CCR6 receptor modulator

Abstract

The present invention relates to compounds of formula (I), their synthesis and use as CCR6 receptor modulators, for example for the prevention or treatment of inflammatory / autoimmune diseases / disorders and cancer. [Formula 1] TIFF2024539987000045.tif76155

Description

[Technical Field]

[0001] The present invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, and their use as CCR6 receptor modulators in the treatment or prevention of various diseases, conditions, or disorders that are improved by modulation of the receptor. Furthermore, the present invention relates to pharmaceutical compositions having one or more compounds of formula (I) and related aspects such as methods for producing said compounds. [Background technology]

[0002] Chemokine receptors are a family of G protein-coupled receptors (GPCRs) that recognize and bind to peptide chemokine ligands. The primary function of chemokine receptors and their ligands is to induce trafficking of leukocytes to and from lymphoid organs and tissues, both in the steady state and in association with infection or inflammation. In addition, chemokine signaling events can trigger the activation of integrin molecules on the surface of immune cells, enabling strong adhesion to activated endothelium and promoting migration from the blood to inflammatory tissues (Montresor A, Frontiers in Imm., 2012; Meissner A, Blood, 2003). Chemokine receptor 6 (CCR6, also known as BN-1, CC CKR-6, CD196, CKRL3, CMKBR6, DCR2, DRY6, GPR29, GPRCY4, STRL22) is a GPCR primarily expressed on effector CD4+ T helper cells, but is also present on B cells, CD8+ cytotoxic T cells, regulatory T cells (Treg), immature dendritic cells (DCs), and type 3 innate lymphoid cells (ILC3s) (Cua DJ, Nat Rev Immunol. 2010 July; 10(7):479-89. doi:10.1038 / nri2800). CCR6 binds to the chemokine CCL20 (chemokine (CC motif) ligand 20) (Greaves DR, J Exp Med. September 15, 1997; 186(6):837-44. doi:10.1084 / jem.186.6.837.).CCL20 is also known as macrophage inflammatory protein 3a (MIP-3a), liver and activation-regulated chemokine (LARC), or Exodus-1 (Schutyser E, Cytokine Growth Factor Rev. 2003 / 01;14(5):409-26.doi:10.1016 / s1359-6101 (03)00049-2). The CCR6 / CCL20 interaction regulates the humoral response in the intestinal mucosa and is necessary for lymphocyte homeostasis in the small intestinal mucosa (Cook DN, Immunity. 2000 / 05;12(5):495-503.doi:10.1016 / s1074-7613(00)80201-0). Under steady-state conditions, CCR6 and CCL20 regulate IgA production in the intestinal tract. CCL20 expressed in Peyer's patches guides CCR6+IgA+B cells to the mucosa, releasing secretory IgA into the intestinal lumen (Lin YL, Front Immunol, 2017;8:805.doi:10.3389 / fimmu.2017.00805;Reboldi A, Science. May 13, 2016;352(6287):aaf4822.doi:10.1126 / science.aaf4822). Under inflammatory conditions, CCL20 expression is increased in both endothelial and epithelial cells (Harper EG, J Invest Dermatol. 2009 September; 129(9): 2175-83. doi: 10.1038 / jid.2009.65; PLoS One. 2015; 10(11): e0141710. doi: 10.1371 / journal.pone.0141710). In tissue fibroblasts (Hattori T, Mediators Inflamm. 2015; 2015: 436067. doi: 10.1155 / 2015 / 436067), interleukin (IL)-17A is strongly upregulated by pro-inflammatory cytokines including IL-17A, TNFα, and IL-1β. Interleukin (IL)-17A expression is limited to cells expressing the transcription factor RORgt (Cell. September 22, 2006; 126(6): 1121-33. doi: 10.1016 / j.cell. 2006.07.035). IL-17A expression has been shown to be isolated from CCR6 expression on human T cells (Singh SP, J Immunol. January 1, 2008; 180(1):214-21. doi:10.4049 / jimmunol.180.1.214; Nat Immunol. June 2007; 8(6):639-46. doi:10.1038 / ni1467). CCR6 has also been described as a target gene of RORgt (PLoS One.2017;12(8):e0181868.doi:10.1371 / journal.pone.0181868;Skepner J, J Immunol. March 15, 2014;192(6):2564-75.doi:10.4049 / jimmunol.1302190), and therefore the co-expression of IL-17A and CCR6 in RORgt+ cell types can be explained.

