N-Phenyl-1(phenylsulfonyl)piperidin-4-amine derivatives as CCR6 inhibitors

Abstract

The present invention relates to novel derivatives having the general formula (I) TIFF2026504677000318.tif53170 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 as defined herein, compositions comprising said compounds, methods of making said compounds and methods of using said compounds.

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, ensuring the correct cells are recruited to the correct 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 can be divided into four major subfamilies, designated CC, CXC, CX3C, and C, based on the location of the canonical cysteine ​​residue in the N-terminal region. 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 diverse 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 an important 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 in that it has only one binding partner, forming 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 & Koerner, 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 point to an important role for 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 the most highly associated with the 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 exclusively on-target pharmacology. Summary of the Invention

[0007] A first object of the present invention is to provide compounds of formula (I) [ka] During the ceremony, X 1is 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 may be present in the presence of one or two, particularly one, R 1a is optionally replaced by R 1a But C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, cyano, -CONHR 1b , C 3-6 is cycloalkyl or heterocyclyl, R 1b But C 1-6 alkyl or hydrogen, 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 But C 3-6 cycloalkyl or heterocyclyl, C 3-6 Cycloalkyl and heterocyclyl may be present in one or two, especially one R 6a is optionally replaced by R 6a But C 1-6 haloalkyl, cyano or halogen; R 7 is hydrogen, The compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0008] A second object of the present invention is a compound of formula (I) [ka] During the ceremony, 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 or heteroaryl, and the aryl and heteroaryl are each independently one or two, particularly one R 1a is optionally replaced by R 1a But C 1-6 Alkyl, oxo, cyano, -CONHR 1b , C 3-6 cycloalkyl, or heterocyclyl; R 1b is hydrogen or C 1-6 is alkyl, 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 But C 3-6 cycloalkyl or heterocyclyl, C 3-6 Cycloalkyl and heterocyclyl may be present in one or two, especially one R 6a is optionally replaced by R 6a But C 1-6haloalkyl, cyano or halogen; R 7 is hydrogen, The present invention relates to a compound or a pharmaceutically acceptable salt thereof.

[0009] The third object of the present invention is to 1 is N and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: In the formula, R 5 and R 4 is as defined above [ka] where X 2 , X 3 , R 2 and R 3 Compounds of formula (III) wherein [ka] In the formula, R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above; and [ka] The compound (IV) is reacted with 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 to form one or more C 1-6Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] React with R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above, forming a compound of formula (VI) [ka] The compound of formula (VI) is reacted with an acid to form R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 forming a compound of formula (VII) wherein [ka] The compound of formula (VII) is reacted with R 8 is a halogen and R 6 , R 7 , and X 5 Compounds of formula (VIII) wherein [ka] to form a compound of formula (I); A method comprising:

[0010] The fourth object of the present invention is to 1 is N and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: In the formula, R 4 and R 5 is as defined above [ka] , R 8 is a halogen and R 6 , R 7 , and X 5 Compounds of formula (VIII) wherein [ka] React with R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above, forming a compound of formula (X); [ka] The compound of formula (X) is reacted with an acid to form R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XI) wherein [ka] The compound of formula (XI) is reacted with X 2 , X 3 , R 2 , and R 3 is as defined above [ka] React with X 2 , X 3 , R 2 , R 3 , R 4 , R6 , R 7 , X 5 , and R 5 forming a compound of formula (XII) wherein [ka] The compound of formula (XII) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0011] The fifth object of the present invention is to 1 is N and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: In the formula, R 5 and R 4 is as defined above [ka] , R 1 , R 2 , R 3 , X 2 , and X 3 Compounds of formula (XVII) wherein [ka] React with R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above, forming a compound of formula (XX); [ka] The compound of formula (XX) is 5 , R 6 , and R 7 Compounds of formula (XVI) wherein [ka] to form a compound of formula (I); a method comprising: In the formula, R 5 and R 4 is as defined above [ka] where X 2 , X 3 , R 2 and R 3 Compounds of formula (III) wherein [ka] In the formula, R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above; and [ka] The compound of formula (XIX) is reacted with X 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above with said compound of formula (XVI) to form a compound of formula (XII); [ka] The compound of formula (XII) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

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

[0013] The seventh object of the present invention is to 1 is C and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: In the formula, R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above, [ka] with an acid to form a compound of formula R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above; and forming a compound of formula (XXVIII) [ka] The compound of formula (XXVIII) is reacted with R 8 is a halogen and R 6 , R 7 , and X 5 Compounds of formula (VIII) wherein [ka] React with R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXIX), [ka] The compound of formula (XXIX) is reacted with R1 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0014] The eighth object of the present invention is to 1 is C and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: R 4 and R 5 is as defined above [ka] is reacted with mesyl chloride to give R 4 and R 5 forming a compound of formula (XXXII) wherein [ka] The compound of formula (XXXII) is reacted with R 2 , R 3 , X 2 , and X 3 is as defined above [ka] In the formula, R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above; and [ka] The compound (XXXIII) is reacted with an oxidizing agent to form R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXXIV), [ka] The compound (XXXIV) is reacted with an acid to form R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXXV), [ka] The compound of formula (XXXV) is reacted with X 5 , R 6 , and R 7 Compounds of formula (XVI) wherein [ka] By reacting with the compound of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X5 , X 2 , and X 3 is as defined above to form a compound of formula (XXIX), [ka] The compound of formula (XXIX) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0015] The ninth object of the present invention is to 1 is C and X 4 is N, or a pharmaceutically acceptable salt thereof, comprising the steps of: In the formula, R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above, [ka] with an acid to form a compound of formula R 2 , R 3 , R 4 , R5 , X 2 and X 3 is as defined above; and forming a compound of formula (XXXVI) [ka] The compound of formula (XXXVI) is reacted with X 5 , R 6 , and R 7 Compounds of formula (XVI) wherein [ka] React with R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXXVII), [ka] The compound of formula (XXXVII) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to form R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXXVIII), [ka] The compound of formula (XXXVIII) is reacted with R 1 is as defined above, and R 9 and R 10 is hydrogen or R 9and R 10 independently C 1-6 alkyl, or R 9 and R 10 together with the oxygen atoms to which they are attached to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0016] The tenth object of the present invention is to 1 and X 4 is N, or a pharmaceutically acceptable salt thereof, comprising the steps of: R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above [ka] , R 2 , R 3 , X 2 and X 3 is as defined above [ka] React with R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 , and R 5is as defined above to form a compound of formula (XL), [ka] The compound (XL) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to form R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XLI), wherein [ka] The compound (XLI) is reacted with di-tert-butyl dicarbonate and a base to give R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above to form a compound of formula (XLI), [ka] The compound (XLII) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] React with R 1 , R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XLIII), wherein [ka] reacting said compound of formula (XLIII) with an acid to form a compound of formula (I); A method comprising:

[0017] An eleventh object of the present invention is a pharmaceutical composition comprising a compound of formula (I) 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, comprising 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 give a solution with 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] "Amino," alone or in combination with other groups, refers to NH2.

[0025] "Aromatic" is used in the literature, especially in the IUPAC Compendium of Chemical Terminology, 2 nd Edition, ADMcNaught & A. Wilkinson (Eds.). Blackwell Scientific Publications, Oxford (1997).

[0026] "Aryl" means a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 5 to 14 carbon ring atoms ("C 5-14"-aryl"). Bicyclic aryl ring systems include fused bicycles having two fused 5-membered aryl rings (designated 5-5), fused bicycles having a 5-membered aryl ring and a fused 6-membered aryl ring (designated 5-6 and 6-5), and bicycles 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.

[0027] "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.

[0028] "Cyano," alone or in combination with other groups, refers to CN (ie, nitrile).

[0029] "C 3-6"Cycloalkyl" refers to saturated or partially unsaturated carbocyclic moieties having monocyclic, bicyclic (including bridged bicyclic and cycloalkyl spiro) rings. 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. Cycloalkyl moieties can be attached in a "spirocycloalkyl" or "cycloalkylspiro" fashion, such as "spirocyclopropyl."

[0030] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo, especially chloro or fluoro.

[0031] "Haro-C 1-6 "Alkyl" refers to a C 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 refers to perhaloC alkyl as defined herein. More particularly, halo-C 1-6 Alkyl is trifluoromethyl, difluoromethyl or fluoromethyl. Most particularly halo-C 1-6 The alkyl is trifluoroalkyl (-CF3).

[0032] "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 can be 5 to 6-membered. Bicyclic heteroaryl ring systems include fused bicyclic rings having two fused 5-membered heteroaryl rings (designated 5-5), fused bicyclic rings having a 5-membered heteroaryl ring and a fused 6-membered heteroaryl ring (designated 5-6 and 6-5), and bicyclic rings having two fused 6-membered heteroaryl rings (designated 6-6). An example of a bicyclic heteroaryl is an N-containing bicyclic heteroaryl such as pyridinyl. Heteroaryl groups can 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, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiazolyl, benzothiazolyl, and benzothiazolyl. nyl, benzothiophenyl, indolyl, indolyl, 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, furopyridazinyl, furopyrimidinyl, and furopyrazinyl.Particular examples of heteroaryl moieties include indolyl, indazolyl, imidazopyridinyl, phenyl or pyridyl, more particularly imidazopyridinyl, indolyl, imidazopyridinyl or indazolyl.

[0033] "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 certain 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 (C-C)C 1-6It can be substituted with an alkyl or group. The heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Any heterocycle ring atom can be optionally substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, isoindolinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, pyrrolidine 1-oxide, N-hydroxypiperidine, piperidinyl, oxa-azospirononanyl, diazaspirodecanyl, oxa-diazaspirodecanyl, diazaspironoundecanyl, azaspirononanyl, oxetanyl, 1-methylpyrrolidine N-oxide, diazirinyl, and quinuclidinyl. The term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl. In particular, heterocycle refers to piperidinyl, oxa-azaspirononanyl, diazaspirodecanyl, oxa-diazaspirodecanyl, diazaspironoundecanyl, azaspirononanyl, or oxetanyl.

[0034] 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 gastrointestinal cancers, which are 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).

[0035] "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.

[0036] 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., from the replacement of one hydrogen to the 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.

[0037] "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 comes out more slowly than normal. At the end of 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).

[0038] "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 "Aryl group optionally substituted with alkyl group" means C 1-6 The alkyl may be present but need not be present, and the description is provided for the aryl group as 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.

[0039] "Optionally substituted" means unsubstituted or substituted. Generally, the substituents can be the same or different.

[0040] "Oxidizing agent" refers to one or more suitable electron acceptors or electron sharers, and can be an element, a combination of elements, a compound, or a combination of compounds, including a reducing compound, which may be a vapor, solid, or liquid at process conditions. An example of an oxidizing agent is mCPBA (meta-chloroperoxybenzoic acid).

[0041] "Oxo", alone or in combination with other groups, refers to =O.

[0042] "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.

[0043] More particularly, pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, hydrobromide, sulfate, phosphate, and methanesulfonate salts.

[0044] "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.

[0045] "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, as used herein, substitution 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.

[0046] A "therapeutically effective amount" refers to the 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 disease 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.

[0047] A "therapeutically inert carrier" refers to any non-toxic ingredient, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, or lubricant, that has no therapeutic activity and is used in formulating a pharmaceutical product. DETAILED DESCRIPTION OF THE INVENTION

[0048] In one embodiment, the present invention provides a compound of formula (I): [ka] During the ceremony, 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 may be present in the presence of one or two, particularly one, R 1a is optionally replaced by R 1a But C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, cyano, -CONHR 1b, C 3-6 is cycloalkyl or heterocyclyl, R 1b But C 1-6 alkyl or hydrogen, 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 But C 3-6 cycloalkyl or heterocyclyl, C 3-6 Cycloalkyl and heterocyclyl may be present in one or two, especially one R 6a is optionally replaced by R 6a But C 1-6 haloalkyl, cyano or halogen; R 7 is hydrogen, The present invention relates to a compound or a pharmaceutically acceptable salt thereof.

[0049] In another embodiment, the present invention provides a compound of formula (I): [ka] During the ceremony, 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 1is aryl or heteroaryl, where aryl and heteroaryl are aryls or heteroaryls, each of which may be selected from one or two, in particular one, R 1a is optionally replaced by R 1a is C 1-6 Alkyl, oxo, cyano, -CONHR 1b , C 3-6 cycloalkyl, or heterocyclyl; R 1b is hydrogen or C 1-6 is alkyl, 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 But C 3-6 cycloalkyl or heterocyclyl, C 3-6 Cycloalkyl and heterocyclyl may be present in one or two, especially one R 6a is optionally replaced by R 6a But C 1-6 haloalkyl, cyano or halogen; R 7 is hydrogen, The present invention relates to compounds and pharmaceutically acceptable salts thereof.

[0050] A particular embodiment of the present invention comprises: X 2 is CH, X 3 is CH, X 5 is CH, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, The present invention relates to compounds of formula (I) or (I') as described herein.

[0051] A particular embodiment of the present invention is 4 is O; or a pharmaceutically acceptable salt thereof.

[0052] A particular embodiment of the present invention is 4 is NH.

[0053] A particular embodiment of the present invention is 5 is N; or a pharmaceutically acceptable salt thereof.

[0054] A particular embodiment of the present invention is 1 is CH; or a pharmaceutically acceptable salt thereof.

[0055] A particular embodiment of the present invention is 1 is N, or a pharmaceutically acceptable salt thereof.

[0056] Certain embodiments of the present invention relate to compounds of formula (I), (I'), (I'') or (I''') or a pharmaceutically acceptable salt thereof, as described herein, wherein R 1 is phenyl, pyridyl or N-containing bicyclic heteroaryl, and phenyl, pyridyl and N-containing bicyclic heteroaryl are each independently selected from one or two, especially one, R 1a is optionally replaced by

[0057] A particular embodiment of the present invention is 1is indolyl, triazolopyridyl, triazolopyrazinyl, indazolyl, imidazopyridinyl, phenyl or pyridyl, and indolyl, indazolyl, imidazopyridinyl, phenyl and pyridyl are optionally present at one R 1a or a pharmaceutically acceptable salt thereof.

[0058] A particular embodiment of the present invention is 1 is imidazopyridinyl, cyanoindolyl, isopropylimidazopyridinyl, methylindazolyl, methylimidazopyridinyl, (methylcarbamoyl)phenyl, (methylcarbamoyl)pyridyl, carbamoylphenyl, or cyanophenyl, as described herein.

[0059] A particular embodiment of the present invention is 1 is imidazo[1,2-a]pyridin-6-yl, (3-cyano-1H-indol-5-yl), (3-isopropylimidazo[1,2-a]pyridin-6-yl), (3-methyl-1H-indazol-5-yl), (3-methylimidazo[1,2-a]pyridin-6-yl), [3-(methylcarbamoyl)phenyl], [4-(methylcarbamoyl)phenyl], [6-(methylcarbamoyl)-3-pyridyl], (4-carbamoylphenyl) or (4-cyanophenyl), as defined herein.

[0060] A particular embodiment of the present invention is 1 is imidazopyridyl, indolyl, triazolopyridyl or triazolopyrazyl, and imidazopyridyl, indolyl, triazolopyridyl and triazolopyrazyl are optionally substituted by one or two R 1aor a pharmaceutically acceptable salt thereof.

[0061] A particular embodiment of the present invention is 1 is methylimidazopyridyl, cyanoindolyl, imidazopyridyl, isopropylimidazopyridinyl, isopropyltriazolopyridyl, isopropyltriazolopyrazyl, methyltriazolopyridyl, difluoromethyltriazolopyridyl, methylisopropyltriazolopyridyl, or a pharmaceutically acceptable salt thereof.

[0062] A particular embodiment of the present invention is 1 is imidazopyridinyl, cyanoindolyl, isopropylimidazopyridinyl, or methylindazolyl, or a pharmaceutically acceptable salt thereof.

[0063] A particular embodiment of the present invention is 1a is methyl, isopropyl, cyano, —CONH2, —CONH(Me), or difluoromethyl, or a pharmaceutically acceptable salt thereof.

[0064] A particular embodiment of the present invention is 1a is methyl, isopropyl, cyano, or difluoromethyl;

[0065] A particular embodiment of the present invention is 1a is methyl, isopropyl, cyano, —CONH 2 , —CONH(Me), or a pharmaceutically acceptable salt thereof.

[0066] A particular embodiment of the present invention is 1b is methyl or hydrogen; or a pharmaceutically acceptable salt thereof.

[0067] Certain embodiments of the present invention relate to compounds of formula (I), (I'), (I'') or (I''') or a pharmaceutically acceptable salt thereof, as described herein, wherein R 6 is cyclopropyl or one R 6a and oxetanyl optionally substituted with

[0068] A particular embodiment of the present invention is 6 is (trifluoromethyl)cyclopropyl, cyanocyclopropyl, cyclopropyl, or oxetanyl, or a pharmaceutically acceptable salt thereof.

[0069] A particular embodiment of the present invention is 6 is [1-(trifluoromethyl)cyclopropyl], (1-cyanocyclopropyl), oxetan-3-yl, (2,2-difluorocyclopropyl), cyclopropyl;

[0070] A particular embodiment of the present invention is 6 is (trifluoromethyl)cyclopropyl.

[0071] A particular embodiment of the present invention is 6a is trifluoromethyl, cyano; or a pharmaceutically acceptable salt thereof.

[0072] A particular embodiment of the present invention is 6a is trifluoromethyl.

[0073] A particular embodiment of the present invention comprises: X 1 is CH or N, X 2 is CH, X 3 is CH, X 4 is O, X 5 is CH or N, R 1 is imidazopyridyl, indolyl, triazolopyridyl, or triazolopyrazyl, wherein imidazopyridyl, indolyl, triazolopyridyl, and triazolopyrazyl are substituted with one or two R 1a is optionally replaced by R 1a is methyl, isopropyl, cyano or difluoromethyl; R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 But one R 6a is cyclopropyl optionally substituted with R 6a is trifluoromethyl, R 7 is hydrogen, The present invention relates to a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0074] A particular embodiment of the present invention comprises: X 1 is CH or N, X 2 is CH, X 3 is CH, X 4 is O, X 5 is CH or N, R 1 is methylimidazopyridyl, cyanoindolyl, imidazopyridyl, isopropylimidazopyridinyl, isopropyltriazolopyridyl, isopropyltriazolopyrazyl, methyltriazolopyridyl, difluoromethyltriazolopyridyl, methylisopropyltriazolopyridyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is (trifluoromethyl)cyclopropyl, R 7 is hydrogen, The present invention relates to a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0075] A particular embodiment of the invention is where the compound is a compound of formula (I') [ka] and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 2 , X 3 , X 4 and X 5 has the same meaning as above, or a pharmaceutically acceptable salt thereof.

[0076] A particular embodiment of the invention is where the compound is a compound of formula (I″) [ka] and R 1 , R 6 , X 1 , X 4 and X 5 has the same meaning as above, or a pharmaceutically acceptable salt thereof.

[0077] A particular embodiment of the invention is where the compound is of formula (I''') [ka] and R 1 , R 6 , X 1 , X 4 and X 5 has the same meaning as above, or a pharmaceutically acceptable salt thereof.

