of formula (II) 5 and R 4 is as defined above), [ka] A compound of formula (III) 2 , X 3 , R 2 and R 3 is as defined above) to [ka] A compound of formula (IV) 3 , R 2 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound (IV) is reacted with a compound of formula (V) 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (VI) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (VI) is reacted with an acid to form a compound of formula (VII), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (VII) is reacted with a compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] forming a compound of formula (I).

[0009] A third object of the present invention is a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, comprising: 1 is N and X 4is O, A compound of formula (IX) 4 and R 5 is as defined above), [ka] A compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] A compound of formula (X) 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound of formula (VIII) is reacted with an acid to give a compound of formula (XI), 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound of formula (XI) is reacted with a compound of formula (III) 2 , X 3 , R 2 and R 3 is as defined above) to [ka] A compound of formula (XII) 2 , X3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above), [ka] The compound of formula (XII) is reacted with a compound of formula (V) 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0010] A fourth object of the present invention is a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, comprising the steps of: 1 is N and X 4 is O, A compound of formula (XVIII) 5 and R 4 is as defined above), [ka] A compound of formula (XVII) 1 , R 2 , R 3 , X2 and X 3 , as defined above), [ka] A compound of formula (XX) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XX) is reacted with a compound of formula (XVI) 5 , R 6 and R 7 is as defined above) to [ka] forming a compound of formula (I) or A compound of formula (XVIII) 5 and R 4 is as defined above), [ka] A compound of formula (III) 2 , X 3 , R 2 and R 3 is as defined above) to [ka] A compound of formula (XIX) 2 , R 3 , R 4 , R 5 , X2 and X 3 is as defined above), [ka] The compound of formula (XIX) is reacted with the compound of formula (XVI) to form a compound of formula (XII), 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above), [ka] The compound of formula (XII) is reacted with a compound of formula (V) 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0011] A fifth object of the present invention is a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, comprising the steps of: 1 is C and X 4 is O, A compound of formula (XXI) 4 and R 5 is as defined above), [ka] and mesyl chloride to give a compound of formula (XXII), 4 and R 5 is as defined above), [ka] The compound of formula (XXII) is converted into a compound of formula (XXIII) (wherein R 2 , R 3 , X 2 and X 3 is as defined above) to [ka] A compound of formula (XXIV) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXIV) is reacted with an oxidizing agent to produce a compound of formula (XXV), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXV) is reacted with a compound of formula (V) (wherein R 1is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (XXVI) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXVI) is reacted with an acid to give a compound of formula (XXVII), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXVII) is reacted with a compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] forming a compound of formula (I).

[0012] A sixth object of the present invention is a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, comprising the steps of: 1 is C and X 4 is O, A compound of formula (XXV) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] with an acid to give a compound of formula (XXVIII), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXVIII) is reacted with a compound of formula (VIII) (wherein R 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] A compound of formula (XXIX) 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3is as defined above), [ka] The compound of formula (XXIX) is reacted with a compound of formula (V) (wherein R 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0013] A seventh object of the present invention is a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, comprising: 1 is C and X 4 is O, A compound of formula (XXXI) 4 and R 5 is as defined above), [ka] A compound of formula (XXXII) 4 and R 5 is as defined above) to [ka] The compound of formula (XXXII) is reacted with a compound of formula (XXIII) 2 , R 3 , X 2 and X 3 is as defined above) to [ka] A compound of formula (XXXIII) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound (XXXIII) is reacted with an oxidizing agent to give a compound of formula (XXXIV), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound (XXXIV) is reacted with an acid to give a compound of formula (XXXV), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXXV) is reacted with a compound of formula (XVI) 5 , R 6 and R 7 is as defined above) to [ka] A compound of formula (XXIX) 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXIX) is reacted with a compound of formula (V) (wherein R 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0014] An eighth object of the present invention is a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, comprising: 1 is C and X 4 is N, A compound of formula (XXXIII) 2 , R 3 , R 4 , R 5 , X 2 and X 3is as defined above), [ka] with an acid to give a compound of formula (XXXVI), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXXVI) is reacted with a compound of formula (XVI) 5 , R 6 and R 7 is as defined above) to [ka] A compound of formula (XXXVII) 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXXVII) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to give a compound of formula (XXXVIII), 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXXVIII) is reacted with a compound of formula (V) (wherein R 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 C alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0015] A ninth object of the present invention is a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, comprising: 1 is C and X 4 is N, A compound of formula (XI) 4 , R 6 , R 7 , X 5 , and R 5 is as defined above), [ka] A compound of formula (XXIII) 2 , R 3 , X 2 and X 3 is as defined above) to [ka] A compound of formula (XL) 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound (XL) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to give a compound of formula (XLI), 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound (XLI) is reacted with di-tert-butyl dicarbonate and a base to give a compound of formula (XLII), 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound (XLII) is reacted with a compound of formula (V) 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (XLIII) 1 , R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] reacting said compound of formula (XLIII) with an acid to form a compound of formula (I).

[0016] A tenth object of the present invention is a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, comprising: 1 is C and X 4 is N, A compound of formula (XXIV) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] A compound of formula (V), wherein R 1 is as defined above, and R9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 C alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (XLIV) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XLIV) is reacted with an acid to give a compound of formula (XLV), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XLV) is reacted with a compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] A compound of formula (XLVI) 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined above), [ka] reacting said compound of formula (XLVI) with ammonium carbamate and (diacetoxyiodo)benzene to form a compound of formula (I).

[0017] An eleventh object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] A twelfth object of the present invention is a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment, prevention and / or delay of inflammatory autoimmune diseases.

[0019] A thirteenth object of the present invention is a method for treating, preventing and / or delaying the progression of inflammatory autoimmune diseases, which method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.

[0021] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0022] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0023] definition "Acid" refers to a compound that can provide a proton according to the Bronsted definition and dissociate into a proton and a counterion in water at 25°C to provide a solution having a neutral pH or lower. Specific examples of acids include phosphoric acid (orthophosphoric acid), sulfuric acid, nitric acid, phosphinic acid, phosphonic acid, diphosphonic acid, hydrochloric acid, pyrophosphoric acid, metaphosphoric acid, and nitrous acid. These acids can be used in the form of metal salts, ammonium salts, etc., and the acid in particular refers to hydrochloric acid.

[0024] "C 1~6 "Alkoxy" means a C, as defined above, attached to the parent molecular moiety through an oxygen atom. 1~6 Unless otherwise specified, an alkoxy group contains 1 to 6 carbon atoms ("C 1~6 In some particular embodiments, an alkoxy group contains 1 to 4 carbon atoms. In yet other embodiments, an alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0025] "Amino", alone or in combination with other groups, refers to NH2.

[0026] "Aromatic" is a well-known term in the literature, especially in the IUPAC Compendium of Chemical Terminology, 2 nd This refers to the conventional concept of aromaticity as defined in A.D. McNaught & A. Wilkinson (Eds.), Blackwell Scientific Publications, Oxford (1997).

[0027] "Aryl" means a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 5 to 14 carbon ring atoms ("C5~14 "aryl" refers to a bicyclic ring system having two fused 5-membered aryl rings (designated 5-5), a fused bicyclic ring having a 5-membered aryl ring and a fused 6-membered aryl ring (designated 5-6 and 6-5), and a bicyclic ring having two fused 6-membered aryl rings (designated 6-6). The aryl group may be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. In particular, aryl refers to phenyl.

[0028] A "base" refers to a compound having at least one electronegative group capable of accepting a hydrogen ion.

[0029] "C 1~6 "Alkyl" refers to a saturated, linear (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof, having the specified number of carbon atoms (i.e., C1-6 means 1 to 10 carbon atoms). 1~6 The alkyl group may have 1 to 6 carbon atoms, 2 to 6 carbon atoms ("C2-6 alkyl"), or 1 to 4 carbon atoms ("C 1~4 C 1~6 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; homologs and isomers of, for example, n-pentyl, n-hexyl, and the like.

[0030] "Cyano," alone or in combination with other groups, refers to CN (ie, nitrile).

[0031] "C3-6 cycloalkyl" refers to a monocyclic, bicyclic (including bridged bicyclic and cycloalkyl spiro moieties), or tricyclic ring and 3 to 10 carbon atoms (i.e., (C3-C 10(C-C)cycloalkyl) refers to a saturated or partially unsaturated carbocyclic moiety having a carbon atom. The cycloalkyl moiety can be optionally substituted with one or more substituents. In certain embodiments, the cycloalkyl contains 3 to 8 carbon atoms (i.e., (C-C)cycloalkyl). In other certain embodiments, the cycloalkyl contains 3 to 6 carbon atoms (i.e., (C-C)cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and their partially unsaturated (cycloalkenyl) derivatives (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl, and bicyclo[1.1.1]pentane. The cycloalkyl moieties may be attached in a "spirocycloalkyl" or "cycloalkylspiro" fashion, such as in "spirocyclopropyl."

[0032] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo, especially chloro or fluoro.

[0033] "Haro-C 1~6 "Alkyl" means a C1-6C alkyl group as defined above, substituted with one or more halogen atoms, in particular 1 to 3 halogen atoms. 1~6 It refers to alkyl. More specifically, halo-C 1~6 Alkyl is chloro- and fluoro-C 1~6 In some particular embodiments, halo-C 1~6 Alkyl is a perhaloC1-3C alkyl group as defined herein. 1~6 It refers to alkyl. More specifically, halo-C 1~6 Alkyl is trifluoromethyl, difluoromethyl or fluoromethyl. Most particularly halo-C 1~6 The alkyl is trifluoroalkyl (-CF3).

[0034] "Haloalkoxy" refers to the C of an alkoxy group. 1~6It refers to an alkoxy group in which at least one halogen replaces each H in the hydrocarbon that makes up the alkyl portion. Examples of haloalkoxy groups are difluoromethoxy (-OCHF2) and trifluoromethoxy (-OCF3).

[0035] "Heteroaryl" refers to an aromatic heterocyclic monocyclic, bicyclic, or tricyclic ring system of 5 to 14 ring atoms, preferably 5 to 10 ring atoms, and more preferably 5 to 6 ring atoms, containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In some embodiments, the monocyclic heteroaryl ring may be 5- or 6-membered. Bicyclic heteroaryl ring systems include fused bicycles having two fused 5-membered heteroaryl rings (designated 5-5), fused bicycles having a 5-membered heteroaryl ring and a fused 6-membered heteroaryl ring (designated 5-6 and 6-5), and bicycles having two fused 6-membered heteroaryl rings (designated 6-6). Heteroaryl groups may be optionally substituted as defined herein. Examples of heteroaryl moieties include indazolyl, indolyl, isoindolinyl, triazolopyridinyl, imidazopyridinyl, imidazopyrazinyl, indolinyl, pyridyl, triazolopyridazinyl, isoquinolinyl, pyridazinyl, triazolopyrazinyl, pyrrolotriazinyl, spirocyclopropaneindolinyl, pyrrolyl, furanylthienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, and benzothienyl. , benzothiophenylindolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, fluoropyridazinyl, fluoropyrimidinyl, and fluoropyrazinyl.Examples of heteroaryl moieties include indazolyl, indolyl, isoindolinyl, triazolopyridinyl, imidazopyridinyl, imidazopyrazinyl, indolinyl, pyridyl, triazolopyridazinyl, isoquinolinyl, pyridazinyl, triazolopyrazinyl, pyrrolotriazinyl, spirocyclopropaneindolinyl, pyrrolyl, furanylthienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, and benzothienyl. , benzothiophenylindolyl, aza-indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, fluoropyridazinyl, fluoropyrimidinyl, and fluoropyrazinyl.

[0036] "Heterocycle" or "heterocyclyl" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-membered monocyclic, 7-, 8-, 9-, and 10-membered bicyclic (including bridged bicyclic and cycloalkyl spiro moieties), or 10-, 11-, 12-, 13-, 14-, and 15-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from oxygen, nitrogen, and sulfur within the ring, with the remaining ring atoms being carbon. In some embodiments, the heterocycle is a heterocycloalkyl. In particular embodiments, heterocycle or heterocyclyl refers to a 4-, 5-, 6-, or 7-membered heterocycle. When used in reference to a ring atom of a heterocycle, nitrogen or sulfur may also be in oxidized form, and nitrogen may be oxidized to one or more (C1-C6)C 1~6The heterocyclic ring may be substituted with an alkyl or alkyl group. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any ring atom of the heterocyclic ring may be optionally substituted with one or more substituents described herein.

[0037] The term "inflammatory bowel disease" or "IBD" refers to a number of diseases associated with inflammation of the small intestine, large intestine (colon), rectum, or anus (anal sphincter), and may specifically include ulcerative colitis and Crohn's disease, both of which include proctitis. As used in this context, the term "IBD" also includes GI tract cancer, which is a possible consequence of gastrointestinal (GI) tract inflammation. As used herein, the term "gastrointestinal tract" or "GI tract" refers to the small intestine, large intestine (colon), rectum, or anus (anal sphincter).

[0038] "Moiety" and "substituent" refer to an atom or a group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds, thereby forming a part of the molecule.

[0039] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitutions, i.e., replacement of one hydrogen to replacement of all hydrogens by substituents; particularly "one or more" refers to one, two, or three; most particularly "one or more" refers to one or two.

[0040] "Obstructive pulmonary disease" refers to any disease that narrows or blocks the airways in the lungs, preventing the patient from fully exhaling. Due to lung damage or narrowing of the airways within the lungs, exhalation occurs more slowly than normal. At the end of a complete exhalation, an abnormally large amount of air may still remain in the lungs. Examples of obstructive pulmonary diseases are asthma, bronchiectasis, bronchitis, and chronic obstructive pulmonary disease (COPD).

[0041] "Optional" or "optionally" means that the subsequently described event or circumstance may occur but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "C 1~6 The term "aryl group optionally substituted with an alkyl group" refers to C 1~6 The description also includes the fact that alkyl may be present but need not be present, and that aryl groups are C 1~6 The situation where the alkyl group is substituted and the aryl group is C 1~6 This is meant to include situations where the group is not substituted with an alkyl group.

[0042] "Optionally substituted" means unsubstituted or substituted. Generally, the substituents can be the same or different.

[0043] "Oxidizing agent" refers to one or more suitable electron acceptors or electron sharers, which may be an element, a combination of elements, a compound, or a combination of compounds, including a reducing compound, and may be a vapor, solid, or liquid at process conditions. An example of an oxidizing agent is mCPBA (meta-chloroperoxybenzoic acid).

[0044] "Oxo", alone or in combination with other groups, refers to =O.

[0045] "Pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like.

[0046] More particularly, pharmaceutically acceptable salts of the compounds of formula (I) are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

[0047] "Protecting group" refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction, in the sense conventionally associated with synthetic chemistry, can be carried out selectively at an otherwise unprotected reactive site. The protecting group can be removed at an appropriate time. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups, or hydroxy-protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). An even more particular protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Hutts, 5th Ed., 2014, John Wiley & Sons, NY.

[0048] "Substituted" refers to the replacement of at least one hydrogen atom of a compound or moiety with another substituent or moiety. For example, the term "haloalkyl" refers to C 1~6

[0033] In one aspect, substitution, as used herein, refers to the fact that one or more hydrogen atoms of an alkyl (defined below) have been replaced with one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one aspect, substitution, as used herein, refers to the replacement of at least one hydrogen atom of a compound or moiety described herein with a halogen or C 1~6 It may refer to substitution with alkyl.

[0049] A "therapeutically effective amount" refers to that amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the condition being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors. DETAILED DESCRIPTION OF THE INVENTION

[0050] In one embodiment, the present invention provides a compound of formula (I) [ka] (In the formula, X 1 is CH or N, X 2 is CH or N, X 3 is CH or N, X 4 is O or NH, X 5 is CH or N, R 1 is aryl, heterocyclyl, or heteroaryl, and aryl, heterocyclyl, and heteroaryl are each independently selected from the group consisting of one or more R 1a may be substituted with R 1a is C 1~6 Alkyl, oxo, cyano, carbamoyl, C 1~6 Alkylcarbamoyl-, C 1~6 Alkoxy C 1~6 Alkyl-, C 3~6 cycloalkyl, or heterocyclyl; R 2 is hydrogen or halogen, R 3 is hydrogen or halogen, R4 is hydrogen, halogen or C 1~6 is alkyl, R 5 is hydrogen, halogen or C 1~6 is alkyl, R 6 -OR 6a , -SR 6b or hydrogen, R 6a is C 1~6 is haloalkyl, R 6b is C 1~6 is haloalkyl, R 7 -OR 7a , -SR 7b or hydrogen, R 7a is C 1~6 is haloalkyl, R 7b is C 1~6 is haloalkyl, However, R 6 and R 7 must be different, R 6 or R 7 is hydrogen), and pharmaceutically acceptable salts thereof.

[0051] Certain embodiments of the present invention are compounds of formula (I) or (I') as described herein, wherein: X 2 is CH, X 3 is CH, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen or C 1~6 alkyl).

[0052] A particular embodiment of the present invention is 1is CH, or a pharmaceutically acceptable salt thereof.

[0053] A particular embodiment of the present invention is 1 is N; or a pharmaceutically acceptable salt thereof.

[0054] A particular embodiment of the present invention is 4 is O; or a pharmaceutically acceptable salt thereof.

[0055] A particular embodiment of the present invention is 4 is NH.

[0056] A particular embodiment of the present invention is 5 is CH, or a pharmaceutically acceptable salt thereof.

[0057] A particular embodiment of the present invention is 5 is N; or a pharmaceutically acceptable salt thereof.

[0058] A particular embodiment of the present invention is 1 is imidazopyridinyl, triazolopyridinyl, pyridyl, phenyl, indolyl, isoindolinyl, or indazolyl, wherein imidazopyridinyl, triazolopyridinyl, phenyl, indolyl, isoindolinyl, and indazolyl are substituted by one or more R 1a or a pharmaceutically acceptable salt thereof.

[0059] A particular embodiment of the present invention is 1is isopropylimidazopyridinyl, oxo-triazolopyridinyl, imidazopyridinyl, cyanophenyl, methylimidazopyridinyl, cyano-indolyl, oxoisoindolinyl, carbamoylphenyl, (methylcarbamoyl)phenyl, methyl-indazolyl, phenyl, cyano-indazolyl, cyanoimidazopyridinyl, methyl-triazolopyridinyl, (methoxymethyl)-triazolopyridinyl or cyclopentyl-triazolopyridinyl;

[0060] A particular embodiment of the present invention is 1 (3-isopropylimidazo[1,2-a]pyridin-6-yl), (3-oxo-2H-[1,2,4]triazolo[4,3-a]pyridin-6-yl), imidazo[1,2-a]pyridin-6-yl, (4-cyanophenyl), (3-methylimidazo[1,2-a]pyridin-6-yl), (3-cyano-1H-indol-5-yl), (3-isopropyl-8-methyl-imidazo[1,2-a]pyridin-6-yl), (2-carbamoyl-4-pyridyl), (3-oxoisoindolin-5-yl), (3-carbamoylphenyl), [3-(methylcarbamoyl)phenyl], (3-methyl-1H-indol-5-yl), or a pharmaceutically acceptable salt thereof.

[0061] A particular embodiment of the present invention is 1is cyano-indazolyl, cyano-indolyl, methyl-indazolyl, oxo-triazolopyridinyl, isopropylimidazopyridinyl, or cyclopentyl-triazolopyridinyl;

[0062] A particular embodiment of the present invention is 1 is cyano-indazolyl, cyano-indolyl, methyl-indazolyl, oxo-triazolopyridinyl, isopropylimidazopyridinyl, or cyclopentyl-triazolopyridinyl;

[0063] A particular embodiment of the present invention is 1 is indazolyl, indolyl, indazolyl, imidazopyridinyl, or triazolopyridinyl, and indazolyl, indolyl, indazolyl, imidazopyridinyl, and triazolopyridinyl are substituted by one or more R 1a or a pharmaceutically acceptable salt thereof.

[0064] A particular embodiment of the present invention is 1 is indazolyl, indolyl, indazolyl, imidazopyridinyl or triazolopyridinyl, and indazolyl, indolyl, indazolyl, imidazopyridinyl and triazolopyridinyl are optionally substituted with one or more of cyano, methyl, oxo, isopropyl or cyclopentyl, or a pharmaceutically acceptable salt thereof.

[0065] A particular embodiment of the present invention is 1is (3-cyano-1H-indol-5-yl), (3-methyl-1H-indazol-5-yl), (3-cyano-1H-indazol-5-yl), (3-oxo-2H-[1,2,4]triazolo[4,3-a]pyridin-6-yl), (3-isopropylimidazo[1,2-a]pyridin-6-yl), or cyclopentyl-triazolopyridinyl;

[0066] A particular embodiment of the present invention is 1a is isopropyl, methyl, oxo, cyano, carbamoyl, methylcarbamoyl, or methoxymethyl, or a pharmaceutically acceptable salt thereof.

[0067] A particular embodiment of the present invention is 1a is cyano, methyl, oxo, isopropyl, or cyclopentyl; or a pharmaceutically acceptable salt thereof.

[0068] A particular embodiment of the present invention is 6 is -SCF3, -OCF3, -OCHF2, or hydrogen, or a pharmaceutically acceptable salt thereof.

[0069] A particular embodiment of the present invention is 6 is -SCF3, or -OCF3, or a pharmaceutically acceptable salt thereof.

[0070] A particular embodiment of the present invention is 6a is —CF 3 , or —CHF 2 , or a pharmaceutically acceptable salt thereof.

[0071] A particular embodiment of the present invention is 6bis —CF 3 , or a pharmaceutically acceptable salt thereof.

[0072] A particular embodiment of the present invention is 7 is -OCF3, -SCF3, -OCHF2, or hydrogen, or a pharmaceutically acceptable salt thereof.

[0073] A particular embodiment of the present invention is 7 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0074] A particular embodiment of the present invention is 7a is —CF 3 , or —CHF 2 , or a pharmaceutically acceptable salt thereof.

[0075] A particular embodiment of the present invention is 7b is —CF 3 , or a pharmaceutically acceptable salt thereof.

[0076] A particular embodiment of the present invention is 5 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

[0077] Certain embodiments of the present invention are those in which R 1 is indazolyl, indolyl, indazolyl, imidazopyridinyl or triazolopyridinyl, wherein the indazolyl, indolyl, indazolyl, imidazopyridinyl and triazolopyridinyl are optionally substituted with one or more of cyano, methyl, oxo, isopropyl, or cyclopentyl; R 6 is -SCF3 or -OCF3, and R 2 , R 3 , R 4 , R 5 , R7 , X 1 , X 2 , X 3 , X 4 and X 5 is as defined above, or a pharmaceutically acceptable salt thereof.