[0003] Certain disclosures in the prior art may be considered relevant to the modulation of CCR6. For example, Tawaraishia et al. (Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 18, 2018, pp. 3067-3072, ISSN 0960-894X, https: / / doi.org / 10.1016 / j.bmcl.2018.07.042) disclose a series of benzenesulfonyl-aminocyclohexane derivatives as selective CCR6 inhibitors. CN103588697 teaches sulfonamide derivatives as CCR6 antagonists and their use in the treatment of CCR6-mediated diseases such as autoimmune diseases, inflammation, psoriasis, multiple sclerosis, or cancer. WO2014 / 075580 describes the use of aurintricarboxylic acid for targeting chemokine receptors. WO2015 / 084842 teaches certain sulfonamides that may be used in the treatment of CCR6-related diseases. WO2017 / 087607, WO2010 / 131145, WO2013 / 061004, WO2013 / 061005, WO2019 / 036374 and WO2020 / 058869 provide certain cyclobutendiones for use in the treatment of chemokines / CCR6-related diseases. WO2019 / 136370 teaches treatments for certain types of psoriasis. WO2019 / 147862 suggests azetidine derivatives that may be used as chemokine modifiers. WO2021219849 relates to certain CCR6 receptor modifiers.

[0004] Furthermore, WO1999 / 43664 discloses certain pyrrolidinones having anti-inflammatory and analgesic properties. WO2019 / 105915 provides certain heterocyclic compounds that may be used as MAGL inhibitors. WO2015 / 057626, US2015 / 0105366, WO2014 / 062658, WO2015 / 057205 and Tanis VM et al. (Bioorg Med Chem Lett. June 15, 2019; 29(12):1463-1470. doi:10.1016 / j.bmcl.2019.04.021) relate to RORyt receptor modulators that may be used for the treatment of rheumatoid arthritis or psoriasis. WO03 / 022808 proposes certain azetidine derivatives for use as insecticides. WO2008 / 103426 and WO2007 / 022351 disclose certain quaternary ammonium compounds useful as muscarinic receptor antagonists. WO2006 / 136830 teaches certain heteroaryl-alkylamines as protein kinase inhibitors. WO91 / 13359 proposes heterocyclic cholinergic activators. US3458635 teaches certain pyrrolidines that may be used for the treatment of depression. GB1304650 discloses antispasmodic pyrrolidines. US3479370, US3 489769, US3499002, US3542807, and US3651085 relate to specific pyrrolidines having analgesic / sedative activity.

[0005] The CCR6 modulators of the present invention are considered useful, either alone or in combination, for the treatment or prevention of the following diseases or disorders: Rheumatoid arthritis (RA) causes chronic inflammation of the joints, and chemokines control the infiltration of the inflamed synovial membrane by inflammatory cells. RA is characterized by increased release of CCL20 and subsequent recruitment of CCR6+ T cells to the inflamed joints. CCL20 is highly expressed in the synovial fluid of RA (Hirota, J Exp Med. November 26, 2007; 204(12):2803-12. doi:10.1084 / jem.20071397; Matsui T, Clin Exp Immunol. July 2001; 125(1):155-61. doi:10.1046 / j.1365-2249.2001.01542.x). In patients with rheumatoid arthritis (RA), CCR6+ Th cells have been found in the inflamed synovial membrane, and an increased proportion of peripheral blood CCR6+ Th cells has been observed in patients with early-stage RA (van Hamburg JP, Arthritis Rheum. January 2011; 63(1):73-83.doi:10.1002 / art.30093; Leipe J Arthritis Rheum. October 2010; 62(10):2876-85.doi:10.1002 / art.27622; Nistala K, Arthritis Rheum. March 2008; 58(3):875-87.doi:10.1002 / art.23291). CCL20 production is known to be upregulated in synovial culture tissue (synovium explants) or fibroblast-like synovial cells derived from RA patients after stimulation with TNF-α, IL-1β, and IL-17 (Matsui T, Clin Exp Immunol. July 2001; 125(1):155-61. doi:10.1046 / j.1365-2249.2001.01542.x; J Immunol. November 15, 2001; 167(10):6015-20. doi:10.4049 / jimmunol.167.10.6015; Chevrel G, Ann Rheum Dis. August 2002; 61(8)730-3. doi:10.1136 / ard.61.8.730).CCR6+ B cells have been reported in the synovium of RA, and contribute to the pathogenesis through antigen presentation, autoantibody production and / or inflammatory cytokine production. Furthermore, Rituximab is an effective treatment for RA (Cohen SB, Arthritis Rheum. September 2006;54(9):2793-806.doi:10.1002 / art.22025), which supports the role of CCR6+ B cells in the pathogenesis of RA. In addition, CCR6-deficient mice have impaired IgG1-dependent memory B cell responses (J Immunol. January 15, 2015;194(2):505-13.doi:10.4049 / jimmunol.1401553). Preclinical rodent models have shown that the severity of joint inflammation in the collagen-induced arthritis (CIA) model is lower in CCR6-deficient mice. It was observed that the production of collagen-specific antibodies was decreased in CCR6-deficient mice compared with wild-type mice, and joint inflammation was also decreased (J Cell Mol Med. November 2018;22(11):5278-5285.doi:10.1111 / jcmm.13783). Furthermore, depletion of CCR6+ cells reduced the severity of SKG arthritis (Hirota K, J Exp Med. November 26, 2007;204(12):2803-12.doi:10.1084 / jem.20071397).