[0078] A particular embodiment of the invention is a compound of formula (I'") [ka] During the ceremony, X 1 is CH or N, X 4 is O, X 5 is CH or N, R 1 is phenyl, pyridine or N-containing bicyclic heteroaryl, where phenyl, pyridine and N-containing bicyclic heteroaryl are selected from the group consisting of one or two, especially one, R 1a is optionally replaced by R 1a is methyl, isopropyl, cyano, -CONH2, -CONH(Me) or difluoromethyl; R 6ais trifluoromethyl or cyano; The present invention relates to a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0079] A particular embodiment of the invention is a compound of formula (I'") [ka] During the ceremony, X 1 is CH or N, X 4 is O, X 5 is CH or N, R 1 is imidazopyridyl, indolyl, triazolopyridyl, or triazolopyrazyl, wherein imidazopyridyl, indolyl, triazolopyridyl, and triazolopyrazyl are each independently selected from the group consisting of one or two R 1a is optionally replaced by R 1a is methyl, isopropyl, cyano or difluoromethyl; R 6a is trifluoromethyl, The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.

[0080] A particular embodiment of the present invention comprises: 4'-[(4-{[4-(1-cyanocyclopropyl)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-3-carboxamide; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; N-methyl-5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-(4-cyclopropylphenyl)-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 5-[4-({4-[(4-cyclopropylphenyl)amino]piperidin-1-yl}sulfonyl)phenyl]-1H-indole-3-carbonitrile; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone; 4-(2,2-Difluorocyclopropyl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 1-(4-{[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]amino}phenyl)cyclopropane-1-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; 4-(Oxetan-3-yl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 5-(4-{[trans-4-{[4-(oxetan-3-yl)phenyl]amino}cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-[(trans)-4-(4-{3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-[(trans)-4-(4-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; 1-(6-{[1-(4-{2-methoxy-7-azaspiro[3.5]nonan-7-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 2-(1-{4-[(4-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}piperidin-4-yl)acetamide; [(1-{4-[(4-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}piperidin-4-yl)methyl]urea; 1-(6-{[1-(4-{8,10-dioxo-3,9-diazaspiro[5.5]undecan-3-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{2-oxo-3-oxa-1,8-diazaspiro[4.5]decan-8-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{1-oxo-2,8-diazaspiro[4.5]decan-8-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{2-oxa-7-azaspiro[3.5]nonan-7-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[(trans)-4-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-{6-[(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile; 1-{6-[(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-{6-[(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]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-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 6-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; N-(1-{4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; 4-(4-{[4-({5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; or N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine or a pharmaceutically acceptable salt thereof.

[0081] A particular embodiment of the present invention comprises: 4'-[(4-{[4-(1-cyanocyclopropyl)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-3-carboxamide; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; N-methyl-5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-(4-cyclopropylphenyl)-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 5-[4-({4-[(4-cyclopropylphenyl)amino]piperidin-1-yl}sulfonyl)phenyl]-1H-indole-3-carbonitrile; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone; 4-(2,2-Difluorocyclopropyl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 1-(4-{[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]amino}phenyl)cyclopropane-1-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; 4-(Oxetan-3-yl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 5-(4-{[trans-4-{[4-(oxetan-3-yl)phenyl]amino}cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; or N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline or a pharmaceutically acceptable salt thereof.

[0082] A particular embodiment of the present invention comprises: 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-(1-{4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]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-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; or N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine or a pharmaceutically acceptable salt thereof.

[0083] A particular embodiment of the present invention comprises: 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; or N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline 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: R 5 and R 4 is as defined above, [ka] where X 2 , X 3 , R 2 and R 3 Compounds of formula (III) wherein [ka] In the formula, R 2 , R 3 , R 4 , R 5 , X 2 and X 3 forming compound (IV), wherein [ka] The compound (IV) is reacted with R 1 is as defined above, 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] React with R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above, forming a compound of formula (VI) [ka] The compound of formula (VI) is reacted with an acid to form R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 forming a compound of formula (VII) wherein [ka] The compound of formula (VII) is reacted with R 8 is a halogen and R 6 , R 7 , and X 5 Compounds of formula (VIII) wherein [ka] to form a compound of formula (I); A method comprising:

[0087] The present invention is 1 is N and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: R 4 and R 5 is as defined above [ka] , R 8 is a halogen and R 6 , R 7 , and X 5 Compounds of formula (VIII) wherein [ka] React with R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above, forming a compound of formula (X); [ka] The compound of formula (X) is reacted with an acid to form R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XI) wherein [ka] The compound of formula (XI) is reacted with X 2 , X 3 , R 2 , and R 3 is as defined above [ka] React with X 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XII) wherein [ka] The compound of formula (XII) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0088] The present invention is 1 is N and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: R 5 and R 4 is as defined above [ka] , R 1 , R 2 , R 3 , X 2 , and X 3 Compounds of formula (XVII) wherein [ka] React with R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above, forming a compound of formula (XX); [ka] The compound of formula (XX) is 5 , R 6 , and R 7 Compounds of formula (XVI) wherein [ka] to form a compound of formula (I); a method comprising: R 5 and R 4 is as defined above [ka] where X 2 , X 3 , R 2 and R 3 Compounds of formula (III) wherein [ka] In the formula, R 2 , R 3 , R4 , R 5 , X 2 and X 3 is as defined above; and [ka] The compound of formula (XIX) is reacted with X 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above with said compound of formula (XVI) to form a compound of formula (XII); [ka] The compound of formula (XII) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0089] The present invention is 1 is C and X 4is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: In the formula, R 4 and R 5 is as defined above [ka] is reacted with mesyl chloride to give R 4 and R 5 forming a compound of formula (XXII) wherein [ka] The compound of formula (XXII) is reacted with R 2 , R 3 , X 2 , and X 3 is as defined above [ka] In the formula, R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above; and forming a compound of formula (XXIV) [ka] The compound of formula (XXIV) is reacted with an oxidizing agent to form R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXV), [ka] The compound of formula (XXV) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] React with R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXVI), [ka] The compound of formula (XXVI) is reacted with an acid to form R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 forming a compound of formula (XXVII), wherein [ka] The compound of formula (XXVII) is reacted with R 8 is a halogen and R 6 , R 7 , and X 5 Compounds of formula (VIII) wherein [ka] to form a compound of formula (I); A method comprising:

[0090] The present invention is 1 is C and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above, [ka] with an acid to form a compound of formula R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above; and forming a compound of formula (XXVIII) [ka] The compound of formula (XXVIII) is reacted with R 8 is a halogen and R 6 , R 7 , and X 5 Compounds of formula (VIII) wherein [ka] React with R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 , and X 3is as defined above to form a compound of formula (XXIX), [ka] The compound of formula (XXIX) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0091] The present invention is 1 is C and X 4 is O, or a pharmaceutically acceptable salt thereof, comprising the steps of: R 4 and R 5 is as defined above [ka] is reacted with mesyl chloride to give R 4 and R 5 forming a compound of formula (XXXII) wherein [ka] The compound of formula (XXXII) is reacted with R2 , R 3 , X 2 , and X 3 is as defined above [ka] In the formula, R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above; and [ka] The compound (XXXIII) is reacted with an oxidizing agent to form R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXXIV), [ka] The compound (XXXIV) is reacted with an acid to form R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXXV), [ka] The compound of formula (XXXV) is reacted with X 5 , R 6 , and R 7 Compounds of formula (XVI) wherein [ka] React with R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXIX), [ka] The compound of formula (XXIX) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0092] The present invention is 1 is C and X 4 is N, or a pharmaceutically acceptable salt thereof, comprising: R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined above, [ka] with an acid to form a compound of formula R 2 , R 3 , R 4 , R 5 , X 2 and X 3 A process for preparing a salt of formula (XXXVI), wherein [ka] The compound of formula (XXXVI) is reacted with X 5 , R 6 , and R 7 Compounds of formula (XVI) wherein [ka] React with R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXXVII), [ka] The compound of formula (XXXVII) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to form R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 , and X 3 is as defined above to form a compound of formula (XXXVIII), [ka] The compound of formula (XXXVIII) is reacted with 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0093] The present invention is 1 and X 4 is N, or a pharmaceutically acceptable salt thereof, comprising: R 4 , R 6 , R 7 , X 5 , and R 5 is as defined above [ka] , R 2 , R 3 , X 2 and X 3 is as defined above [ka] React with R 2 , R 3 , X 2 , X 3 , R 4 , R6 , R 7 , X 5 , and R 5 is as defined above to form a compound of formula (XL), [ka] The compound (XL) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to form R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XLI), wherein [ka] The compound (XLI) is reacted with di-tert-butyl dicarbonate and a base to give R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XLI) wherein [ka] The compound (XLII) is reacted with 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 to form one or more C 1-6Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] React with R 1 , R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XLIII), wherein [ka] reacting said compound of formula (XLIII) with an acid to form a compound of formula (I); A method comprising:

[0094] 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.

[0095] 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 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, etc. is mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, solvents, etc. can 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. When synthetic intermediates and final products contain potentially reactive functional groups, such as amino, hydroxyl, thiol, and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to use protected forms of the intermediates. Methods for the selection, introduction, and subsequent removal of protecting groups are well known to those skilled in the art. Compounds obtained using the general reaction sequences may be of insufficient purity. The compound can be purified by any of the purification methods for organic compounds, such as crystallization or silica gel column chromatography, alumina column chromatography, 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 have been characterized, for example, using LC-MS, NMR, and / or specific rotation.

[0096] Abbreviations used in these experimental details are listed below; additional abbreviations should be considered known to those skilled in the art of synthetic chemistry.

[0097] Abbreviations used herein are as follows: rt: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; EtOH: ethanol; TEA: triethylamine; HOAc: acetic acid; BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; BOC: tert-butyloxycarbonyl; N: normal; DMF: dimethylformamide; t-BuONa: sodium tertiary butoxide.

[0098] Chemical names are IUPAC preferred names.

[0099] 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.

[0100] General Procedure Scheme 1: [ka]

[0101] 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.

[0102] Scheme 1 shows X 1 =N and X 4 Routes for the synthesis of derivatives of the invention having formula (I) where =O are described.

[0103] These compounds are, for example, 4 and R 5 has the above-mentioned meaning, which can be obtained by coupling with a sulfonyl chloride of formula (III), 2 , X3 , R 2 and R 3 The corresponding sulfonamide of formula (IV), wherein R1 has the above-mentioned meaning, can be formed. The derivative of formula (VI) can be prepared by coupling the derivative of formula (IV) with commercially available boronic acids or boronic esters of formula (V), wherein R1 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 derivative of formula (VII), wherein X, can be converted under Buchwald conditions, for example, using Pd2(dba)3, BINAP, and Cs2CO3 as base. 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 can be converted into derivatives of formula (I), which have the meanings as previously described.

[0104] Scheme 2: [ka]

[0105] 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 shows X 1 =N and X 4 An alternative route for the synthesis of derivatives of the invention having formula (I) where =O is described.

[0107] The compounds of the present invention can be prepared, for example, under Buchwald conditions, by reacting the compound of formula X 2 , X 3 , R 2 , R 3 , R 4 and R 5 is a commercially available protected 4-aminopiperidine derivative of formula (IX) having the above-mentioned meaning, in which R 8 is a halogen, and X 5 , R 6 and R 7 can be obtained by coupling with an aryl halide derivative of formula (VIII), having the meanings given above, 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). Alternatively, the protected N-phenylpiperidin-4-amine derivative of formula (X) can be obtained by coupling with an aryl halide derivative of formula (VIII), having the meanings given above, to give the corresponding protected N-phenylpiperidin-4-amine derivative of formula (XI), 4 and R 5 has the above-mentioned meaning, and N-protected piperidin-4-one derivatives of formula (XV), in which X 5 , R 6 and R 7 The derivatives of formula (I) can be prepared under reductive amination conditions starting from aniline derivatives of formula (XVI), in which R has the meaning given above. The derivatives of formula (I) can be prepared by reacting a 4-aminopiperidine derivative (XI) with a derivative of formula (XI) in which R 1 , R 2 , R 3 , X 2 and X 3can be prepared by direct coupling with commercially available sulfonyl chlorides (XVII) having the above meaning. Alternatively, derivatives of 4-aminopiperidine derivatives (XI) can be coupled with 4-bromosulfonyl derivatives of formula (III) to give 1-(4-bromobenzenesulfonyl)-N-phenylpiperidin-4-amine derivatives of formula (XII), from which derivatives of formula (I) can be prepared by coupling derivatives of formula (XII) with commercially available boronic acids, or 1 can be prepared by direct coupling with a boronic ester of formula (V), having the aforementioned meaning, for example under Suzuki conditions using Pd(PPh3)4 and NaHCO3 in a dioxane / water mixture, or by first converting a piperidine derivative of formula (XII) into the corresponding boronic ester derivative of formula (XIII), which can then be reacted under Suzuki conditions with an R1-halide of formula (XIV), where R1 has the aforementioned meaning.

[0108] Scheme 3: [ka]

[0109] Conditions: i) TEA, CHCl, benzenesulfonyl chloride (XVII) rt; ii) aniline (XVI), 2-methylpyridine borane complex, CHOH, HOAc, rt; iii) 4-bromosulfonyl chloride (III), TEA, rt; iv) aniline (XVI), 2-methylpyridine borane complex, CHOH, HOAc, rt; v) R 1 -Boronic acid / ester (V), Pd(PPh3)4, NaHCO3, 1,4-dioxane / water, 110°C.

[0110] Scheme 3 shows X 1 =N and X 4 An alternative route for the synthesis of derivatives of the invention having formula (I) where =O is described.

[0111] In the formula, R 4 and R 5Starting from commercially available piperidin-4-one derivatives of formula (XVIII), in which R has the above-mentioned meaning, 1-(benzenesulfonyl)piperidin-4-one derivatives of formula (XX) can be prepared by converting a derivative of formula (XVIII) into a 1-(benzenesulfonyl)piperidin-4-one derivative of formula (XX), in which R 1 , R 2 , R 3 , X 2 and X 3 can be prepared by coupling a 1-(benzenesulfonyl)piperidin-4-one derivative of formula (XX) with a benzenesulfonyl chloride derivative of formula (XVII), having the meaning given above, under reductive amination conditions to give a 1-(benzenesulfonyl)piperidin-4-one derivative of formula (XX), in which X 5 , R 6 and R 7 has the meaning given above, may be coupled with an appropriate aniline derivative of formula (XVI) to give the corresponding derivative of formula (I).

[0112] Alternatively, a derivative of the piperidin-4-one derivative of formula (XVIII) can be prepared by reacting the derivative of the piperidin-4-one derivative of formula (XVIII) with a compound of formula (XVIII) 2 , X 3 , R 2 and R 3 can be coupled with a 4-bromosulfonyl derivative of formula (III), as defined above, to give a 1-(4-bromobenzenesulfonyl)piperidin-4-one derivative of formula (XIX), which can be converted under reductive amination conditions to a 1-(4-bromobenzenesulfonyl)piperidin-4-one derivative of formula (XIX), in which X 5 , R 6 and R 7 can be converted to the corresponding derivative of formula (XII) using an appropriate aniline derivative of formula (XVI), as defined above. Under Suzuki conditions, for example, using Pd(PPh3)4 and NaHCO3 in a dioxane / water mixture, the bromophenyl derivative of formula (XII) can be converted to the corresponding derivative of formula (XII) using commercially available boronic acids, or 1 has the meaning given above, can be coupled with a boronic ester of formula (V) to give the corresponding derivative of formula (I).

[0113] Scheme 4: [ka]

[0114] 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.

[0115] Scheme 4 shows X 1 =C and X 4 Routes for the synthesis of derivatives of the invention having formula (I) where =O are described.

[0116] As shown in Scheme 4, the derivatives of the present invention having formula (I) can be readily prepared by one skilled in the art of organic chemistry, where R 4 and R 5The N-Boc-protected cis-4-aminocyclohexan-1-ol derivatives of formula (XXI), in which ##STR00010## has the meaning as defined above, can be obtained by coupling 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]cyclohexan-1-amine derivatives of formula (XXIV) via nucleophilic substitution with 4-bromobenzene-1-thiol derivatives of formula (XXIII) using a suitable base, such as CsCO, which can be oxidized to the corresponding N-Boc-protected sulfonyl derivatives of formula (XXV) using, for example, mCPBA as an oxidizing agent. These sulfonyl derivatives of formula (XXV) can then be coupled with a suitable boronic acid or boronic ester of formula (V) under Suzuki conditions, for example using Pd(PPh3)4 as a catalyst, to form the corresponding derivatives of formula (XXVI). After removing the Boc group of the derivatives of formula (XXVI) under acidic conditions, for example using TFA, the resulting derivatives of formula (XXVII) can be converted to the corresponding derivatives of formula (XXVII) under Buchwald conditions, for example, by the addition of a methyl group to the derivatives of formula (XXVII) in which R 8 is a halogen, and X 5 , R 6 and R 7 can be prepared by the reaction of X with a suitable aryl halide (VIII) having the above-mentioned meaning, for example, with 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 can be converted into derivatives of formula (I) having the above mentioned meanings.

[0117] Scheme 5: [ka]

[0118] 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 (XIV), Pd(PPh3)4, 2N K2CO3, toluene / ethanol, 90°C.

[0119] Scheme 5 shows X 1 =C and X 4 An alternative route for the synthesis of derivatives of the invention having formula (I) where =O is described.

[0120] Alternatively, 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 under Buchwald conditions as described above to a derivative of formula (XXIX). The derivative of formula (XXIX) can be converted to a derivative of formula (XXIX) using, for example, Pd(PPh3)4 as a catalyst with an appropriate boronic acid under Suzuki conditions, or 1 has the above meaning, or by reacting the derivative of formula (XXIX) with a suitable R 1 -halides to the corresponding boronic esters of formula (XXX).

[0121] Scheme 6: [ka]

[0122] Conditions: i) CH3SO2Cl, Et3N, CH2Cl2, rt; ii) 4-bromobenzenethiol (XXIII), Cs2CO3, acetone, 60 °C; iii) mCPBA, ethyl acetate, rt; iv) 2NHCl, 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.

[0123] Scheme 6 shows X 1 =C and X 4 An alternative route for the synthesis of derivatives of the invention having formula (I) where =O is described.

[0124] These compounds are, for example, 4 and R 5 can be obtained starting from readily available keto-protected 4-hydroxycyclohexan-1-one derivatives of formula (XXXI) as previously defined, in which the hydroxyl group is converted to a suitable leaving group, for example, mesyl or tosyl, to give derivatives of formula (XXXII), which can be reacted with 4-bromobenzenethiol derivatives of formula (XXIII) to form phenylsulfanyl derivatives of formula (XXXIII). After oxidation of 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 give 4-hydroxycyclohexanone derivatives of formula (XXXV), in which X 5 , R 6 and R 7The derivative of formula (I) can then be coupled to a derivative of formula (XXIX) with a commercially available boronic acid or a phenyl amine derivative of formula (XXIX), where R 1 has the above-mentioned meaning, for example under Suzuki conditions using Pd(PPh3)4 and NaHCO3 in a dioxane / water mixture, or by first converting the derivative of formula (XXIX) into the corresponding boronic acid or boronic ester of formula (XXX), which is then converted under Suzuki conditions into the corresponding boronic acid or boronic ester of formula (XIV), where R1 has the above-mentioned meaning, 1 -Halogenated amines can be prepared by reacting them with halogenated amines.