[0078] A particular embodiment of the invention is where the compound is a compound of formula (I') [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 2 , X 3 , X 4 and X 5 is as defined above, and X 1 is CH; or a pharmaceutically acceptable salt thereof. A particular embodiment of the present invention is where the compound is a compound of formula (I") [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , X 1 , and X 5 is as defined above, and R 6 is —SCF3 or —OCF3, or a pharmaceutically acceptable salt thereof. A particular embodiment of the present invention comprises: R 1is indazolyl, indolyl, indazolyl, imidazopyridinyl or triazolopyridinyl, wherein the indazolyl, indolyl, indazolyl, imidazopyridinyl and triazolopyridinyl are optionally substituted with one or more cyano, methyl, oxo, isopropyl, or cyclopentyl; X 1 is CH or N, X 5 is CH or N, R 6 is —SCF3 or —OCF3.

[0079] A particular embodiment of the present invention comprises: R 1 is midazopyridinyl, triazolopyridinyl, phenyl, indolyl, isoindolinyl or indazolyl, and imidazopyridinyl, triazolopyridinyl, phenyl, indolyl, isoindolinyl and indazolyl are each independently selected from the group consisting of one or more R 1a is optionally replaced by X 1 is CH or N, X 5 is CH or N, R 7 is -OCF3, -SCF3, -OCHF2, or hydrogen; R 6 is -SCF3, -OCF3, -OCHF2, or hydrogen; However, R 6 and R 7 must be different, R 6 or R 7 is hydrogen.

[0080] A particular embodiment of the present invention comprises: {4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl}[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -sulfanone; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonimidoyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -sulfanone; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclohexyl](imino)-λ 6 -sulfanone; 4'-{[trans-4-{[4-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine; 5-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; 4-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 5-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; N-methyl-4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indazole-3-carbonitrile; 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{[1,1'-biphenyl]-4-sulfonyl}-2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; N-methyl-4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; N-[4-(difluoromethoxy)phenyl]-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 6-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 5-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(difluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}imidazo[1,2-a]pyridine-3-carbonitrile; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-{4-[3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-(4-{3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 4-(4-{[4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[trans-4-{[3-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; 6-{4-[(4-{[3-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[3-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine 4-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}pyridine-2-carboxamide; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; 4-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine; N-[trans-4-(4-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine; or 6-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one or a pharmaceutically acceptable salt thereof.

[0081] A particular embodiment of the present invention comprises: {4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl}[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -sulfanone; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonimidoyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -sulfanone; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclohexyl](imino)-λ 6 -sulfanone; 4'-{[trans-4-{[4-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine; 5-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; 4-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 5-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; N-methyl-4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indazole-3-carbonitrile; 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{[1,1'-biphenyl]-4-sulfonyl}-2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; N-methyl-4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; N-[4-(difluoromethoxy)phenyl]-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 6-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 5-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(difluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}imidazo[1,2-a]pyridine-3-carbonitrile; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-{4-[3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-(4-{3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 4-(4-{[4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[trans-4-{[3-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; 6-{4-[(4-{[3-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; or 4'-[(4-{[3-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile or a pharmaceutically acceptable salt thereof.

[0082] A particular embodiment of the present invention comprises: 5-[4-[4-[4-(trifluoromethylsulfanyl)anilino]cyclohexyl]sulfonylphenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indazole-3-carbonitrile; 6-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-[4-(3-isopropylimidazo[1,2-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-[4-(3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; or 6-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one or a pharmaceutically acceptable salt thereof.

[0083] A particular embodiment of the present invention comprises: 5-[4-[4-[4-(trifluoromethylsulfanyl)anilino]cyclohexyl]sulfonylphenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indazole-3-carbonitrile; 6-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-[4-(3-isopropylimidazo[1,2-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; or 1-[4-(3-Cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine or a pharmaceutically acceptable salt thereof.

[0084] A further object of the present invention are all forms of optically pure enantiomers, racemates or diastereomeric mixtures of the compounds of formula (I) or (I').

[0085] Manufacturing method Processes for preparing the compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, are also an object of the present invention.

[0086] The present invention is 1 is N and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (II) 5 and R 4 is as defined above), [ka] A compound of formula (III) 2 , X 3 , R 2 and R 3 is as defined above) to [ka] A compound of formula (IV) 3 , R 2 , R 4 , R5 , X 2 and X 3 is as defined above), [ka] The compound (IV) is reacted with a compound of formula (V) 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (VI) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (VI) is reacted with an acid to form a compound of formula (VII), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (VII) is reacted with a compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] forming a compound of formula (I).

[0087] The present invention is 1 is N and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (II) 5 and R 4 is as defined above), [ka] A compound of formula (III) 2 , X 3 , R 2 and R 3 is as defined above) to [ka] A compound of formula (IV) 3 , R 2 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound (IV) is reacted with a compound of formula (V) 1 is as defined above, and R 9 and R10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (VI) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (VI) is reacted with an acid to form a compound of formula (VII), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (VII) is reacted with a compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] forming a compound of formula (I).

[0088] The present invention is 1 is N and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (IX) 4 and R 5 is as defined above), [ka] A compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] A compound of formula (X) 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound of formula (X) is reacted with an acid to form a compound of formula (XI), 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound of formula (XI) is reacted with a compound of formula (III) 2 , X 3 , R 2 and R 3is as defined above) to [ka] A compound of formula (XII) 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above), [ka] The compound of formula (XII) is reacted with a compound of formula (V) 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0089] The present invention is 1 is N and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (XVIII) 5 and R 4 is as defined above), [ka] A compound of formula (XVII) 1 , R 2 , R 3 , X 2 and X 3 , as defined above), [ka] A compound of formula (XX) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XX) is reacted with a compound of formula (XVI) 5 , R 6 and R 7 is as defined above) to [ka] forming a compound of formula (I) or A compound of formula (XVIII) 5 and R 4 is as defined above), [ka] A compound of formula (III) 2 , X 3 , R 2 and R 3 is as defined above) to [ka] A compound of formula (XIX) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XIX) is reacted with the compound of formula (XVI) to form a compound of formula (XII), 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above), [ka] The compound of formula (XII) is reacted with a compound of formula (V) 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0090] The present invention is 1 is C and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (XXI) 4 and R 5 is as defined above), [ka] and mesyl chloride to give a compound of formula (XXII), 4 and R 5 is as defined above), [ka] The compound of formula (XXII) is converted into a compound of formula (XXIII) (wherein R 2 , R 3 , X 2 and X 3 is as defined above) to [ka] A compound of formula (XXIV) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXIV) is reacted with an oxidizing agent to produce a compound of formula (XXV), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXV) is reacted with a compound of formula (V) (wherein R 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (XXVI) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXVI) is reacted with an acid to give a compound of formula (XXVII), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXVII) is reacted with a compound of formula (VIII) 8 is a halogen and R6 , R 7 and X 5 is as defined above) to [ka] forming a compound of formula (I).

[0091] The present invention is 1 is C and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (XXV) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] with an acid to give a compound of formula (XXVIII), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXVIII) is reacted with a compound of formula (VIII) (wherein R 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] A compound of formula (XXIX) 2 , R 3 , R4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXIX) is reacted with a compound of formula (V) (wherein R 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0092] The present invention is 1 is C and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (XXXI) 4 and R 5 is as defined above), [ka] A compound of formula (XXXII) 4 and R 5 is as defined above) to [ka] The compound of formula (XXXII) is reacted with a compound of formula (XXIII) 2 , R 3 , X 2 and X 3 is as defined above) to [ka] A compound of formula (XXXIII) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound (XXXIII) is reacted with an oxidizing agent to give a compound of formula (XXXIV), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound (XXXIV) is reacted with an acid to give a compound of formula (XXXV), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXXV) is reacted with a compound of formula (XVI) 5 , R6 and R 7 is as defined above) to [ka] A compound of formula (XXIX) 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXIX) is reacted with a compound of formula (V) (wherein R 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0093] The present invention is 1 is C and X 4 is N, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (XXXIII) 2 , R 3 , R4 , R 5 , X 2 and X 3 is as defined above), [ka] with an acid to give a compound of formula (XXXVI), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXXVI) is reacted with a compound of formula (XVI) 5 , R 6 and R 7 is as defined above) to [ka] A compound of formula (XXXVII) 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XXXVII) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to give a compound of formula (XXXVIII), 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X2 and X 3 is as defined above), [ka] The compound of formula (XXXVIII) is reacted with a compound of formula (V) (wherein R 1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 C alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0094] The present invention is 1 and X 4 is N, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (XI) 4 , R 6 , R 7 , X 5 , and R 5 is as defined above), [ka] A compound of formula (XXIII) 2 , R 3 , X 2 and X 3 is as defined above) to [ka] A compound of formula (XL) 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound (XL) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to give a compound of formula (XLI), 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound (XLI) is reacted with di-tert-butyl dicarbonate and a base to give a compound of formula (XLII), 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] The compound (XLII) is reacted with a compound of formula (V) 1 is as defined above, and R 9 and R10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (XLIII) 1 , R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined above), [ka] reacting said compound of formula (XLIII) with an acid to form a compound of formula (I).

[0095] The present invention is 1 is C and X 4 is N, or a pharmaceutically acceptable salt thereof, comprising the steps of: A compound of formula (XXIV) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] A compound of formula (V), wherein R1 is as defined above, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 C alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (XLIV) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XLIV) is reacted with an acid to give a compound of formula (XLV), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above), [ka] The compound of formula (XLV) is reacted with a compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined above) to [ka] A compound of formula (XLVI) 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined above), [ka] reacting said compound of formula (XLVI) with ammonium carbamate and (diacetoxyiodo)benzene to form a compound of formula (I). [Example]

[0096] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods refer to the synthesis of specific compounds of the invention, it will be understood that the following general methods, and others known to those of skill in the art, can be applied to all compounds and each subclass and species of these compounds, as described herein.

[0097] General Preparation Method The compounds described herein, including compounds of general formula (I), can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. Many of the reactions can also be carried out under microwave conditions, using conventional heating, or utilizing other techniques, such as solid-phase reagents / scavengers or flow chemistry. It is also possible to use variants in these reactions that are known to those skilled in the art but are not mentioned in more detail. For example, when a particular acid, base, reagent, coupling agent, solvent, or the like is mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, solvents, or the like may be used and are within the scope of the present invention. Furthermore, other methods for preparing the compounds of the present invention will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Many of the reactions can also be carried out under microwave conditions, using conventional heating, or utilizing other techniques, such as solid-phase reagents / scavengers or flow chemistry. Methods for the selection, introduction, and subsequent removal of protecting groups are well known to those skilled in the art. Compounds obtained using a general reaction sequence may be of insufficient purity. The compounds can be purified by any of the purification methods for organic compounds, such as crystallization or silica gel, alumina, or C18 column chromatography using different solvents in suitable ratios. All possible stereoisomers are contemplated within the scope of the present invention. In the following description, variables have the above meanings unless otherwise indicated. All final compounds are characterized using, for example, LC-MS, NMR, and / or specific rotation measurements.

[0098] Abbreviations used in these experimental details are listed below; additional abbreviations should be considered known to those skilled in the art of synthetic chemistry.

[0099] Abbreviations used herein are as follows: rt: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; EtOH: ethanol; EtOAc: ethyl acetate; TEA: triethylamine; BINAP: 2,2-bis(diphenylphosphino)-1,1'-binaphthyl; BOC: tert-butyloxycarbonyl; t-BuONa: trisodium butyrate; N: normal; DMF: dimethylformamide; HOAc; acetic acid.

[0100] Chemical names are preferred IUPAC names.

[0101] If both chemical structure and chemical name are used to refer to a compound and an ambiguity exists between the structure and the name, the structure takes precedence.

[0102] General Procedure Scheme 1: [ka] Conditions: i) TEA, CH2Cl2, sulfonyl chloride (III), rt; ii) R 1 -boronic acid / ester (V), Pd(PPh3)4, NaHCO3, 1,4-dioxane / water, 110 °C; iii) TFA, CH2Cl2, rt; iv) Pd2(dba)3, aryl halide (VIII), Cs2CO3, BINAP.

[0103] Scheme 1 describes a route for synthesizing derivatives of the invention having formula (I) when X1 = N and X4 = O.

[0104] These compounds can be obtained, for example, by starting from the readily available protected 4-aminopiperidine of formula (II), R 4 and R 5 has the meaning as defined above, which can be combined with the sulfonyl chloride of formula (III), X 2 , X 3 、 R 2 and R 3has the above-mentioned meaning, forming the corresponding sulfonamide of formula (IV). Derivatives of formula (VI) can be prepared by coupling the derivative of formula (IV) with commercially available boronic acids or boronic esters of formula (V), where R has the above-mentioned meaning, under Suzuki conditions, for example, using Pd(PPh3)4 and NaHCO3 in a dioxane / water mixture. After deprotection of the amine under acidic conditions, for example, using TFA or aqueous HCl, the resulting aminopiperidine derivatives of formula (VII) can be converted to derivatives of formula (I), where X has the above-mentioned meaning, under Buchwald conditions, for example, using Pd2(dba)3, BINAP, and Cs2CO3 as bases. 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 has the meaning given above.

[0105] Scheme 2: [ka] Conditions: i) Pd2(dba)3, aryl(VIII) halide, Cs2CO3, BINAP; ii) TFA, CH2Cl2, rt; iii) TEA, CH2Cl2, sulfonyl(III) chloride, rt; iv) R 1 Boronic acid / ester (V), Pd(PPh3)4, NaHCO3, 1,4-dioxane / water, 110°C; v) bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, DMF, 75°C; vi) R 1 Halide (XIV), Pd(PPh3)4, 2N K2CO3, toluene / ethanol, 90°C; vii) TEA, CH2Cl2, sulfonyl chloride (XVII), rt; viii) aniline (XVI), 2-methylpyridine borane complex, CH3OH, HOAc, rt.

[0106] Scheme 2 describes an alternative route for the synthesis of derivatives of the invention having formula (I) when X1 = N and X4 = O.

[0107] The compounds of the present invention can be prepared, for example, from commercially available protected 4-aminopiperidine derivatives of formula (IX) 2 , X 3 , R 2 , R 3 , R 4 and R 5 has the meaning given above) and halogenated aryl derivatives of formula (VIII) 8 is a halogen, and X 5 , R 6 and R 7 has the meaning given above) under Buchwald conditions to give the corresponding protected N-phenylpiperidin-4-amine derivative of formula (X), which after deprotection under acidic conditions, for example using TFA, gives the 4-aminopiperidine derivative of formula (XI). In an alternative method, under reductive amination conditions, the N-phenylpiperidin-4-amine derivative of formula (X) can be converted to an N-protected piperidin-4-one derivative of formula (XV), 4 and R 5 has the meaning given above), and aniline derivatives of formula (XVI) 5 , R 6 and R 7 The derivatives of formula (I) can be prepared by direct coupling of the 4-aminopiperidine derivative (XI) with commercially available sulfonyl chlorides (XVII), in which R 1 , R 2 , R 3 , X 2 , and X 3Alternatively, the derivatives of 4-aminopiperidine derivatives (XI) can be coupled with 4-bromosulfonyl derivatives of formula (III) to obtain 1-(4-bromobenzenesulfonyl)-N-phenylpiperidin-4-amine derivatives of formula (XII), from which the derivatives of formula (XII) can be converted to commercially available boronic acids or boronic esters of formula (V) (wherein R 1 has the above-mentioned meaning) or by first converting the piperidine derivative of formula (XII) into the corresponding boronic ester derivative of formula (XIII), which can then be reacted under Suzuki conditions with the R1 halide of formula (XIV), where R1 has the above-mentioned meaning), the derivatives of formula (I) can be prepared.

[0108] Scheme 3: [ka] Conditions: i) TEA, CHCl, benzenesulfonyl chloride (XVII) rt; ii) aniline (XVI), 2-methylpiperidine borane complex, CHOH, HOAc, rt; iii) 4-bromosulfonyl chloride (III), TEA, rt; iv) aniline (XVI), 2-methylpiperidine borane complex, CHOH, HOAc, rt; v) R 1 Boronic acid / ester (V), Pd(PPh3)4, NaHCO3, 1,4-dioxane / water, 110°C.

[0109] Scheme 3 describes a route for synthesizing derivatives of the invention having formula (I) when X1 = N and X4 = O.

[0110] R 4 and R 5Starting from commercially available piperidin-4-one derivatives of formula (XVIII), in which R has the aforementioned meaning, 1-(benzenesulfonyl)piperidin-4-one derivatives of formula (XX) can be prepared by coupling the derivatives of formula (XVIII) with benzenesulfonyl chloride derivatives of formula (XVII), in which R 1 , R 2 , R 3 , X 2 and X 3 The 1-(benzenesulfonyl)piperidin-4-one derivative of formula (XX) can then be coupled with an appropriate aniline derivative of formula (XVI) under reductive amination conditions to give the corresponding derivative of formula (I). 5 , R 6 and R 7 has the meaning given above.

[0111] Alternatively, a derivative of a piperidin-4-one derivative of formula (XVIII) can be coupled with a 4-bromosulfonyl derivative of formula (III), wherein X 2 , X 3 、 R 2 and R 3 has the above-mentioned meaning, and 1-(4-bromobenzenesulfonyl)piperidin-4-one derivatives of formula (XIX) can be obtained, which can be converted into the corresponding derivatives of formula (XII) using appropriate aniline derivatives of formula (XVI) under reductive amination conditions, in which X 5 , R 6 and R 7 has the above meaning. For example, under Suzuki conditions using Pd(PPh3)4 and NaHCO3 in a dioxane / water mixture, the bromophenyl derivative of formula (XII) can be converted to a bromophenyl derivative of formula (V) (wherein R 1 has the meaning given above) to give the corresponding derivatives of formula (I).

[0112] Scheme 4: [ka] Conditions: i) mesyl chloride, TEA, 0 °C to rt; ii) 4-bromobenzenethiol (XXIII), Cs2CO3, acetone, 60 °C; iii) mCPBA, ethyl acetate, rt; iv) R 1 Boronic acid / ester (V), Pd(PPh3)4, 2N K2CO3, toluene / ethanol, 90°C; v) TFA, CH2Cl2, rt; vi) Pd2(dba)3, aryl halide (VIII), Cs2CO3, BINAP.

[0113] Scheme 4 describes a route for the synthesis of derivatives of the invention having formula (I) when X1 = C and X4 = O.

[0114] As shown in Scheme 4, the derivatives of the present invention having formula (I) can be prepared by converting N-Boc protected cis-4-aminocyclohexan-1-ol derivatives of formula (XXI) (wherein R 4 and R 5 (having the meaning as defined above) with mesyl chloride under basic conditions to give the corresponding N-Boc-protected cis-4-aminocyclohexylmethanesulfonate derivatives of formula (XXII). These sulfonate derivatives of formula (XXII) can be converted to N-Boc-protected 4-[(4-bromophenyl)sulfanyl]cyclohexane-1-amine derivatives of formula (XXIV) via a nucleophilic substitution reaction with a 4-bromobenzene-1-thiol derivative of formula (XXIII) using a suitable base, e.g., CsCO, which can be oxidized to the corresponding N-Boc-protected sulfonyl derivatives of formula (XXV) using, e.g., mCPBA as an oxidizing agent. These sulfonyl derivatives of formula (XXV) can then be coupled with an appropriate boronic acid or boronic ester of formula (V) under Suzuki conditions, e.g., using Pd(PPh) as a catalyst, to form the corresponding derivatives of formula (XXVI). After removing the Boc group of the derivative of formula (XXVI) under acidic conditions, for example using TFA, the resulting derivative of formula (XXVII) can be converted to the appropriate aryl halide (VIII) (wherein R 8is a halogen, and X 5 , R 6 and R 7 has the above meaning) to give derivatives of formula (I) (wherein X has the above meaning) using, for example, Pd2(dba)3, BINAP and a suitable base, for example Cs2CO3. 2 , X 3 , X 5 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 has the meaning given above).

[0115] Scheme 5: [ka] Conditions: i) TFA, CH2Cl2, rt; ii) Pd2(dba)3, aryl halide(VIII), Cs2CO3, BINAP; iii) R 1 Boronic acid / ester (V), Pd(PPh3)4, 2N K2CO3, toluene / ethanol, 90°C; iv) bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, DMF, 75°C; v) R 1 Halide (XIII), Pd(PPh3)4, 2N K2CO3, toluene / ethanol, 90°C.

[0116] Scheme 5 describes a route for synthesizing derivatives of the invention having formula (I) when X1 = C and X4 = O.

[0117] In an alternative method, the Boc group of the derivative of formula (XXV) can first be removed under acidic conditions, for example using TFA, to give an amino derivative of formula (XXVIII), which can be converted to a derivative of formula (XXIX) under Buchwald conditions, as described above. The derivative of formula (XXIX) can then be reacted with a suitable boronic acid or boronic ester of formula (V) (wherein R 1have the above meanings), or by reaction of a derivative of formula (XXIX) with the corresponding boronic acid / ester of formula (XXX) (which can further be converted to a suitable R 1 The derivatives of formula (I) can be converted by first converting them to the corresponding aryl groups (which can be further reacted with a halide).

[0118] Scheme 6: [ka] Conditions: i) CH3SO2Cl, Et3N, CH2Cl2, rt; ii) 4-bromobenzenethiol (XXIII), Cs2CO3, acetone, 60 °C; iii) mCPBA, ethyl acetate, rt; iv) 2N HCl, THF, rt; v) aniline (XVI), 2-methylpyridine borane complex, CH3OH, HOAc, rt; vi) bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, DMF, 75 °C; vii) R 1 Halide (XIV), 2N K2CO3, toluene / ethanol, Pd(PPh3)4, 90°C; viii) R 1 Boronic acid / ester (V), Pd(PPh3)4, 2N K2CO3, toluene / ethanol, 90°C.

[0119] Scheme 6 describes a route for the synthesis of derivatives of the invention having formula (I) when X1 = C and X4 = O.

[0120] These compounds can be prepared, for example, from readily available keto-protected 4-hydroxycyclohexan-1-ones of formula (XXXI) 4 and R 5has the meaning given above), in which the hydroxyl group is converted to a suitable leaving group, for example a mesyl or tosyl group, to give derivatives of formula (XXXII), which can be reacted with a 4-bromobenzenethiol derivative of formula (XXIII) to form phenylsulfanyl derivatives of formula (XXXIII). After oxidation of the sulfur, the formed sulfonyl derivatives of formula (XXXIV) can be deprotected under acid conditions, for example using mCPBA, to give sulfonylcyclohexanone derivatives of formula (XXXV). These sulfonylcyclohexanone derivatives of formula (XXXV) can be converted under reductive amination conditions to anilines of formula (XVI), in which X 5 , R 6 and R 7 has the meaning given above) to give the corresponding N-phenylpiperidin-4-amine derivative of formula (XXIX). The derivative of formula (I) can then be converted to a commercially available boronic acid or boronic ester of formula (V) (wherein R 1 has the meaning given above), or by coupling the derivative of formula (XXIX) with the corresponding boronic acid or boronic ester of formula (XXX), which can then be converted under Suzuki conditions to the R-halide of formula (XIV), 1 can be prepared by first converting into ) which can be reacted with ) having the above meaning.