[0006] CCR6+ Th17 cells are increased in the peripheral blood of patients with ankylosing spondylitis (Shen H, Arthritis Rheum. June 2009;60(6):1647-56.doi:10.1002 / art.24568). Circulating interleukin-17-secreting interleukin-23 receptor-positive γ / δ T cells have also been reported in patients with active ankylosing spondylitis (Kenna TJ, Arthritis Rheum. May 2012;64(5):1420-9.doi:10.1002 / art.33507 ). Secukinumab, an IL-17A inhibitor, has been shown to be effective in ankylosing spondylitis (AS) (Baeten D, N Engl J Med. December 24, 2015; 373(26):2534-48. doi: 10.1056 / NEJMoa1505066). The expression of CD32B on memory B cells is increased in AS and has been associated with disease activity. Furthermore, within the synovial compartment of AS patients, CCR6 + cytotoxic T cells and CD32B + memory B cells were significantly increased (Sueur A, Clin Exp Rheumatol. November 20, 2019; PMID: 31820725).

[0007] Psoriasis is a common autoimmune skin disease. The role of Th17-related cytokines has been clinically validated, and their role in psoriatic inflammation has been confirmed (Paul C, J Eur Acad Dermatol Venereol. June 2015;29(6):1082-90.doi:10.1111 / jdv.12751). An IL-17R blocking antibody (brodalumab, AMG 827) has also been shown to reduce the clinical symptoms of psoriasis and decrease CCL20 expression in skin biopsies of psoriasis patients (Papp KA, N Engl J Med. March 29, 2012;366(13):1181-9.doi:10.1056 / NEJMoa1109017). Furthermore, an IL-23 neutralizing antibody (guselkumab) has been shown to be effective in reducing psoriatic inflammation (Reich K, Lancet. September 7, 2019; 394(10201):831-839. doi:10.1016 / S0140-6736(19)31773-8). In CCR6-deficient mice, psoriatic skin lesions did not progress after intradermal injection of IL-23 (Hedrick MN, J Clin Invest. August 2009; 119(8):2317-29. doi:10.1172 / jci37378). Small molecule CCR6 antagonists were also shown to be effective in Aldara and IL-36α-injection mouse models of psoriasis (Campbell JJ, J Immunol. 2019 / 3 / 15;202(6):1687-1692.doi:10.4049 / jimmunol.1801519;Campbell JJ, J Immunol. November 1, 2017;199(9):3129-3136.doi:10.4049 / jimmunol.1700826). Furthermore, CCR6-deficient mice were shown to be protected from imiquimod-induced auricular swelling (Yu S, J Invest Dermatol. February 2019;139(2):485-488.doi:10.1016 / j.jid.2018.07.036).