[0125] Scheme 7: [ka]

[0126] Conditions: i) 2NHCl, 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 1 -Halide (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.

[0127] Scheme 7 shows X 1 =C and X 4 A route for synthesizing derivatives of the invention having formula (I) where =N is described.

[0128] 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). 5 , R 6 and R 7 The derivatives of formula (XXXVIII) can be prepared by coupling with an appropriate aniline derivative of formula (XVI), where R has the aforementioned meaning, to obtain the corresponding N-[4-(phenylsulfanyl)cyclohexyl]aniline derivative of formula (XXXVII). The derivatives of formula (XXXVIII) can be prepared by converting the derivatives of formula (XXXVII) to the corresponding sulfoximine derivatives by using ammonium carbamate, (diacetoxyiodo)benzene, and CHCN in CHOH. Finally, the derivatives of formula (XXXVIII) can be converted to derivatives of formula (I) by reaction with an appropriate boronic acid or boronic ester of formula (V), where R has the aforementioned meaning, under Suzuki conditions, for example using Pd(PPh) as catalyst, or by first converting the derivatives of formula (XXXVIII) to their corresponding boronic esters of formula (XXXIX), which can then be further converted to derivatives of formula (I) under Suzuki conditions, as described above, with an appropriate R 1 -Can react with halides.

[0129] Scheme 8: [ka]

[0130] 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.

[0131] Scheme 8 describes a route for synthesizing derivatives of the invention having formula (I) when X1 and X4 are N.

[0132] In the formula, X 5 , R 4 , R 5 , R 6 and R 7 has the above-mentioned meaning, for example by using Cs2CO3 as base to prepare an N-phenylpiperidin-4-amine derivative of formula (XI) in which X 2 , X 3 , R 2 and R 3 The N-phenyl-1-(phenylsulfanyl)piperidin-4-amine derivatives of formula (XL) can be converted to the corresponding sulfonimide amide derivatives of formula (XLI) by reaction with a 4-bromobenzene-1-thiol derivative of formula (XXIII), where X has the meaning as defined above. The derivatives of formula (XL) can be converted to the corresponding sulfonimide amide derivatives of formula (XLI) by using ammonium carbamate, (diacetoxyiodo)benzene, and CHCN in CHOH. After protecting the sulfonimide amide nitrogen with, for example, a Boc group, the derivatives of formula (XLII) can be reacted with an appropriate boronic acid of formula (V) under Suzuki conditions as described above to obtain the derivatives of formula (XLIII). In the final step, the Boc group is removed under acidic conditions to give the derivatives of formula (XLIII) in which X 2 , X 3 , X 5 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 has the above-mentioned meaning, the corresponding derivatives of formula (I) can be obtained.

[0133] Pharmaceutical Compositions and Methods of 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.

[0134] 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.

[0135] Another embodiment of the present invention is a pharmaceutical composition as described herein further comprising an additional therapeutic agent.

[0136] Indications The compounds of formula (I), or (I') described herein may be used in an effective amount to treat subjects, particularly humans, suffering from inflammatory autoimmune diseases.

[0137] One embodiment of the present invention is a compound, as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0138] One embodiment of the present invention is a compound, as described herein, or a pharmaceutically acceptable salt thereof, for use in treating, preventing and / or delaying inflammatory autoimmune diseases.

[0139] 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.

[0140] 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, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

[0141] 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 progression of psoriatic disease, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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) (a) inhibiting one or more points in the biological cascade that leads to or contributes to the condition, or (b) interfering with 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. Preventive 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 lupus erythematosus. [Example]

[0146] Example 1: 4'-[(4-{[4-(1-cyanocyclopropyl)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile [ka]

[0147] 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) was obtained, which was used in the next step without further purification.

[0148] 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 2M aqueous K2CO3 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 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 to give tert-Butyl N-[1-({4'-cyano-[1,1'-biphenyl]-4-yl}sulfonyl)piperidin-4-yl]carbamate (500 mg) was obtained as a brown oil which was used in the next step without further purification.

[0149] iii) To a solution of the product obtained in the previous step (500 mg) in ethyl acetate (20 mL) was added a 2N HCl solution in diethyl ether (5.7 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to give: 4'-[(4-aminopiperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile hydrochloride (500 mg) was obtained, which was used in the next step without further purification.

[0150] iv) Under a nitrogen atmosphere, to a suspension of the product obtained in the previous step (50 mg), 1-(4-bromophenyl)cyclopropane-1-carbonitrile (29 mg), Cs2CO3 (216 mg), and BINAP (9.1 mg) in toluene (3 mL) was added Pd2(dba)3 (6.1 mg). 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-(1-cyanocyclopropyl)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile(9 mg) was obtained as a white solid. MS (ES + ) m / z 483.1 (M+H) + .

[0151] 1 H NMR(400MHz,DMSO)δ8.09-7.96(m,6H),7.92-7.84(m,2H),7.04-6.96(m,2H),6.57-6.49(m,2H),5.63(d,J=8.2Hz,1H),3.64-3 .56(m,2H),3.30-3.22(m,1H),2.62-2.53(m,2H),1.99-1.91(m,2H),1.59-1.51(m,2H),1.48-1.32(m,2H),1.30-1.23(m,2H).

[0152] Example 2: 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine. [ka]

[0153] i) Under a nitrogen atmosphere, to a suspension of tert-butyl 4-aminopiperidine-1-carboxylate (1.0 g), t-BuONa (2.88 g), 1-bromo-4-[1-(trifluoromethyl)cyclopropyl]benzene (1.59 g), and Xantphos (690 mg) in toluene (6 mL) was added Pd2(dba)3 (460 mg). The reaction mixture was stirred overnight at 90 °C in a microwave. After cooling to room temperature, the reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified on SiO2 using 10% to 100% ethyl acetate in heptane as the eluent. tert-Butyl 4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidine-1-carboxylate (0.7 g) was obtained as a yellow solid.

[0154] ii) A solution of 5N hydrochloric acid in 2-propanol (3.6 mL) was added to a solution of the product obtained in the previous step (0.7 g) in ethyl acetate (10 mL) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was concentrated under reduced pressure. N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine hydrochloride(0.7 g) was obtained as a white solid, which was used in the next step without further purification.

[0155] iii) To a suspension of the product obtained in the previous step (0.58 g) in ethyl acetate (15 mL) and triethylamine (1.3 mL) at room temperature, 4-bromobenzene-1-sulfonyl chloride (506 mg) was added in portions. 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 dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified on SiO using 40% ethyl acetate in heptane as the eluent. 1-(4-Bromobenzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine (1.0 g) was obtained as a white solid.

[0156] iv) Under a nitrogen atmosphere, Pd(PPh) (11 mg) was added to a suspension of the product obtained in the previous step (100 mg), {3-methylimidazo[1,2-a]pyridin-6-yl}boronic acid (38 mg), and NaHCO (83 mg) in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL). The reaction mixture was stirred in a microwave at 100 °C for 2 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 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. [(4-{3-methylimidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-{[4-(pentafluoro-λ 6 -sulfanyl)phenyl]amino}cyclohexyl]imino-λ 6 -sulfanyl]one (45 mg) was obtained as a white solid. MS (ES + ) m / z 555.4 (M+H) + .

[0157] 1H NMR(400MHz,DMSO)δ12.79(s,1H),8.13(s,1H),8.06-7.90(m,2H),7.88-7.78(m,2 H),7.74(dd,J=8.8,1.7Hz,1H),7.60(dd,J=8.7,0.8Hz,1H),7.11-7.02(m,2H),6.5 6-6.48(m,2H),5.66(d,J=8.0Hz,1H),3.63-3.56(m,2H),3.32-3.19(m,1H),2.59- 2.55(m,5H),2.03-1.92(m,2H),1.50-1.36(m,2H),1.23-1.12(m,2H),0.94(s,2H).

[0158] Examples 3-9 were prepared following a similar procedure to that described for Example 2, using the appropriate (hetero)aryl halide in step I and the appropriate boronic ester or boronic acid in step iv.

[0159] Examples 3 to 9 Example 3: 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine [ka] MS(ES + ) m / z 555.4.2 (M+H) + .

[0160] 1 H NMR(400MHz,DMSO)δ8.71(s,1H),8.14-8.06(m,2H),7.91-7.83(m,2H),7 .77-7.68(m,2H),7.51(s,1H),7.12-7.05(m,2H),6.56-6.47(m,2H),5.6 7(d,J=8.0Hz,1H),3.64-3.56(m,2H),3.45-3.21(m,1H),2.62-2.52(m,5 H),2.00-1.93(m,2H),1.49-1.34(m,2H),1.23-1.16(m,2H),0.94(s,2H).

[0161] Building blocks: step i: 1-bromo-4-[1-(trifluoromethyl)cyclopropyl]benzene; step iv: {3-methylimidazo[1,2-a]pyridin-6-yl}boronic acid.

[0162] Example 4: N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-3-carboxamide. [ka] MS(ES + ) m / z 558.4 (M+H) + .

[0163] 1 H NMR(400MHz,DMSO)δ8.65-8.59(m,1H),8.21(t,J=1.8,1.8Hz,1H),8.06-7.99(m,2H),7.95 -7.90(m,2H),7.90-7.84(m,2H),7.63(t,J=7.7,7.7Hz,1H),7.08(d,J=8.4Hz,2H),6.55-6. 48(m,2H),5.67(d,J=8.1Hz,1H),3.63-3.56(m,2H),3.29-3.20(m,1H),2.84(d,J=4.5Hz,3H ),2.62-2.54(m,2H),1.99-1.92(m,2H),1.48-1.36(m,2H),1.26-1.12(m,2H),0.94(s,2H).

[0164] Building blocks: step i: 1-bromo-4-[1-(trifluoromethyl)cyclopropyl]benzene; step iv: [3-(methylcarbamoyl)phenyl]boronic acid.

[0165] Example 5: N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide. [ka] MS(ES + ) m / z 558.4 (M+H) + .

[0166] 1 H NMR(400MHz,DMSO)δ8.57-8.53(m,1H),8.05-7.96(m,4H),7.94-7.81(m,4H),7.08(d,J=8.5Hz,2H),6.55-6.47(m,2H),5.66(d,J=8.1Hz,1H),3.6 3-3.55(m,2H),3.31-3.23(m,1H),2.82(d,J=4.5Hz,3H),2.61-2.54(m,2 H),1.99-1.92(m,2H),1.48-1.36(m,2H),1.23-1.16(m,2H),0.94(s,2H).

[0167] Building blocks: step i: 1-bromo-4-[1-(trifluoromethyl)cyclopropyl]benzene; step iv: [4-(methylcarbamoyl)phenyl]boronic acid.

[0168] Example 6: N-methyl-5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide. [ka] MS(ES + ) m / z 559.4 (M+H) +

[0169] 1H NMR(400MHz,DMSO)δ9.04(dd,J=2.3,0.8Hz,1H),8.86(q,J=5.0,4.8,4.8Hz,1H),8.38(dd,J=8.2 ,2.3Hz,1H),8.16(dd,J=8.2,0.8Hz,1H),8.14-8.09(m,2H),7.96-7.86(m,2H),7.11-7.05(m,2H ),6.55-6.47(m,2H),5.67(d,J=8.0Hz,1H),3.64-3.56(m,2H),3.30-3.21(m,1H),2.86(d,J=4.8 Hz,3H),2.62-2.53(m,2H),1.99-1.92(m,2H),1.48-1.36(m,2H),1.23-1.16(m,2H),0.94(s,2H).

[0170] Building blocks: step i: 1-bromo-4-[1-(trifluoromethyl)cyclopropyl]benzene; step iv: N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide.

[0171] Example 7: 4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide. [ka] MS(ES + ) m / z 544.3 (M+H) +

[0172] 1H NMR(400MHz,DMSO)δ8.09(s,1H),8.06-8.00(m,4H),7.91-7.81(m,4H),7.46(s,1H),7.11-7.05(m,2H),6.55-6.47(m,2H),5.66(d,J=8. 1Hz,1H),3.63-3.56(m,2H),3.30-3.21(m,1H),2.62-2.55(m,2H),1.99-1.92(m,2H),1.48-1.35(m,2H),1.26-1.16(m,2H),0.94(s,2H).

[0173] Building blocks: step i: 1-bromo-4-[1-(trifluoromethyl)cyclopropyl]benzene; step iv: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.

[0174] Example 8: 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile. [ka] MS(ES + ) m / z 565.4 (M+H) + .

[0175] 1 H NMR(400MHz,DMSO)δ12.33(s,1H),8.35(s,1H),8.06-8.01(m,2H),8.00(t,J=1.3 ,1.3Hz,1H),7.88-7.79(m,2H),7.70(t,J=1.1,1.1Hz,2H),7.12-7.02(m,2H),6.5 6-6.48(m,2H),5.66(d,J=8.1Hz,1H),3.64-3.56(m,2H),3.32-3.21(m,1H),2.61- 2.52(m,2H),2.00-1.92(m,2H),1.50-1.36(m,2H),1.23-1.15(m,2H),0.94(s,2H)

[0176] Building blocks: step i: 1-bromo-4-[1-(trifluoromethyl)cyclopropyl]benzene; step iv: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile.

[0177] Example 9: 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine. [ka] MS(ES + ) m / z 541.4 (M+H) + .

[0178] 1 H NMR(400MHz,DMSO)δ9.10(dd,J=1.9,1.1Hz,1H),8.04-7.98(m,3H),7.89-7.84(m ,2H),7.72(d,J=9.4Hz,1H),7.67(dd,J=9.7,1.6Hz,2H),7.12-7.05(m,2H),6.56- 6.48(m,2H),5.67(d,J=8.1Hz,1H),3.64-3.55(m,2H),3.31-3.23(m,1H),2.62-2 .52(m,2H),1.99-1.92(m,2H),1.49-1.36(m,2H),1.26-1.14(m,2H),0.94(s,2H).

[0179] Building blocks: step i: 1-bromo-4-[1-(trifluoromethyl)cyclopropyl]benzene; step iv: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.

[0180] Example 10: 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine. [ka]

[0181] i) To a suspension of 1-(4-bromobenzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine (Example 2, Step iii, 176 mg), bis(pinacolato)diboron (133 mg), and potassium acetate (103 mg) in 1,4-dioxane (4 mL) purged with N gas, PdCl(dppf).CHCl (13 mg) was added. The reaction mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was poured into water, and the product was extracted into CHCl. ​​The organic layer was washed with brine, dried over MgSO, and concentrated under reduced pressure to give N-[4-(pentafluoro-λ 6 -sulfanyl)phenyl]-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]piperidin-4-amine (190 mg) was obtained as a black solid, which was used in the next step without further purification.

[0182] ii) Under a nitrogen atmosphere, Pd(PPh) (11 mg) was added to a suspension of the product obtained in the previous step (190 mg), 6-bromo-3-(propan-2-yl)imidazo[1,2-a]pyridine (117 mg), and NaHCO (148 mg) in a mixture of 1,4-dioxane (4 mL) and water (1 mL). The reaction mixture was stirred in a microwave at 120 °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 MgSO, filtered, and concentrated under reduced pressure. The residue was purified on a C18 column using 10% to 60% CHCN 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-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine (55 mg) was obtained as a white solid. MS (ES + ) m / z 583.4 (M+H) + .

[0183] 1H NMR(400MHz,DMSO)δ8.74-8.69(m,1H),8.12-8.05(m,2H),7.89-7.82(m,2H),7.70(dd,J=9.4,0.9Hz,1 H),7.63(dd,J=9.4,1.8Hz,1H),7.46(d,J=0.8Hz,1H),7.08(d,J=8.3Hz,2H),6.56-6.48(m,2H),5.67(d ,J=8.1Hz,1H),3.65-3.58(m,2H),3.52(p,J=6.9,6.9,6.8,6.8Hz,1H),3.33-3.22(m,1H),2.61-2.54( m,2H),2.00-1.93(m,2H),1.49-1.40(m,2H),1.37(s,3H),1.36(s,3H),1.26-1.12(m,2H),0.94(s,2H).

[0184] Example 11: N-(4-cyclopropylphenyl)-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine. [ka]

[0185] 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 precipitated overnight and the solid was filtered and dried under reduced pressure to give: 1-(4-Bromobenzenesulfonyl)piperidin-4-one (15.1 g) was obtained as an off-white solid, which was used in the next step without further purification.

[0186] ii) Under a nitrogen atmosphere, 2-methylpyridine borane complex (51 mg) was added at 0° C. to a solution of the product obtained in the previous step (150 mg), 4-cyclopropylaniline hydrochloride (80 mg), and trifluoroacetic acid (300 μL) in methanol (3 mL). The reaction mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, 2N aqueous HCl (20 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 5N aqueous NaOH (20 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. The resulting brown oil was purified on SiO using 30% ethyl acetate in heptane as the eluent to give 1-(4-Bromobenzenesulfonyl)-N-(4-cyclopropylphenyl)piperidin-4-amine (146 mg) was obtained as a brown solid, which was used in the next step without further purification.

[0187] iii) Under a nitrogen atmosphere, Pd(PPh3)4 (19 mg) was added to a suspension of the product obtained in the previous step (146 mg), (3-methyl-1H-indazol-5-yl)boronic acid (65 mg), and NaHCO3 (169 mg) in a mixture of 1,4-dioxane (3 mL) and water (3 mL). The reaction mixture was stirred in a microwave at 110 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered through Celite, 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. N-(4-cyclopropylphenyl)-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine (27 mg) was obtained as a white solid. MS (ES + ) m / z 487.3 (M+H) + .

[0188] 1H NMR(400MHz,DMSO)δ12.78(s,1H),8.13(dd,J=1.8,0.8Hz,1H),8.05-7.98(m,2H),7.85-7.80(m,2H) ,7.75(dd,J=8.8,1.7Hz,1H),7.59(dd,J=8.7,0.8Hz,1H),6.79-6.71(m,2H),6.49-6.41(m,2H),5.22 (d,J=8.3Hz,1H),3.63-3.55(m,2H),3.25-3.16(m,1H),2.57(s,3H),2.55-2.52(m,2H),1.99-1.92(m ,2H),1.71(tt,J=8.4,8.4,5.1,5.1Hz,1H),1.46-1.33(m,2H),0.81-0.70(m,2H),0.50-0.41(m,2H).

[0189] Following a similar procedure as described for Example 11, using the appropriate boronic ester or boronic acid in step iii, Example 12 was prepared.

[0190] Example 12: 5-[4-({4-[(4-cyclopropylphenyl)amino]piperidin-1-yl}sulfonyl)phenyl]-1H-indole-3-carbonitrile. [ka] MS(ES + ) m / z 497.3 (M+H) + .