[0121] Scheme 7: [ka] Conditions: i) 2N HCl, THF, rt; ii) aniline (XVI), 2-methylpyridine borane complex, CHOH, HOAc, rt; iii) ammonium carbamate, (diacetoxyiodo)benzene, CHOH, CHCN, rt; iv) bis(pinacolato)diboron, KOAc, Pd(dppf)Cl, DMF, 75°C; v) R 1Halide (XIV), 2N K2CO3, toluene / ethanol, Pd(PPh3)4, 90°C; vi) R 1 Boronic acid / ester (V), Pd(PPh3)4, 2N K2CO3, toluene / ethanol, 90°C.

[0122] Scheme 7 describes a route for the synthesis of derivatives of the invention having formula (I) when X1 = C and X4 = N.

[0123] The keto-protected sulfanyl derivative of formula (XXXIII) can be deprotected under acidic conditions, for example using HCl or TFA, to give the 4-(phenylsulfanyl)cyclohexan-1-one derivative of formula (XXXVI). The derivative of formula (XXXVI) can be converted under reductive amination conditions to a suitable aniline derivative of formula (XVI), where X 5 , R 6 and R 7 has the above-mentioned meaning) to give the corresponding N-[4-(phenylsulfanyl)cyclohexyl]aniline derivative of formula (XXXVII). Derivatives of formula (XXXVIII) can be prepared by converting the derivative of formula (XXXVII) to the corresponding sulfoximine derivative by using ammonium carbamate, (diacetoxyiodo)benzene and CHCN in CHOH. Finally, derivatives of formula (XXXVIII) can be prepared by reaction with a suitable boronic acid or boronic ester of formula (V) (wherein R has the above-mentioned meaning) under Suzuki conditions, for example using Pd(PPh) as a catalyst, or by coupling the derivative of formula (XXXVIII) with the corresponding boronic ester of formula (XXXIX) (which can further be converted to the appropriate R of formula (XIV) under Suzuki conditions, as described above). 1 -halides) to give derivatives of formula (I).

[0124] Scheme 8: [ka] Conditions: i) 4-bromobenzenethiol (XXIII), CsCO, acetone, 60 °C; ii) ammonium carbamate, (diacetoxyiodo)benzene, CHOH, CHCN, rt; iii) NaH, di-tert-butyl dicarbonate, THF, rt; iv) R 1 -boronic acid / ester (V), Pd(PPh3)4, 2N K2CO3, toluene / ethanol, 90°C; v) 5N HCl, 2-propanol, rt.

[0125] Scheme 8 describes a route for synthesizing derivatives of the invention having formula (I) when X1 and X4 are N.

[0126] N-phenylpiperidin-4-amine derivatives of formula (XI) 5 , R 4 , R 5 , R 6 and R 7 has the above-mentioned meaning) can be obtained by using, for example, Cs2CO3 as a base, the 4-bromobenzene-1-thiol derivative of formula (XXIII) 2 , X 3 , R 2 and R 3 has the meaning given above). The derivatives of formula (XL) can be converted to the corresponding sulfonimidamide derivatives of formula (XLI) by using ammonium carbamate, (diacetoxyiodo)benzene and CHCN in CHOH. After protecting the sulfonimidamide nitrogen with, for example, a Boc group, the derivatives of formula (XLII) can be reacted with a suitable boronic acid or boronic ester of formula (V) under Suzuki conditions as described above to give the derivatives of formula (XLIII). In the final step, the Boc group can be removed under acidic conditions to give the corresponding derivatives of formula (I) (wherein X 2 , X 3 , X 5 , R 1 , R 2 , R 3 , R 4 , R5 , R 6 and R 7 has the meaning given above).

[0127] Scheme 9: [ka] Conditions: i) R 1 -boronic acid / ester (V), Pd(PPh3)4, 2N K2CO3, toluene / ethanol, 90°C; ii) 5N HCl (aq) , 2-propanol, rt; iii) aryl bromide (VIII), t-BuONa, Xantphos, Pd2(dba)3, rt; iv) ammonium carbamate, (diacetoxyiodo)benzene, CH3OH, CH3CN, rt.

[0128] Scheme 9 describes an alternative route for the synthesis of derivatives of the invention having formula (I) when X1 = C and X4 = N.

[0129] The N-protected N-(4-bromophenyl)sulfanylcyclohexyl derivative of formula (XXIV) can be first coupled to a suitable boronic acid or boronic ester (V) (wherein R1 has the above-mentioned meaning) under the aforementioned Suzuki conditions, and the N-protected phenylsulfanylcyclohexyl derivative of formula (XLIV) can be deprotected under acidic conditions using, for example, HCl or TFA to give the phenylsulfanylcyclohexyl derivative of formula (XLV). The derivative of formula (XLV) can then be converted to a suitable aryl halide (VIII) (wherein R1 has the above-mentioned meaning) under Buchwald conditions using Pd2(dba)3, Xantphos, and t-BuONa as bases. 8 is halogen, and X5, R6 and R7 have the above meanings) to give a derivative of formula (XLVI), which can finally be converted to the corresponding sulfoximine derivative of formula (I) by using ammonium carbamate in CH3OH, (diacetoxyiodo)benzene and CH3CN.

[0130] Pharmaceutical Compositions and Administration Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0131] Another embodiment of the present invention is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0132] Another embodiment of the present invention is a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0133] Indications The compounds of formula (I), (I') described herein may be used in an effective amount to treat subjects, particularly humans, suffering from inflammatory autoimmune diseases.

[0134] One embodiment of the present invention is a compound, or a pharmaceutically acceptable salt thereof, described herein for use as a therapeutically active substance.

[0135] One embodiment of the present invention is a compound, or a pharmaceutically acceptable salt thereof, as described herein for use in treating, preventing and / or delaying inflammatory autoimmune diseases.

[0136] One embodiment of the present invention is a compound, as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of psoriatic disease, asthma, inflammatory bowel disease (IBD), Crohn's disease, obstructive pulmonary disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

[0137] In one embodiment of the present invention, there is provided a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of psoriatic disease, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

[0138] In one embodiment of the present invention are compounds as described herein or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment, prevention and / or delay of progression of psoriatic disease, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

[0139] One embodiment of the present invention is a compound as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of inflammatory autoimmune diseases.

[0140] In a further embodiment, the present invention provides a method for treating, preventing and / or delaying the progression of an inflammatory autoimmune disease, comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0141] In a further embodiment, the present invention provides a method for the treatment, prevention and / or delay of progression of psoriatic disease, asthma, inflammatory bowel disease (IBD), Crohn's disease, obstructive pulmonary disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis, comprising administering a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof.

[0142] As used herein, the terms "treatment" or "treating" and grammatical variations thereof refer to therapeutic therapy. With respect to a particular condition, treating means: (1) ameliorating the condition or one or more biological manifestations of the condition; (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition, or (b) one or more biological manifestations of the condition; (3) alleviating one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the condition or one or more biological manifestations of the condition. Prophylactic therapy using the methods and / or compositions of the present invention is also contemplated. Those skilled in the art will understand that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or its biological manifestations, or to delay the onset of such a condition or its biological manifestations. Preventive therapy is appropriate, for example, when a subject is considered to be at high risk of developing psoriatic disease, asthma, inflammatory bowel disease (IBD), Crohn's disease, obstructive pulmonary disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis, for example, when a subject has a strong family history of psoriatic disease, asthma, inflammatory bowel disease (IBD), Crohn's disease, obstructive pulmonary disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.

[0143] Example Example 1: 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile. [ka] i) To a solution of tert-butyl N-(piperidin-4-yl)carbamate (1.0 g) and triethylamine (2.1 mL) in THF (40 mL) was added 4-bromobenzene-1-sulfonyl chloride (1.4 g) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to give tert-butyl N-[1-(4-bromobenzenesulfonyl)piperidin-4-yl]carbamate (2.0 g), which was used in the next step without further purification.

[0144] ii) Under a nitrogen atmosphere, Pd(PPh3)4 (14 mg) was added to a suspension of the product obtained in the previous step (500 mg), (4-cyanophenyl)boronic acid (180 mg), and aqueous 2MK2CO3 solution (6.0 mL) in a mixture of toluene (13 mL) and ethanol (1.5 mL). The reaction mixture was stirred in a microwave at 90 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give tert-butyl N-[1-({4'-cyano-[1,1'-biphenyl]-4-yl}sulfonyl)piperidin-4-yl]carbamate (500 mg) as a brown oil, which was used in the next step without further purification.

[0145] iii) To a solution of the product obtained in the previous step (500 mg), a 2N solution of HCl in diethyl ether (5.7 mL) was added at room temperature. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure to give 4'-[(4-aminopiperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile hydrochloride (500 mg), which was used in the next step without further purification.

[0146] iv) Under a nitrogen atmosphere, Pd2(dba)3 (6.1 mg) was added to a suspension of the product obtained in the previous step (50 mg), 1-bromo-4-(trifluoromethoxy)benzene (32 mg), Cs2CO3 (215 mg), and BINAP (9.1 mg) in toluene (3 mL). The reaction mixture was stirred overnight at 90 °C in a microwave. After cooling to room temperature, the reaction mixture was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 90% CH3CN in water as the eluent to give the title compound 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile (29 mg) as a white solid. MS (ES) + ) m / z 502.1 (M+H) + .

[0147] 1 H NMR(400MHz,DMSO)δ8.08-8.03(m,2H),8.03-7.97(m,4H),7.90-7.85(m,2H),7.03-6.97(m,2H),6.61-6.55(m,2H),5.8 2-5.77(d,J=8.1Hz,1H),3.66-3.55(m,2H),3.31-3.20(m,1H),2.63-2.54(m,2H),2.05-1.88(m,2H),1.49-1.34(m,2H).

[0148] Example 2 was prepared following a similar procedure as described for Example 1, using the appropriate aryl halide in step iv.

[0149] Example 2: 4'-[(4-{[3-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile [ka] MS(ES + ) m / z 484.1(M+H) + . 1H NMR(400MHz,DMSO)δ8.08-8.03(m,2H),8.03-7.96(m,4H),7.91-7.85(m,2H),7.28-6.87(t ,J=74.8Hz,1H),7.06-6.99(t,J=8.1Hz,1H),6.44-6.38(ddd,J=8.3,2.1,0.9Hz,1H),6.33 -6.27(t,J=2.2Hz,1H),6.28-6.22(dd,J=7.9,2.2Hz,1H),5.86-5.80(d,J=8.2Hz,1H),3.6 7-3.55(m,2H),3.30-3.23(m,1H),2.62-2.54(m,2H),2.02-1.89(m,2H),1.49-1.32(m,2H).

[0150] Building Block: Step iv: 1-Bromo-3-(trifluoromethoxy)benzene.

[0151] Example 3: 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one. [ka] i) Under a nitrogen atmosphere, Pd2(dba)3 (229 mg) was added to a suspension of tert-butyl 4-aminopiperidine-1-carboxylate (1.0 g), t-BuONa (1.2 g), 1-bromo-4-(trifluoromethoxy)benzene (890 μL), and Xantphos (347 mg) in toluene (10 mL). The reaction mixture was stirred in a microwave at 90 °C for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on SiO2 using 0% to 100% ethyl acetate in heptane as the eluent to give tert-butyl 4-{[4-(trifluoromethoxy)phenyl]amino}piperidine-1-carboxylate (0.9 g) as a yellow solid.

[0152] ii) TFA (1.9 mL) was added to a solution of the product obtained in the previous step (0.9 g) in CHCl (10 mL), and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was concentrated in vacuo to give N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; trifluoroacetic acid (1.7 g) as a white solid, which was used in the next step without further purification.

[0153] iii) To a suspension of the product obtained in the previous step (0.98 g) and triethylamine (1.4 mL) in CHCl (25 mL) was added 4-bromobenzene-1-sulfonyl chloride (613 mg) in portions at room temperature. The reaction mixture was stirred overnight at room temperature and quenched by the addition of water. The product was extracted into CHCl, and the combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting brown oil was dissolved in a small amount of ethyl acetate, and heptane was added. The product was allowed to precipitate overnight, and the solid was filtered off and dried under reduced pressure to give 1-(4-bromobenzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine (0.95 g) as a white solid.

[0154] iv) Under a nitrogen atmosphere, to a suspension of the product obtained in the previous step (100 mg), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (62 mg), and 2 M aqueous KCO solution (1.0 mL) in a mixture of toluene (9 mL) and ethanol (1 mL) was added Pd(PPh) (11 mg). The reaction mixture was stirred in a microwave at 100 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 90% CHCN in water as the eluent to give the title compound 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one (16 mg) as a white solid. MS (ES)+ ) m / z 532.2(M+H) + .

[0155] 1 H NMR(400MHz,DMSO)δ8.77-8.64(s,1H),8.09-8.03(m,2H),8.03-7.99(m,2H), 7.89-7.82(m,2H),7.77-7.72(m,1H),7.07-6.93(dd,J=8.7,1.3Hz,2H),6.66- 6.52(m,2H),5.86-5.71(d,J=8.0Hz,1H),4.49-4.43(s,2H),3.67-3.55(m,2H ),3.32-3.21(m,1H),2.64-2.53(m,2H),2.04-1.89(m,2H),1.51-1.35(m,2H).

[0156] Following a similar procedure as described for Example 3, Examples 4-12 were prepared using the appropriate (hetero)aryl halide in step i and the appropriate boronic ester or boronic acid in step iv.

[0157] Examples 4 to 12 Example 4: N-methyl-4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide. [ka] MS(ES + ) m / z 534.2(M+H) + . 1H NMR(400MHz,DMSO)δ8.66-8.59(m,1H),8.25-8.17(t,J=1.8Hz,1H),8.06-8.00(m,2H) ,7.95-7.90(m,2H),7.89-7.85(m,2H),7.66-7.60(t,J=7.8Hz,1H),7.05-6.95(m,2H) ,6.62-6.55(m,2H),5.83-5.76(d,J=8.0Hz,1H),3.67-3.55(m,2H),3.31-3.21(m,1H) ,2.89-2.79(d,J=4.5Hz,3H),2.62-2.52(m,2H),2.03-1.92(m,2H),1.52-1.34(m,2H).

[0158] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iv: [3-(methylcarbamoyl)phenyl]boronic acid.

[0159] Example 5: 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide [ka] MS(ES + ) m / z 520.2 (M+H) + . 1 H NMR(400MHz,DMSO)δ8.26(t,J=1.8,1.8Hz,1H),8.16(s,1H),8.06-8.01(m,2H),7.94 (tdd,J=7.8,7.8,2.3,1.2Hz,2H),7.89-7.84(m,2H),7.62(t,J=7.8,7.8Hz,1H),7.4 9(s,1H),7.00(d,J=8.1Hz,2H),6.62-6.54(m,2H),5.79(d,J=8.1Hz,1H),3.64-3.56 (m,2H),3.31-3.22(m,1H),2.60-2.54(m,2H),2.00-1.93(m,2H),1.49-1.34(m,2H).

[0160] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iv: (3-carbamoylphenyl)boronic acid.

[0161] Example 6: 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] MS(ES + ) m / z 531.2(M+H) + . 1 H NMR(400MHz,DMSO)δ12.79(s,1H),8.13(dd,J=1.8,0.9Hz,1H),8.06-7.98(m,2H) ,7.86-7.78(m,2H),7.74(dd,J=8.7,1.7Hz,1H),7.59(d,J=8.8Hz,1H),7.00(d,J =8.2Hz,2H),6.62-6.54(m,2H),5.78(d,J=8.0Hz,1H),3.64-3.55(m,2H),3.30-3 .24(m,1H),2.57(s,2H),2.60-2.52(m,3H),2.01-1.93(m,2H),1.50-1.36(m,2H).

[0162] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iv: (3-methyl-1H-indazol-5-yl)boronic acid.

[0163] Example 7: 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile. [ka] MS(ES + ) m / z 503.2(M+H) + . 1H NMR(400MHz,DMSO)δ8.06-8.01(m,2H),8.00(d,J=1.6Hz,3H),7.94(d,J=2.9Hz,1H),7.90-7.85(m,2H),7.45-7.36(m,1H),6.85(d,J=7 .3Hz,1H),6.50(dd,J=9.1,0.6Hz,1H),3.75-3.63(m,1H),3.61-3.53(m,2H),2.65-2.57(m,2H),2.04-1.89(m,2H),1.56-1.42(m,2H).

[0164] Building blocks: step i: 2-chloro-5(trifluoromethoxy)pyridine; step iv: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile.

[0165] Example 8: 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one. [ka] MS(ES + ) m / z 533.2(M+H) + .

[0166] 1 H NMR(400MHz,DMSO)δ8.73(s,1H),8.12-8.04(m,4H),7.99(d,J=2.9Hz,1H),7. 94-7.86(m,2H),7.83-7.76(m,1H),7.46(ddd,J=9.2,3.0,1.0Hz,1H),6.91(d, J=7.3Hz,1H),6.55(d,J=9.2Hz,1H),4.51(s,2H),3.81-3.69(m,1H),3.66-3. 58(m,2H),2.66(t,J=10.5,10.5Hz,2H),2.07-1.95(m,2H),1.62-1.48(m,2H).

[0167] Building blocks: Step i: 2-chloro-5(trifluoromethoxy)pyridine; Step iv: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one.

[0168] Example 9: 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide. [ka] MS(ES + ) m / z 521.2 (M+H) + . 1 H NMR(400MHz,DMSO)δ8.26(t,J=1.8,1.8Hz,1H),8.15(s,1H),8.05-8.00(m,2H) ),7.98-7.91(m,3H),7.90-7.83(m,2H),7.62(t,J=7.7,7.7Hz,1H),7.49(s,1H ),7.44-7.36(m,1H),6.85(d,J=7.2Hz,1H),6.50(d,J=9.2Hz,1H),3.68(s,1H ),3.61-3.53(m,2H),2.65-2.55(m,2H),2.01-1.93(m,2H),1.56-1.43(m,2H).

[0169] Building blocks: step i: 2-chloro-5(trifluoromethoxy)pyridine; step iv: (3-carbamoylphenyl)boronic acid.

[0170] Example 10: 6-{4-[(4-{[3-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one. [ka] MS(ES + ) m / z 532.2(M+H) + . 1 H NMR(400MHz,DMSO)δ8.69(s,1H),8.03-7.93(m,4H),7.84-7.77(m,2H),7.77-7.72(m,1H),7.57(t,J=8.1,8.1Hz,1H),7.52-7.3 7(m,3H),4.47(s,2H),4.44-4.37(m,1H),3.77(d,J=12.0Hz,2H),2.64-2.55(m,2H),1.95(d,J=12.2Hz,2H),1.36-1.11(m,2H).

[0171] Building blocks: step i: 1-bromo-3-(trifluoromethoxy)benzene; step iv: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one.

[0172] Example 11: 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] MS(ES + ) m / z 517.3(M+H) + . 1 H NMR(400MHz,DMSO)δ9.13-9.07(dd,J=1.9,1.0Hz,1H),8.04-7.99(m,3H),7.92-7.83(m,2H),7.74-7.69(m,1H),7.69-7.64(m,2H),7.04-6.96(m,2) H),6.65-6.54(m,2H),5.83-5.77(d,J=8.0Hz,1H),3.66-3.55(m,2H),3. 31-3.22(m,1H),2.63-2.52(m,2H),2.01-1.92(m,2H),1.50-1.34(m,2H).

[0173] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iv: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.

[0174] Example 12: N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 518.3(M+H) + . 1 H NMR(400MHz,DMSO)δ9.10(dd,J=1.9,1.1Hz,1H),8.05-7.97(m,3H),7.94(d,J=2 .9Hz,1H),7.91-7.83(m,2H),7.72(d,J=9.4Hz,1H),7.67(dd,J=10.7,1.5Hz,2H) ,7.45-7.37(m,1H),6.86(d,J=7.3Hz,1H),6.50(d,J=9.2Hz,1H),3.74-3.63(m, 1H),3.61-3.53(m,2H),2.66-2.56(m,2H),2.01-1.93(m,2H),1.57-1.43(m,2H).

[0175] Building blocks: step i: 2-chloro-5(trifluoromethoxy)pyridine; step iv: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.

[0176] Example 13: 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile. [ka] i) Following a procedure similar to that described in Example 3, steps i-iii, 1-(4-bromobenzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine (1.0 g) was prepared.

[0177] ii) To a suspension of the product from the previous step (1.0 g), bis(pinacolato)diboron (604 mg), and potassium acetate (538 mg) in N2-purged DMF (15 mL) was added PdCl2(dppf).CHCl2 (73 mg). The reaction mixture was heated in a microwave at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was poured into water, and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine as a brown oil (1.2 g), which was used in the next step without further purification.

[0178] iii) Under a nitrogen atmosphere, 2 M aqueous K2CO3 solution (1.1 mL) was added to a suspension of the product obtained in the previous step (238 mg), 5-bromo-1H-indole-3-carbonitrile (50 mg), and Pd(PPh3)4 (13 mg) in a mixture of toluene (4.5 mL) and ethanol (0.5 mL). The reaction mixture was stirred in a microwave at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 90% acetonitrile in water as the eluent to give the title compound 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile (20 mg) as a white solid. MS(ES + ) m / z 531.2(M+H) + .

[0179] 1 H NMR(400MHz,DMSO)δ12.36(s,1H),8.34(s,1H),8.07-8.02(m,2H),8.00(t,J=1.3,1.3Hz,1H),7.87-7.79(m,2H),7.74-7.63(m,2H),6.99(d,J=8. 1Hz,2H),6.63-6.54(m,2H),5.78(d,J=8.0Hz,1H),3.64-3.57(m,2H),3. 31-3.21(m,1H),2.62-2.52(m,2H),2.01-1.93(m,2H),1.50-1.36(m,2H).

[0180] Following a similar procedure as described for Example 13, using the appropriate (hetero)aryl halides in step i and step iii, Examples 14-22 were prepared.

[0181] Examples 14 to 22 Example 14: 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indazole-3-carbonitrile. [ka] MS(ES + ) m / z 542.2(M+H) + . 1 H NMR(400MHz,DMSO)δ14.50(s,1H),8.27(dd,J=1.6,0.9Hz,1H),8.14-8.06(m,2H),7.9 5(dd,J=8.8,1.6Hz,1H),7.91(dd,J=8.8,0.9Hz,1H),7.88-7.83(m,2H),7.00(dq,J=7 .9,1.0,1.0,1.0Hz,2H),6.62-6.54(m,2H),5.79(d,J=8.0Hz,1H),3.66-3.57(m,2H), 3.29-3.22(m,0H),2.64-2.54(m,2H),1.97(dd,J=13.4,3.7Hz,2H),1.49-1.37(m,2H).

[0182] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iii: 5-bromo-1H-indazole-3-carbonitrile.