[0008] Anti-CCR6 neutralizing antibodies also demonstrated efficacy against Aldara-induced auricular swelling in mice (Robert R, JCI Insight. 2017 Aug. 3;2(15):e94821. Published online 2017 Aug. 3 doi:10.1172 / jci.insight.94821). Engineered disulfide-linked CCL20 dimers that bind to CCR6 but inhibit T cell migration were shown to reduce skin swelling in an IL-23-dependent mouse model of psoriasis (Getschman AE, Proc Natl Acad Sci US A. 2017 Nov. 21;114(47):12460-12465.doi:10.1073 / pnas.1704958114). In other words, these data indicate that a positive feedback loop consisting of epithelial and dermal CCL20 production, strong recruitment of CCR6+ T cells to inflamed psoriatic skin, their activation by IL-23, and their expression of IL-17A and IL-22 drives the pathogenic Th17 response in psoriatic skin lesions. Therefore, inhibition of CCR6 is recognized as a promising therapeutic tool for treating psoriasis (Hedrick MN, Expert Opin Ther Targets. September 2010; 14(9):911-22. doi:10.1517 / 14728222.2010.504716; Mabuchi T, J Dermatol Sci. January 2012; 65(1):4-11.doi:10.1016 / j.jdermsci.2011.11.007). CCR6 expression has been shown to be upregulated in the synovial fluid of patients with psoriatic arthritis (PsA) (Dolcino M, PLoS One. June 18, 2015;10(6):e0128262.doi:10.1371 / journal.pone.0128262). IL-17A and GM-CSF expressing CD4+ T cells isolated from the synovial fluid of PsA patients also expressed CCR6 (Al-Mossawi et al., Nat Commun. November 15, 2017;8(1):1510.doi:10.1038 / s41467-017-01771-2). It has been shown that CCL20 is significantly upregulated in the synovial fluid of PsA patients (Melis L, Ann Rheum Dis. March 2010; 69(3):618-23. doi:10.1136 / ard.2009.107649).

[0009] In further inflammatory skin disorders, including rosacea, CCL20 levels have been shown to be significantly elevated in inflamed skin (Buhl T, JID, 2015).

[0010] CCR6 and CCL20 levels are significantly elevated in active Crohn's disease (CD) and ulcerative colitis (UC) (Skovdahl et al., PLoS One. November 4, 2015; 10(11):e0141710.doi:10.1371 / journal.pone.0141710). Increased CCL20 production by enterocytes has been suggested to play an important role in lymphocyte recruitment to the colonic epithelium in irritable bowel syndrome (IBD) (Kwon JH, Gut. December 2002; 51(6):818-26.doi:10.1136 / gut.51.6.818). CCL20 and CCR6 expression also correlate with the histological severity of rectal tissue resected from UC patients. CCL20 expression in chronic ulcerative colitis (UC) is higher than in acute UC after pathological examination (Uchida K, Gastroenterol Res Pract. 2015;2015:856532.doi:10.1155 / 2015 / 856532). Compared to healthy controls, CCL20 expression was significantly upregulated in PBMCs of UC patients. The UC group treated with sulfasalazine and GC showed reduced CCL20 expression in PBMCs, which was associated with disease recovery. TNFα or IL-1β-induced CCL20 secretion was significantly reduced by sulfasalazine and / or GC treatment of human intestinal epithelial cell lines (Lee HJ, 2 Inflamm Bowel Dis. 2005 / December;11(12):1070-9.doi:10.1097 / 01.mib.0000187576.26043.ac). CCR6 deficiency caused a reduction in intestinal pathology in mice treated with dextran sulfate sodium (DSS) to induce chronic inflammation (Varona R, Eur J Immunol. 2003 / October;33(10):2937-46.doi:10.1002 / eji.200324347).

[0011] Th17 cells expressing CCR6 have been shown to be important effectors in dry eye disease (DED) (an inflammatory state of the ocular surface that can lead to corneal perforation). In a DED mouse model, neutralization of CCL20 with an antibody reduced Th17 recruitment to the ocular surface and improved clinical outcomes (Dohlman TH, Invest Ophthalmol Vis Sci. June 12, 2013; 54(6):4081-91. doi:10.1167 / iovs.12-11216). Therefore, inhibition of the CCR6 / CCL20 system has been proposed as a therapeutic mechanism for treating DED.