[0191] 1H NMR(400MHz,DMSO)δ12.36(s,1H),8.34(s,1H),8.06-8.01(m,2H),7.99(t,J=1.3,1.3Hz,1H ),7.86-7.78(m,2H),7.70(d,J=1.3Hz,2H),6.79-6.71(m,2H),6.49-6.41(m,2H),5.22(d,J =8.4Hz,1H),3.63-3.56(m,2H),3.27-3.16(m,1H),2.62-2.53(m,2H),1.99-1.91(m,2H),1. 71(tt,J=8.4,8.4,5.1,5.1Hz,1H),1.46-1.34(m,2H),0.81-0.70(m,2H),0.50-0.41(m,2H).

[0192] Building Blocks: Step ii: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile.

[0193] Example 13: (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone. [ka]

[0194] i) To a 0° C. cooled solution of 4-hydroxycyclohexanone monoethylene ketal (50 g) and EtN (57 mL) in CHCl (100 mL) was added dropwise a solution of methanesulfonyl chloride (32 mL) in CHCl (100 mL). The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was poured into saturated aqueous NaHCO 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-Dioxaspiro[4.5]decan-8-yl methanesulfonate was obtained as a yellow oil (82 g) which was used in the next step without further purification.

[0195] ii) To a suspension of the product obtained in the previous step (74.7 g) and Cs2CO3 (257.4 g) in acetone (1500 mL) was added 4-bromothiophenol (89.6 g) at room temperature. The reaction mixture was stirred at 60 °C overnight. After the reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added. The product was extracted into ethyl acetate, and the combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting brown oil (130 g) was purified on SiO2 using 0% to 100% EtOAc in heptane as the eluent to give: 8-[(4-bromophenyl)sulfanyl]-1,4-dioxaspiro[4.5]decane was obtained as a clear oil (64.7 g) which slowly solidified.

[0196] iii) To a suspension of the product (5 g) obtained in the previous step and ammonium carbamate (1.8 g) in a mixture of methanol (10 mL) and acetonitrile (10 mL), (diacetoxyiodo)benzene (10.2 g) was added at room temperature. The reaction mixture was stirred at room temperature in an open flask for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. At this stage, the cis / trans mixture was separated on a C18 column using 10% to 100% aqueous acetonitrile. [(4-bromophenyl)({1,4-dioxaspiro[4.5]decan-8-yl})imino-λ 6 -sulfanyl]one (5.3g) was obtained.

[0197] iv) 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. Upon 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.

[0198] v) To a solution of 4-[1-(trifluoromethyl)cyclopropyl]aniline hydrochloride (950 mg) in a mixture of CHCl (9 mL) and methanol (1 mL), SillaBond® carbonate (Si—CO) was added, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was filtered and concentrated under reduced pressure to give 4-[1-(trifluoromethyl)cyclopropyl]aniline. To a solution of the product obtained in the previous step (998 mg), 4-[1-(trifluoromethyl)cyclopropyl]aniline, and HOAc (2 mL) in methanol (10 mL) was added 2-methylpyridine borane complex (1.46 g) at 0° C. The reaction mixture was stirred overnight at room temperature. After completion, the reaction mixture was concentrated under reduced pressure and cooled to 0° C., followed by the addition of 2N aqueous HCl (5 mL). After stirring at 0° C. for 1 hour, a 5N aqueous solution of NaOH 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 eluent. (4-Bromophenyl)[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone (400 mg) was obtained as a white solid.

[0199] vi) 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)imidazo[1,2-a]pyridine (61 mg), and NaHCO3 (84 mg) in a mixture of 1,4-dioxane (4 mL) and water (1 mL) was added Pd(PPh3)4 (12 mg). The reaction mixture was stirred in a microwave at 120 °C for 1 h. After cooling to room temperature, the product was extracted into EtOAc, and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting brown solid was purified on a C18 column using 60% to 95% acetonitrile in water as the eluent to give the title compound. (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone was obtained as a white solid (48 mg). MS (ES + ) m / z 539.4 (M+H) + .

[0200] 1 H NMR(400MHz,DMSO)δ9.09(t,J=1.5,1.5Hz,1H),8.02-8.00(m,1H),8.00-7.93(m,4H),7.71(d,J=9.4Hz,1H),7.69-7.64(m,2H),7.12-7.05(m,2H) ,6.55-6.47(m,2H),5.57(d,J=7.9Hz,1H),4.26(s,1H),3.13-3.03(m,2H ),2.06-1.95(m,4H),1.58-1.40(m,2H),1.26-1.10(m,4H),0.94(s,2H).

[0201] Example 14: 4-(2,2-Difluorocyclopropyl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline. [ka]

[0202] i) To a suspension of tert-butyl N-[4-(methanesulfonyloxy)cyclohexyl]carbamate (43.7 g) and Cs2CO3 (120.6 g) in acetone (400 mL) was added 4-bromothiophenol (42.0 g) at room temperature. The reaction mixture was stirred at 60°C overnight. Upon completion, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in a water / ethyl acetate mixture and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over 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 (36.5g) was obtained as a white solid.

[0203] ii) To a solution of the product obtained in the previous step (23 g) in ethyl acetate (200 mL) was added mCPBA (51.4 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, water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. To remove the last traces of 3-chlorobenzoic acid, the resulting white solid was dissolved in ethyl acetate and stirred for 30 minutes in the presence of silica-bound carbonate. The mixture was filtered and concentrated under reduced pressure to give the filtrate. tert-Butyl N-[trans-4-(4-bromobenzenesulfonyl)cyclohexyl]carbamate (12.9 g) was obtained as a white solid.

[0204] iii) Under a nitrogen atmosphere, to a solution of the product obtained in the previous step (2.0 g), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (1.5 l), and NaHCO3 (2.4 g) in a mixture of 1,4-dioxane (12 mL) and water (3 mL) was added Pd(PPh3)4 (276 mg). The reaction mixture was stirred 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 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 100% acetonitrile in water as the eluent. tert-Butyl N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]carbamate (2.2 g) was obtained as a clear solid.

[0205] iv) To a solution of the product obtained in the previous step (2.0 g) in ethyl acetate (40 mL) was added a 5N HCl solution in 2-propanol (8.9 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was concentrated under reduced pressure to give trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexane-1-amine hydrochloride (1.9 g) was obtained as a yellow solid, which was used in the next step without further purification.

[0206] v) Under a nitrogen atmosphere, to a suspension of the product obtained in the previous step (100 mg), 1-bromo-4-(2,2-difluorocyclopropyl)benzene (71 mg), sodium tert-butoxide (147 mg), and Xantphos (37 mg) in toluene (15 mL) was added Pd2(dba)3 (23 mg). The reaction mixture was stirred overnight at 100 °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-(2,2-Difluorocyclopropyl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline (10 mg) was obtained as a white solid. MS (ES + ) m / z 508.3 (M+H) + .

[0207] 1 H NMR(400MHz,DMSO)δ9.11(t,J=1.4,1.4Hz,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=9.5,1.9Hz,1H),7.66(d,J=1.2Hz,1H),6.95-6.89(m,2H),6.57-6.4 9(m,2H),5.42(d,J=8.1Hz,1H),3.38-3.34(m,1H),3.20-3.09(m,1H),2.76(td,J=12.7,12.7,8.1Hz ,1H),2.10-1.95(m,4H),1.89-1.75(m,1H),1.74-1.61(m,1H),1.61-1.47(m,2H),1.22-1.10(m,2H).

[0208] Example 15 was prepared following a similar procedure as described for Example 14, using the appropriate boronic ester or boronic acid in step iii and the appropriate (hetero)aryl halide in step v.

[0209] Example 15: 1-(4-{[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]amino}phenyl)cyclopropane-1-carbonitrile. [ka] MS(ES + ) m / z 497.3 (M+H) +

[0210] 1 H NMR(400MHz,DMSO)δ9.11(dd,J=1.9,1.1Hz,1H),8.05-8.02(m,2H),8.01(t,J=0.9,0.9Hz,1H ),7.99-7.94(m,2H),7.72(dt,J=9.5,0.9,0.9Hz,1H),7.68(dd,J=9.5,1.9Hz,1H),7.66(d,J= 1.2Hz,1H),7.05-6.97(m,2H),6.59-6.51(m,2H),5.58(d,J=8.1Hz,1H),3.38-3.33(m,1H),3 .22-3.11(m,1H),2.10-1.95(m,4H),1.62-1.47(m,4H),1.31-1.25(m,2H),1.21-1.10(m,2H).

[0211] Building blocks: step iii: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine; step v: 1-(4-bromophenyl)cyclopropane-1-carbonitrile.

[0212] Example 16: 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile. [ka]

[0213] 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) was obtained as an oil which slowly solidified. The product was used in the next step without further purification.

[0214] ii) To a suspension of the product obtained in the previous step (3.3 g) and cesium carbonate (5.46 g) in acetone (50 mL) was added 4-bromobenzene-1-thiol (2.64 g). 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 SiO2 using 0% to 60% ethyl acetate in heptane as the eluent. 8-[(4-bromophenyl)sulfanyl]-1,4-dioxaspiro[4.5]decane (3.68g) was obtained as a white solid.

[0215] iii) To a solution of the product obtained in the previous step (3.68 g) in ethyl acetate (50 mL) was added 3-chloroperbenzoic acid (9.64 g) and the reaction mixture was stirred at room temperature overnight. 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 eluent. 8-(4-Bromobenzenesulfonyl)-1,4-dioxaspiro[4.5]decane (3.68g) was obtained as a white solid.

[0216] 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. Upon completion, the reaction mixture was washed with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-(4-Bromobenzenesulfonyl)cyclohexan-1-one (3.0 g) was obtained as a white solid, which was used in the next step without further purification.

[0217] v) To a suspension of the product obtained in the previous step (501 mg) and 4-[1-(trifluoromethyl)cyclopropyl]aniline hydrochloride (498 mg) in a mixture of HOAc (1 mL) in CHOH (10 mL) was added 2-methylpyridine borane complex (183 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 2N aqueous HCl (5 mL) was added at 0 °C. After stirring at 0 °C for 1 h, 5N 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 eluent to give N-[trans-4-(4-bromobenzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline (69 mg) was obtained as a white solid.

[0218] vi) Under a nitrogen atmosphere, to a solution of the product obtained in the previous step (69 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile (53 mg), and NaHCO3 (62 mg) in a mixture of 1,4-dioxane (4 mL) and ethanol (1 mL) was added Pd(PPh3)4 (10 mg). The reaction mixture was stirred in a microwave at 120 °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 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 60% to 95% acetonitrile in water as the eluent to give the title compound. 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile (48 mg) was obtained as a white solid. MS (ES + ) m / z 564.4 (M+H)+ .

[0219] 1 H 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),7.96-7.89(m,2H),7.71(t,J=1.0,1.0Hz,2H),7.09(d,J=8.5Hz,2 H),6.58-6.49(m,2H),5.60(d,J=8.0Hz,1H),3.40-3.34(m,1H),3.21-3.11(m,1 H),2.09-1.94(m,4H),1.61-1.46(m,2H),1.27-1.10(m,4H),1.00-0.90(m,2H).

[0220] Following a similar procedure as described for Example 16, using the appropriate aniline in step v and the appropriate boronic ester or boronic acid in step vi, Examples 17-19 were prepared.

[0221] Examples 17 to 19 Example 17: N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline [ka] MS(ES + ) m / z 540.4 (M+H) +

[0222] 1H NMR(400MHz,DMSO)δ9.11(dd,J=1.9,1.1Hz,1H),8.06-8.02(m,2H),8.02-8.00(m,1H),7. 99-7.94(m,2H),7.72(dt,J=9.4,0.9,0.9Hz,1H),7.68(dd,J=9.5,1.9Hz,1H),7.66(d,J=1 .2Hz,1H),7.13-7.05(m,2H),6.57-6.49(m,2H),5.60(d,J=8.0Hz,1H),3.39-3.34(m,1H) ,3.22-3.11(m,1H),2.11-1.95(m,4H),1.61-1.47(m,2H),1.26-1.10(m,4H),0.95(s,2H).

[0223] Building blocks: step v: 4-[1-(trifluoromethyl)cyclopropyl]aniline; step vi: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.

[0224] Example 18: 4-(Oxetan-3-yl)-N-[trans-4-(4-[imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline. [ka] MS(ES + ) m / z 488.4 (M+H) +

[0225] 1H NMR(400MHz,DMSO)δ9.11(dd,J=1.9,1.1Hz,1H),8.05-8.02(m,2H),8.01(s,1H),7.98-7.95(m,2H),7.72 (d,J=9.4Hz,1H),7.68(dd,J=9.5,1.9Hz,1H),7.66(d,J=1.2Hz,1H),7.11-7.03(m,2H),6.60-6.52(m,2H) ,5.36(d,J=8.1Hz,1H),4.84(dd,J=8.4,5.7Hz,2H),4.52(dd,J=7.0,5.7Hz,2H),4.05(ddd,J=15.4,8.4, 7.0Hz,1H),3.37-3.27(m,1H),3.21-3.10(m,1H),2.11-1.95(m,4H),1.61-1.47(m,2H),1.22-1.10(m,2H)

[0226] Building blocks: step v: 4-(oxetan-3-yl)aniline; step vi: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine.

[0227] Example 19: 5-(4-{[trans-4-{[4-(oxetan-3-yl)phenyl]amino}cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile. [ka] MS(ES + ) m / z 512.3 (M+H) +

[0228] 1H NMR(400MHz,DMSO)δ12.37(s,1H),8.35(s,1H),8.09-8.04(m,2H),8.01(t,1H),7.96-7 .89(m,2H),7.75-7.66(m,2H),7.11-7.03(m,2H),6.61-6.52(m,2H),5.36(d,J=8.2Hz,1 H),4.84(dd,J=8.4,5.7Hz,2H),4.52(dd,J=7.0,5.7Hz,2H),4.11-3.99(m,1H),3.32-3 .24(m,1H),3.21-3.10(m,1H),2.11-1.93(m,4H),1.61-1.47(m,2H),1.22-1.11(m,2H).

[0229] Building blocks: step v: 4-(oxetan-3-yl)aniline; step vi: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile.

[0230] Example 20: N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline. [ka]

[0231] i) To a suspension of N-[trans-4-(4-bromobenzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline (Example 16, Step v, 300 mg), bis(pinacolato)diboron (133 mg), and potassium acetate (228 mg) in N2 gas-purged 1,4-dioxane (10 mL) was added PdCl2(dppf).CHCl2 (30 mg). The reaction mixture was heated in a microwave at 100 °C overnight. After cooling to room temperature, the reaction mixture was poured into water and the product was extracted into CHCl2. 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]-4-[1-(trifluoromethyl)cyclopropyl]aniline(210 mg) was obtained as a black solid which was used in the next step without further purification.

[0232] ii) Under a nitrogen atmosphere, Pd(PPh) (11 mg) was added to a suspension of the product obtained in the previous step (210 mg), 6-bromo-3-(propan-2-yl)imidazo[1,2-a]pyridine (114 mg), and NaHCO (173 mg) in a mixture of 1,4-dioxane (4 mL) and water (1 mL). The reaction mixture was stirred in a microwave at 120 °C for 30 min. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, 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 a C18 column using 20% ​​to 95% CHCN 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]-4-[1-(trifluoromethyl)cyclopropyl]aniline (55 mg) was obtained as a white solid. MS (ES + ) m / z 582.4 (M+H) + .

[0233] 1 H NMR(400MHz,DMSO)δ8.77(t,J=1.4,1.4Hz,1H),8.14-8.07(m,2H),8.00-7.93(m,2H),7.73(dd,J= 9.5,1.0Hz,1H),7.69(dd,J=9.5,1.7Hz,1H),7.51(s,1H),7.13-7.06(m,2H),6.57-6.49(m,2H),5. 61(d,J=7.9Hz,1H),3.53(p,J=6.8,6.8,6.8,6.8Hz,1H),3.42-3.27(m,1H),3.22-3.09(m,1H),2.0 9-1.95(m,4H),1.62-1.47(m,2H),1.37(s,3H),1.36(s,3H),1.24-1.10(m,4H),0.97-0.93(m,2H).

[0234] Following a procedure similar to that described for Example 20, using the appropriate (hetero)aryl halide in step ii, Examples 21 and 22 were prepared.

[0235] Example 21: N-[(trans)-4-(4-{3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline. [ka] MS(ES + ) m / z 554.4 (M+H) +

[0236] 1 H NMR(400MHz,DMSO)δ11.55-11.43(d,J=2.5Hz,1H),8.65-8.59(d,J=2.2Hz,1H),8.37-8.29(d,J=2. 2Hz,1H),8.12-8.01(m,2H),7.99-7.90(m,2H),7.34-7.29(dd,J=2.3,1.2Hz,1H),7.14-7.04(m,2H) ,6.62-6.47(m,2H),5.65-5.57(d,J=8.0Hz,1H),3.31-3.27(m,1H),3.21-3.10(dt,J=14.8,5.5Hz, 1H),2.40-2.28(s,3H),2.10-1.93(m,4H),1.63-1.46(m,2H),1.26-1.09(m,4H),1.00-0.89(m,2H).

[0237] Building Blocks: Step ii: 5-Bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine.

[0238] Example 22: N-[(trans)-4-(4-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline. [ka] MS(ES + ) m / z 555.4 (M+H) +

[0239] 1 H NMR(400MHz,DMSO)δ13.47-13.30(m,1H),8.96-8.86(d,J=2.2Hz,1H),8.72-8.60(d,J =2.2Hz,1H),8.20-8.04(m,2H),8.04-7.90(m,2H),7.23-7.03(d,J=8.3Hz,2H),6.62-6 .46(m,2H),5.69-5.51(d,J=8.0Hz,1H),3.39-3.35(m,1H),3.24-3.09(m,1H),2.61-2. 55(s,3H),2.09-1.94(m,4H),1.63-1.46(m,2H),1.27-1.09(m,4H),0.99-0.91(s,2H).

[0240] Example 23: 1-(6-{[1-(4-{2-methoxy-7-azaspiro[3.5]nonan-7-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile. [ka]

[0241] i) Pd(OAc)2 (754 mg) enJosiphosSL-J009-1 (1.86 g) in THF (250 mL) In a solution of Under a nitrogen atmosphere, 1-(6-chloropyridin-3-yl)cyclopropane-1-carbonitrile (6.00 g), NaOt-Bu (4.52 g), and tert-butyl 4-aminopiperidine-1-carboxylate (8.07 g) were added. The reaction mixture was stirred in a sealed vial at 100° C. overnight. 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 brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting black oil was purified on SiO2 using 5% to 100% EtOAc in heptane as the eluent to give tert-Butyl 4-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}piperidine-1-carboxylate (6.52 g) was obtained as a white solid.

[0242] ii) To a solution of the product obtained in the previous step (6.52 g) in ethyl acetate (130 mL), a solution of 5N HCl in 2-propanol (100 mL) was added, and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 1-{6-[(piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile hydrochloride (6.3 g) was obtained as a pale yellow solid, which was used in the next step without further purification.