[0183] Example 15: 5-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile. [ka] MS(ES + ) m / z 542.2(M+H) + . 1 H NMR(400MHz,DMSO)δ12.39-12.34(s,1H),8.37-8.31(s,1H),8.07-7.98(m,3H),7.98-7 .93(d,J=2.9Hz,1H),7.87-7.79(m,2H),7.75-7.67(d,J=1.3Hz,2H),7.44-7.37(ddd,J =9.0,3.1,1.1Hz,1H),6.89-6.82(d,J=7.2Hz,1H),6.54-6.47(d,J=9.2Hz,1H),3.76-3 .62(m,1H),3.62-3.50(m,2H),2.66-2.56(m,2H),2.02-1.92(m,2H),1.57-1.43(m,2H).

[0184] Building blocks: step i: 2-chloro-5-(trifluoromethoxy)pyridine; step iii: 5-bromo-1H-indole-3-carbonitrile.

[0185] Example 16: 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] MS(ES + ) m / z 531.3(M+H) + . 1 H NMR(400MHz,DMSO)δ9.02(t,J=1.4,1.4Hz,1H),8.23(dd,J=9.4,1.7Hz,1H) ,8.20-8.12(m,2H),8.04(dd,J=9.3,0.9Hz,1H),7.99-7.90(m,3H),7.04-6. 97(m,2H),6.62-6.54(m,2H),5.80(s,1H),3.67-3.59(m,2H),3.31-3.21(m ,1H),2.66(s,3H),2.62-2.54(m,2H),2.02-1.94(m,2H),1.50-1.38(m,2H).

[0186] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iii: 6-bromo-3-methylimidazo[1,2-a]pyridine.

[0187] Example 17: 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}imidazo[1,2-a]pyridine-3-carbonitrile. [ka] MS(ES + ) m / z 542.3(M+H) + . 1 H NMR(400MHz,DMSO)δ8.98(t,J=1.4,1.4Hz,1H),8.54(s,1H),8.18-8.10(m,2H),8.01(t,J=1.4,1.4Hz,2H),7.93-7.81(m,2H),7.00(d,J=8.2Hz) ,2H),6.62-6.54(m,2H),5.79(d,J=8.0Hz,1H),3.65-3.58(m,2H),3.30 -3.22(m,1H),2.62-2.54(m,2H),2.01-1.93(m,2H),1.49-1.37(m,2H).

[0188] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iii: 6-bromoimidazo[1,2-a]pyridine-3-carbonitrile.

[0189] Example 18: 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] MS(ES + ) m / z 532.3(M+H) + . 1 H NMR(400MHz,DMSO)δ9.37(dd,J=1.9,0.9Hz,1H),8.13-8.09(m,2H),8.06(dd,J=9.3,1.9Hz,1H),7.90-7.82(m,3H),7.03-6.96(m,2H),6.62-6 .54(m,2H),5.79(d,J=8.1Hz,1H),3.65-3.57(m,2H),3.31-3.24(m,1H) ,2.61-2.54(m,2H),2.52(s,3H),2.00-1.93(m,2H),1.48-1.36(m,2H).

[0190] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iii: 6-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine.

[0191] Example 19: 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] MS(ES + ) m / z 532.3(M+H) + . 1H NMR(400MHz,CDCl3)δ8.59(dd,J=7.1,0.9Hz,1H),7.95-7.89(m,2H),7.89-7.78(m,3H),7.22(dd,J=7.1,1.9Hz,1H),7.03-6.95(m, 2H),6.53-6.44(m,2H),3.83-3.75(m,2H),3.57-3.51(m,1H),2.64(s,3H),2.62-2.57(m,2H),2.18-2.10(m,2H),1.60-1.56(m,3H).

[0192] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iii: 7-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine.

[0193] Example 20: 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] MS(ES + ) m / z 559.4(M+H) + . 1 H NMR(400MHz,DMSO)δ9.15(t,J=1.3,1.3Hz,1H),8.30(dd,J=9.4,1.6Hz,1H),8.20 -8.12(m,2H),8.13-8.05(m,2H),7.99-7.90(m,2H),7.07-6.96(m,2H),6.64-6.5 3(m,2H),5.82(s,1H),3.75-3.58(m,3H),3.32-3.20(m,1H),2.58(dd,J=12.4,9. 8Hz,2H),2.04-1.92(m,2H),1.45(t,J=10.4,10.4Hz,2H),1.40(d,J=6.8Hz,6H).

[0194] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iii: 6-bromo-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0195] Example 21: N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 560.3(M+H) + . 1 H NMR(400MHz,DMSO)δ9.17(s,1H),8.33(dd,J=9.4,1.6Hz,1H),8.18-8.08(m,4H),7.99-7.90(m,3H),7.48-7.38(m,1H),6.91(s ,1H),6.51(d,J=9.2Hz,1H),3.76-3.55(m,3H),2.63-2.54(m,2H),2.05-1.93(m,2H),1.59-1.45(m,2H),1.40(d,J=6.8Hz,6H).

[0196] Building blocks: step i: 2-chloro-5-(trifluoromethoxy)pyridine; step iii: 6-bromo-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0197] Example 22: 1-{4-[3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] MS(ES + ) m / z 562.4(M+H) + . 1H NMR(400MHz,DMSO)δ8.85(t,J=1.4,1.4Hz,1H),8.12-8.04(m,2H),7.97(dd,J=9. 6,1.1Hz,1H),7.93-7.88(m,2H),7.87(dd,J=9.6,1.7Hz,1H),7.04-6.97(m,2H), 6.62-6.54(m,2H),5.79(d,J=8.0Hz,1H),5.07(s,2H),3.65-3.56(m,2H),3.35(s ,3H),3.29-3.21(m,0H),2.62-2.52(m,3H),2.02-1.93(m,2H),1.50-1.36(m,2H).

[0198] Building blocks: step i: 1-bromo-4-(trifluoromethoxy)benzene; step iii: 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine.

[0199] Example 23: 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one. [ka] i) Following a procedure similar to that described for Example 13, using 6-bromo-2-[(4-methoxyphenyl)methyl]-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (78 mg) in step iv, 2-[(4-methoxyphenyl)methyl]-6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (60 mg) was prepared as a white solid, which was used in the next step without further purification.

[0200] ii) A solution of the product obtained in the previous step (60 mg) and L-cysteine ​​(17 mg) in trifluoroacetic acid (5 mL) was stirred at 70 °C for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified on a C18 column using 10% to 90% acetonitrile in water as the eluent to give the title compound 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (42 mg) as a white solid. MS (ES) + ) m / z 534.3(M+H) + .

[0201] 1 H NMR(400MHz,DMSO)δ12.62(s,1H),8.23(dd,J=1.8,1.1Hz,1H),8.07-7.99(m,2 H),7.85-7.78(m,2H),7.66(dd,J=9.8,1.8Hz,1H),7.40(dd,J=9.8,1.1Hz,1H) ,7.03-6.96(m,2H),6.62-6.53(m,2H),5.78(d,J=8.1Hz,1H),3.63-3.55(m,2H ),3.33-3.18(m,1H),2.60-2.52(m,2H),1.99-1.92(m,2H),1.48-1.35(m,2H).

[0202] Following a procedure similar to that described for Example 23, using the appropriate aryl halide in Example 3, step i, Example 24 was prepared.

[0203] Example 24: 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one. [ka] MS(ES + ) m / z 535.3(M+H) + . 1 H NMR(400MHz,DMSO)δ12.61(s,1H),8.23(t,J=1.5,1.5Hz,1H),8.05-7.98(m,2 H),7.94(d,J=2.9Hz,1H),7.85-7.78(m,2H),7.66(dd,J=9.8,1.8Hz,1H),7.4 5-7.36(m,2H),6.87(d,J=7.3Hz,1H),6.50(d,J=9.2Hz,1H),3.71-3.64(m,1H ),3.60-3.52(m,2H),2.64-2.55(m,2H),2.00-1.92(m,2H),1.56-1.42(m,2H).

[0204] Building Blocks: Step i: 2-Chloro-5-(trifluoromethoxy)pyridine.

[0205] Example 25: 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] i) To a suspension of piperidin-4-one (1.0 g) and triethylamine (4.2 mL) in CHCl (20 mL) was added [1,1′-biphenyl]-4-sulfonyl chloride (2.8 g) in portions at room temperature. The reaction mixture was stirred at room temperature overnight and quenched by the addition of water. The product was extracted into ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The resulting brown oil was dissolved in a small amount of ethyl acetate, and heptane was added. The product was allowed to precipitate overnight, and the solid was filtered and dried under reduced pressure to give 1-{[1,1′-biphenyl]-4-sulfonyl}piperidin-4-one (1.41 g) as a white solid.

[0206] ii) Under a nitrogen atmosphere, 2-methylpyridine borane complex (17 mg) was added to a solution of the product obtained in the previous step (50 mg), 4-(trifluoromethoxy)aniline (21 μL), and trifluoroacetic acid (0.2 mL) in methanol (2 mL) at 0°C. The reaction mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, 2N aqueous HCl (3 mL) was added at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was basified by adding 6N aqueous NaOH (5 mL), and the product was extracted into CHCl. ​​The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 90% CHCN in water as the eluent to give the title compound 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine (28 mg) as a white solid. MS(ES + ) m / z 477.1(M+H) + .

[0207] 1 H NMR(400MHz,DMSO)δ8.00-7.93(m,2H),7.87-7.80(m,2H),7.80-7.75(m,2H),7.58-7.51(m,2H),7.50-7.44(m,1H),7.03-6.96(m,2H),6 .62-6.54(m,2H),5.78(d,J=8.1Hz,1H),3.63-3.56(m,2H),3.31-3.19(m,1H),2.61-2.54(m,2H),2.00-1.93(m,2H),1.49-1.35(m,2H).

[0208] Following a procedure similar to that described for Example 25, using the appropriate aniline in step ii, Examples 26-30 were prepared.

[0209] Example 26: 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(difluoromethoxy)phenyl]piperidin-4-amine. [ka] MS(ES + ) m / z 514.3(M+H) + . 1 H NMR(400MHz,DMSO)δ8.03-7.93(m,2H),7.86-7.80(m,2H),7.80-7.75(m,2H) ,7.58-7.51(m,2H),7.50-7.44(m,1H),7.11-6.71(t,J=75.3Hz,1H),6.90-6. 84(m,2H),6.61-6.51(m,2H),5.58-5.51(d,J=8.2Hz,1H),3.65-3.55(m,2H) ,3.33-3.17(m,1H),2.63-2.52(m,2H),2.01-1.91(m,2H),1.48-1.34(m,2H).

[0210] Building Block: Step ii: 4-(Difluoromethoxy)aniline.

[0211] Example 27: N-[4-(difluoromethoxy)phenyl]-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine. [ka] i) To a suspension of piperidin-4-one (10.0 g) and triethylamine (27 mL) in CHCl (200 mL) at room temperature, 4-bromobenzene-1-sulfonyl chloride (16.6 g) was added portionwise. The reaction mixture was stirred at room temperature over the weekend and quenched by the addition of water. The product was extracted into CHCl, and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The resulting brown oil was dissolved in a small amount of ethyl acetate, and heptane was added. The product was allowed to precipitate overnight, and the solid was filtered and dried under reduced pressure to give 1-(4-bromobenzenesulfonyl)piperidin-4-one (15.1 g) as an off-white solid, which was used in the next step without further purification.

[0212] ii) Under a nitrogen atmosphere, 2-methylpyridine borane complex (168 mg) was added to a solution of the product obtained in the previous step (500 mg), 4-(difluoromethoxy)aniline (300 mg), and trifluoroacetic acid (1.5 mL) in methanol (15 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, 2N aqueous HCl (5 mL) was added at 0 °C, and the resulting mixture was stirred at room temperature for 0.5 hours. The mixture was basified by the addition of 6N aqueous NaOH (10 mL), and the product was extracted into CHCl. ​​The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give 1-(4-bromobenzenesulfonyl)-N-[4-(difluoromethoxy)phenyl]piperidin-4-amine (766 mg) as a brown solid, which was used in the next step without further purification.

[0213] iii) Under a nitrogen atmosphere, to a suspension of the product obtained in the previous step (100 mg), (3-methyl-1H-indazol-5-yl)boronic acid (55 mg), and NaHCO (105 mg) in a mixture of 1,4-dioxane (4 mL) and water (1 mL) was added Pd(PPh) (12 mg). The reaction mixture was stirred in a microwave at 110 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO, filtered, and concentrated under reduced pressure. The resulting brown oil was purified on a C18 column using 10% to 90% acetonitrile in water as the eluent to give the title compound N-[4-(difluoromethoxy)phenyl]-2-methyl-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine (25 mg) as a white solid. MS (ES) + ) m / z 513.2(M+H) + .

[0214] 1H NMR(400MHz,DMSO)δ12.81-12.76(s,1H),8.16-8.10(dd,J=1.8,0.8Hz,1H),8.06-7.98(m,2H),7. 86-7.78(m,2H),7.78-7.71(dd,J=8.8,1.7Hz,1H),7.63-7.56(dd,J=8.6,0.8Hz,1H),7.11-6.70(t ,J=75.3Hz,1H),6.89-6.83(m,2H),6.60-6.51(m,2H),5.58-5.51(d,J=8.2Hz,1H),3.65-3.55(m,2 H),3.31-3.17(m,1H),2.58-2.56(s,3H),2.60-2.52(m,2H),2.01-1.92(m,2H),1.49-1.34(m,2H).

[0215] Following a similar procedure as described for Example 27, using the appropriate aniline in step ii and the appropriate boronic ester or boronic acid in step iii, Examples 28-30 were prepared.

[0216] Examples 28 to 30 Example 28: 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one. [ka] MS(ES + ) m / z 514.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.71-8.66(s,1H),8.10-7.95(m,5H),7.89-7.81(m,2H),7 .78-7.71(d,J=8.5Hz,1H),7.11-6.70(t,J=75.3Hz,1H),6.89-6.84(m,2H),6.6 0-6.50(m,2H),5.58-5.51(d,J=8.2Hz,1H),4.49-4.44(s,2H),3.64-3.57(m,2 H),3.29-3.21(m,1H),2.62-2.51(m,2H),2.00-1.92(m,2H),1.48-1.34(m,2H).

[0217] Building blocks: step ii: 4-(difluoromethoxy)aniline; step iii: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one.

[0218] Example 29: 5-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile. [ka] MS(ES + ) m / z 523.3(M+H) + . 1 H NMR(400MHz,DMSO)δ13.22-11.37(s,1H),8.38-8.31(s,1H),8.07-8.01(m,2H),8.01 -7.98(t,J=1.3Hz,1H),7.87-7.78(m,2H),7.78-7.65(m,2H),7.11-6.71(t,J=75.3H z,1H),6.89-6.84(m,2H),6.60-6.51(m,2H),5.58-5.51(d,J=8.1Hz,1H),3.65-3.55 (m,2H),3.30-3.17(m,1H),2.59-2.53(m,2H),2.01-1.92(m,2H),1.49-1.34(m,2H).

[0219] Building blocks: step ii: 4-(difluoromethoxy)aniline; step iii: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile.

[0220] Example 30: 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine. [ka] MS(ES + ) m / z 533.3(M+H) + . 1 H NMR(400MHz,DMSO)δ9.11(t,J=1.5,1.5Hz,1H),8.04-8.00(m,3H),7.95-7.82(m,2H),7.73(d,J=9.4Hz,1H),7.71-7.66(m,2H),7.35-7.27(m, 2H),6.68-6.57(m,2H),6.32(d,J=7.9Hz,1H),3.66-3.58(m,2H),3.38 -3.35(m,1H),2.62-2.54(m,2H),2.02-1.93(m,2H),1.52-1.38(m,2H).

[0221] Building blocks: step ii: 4-[(trifluoromethyl)sulfanyl]aniline; step iii: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.

[0222] Example 31: 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethyl)sulfanyl]phenyl]piperidin-4-amine. [ka] i) Following a procedure similar to that described in Example 27, step ii, 4-[(trifluoromethyl)sulfanyl]aniline (97 mg), 1-(4-bromobenzenesulfonyl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine (2.58 g) was prepared as a white solid.

[0223] ii) To a suspension of the product from the previous step (200 mg), bis(pinacolato)diboron (110 mg), and potassium acetate (97 mg) in N2-purged cyclopentyl methyl ether (2 mL) was added PdCl2(dppf).CHCl2 (19 mg). The reaction mixture was heated in a microwave at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water, and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine as a brown oil (290 mg), which was used in the next step without further purification.

[0224] iii) Under a nitrogen atmosphere, to a solution of the product obtained in the previous step (290 mg), 6-bromo-3-(propan-2-yl)-[1,2,4]triazolo[1,2-a]pyridine hydrochloride (41 mg), and NaHCO (73 mg) in a mixture of 1,4-dioxane (4 mL) and water (1 mL) was added Pd(PPh) (17 mg). The reaction mixture was stirred in a microwave at 100 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 20% ​​to 50% acetonitrile in water as the eluent to give the title compound 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine (5 mg) as a white solid. MS (ES)+ ) m / z 575.3(M+H) + .

[0225] 1 H NMR(400MHz,DMSO)δ8.74-8.69(m,1H),8.13-8.05(m,2H),7.90-7.82(m,2H),7.70(dd,J=9.4,0. 9Hz,1H),7.63(dd,J=9.5,1.9Hz,1H),7.47(d,J=0.8Hz,1H),7.35-7.27(m,2H),6.68-6.59(m,2H) ),6.32(d,J=7.8Hz,1H),3.66-3.59(m,2H),3.52(hept,J=6.8,6.8,6.8,6.8,6.8,6.8Hz,1H),3. 39-3.33(m,1H),2.62-2.52(m,2H),2.01-1.94(m,2H),1.53-1.44(m,2H),1.37(d,J=6.8Hz,6H).

[0226] Following a procedure similar to that described in Example 31, using the appropriate aniline in step i and the appropriate (hetero)aryl halide in step iii, Examples 32-34 were prepared.

[0227] Example 32: 1-(4-{3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] MS(ES + ) m / z 586.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.84(t,J=1.5,1.5Hz,1H),8.14-8.06(m,2H),7.92-7.82(m,3H), 7.77(dd,J=9.6,1.7Hz,1H),7.04-6.97(m,2H),6.62-6.54(m,2H),5.79(d,J=8.0Hz,1H ),3.81(p,J=7.9,7.9,7.9,7.9Hz,1H),3.65-3.57(m,2H),3.28-3.23(m,1H),2.62-2. 53(m,2H),2.29-2.16(m,2H),2.03-1.90(m,4H),1.88-1.67(m,4H),1.50-1.36(m,2H).

[0228] Building blocks: step i: 4-(trifluoromethoxy)aniline; step iii: 6-bromo-3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridine.

[0229] Example 33: 1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine. [ka] MS(ES + ) m / z 589.3(M+H) +

[0230] Building blocks: step i: 4-[(trifluoromethyl)sulfanyl]aniline; step iii: 6-bromo-8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0231] Example 34: 4-(4-{[4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide. [ka] MS(ES + ) m / z 537.4(M+H) +

[0232] Building blocks: step i: 4-[(trifluoromethyl)sulfanyl]aniline; step iii: 64-bromopyridine-2-carboxamide.

[0233] Example 35: 1-{[1,1'-biphenyl]-4-sulfonyl}-2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine. [ka] i) Under a nitrogen atmosphere, 2-methylpyridine borane complex (17 mg) was added to a suspension of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (500 mg), 4-(trifluoromethoxy)aniline (21 μL), and trifluoroacetic acid (1 mL) in methanol (10 mL) at 0° C. The reaction mixture was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, 2N aqueous HCl (3 mL) was added at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. The mixture was basified by the addition of 6N aqueous NaOH (5 mL), and the product was extracted into CHCl. ​​The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The residue was purified on SiO2 using 0% to 100% ethyl acetate in heptane as eluent to afford tert-butyl 2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidine-1-carboxylate (694 mg) as a white solid.

[0234] ii) To a solution of the product obtained in the previous step (694 mg), a 4N solution of HCl in 2-propanol was added at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to give 2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine hydrochloride (836 mg), which was used in the next step without further purification.

[0235] iii) To a suspension of the product obtained in the previous step (100 mg) and triethylamine (105 μL) in CHCl (5 mL) was added a solution of [1,1′-biphenyl]-4-sulfonyl chloride (70 mg) in CHCl (5 mL) in portions at room temperature. The reaction mixture was stirred overnight at room temperature and quenched by the addition of water. The product was extracted into CHCl, and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 90% CHCN in water as the eluent to give the title compound 1-{[1,1′-biphenyl]-4-sulfonyl}-2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine (1.41 g) as a white solid. MS (ES) + ) m / z 491.2 (M+H) + .

[0236] 1 H NMR(400MHz,DMSO)δ7.99-7.86(m,4H),7.80-7.72(m,2H),7.56-7.49(m,2H),7.48-7.42 (m,1H),7.00-6.95(d,J=8.8Hz,2H),6.56-6.46(m,2H),5.81-5.74(d,J=7.4Hz,1H),3.83 -3.68(m,1H),3.54-3.41(m,1H),3.29-3.12(m,2H),1.96-1.86(ddt,J=12.8,9.0,4.6Hz ,1H),1.83-1.75(dt,J=14.1,4.1Hz,0H),1.51-1.39(m,2H),1.29-1.22(d,J=6.6Hz,3H).

[0237] Example 36: 4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile. [ka] i) To a suspension of 2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine hydrochloride (Example 35, Step ii, 700 mg) and triethylamine (736 μL) in CHCl (40 mL) was added 4-bromobenzene-1-sulfonyl chloride (495 mg) in portions. The reaction mixture was stirred at room temperature overnight and quenched by the addition of water. The product was extracted into CHCl, and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 90% CHCN in water as the eluent to afford the title compound 1-(4-bromobenzenesulfonyl)-2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine (385 mg) as a white solid.

[0238] ii) Under a nitrogen atmosphere, 2N aqueous NaHCO3 (1.2 mL) was added to a suspension of the product obtained in the previous step (128 mg), (4-cyanophenyl)boronic acid (37 mg), and Pd(PPh3)4 (13 mg) in a mixture of toluene (9 mL) and ethanol (1 mL). The reaction mixture was stirred in a microwave at 100 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting brown oil was purified on a C182 column using 10% to 90% acetonitrile in water as the eluent to give the title compound 4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile (53 mg) as a white solid. MS(ES + ) m / z 516.3(M+H) + .

[0239] 1H NMR(400MHz,DMSO)δ8.09-7.90(m,8H),7.00-6.95(d,J=8.4Hz,3H),6.55-6.47( m,2H),5.82-5.73(d,J=7.4Hz,1H),3.80-3.69(ddd,J=12.5,8.0,3.9Hz,1H),3. 55-3.45(m,1H),3.27-3.16(m,2H),1.96-1.85(ddt,J=12.8,8.9,4.8Hz,1H),1. 83-1.73(dt,J=13.4,4.2Hz,1H),1.53-1.38(m,2H),1.28-1.22(d,J=6.6Hz,3H).