[0012] CCR6 expression has been described in T cells isolated from cerebrospinal fluid of patients with multiple sclerosis (MS) (van Langelaar J, Brain, May 1, 2018; 141(5):1334-1349. doi:10.1093 / brain / awy069). CCR6 expression was also observed on T cells infiltrating the inflamed CNS in experimental autoimmune encephalomyelitis (EAE) (Mony JT, Front Cell Neurosci. 2014;8:187.doi:10.3389 / fncel.2014.00187). Furthermore, CCL20 gene polymorphism was shown to be associated with the MS patient cohort (El Sharkav et al., Gene. February 15, 2019;685:164-169.doi:10.1016 / j.gene.2018.11.006). Preclinical data showed that CCR6 is important for the development of EAE (Reboldi A, Nat Immunol. May 2009;10(5):514-23.doi:10.1038 / ni.1716). This finding has been confirmed by subsequent studies, which have shown that CCR6-deficient mice are resistant to disease induction and have a reduced peak severity. In the same study, vaccination with hCCL20 induced an anti-mouse CCL20 response in host mice, which significantly reduced clinical scores (Abraham M, Clin Immunol. 2017 Oct;183:316-324.doi:10.1016 / j.clim.2017.09.018). However, there is conflicting data regarding the role of CCR6 in the development of EAE (J Neuroimmunol. 2009 Aug 18;213(1-2):91-9.doi:10.1016 / j.jneuroim.2009.05.011). The severity and histopathology of EAE were significantly reduced after injection of anti-CCL20 at the time of the first clinical symptom (Kohler RE, J Immunol. June 15, 2003; 170(12):6298-306. doi:10.4049 / jimmunol.170.12.6298). Anti-CCR6 neutralizing antibody was shown to reduce the severity of EAE in mice (Robert R, JCI Insight. August 3, 2017; 2(15):e94821. Published online on August 3, 2017. doi:10.1172 / jci.insight.94821).IL-6 and IL-17 increase the expression of CCL20 in mouse astrocytes (Meares GP, Glia. May 2012; 60(5): 771-781. doi: 10.1002 / glia.22307).

[0013] It has been proposed that CCR6 and CCL20 affect the kinetics of germinal center (GC) formation and B cell responses, and CCR6 is considered to be a marker memory B cell progenitor in both mouse and human germinal centers (Suan D, Immunity. December 19, 2017; 47(6): 1142-1153.e4. doi: 10.1016 / j.immuni.2017.11.022). In peripheral B cells of patients with systemic lupus erythematosus (SLE), the expression of CCR6 on naive, pre-GC, GC / plasma cell and memory B cells was increased (Lee AYS, Clin Rheumatol. June 2017; 36(6): 1453-1456. doi: 10.1007 / s10067-017-3652-3). CD4+CCR6+ cells may also contribute to disease severity in SLE patients, and have been shown to be increased in anti-DNA+ SLE patients, which correlates with disease severity and erythrocyte sedimentation rate (Zhong W, PeerJ. 2018; 6: e4294. doi: 10.7717 / peerj.4294).

[0014] Increased expression of CCR6 in the salivary glands of patients with primary Sjögren's syndrome (pSS) has been shown [Scand J Immunol. March 2020; 91(3): e12852. doi: 10.1111 / sji.12852]. An increasing trend in CCL20 mRNA expression was also observed. A significant decrease in CCR6+ Th cells (both CCR9- and CCR9+) in the blood circulation of patients with pSS when compared with healthy controls (HC) has been shown [Scand J Immunol. March 2020; 91(3): e12852. doi: 10.1111 / sji.12852].

[0015] In an animal model of autoimmune hepatitis (AIH), administration of anti-TNF-α suppressed hepatic CCL20 expression. Mice treated with anti-CCL20 showed a reduction in AIH. Furthermore, T NFα stimulation enhanced CCL20 expression in hepatocytes. These findings suggest that TNFα is essential for inducing AIH via upregulation of hepatic CCL20 expression, thereby recruiting CCR6+ T cells and driving the disease (Clin Immunol. 2013 / 146(1):15-25.doi:10.1016 / j.clim.2012.10.008).

[0016] The CCR6 regulators of the present invention are thought to be useful, either alone or in combination, for the treatment or prevention of posterior uveitis, allergic conjunctivitis, allergic diseases of the gastrointestinal tract, autoimmune diseases or disorders including type 1 diabetes and endometriosis (Medicina(Kaunas). November 16, 2018; 54(5).doi:10.3390 / medicina54050088). CCR6 modulators are also useful, alone or in combination, for the treatment of ocular surface diseases in which elevated IL-17A levels have been recorded, including meibomian gland dysfunction; GVHD, graft-versus-host disease; autoimmune keratitis, filamentous keratitis, dry eye syndrome with rheumatoid arthritis; dry eye syndrome without systemic disease; and Stevens-Johnson syndrome (J Korean Med Sci. 2011 July; 26(7):938-44. doi:10.3346 / jkms.2011.26.7.938).