[0243] iii) To a solution of the product obtained in the previous step (1, 7 g) and EtN (1, 3 mL) in ethyl acetate (45 mL) was added 4-fluorobenzene-1-sulfonyl chloride (0.70 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by pouring into water. The product was extracted into CHCl, and the combined organic layers were dried over MgSO, filtered and concentrated under vacuum to give 1-(6-{[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile (1.0 g) was obtained as an off-white solid, which was used in the next step without further purification.

[0244] iv) In a capped microwave vial, a mixture of the product from the previous step (75 mg), 2-methoxy-7-azaspiro[3.5]nonane hydrochloride (63 mg), and KCO (91 mg) in NMP (2 mL) was stirred at 130 °C overnight. 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 dried over MgSO, filtered, and concentrated under vacuum, and the resulting oil was purified on a C18 column using 20% ​​to 60% acetonitrile in water as eluent to give the title compound. 1-(6-{[1-(4-{2-methoxy-7-azaspiro[3.5]nonan-7-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile (42 mg) was obtained as a white solid. MS (ES + ) m / z 536.4 (M+H) +

[0245] 1H NMR(400MHz,DMSO)δ7.95-7.91(d,J=2.6Hz,1H),7.53-7.45(d,J=9.0Hz,2H),7.35-7.29(dd,J=8.8,2.6Hz,1H),7.10-7. 03(d,J=9.2Hz,2H),6.67-6.60(d,J=7.3Hz,1H),6.48-6.40(dd,J=8.8,0.8Hz,1H),3.94-3.84(p,J=6.9Hz,1H),3.69-3. 55(td,J=8.8,7.9,5.1Hz,1H),3.50-3.40(m,2H),3.30-3.23(m,2H),3.15-3.10(s,3H),2.46-2.37(m,2H),2.22-2.13(d dd,J=9.9,7.1,2.7Hz,2H),1.97-1.87(dd,J=12.7,3.9Hz,2H),1.69-1.54(m,8H),1.51-1.38(m,2H),1.34-1.29(m,2H).

[0246] Following a procedure similar to that described for Example 23, using the appropriate heterocycle in step iv, Examples 24-29 were prepared.

[0247] Examples 24 to 29 Example 24: 2-(1-{4-[(4-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}piperidin-4-yl)acetamide; [ka] MS(ES + ) m / z 523.4 (M+H) +

[0248] 1H NMR(400MHz,DMSO)δ7.95-7.91(d,J=2.7Hz,1H),7.53-7.45(d,J=9.0Hz,2H),7.35-7.30(dd,J=8.8,2.6Hz,1H),7.30-7.25(s,1H) ,7.08-7.03(d,J=9.2Hz,2H),6.79-6.74(s,1H),6.70-6.62(s,1H),6.47-6.41(d,J=8.8Hz,1H),3.94-3.86(dt,J=13.0,3.3Hz,2H ),3.68-3.56(m,1H),3.50-3.40(m,2H),2.90-2.79(td,J=12.7,2.6Hz,2H),2.46-2.37(td,J=11.7,11.3,2.8Hz,2H),2.04-1.98( d,J=7.1Hz,2H),1.97-1.86(m,3H),1.78-1.69(d,2H),1.60-1.55(m,2H),1.50-1.39(m,2H),1.34-1.28(m,2H),1.27-1.14(m,2H).

[0249] Building Blocks: Step iv: 2-(piperidin-4-yl)acetamide.

[0250] Example 25: [(1-{4-[(4-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}piperidin-4-yl)methyl]urea. [ka] MS(ES + ) m / z 538.4 (M+H) +

[0251] 1H NMR(400MHz,DMSO)δ7.94-7.92(d,J=2.5Hz,1H),7.52-7.44(d,J=9.1Hz,2H),7.37-7.27(dd,J=8.7,2.6Hz,1H),7.09-7.01(d,J =9.2Hz,2H),6.66-6.59(d,J=7.3Hz,1H),6.47-6.40(d,J=8.8Hz,1H),6.07-5.99(t,J=5.9Hz,1H),5.40-5.32(s,2H),3.99-3.8 8(dd,J=9.8,3.5Hz,2H),3.69-3.56(m,1H),3.51-3.39(m,2H),2.94-2.87(t,J=6.3Hz,2H),2.86-2.75(m,2H),2.47-2.37(m,2H) ),2.00-1.85(m,2H),1.78-1.66(d,J=12.7Hz,2H),1.62-1.53(m,2H),1.51-1.37(m,2H),1.35-1.26(m,2H),1.24-1.08(m,2H).

[0252] Building Blocks: Step iv: [(Piperidin-4-yl)methyl]urea.

[0253] Example 26: 1-(6-{[1-(4-{8,10-dioxo-3,9-diazaspiro[5.5]undecan-3-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile. [ka] MS(ES + ) m / z 563.5 (M+H) +

[0254] 1H NMR(400MHz,DMSO)δ10.84-10.70(s,1H),7.94-7.91(d,J=2.6Hz,1H),7.53-7.45(d,J=9.0Hz,2H),7. 34-7.28(dd,J=8.8,2.6Hz,1H),7.09-7.01(d,J=9.1Hz,2H),6.65-6.60(d,J=7.2Hz,1H),6.46-6.40(d ,J=8.8Hz,1H),3.67-3.55(m,1H),3.48-3.41(m,2H),3.41-3.35(m,4H),2.60-2.54(s,4H),2.47-2.3 7(td,J=11.7,2.8Hz,2H),1.95-1.87(m,2H),1.59-1.50(m,6H),1.50-1.39(m,2H),1.34-1.28(m,2H).

[0255] Building Blocks: Step iv: 3,9-Diazaspiro[5.5]undecane-2,4-dione.

[0256] Example 27: 1-(6-{[1-(4-{2-oxo-3-oxa-1,8-diazaspiro[4.5]decan-8-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile. [ka] MS(ES + ) m / z 537.5 (M+H) +

[0257] 1H NMR(400MHz,DMSO)δ8.15-8.11(s,1H),7.93-7.92(d,J=2.4Hz,1H),7.54-7.46(d,J=9.0Hz,2H),7.34-7. 29(dd,J=8.7,2.6Hz,1H),7.13-7.05(d,J=9.1Hz,2H),6.66-6.60(d,J=7.3Hz,1H),6.45-6.41(d,J=8.7Hz ,1H),4.14-4.10(s,2H),3.67-3.56(m,1H),3.53-3.37(m,6H),2.45-2.37(td,J=11.4,2.7Hz,2H),1.96- 1.88(dd,J=13.2,3.7Hz,2H),1.80-1.65(m,4H),1.60-1.54(m,2H),1.50-1.39(m,2H),1.33-1.28(m,2H).

[0258] Building Blocks: Step iv: 3-Oxa-1,8-diazaspiro[4.5]decan-2-one.

[0259] Example 28: 1-(6-{[1-(4-{1-oxo-2,8-diazaspiro[4.5]decan-8-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile. [ka] MS(ES + ) m / z 535.5 (M+H) +

[0260] 1H NMR(400MHz,DMSO)δ7.94-7.92(d,J=2.5Hz,1H),7.64-7.59(s,1H),7.54-7.47(d,J=9.0Hz,2H),7.34-7.28(dd,J=8.8,2.6Hz,1H ),7.12-7.03(d,J=9.1Hz,2H),6.65-6.60(d,J=7.3Hz,1H),6.47-6.42(d,J=8.8Hz,1H),3.90-3.81(dt,J=13.3,4.0Hz,2H),3.70 -3.56(m,1H),3.49-3.40(m,2H),3.24-3.17(t,J=6.8Hz,2H),3.09-2.99(m,2H),2.48-2.39(m,2H),2.06-2.00(t,J=6.8Hz,2H), 1.97-1.87(m,2H),1.77-1.67(td,J=12.7,4.1Hz,2H),1.59-1.54(m,2H),1.52-1.39(dd,J=13.1,3.7Hz,4H),1.34-1.28(m,2H).

[0261] Building Blocks: Step iv: 2,8-Diazaspiro[4.5]decan-1-one.

[0262] Example 29: 1-(6-{[1-(4-{2-oxa-7-azaspiro[3.5]nonan-7-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile. [ka] MS(ES + ) m / z 508.5 (M+H) +

[0263] 1H NMR(400MHz,DMSO)δ7.95-7.90(d,J=2.6Hz,1H),7.54-7.46(d,J=9.0Hz,2H),7.34-7.28(dd,J=8.7,2. 6Hz,1H),7.12-7.04(d,J=9.1Hz,2H),6.66-6.60(d,J=7.3Hz,1H),6.46-6.40(d,J=8.7Hz,1H),4.39-4. 32(s,4H),3.66-3.55(m,1H),3.49-3.40(m,2H),3.31-3.26(d,J=5.4Hz,3H),2.46-2.36(td,J=11.6,2. 8Hz,2H),1.96-1.88(m,2H),1.88-1.81(m,4H),1.60-1.53(m,2H),1.50-1.37(m,2H),1.33-1.27(m,3H)

[0264] Building Blocks: Step iv: 2-Oxa-7-azaspiro[3.5]nonane.

[0265] Example 30: 1-(6-{[(trans)-4-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile. [ka]

[0266] i) tert-Butyl N-[(cis)-4-hydroxycyclohexyl]carbamate (25 g) and triethylamine (21 mL) in CH2Cl2 (100 mL) In a solution of A solution of methanesulfonyl chloride (12 mL) in CH2Cl2 was added at 0°C. The reaction mixture was stirred at room temperature overnight and upon completion was poured into saturated aqueous NaHCO3. The product was extracted into ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give tert-Butyl N-[(cis)-4-(methanesulfonyloxy)cyclohexyl]carbamate (36.3 g) was obtained as a white solid, which was used in the next step without further purification.

[0267] ii) To a suspension of the product obtained in the previous step (34.1 g) and Cs2CO3 (94.6 mL) in acetone (550 mL) was added 4-bromothiophenol (39.5 g). The reaction mixture was stirred at 60 °C overnight. After removing the organic solvent under reduced pressure, the resulting suspension was diluted with water and the product was extracted into ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give tert - Butyl N - [(trans) - 4 - [(4 - Bromophenyl)sulfanyl]cyclohexyl]carbamate (25.3 g) was obtained as an off-white solid, which was used in the next step without further purification.

[0268] iii) To a solution of the product obtained in the previous step (25.3 g) in ethyl acetate (250 mL) was added mCPBA (56.5 g) portionwise at 0° C., and the reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was washed with 1N aqueous NaOH, water, brine, dried over MgSO4, filtered and concentrated under reduced pressure to give tert-Butyl N-[(trans)-4-(4-bromobenzenesulfonyl)cyclohexyl]carbamate (23 g) was obtained as a white solid, which was used in the next step without further purification.

[0269] iv) To a suspension of the product obtained in the previous step (2.0 g), bis(pinacolato)diboron (1.73 g), and potassium acetate (1.11 g) in cyclopentyl methyl ether (15 mL) was purged with N2 gas and PdCl2(dppf).CHCl2 (166 mg) was added. The reaction mixture was heated in a microwave at 100 °C overnight. After cooling to room temperature, the reaction mixture was poured into water and the product was extracted into CHCl2. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give tert-Butyl N-[(trans)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]cyclohexyl]carbamate (2g) was obtained as a black solid, which was used in the next step without further purification.

[0270] v) Under a nitrogen atmosphere, to a suspension of the product obtained in the previous step (2 g), 6-bromo-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (1.43 g), and NaHCO3 (1.44 g) in a mixture of 1,4-dioxane (40 mL) and water (10 mL) was added Pd(PPh3)4 (248 mg). The reaction mixture was stirred at 95 °C over the weekend. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, 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. The residue was purified on a C18 column using 10% to 100% CH3CN in water as the eluent to give tert-butyl N-[(trans)-4-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]carbamate (2.2 g) as a white solid.

[0271] vi) To a solution of the product obtained in the previous step (1.2 g) in ethyl acetate (10 mL) was added a solution of 5N HCl in 2-propanol (4.8 mL) and the reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was concentrated under reduced pressure to give (trans)-4-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}cyclohexan-1-amine (1.1 g) was obtained as a brown solid, which was used in the next step without further purification.

[0272] vii) Pd(OAc)2 (38 mg) and JosiphosSL-J009-1 (93 mg) in THF (5 mL) In solution Under a nitrogen atmosphere, 1-(6-chloro-3-pyridyl)cyclopropanecarbonitrile (150 mg), NaOt-Bu (202 mg), and the product obtained in the previous step (365 mg) were added. The reaction mixture was stirred in a sealed vial at 100°C overnight. 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 brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting black oil was purified on SiO2 using 5% to 100% CH3OH in CH2Cl2 as eluent to give the title product. 1-(6-{[(trans)-4-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile(31 mg) was obtained as a white solid. MS (ES + ) m / z 541.5 (M+H) +

[0273] 1 H NMR(400MHz,DMSO)δ8.96-8.91(t,J=1.4Hz,1H),8.19-8.10(m,2H),8.05-7.97(m,2H),7.96-7.92(m,1H) ),7.92-7.89(d,J=2.4Hz,1H),7.89-7.84(m,1H),7.78-7.72(d,J=9.1Hz,1H),6.94-6.85(d,J=9.2Hz,1H ),3.82-3.71(dt,J=13.6,6.8Hz,1H),3.66-3.52(m,1H),3.50-3.39(m,1H),2.07-2.00(m,4H),1.70-1.6 4(m,2H),1.57-1.47(m,2H),1.46-1.44(s,3H),1.44-1.44(m,2H),1.44-1.42(s,3H),1.37-1.24(m,2H).

[0274] Example 31: 1-{6-[(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile. [ka]

[0275] i) 1-{6-[(piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile hydrochloride (Example 23 To a solution of (1.82 g) (step ii) and DiPEA (4.45 mL) in CHCl (30 mL) was added 4-bromobenzene-1-sulfonyl chloride (1.96 g). The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, dried over MgSO, filtered, and concentrated under vacuum. The resulting brown solid was purified on SiO using 0% to 30% ethyl acetate in heptane as the eluent. 1-(6-{[1-(4-bromobenzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile (1.4 g) was obtained as a white solid.

[0276] ii) Under a nitrogen atmosphere, PdCl2(dppf).CH2Cl2 (78 mg) was added to a suspension of the product obtained in the previous step (900 mg), bis(pinacolato)diboron (728 mg), and potassium acetate (469 mg) in cyclopentyl methyl ether (15 mL). The reaction mixture was stirred at 110 °C for 3 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-[6-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]piperidin-4-yl}amino)pyridin-3-yl]cyclopropane-1-carbonitrile (937 mg) as a brown solid which was used in the next step without further purification.

[0277] iii) Under a nitrogen atmosphere, to a suspension of the product obtained in the previous step (150 mg), 6-bromo-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (90 mg), and NaHCO3 (74 mg) in a mixture of 1,4-dioxane (10 mL) and water (4 mL) was added Pd(PPh3)4 (34 mg). The reaction mixture was stirred overnight in a microwave at 110 °C. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, 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. The residue was purified on a C18 column using 0% to 100% CH3CN in water as the eluent to give the title compound. 1-{6-[(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile (34 mg) was obtained as a white solid. MS (ES + ) m / z 542.4 (M+H) + .

[0278] 1H NMR(400MHz,DMSO)δ8.89-8.82(m,1H),8.16-8.05(m,2H),7.96-7.92(dd,J=2.6,0.8Hz,1H),7.91-7.85(m,3H),7 .80-7.75(m,1H),7.36-7.29(dd,J=8.7,2.6Hz,1H),6.68-6.65(d,J=7.3Hz,1H),6.46-6.42(dd,J=8.7,0.8Hz,1H ),3.80-3.71(dt,J=13.9,6.9Hz,1H),3.70-3.64(m,1H),3.62-3.53(m,2H),2.64-2.55(m,2H),2.00-1.91(dd,J= 13.2,3.9Hz,2H),1.61-1.54(m,2H),1.51-1.46(m,2H),1.46-1.43(s,3H),1.43-1.40(s,3H),1.34-1.28(m,2H).

[0279] Following a similar procedure as described for Example 31, using the appropriate (hetero)aryl halide in step iii, Examples 32-34 were prepared.

[0280] Example 32: 1-{6-[(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile. [ka] MS(ES + ) m / z 556.4 (M+H) +

[0281] 1H NMR(400MHz,DMSO)δ8.73-8.69(t,J=1.1Hz,1H),8.12-8.04(m,2H),7.96-7.90(dd,J=2.6,0.7Hz,1H),7.90-7.84(m, 2H),7.63-7.57(t,J=1.4Hz,1H),7.37-7.30(dd,J=8.7,2.6Hz,1H),6.70-6.62(d,J=7.3Hz,1H),6.48-6.40(dd,J=8. 7,0.8Hz,1H),3.78-3.68(p,J=6.7Hz,1H),3.68-3.63(m,1H),3.63-3.53(m,2H),2.64-2.59(m,3H),2.59-2.53(m,2H) ),2.02-1.89(m,2H),1.60-1.54(m,2H),1.54-1.46(m,2H),1.46-1.43(s,3H),1.43-1.40(s,3H),1.33-1.28(m,2H).

[0282] Building Blocks: Step iv: 6-Bromo-8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine.

[0283] Example 33: 1-(6-{[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile. [ka] MS(ES + ) m / z 499.4 (M+H) +

[0284] 1H NMR(400MHz,DMSO)δ9.12-9.08(dd,J=2.0,1.0Hz,1H),8.04-7.98(m,3H),7.94-7.92(m,1H),7. 89-7.84(m,2H),7.74-7.70(m,1H),7.70-7.65(m,2H),7.35-7.29(dd,J=8.7,2.6Hz,1H),6.70- 6.63(d,J=7.4Hz,1H),6.48-6.40(dd,J=8.8,0.8Hz,1H),3.75-3.64(m,1H),3.63-3.52(m,2H), 2.65-2.56(m,2H),2.01-1.90(m,2H),1.62-1.56(m,2H),1.56-1.43(m,2H),1.35-1.28(m,2H).

[0285] Building Blocks: Step iv: 6-Bromoimidazo[1,2-a]pyridine.

[0286] Example 34: 1-{6-[(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile. [ka] MS(ES + ) m / z 541.4 (M+H) +

[0287] 1H NMR(400MHz,DMSO)δ8.76-8.70(d,J=1.7Hz,1H),8.12-8.05(m,2H),7.96-7.90(d,J=2.5Hz,1H),7.90-7.83(m,2H) ),7.74-7.66(m,1H),7.67-7.59(m,1H),7.51-7.42(s,1H),7.37-7.29(dd,J=8.8,2.6Hz,1H),6.72-6.62(d,J=7.3 Hz,1H),6.50-6.40(d,J=8.8Hz,1H),3.75-3.64(m,1H),3.64-3.56(m,2H),3.56-3.47(m,1H),2.64-2.54(m,2H), 2.02-1.91(m,2H),1.61-1.55(m,2H),1.54-1.43(m,2H),1.40-1.37(s,3H),1.37-1.34(s,3H),1.34-1.28(m,2H).