[0240] Following a similar procedure as described for Example 36, using the appropriate boronic ester or boronic acid in step ii, Examples 37-38 were prepared.

[0241] Examples 37-38 Example 37: 6-{4-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one. [ka] MS(ES + ) m / z 546.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.70-8.65(s,1H),8.07-7.98(m,4H),7.98-7.89(m,2H),7.77-7.69(m,1H), 7.01-6.93(d,J=8.3Hz,2H),6.63-6.47(m,2H),5.81-5.74(d,J=7.5Hz,1H),4.48-4.43(s,2H),3. 80-3.68(ddd,J=12.5,7.9,3.9Hz,1H),3.53-3.41(m,1H),3.30-3.14(m,2H),1.97-1.86(td,J=8. 7,4.4Hz,1H),1.85-1.74(dt,J=13.5,4.3Hz,1H),1.52-1.40(m,2H),1.29-1.23(d,J=6.6Hz,3H).

[0242] Building Block: Step ii: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one.

[0243] Example 38: N-methyl-4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide. [ka] MS(ES + ) m / z 548.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.65-8.57(m,1H),8.24-8.19(t,J=1.8Hz,1H),8.03-7.98(m,2H),7.96-7.89(m,4H),7.66 -7.58(t,J=7.8Hz,1H),7.01-6.95(d,J=8.3Hz,2H),6.55-6.48(m,2H),5.80-5.76(d,J=7.6Hz,1H),3.78-3.69 (ddd,J=12.6,8.1,4.0Hz,1H),3.53-3.45(m,1H),3.28-3.17(m,2H),2.89-2.80(d,J=4.5Hz,3H),1.96-1.86(d dt,J=12.7,8.8,4.8Hz,1H),1.83-1.73(dt,J=13.9,4.6Hz,1H),1.53-1.41(m,2H),1.29-1.23(d,J=6.6Hz,3H).

[0244] Building Block: Step ii: [3-(methylcarbamoyl)phenyl]boronic acid.

[0245] Example 39: 4'-{[trans-4-{[4-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile. [ka] i) To a solution of tert-butyl N-[(1s,4s)-4-hydroxycyclohexyl]carbamate (50.0 g) and triethylamine (42 mL) in CHCl (200 mL) was added dropwise a solution of methanesulfonyl chloride (23 mL) in CHCl (200 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by pouring into saturated aqueous NaHCO. The product was extracted into ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give tert-butyl N-[(1s,4s)-4-(methanesulfonyloxy)cyclohexyl]carbamate as an off-white solid (69.3 g), which was used in the next step without further purification.

[0246] ii) To a suspension of the product obtained in the previous step (68.1 g) and Cs2CO3 (189.1 g) in acetone (600 mL) was added 4-bromothiophenol (79.0 g) at room temperature. The reaction mixture was stirred at 60 °C overnight. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a water / ethyl acetate mixture, and the product was extracted into ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The resulting brown oil was crystallized from acetonitrile to give a white solid. The solid was washed with cold heptane to give tert-butyl N-[trans-4-[(4-bromophenyl)sulfanyl]cyclohexyl]carbamate (38.0 g) as a white solid.

[0247] iii) To a solution of the product obtained in the previous step (2.8 g) in ethyl acetate (6 mL) was added mCPBA (3.1 g), and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water, and the product was extracted into ethyl acetate. The combined organic layers were washed with 1N aqueous NaOH, dried over MgSO, filtered, and concentrated under reduced pressure. The resulting white solid was purified on SiO using 0% to 100% ethyl acetate in heptane as the eluent to give tert-butyl N-[trans-4-(4-bromobenzenesulfonyl)cyclohexyl]carbamate (1.7 g) as a white solid.

[0248] iv) Under a nitrogen atmosphere, (PPh3)4 (14 mg) was added to a solution of the product obtained in the previous step (0.5 g), (4-cyanophenyl)boronic acid (176 mg), and 2N aqueous K2CO3 solution (6 mL) in a mixture of toluene (13 mL) and ethanol (1.5 mL). The reaction mixture was stirred in a microwave oven at 90 °C for 1 hour. After cooling to room temperature, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give tert-butyl N-[trans-4-({4'-cyano-[1,1'-biphenyl]-4-yl}sulfonyl)cyclohexyl]carbamate (0.5 g) as a brown solid, which was used in the next step without further purification.

[0249] v) To a solution of the product obtained in the previous step (500 mg) in ethyl acetate (15 mL) was added 2N aqueous HCl (5.7 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was concentrated under reduced pressure to give 4'-{[trans-4-aminocyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile hydrochloride (500 mg) as a yellow solid, which was used in the next step without further purification.

[0250] vi) Under a nitrogen atmosphere, Pd2(dba)3 (9 mg) was added to a suspension of the product obtained in the previous step (60 mg), 1-bromo-4-(trifluoromethoxy)benzene (46 mg), sodium tert-butoxide (38 mg), and xantphos (11 mg) in toluene (15 mL). The reaction mixture was stirred overnight at 120 °C in a microwave. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting brown oil was purified on a C18 column using 10% to 90% acetonitrile in water as the eluent to give the title compound 4'-{[trans-4-{[4-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile (21 mg) as a white solid. MS (ES) + ) m / z 501.0(M+H) + .

[0251] 1 H NMR(500MHz,CDCl3)δ8.05-7.99(m,2H),7.84-7.79(m,4H),7.77-7.73(m,2H),7.05-7.00(m,2H),6.54-6.48(m,2H),3.55-3.44(s,1H),3.26-3. 17(m,1H),3.06-2.95(tt,J=12.3,3.5Hz,1H),2.34-2.19(m,4H),1.75- 1.63(qd,J=13.2,3.4Hz,2H),1.23-1.09(tdd,J=13.2,11.1,3.3Hz,2H).

[0252] Following a similar procedure as described for Example 39, using the appropriate boronic ester or boronic acid in step iv, Examples 40-43 were prepared.

[0253] Examples 40 to 43 Example 40: 4'-{[trans-4-{[3-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile. [ka] MS(ES + ) m / z 502.0(M+H) + .

[0254] Building blocks: step iv: (4-cyanophenyl)boronic acid; step vi: 1-bromo-3-(trifluoromethoxy)benzene.

[0255] Example 41: N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline. [ka] MS(ES + ) m / z 530.3(M+H) +. 1 H NMR(400MHz,DMSO)δ8.75(s,1H),8.15-8.08(m,2H),8.00-7.94(m,2H),7.75(s,2H),7.54(s,1H),7.00(d,J=8.5Hz,2H),6.63-6.55(m, 2H),5.73(d,J=8.0Hz,1H),3.38-3.34(m,1H),3.17-3.13(m,1H),2.57(s,3H),2.09-1.94(m,4H),1.61-1.47(m,2H),1.26-1.10(m,2H).

[0256] Building blocks: step iv: {3-methylimidazo[1,2-a]pyridin-6-yl}boronic acid; step vi: 1-iodo-4-(trifluoromethoxy)benzene.

[0257] Example 42: N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 502.0(M+H) + . 1 H NMR(400MHz,DMSO)δ8.71-8.66(m,1H),8.14-8.06(m,2H),7.99-7.92(m,3H),7.68( dd,J=9.4,1.0Hz,1H),7.63(dd,J=9.4,1.7Hz,1H),7.43(d,J=1.0Hz,1H),7.42-7.37 (m,1H),6.80(d,J=7.4Hz,1H),6.49(dd,J=9.1,0.7Hz,1H),3.59-3.54(m,1H),3.37 -3.33(m,1H),2.55(s,3H),2.10-1.97(m,4H),1.52-1.39(m,2H),1.29-1.16(m,2H).

[0258] Building blocks: step iv: {3-methylimidazo[1,2-a]pyridin-6-yl}boronic acid; step vi: 2-chloro-5-(trifluoromethoxy)pyridine.

[0259] Example 43: N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline. [ka] MS(ES + ) m / z 516.3(M+H) + . 1H NMR(400MHz,DMSO)δ9.11(dd,J=1.8,1.1Hz,1H),8.06-8.02(m,2H),8.01(s,1H),7 .99-7.94(m,2H),7.72(d,J=9.4Hz,1H),7.68(dd,J=9.5,1.8Hz,1H),7.66(d,J=1. 2Hz,1H),7.04-6.97(m,2H),6.64-6.55(m,2H),5.73(d,J=8.0Hz,1H),3.42-3.37( m,1H),3.19-3.12(m,1H),2.10-1.95(m,4H),1.61-1.48(m,2H),1.26-1.10(m,2H).

[0260] Building Blocks: Step iv: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine; Step vi: 1-iodo-4-(trifluoromethoxy)benzene

[0261] Example 44: 5-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile. [ka] i) A solution of methanesulfonyl chloride (1.3 mL) in CHCl (10 mL) was added dropwise to a solution of 4-hydroxycyclohexanone monoethylene ketal (2.0 g) and triethylamine (2.3 mL) in CHCl (15 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was quenched by pouring into saturated aqueous NaHCO. The layers were separated, and the aqueous layer was washed with CHCl. ​​The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The resulting yellow oil was dissolved in heptane, the precipitated solid was filtered, and the filtrate was concentrated under reduced pressure to give 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (3.3 g) as an oil that slowly solidified. The product was used in the next step without further purification.

[0262] ii) 4-Bromobenzene-1-thiol (2.64 g) was added to a suspension of the product obtained in the previous step (3.3 g) and cesium carbonate (5.46 g) in acetone (50 mL). The reaction mixture was stirred at 60 °C overnight. After cooling to room temperature, the reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting oil was purified on SiO using 0% to 60% ethyl acetate in heptane as the eluent to give 8-[(4-bromophenyl)sulfanyl]-1,4-dioxaspiro[4.5]decane (3.68 g) as a white solid.

[0263] iii) 3-Chloroperbenzoic acid (9.64 g) was added to a solution of the product obtained in the previous step (3.68 g) in ethyl acetate (50 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with saturated NaHCO3 solution, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on SiO2 using 0% to 100% ethyl acetate in heptane as the eluent to give 8-(4-bromobenzenesulfonyl)-1,4-dioxaspiro[4.5]decane (3.68 g) as a white solid.

[0264] iv) To a solution of the product obtained in the previous step (3.5 g) in THF (50 mL) was added 2N aqueous HCl (39 mL) at room temperature, and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give 4-(4-bromobenzenesulfonyl)cyclohexan-1-one (3.0 g) as a white solid, which was used in the next step without further purification.

[0265] v) To a suspension of the product obtained in the previous step (505 mg) and 4-[(trifluoromethyl)sulfanyl]aniline (390 mg) in a mixture of HOAc (1 mL) in CHOH (11 mL) was added 2-methylpyridine borane complex (180 mg) at 0 °C. After removing the ice bath, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 2 N aqueous HCl (5 mL) was added at 0 °C. After stirring at 0 °C for 1 h, 5 N aqueous NaOH (5 mL) was added, and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified on SiO using 0% to 50% ethyl acetate in heptane as the eluent to give N-[trans-4-(4-bromobenzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline (532 mg) as a white solid.

[0266] vi) Under a nitrogen atmosphere, to a solution of the product obtained in the previous step (530 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile (360 mg), and NaHCO (462 mg) in a mixture of 1,4-dioxane (8 mL) and ethanol (2 mL) was added Pd(PPh) (66 mg). The reaction mixture was stirred in a microwave at 120 °C for 1 hour. After cooling to room temperature, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified on SiO2 using 0% to 80% ethyl acetate in heptane as eluent to give the title compound 5-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile (248 mg) as a white solid. MS (ES) + ) m / z 556.3(M+H) + .

[0267] 1H NMR(400MHz,DMSO)δ12.37(s,1H),8.35(s,1H),8.09-8.03(m,2H),8.01(t,J=1.2,1.2Hz,1H),7.95-7.89(m,2H),7.75-7.66(m,2H),7.35-7.27( m,2H),6.69-6.61(m,2H),6.27(d,J=7.7Hz,1H),3.40-3.34(m,1H),3.2 8-3.15(m,1H),2.09-1.95(m,4H),1.63-1.48(m,2H),1.27-1.13(m,2H).

[0268] Following a similar procedure as described for Example 44, using the appropriate aniline in step v and the appropriate boronic ester or boronic acid in step vi, Examples 45-46 were prepared.

[0269] Example 45: N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline. [ka] MS(ES + ) m / z 532.3(M+H) + . 1 H NMR(400MHz,DMSO)δ9.11(s,1H),8.06-8.02(m,2H),8.01(s,1H),7.99-7.94(m ,2H),7.72(d,J=9.4Hz,1H),7.68(dd,J=9.4,1.8Hz,1H),7.66(d,J=1.2Hz,1H) ,7.35-7.28(m,2H),6.69-6.61(m,2H),6.27(d,J=7.8Hz,1H),3.41-3.34(m,1H ),3.27-3.18(m,1H),2.10-1.95(m,4H),1.65-1.46(m,2H),1.30-1.11(m,2H).

[0270] Building Blocks: Step v: 4-[(trifluoromethyl)sulfanyl]aniline Step vi: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.

[0271] Example 46: N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline. [ka] MS(ES + ) m / z 532.3(M+H) + . 1 H NMR(400MHz,DMSO)δ9.14-9.08(m,1H),8.06-8.02(m,2H),8.01(s,1H),8.01-7.93(m,2H),7.75-7.63(m,3H),7.17(dd,J=8.3,7.6Hz,1H),6.86( s,1H),6.82-6.72(m,2H),5.94(d,J=7.9Hz,1H),3.40-3.34(m,1H),3.2 6-3.17(m,1H),2.08-1.94(m,4H),1.63-1.50(m,2H),1.26-1.12(m,2H).

[0272] Building blocks: Step v: 3-[(trifluoromethyl)sulfanyl]aniline Step vi: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.

[0273] Example 47: 5N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline. [ka] i) Following a procedure similar to that described in Example 44, step ii, 3-[(trifluoromethyl)sulfanyl]aniline, N-[trans-4-(4-bromobenzenesulfonyl)cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline, was prepared as a white solid.

[0274] ii) To a suspension of the product from the previous step (150 mg), bis(pinacolato)diboron (152 mg), and potassium acetate (103 mg) in N2-purged cyclopentyl methyl ether (2 mL) was added PdCl2(dppf).CHCl2 (11 mg). The reaction mixture was heated in a microwave at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water, and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give N-[trans-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline as a brown oil (295 mg), which was used in the next step without further purification.

[0275] iii) Under a nitrogen atmosphere, to a solution of the product obtained in the previous step (295 mg), 6-bromo-3-(propan-2-yl)-[1,2,4]triazolo[1,2-a]pyridine (143 mg), and NaHCO (228 mg) in a mixture of 1,4-dioxane (6 mL) and water (1.5 mL) was added Pd(PPh) (31 mg). The reaction mixture was stirred in a microwave at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 20% ​​to 50% acetonitrile in water as the eluent to give the title compound N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline (112 mg) as a white solid. MS (ES)+ ) m / z 574.3(M+H) + .

[0276] 1 H NMR(400MHz,DMSO)δ8.73(s,1H),8.14-8.06(m,2H),8.00-7.91(m,2H),7.69(dd,J=9.4,1.0H z,1H),7.63(dd,J=9.4,1.8Hz,1H),7.46(s,1H),7.19-7.13(m,1H),6.86(s,1H),6.83-6.72(m ,2H),5.94(d,J=7.9Hz,1H),3.51(h,J=6.8,6.8,6.8,6.8,6.8Hz,1H),3.40-3.34(m,1H),3.29 -3.17(m,1H),2.07-1.95(m,4H),1.64-1.50(m,2H),1.36(d,J=6.8Hz,6H),1.26-1.10(m,2H).

[0277] Following a similar procedure as described for Example 47, using the appropriate aniline in step i and the appropriate (hetero)aryl halide in step iii, Examples 48-50 were prepared.

[0278] Example 48: N-[trans-4-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline. [ka] MS(ES + ) m / z 588.3(M+H) + 1H NMR(400MHz,DMSO)δ8.59(s,1H),8.13-8.05(m,2H),7.99-7.91(m,2H),7.49(t,J=1.5,1.5Hz,1 H),7.41(s,1H),7.35-7.27(m,2H),6.69-6.61(m,2H),6.28(d,J=7.8Hz,1H),3.49(hept,J=6.7, 6.7,6.7,6.7,6.6,6.6Hz,1H),3.41-3.34(m,1H),3.23(dd,J=7.6,3.7Hz,0H),2.57(s,3H),2.02 (t,J=16.0,16.0Hz,4H),1.63-1.48(m,2H),1.36(d,J=6.8Hz,6H),1.21(dd,J=21.9,9.2Hz,3H).

[0279] Building blocks: step i: 4-[(trifluoromethyl)sulfanyl]aniline step iii: 6-bromo-8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0280] Example 49: 4-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)pyridine-2-carboxamide. [ka] MS(ES + ) m / z 536.3(M+H) + 1 H NMR(400MHz,DMSO)δ8.78(dd,J=5.1,0.8Hz,1H),8.38(dd,J=1.9,0.8Hz,1H),8 .23(d,J=2.6Hz,1H),8.20-8.13(m,2H),8.06-7.98(m,3H),7.77(d,J=2.6Hz,1H ),7.35-7.27(m,2H),6.69-6.61(m,2H),6.27(d,J=7.8Hz,1H),3.45-3.34(m,1 H),3.26-3.18(m,1H),2.08-1.95(m,4H),1.62-1.49(m,2H),1.27-1.14(m,2H).

[0281] Building Blocks: Step i: 4-[(trifluoromethyl)sulfanyl]aniline Step iii: 4-Bromopyridine-2-carboxamide

[0282] Example 50: 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one. [ka] MS(ES + ) m / z 549.3(M+H) + . 1 H NMR(400MHz,DMSO)δ12.61(s,1H),8.25(t,J=1.5,1.5Hz,1H),8.09-8.02(m,2H) ,7.96-7.88(m,2H),7.67(dd,J=9.8,1.8Hz,1H),7.39(dd,J=9.8,1.1Hz,1H),7.3 6-7.28(m,2H),6.69-6.61(m,2H),6.27(d,J=7.8Hz,1H),3.38(s,1H),3.22(dt, J=8.1,3.9,3.9Hz,1H),2.09-1.94(m,4H),1.63-1.46(m,2H),1.29-1.11(m,2H).

[0283] Building blocks: step i: 4-[(trifluoromethyl)sulfanyl]aniline step iii: 6-bromo-2-[(4-methoxyphenyl)methyl]-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one.

[0284] Example 51: {4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl}[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone. [ka] i) To a suspension of 8-[(4-bromophenyl)sulfanyl]-1,4-dioxaspiro[4.5]decane (Example 44, step ii (5 g)) and ammonium carbamate (1.8 g) in a mixture of methanol (10 mL) and acetonitrile (10 mL) at room temperature was added (diacetoxyiodo)benzene (10.2 g). The reaction mixture was stirred at room temperature in an open flask for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. At this stage, the cis / trans mixture was separated at C18 using 10% to 100% acetonitrile in water to give (4-bromophenyl)({1,4-dioxaspiro[4.5]decan-8-yl})(imino)-λ 6 -Sulfanilon (5.3g) was obtained.

[0285] ii) To a solution of the product obtained in the previous step (5.3 g) in THF (100 mL) was added 2N aqueous HCl (110 mL) and the reaction mixture was stirred at room temperature overnight. After completion, the organic solvent was removed under reduced pressure and the remaining aqueous layer was washed with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 4-[(4-bromophenyl)oxo-λ]. 6 -sulfanyl]cyclohexan-1-one was obtained as a yellowish oil (4.6 g) which was used in the next step without further purification.

[0286] iii) To a solution of the product obtained in the previous step (1.0 g), 4-[(trifluoromethyl)sulfanyl]aniline (794 mg), and HOAc (1 mL) in methanol (20 mL) was added 2-methylpyridine borane complex (440 mg) at 0 °C. The reaction mixture was stirred overnight at room temperature. Upon completion, the reaction mixture was cooled to 0 °C, followed by the addition of 2 N aqueous HCl (3 mL). After stirring at 0 °C for 1 h, 5 N aqueous NaOH (6.6 mL) was added. The product was extracted into EtOAc, and the combined organic layers were washed with water, brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified on SiO using 0% to 95% ethyl acetate in heptane as the eluent to give (4-bromophenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -sulfanone (400 mg) was obtained as a white solid.

[0287] iv) To a suspension of the product obtained in the previous step (300 mg), bis(pinacolato)diboron (206 mg), and potassium acetate (133 mg) in cyclopentyl methyl ether (15 mL) purged with N2 gas, PdCl2(dppf).CHCl2 (22 mg) was added. The reaction mixture was heated in a microwave at 110 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give [trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl][4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl](imino)-λ 6 -sulfanone was obtained as a brown oil (384 mg) which was used in the next step without further purification.

[0288] v) Under a nitrogen atmosphere, to a solution of the product obtained in the previous step (192 mg), 6-bromo-3-(propan-2-yl)-[1,2,4]triazolo[1,2-a]pyridine (93 mg), and NaHCO (90 mg) in a mixture of 1,4-dioxane (10 mL) and water (4 mL) was added Pd(PPh) (13 mg). The reaction mixture was stirred in a microwave at 110 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 50% acetonitrile in water as the eluent to give the title compound {4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl}[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -sulfanone (40 mg) was obtained as a white solid. MS (ES + ) m / z 573.4(M+H) + .

[0289] 1 H NMR(400MHz,DMSO)δ8.70(s,1H),8.08-8.00(m,2H),7.99-7.92(m,2H),7.69(dd,J=9.4,0 .9Hz,1H),7.62(dd,J=9.4,1.8Hz,1H),7.46(d,J=0.7Hz,1H),7.34-7.26(m,2H),6.67-6.5 9(m,2H),6.25(d,J=7.7Hz,1H),4.26(s,1H),3.52(p,J=6.8,6.8,6.8,6.8Hz,1H),3.21-3. 05(m,2H),2.10-1.96(m,4H),1.60-1.42(m,2H),1.36(d,J=6.8Hz,6H),1.26-1.11(m,2H).

[0290] Example 52: (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone. [ka] i) Under a nitrogen atmosphere, Pd(PPh3)4 (21 mg) was dissolved in a mixture of 1,4-dioxane (10 mL) and water (3 mL) to prepare (4-bromophenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -sulfanone (Example 51, step iii (100 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (48 mg) and NaHCO3 (45 mg) were added to a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (48 mg) and NaHCO3 (45 mg). The reaction mixture was stirred in a microwave at 110 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and the product was extracted into ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 50% acetonitrile in water as eluent to give the title compound (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -sulfanone (26 mg) was obtained as a white solid. MS (ES + ) m / z 531.3(M+H) + .

[0291] 1 H NMR(400MHz,DMSO)δ9.09(s,1H),8.01(s,1H),8.00-7.93(m,4H),7.71(d,J=9.4Hz,1H),7.69-7.63(m,2H),7.35-7.27(m,2H),6. 67-6.59(m,2H),6.25(d,J=7.8Hz,1H),4.27(s,1H),3.20-3.05(m,2H),2.11-1.96(m,4H),1.59-1.41(m,2H),1.26-1.11(m,2H).