[0017] The CCR6 modulators of the present invention are considered useful, either alone or in combination, for the treatment or prevention of malignant diseases. Modulation of the CCR6 / CCL20 system using siRNA, shRNA, CCR6 knockout animals, CCL20 ligand treatment, or antibodies has been shown to alter tumor growth and metastasis processes in experimental disease models, either as monotherapy or in combination with immunotherapy (particularly PD1 and / or PDL1 blockade) for the prevention or treatment of cancer.

[0018] The potential of therapies that modulate this system for the treatment of malignant tumors has been described in tumor mouse models using silencing of CCR6 or CCL20 with small interfering RNA (siRNA) or small hairpin RNA (shRNA). Specifically, in a mouse model of cutaneous T-cell lymphoma (My-La cells), Abe et al. reported that administration of CCR6-targeted siRNA extended the survival of animals compared to control animals (Oncotarget. January 31, 2017; 8(5)7572-7585. doi:10.18632 / oncotarget.13810.). Using a different approach, Ito et al. showed that mice injected with T lymphoma cells (My-La) containing a CCR6 silencing siRNA construct survived significantly longer than mice injected with control cells (Blood. March 6, 2014; 123(10): 1499-511. doi: 10.1182 / blood-2013-09-527739.). Zhu and collaborators showed that silencing CCR6 in cancer cells with shRNA reduced the mean volume and weight of tumor nodules in mice subcutaneously injected with a set of colorectal cancer cell lines (PMID Biochim Biophys Acta Mol Basis Dis. February 2018; 1864(2): 387-397. doi: 10.1016 / j.bbadis. 2017.10.033.). In a glioblastoma xenograft model using patient-derived glioblastoma cell lines, mice injected with cells containing an shRNA construct that silences CCR6 expression survived longer than mice injected with control cells. Furthermore, histological and immunohistochemical examinations revealed that tumors formed by glioma cells containing CCR6-targeting shRNA were significantly smaller and exhibited significantly reduced tumor angiogenesis compared to control tumors. These data further support the concept that CCR6 signaling enhances the oncogenic potential of malignant tumors, including lymphoma, colorectal tumors, and glioblastoma (Oncogene. 2018 / June; 37(23):3070-3087. doi:10.1038 / s41388-018-0182-7). Specifically, CCR6 knockout animals were used... The involvement of the CCR6 / CCL20 system in tumorigenesis has been reported in the literature. In the CMT93 mouse model of colorectal cancer (CRC), T regulatory cell invasion was completely inhibited in tumors of CCR6-deficient mice compared to wild-type animals. The reported data further suggest that the homing and trafficking of tumor-infiltrating T regulatory cells to tumors is dependent on the chemokine receptor CCR6 in vivo (PLoS One, April 29, 2011; 6(4):e19495.doi:10.1371 / journal.pone.0019495). According to Nandi et al., in a mouse model of spontaneous intestinal tumorigenesis, mice lacking CCR6 [APCMIN / + mice, heterozygous for mutations in the adenomatous polyposis coli (APC) gene] showed reduced incidence of spontaneous intestinal tumorigenesis (PLoS One.2014;9(5):e97566.doi:10.1371 / journal.pone.0097566.).

[0019] The potential role of the CCR6 / CCL20 system in tumorigenesis has also been demonstrated by administration of recombinant CCL20 chemokine. Specifically, in a mouse model of colorectal cancer (CMT93 cells), Liu et al. showed that tumor size was significantly increased in mice treated with recombinant mouse CCL20 compared to PBS controls, suggesting an important role of CCL20 in the proliferation and development of colorectal cancer (PLoS One. April 29, 2011; 6(4):e19495.doi:10.1371 / journal.pone.0019495.).