[0288] Building Blocks: Step iv: 6-Bromo-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0289] Example 35: 1-(6-{[1-(4-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile. [ka]

[0290] i) Following a procedure similar to that described for Example 31, in step iii, 1-(6-{[1-(4-{2-[(4-methoxyphenyl)methyl]-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile (71 mg) was prepared using 6-bromo-2-[1,2,4]-2H,3H-triazolo[4,3-a]pyridin-3-one (109 mg).

[0291] ii) The product obtained in the previous step (71 To a solution of 1 mg of HCl in 5 mL of TFA was added L-cysteine ​​(20 g). The reaction mixture was stirred at 70° C. overnight. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The resulting brown solid was purified on a C18 column using 10% to 100% CH3CN in HO as the eluent to give the title product. 1-(6-{[1-(4-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile (28 mg) was obtained as a white solid. MS (ES + ) m / z 516.4 (M+H) + .

[0292] 1 H NMR(400MHz,DMSO)δ12.74-12.50(s,1H),8.32-8.16(t,J=1.5Hz,1H),8.07-7.98(m,2H),7.96-7.90(d,J =2.5Hz,1H),7.86-7.78(m,2H),7.70-7.64(dd,J=9.9,1.8Hz,1H),7.43-7.36(dd,J=9.9,1.0Hz,1H),7.36 -7.29(dd,J=8.7,2.6Hz,1H),6.69-6.62(d,J=7.4Hz,1H),6.47-6.40(m,1H),3.75-3.62(m,1H),3.62-3. 49(m,2H),2.64-2.54(m,2H),2.01-1.88(m,2H),1.61-1.54(m,2H),1.54-1.42(m,2H),1.34-1.27(m,2H).

[0293] Example 36: N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine. [ka]

[0294] i) Pd(OAc)2 (99 mg) enJosiphosSL-J009-1 (238 mg) in THF (20 mL) In solution Under a nitrogen atmosphere, 2-chloro-5-[1-(trifluoromethyl)cyclopropyl]pyridine (850 mg), NaOt-Bu (579 mg), and tert-butyl 4-aminopiperidine-1-carboxylate (860 mg) were added. The reaction mixture was stirred in a sealed vial at 100° C. overnight. 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 brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting brown oil was purified on SiO2 using 0% to 70% EtOAc in heptane as the eluent to give tert-Butyl 4-({5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-yl}amino)piperidine-1-carboxylate (993 mg) was obtained as a white solid.

[0295] ii) To a solution of the product obtained in the previous step (993 mg) in ethyl acetate (20 mL) was added a solution of 5N HCl in 2-propanol (10 mL) and the reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-(piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine hydrochloride (925 mg) was obtained as a pale yellow solid, which was used in the next step without further purification.

[0296] iii) To a solution of the product obtained in the previous step (925 mg) and triethylamine (10 mL) in CHCl (30 mL) was added 4-bromobenzene-1-sulfonyl chloride (802 mg). The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, dried over MgSO, filtered, and concentrated under vacuum. The resulting brown solid was purified on SiO using 0% to 40% ethyl acetate in heptane as the eluent to give N-[1-(4-bromobenzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine (1.21 g) was obtained as a white solid.

[0297] iv) Under a nitrogen atmosphere, PdCl2(dppf).CHCl2 (36 mg) was added to a suspension of the product obtained in the previous step (500 mg), bis(pinacolato)diboron (377 mg), and potassium acetate (291 mg) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 110 °C overnight. 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-{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]piperidin-4-yl}-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine (550 mg) was obtained as a brown solid which was used in the next step without further purification.

[0298] v) Under a nitrogen atmosphere, to a suspension of the product obtained in the previous step (109 mg), 6-bromo-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (73 mg), and NaHCO3 (90 mg) in a mixture of 1,4-dioxane (4 mL) and water (1 mL) was added Pd(PPh3)4 (13 mg). The reaction mixture was stirred overnight in a microwave at 110 °C. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, 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. The residue was purified on a C18 column using 30% to 95% CH3CN in water as the eluent to give the title compound. N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine (60 mg) was obtained as a white solid. MS (ES + ) m / z 585.4 (M+H) + .

[0299] 1H NMR(400MHz,DMSO)δ8.87-8.83(t,J=1.4Hz,1H),8.14-8.06(m,2H),7.97-7.92(d,J=2.4Hz,1H),7.91-7. 85(m,3H),7.80-7.75(m,1H),7.41-7.35(dd,J=8.6,2.4Hz,1H),6.72-6.65(d,J=7.3Hz,1H),6.45-6.39(d d,J=8.7,0.8Hz,1H),3.79-3.71(m,1H),3.71-3.65(m,1H),3.62-3.53(m,2H),2.63-2.55(m,2H),2.00-1. 92(m,2H),1.56-1.46(m,2H),1.45-1.44(s,3H),1.44-1.40(s,3H),1.26-1.20(m,2H),1.01-0.95(m,2H).

[0300] Following a similar procedure as described for Example 36, using the appropriate (hetero)aryl halide in step v, Examples 37-39 were prepared.

[0301] Example 37: N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine. [ka] MS(ES + ) m / z 542.4 (M+H) +

[0302] 1H NMR(400MHz,DMSO)δ9.12-9.08(dd,J=1.8,1.1Hz,1H),8.04-7.98(m,3H),7.97-7.93(d,J=2.3Hz, 1H),7.89-7.84(m,2H),7.74-7.69(m,1H),7.69-7.64(m,2H),7.40-7.35(dd,J=8.6,2.4Hz,1H),6 .71-6.64(d,J=7.3Hz,1H),6.47-6.39(dd,J=8.7,0.8Hz,1H),3.76-3.63(m,1H),3.62-3.51(m,2H ),2.65-2.56(m,2H),2.02-1.90(m,2H),1.56-1.42(m,2H),1.28-1.18(m,2H),1.01-0.93(m,2H).

[0303] Building Blocks: Step v: 6-Bromoimidazo[1,2-a]pyridine.

[0304] Example 38: N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine. [ka] MS(ES + ) m / z 584.4 (M+H) +

[0305] 1H NMR(400MHz,DMSO)δ8.74-8.70(dd,J=1.8,1.0Hz,1H),8.11-8.05(m,2H),7.97-7.92(d,J=2.3Hz,1H),7.90-7 .83(m,2H),7.72-7.66(m,1H),7.66-7.61(m,1H),7.48-7.45(d,J=0.7Hz,1H),7.42-7.34(dd,J=8.7,2.4Hz,1 H),6.72-6.65(d,J=7.3Hz,1H),6.46-6.39(dd,J=8.7,0.8Hz,1H),3.76-3.63(m,1H),3.62-3.55(m,2H),3.55 -3.46(m,1H),2.64-2.54(m,2H),2.01-1.91(m,2H),1.57-1.43(m,2H),1.26-1.21(m,2H),1.04-0.95(m,2H).

[0306] Building Blocks: Step v: 6-Bromo-3-(propan-2-yl)imidazo[1,2-a]pyridine.

[0307] Example 39: N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine. [ka] MS(ES + ) m / z 586.4 (M+H) +

[0308] 1H NMR(400MHz,DMSO)δ9.58-9.47(d,J=1.5Hz,1H),9.30-9.18(d,J=1.6Hz,1H),8.47-8.36(m,2H),7.96-7.93( d,J=2.4Hz,1H),7.93-7.88(m,2H),7.40-7.34(dd,J=8.7,2.5Hz,1H),6.70-6.65(d,J=7.3Hz,1H),6.44-6.3 9(m,1H),3.85-3.75(dt,J=13.7,6.9Hz,1H),3.75-3.63(m,1H),3.62-3.52(m,2H),2.66-2.57(m,2H),2.00- 1.90(m,2H),1.55-1.49(m,2H),1.48-1.46(s,2H),1.46-1.45(s,3H),1.26-1.20(m,2H),1.01-0.95(m,2H).

[0309] Building Blocks: Step v: 6-Bromo-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine.

[0310] Following a procedure similar to that described for Example 10, using the appropriate (hetero)aryl halide in step ii, Examples 40-43 were prepared.

[0311] Example 40: 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine. [ka] MS(ES + ) m / z 584.4 (M+H) +

[0312] 1H NMR(400MHz,DMSO)δ8.88-8.82(t,J=1.4Hz,1H),8.14-8.07(m,2H),7.95-7.84(dd,J=8.5,1.7Hz,3H) ,7.83-7.75(dd,J=9.6,1.6Hz,1H),7.16-7.05(m,2H),6.57-6.45(m,2H),5.70-5.63(d,J=8.0Hz,1H), 3.82-3.67(hept,J=6.8Hz,1H),3.67-3.56(m,2H),3.31-3.22(m,1H),2.62-2.54(m,2H),2.02-1.91( m,2H),1.46-1.44(s,3H),1.44-1.42(s,3H),1.42-1.36(m,2H),1.23-1.17(m,2H),0.99-0.90(m,2H).

[0313] Building Blocks: Step v: 6-Bromo-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine.

[0314] Example 41: 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine. [ka] MS(ES + ) m / z 585.4 (M+H) +

[0315] 1H NMR(400MHz,DMSO)δ9.57-9.49(d,J=1.5Hz,1H),9.27-9.19(d,J=1.6Hz,1H),8.49-8.40(m,2H),7. 93-7.88(m,2H),7.11-7.04(d,J=8.3Hz,2H),6.56-6.47(m,2H),5.73-5.63(d,J=8.0Hz,1H),3.85-3 .75(dt,J=13.7,6.9Hz,1H),3.67-3.55(m,2H),3.30-3.21(m,1H),2.61-2.54(m,2H),1.99-1.91(m, 2H),1.49-1.47(s,3H),1.47-1.44(s,3H),1.44-1.35(m,2H),1.23-1.16(m,2H),0.98-0.90(m,2H).

[0316] Building Blocks: Step v: 6-Bromo-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine.

[0317] Example 42: 1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine. [ka] MS(ES + ) m / z 556.4 (M+H) +

[0318] 1H NMR(400MHz,DMSO)δ8.83-8.78(t,J=1.3Hz,1H),8.16-8.08(m,2H),7.93-7.86(m, 3H),7.86-7.78(m,1H),7.13-7.06(dd,J=6.7,1.8Hz,2H),6.56-6.48(m,2H),5.92- 5.42(s,1H),3.65-3.58(m,2H),3.32-3.21(m,1H),2.82-2.75(s,3H),2.63-2.53( m,2H),2.02-1.89(m,2H),1.50-1.36(m,2H),1.25-1.14(m,2H),1.00-0.85(m,2H).

[0319] Building Blocks: Step v: 6-Bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine.

[0320] Example 43: 6-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one. [ka]

[0321] i) following a procedure similar to that described for Example 10, in step v, 6-bromo-2-[1,2,4]-2H,3H-triazolo[4,3-a]pyridin-3-one (200 mg), 2-[(4-Methoxyphenyl)methyl]-6-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (91 mg) was prepared.

[0322] ii) To a solution of the product obtained in the previous step (91 mg) in TFA (4 mL) was added L-cysteine ​​(23 mg). The reaction mixture was stirred at 70 °C overnight. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The resulting brown solid was purified on a C18 column using 10% to 100% CH3CN in H2O as the eluent to give the title product. 6-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (42 mg) was obtained as a white solid. MS (ES+ ) m / z 558.4 (M+H) + .

[0323] 1 H NMR(400MHz,DMSO)δ12.72-12.50(s,1H),8.28-8.17(t,J=1.5Hz,1H),8.08-8.00(m,2H),7.86-7. 77(m,2H),7.71-7.63(dd,J=9.8,1.8Hz,1H),7.46-7.34(dd,J=9.9,1.0Hz,1H),7.13-7.02(m,2H), 6.56-6.48(dd,J=6.9,1.7Hz,2H),5.71-5.62(d,J=8.1Hz,1H),3.64-3.54(m,2H),3.29-3.20(m,1 H),2.60-2.54(m,2H),1.98-1.90(m,2H),1.50-1.34(m,2H),1.23-1.18(m,2H),0.98-0.90(m,2H).

[0324] Following a procedure similar to that described for Example 36, using the appropriate (hetero)aryl halide in step v, Examples 44-46 were prepared.

[0325] Example 44: N-(1-{4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine. [ka] MS(ES + ) m / z 593.4 (M+H) +

[0326] 1H NMR(400MHz,MeOD-d4)δ=8.82(s,1H),8.05-7.94(m,6H),7.92(d,J=2.0Hz,1H),7.68-7.41(m,2H),6.46(d,J=8.8Hz,1H),3. 78-3.71(m,2H),3.70-3.63(m,1H),2.66-2.61(m,2H),2.08-2.04(m,2H),1.63-1.52(m,2H),1.30-1.25(m,2H),0.96(s,2H)

[0327] Building Blocks: Step v: 6-Bromo-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.

[0328] Example 45: 4-(4-{[4-({5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide. [ka] MS(ES + ) m / z 546.4 (M+H) +

[0329] 1 H NMR(400MHz,MeOD-d4)δ=8.76(d,J=5.2Hz,1H),8.45(s,1H),8.07-8.03(m,2H),7.98-7.94(m,2H),7.93-7.90(m,2H),7.44(dd,J=2.4,8.8Hz,1H),6 .45(d,J=8.8Hz,1H),3.74-3.71(m,2H),3.69-3.63(m,1H),2.70-2.61(m, 2H),2.10-2.01(m,2H),1.64-1.52(m,2H),1.29-1.25(m,2H),0.95(s,2H).

[0330] Building Blocks: Step v: 4-Bromopyridine-2-carboxamide.

[0331] Example 46: N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine. [ka] MS(ES + ) m / z 599.4 (M+H) +

[0332] 1 H NMR(400MHz,MeOD-d4)δ=8.54(s,1H),8.02-7.97(m,2H),7.95-7.90(m,3H),7 .61(s,1H),7.44(dd,J=2.4,8.8Hz,1H),6.45(d,J=8.8Hz,1H),3.78-3.71(m,2 H),3.67(d,J=6.4,13.6Hz,2H),2.69(s,3H),2.67-2.58(m,2H),2.11-2.02(m, 2H),1.64-1.55(m,2H),1.53(d,J=7.2Hz,6H),1.31-1.24(m,2H),0.96(s,2H).

[0333] Building Blocks: Step v: 6-Bromo-8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine.

[0334] Example 47: N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine. [ka] MS(ES + ) m / z 557.4 (M+H) +

[0335] 1H NMR(400MHz,DMSO-d6)δ=8.77(s,1H),8.09(d,J=8.4Hz,2H),7.94(d,J=2.0Hz,1H), 7.91-7.83(m,3H),7.81-7.73(m,1H),7.37(dd,J=2.0,8.4Hz,1H),6.67(d,J=7.2Hz, 1H),6.41(d,J=8.8Hz,1H),3.73-3.62(m,1H),3.61-3.52(m,2H),2.77(s,3H),2.62 -2.53(m,2H),2.00-1.91(m,2H),1.55-1.43(m,2H),1.28-1.18(m,2H),0.97(s,2H).

[0336] Building Block: Step v: 6-Bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine

[0337] 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-inducible CREB binding to the CRE element within 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 after transfection, cells were harvested and diluted to 0.75 million cells / ml in culture medium (DMEM, 10% FBS, 1x penicillin / streptomycin (Gibco 15140)). Compounds were serially diluted 2.5-fold in DMSO. Further dilutions were made in assay medium (DMEM, 10% FBS, 1x penicillin / streptomycin, 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 vector backbone. Relative LogIC50 values ​​were determined using GraphPad Prism 9 using a four-parameter dose-response model.

[0338] 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). Percent inhibition values ​​were calculated based on the low and high signals obtained with 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.

[0339] 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 at 37°C for 30 minutes 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). Percent inhibition values ​​were calculated based on the low and high signals obtained with 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.

[0340] The table below shows data for selected compounds. [Table 1] TIFF2026504677000185.tif217170 TIFF2026504677000186.tif217170 TIFF2026504677000187.tif193170

[0341] Aspects Aspect 1. A compound of formula (I): [ka] During the ceremony, 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 may be present in the presence of one or two, particularly one, R 1a is optionally replaced by R 1a But C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, cyano, -CONHR 1b , C 3-6 is cycloalkyl or heterocyclyl, R 1b But C 1-6 alkyl or hydrogen, 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 But C 3-6 cycloalkyl or heterocyclyl, C 3-6Cycloalkyl and heterocyclyl may be present in one or two, especially one R 6a is optionally replaced by R 6a But C 1-6 haloalkyl, cyano or halogen; R 7 is hydrogen, The present invention relates to a compound or a pharmaceutically acceptable salt thereof.

[0342] Aspect 2. A compound of Aspect 1 of Formula (I), [ka] During the ceremony, 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 or heteroaryl, and the aryl and heteroaryl are each independently one or two, particularly one R 1a is optionally replaced by R 1a But C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, cyano, -CONHR 1b , C 3-6 is cycloalkyl or heterocyclyl, R 1b But C 1-6 alkyl or hydrogen, R 2 is hydrogen or halogen, R 3 is hydrogen or halogen, R 4 is hydrogen, halogen or C 1-6 is alkyl, R5 is hydrogen, halogen or C 1-6 is alkyl, R 6 But C 3-6 cycloalkyl or heterocyclyl, C 3-6 Cycloalkyl and heterocyclyl may be present in one or two, especially one R 6a is optionally replaced by R 6a But C 1-6 haloalkyl, cyano or halogen; R 7 is hydrogen, The compound of embodiment 1, wherein the compound is a compound or a pharmaceutically acceptable salt thereof.

[0343] Aspect 3. A compound according to aspect 1 or 2, X 2 is CH, X 3 is CH, X 5 is CH, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, 3. A compound according to embodiment 1 or 2.

[0344] Aspect 4.X 4 is O.

[0345] Aspect 5.X 4 The compound according to any one of embodiments 1 to 4, wherein

[0346] Aspect 6.X 5 The compound according to any one of aspects 1 to 5, wherein is N.

[0347] Aspect 7.X 1 A compound according to any one of aspects 1 to 6, wherein is CH.

[0348] Aspect 8.X 1 The compound according to any one of aspects 1 to 7, wherein is N.

[0349] Aspect 9.R 1 is phenyl, pyridyl or N-containing bicyclic heteroaryl, and phenyl, pyridyl and N-containing bicyclic heteroaryl may be present in one or two, especially one R 1a A compound according to any one of aspects 1 to 8, optionally substituted with

[0350] Aspect 10.R 1 is indolyl, triazolopyridyl, triazolopyrazinyl, indazolyl, imidazopyridinyl, phenyl or pyridyl, and indolyl, indazolyl, imidazopyridinyl, phenyl and pyridyl are each independently selected from the group consisting of one R 1a A compound according to any one of aspects 1 to 9, optionally substituted with

[0351] Aspect 11.R 1 is imidazopyridinyl, cyanoindolyl, isopropylimidazopyridinyl, methylindazolyl, methylimidazopyridinyl, (methylcarbamoyl)phenyl, (methylcarbamoyl)pyridyl, carbamoylphenyl, or cyanophenyl.