[0292] Example 53: 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonimidoyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one. [ka] i) Following a procedure similar to that described for Example 51, step v, 6-bromo-2-[(4-methoxyphenyl)methyl]-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (130 mg) was used to prepare 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]oxo-λ 6 -sulfanyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (91 mg) was prepared as a white solid.

[0293] ii) A solution of the product obtained in the previous step (91 mg) and L-cysteine ​​(21 mg) in trifluoroacetic acid (2.6 mL) was stirred overnight at 70 °C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified on a C18 column using 0% to 10% acetonitrile in water as the eluent to give the title compound 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]oxo-λ 6 (-sulfanyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (28 mg) was obtained as a white solid. MS (ES + ) m / z 548.3(M+H) + .

[0294] 1H NMR(400MHz,DMSO)δ12.60(s,1H),8.21(t,J=1.5,1.5Hz,1H),8.03-7.95(m, 2H),7.95-7.88(m,2H),7.67(dd,J=9.9,1.8Hz,1H),7.39(dd,J=9.9,1.1Hz,1 H),7.35-7.26(m,2H),6.67-6.59(m,2H),6.25(d,J=7.7Hz,1H),4.26(s,1H) ,3.19-3.04(m,2H),2.06-1.94(m,4H),1.57-1.40(m,2H),1.26-1.14(m,2H).

[0295] Example 54: (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclohexyl](imino)-λ 6 -Sulfanone. [ka] i) Under a nitrogen atmosphere, Pd(PPh) (299 mg) was added to a suspension of tert-butyl N-[trans-4-[(4-bromophenyl)sulfanyl]cyclohexyl]carbamate (Example 39, Step ii) (2.0 g), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (1.64 g), and NaHCO (2.61 g) in a mixture of 1,4-dioxane (12 mL) and water (3 mL). The reaction mixture was stirred in a microwave at 120 °C for 2 hours. After cooling to room temperature, the product was extracted into EtOAc, and the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting brown solid was purified on a C18 column using 10% to 100% acetonitrile in water as the eluent to give tert-butyl N-[trans-4-[(4-{imidazo[1,2-a]pyridin-6-yl}phenyl)sulfanyl]cyclohexyl]carbamate as a white solid (2.0 g).

[0296] ii) To a solution of the product obtained in the previous step (2.0 g) in ethyl acetate (50 mL) was added a 5N HCl solution in 2-propanol (9.44 mL), and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was concentrated under reduced pressure to give trans-4-[(4-{imidazo[1,2-a]pyridin-6-yl}phenyl)sulfanyl]cyclohexan-1-amine hydrochloride as a yellow oil (1.9 g), which was used in the next step without further purification.

[0297] iii) Under a nitrogen atmosphere, Pd2(dba)3 (76 mg) was added to a suspension of the product obtained in the previous step (300 mg), 2-chloro-5-(trifluoromethoxy)pyridine (165 mg), t-BuONa (481 mg), and Xantphos (121 mg) in toluene (5 mL). The reaction mixture was stirred overnight at 100 °C in a microwave. After cooling to room temperature, the reaction mixture was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 100% CH3CN in water as the eluent to give the title compound N-[trans-4-[(4-{imidazo[1,2-a]pyridin-6-yl}phenyl)sulfanyl]cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine (90 mg) as a white solid.

[0298] iv) To a suspension of the product obtained in the previous step (90 mg) and ammonium carbamate (22 mg) in methanol (5 mL) at room temperature was added (diacetoxyiodo)benzene (126 mg). The reaction mixture was stirred at room temperature in an open flask for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The resulting brown solid was purified on a C18 column using 10% to 90% acetonitrile in water as the eluent to give the title compound (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclohexyl](imino)-λ 6 -sulfanone (22 mg) was obtained as a white solid. MS (ES) + ) m / z 516.3(M+H) + .

[0299] 1 H NMR(400MHz,DMSO)δ9.09(dd,J=1.8,1.1Hz,1H),8.00(s,1H),7.98-7.94(m,5H),7.73-7.63(m,3H),7.43-7.35(m,1H),6.77(d,J=7.5Hz) ,1H),6.48(d,J=9.4Hz,1H),4.27(s,1H),3.57-3.49(m,1H),3.12-3.08(m,1H),2.05-1.99(m,4H),1.52-1.33(m,2H),1.27-1.12(m,2H)

[0300] Following a procedure similar to that described for Example 13, using the appropriate (hetero)aryl halides in step i and step iii, Examples 55-71 were prepared.

[0301] Examples 55 to 71 Example 55: N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 574.4(M+H) + . 1H NMR(400MHz,DMSO)δ8.61-8.55(m,1H),8.10-8.03(m,2H),7.98-7.92(d,J=2.9Hz,1H),7.89-7.8 1(m,2H),7.51-7.45(s,1H),7.45-7.38(m,2H),6.91-6.84(d,J=7.2Hz,1H),6.54-6.46(d,J=9.2H z,1H),3.73-3.62(m,1H),3.62-3.54(m,2H),3.54-3.42(dt,J=13.5,6.8Hz,1H),2.63-2.58(m,2H ),2.58-2.56(s,3H),2.02-1.93(m,2H),1.59-1.43(m,2H),1.38-1.36(s,3H),1.36-1.33(s,3H).

[0302] Building blocks: step i: 2-chloro-5-(trifluoromethoxy)pyridine; step iii: 6-bromo-8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0303] Example 56: N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 561.4(M+H) + . 1H NMR(400MHz,DMSO)δ8.87-8.82(t,J=1.3Hz,1H),8.14-8.05(m,2H),7.96-7.91(d,J=2.9Hz,1H),7.9 1-7.85(m,3H),7.80-7.75(m,1H),7.45-7.37(ddd,J=9.1,2.9,1.1Hz,1H),6.89-6.83(d,J=7.2Hz,1 H),6.54-6.47(d,J=9.2Hz,1H),3.78-3.70(dt,J=13.8,6.9Hz,1H),3.70-3.63(m,1H),3.63-3.54(m ,2H),2.64-2.54(m,2H),2.02-1.92(m,2H),1.57-1.47(m,2H),1.45-1.43(s,3H),1.43-1.41(s,3H).

[0304] Building blocks: step i: 2-chloro-5-(trifluoromethoxy)pyridine; step iii: 6-bromo-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine.

[0305] Example 57: N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 575.4(M+H) + . 1H NMR(400MHz,DMSO)δ8.75-8.68(t,J=1.3Hz,1H),8.15-8.05(m,2H),7.97-7.92(d,J=2.9Hz,1H),7 .92-7.84(m,2H),7.64-7.59(t,J=1.4Hz,1H),7.45-7.38(m,1H),6.90-6.84(d,J=7.2Hz,1H),6.5 5-6.47(d,J=9.1Hz,1H),3.76-3.68(m,1H),3.67-3.62(m,1H),3.62-3.54(m,2H),2.62-2.59(s,3 H),2.59-2.54(m,2H),2.02-1.93(m,2H),1.56-1.46(m,2H),1.45-1.43(s,3H),1.43-1.39(s,3H).

[0306] Building blocks: step i: 2-chloro-5-(trifluoromethoxy)pyridine; step iii: 6-bromo-8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine.

[0307] Example 58: 4-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}pyridine-2-carboxamide. [ka] MS(ES + ) m / z 522.3(M+H) + .

[0308] 1H NMR(400MHz,DMSO)δ8.80-8.75(dd,J=5.1,0.8Hz,1H),8.40-8.36(dd,J=2.1,0.8Hz,1H),8.26-8.20(d,J=2.8H z,1H),8.18-8.10(m,2H),8.05-7.99(dd,J=5.2,2.0Hz,1H),7.97-7.93(d,J=2.9Hz,1H),7.93-7.88(m,2H),7.8 0-7.75(d,J=2.8Hz,1H),7.44-7.38(dtd,J=9.1,1.9,1.0Hz,1H),6.89-6.84(d,J=7.3Hz,1H),6.52-6.47(dd,J= 9.2,0.7Hz,1H),3.75-3.63(m,1H),3.62-3.52(m,2H),2.67-2.59(m,2H),2.01-1.91(m,2H),1.55-1.42(m,2H).

[0309] Building blocks: step i: 2-chloro-5-(trifluoromethoxy)pyridine; step iii: 4-bromopyridine-2-carboxamide.

[0310] Example 59: N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 562.4(M+H) + . 1H NMR(400MHz,DMSO)δ9.55-9.49(d,J=1.6Hz,1H),9.26-9.20(d,J=1.7Hz,1H),8.50-8.38(m,2H), 7.95-7.93(d,J=2.9Hz,1H),7.93-7.88(m,2H),7.44-7.38(m,1H),6.87-6.82(d,J=7.2Hz,1H),6 .53-6.46(d,J=9.2Hz,1H),3.85-3.73(hept,J=6.9Hz,1H),3.73-3.62(m,1H),3.62-3.53(m,2H) ,2.66-2.57(m,2H),2.02-1.91(m,2H),1.55-1.49(m,2H),1.49-1.46(s,3H),1.46-1.43(s,3H).

[0311] Building blocks: step i: 2-chloro-5-(trifluoromethoxy)pyridine; step iii: 6-chloro-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine.

[0312] Example 60: N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 562.4(M+H) + . 1H NMR(400MHz,DMSO)δ8.81-8.76(t,J=1.4Hz,1H),8.15-8.07(m,2H),7.98-7.93(d,J=2.8Hz,1 H),7.91-7.87(m,2H),7.86-7.84(d,J=1.0Hz,1H),7.81-7.76(m,1H),7.44-7.39(ddd,J=9.1, 3.0,1.2Hz,1H),6.88-6.85(d,J=7.2Hz,1H),6.53-6.48(d,J=9.2Hz,1H),3.74-3.62(m,1H),3 .62-3.54(m,2H),2.80-2.77(s,3H),2.64-2.56(m,2H),2.05-1.92(m,2H),1.59-1.42(m,2H).

[0313] Building blocks: step i: 2-chloro-5-(trifluoromethoxy)pyridine; step iii: 6-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine.

[0314] Example 61: N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine. [ka] MS(ES + ) m / z 590.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.61-8.55(s,1H),8.17-8.11(d,J=2.4Hz,1H),8.10-8.04(m,2H),7.88-7.81(m,2H),7.61- 7.55(dd,J=8.8,2.4Hz,1H),7.49-7.46(t,J=1.4Hz,1H),7.43-7.39(d,J=0.8Hz,1H),7.36-7.30(d,J=7.2Hz,1H ),6.57-6.51(dd,J=8.8,0.8Hz,1H),3.82-3.70(m,1H),3.65-3.55(m,2H),3.54-3.45(dt,J=13.6,6.8Hz,1H),2 .64-2.58(m,2H),2.58-2.56(s,3H),2.02-1.94(m,2H),1.60-1.45(m,2H),1.38-1.36(s,3H),1.36-1.33(s,3H).

[0315] Building blocks: step i: 2-chloro-5-[(trifluoromethyl)sulfanyl]pyridine; step iii: 6-bromo-8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0316] Example 62: N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine. [ka] MS(ES + ) m / z 534.3(M+H) + . 1H NMR(400MHz,DMSO)δ9.14-9.07(dd,J=1.8,1.1Hz,1H),8.17-8.11(d,J=2.4Hz,1H),8. 04-7.98(m,3H),7.90-7.84(m,2H),7.74-7.70(m,1H),7.70-7.65(m,2H),7.60-7.56(d d,J=8.8,2.5Hz,1H),7.34-7.27(d,J=7.3Hz,1H),6.57-6.51(d,J=9.0Hz,1H),3.84-3. 70(m,1H),3.65-3.55(m,2H),2.67-2.56(m,2H),2.03-1.93(m,2H),1.57-1.46(m,2H).

[0317] Building blocks: step i: 2-chloro-5-[(trifluoromethyl)sulfanyl]pyridine; step iii: 6-bromoimidazo[1,2-a]pyridine.

[0318] Example 63: 4-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide. [ka] MS(ES + ) m / z 538.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.82-8.75(dd,J=5.2,0.8Hz,1H),8.41-8.32(dd,J=1.8,0.8Hz,1H),8.28-8.20( d,J=2.7Hz,1H),8.20-8.10(m,3H),8.06-7.98(dd,J=5.2,1.9Hz,1H),7.96-7.88(m,2H),7.82-7.75( d,J=2.8Hz,1H),7.62-7.55(dd,J=8.9,2.5Hz,1H),7.43-7.32(d,J=7.4Hz,1H),6.57-6.53(d,J=8.8H z,1H),3.86-3.71(m,1H),3.67-3.54(m,2H),2.66-2.59(m,2H),1.99-1.93(m,2H),1.57-1.44(m,2H).

[0319] Building blocks: step i: 2-chloro-5-[(trifluoromethyl)sulfanyl]pyridine; step iii: 4-bromopyridine-2-carboxamide.

[0320] Example 64: N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine. [ka] MS(ES + ) m / z 576.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.77-8.69(t,J=1.4Hz,1H),8.18-8.11(d,J=2.4Hz,1H),8.11-8.05(m,2H),7.91-7.83( m,2H),7.74-7.67(m,1H),7.66-7.61(m,1H),7.61-7.54(dd,J=8.9,2.4Hz,1H),7.47-7.46(s,1H),7.34-7.3 0(d,J=7.2Hz,1H),6.58-6.52(d,J=8.9Hz,1H),3.82-3.70(m,1H),3.66-3.56(m,2H),3.56-3.47(dt,J=13.6 ,6.8Hz,1H),2.65-2.55(m,2H),2.02-1.94(m,2H),1.62-1.45(m,2H),1.39-1.36(s,3H),1.36-1.34(s,3H).

[0321] Building blocks: step i: 2-chloro-5-[(trifluoromethyl)sulfanyl]pyridine; step iii: 6-bromo-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0322] Example 65: N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine. [ka] MS(ES + ) m / z 577.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.88-8.83(t,J=1.4Hz,1H),8.17-8.13(d,J=2.4Hz,1H),8.13-8.06(m,2H) ,7.91-7.84(m,3H),7.80-7.75(m,1H),7.62-7.55(dd,J=8.9,2.5Hz,1H),7.35-7.28(d,J=7.2H z,1H),6.57-6.50(dd,J=8.8,0.8Hz,1H),3.81-3.69(dt,J=13.7,6.8Hz,2H),3.64-3.56(m,2H) ,2.65-2.56(m,2H),2.02-1.93(m,2H),1.59-1.45(m,2H),1.45-1.43(s,3H),1.43-1.41(s,3H).

[0323] Building blocks: step i: 2-chloro-5-[(trifluoromethyl)sulfanyl]pyridine; step iii: 6-bromo-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine.

[0324] Example 66: N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine. [ka] MS(ES + ) m / z 578.3(M+H) + . 1H NMR(400MHz,DMSO)δ9.56-9.48(d,J=1.5Hz,1H),9.26-9.20(d,J=1.7Hz,1H),8.48-8.39(m, 2H),8.17-8.10(d,J=2.4Hz,1H),7.96-7.88(m,2H),7.63-7.53(dd,J=8.9,2.5Hz,1H),7.37- 7.25(d,J=7.3Hz,1H),6.55-6.52(d,J=8.9Hz,1H),3.85-3.69(m,2H),3.64-3.54(m,2H),2. 66-2.56(m,2H),2.01-1.92(m,2H),1.58-1.49(m,2H),1.48-1.46(s,3H),1.46-1.45(s,3H).

[0325] Building blocks: step i: 2-chloro-5-[(trifluoromethyl)sulfanyl]pyridine; step iii: 6-chloro-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine.

[0326] Example 67: N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine. [ka] MS(ES + ) m / z 549.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.79-8.76(t,J=1.4Hz,1H),8.15-8.13(d,J=2.4Hz,1H),8.12-8 .08(m,2H),7.91-7.87(m,2H),7.86-7.84(d,J=1.0Hz,1H),7.80-7.76(m,1H),7.61-7 .56(dd,J=8.9,2.5Hz,1H),7.33-7.29(d,J=7.2Hz,1H),3.81-3.68(m,1H),3.64-3.5 5(m,2H),2.84-2.75(s,3H),2.66-2.55(m,2H),2.03-1.93(m,2H),1.61-1.43(m,2H).

[0327] Building blocks: step i: 2-chloro-5-[(trifluoromethyl)sulfanyl]pyridine; step iii: 6-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine.

[0328] Example 68: N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine. [ka] MS(ES + ) m / z 591.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.74-8.68(s,1H),8.17-8.12(d,J=2.4Hz,1H),8.12-8.04(m,2 H),7.91-7.85(m,2H),7.62-7.55(m,2H),7.34-7.28(d,J=7.2Hz,1H),6.57-6.50(d ,J=8.9Hz,1H),3.82-3.65(m,2H),3.65-3.55(m,2H),2.61-2.60(s,3H),2.60-2.54 (m,2H),2.03-1.93(m,2H),1.59-1.46(m,2H),1.45-1.43(s,3H),1.43-1.40(s,3H).

[0329] Building blocks: step i: 2-chloro-5-[(trifluoromethyl)sulfanyl]pyridine; step iii: 6-bromo-8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine.

[0330] Example 69: N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 574.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.60-8.54(s,1H),8.09-8.02(m,2H),8.02-7.97(d,J=5.8Hz,1H),7.88-7.82(m,2H), 7.51-7.43(t,J=1.5Hz,1H),7.43-7.39(s,1H),6.98-6.91(d,J=7.3Hz,1H),6.43-6.39(m,1H),6.38-6.31 (s,1H),3.78-3.65(m,1H),3.62-3.53(m,J=11.7,4.1Hz,2H),3.53-3.43(dt,J=13.5,6.8Hz,1H),2.64-2. 58(m,2H),2.58-2.55(s,3H),2.00-1.94(m,2H),1.57-1.44(m,2H),1.38-1.36(s,3H),1.36-1.33(s,3H).

[0331] Building blocks: step i: 2-chloro-4-(trifluoromethoxy)pyridine; step iii: 6-bromo-8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0332] Example 70: N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 561.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.87-8.82(t,J=1.4Hz,1H),8.12-8.07(m,2H),8.01-7.97(d,J=5. 8Hz,1H),7.91-7.85(m,3H),7.80-7.74(m,1H),6.98-6.88(d,J=7.3Hz,1H),6.44-6.40( m,1H),6.37-6.32(s,1H),3.81-3.66(m,2H),3.63-3.52(dt,J=12.5,4.1Hz,2H),2.66-2 .56(m,2H),2.03-1.93(m,2H),1.56-1.47(m,2H),1.45-1.43(s,3H),1.43-1.41(s,3H).

[0333] Building blocks: step i: 2-chloro-4-(trifluoromethoxy)pyridine; step iii: 6-bromo-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine.

[0334] Example 71: N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 575.3(M+H) + . 1H NMR(400MHz,DMSO)δ8.74-8.68(dd,J=1.4,0.8Hz,1H),8.13-8.05(m,2H),8.03-7.97(d,J=5.8Hz ,1H),7.92-7.83(m,2H),7.63-7.58(t,J=1.4Hz,1H),6.98-6.90(d,J=7.2Hz,1H),6.46-6.39(m, 1H),6.38-6.32(s,1H),3.78-3.65(dt,J=13.7,6.9Hz,2H),3.64-3.54(m,2H),2.61-2.60(s,3H) ,2.60-2.55(m,2H),2.03-1.92(m,2H),1.58-1.45(m,2H),1.45-1.43(s,3H),1.43-1.41(s,3H).

[0335] Building blocks: step i: 2-chloro-4-(trifluoromethoxy)pyridine; step iii: 6-bromo-8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine.

[0336] Following a similar procedure as described for Example 47, using the appropriate aniline in step i and the appropriate boronic ester or boronic acid in step iii, Example 72 was prepared.

[0337] Example 72: N-[trans-4-(4-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline. [ka] MS(ES + ) m / z 547.3(M+H) + . 1H NMR(400MHz,DMSO)δ13.51-13.31(s,1H),8.97-8.90(d,J=2.2Hz,1H),8.68-8. 63(d,J=2.2Hz,1H),8.16-8.07(m,2H),8.02-7.93(m,2H),7.36-7.29(m,2H),6. 70-6.60(m,2H),6.33-6.24(d,J=7.7Hz,1H),3.42-3.35(m,1H),3.29-3.17(m,1 H),2.61-2.56(s,3H),2.07-1.95(m,4H),1.64-1.49(m,2H),1.32-1.14(m,2H).

[0338] Building blocks: step i: 4-[(trifluoromethyl)sulfanyl]aniline; step iii: 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine.

[0339] Following a similar procedure as described for Example 39, using the appropriate boronic ester or boronic acid in step iv and the appropriate (hetero)aryl halide in step vi, Example 73 was prepared.

[0340] Example 73: N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine. [ka] MS(ES + ) m / z 517.3(M+H) + . 1H NMR(400MHz,DMSO)δ9.16-9.11(t,J=1.5Hz,1H),8.06-8.00(m,3H),7.99-7.94(m,3H),7.74-7.70(m,1H),7.70-7.66(m,1H) ,7.66-7.65(d,J=1.2Hz,1H),3.63-3.49(m,1H),3.40-3.34(m,1H),2.11-1.96(m,4H),1.58-1.37(m,2H),1.32-1.15(m,2H).

[0341] Building blocks: step iv: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine; step vi: 2-chloro-5-(trifluoromethoxy)pyridine.

[0342] Following a procedure similar to that described for Example 23, using the appropriate aryl halide in Example 3, step i, Example 74 was prepared.

[0343] Example 74: 6-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one. [ka] MS(ES + ) m / z 535.3(M+H) + . 1H NMR(400MHz,DMSO)δ12.72-12.46(s,1H),8.25-8.19(t,J=1.4Hz,1H),8.17-8.11(d,J=2.4Hz,1H) ,8.05-7.97(m,2H),7.86-7.78(m,2H),7.70-7.62(dd,J=9.9,1.8Hz,1H),7.62-7.53(dd,J=8.8,2. 5Hz,1H),7.43-7.35(dd,J=9.8,1.1Hz,1H),7.34-7.28(d,J=7.2Hz,1H),6.57-6.49(d,J=8.9Hz,1 H),3.82-3.69(m,1H),3.64-3.52(m,2H),2.65-2.56(m,2H),2.02-1.92(m,2H),1.61-1.42(m,2H).

[0344] Building Blocks: Step i: 2-Chloro-5-[(trifluoromethyl)sulfanyl]pyridine.