[0020] Specifically, the potential role of the CCR6 / CCL20 system in tumor promotion has been demonstrated in the literature using mouse models with neutralizing CCL20 antibodies. Ikeda and collaborators used a mouse model of specific cutaneous T-cell lymphoma (CTCL). In this model, animals die due to metastasis of CTCL cells to multiple organs. However, administration of neutralizing CCL20 antibodies significantly extended the survival of xenografted mice (Oncotarget. March 22, 2016; 7(12): 13563-74. doi: 10.18632 / oncotarget.6916.). Lee and collaborators described how administration of anti-CCL20 antibody prevented the development of bone metastases, one of the major metastatic sites of breast cancer in humans, in a mouse model of metastatic breast cancer (MDA-MB-231 cells were injected into the left ventricle of nude mice) (Sci Rep. 2017 Aug. 29;7(1):9610.doi:10.1038 / s41598-017-09040-4.). In a humanized mouse model of nasopharyngeal carcinoma, Mrizak et al. observed that injection of anti-CCL20 monoclonal antibody into mice significantly reduced the recruitment of T regulatory cells into tumors compared to sham-treated animals (J Natl Cancer Inst. 2015 Jan.;107(1):363.doi:10.1093 / jnci / dju363.). In addition, in a mouse model of hepatocellular carcinoma (Hepa1-6 cells), blocking CCL20 activity in immune-responsive mice using an anti-CCL20 antibody reduced tumor development and suppressed tumor growth and distal metastasis. Furthermore, the authors reported that tumor angiogenesis was significantly inhibited with CCL20 neutralization in this mouse model (He et al., PMID 28560063-Am J Cancer Res. 2017;7(5):1151-1163). Using the same mouse model, administration of an anti-CCL20 neutralizing antibody significantly reduced the infiltration of T regulatory cells, particularly CCR6-positive T regulatory cells, into the tumor and significantly reduced tumor growth. When mice were treated with an anti-PDL-1 antibody, the antitumor activity was further enhanced.In other words, these data suggest that CCL20 blockade can suppress anti-PD-L1 resistance in a mouse model of hepatocellular carcinoma by inhibiting the recruitment of T regulatory cells to tumors (Hepatology. 2019 July; 70(1): 198-214. doi: 10.1002 / hep.30593.).

[0021] Specifically, the potential role of the CCR6 / CCL20 system in tumor metastasis has been described in the literature. Dellacasagrande et al. reported that in a mouse model of plasma cell tumor, tumor cells disseminated to the liver (by sc injection of mouse plasma cell tumor (MOPC315)) overexpressed functional CCR6 compared to tumor cells from the primary tumor. The same authors found that CCR6 was overexpressed in small liver metastases of colon, thyroid, and ovarian cancers compared to normal liver (Scand J Immunol. June 2003; 57(6): 534-44. doi: 10.1046 / j. 1365-3083. 2003. 01263.x.).

[0022] Furthermore, the CCR6 modulators of the present invention, either alone or in combination, are considered useful for the treatment or prevention of cancers in which the expression of CCR6 and / or CCL20 correlates with disease progression and resistance to standard treatment. Specifically, the correlation between CCR6 expression and disease progression has been described in the literature for a vast number of cancers. For example, in renal cell carcinoma, CCR6 expression correlates with reduced overall survival (Cancers (Basel). December 30, 2019; 12(1). doi:10.3390 / cancersl2010089). In colorectal cancer, tumor expression of CCR6 is positively correlated with metastasis, and upregulation of CCR6 predicts low survival rates, short disease-free survival (PLoS One.2014;9(6):e101137.doi:10.1371 / journal.pone.0101137.) and low 5-year overall survival (Biochim Biophys Acta Mol Basis Dis. February 2018;1864(2):387-397.doi:10.1016 / j.bbadis.2017.10.033.). In ovarian cancer, high CCR6 mRNA expression is also correlated with a poor prognosis (Cancer Lett. March 1, 2020;472:59-69.doi:10.1016 / j.canlet.2019.12.024.). CCR6 expression correlates with aggressiveness in rectal cancer; in fact, high levels of CCR6 protein expression are more common in non-responders to radiotherapy than in responders (Cancer Res Treat. 2018 / October; 50(4):1203-1213. doi:10.4143 / crt.2017.538.). In prostate cancer, CCR6 expression levels correlated with the clinical and pathological features of more advanced and aggressive disease (J Cancer Res Clin Oncol. 2008 / November; 134(11):1181-9. doi:10.1007 / s00432-008-0403-5.). In non-small cell lung cancer (NSCLC), high CCR6 expression is associated with shorter disease-free survival and increases the risk of disease recurrence fivefold, regardless of disease stage (PLoS One.2011;6(9):e24856.doi:10.1371 / journal.pone.0024856.).Hepatocellular carcinoma patients with increased infiltration of CCR6-positive immune cells into tumor tissue had a poor prognosis (Am J Cancer Res. 2017;7(5):1151-1163).