[0352] Aspect 12.R 1 is imidazo[1,2-a]pyridin-6-yl, (3-cyano-1H-indol-5-yl), (3-isopropylimidazo[1,2-a]pyridin-6-yl), (3-methyl-1H-indazol-5-yl), (3-methylimidazo[1,2-a]pyridin-6-yl), [3-(methylcarbamoyl)phenyl], [4-(methylcarbamoyl)phenyl], [6-(methylcarbamoyl)-3-pyridyl], (4-carbamoylphenyl), or (4-cyanophenyl).

[0353] Aspect 13.R 1is imidazopyridyl, indolyl, triazolopyridyl or triazolopyrazyl, and imidazopyridyl, indolyl, triazolopyridyl and triazolopyrazyl have one or two R 1a 13. The compound of any one of aspects 1 to 12, optionally substituted with

[0354] Aspect 14.R 1 14. The compound of any one of aspects 1 to 13, wherein is methylimidazopyridyl, cyanoindolyl, imidazopyridyl, isopropylimidazopyridinyl, isopropyltriazolopyridyl, isopropyltriazolopyrazyl, methyltriazolopyridyl, difluoromethyltriazolopyridyl, methylisopropyltriazolopyridyl.

[0355] Aspect 15.R 1 Aspect 15. The compound of any one of aspects 1-14, wherein is imidazopyridinyl, cyanoindolyl, isopropylimidazopyridinyl, or methylindazolyl.

[0356] Aspect 16.R 1a Aspect 16. The compound of any one of aspects 1-15, wherein is methyl, isopropyl, cyano, -CONH2, -CONH(Me), or difluoromethyl.

[0357] Aspect 17.R 1a Aspect 16. The compound according to any one of aspects 1 to 15, wherein is methyl, isopropyl, cyano, or difluoromethyl.

[0358] Aspect 18.R 1a Aspect 17. The compound of any one of aspects 1-16, wherein is methyl, isopropyl, cyano, -CONH2, or -CONH(Me).

[0359] Aspect 19.R 1b Aspect 19. The compound according to any one of aspects 1 to 18, wherein is methyl or hydrogen.

[0360] Aspect 20.R 6 But one R 6aA compound according to any one of aspects 1 to 19, wherein R is cyclopropyl optionally substituted with R.

[0361] Aspect 21.R 6 The compound according to any one of aspects 1 to 20, wherein is (trifluoromethyl)cyclopropyl, cyanocyclopropyl, cyclopropyl.

[0362] Aspect 22.R 6 22. The compound of any one of aspects 1 to 21, wherein is [1-(trifluoromethyl)cyclopropyl], (1-cyanocyclopropyl), oxetan-3-yl, (2,2-difluorocyclopropyl), cyclopropyl.

[0363] Aspect 23.R 6 A compound according to any one of aspects 1 to 22, wherein is (trifluoromethyl)cyclopropyl.

[0364] Aspect 24.R 6a Aspect 24. The compound of any one of aspects 1 to 23, wherein is trifluoromethyl or cyano.

[0365] Aspect 25.R 6a Aspect 25. The compound according to any one of aspects 1 to 24, wherein is trifluoromethyl.

[0366] Aspect 26. A compound according to any one of aspects 1 to 25, wherein: X 1 is CH or N, X 2 is CH, X 3 is CH, X 4 is O, X 5 is CH or N, R 1 is imidazopyridyl, indolyl, triazolopyridyl, or triazolopyrazyl, wherein imidazopyridyl, indolyl, triazolopyridyl, and triazolopyrazyl are substituted with one or two R1a is optionally replaced by R 1a is methyl, isopropyl, cyano or difluoromethyl; R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 But one R 6a is cyclopropyl optionally substituted with R 6a is trifluoromethyl, R 7 is hydrogen, The compound of embodiment 1, wherein the compound is a compound or a pharmaceutically acceptable salt thereof.

[0367] Aspect 27. A compound according to any one of Aspects 1 to 26, wherein: X 1 is CH or N, X 2 is CH, X 3 is CH, X 4 is O, X 5 is CH or N, R 1 is methylimidazopyridyl, cyanoindolyl, imidazopyridyl, isopropylimidazopyridinyl, isopropyltriazolopyridyl, isopropyltriazolopyrazyl, methyltriazolopyridyl, difluoromethyltriazolopyridyl, methylisopropyltriazolopyridyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6is (trifluoromethyl)cyclopropyl, R 7 is hydrogen, The compound of embodiment 1, wherein the compound is a compound or a pharmaceutically acceptable salt thereof.

[0368] Aspect 28. Compound of Formula (I') [ka] 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 A compound according to any one of aspects 1 to 27, wherein is as defined in any one of aspects 1 to 27.

[0369] Aspect 29. Compound of Formula (I″) [ka] wherein R 1 , R 6 , X 1 , X 4 and X 5 A compound according to any one of aspects 1 to 27, wherein is as defined in any one of aspects 1 to 27.

[0370] Aspect 30. Compound of Formula (I''') [ka] wherein R 1 , R 6a , X 1 , X 4 and X 5A compound according to any one of aspects 1 to 29, wherein is as defined in any one of aspects 1 to 27.

[0371] Aspect 31. A compound of formula (I'''), [ka] During the ceremony, X 1 is CH or N, X 4 is O, X 5 is CH or N, R 1 is phenyl, pyridine or N-containing bicyclic heteroaryl, where phenyl, pyridine and N-containing bicyclic heteroaryl are selected from the group consisting of one or two, especially one, R 1a is optionally replaced by R 1a is methyl, isopropyl, cyano, -CONH2, -CONH(Me) or difluoromethyl; R 6a is trifluoromethyl or cyano; A compound according to any one of aspects 1 to 30.

[0372] Aspect 32. A compound of formula (I'''), [ka] During the ceremony, X 1 is CH or N, X 4 is O, X 5 is CH or N, R 1 is imidazopyridyl, indolyl, triazolopyridyl, or triazolopyrazyl, wherein imidazopyridyl, indolyl, triazolopyridyl, and triazolopyrazyl are each independently selected from the group consisting of one or two R 1a is optionally replaced by R 1a is methyl, isopropyl, cyano or difluoromethyl; R 6a is trifluoromethyl, A compound according to any one of aspects 1 to 30, or a pharmaceutically acceptable salt thereof.

[0373] Aspect 33. A compound according to any one of aspects 1 to 32, 4'-[(4-{[4-(1-cyanocyclopropyl)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-3-carboxamide; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; N-methyl-5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-(4-cyclopropylphenyl)-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 5-[4-({4-[(4-cyclopropylphenyl)amino]piperidin-1-yl}sulfonyl)phenyl]-1H-indole-3-carbonitrile; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone; 4-(2,2-Difluorocyclopropyl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 1-(4-{[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]amino}phenyl)cyclopropane-1-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; 4-(Oxetan-3-yl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 5-(4-{[trans-4-{[4-(oxetan-3-yl)phenyl]amino}cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-[(trans)-4-(4-{3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-[(trans)-4-(4-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; 1-(6-{[1-(4-{2-methoxy-7-azaspiro[3.5]nonan-7-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 2-(1-{4-[(4-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}piperidin-4-yl)acetamide; [(1-{4-[(4-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}piperidin-4-yl)methyl]urea; 1-(6-{[1-(4-{8,10-dioxo-3,9-diazaspiro[5.5]undecan-3-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{2-oxo-3-oxa-1,8-diazaspiro[4.5]decan-8-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{1-oxo-2,8-diazaspiro[4.5]decan-8-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{2-oxa-7-azaspiro[3.5]nonan-7-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[(trans)-4-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-{6-[(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile; 1-{6-[(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-{6-[(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]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-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 6-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; N-(1-{4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine 4-(4-{[4-({5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; or N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine A compound selected from:

[0374] Aspect 34. A compound according to any one of Aspects 1 to 33, 4'-[(4-{[4-(1-cyanocyclopropyl)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-3-carboxamide; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; N-methyl-5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-(4-cyclopropylphenyl)-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 5-[4-({4-[(4-cyclopropylphenyl)amino]piperidin-1-yl}sulfonyl)phenyl]-1H-indole-3-carbonitrile; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl](imino)-λ 6 -Sulfanone; 4-(2,2-Difluorocyclopropyl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 1-(4-{[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]amino}phenyl)cyclopropane-1-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; 4-(Oxetan-3-yl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 5-(4-{[trans-4-{[4-(oxetan-3-yl)phenyl]amino}cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; or N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline A compound selected from:

[0375] Aspect 35. A compound according to any one of aspects 1 to 34, 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-(1-{4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]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-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; or N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine A compound selected from:

[0376] Aspect 36. A compound according to any one of aspects 1 to 35, 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; or N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline A compound selected from:

[0377] Aspect 37. wherein X 1 is N and X 4 A method for preparing a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 36, wherein is O, comprising the steps of: R 5 and R 4 as defined in any one of aspects 1 to 36. [ka] , X 2 , X 3 , R 2 and R 3 as defined in any one of aspects 1 to 36. [ka] React with R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined in any one of aspects 1 to 36; and [ka] The compound (IV) is reacted with R 1 is as defined in any one of aspects 1 to 36, 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] React with R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined in any one of aspects 1 to 36, forming a compound of formula (VI) [ka] The compound of formula (VI) is reacted with an acid to form R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 forming a compound of formula (VII), wherein: [ka] The compound of formula (VII) is reacted with R 8 is a halogen and R 6 , R 7 , and X 5 as defined in any one of aspects 1 to 36. [ka] to form a compound of formula (I); A method comprising:

[0378] Aspect 38.X 1 is N and X 4 A method for preparing a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 36, wherein is O, comprising the steps of: R 4 and R 5 as defined in any one of aspects 1 to 36. [ka] , R 8 is a halogen and R 6 , R 7 , and X 5 as defined in any one of aspects 1 to 36. [ka] React with R 4 , R 6 , R 7 , X 5 , and R 5 is as defined in any one of aspects 1 to 36, forming a compound of formula (X); [ka] The compound of formula (X) is reacted with an acid to form R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XI), wherein: [ka] The compound of formula (XI) is reacted with X 2 , X 3 , R 2 , and R 3 is as defined in any one of aspects 1 to 36. [ka] React with X 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XII), wherein: [ka] The compound of formula (XII) is reacted with R 1 is as defined in any one of aspects 1 to 36, 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0379] Aspect 39.X 1 is N and X 4 A method for preparing a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 36, wherein is O, comprising the steps of: In the formula, R 5 and R 4 as defined in any one of aspects 1 to 36. [ka] , R 1 , R 2 , R 3 , X 2 , and X 3 as defined in any one of aspects 1 to 36. [ka] React with R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3is as defined in any one of aspects 1 to 36, and forming a compound of formula (XX). [ka] The compound of formula (XX) is 5 , R 6 , and R 7 as defined in any one of aspects 1 to 36. [ka] to form a compound of formula (I), or R 5 and R 4 as defined in any one of aspects 1 to 36. [ka] , X 2 , X 3 , R 2 and R 3 as defined in any one of aspects 1 to 36. [ka] React with R 2 , R 3 , R 4 , R 5 , X 2 and X 3 forming a compound of formula (XIX), wherein: [ka] The compound of formula (XIX) is reacted with X 2 , X 3 , R 2 , R 3 , R 4 , R 6 , R7 , X 5 , and R 5 as defined in any one of aspects 1 to 36 with said compound of formula (XVI) to form a compound of formula (XII); [ka] The compound of formula (XII) is reacted with R 1 is as defined in any one of aspects 1 to 36, 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0380] Aspect 40.X 1 is C and X 4 A method for preparing a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 36, wherein is O, comprising the steps of: R 4 and R 5 as defined in any one of aspects 1 to 36. [ka] is reacted with mesyl chloride to give R 4 and R 5forming a compound of formula (XXII), wherein: [ka] The compound of formula (XXII) is reacted with R 2 , R 3 , X 2 , and X 3 is as defined in any one of aspects 1 to 36. [ka] React with R 2 , R 3 , R 4 , R 5 , X 2 and X 3 forming a compound of formula (XXIV), wherein: [ka] The compound of formula (XXIV) is reacted with an oxidizing agent to form R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined in any one of aspects 1 to 36, forming a compound of formula (XXV). [ka] The compound of formula (XXV) is reacted with R 1 is as defined in any one of aspects 1 to 36, and R 9 and R 10 is hydrogen or R 9 and R 10 independently C 1-6 alkyl, or R 9 and R 10together with the oxygen atoms to which they are attached to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] React with R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined in any one of aspects 1 to 36, forming a compound of formula (XXVI); [ka] The compound of formula (XXVI) is reacted with an acid to form R 1 , R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 as defined in any one of aspects 1 to 36. [ka] The compound of formula (XXVII) is reacted with R 8 is a halogen and R 6 , R 7 , and X 5 as defined in any one of aspects 1 to 36. [ka] to form a compound of formula (I); A method comprising:

[0381] Aspect 41. wherein X 1 is C and X4 A method for preparing a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 36, wherein is O, comprising the steps of: R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 36. [ka] is reacted with an acid to give R 2 , R 3 , R 4 , R 5 , X 2 and X 3 is as defined in any one of aspects 1 to 36, forming a compound of formula (XXVIII); [ka] The compound of formula (XXVIII) is reacted with R 8 is a halogen and R 6 , R 7 , and X 5 as defined in any one of aspects 1 to 36. [ka] React with 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 36, forming a compound of formula (XXIX); [ka] The compound of formula (XXIX) is reacted with R 1 is as defined in any one of aspects 1 to 36, 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0382] Aspect 42.X 1 is C and X 4 A method for preparing a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 36, wherein is O, comprising the steps of: R 4 and R 5 as defined in any one of aspects 1 to 36. [ka] is reacted with mesyl chloride to give R 4 and R 5 forming a compound of formula (XXXII), wherein: [ka] The compound of formula (XXXII) is reacted with R 2 , R 3 , X 2 , and X3 is as defined in any one of aspects 1 to 36. [ka] React with R 2 , R 3 , R 4 , R 5 , X 2 and X 3 forming a compound of formula (XXIII), wherein: [ka] The compound (XXXIII) is reacted with an oxidizing agent to form R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 is as defined in any one of aspects 1 to 36, forming a compound of formula (XXXIV); [ka] The compound (XXXIV) is reacted with an acid to form R 2 , R 3 , R 4 , R 5 , X 2 , and X 3 forming a compound of formula (XXXV), wherein: [ka] The compound of formula (XXXV) is reacted with X 5 , R 6 , and R 7 as defined in any one of aspects 1 to 36. [ka] React with 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 36, forming a compound of formula (XXIX); [ka] The compound of formula (XXIX) is reacted with R 1 is as defined in any one of aspects 1 to 36, 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0383] Aspect 43.X 1 is C and X 4 A method for preparing a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 36, wherein is N, comprising the steps of: R 2 , R 3 , R 4 , R 5 , X 2 and X 3as defined in any one of aspects 1 to 36. [ka] is reacted with an acid to give R 2 , R 3 , R 4 , R 5 , X 2 and X 3 forming a compound of formula (XXXVI), wherein: [ka] The compound of formula (XXXVI) is reacted with X 5 , R 6 , and R 7 as defined in any one of aspects 1 to 36. [ka] React with 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 36, forming a compound of formula (XXXVII); [ka] The compound of formula (XXXVII) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to form R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 5 , X 2 , and X 3is as defined in any one of aspects 1 to 36, forming a compound of formula (XXXVIII); [ka] The compound of formula (XXXVIII) is reacted with R 1 is as defined in any one of aspects 1 to 36, 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] to form a compound of formula (I); A method comprising:

[0384] Aspect 44.X 1 and X 4 A method for preparing a compound of Formula (I) or Formula (I') or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 36, wherein is N, comprising the steps of: R 4 , R 6 , R 7 , X 5 , and R 5 is as defined in any one of aspects 1 to 36. [ka] , R 2 , R 3 , X 2 and X 3is as defined in any one of aspects 1 to 36. [ka] React with 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 36, forming a compound of formula (XL); [ka] The compound (XL) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to form R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XLI), wherein: [ka] The compound (XLI) is reacted with di-tert-butyl dicarbonate and a base to give 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 36, forming a compound of formula (XLI); [ka] The compound (XLII) is reacted with R 1 is as defined in any one of aspects 1 to 36, 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 to form one or more C 1-6 Optionally substituted with alkyl, especially four C 1-6 Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl [ka] React with R 1 , R 2 , R 3 , X 2 , X 3 , R 4 , R 6 , R 7 , X 5 , and R 5 forming a compound of formula (XLIII), wherein: [ka] reacting said compound of formula (XLIII) with an acid to form a compound of formula (I); A method comprising:

[0385] Embodiment 45. A compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, when prepared according to any one of embodiments 37 to 44.

[0386] Embodiment 46. A compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0387] Embodiment 47. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0388] Embodiment 48. The pharmaceutical composition of embodiment 47, further comprising an additional therapeutic agent.

[0389] Embodiment 49. A compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of an inflammatory autoimmune disease.

[0390] Embodiment 50. A compound according to any one of embodiments 1 to 36, 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.

[0391] Embodiment 51. A compound according to any one of embodiments 1 to 36, 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.

[0392] Embodiment 52. Use of a compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of progression of an inflammatory autoimmune disease.

[0393] Embodiment 53. Use of a compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt 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.

[0394] Embodiment 54. 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 embodiments 1 to 36, or a pharmaceutically acceptable salt thereof.

[0395] Embodiment 55. 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 embodiments 1 to 36, or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of formula (I) 【Chemistry 1】 During the ceremony, 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 one or two, particularly one, R １ａ is optionally replaced by R １ａ But C １－６ Alkyl, C １－６ Haloalkyl, oxo, cyano, -CONHR １ｂ , C ３－６ is cycloalkyl or heterocyclyl, R １ｂ But C １－６ alkyl or hydrogen, 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 But C ３－６ cycloalkyl or heterocyclyl, C ３－６ Cycloalkyl and heterocyclyl may be present in one or two, especially one R ６ａ is optionally replaced by R ６ａ But C １－６ haloalkyl, cyano or halogen; R ７ is hydrogen, A compound or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I) 【Chemistry 2】 During the ceremony, 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 or heteroaryl, and the aryl and heteroaryl are each independently one or two, particularly one R １ａ is optionally replaced by R １ａ But C １－６ Alkyl, C １－６ Haloalkyl, oxo, cyano, -CONHR １ｂ , C ３－６ is cycloalkyl or heterocyclyl, R １ｂ But C １－６ alkyl or hydrogen, 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 But C ３－６ cycloalkyl or heterocyclyl, C ３－６ Cycloalkyl and heterocyclyl may be present in one or two, especially one R ６ａ is optionally replaced by R ６ａ But C １－６ haloalkyl, cyano or halogen; R ７ is hydrogen, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. X ２ is CH, X ３ is CH, X ５ is CH, R ２ is hydrogen, R ３ is hydrogen, R ４ is hydrogen, R ５ is hydrogen, 3. The compound of claim 1 or 2.