[0345] Human CCR6-CRE reporter assay 293FT cells were transfected with two constructs using TransIT-293 (Mirus). The first construct (pGL4.29, Promega) expressed the luciferase reporter gene luc2P in response to cAMP-induced CREB binding to the CRE element in its promoter. The second construct contained the human CCR6 open reading frame in a pUNO1 backbone under the control of an enhanced CMV promoter (InVivoGen). 48 h posttransfection, cells were harvested and diluted to 750,000 cells / ml in culture medium (DMEM, 10% FBS, 1x PEN / Strep (Gibco 15140)). Compounds were serially diluted 2.5-fold in DMSO. Further dilutions were made in assay medium (DMEM, 10% FBS, 1x PEN / Strep, 6 μM Forskolin, 6 nM CCL20). Four microliters of compound solution was added to a white MW384 plate, followed by 20 μl of cell suspension. The final DMSO concentration in the assay was 0.1%. The MW384 plate was placed in an incubator at 37°C and 5% CO2 for 5 hours. Luciferase activity was determined by adding 24 μl of a 2.5-fold diluted BriteLite luciferase solution (Perkin Elmer) and then measuring luminescence using a VICTOR plate reader (Perkin Elmer). To deselect compounds that did not specifically bind to CCR6, an assay was also performed using transfected 293FT cells in which CCR6 was replaced with an empty vector using the same backbone. Relative LogIC50 values ​​were determined using GraphPad Prism 9 using a four-parameter dose-response model.

[0346] CHO-K1 CCR6 chemotaxis assay against CCL20 Cells overexpressing human CCR6 were used in the chemotaxis assay (DiscoverX, cAMP Hunter™ CHO-K1 CCR6 Gi cell line). The growth medium for these cells consisted of DMEM / F12, non-essential amino acids (1x NEAA, Gibco 11140050), 10% FBS, and 1x penicillin / streptomycin (Gibco 15140). For the chemotaxis assay, Corning Transwell plates with 8 μm pore size were used (Corning 351164). Cells were harvested using trypsin and diluted to 4x10^6 cells / ml in chemotaxis medium (DMEM, 0.25% BSA, penicillin / streptomycin). Compounds were serially diluted 4-fold in DMSO. Further dilutions were performed in chemotaxis medium. Cells were incubated with the test compounds at 37°C for 30 minutes before the assay was initiated (2x10^6 cells / ml). The final DMSO concentration in the assay was 0.2%. Transwell plate wells were filled with 200 μl of chemotaxis medium containing 100 ng / ml CCL20 (R&D systems 360-MP). 50 μl of cell / compound suspension was added to the Transwell plate insert (100,000 cells / insert). The Transwell plate was placed in a 37°C, 5% CO2 incubator for 4 hours. After 4 hours, the number of migrated cells was quantified using CellTiter Glo (Promega). Percentage inhibition values ​​were calculated based on the low and high signals obtained for 0.2% DMSO in chemotaxis medium without and with CCL20, respectively. Relative LogIC50 values ​​were determined using GraphPad Prism 9 using a four-parameter dose-response model.

[0347] CD4+ T cell chemotaxis assay for CCL20 Human CD4+ T cells were isolated from buffy coats of healthy donors using a CD4+ T cell isolation kit (Miltenyi Biotec 130-096-533). Isolated T cells were stimulated overnight with anti-CD3 and anti-CD28 antibodies (Biolegend 300314 / 302934) in growth medium (RPMI 1640, 10% heat-inactivated FBS, 1x penicillin / streptomycin (Gibco 15140)). For chemotaxis assays, Corning Transwell plates with 5 μm pores were used (Corning 3388). T cells were counted and diluted to 6 x 10^6 cells / ml in chemotaxis medium (RPMI 1640, 1% BSA, penicillin / streptomycin). Compounds were serially diluted 4-fold in DMSO. Further dilutions were performed in chemotaxis medium. Cells were incubated with test compounds for 30 minutes at 37°C before the assay was initiated (3 x 10^6 cells / ml). The final DMSO concentration in the assay was 0.2%. Transwell plate wells were filled with 200 μl of chemotaxis medium containing 150 ng / ml CCL20 (R&D systems 360-MP). 50 μl of cell / compound suspension was added to the Transwell plate insert (150,000 cells / insert). The Transwell plate was placed in a 37°C, 5% CO2 incubator for 3 hours. After 3 hours, the number of migrated cells was quantified using CellTiter Glo (Promega). Percentage inhibition values ​​were calculated based on the low and high signals obtained for 0.2% DMSO in chemotaxis medium without and with CCL20, respectively. Relative LogIC50 values ​​were determined using GraphPad Prism 9 using a four-parameter dose-response model.

[0348] The table below shows data for selected compounds. [Table 1] TIFF2026504498000227.tif242169 [Table 2] [Table 3] [Table 4] (A) refers to compound 10 by TAWARAISHI TAISUKE ET AL. “Identification of a novel series of potent and selective CCR6 inhibitors as biological probes”, BIOORGANIC&MEDICINAL CHEMISTRY LETTERS,ELSEVIER,AMSTERDAM NL, vol.28,no.18,30 July 2018(2018-07-30),pages 3067-3072,XP085456366, ISSN:0960-894X,DOI:10.1016 / J.BMCL.2018.07.042

[0349] Aspects Aspect 1. Compounds of Formula (I) [ka] (In the formula, X 1 is CH or N, X 2 is CH or N, X 3 is CH or N, X 4 is O or NH, X 5 is CH or N, R 1 is aryl, heterocyclyl, or heteroaryl, and aryl, heterocyclyl, and heteroaryl are each independently selected from the group consisting of one or more R 1a may be substituted with R 1a is C1~6 Alkyl, oxo, cyano, carbamoyl, C 1~6 Alkylcarbamoyl-, C 1~6 Alkoxy C 1~6 Alkyl-, C 3~6 cycloalkyl, or heterocyclyl; R 2 is hydrogen or halogen, R 3 is hydrogen or halogen, R 4 is hydrogen, halogen or C 1~6 is alkyl, R 5 is hydrogen, halogen or C 1~6 is alkyl, R 6 -OR 6a , -SR 6b or hydrogen, R 6a is C 1~6 is haloalkyl, R 6b is C 1~6 is haloalkyl, R 7 -OR 7a , -SR 7b or hydrogen, R 7a is C 1~6 is haloalkyl, R 7b is C 1~6 is haloalkyl, However, R 6 and R 7 must be different, R 6 or R 7 is hydrogen), and pharmaceutically acceptable salts thereof.

[0350] Aspect 2. X 2 is CH, X 3 is CH, R 2 is hydrogen, R 3 is hydrogen, R4 is hydrogen, R 5 is hydrogen or C 1~6 The compound according to embodiment 1, wherein the aryl group is alkyl.

[0351] Aspect 3.X 1 The compound according to any one of aspects 1 to 2, wherein

[0352] Aspect 4.X 1 is N.

[0353] Aspect 5.X 4 The compound according to any one of aspects 1 to 4, wherein is O.

[0354] Aspect 6.X 4 A compound according to any one of aspects 1 to 4, wherein is NH.

[0355] Aspect 7.X 5 A compound according to any one of aspects 1 to 6, wherein is CH.

[0356] Aspect 8.X 5 The compound of any one of aspects 1 to 6, wherein is N.

[0357] Aspect 9.R 1 is imidazopyridinyl, triazolopyridinyl, phenyl, indolyl, isoindolinyl or indazolyl, and imidazopyridinyl, triazolopyridinyl, phenyl, indolyl, isoindolinyl and indazolyl are each independently selected from the group consisting of one or more R 1a A compound according to any one of aspects 1 to 8, optionally substituted with

[0358] Aspect 10.R 1 is indazolyl, indolyl, indazolyl, imidazopyridinyl or triazolopyridinyl, and indazolyl, indolyl, indazolyl, imidazopyridinyl and triazolopyridinyl are each independently selected from the group consisting of one or more R 1a A compound according to any one of aspects 1 to 9, optionally substituted with

[0359] Aspect 11.R 1 is indazolyl, indolyl, indazolyl, imidazopyridinyl, or triazolopyridinyl, wherein indazolyl, indolyl, indazolyl, imidazopyridinyl, and triazolopyridinyl are optionally substituted with one or more cyano, methyl, oxo, isopropyl, or cyclopentyl.

[0360] Aspect 12.R 1 is isopropylimidazopyridinyl, oxo-triazolopyridinyl, imidazopyridinyl, cyanophenyl, methylimidazopyridinyl, cyano-indolyl, oxoisoindolinyl, carbamoylphenyl, (methylcarbamoyl)phenyl, methyl-indazolyl, phenyl, cyano-indazolyl, cyanoimidazopyridinyl, methyl-triazolopyridinyl, (methoxymethyl)-triazolopyridinyl, or cyclopentyl-triazolopyridinyl.

[0361] Aspect 13.R 1(3-isopropylimidazo[1,2-a]pyridin-6-yl), (3-oxo-2H-[1,2,4]triazolo[4,3-a]pyridin-6-yl), imidazo[1,2-a]pyridin-6-yl, (4-cyanophenyl), (3-methylimidazo[1,2-a]pyridin-6-yl), (3-cyano-1H-indol-5-yl), (3-isopropyl-8-methyl-imidazo[1,2-a]pyridin-6-yl), (2-carbamoyl-4-pyridyl), (3-oxoisoindolin-5-yl), (3-carbamoylphenyl), [3-(methylcarbamoyl)phenyl] , (3-methyl-lH-indazol-5-yl), phenyl, (3-cyano-lH-indazol-5-yl), (3-cyanoimidazo[l,2-a]pyridin-6-yl), (2-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl), (2-methyl-[l,2,4]triazolo[l,5-a]pyridin-7-yl), [3-(methoxymethyl)-[l,2,4]triazolo[4,3-a]pyridin-6-yl], or (3-cyclopentyl-[l,2,4]triazolo[4,3-a]pyridin-6-yl).

[0362] Aspect 14.R 1 13. The compound according to any one of aspects 1 to 9 and 12, wherein is cyano-indazolyl, cyano-indolyl, methyl-indazolyl, oxo-triazolopyridinyl, isopropylimidazopyrrolidinyl, or cyclopentyl-triazolopyridinyl.

[0363] Aspect 15.R 1 is (3-cyano-1H-indol-5-yl), (3-methyl-1H-indazol-5-yl), (3-cyano-1H-indazol-5-yl), (3-oxo-2H-[1,2,4]triazolo[4,3-a]pyridin-6-yl), (3-isopropylimidazo[1,2-a]pyridin-6-yl), or cyclopentyl-triazolopyridinyl.

[0364] Aspect 16.R1a 16. The compound according to any one of aspects 1 to 15, wherein is isopropyl, methyl, oxo, cyano, carbamoyl, methylcarbamoyl, or methoxymethyl.

[0365] Aspect 17.R 1a Aspect 17. The compound of any one of aspects 1 to 16, wherein is cyano, methyl, oxo, isopropyl, or cyclopentyl.

[0366] Aspect 18.R 6 A compound according to any one of aspects 1 to 17, wherein is -SCF3, -OCF3, -OCHF2, or hydrogen.

[0367] Aspect 19.R 6 is —SCF3 or —OCF3.

[0368] Aspect 20.R 6a A compound according to any one of aspects 1 to 19, wherein is —CF 3 or —CHF 2 .

[0369] Aspect 21.R 6b Aspect 21. The compound of any one of aspects 1-20, wherein is —CF 3 .

[0370] Aspect 22.R 7 22. The compound of any one of aspects 1 to 21, wherein is —OCF 3 , —SCF 3 , —OCHF 2 , or hydrogen.

[0371] Aspect 23.R 7 Aspect 23. The compound of any one of aspects 1-22, wherein is hydrogen.

[0372] Aspect 24.R 7a A compound according to any one of aspects 1 to 23, wherein is —CF 3 or —CHF 2 .

[0373] Aspect 25.R 7b A compound according to any one of aspects 1 to 23, wherein is —CF 3 .

[0374] Aspect 26.R 5 Aspect 26. The compound according to any one of aspects 1 to 25, wherein is hydrogen or methyl.

[0375] Aspect 27.R 1 is indazolyl, indolyl, indazolyl, imidazopyridinyl or triazolopyridinyl, wherein the indazolyl, indolyl, indazolyl, imidazopyridinyl and triazolopyridinyl are optionally substituted with one or more of cyano, methyl, oxo, isopropyl, or cyclopentyl; R 6 is -SCF3 or -OCF3, and R 2 , R 3 , R 4 , R 5 , R 7 , X 1 , X 2 , X 3 , X 4 and X 5 27. The compound according to any one of embodiments 1 to 26, wherein:

[0376] Aspect 28. The compound is a compound of formula (I') [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 2 , X 3 , X 4 and X 5 is as defined in any one of aspects 1 to 27, and X 1 The compound according to any one of aspects 1 to 27, wherein is CH.

[0377] Aspect 29. The compound is a compound of formula (I") [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , X 1 and X 5 is as described in any one of aspects 1 to 27, and R 6 A compound according to any one of embodiments 1 to 27, wherein

[0378] Aspect 30. {4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl}[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonimidoyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclohexyl](imino)-λ 6 -Sulfanone; 4'-{[trans-4-{[4-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine; 5-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; 4-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 5-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; N-methyl-4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indazole-3-carbonitrile; 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{[1,1'-biphenyl]-4-sulfonyl}-2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; N-methyl-4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; N-[4-(difluoromethoxy)phenyl]-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 6-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 5-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(difluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}imidazo[1,2-a]pyridine-3-carbonitrile; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-{4-[3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-(4-{3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 4-(4-{[4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[trans-4-{[3-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; 6-{4-[(4-{[3-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; or 4'-[(4-{[3-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile 30. The compound according to any one of aspects 1 to 29, selected from:

[0379] Aspect 31. {4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl}[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonimidoyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ6 -Sulfanone; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclohexyl](imino)-λ 6 -Sulfanone; 4'-{[trans-4-{[4-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine; 5-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; 4-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 5-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; N-methyl-4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indazole-3-carbonitrile; 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{[1,1'-biphenyl]-4-sulfonyl}-2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; N-methyl-4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; N-[4-(difluoromethoxy)phenyl]-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 6-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 5-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 1-{[1,1'-biphenyl]-4-sulfonyl}-N-[4-(difluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}imidazo[1,2-a]pyridine-3-carbonitrile; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-{4-[3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-(4-{3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 4-(4-{[4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[trans-4-{[3-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; 6-{4-[(4-{[3-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[3-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; 4-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}pyridine-2-carboxamide; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; 4-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine; N-[trans-4-(4-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine; or 6-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one 31. The compound according to any one of aspects 1 to 30, selected from:

[0380] Aspect 32. 5-[4-[4-[4-(trifluoromethylsulfanyl)anilino]cyclohexyl]sulfonylphenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indazole-3-carbonitrile; 6-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-[4-(3-isopropylimidazo[1,2-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; or 1-[4-(3-Cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine or a pharmaceutically acceptable salt thereof.

[0381] Aspect 33. 5-[4-[4-[4-(trifluoromethylsulfanyl)anilino]cyclohexyl]sulfonylphenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indazole-3-carbonitrile; 6-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-[4-(3-isopropylimidazo[1,2-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-[4-(3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; or 6-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one 33. The compound according to any one of aspects 1 to 32, selected from:

[0382] Aspect 34. A method for preparing a compound of formula (I) or (I') according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, comprising: 1 is N and X 4 is O, A compound of formula (II) 5 and R 4 is as defined in any one of aspects 1 to 33), [ka] A compound of formula (III) 2 , X 3 , R 2 and R 3 is as defined in any one of aspects 1 to 33, [ka] A compound of formula (IV) 3 , R 2 , R 4 , R 5 , X 2 and X 3is as defined in any one of aspects 1 to 33; and [ka] The compound (IV) is reacted with a compound of formula (V) 1 is as defined in any one of aspects 1 to 33, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (VI) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (VI) is reacted with an acid to form a compound of formula (VII), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (VII) is reacted with a compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined in any one of aspects 1 to 33, [ka] forming a compound of formula (I).

[0383] Aspect 35. A method for preparing a compound of formula (I) or (I') according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, comprising: 1 is N and X 4 is O, A compound of formula (IX) 5 and R 4 is as defined in any one of aspects 1 to 33), [ka] A compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined in any one of embodiments 1 to 33), [ka] A compound of formula (X) 4 , R 6 , R 7 , X 5 and R 5 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (X) is reacted with an acid to form a compound of formula (XI), 4 , R 6 , R 7 , X 5 and R 5 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XI) is reacted with a compound of formula (III) 2 , X 3 , R 2 and R 3 is as defined in any one of embodiments 1 to 33), [ka] A compound of formula (XII) 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XII) is reacted with a compound of formula (V) 1 is as defined in any one of aspects 1 to 33, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0384] Aspect 36. A method for preparing a compound of formula (I) or (I') according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, comprising: 1 is N and X 4 is O, A compound of formula (XVIII) 5 and R 4 is as defined in any one of aspects 1 to 33), [ka] A compound of formula (XVII) 1 , R 2 , R 3 , X 2 and X 3 is as defined in any one of aspects 1 to 33, [ka] A compound of formula (XX) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XX) is reacted with a compound of formula (XVI) 5 , R 6 and R 7is as defined in any one of embodiments 1 to 33), [ka] forming a compound of formula (I) or A compound of formula (XVIII) 5 and R 4 is as defined in any one of aspects 1 to 33), [ka] A compound of formula (III) 2 , X 3 , R 2 and R 3 is as defined in any one of aspects 1 to 33, [ka] A compound of formula (XIX) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XIX) is reacted with the compound of formula (XVI) to form a compound of formula (XII), 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XII) is reacted with a compound of formula (V) 1 is as defined in any one of aspects 1 to 33, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0385] Aspect 37. A method for preparing a compound of formula (I) or (I') according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, comprising: 1 is C and X 4 is O, A compound of formula (XXI) 4 and R 5 is as defined in any one of aspects 1 to 33), [ka] and mesyl chloride to give a compound of formula (XXII), 4 and R 5 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXII) is converted into a compound of formula (XXIII) (wherein R2 , R 3 , X 2 and X 3 is as defined in any one of embodiments 1 to 33), [ka] A compound of formula (XXIV) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXIV) is reacted with an oxidizing agent to produce a compound of formula (XXV), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXV) is reacted with a compound of formula (V) (wherein R 1 is as defined in any one of aspects 1 to 33, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (XXVI) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXVI) is reacted with an acid to give a compound of formula (XXVII), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXVII) is reacted with a compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X 5 is as defined in any one of embodiments 1 to 33), [ka] forming a compound of formula (I).

[0386] Aspect 38. A method for preparing a compound of formula (I) or (I') according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, comprising: 1 is C and X 4 is O, A compound of formula (XXV) 2 , R 3 , R4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33), [ka] with an acid to give a compound of formula (XXVIII), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXVIII) is reacted with a compound of formula (VIII) (wherein R 8 is a halogen and R 6 , R 7 and X 5 is as defined in any one of embodiments 1 to 33), [ka] A compound of formula (XXIX) 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXIX) is reacted with a compound of formula (V) (wherein R 1 is as defined in any one of aspects 1 to 33, and R 9 and R 10is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0387] Aspect 39. A method for preparing a compound of formula (I) or (I') according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, comprising: 1 is C and X 4 is O, A compound of formula (XXXI) 4 and R 5 is as defined in any one of aspects 1 to 33), [ka] A compound of formula (XXXII) 4 and R 5 is as defined in any one of embodiments 1 to 33), [ka] The compound of formula (XXXII) is reacted with a compound of formula (XXIII) 2 , R 3 , X 2 and X 3 is as defined in any one of embodiments 1 to 33), [ka] A compound of formula (XXXIII) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound (XXXIII) is reacted with an oxidizing agent to give a compound of formula (XXXIV), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXXIV) is reacted with an acid to give a compound of formula (XXXV), 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXXV) is reacted with a compound of formula (XVI) 5 , R 6 and R 7 is as defined in any one of embodiments 1 to 33), [ka] A compound of formula (XXIX) 2 , R 3 , R 4 , R 5, R 6 , R 7 , X 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXIX) is reacted with a compound of formula (V) (wherein R 1 is as defined in any one of aspects 1 to 33, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0388] Aspect 40.X 1 is C and X 4 A process for preparing a compound of Formula (I) or (I') according to any one of Aspects 1 to 33, or a pharmaceutically acceptable salt thereof, wherein A compound of formula (XXXIII) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33), [ka] with an acid to give a compound of formula (XXXVI), 2 , R, R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXXVI) is reacted with a compound of formula (XVI) 5 , R 6 and R 7 is as defined in any one of embodiments 1 to 33), [ka] A compound of formula (XXXVII) 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXXVII) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to give a compound of formula (XXXVIII), 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XXXVIII) is reacted with a compound of formula (V) (wherein R 1 is as defined in any one of aspects 1 to 33, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] forming a compound of formula (I).

[0389] Aspect 41. A method for preparing a compound of formula (I) or (I') according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, comprising: 1 is C and X 4 is N, A compound of formula (XI) 4 , R 6 , R 7 , X 5 and R 5 is as defined in any one of aspects 1 to 33), [ka] A compound of formula (XXIII) 2 , R 3 , X 2 and X 3 is as defined in any one of embodiments 1 to 33), [ka] A compound of formula (XL) 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XL) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to give a compound of formula (XLI), 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XLI) is reacted with di-tert-butyl dicarbonate and a base to give a compound of formula (XLII), 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XLII) is reacted with a compound of formula (V) (wherein R 1 is as defined in any one of aspects 1 to 33, and R 9 and R10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (XLIII) 1 , R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 and R 5 is as defined in any one of aspects 1 to 33; and [ka] reacting said compound of formula (XLIII) with an acid to form a compound of formula (I).

[0390] Aspect 42.X 1 is C and X 4 A process for preparing a compound of Formula (I) or (I') according to any one of Aspects 1 to 33, or a pharmaceutically acceptable salt thereof, wherein A compound of formula (XXIV) 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33), [ka] The compound of formula (V) (wherein R 1 is as defined in any one of aspects 1 to 33, and R 9 and R 10 is hydrogen or R 9 and R 10 independently, C 1~6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached, form one or more C 1~6 Optionally substituted with alkyl, especially four C 1~6 to form a 3- to 14-membered heterocyclyl optionally substituted with alkyl, [ka] A compound of formula (XLIV) 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XLIV) is reacted with an acid to give a compound of formula (XLV), 1 , R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] The compound of formula (XLV) is reacted with a compound of formula (VIII) 8 is a halogen and R 6 , R 7 and X5 is as defined in any one of aspects 1 to 33, [ka] A compound of formula (XLVI) 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 and X 3 is as defined in any one of aspects 1 to 33; and [ka] reacting said compound of formula (XLVI) with ammonium carbamate and (diacetoxyiodo)benzene to form a compound of formula (I).

[0391] Aspect 43. A compound according to any one of Aspects 1 to 33, or a pharmaceutically acceptable salt thereof, when prepared according to the method of any one of Aspects 34 to 42.

[0392] Aspect 44. A compound according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0393] Aspect 45. A pharmaceutical composition comprising a compound according to any one of Aspects 1 to 33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0394] Embodiment 46. The pharmaceutical composition of embodiment 45, further comprising an additional therapeutic agent.

[0395] Embodiment 47. A compound according to any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of an inflammatory autoimmune disease.

[0396] Aspect 48. A compound according to any one of Aspects 1 to 33, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of psoriatic disease, asthma, inflammatory bowel disease (IBD), Crohn's disease, obstructive pulmonary disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

[0397] Aspect 49. A compound according to any one of Aspects 1 to 33, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of psoriatic disease, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

[0398] Aspect 50. Use of a compound according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of an inflammatory autoimmune disease.

[0399] Aspect 51. Use of a compound according to any one of aspects 1 to 33, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of psoriatic disease, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

[0400] Aspect 52. A method for treating, preventing, and / or delaying the progression of an inflammatory autoimmune disease, comprising administering a therapeutically effective amount of a compound according to any one of Aspects 1 to 33, or a pharmaceutically acceptable salt thereof.

[0401] Aspect 53. A method for treating, preventing and / or delaying progression of psoriatic disease, asthma, inflammatory bowel disease (IBD), Crohn's disease, obstructive pulmonary disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis, comprising administering a therapeutically effective amount of a compound according to any one of Aspects 1 to 33, or a pharmaceutically acceptable salt thereof.

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, X １ is CH or N, X ２ is CH or N, X ３ is CH or N, X ４ is O or NH, X ５ is CH or N, R １ is aryl, heterocyclyl, or heteroaryl, where aryl, heterocyclyl, and heteroaryl are each independently selected from one or more R １ａ is optionally replaced by R １ａ is C １～６ Alkyl, oxo, cyano, carbamoyl, C １～６ Alkylcarbamoyl-, C １～６ Alkoxy C １～６ Alkyl-, C ３～６ is cycloalkyl or heterocyclyl, R ２ is hydrogen or halogen, R ３ is hydrogen or halogen, R ４ is hydrogen, halogen or C １～６ is alkyl, R ５ is hydrogen, halogen or C １～６ is alkyl, R ６ is -OR ６ａ , -SR ６ｂ or hydrogen, R ６ａ is C １～６ is haloalkyl, R ６ｂ is C １～６ is haloalkyl, R ７ is -OR ７ａ , -SR ７ｂ or hydrogen, R ７ａ is C １～６ is haloalkyl, R ７ｂ is C １～６ is haloalkyl, However, R ６ and R ７ must be different and R ６ or R ７ is hydrogen), and pharmaceutically acceptable salts thereof.

2. X ２ is CH, X ３ is CH, R ２ is hydrogen, R ３ is hydrogen, R ４ is hydrogen, R ５ is hydrogen or C １～６ The compound of claim 1 , wherein the aryl group is alkyl.

3. X １ 3. The compound of claim 1 or 2, wherein is CH.

4. X １ 3. The compound of claim 1 or 2, wherein is N.

5. X ４ The compound according to any one of claims 1 to 4, wherein is O.

6. X ４ The compound of any one of claims 1 to 4, wherein is NH.

7. X ５ The compound of any one of claims 1 to 6, wherein is CH.

8. X ５ The compound according to any one of claims 1 to 6, wherein is N.

9. R １ is imidazopyridinyl, triazolopyridinyl, phenyl, indolyl, isoindolinyl, or indazolyl, wherein imidazopyridinyl, triazolopyridinyl, phenyl, indolyl, isoindolinyl, and indazolyl are each independently selected from the group consisting of one or more R １ａ The compound of any one of claims 1 to 8, optionally substituted with

10. R １ is isopropylimidazopyridinyl, oxo-triazolopyridinyl, imidazopyridinyl, cyanophenyl, methylimidazopyridinyl, cyano-indolyl, oxoisoindolinyl, carbamoylphenyl, (methylcarbamoyl)phenyl, methyl-indazolyl, phenyl, cyano-indazolyl, cyanoimidazopyridinyl, methyl-triazolopyridinyl, (methoxymethyl)-triazolopyridinyl or cyclopentyl-triazolopyridinyl.

11. R １ (3-isopropylimidazo[1,2-a]pyridin-6-yl), (3-oxo-2H-[1,2,4]triazolo[4,3-a]pyridin-6-yl), imidazo[1,2-a]pyridin-6-yl, (4-cyanophenyl), (3-methylimidazo[1,2-a]pyridin-6-yl), (3-cyano-1H-indol-5-yl), (3-isopropyl-8-methyl-imidazo[1,2-a]pyridin-6-yl), (2-carbamoyl-4-pyridyl), (3-oxoisoindolin-5-yl), (3-carbamoylphenyl), [3-(methylcarbamoyl)phenyl] 11. The compound according to any one of claims 1 to 10, wherein the compound is selected from the group consisting of (3-methyl-1H-indazol-5-yl), (3-methyl-1H-indazol-5-yl), phenyl, (3-cyano-1H-indazol-5-yl), (3-cyanoimidazo[1,2-a]pyridin-6-yl), (2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl), (2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl), [3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl], and (3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl).

12. R １ The compound of any one of claims 1 to 10, wherein is cyano-indazolyl, cyano-indolyl, methyl-indazolyl, oxo-triazolopyridinyl, isopropylimidazopyrrolidinyl or cyclopentyl-triazolopyridinyl.

13. R １ is (3-cyano-1H-indol-5-yl), (3-methyl-1H-indazol-5-yl), (3-cyano-1H-indazol-5-yl), (3-oxo-2H-[1,2,4]triazolo[4,3-a]pyridin-6-yl), (3-isopropylimidazo[1,2-a]pyridin-6-yl) or cyclopentyl-triazolopyridinyl.

14. R １ａ The compound of any one of claims 1 to 13, wherein is isopropyl, methyl, oxo, cyano, carbamoyl, methylcarbamoyl or methoxymethyl.

15. R ６ But, -SCF ３ , -OCF ３ , -OCHF ２ or hydrogen.

16. R ６ But, -SCF ３ or -OCF ３ The compound according to any one of claims 1 to 15,

17. R ６ａ But, -CF ３ or -CHF ２ The compound according to any one of claims 1 to 16,

18. R ６ｂ Ga-CF ３ The compound according to any one of claims 1 to 16,

19. R ７ But, -OCF ３ , -SCF ３ , -OCHF ２ or hydrogen.

20. R ７ The compound according to any one of claims 1 to 19, wherein is hydrogen.

21. R ７ａ But, -CF ３ or -CHF ２ The compound according to any one of claims 1 to 20,

22. R ７ｂ Ga-CF ３ The compound according to any one of claims 1 to 20,

23. R ５ The compound of any one of claims 1 to 22, wherein is hydrogen or methyl.

24. Formula (I') 【Chemistry 2】 The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , X ２ , X ３ , X ４ and X ５ is as defined in any one of claims 1 to 23, and X １ is CH.

25. Formula (I″) 【Transformation 3】 The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and R １ , X １ and X ５ is as defined in any one of claims 1 to 23, and R ６ is as defined in claim 16.

26. {4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl}[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ ６ - sulfanone; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonimidoyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ ６ - sulfanone; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclohexyl](imino)-λ ６ - sulfanone; 4'-{[trans-4-{[4-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine; 5-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; 4-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 5-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; N-methyl-4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indazole-3-carbonitrile; 1-{[1,1′-biphenyl]-4-sulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{[1,1′-biphenyl]-4-sulfonyl}-2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; N-methyl-4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; N-[4-(difluoromethoxy)phenyl]-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 6-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 5-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 1-{[1,1′-biphenyl]-4-sulfonyl}-N-[4-(difluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}imidazo[1,2-a]pyridine-3-carbonitrile; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-{4-[3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-(4-{3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 4-(4-{[4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[trans-4-{[3-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; 6-{4-[(4-{[3-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; or 4'-[(4-{[3-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile The compound according to any one of claims 1 to 25, selected from:

27. {4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl}[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ ６ - sulfanone; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonimidoyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl](imino)-λ ６ - sulfanone; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}cyclohexyl](imino)-λ ６ - sulfanone; 4'-{[trans-4-{[4-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; N-[trans-4-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine; 5-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-(trifluoromethoxy)aniline; 6-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; 4-(4-{[trans-4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 5-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; N-methyl-4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 5-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indazole-3-carbonitrile; 1-{[1,1′-biphenyl]-4-sulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{[1,1′-biphenyl]-4-sulfonyl}-2-methyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 6-{4-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; N-methyl-4'-[(2-methyl-4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-3-carboxamide; N-[4-(difluoromethoxy)phenyl]-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 6-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 5-{4-[(4-{[4-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-1H-indole-3-carbonitrile; 1-{[1,1′-biphenyl]-4-sulfonyl}-N-[4-(difluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}imidazo[1,2-a]pyridine-3-carbonitrile; 6-{4-[(4-{[4-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-(4-{2-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-{4-[3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 6-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 1-(4-{3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[(trifluoromethyl)sulfanyl]phenyl}piperidin-4-amine; 4-(4-{[4-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[trans-4-{[3-(trifluoromethoxy)phenyl]amino}cyclohexyl]sulfonyl}-[1,1'-biphenyl]-4-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-3-[(trifluoromethyl)sulfanyl]aniline; 6-{4-[(4-{[3-(trifluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}-2,3-dihydro-1H-isoindol-1-one; 4'-[(4-{[3-(difluoromethoxy)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; 4-{4-[(4-{[5-(trifluoromethoxy)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}pyridine-2-carboxamide; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-(trifluoromethoxy)pyridin-2-amine; N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; 4-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-4-(trifluoromethoxy)pyridin-2-amine; N-[trans-4-(4-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[(trifluoromethyl)sulfanyl]aniline; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-5-(trifluoromethoxy)pyridin-2-amine; or 6-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one The compound according to any one of claims 1 to 26, selected from:

28. 5-[4-[4-[4-(trifluoromethylsulfanyl)anilino]cyclohexyl]sulfonylphenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indazole-3-carbonitrile; 6-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-[4-(3-isopropylimidazo[1,2-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; or 1-[4-(3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine The compound according to any one of claims 1 to 27, selected from:

29. 5-[4-[4-[4-(trifluoromethylsulfanyl)anilino]cyclohexyl]sulfonylphenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indole-3-carbonitrile; 5-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-1H-indazole-3-carbonitrile; 6-[4-[[4-[4-(trifluoromethoxy)anilino]-1-piperidyl]sulfonyl]phenyl]-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one; 1-[4-(3-isopropylimidazo[1,2-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; 1-[4-(3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl]sulfonyl-N-[4-(trifluoromethoxy)phenyl]piperidin-4-amine; N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[(trifluoromethyl)sulfanyl]pyridin-2-amine; or 6-(4-{[4-({5-[(trifluoromethyl)sulfanyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one The compound according to any one of claims 1 to 28, selected from:

30. A method for preparing a compound of formula (I) or (I') according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, comprising the steps of: １ is N and X ４ is O, A compound of formula (II) ５ and R ４ is as defined in any one of claims 1 to 29) 【Chemistry 4】 with a compound of formula (III) ２ , X ３ , R ２ and R ３ is as defined in any one of claims 1 to 29) 【Transformation 5】 to produce a compound of formula (IV), ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Transformation 6】 forming The compound (IV) is reacted with a compound of formula (V) １ is as defined in any one of claims 1 to 29, and R ９ and R １０ is hydrogen, or R ９ and R １０ are independently １～６ alkyl, or R ９ and R １０ together with the oxygen atoms to which they are attached, form one or more C １～６ Optionally substituted with alkyl, especially 4 C １～６ forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl; 【Transformation 7】 to give a compound of formula (VI), １ , R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29), 【Transformation 8】 The compound of formula (VI) is reacted with an acid to give a compound of formula (VII), １ , R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 9】 forming The compound of formula (VII) is converted into a compound of formula (VIII) ８ is a halogen, and R ６ , R ７ and X ５ is as defined in any one of claims 1 to 29) 【Chemistry 10】 to form a compound of formula (I) A method comprising:

31. A compound of formula (I) or (I') according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof (wherein X １ is N and X ４ is O, A compound of formula (IX) ４ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 11】 with a compound of formula (VIII) ８ is a halogen, and R ６ , R ７ and X ５ is as defined in any one of claims 1 to 29) 【Chemistry 12】 to produce a compound of formula (X) ４ , R ６ , R ７ , X ５ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 13】 forming The compound of formula (X) is reacted with an acid to give a compound of formula (XI), ４ , R ６ , R ７ , X ５ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 14】 forming The compound of formula (XI) is reacted with a compound of formula (III) ２ , X ３ , R ２ and R ３ is as defined in any one of claims 1 to 29) 【Chemistry 15】 to give a compound of formula (XII), ２ , X ３ , R ２ , R ３ , R ４ , R ６ , R ７ , X ５ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 16】 forming The compound of formula (XII) is reacted with a compound of formula (V) １ is as defined in any one of claims 1 to 29, and R ９ and R １０ is hydrogen, or R ９ and R １０ are independently １～６ alkyl, or R ９ and R １０ together with the oxygen atoms to which they are attached, form one or more C １～６ Optionally substituted with alkyl, especially 4 C １～６ forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl; 【Chemistry 17】 to form a compound of formula (I) A method comprising:

32. A compound of formula (I) or (I') according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof (wherein X １ is N and X ４ is O, A compound of formula (XVIII) ５ and R ４ is as defined in any one of claims 1 to 29) [Chemistry 18] with a compound of formula (XVII) １ , R ２ , R ３ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 19】 to give a compound of formula (XX) １ , R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 20】 forming The compound of formula (XX) is reacted with a compound of formula (XVI) ５ , R ６ and R ７ is as defined in any one of claims 1 to 29) 【Chemistry 21】 to form a compound of formula (I) Contains or Or, A compound of formula (XVIII) ５ and R ４ is as defined in any one of claims 1 to 29) 【Chemistry 22】 with a compound of formula (III) ２ , X ３ , R ２ and R ３ is as defined in any one of claims 1 to 29) 【Chemistry 23】 to give a compound of formula (XIX), ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 24】 forming Reacting the compound of formula (XIX) with the compound of formula (XVI) to give a compound of formula (XII), ２ , X ３ , R ２ , R ３ , R ４ , R ６ , R ７ , X ５ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 25】 forming The compound of formula (XII) is reacted with a compound of formula (V) １ is as defined in any one of claims 1 to 29, and R ９ and R １０ is hydrogen, or R ９ and R １０ are independently １～６ alkyl, or R ９ and R １０ together with the oxygen atoms to which they are attached, form one or more C １～６ Optionally substituted with alkyl, especially 4 C １～６ forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl; 【Chemistry 26】 to form a compound of formula (I) A method comprising:

33. A compound of formula (I) or (I') according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof (wherein X １ is C and X ４ is O, A compound of formula (XXI) ４ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 27】 with mesyl chloride to give a compound of formula (XXII), ４ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 28】 forming The compound of formula (XXII) is converted into a compound of formula (XXIII) ２ , R ３ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 29】 to produce a compound of formula (XXIV), ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Transformation 30】 forming The compound of formula (XXIV) is reacted with an oxidizing agent to give a compound of formula (XXV), ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 31】 forming The compound of formula (XXV) is reacted with a compound of formula (V) (wherein R １ is as defined in any one of claims 1 to 29, and R ９ and R １０ is hydrogen, or R ９ and R １０ are independently １～６ alkyl, or R ９ and R １０ together with the oxygen atoms to which they are attached, form one or more C １～６ Optionally substituted with alkyl, especially 4 C １～６ forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl; 【Chemistry 32】 to give a compound of formula (XXVI), １ , R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Transformation 33】 forming The compound of formula (XXVI) is reacted with an acid to give a compound of formula (XXVII), １ , R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Transformation 34】 forming The compound of formula (XXVII) is reacted with a compound of formula (VIII) ８ is a halogen, and R ６ , R ７ and X ５ is as defined in any one of claims 1 to 29) 【Chemistry 35】 to form a compound of formula (I) A method comprising:

34. A compound of formula (I) or (I') according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof (wherein X １ is C and X ４ is O, A compound of formula (XXV) ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Transformation 36】 with an acid to give a compound of formula (XXVIII), ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 37】 forming The compound of formula (XXVIII) is reacted with a compound of formula (VIII) ８ is a halogen, and R ６ , R ７ and X ５ is as defined in any one of claims 1 to 29) 【Transformation 38】 to give a compound of formula (XXIX), ２ , R ３ , R ４ , R ５ , R ６ , R ７ , X ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 39】 forming The compound of formula (XXIX) is reacted with a compound of formula (V) １ is as defined in any one of claims 1 to 29, and R ９ and R １０ is hydrogen, or R ９ and R １０ are independently １～６ alkyl, or R ９ and R １０ together with the oxygen atoms to which they are attached, form one or more C １～６ Optionally substituted with alkyl, especially 4 C １～６ forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl; 【Chemistry 40】 to form a compound of formula (I) A method comprising:

35. A compound of formula (I) or (I') according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof (wherein X １ is C and X ４ is O, A compound of formula (XXXI) ４ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 41】 with mesyl chloride to give a compound of formula (XXXII), ４ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 42】 forming The compound of formula (XXXII) is converted into a compound of formula (XXIII) ２ , R ３ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 43】 to produce a compound of formula (XXXIII), ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 44】 forming The compound of formula (XXXIII) is reacted with an oxidizing agent to give a compound of formula (XXXIV), ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 45】 forming The compound of formula (XXXIV) is reacted with an acid to give a compound of formula (XXXV), ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 46】 forming The compound of formula (XXXV) is reacted with a compound of formula (XVI) ５ , R ６ and R ７ is as defined in any one of claims 1 to 29) 【Chemistry 47】 to give a compound of formula (XXIX), ２ , R ３ , R ４ , R ５ , R ６ , R ７ , X ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 48】 forming The compound of formula (XXIX) is reacted with a compound of formula (V) １ is as defined in any one of claims 1 to 29, and R ９ and R １０ is hydrogen, or R ９ and R １０ are independently １～６ alkyl, or R ９ and R １０ together with the oxygen atoms to which they are attached, form one or more C １～６ Optionally substituted with alkyl, especially 4 C １～６ forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl; 【Chemistry 49】 to form a compound of formula (I) A method comprising:

36. A compound of formula (I) or (I') according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof (wherein X １ is C and X ４ is N, A compound of formula (XXXIII) ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) [Transformation 50] with an acid to give a compound of formula (XXXVI), ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 51】 forming The compound of formula (XXXVI) is reacted with a compound of formula (XVI) ５ , R ６ and R ７ is as defined in any one of claims 1 to 29) 【Chemistry 52】 to give a compound of formula (XXXVII), ２ , R ３ , R ４ , R ５ , R ６ , R ７ , X ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 53】 forming The compound of formula (XXXVII) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to give a compound of formula (XXXVIII), ２ , R ３ , R ４ , R ５ , R ６ , R ７ , X ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 54】 forming The compound of formula (XXXVIII) is reacted with a compound of formula (V) １ is as defined in any one of claims 1 to 29, and R ９ and R １０ is hydrogen, or R ９ and R １０ are independently １～６ alkyl, or R ９ and R １０ together with the oxygen atoms to which they are attached, form one or more C １～６ Optionally substituted with alkyl, especially 4 C １～６ forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl; 【Transformation 55】 to form a compound of formula (I) A method comprising:

37. A compound of formula (I) or (I') according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof (wherein X １ and X ４ is N, A compound of formula (XI) ４ , R ６ , R ７ , X ５ and R ５ is as defined in any one of claims 1 to 29) 【Transformation 56】 with a compound of formula (XXIII) ２ , R ３ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemistry 57】 to give a compound of formula (XL) ２ , R ３ , X ２ , X ３ , R ４ , R ６ , R ７ , X ５ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 58】 forming The compound of formula (XL) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to give a compound of formula (XLI), ２ , R ３ , X ２ , X ３ , R ４ , R ６ , R ７ , X ５ and R ５ is as defined in any one of claims 1 to 29) 【Chemistry 59】 forming The compound of formula (XLI) is reacted with di-tert-butyl dicarbonate and a base to give a compound of formula (XLII), ２ , R ３ , X ２ , X ３ , R ４ , R ６ , R ７ , X ５ and R ５ is as defined in any one of claims 1 to 29) 【Transformation 60】 forming The compound of formula (XLII) is reacted with a compound of formula (V) １ is as defined in any one of claims 1 to 29, and R ９ and R １０ is hydrogen, or R ９ and R １０ are independently １～６ alkyl, or R ９ and R １０ together with the oxygen atoms to which they are attached, form one or more C １～６ Optionally substituted with alkyl, especially 4 C １～６ forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl; 【Chemistry 61】 to give a compound of formula (XLIII), １ , R ２ , R ３ , X ２ , X ３ , R ４ , R ６ , R ７ , X ５ and R ５ is as defined in any one of claims 1 to 29) 【Transformation 62】 forming reacting said compound of formula (XLIII) with an acid to form a compound of formula (I) A method comprising:

38. A compound of formula (I) or (I') according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof (wherein X １ is C and X ４ is N, A compound of formula (XXIV) ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Transformation 63】 with a compound of formula (V), １ is as defined in any one of claims 1 to 29, and R ９ and R １０ is hydrogen, or R ９ and R １０ are independently １～６ alkyl, or R ９ and R １０ together with the oxygen atoms to which they are attached, form one or more C １～６ Optionally substituted with alkyl, especially 4 C １～６ forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl; 【Chemistry 64】 to give a compound of formula (XLIV), １ , R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Transformation 65】 forming The compound of formula (XLIV) is reacted with an acid to give a compound of formula (XLV), １ , R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Chemical Formula 66】 forming The compound of formula (XLV) is reacted with a compound of formula (VIII) ８ is a halogen, and R ６ , R ７ and X ５ is as defined in any one of claims 1 to 29) 【Transformation 67】 to give a compound of formula (XLVI), １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , X ５ , X ２ and X ３ is as defined in any one of claims 1 to 29) 【Transformation 68】 forming reacting said compound of formula (XLVI) with ammonium carbamate and (diacetoxyiodo)benzene to form a compound of formula (I) A method comprising:

39. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, when prepared according to any one of claims 30 to 38.

40. 30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

41. A pharmaceutical composition comprising the compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

42. The pharmaceutical composition of claim 341, further comprising an additional therapeutic agent.

43. 30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of an inflammatory autoimmune disease.

44. 30. A compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof for use in the treatment, prevention and / or delay of progression of psoriatic disease, asthma, inflammatory bowel disease (IBD), Crohn's disease, obstructive pulmonary disease ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

45. 30. A compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof for use in the treatment, prevention and / or delay of progression of psoriatic diseases, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

46. 30. Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of inflammatory autoimmune diseases.

47. 30. Use of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment, prevention and / or delay of psoriatic diseases, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

48. 30. A method for treating, preventing and / or delaying the progression of an inflammatory autoimmune disease, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

49. A method for the treatment, prevention and / or delay of progression of psoriatic disease, asthma, inflammatory bowel disease (IBD), Crohn's disease, obstructive pulmonary disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis, which method comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

50. The invention described hereinabove.

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