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

5. X ４ 5. The compound of claim 1 or 4, wherein is NH.

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

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

8. X １ The compound according to any one of claims 1 to 7, wherein is N.

9. R １ is phenyl, pyridyl or N-containing bicyclic heteroaryl, and phenyl, pyridyl and N-containing bicyclic heteroaryl are present in one or two, especially one R １ａ The compound of any one of claims 1 to 8, optionally substituted with

10. R １ is indolyl, triazolopyridyl, triazolopyrazinyl, indazolyl, imidazopyridinyl, phenyl or pyridyl, and indolyl, indazolyl, imidazopyridinyl, phenyl and pyridyl are each independently selected from the group consisting of one R １ａ 10. The compound of any one of claims 1 to 9, optionally substituted with

11. R １ is imidazopyridinyl, cyanoindolyl, isopropylimidazopyridinyl, methylindazolyl, methylimidazopyridinyl, (methylcarbamoyl)phenyl, (methylcarbamoyl)pyridyl, carbamoylphenyl or cyanophenyl.

12. R １ is imidazo[1,2-a]pyridin-6-yl, (3-cyano-1H-indol-5-yl), (3-isopropylimidazo[1,2-a]pyridin-6-yl), (3-methyl-1H-indazol-5-yl), (3-methylimidazo[1,2-a]pyridin-6-yl), [3-(methylcarbamoyl)phenyl], [4-(methylcarbamoyl)phenyl], [6-(methylcarbamoyl)-3-pyridyl], (4-carbamoylphenyl) or (4-cyanophenyl).

13. R １ is imidazopyridyl, indolyl, triazolopyridyl or triazolopyrazyl, and imidazopyridyl, indolyl, triazolopyridyl and triazolopyrazyl are each independently one or two R １ａ 13. The compound of any one of claims 1 to 12, optionally substituted with:

14. R １ The compound according to any one of claims 1 to 13, wherein is methylimidazopyridyl, cyanoindolyl, imidazopyridyl, isopropylimidazopyridinyl, isopropyltriazolopyridyl, isopropyltriazolopyrazyl, methyltriazolopyridyl, difluoromethyltriazolopyridyl, or methylisopropyltriazolopyridyl.

15. R １ The compound of any one of claims 1 to 14, wherein is imidazopyridinyl, cyanoindolyl, isopropylimidazopyridinyl or methylindazolyl.

16. R １ａ Methyl, isopropyl, cyano, -CONH ２ , -CONH(Me) or difluoromethyl.

17. R １ａ The compound of any one of claims 1 to 16, wherein is methyl, isopropyl, cyano or difluoromethyl.

18. R １ａ Methyl, isopropyl, cyano, -CONH ２ 17. The compound according to any one of claims 1 to 16, wherein the compound is -CONH(Me).

19. R １ｂ The compound of any one of claims 1 to 18, wherein is methyl or hydrogen.

20. R ６ But one R ６ａ 20. The compound of any one of claims 1 to 19, wherein the cyclopropyl group is cyclopropyl optionally substituted with .

21. R ６ The compound according to any one of claims 1 to 20, wherein is (trifluoromethyl)cyclopropyl, cyanocyclopropyl, cyclopropyl.

22. R ６ The compound according to any one of claims 1 to 21, wherein is [1-(trifluoromethyl)cyclopropyl], (1-cyanocyclopropyl), oxetan-3-yl, (2,2-difluorocyclopropyl), cyclopropyl.

23. R ６ The compound of any one of claims 1 to 22, wherein is (trifluoromethyl)cyclopropyl.

24. R ６ａ The compound of any one of claims 1 to 23, wherein is trifluoromethyl or cyano.

25. R ６ａ The compound of any one of claims 1 to 24, wherein is trifluoromethyl.

26. Compound of formula (I') 【Transformation 3】 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 A compound according to any one of claims 1 to 25, wherein is as defined in any one of claims 1 to 25.

27. Compounds of formula (I'') 【Chemistry 4】 wherein R １ , R ６ , X １ , X ４ and X ５ A compound according to any one of claims 1 to 26, wherein

28. Compounds of Formula (I''') 【Transformation 5】 wherein R １ , R ６ａ , X １ , X ４ and X ５ A compound according to any one of claims 1 to 27, wherein

29. 4'-[(4-{[4-(1-cyanocyclopropyl)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-3-carboxamide; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; N-methyl-5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-(4-cyclopropylphenyl)-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 5-[4-({4-[(4-cyclopropylphenyl)amino]piperidin-1-yl}sulfonyl)phenyl]-1H-indole-3-carbonitrile; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl](imino)-λ ６ - sulfanone; 4-(2,2-difluorocyclopropyl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 1-(4-{[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]amino}phenyl)cyclopropane-1-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; 4-(oxetan-3-yl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 5-(4-{[trans-4-{[4-(oxetan-3-yl)phenyl]amino}cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-[(trans)-4-(4-{3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-[(trans)-4-(4-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; 1-(6-{[1-(4-{2-methoxy-7-azaspiro[3.5]nonan-7-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 2-(1-{4-[(4-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}piperidin-4-yl)acetamide; [(1-{4-[(4-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}piperidin-1-yl)sulfonyl]phenyl}piperidin-4-yl)methyl]urea; 1-(6-{[1-(4-{8,10-dioxo-3,9-diazaspiro[5.5]undecan-3-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{2-oxo-3-oxa-1,8-diazaspiro[4.5]decan-8-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{1-oxo-2,8-diazaspiro[4.5]decan-8-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{2-oxa-7-azaspiro[3.5]nonan-7-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-(6-{[(trans)-4-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-{6-[(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile; 1-{6-[(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; 1-{6-[(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)amino]pyridin-3-yl}cyclopropane-1-carbonitrile; 1-(6-{[1-(4-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]amino}pyridin-3-yl)cyclopropane-1-carbonitrile; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; N-[1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; N-(1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]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-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 6-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one; N-(1-{4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; 4-(4-{[4-({5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-yl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; N-(1-{4-[8-methyl-3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; or N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine The compound according to any one of claims 1 to 28, selected from:

30. 4'-[(4-{[4-(1-cyanocyclopropyl)phenyl]amino}piperidin-1-yl)sulfonyl]-[1,1'-biphenyl]-4-carbonitrile; 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methylimidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-3-carboxamide; N-methyl-4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; N-methyl-5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)pyridine-2-carboxamide; 4'-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}-[1,1'-biphenyl]-4-carboxamide; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 1-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-(4-cyclopropylphenyl)-1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]piperidin-4-amine; 5-[4-({4-[(4-cyclopropylphenyl)amino]piperidin-1-yl}sulfonyl)phenyl]-1H-indole-3-carbonitrile; (4-{imidazo[1,2-a]pyridin-6-yl}phenyl)[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl](imino)-λ ６ - sulfanone; 4-(2,2-difluorocyclopropyl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 1-(4-{[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]amino}phenyl)cyclopropane-1-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; 4-(oxetan-3-yl)-N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]aniline; 5-(4-{[trans-4-{[4-(oxetan-3-yl)phenyl]amino}cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; or N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline 30. The compound according to any one of claims 1 to 29, selected from:

31. 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; N-(1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-{4-[3-(propan-2-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzenesulfonyl}-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; N-(1-{4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzenesulfonyl}piperidin-4-yl)-5-[1-(trifluoromethyl)cyclopropyl]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-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine; or N-[1-(4-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzenesulfonyl)piperidin-4-yl]-5-[1-(trifluoromethyl)cyclopropyl]pyridin-2-amine The compound according to any one of claims 1 to 30, selected from:

32. 1-[4-(3-methyl-1H-indazol-5-yl)benzenesulfonyl]-N-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}piperidin-4-amine; 5-(4-{[4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)piperidin-1-yl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; 5-(4-{[trans-4-({4-[1-(trifluoromethyl)cyclopropyl]phenyl}amino)cyclohexyl]sulfonyl}phenyl)-1H-indole-3-carbonitrile; N-[trans-4-(4-{imidazo[1,2-a]pyridin-6-yl}benzenesulfonyl)cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline; or N-[trans-4-{4-[3-(propan-2-yl)imidazo[1,2-a]pyridin-6-yl]benzenesulfonyl}cyclohexyl]-4-[1-(trifluoromethyl)cyclopropyl]aniline The compound according to any one of claims 1 to 31, selected from:

33. X １ is N and X ４ A process for preparing a compound of formula (I) or formula (I') according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R ５ and R ４ as defined in any one of claims 1 to 32. 【Transformation 6】 To, X ２ , X ３ , R ２ and R ３ as defined in any one of claims 1 to 32. 【Transformation 7】 React with R ２ , R ３ , R ４ , R ５ , X ２ , and X ３ is as defined in any one of claims 1 to 32, and 【Transformation 8】 The compound (IV) is reacted with R １ is as defined in any one of claims 1 to 32, and R ９ and R １０ is hydrogen, or R ９ and R １０ became independent and became 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 4 C １－６ Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl 【Chemistry 9】 React with R １ , R ２ , R ３ , R ４ , R ５ , X ２ , and X ３ is as defined in any one of claims 1 to 32, forming a compound of formula (VI) 【Chemistry 10】 The compound of formula (VI) is reacted with an acid to form R １ , R ２ , R ３ , R ４ , R ５ , X ２ , and X ３ forming a compound of formula (VII) wherein 【Chemistry 11】 The compound of formula (VII) is reacted with R ８ is a halogen, and R ６ , R ７ , and X ５ as defined in any one of claims 1 to 32. 【Chemistry 12】 to form a compound of formula (I); A method comprising:

34. X １ is N and X ４ A process for preparing a compound of formula (I) or formula (I') according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R ４ and R ５ as defined in any one of claims 1 to 32. 【Chemistry 13】 , R ８ is a halogen, and R ６ , R ７ , and X ５ as defined in any one of claims 1 to 32. 【Chemistry 14】 React with R ４ , R ６ , R ７ , X ５ , and R ５ is as defined in any one of claims 1 to 32, forming a compound of formula (X) 【Chemistry 15】 The compound of formula (X) is reacted with an acid to form R ４ , R ６ , R ７ , X ５ , and R ５ forming a compound of formula (XI), wherein 【Chemistry 16】 The compound of formula (XI) is ２ , X ３ , R ２ , and R ３ as defined in any one of claims 1 to 32. 【Chemistry 17】 React with X 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 32, forming a compound of formula (XII) [Chemistry 18] The compound of formula (XII) is reacted with R １ is as defined in any one of claims 1 to 32, and R ９ and R １０ is hydrogen, or R ９ and R １０ became independent and became 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 4 C １－６ Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl 【Chemistry 19】 to form a compound of formula (I); A method comprising:

35. X １ is N and X ４ A process for preparing a compound of formula (I) or formula (I') according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R ５ and R ４ as defined in any one of claims 1 to 32. 【Chemistry 20】 , R １ , R ２ , R ３ , X ２ , and X ３ as defined in any one of claims 1 to 32. 【Chemistry 21】 React with R １ , R ２ , R ３ , R ４ , R ５ , X ２ , and X ３ forming a compound of formula (XX), wherein 【Chemistry 22】 The compound of formula (XX) is ５ , R ６ , and R ７ as defined in any one of claims 1 to 32. 【Chemistry 23】 to form a compound of formula (I), or R ５ and R ４ as defined in any one of claims 1 to 32. 【Chemistry 24】 To, X ２ , X ３ , R ２ and R ３ as defined in any one of claims 1 to 32. 【Chemistry 25】 React with R ２ , R ３ , R ４ , R ５ , X ２ and X ３ forming a compound of formula (XIX), wherein 【Chemistry 26】 The compound of formula (XIX) is ２ , X ３ , R ２ , R ３ , R ４ , R ６ , R ７ , X ５ , and R ５ with said compound of formula (XVI), wherein 【Chemistry 27】 The compound of formula (XII) is reacted with R １ is as defined in any one of claims 1 to 32, and R ９ and R １０ is hydrogen, or R ９ and R １０ became independent and became 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 4 C １－６ Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl 【Chemistry 28】 to form a compound of formula (I); A method comprising:

36. X １ is C and X ４ A process for preparing a compound of formula (I) or formula (I') according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R ４ and R ５ Compounds of formula (XXI) wherein: 【Chemistry 29】 is reacted with mesyl chloride to give R ４ and R ５ forming a compound of formula (XXII), wherein 【Transformation 30】 The compound of formula (XXII) is reacted with R ２ , R ３ , X ２ , and X ３ is as defined in any one of claims 1 to 32. 【Chemistry 31】 React with R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 32, forming a compound of formula (XXIV) 【Chemistry 32】 Reacting said compound of formula (XXIV) with an oxidizing agent to form R ２ , R ３ , R ４ , R ５ , X ２ , and X ３ is as defined in any one of claims 1 to 32, forming a compound of formula (XXV) 【Transformation 33】 The compound of formula (XXV) is reacted with R １ is as defined in any one of claims 1 to 32, and R ９ and R １０ is hydrogen, or R ９ and R １０ became independent and became 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 4 C １－６ Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl 【Transformation 34】 React with R １ , R ２ , R ３ , R ４ , R ５ , X ２ , and X ３ is as defined in any one of claims 1 to 32, and 【Chemistry 35】 Reacting said compound of formula (XXVI) with an acid to form R １ , R ２ , R ３ , R ４ , R ５ , X ２ , and X ３ forming a compound of formula (XXVII), wherein 【Transformation 36】 The compound of formula (XXVII) is reacted with R ８ is a halogen, and R ６ , R ７ , and X ５ as defined in any one of claims 1 to 32. 【Chemistry 37】 to form a compound of formula (I); A method comprising:

37. X １ is C and X ４ A method for preparing a compound of formula (I) or formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, wherein R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 32. 【Transformation 38】 is reacted with an acid to give R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 32, forming a compound of formula (XXVIII) 【Chemistry 39】 The compound of formula (XXVIII) is reacted with R ８ is a halogen, and R ６ , R ７ , and X ５ as defined in any one of claims 1 to 32. 【Chemistry 40】 React with 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 32, forming a compound of formula (XXIX) 【Chemistry 41】 The compound of formula (XXIX) is reacted with R １ is as defined in any one of claims 1 to 32, and R ９ and R １０ is hydrogen, or R ９ and R １０ became independent and became 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 4 C １－６ Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl 【Chemistry 42】 to form a compound of formula (I); A method comprising:

38. X １ is C and X ４ A process for preparing a compound of formula (I) or formula (I') according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R ４ and R ５ as defined in any one of claims 1 to 32. 【Chemistry 43】 is reacted with mesyl chloride to give R ４ and R ５ forming a compound of formula (XXXII), wherein 【Chemistry 44】 The compound of formula (XXXII) is reacted with R ２ , R ３ , X ２ , and X ３ is as defined in any one of claims 1 to 32. 【Chemistry 45】 React with R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 32, forming a compound of formula (XXXIII) 【Chemistry 46】 The compound (XXXIII) is reacted with an oxidizing agent to form R ２ , R ３ , R ４ , R ５ , X ２ , and X ３ is as defined in any one of claims 1 to 32, forming a compound of formula (XXXIV) 【Chemistry 47】 The compound (XXXIV) is reacted with an acid to form R ２ , R ３ , R ４ , R ５ , X ２ , and X ３ forming a compound of formula (XXXV), wherein 【Chemistry 48】 The compound of formula (XXXV) is reacted with X ５ , R ６ , and R ７ as defined in any one of claims 1 to 32. 【Chemistry 49】 React with 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 32, forming a compound of formula (XXIX) [Transformation 50] The compound of formula (XXIX) is reacted with R １ is as defined in any one of claims 1 to 32, and R ９ and R １０ is hydrogen, or R ９ and R １０ became independent and became 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 4 C １－６ Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl 【Chemistry 51】 to form a compound of formula (I); A method comprising:

39. X １ is C and X ４ A process for preparing a compound of formula (I) or formula (I') according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R ２ , R ３ , R ４ , R ５ , X ２ and X ３ is as defined in any one of claims 1 to 32. 【Chemistry 52】 is reacted with an acid to give R ２ , R ３ , R ４ , R ５ , X ２ and X ３ forming a compound of formula (XXXVI), wherein 【Chemistry 53】 The compound of formula (XXXVI) is reacted with X ５ , R ６ , and R ７ is as defined in any one of claims 1 to 32. 【Chemistry 54】 React with 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 32, forming a compound of formula (XXXVII) 【Transformation 55】 The compound of formula (XXXVII) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to form 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 32, forming a compound of formula (XXXVIII) 【Transformation 56】 The compound of formula (XXXVIII) is reacted with R １ is as defined in any one of claims 1 to 32, and R ９ and R １０ is hydrogen, or R ９ and R １０ became independent and became 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 4 C １－６ Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl 【Chemistry 57】 to form a compound of formula (I); A method comprising:

40. X １ and X ４ A process for preparing a compound of formula (I) or formula (I') according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R ４ , R ６ , R ７ , X ５ , and R ５ is as defined in any one of claims 1 to 32. 【Chemical Formula 58】 , R ２ , R ３ , X ２ and X ３ is as defined in any one of claims 1 to 32, 【Chemistry 59】 React with 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 32, forming a compound of formula (XL) 【Transformation 60】 The compound (XL) is reacted with ammonium carbamate and (diacetoxyiodo)benzene to form R ２ , R ３ , X ２ , X ３ , R ４ , R ６ , R ７ , X ５ , and R ５ forming a compound of formula (XLI), wherein 【Chemistry 61】 The compound (XLI) is reacted with di-tert-butyl dicarbonate and a base to obtain 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 32, forming a compound of formula (XLII) 【Transformation 62】 The compound (XLII) is reacted with R １ is as defined in any one of claims 1 to 32, and R ９ and R １０ is hydrogen, or R ９ and R １０ became independent and became 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 4 C １－６ Compounds of formula (V) forming a 3- to 14-membered heterocyclyl optionally substituted with alkyl 【Transformation 63】 React with R １ , R ２ , R ３ , X ２ , X ３ , R ４ , R ６ , R ７ , X ５ , and R ５ forming a compound of formula (XLIII), wherein 【Chemistry 64】 reacting said compound of formula (XLIII) with an acid to form a compound of formula (I); A method comprising:

41. 41. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, when prepared according to any one of claims 33 to 40.

42. A compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

43. A pharmaceutical composition comprising the compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

44. 44. The pharmaceutical composition of claim 43, further comprising an additional therapeutic agent.

45. 33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and / or delay of progression of an inflammatory autoimmune disease.

46. 33. A compound according to any one of claims 1 to 32, 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.

47. 33. A compound according to any one of claims 1 to 32, 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.

48. 33. Use of a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of inflammatory autoimmune diseases.

49. 33. Use of a compound according to any one of claims 1 to 32, 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.

50. 33. 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 32 or a pharmaceutically acceptable salt thereof.

51. 33. 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 32 or a pharmaceutically acceptable salt thereof.

Images