[0023] Similar to CCR6, the expression of its ligand, CCL20, has been reported to correlate with poor disease outcomes for several indications. Specifically, in breast cancer, elevated CCL20 expression was significantly correlated with decreased overall disease-free survival, decreased metastasis-free survival (Sci Rep. 2017 August 29;7(1):9610.doi:10.1038 / s41598-017-09040-4.), increased histological malignancy, elevated KI67 index, and axillary lymph node metastasis. Furthermore, CCL20 expression in breast tumors was positively correlated with the expression of FOXP3, a marker for T regulatory cells. Overall survival was lowest in patients with axillary lymph node metastasis and simultaneous elevations of CCL20 expression and FOXP3-positive T regulatory cells (Medicine (Baltimore). December 2019; 98(50):e18403.doi:10.1097 / MD.0000000000018403.). In NSCLC, elevated CCL20 expression was correlated with decreased overall survival (Biomed Pharmacother.2015 February;69:242-8.doi:10.10 16 / j.biopha.2014.12.008.) (Cancer Lett. 10 July 2015; 363(1): 60-70. doi: 10.1016 / j.canlet.2015.04.005.). Similar to NSCLC, patients with hepatocellular carcinoma accompanied by increased CCL20 expression had shorter overall survival and recurrence-free survival. The same authors describe that CCL20 expression was significantly correlated with tumor size, number of tumors, vascular invasion, tumor differentiation and tumor recurrence (J Gastrointest Surg. April 2012; 16(4): 828-36. doi: 10.1007 / s11605-011-1775-4.). In addition to CCR6 or CCL20 alone, the correlation between co-expression of CCR6 / CCL20 and disease progression is described in the literature. Indeed, overexpression of both CCL20 and CCR6 has been detected in high-grade glioma tissues rather than low-grade tissues, and increased with increasing World Health Organization (WHO) tumor grade. Notably, glioma patients with CCL20 / CCR6 co-expression had the shortest overall survival (Med Oncol. December 2012; 29(5): 3491-7. doi: 10.1007 / s12032-012-0314-9.).

[0024] Furthermore, CCR6 and / or CCL20 expression correlates with enhanced chemoresistance and is associated with metastasis. Indeed, expression of CCL20 may increase chemotherapeutic resistance in breast cancer cells (PLoS Biol. July 2018; 16(7): e2005869. doi: 10.1371 / journal.pbio.2005869.). Rubie et al. describe that significant upregulation of CCL20 / CCR6 was observed (by RT-PCR) in human samples of colorectal liver metastasis (CRLM) and hepatocellular carcinoma (HCC). Furthermore, CCL20 is significantly overexpressed in colorectal liver metastases compared to primary HCC, which indicates the involvement of the CCL20 / CCR6 ligand-receptor pair in the carcinogenesis and progression of hepatic malignancies (World J Gastroenterol. 7 November 2006; 12(41): 6627-33. doi: 10.3748 / wjg.v12.i41.6627.).

[0025] The CCR6 modulators of the present invention are considered useful, either alone or in combination, in the treatment or prevention of diseases or disorders in which CCR6 and / or CCL20 are expressed or overexpressed in patient samples or cancer cell lines. Specifically, the literature describes the expression of the chemokine receptor CCR6 in several types of cancer or cancer cell lines. Lu and collaborators described that CCR6 expression is higher in laryngeal cancer tissue than in their normal controls. The authors also reported that CCR6 is expressed in common laryngeal cancer cells such as TU212, M4E, M2E, and Hep-2 (Biomed Pharmacother. 2017 / 1;85:486-492 doi:10.1016 / j.biopha.2016.11.055.). Based on gene expression data from malignant melanoma, and along with reported biological networks, the CCR6 gene was described and characterized as a useful factor involved in immune response and tumor growth (PLoS One.2018;13(1):e0190447.doi:10.1371 / journal.pone.0190447.). Whole exome sequencing of 21 MALT lymphomas of the salivary glands and thyroid gland revealed the expression of CCR6 (Haematologica.2018 August;103(8):1329-1336.doi:10.3324 / haematol.2018.191601.). In samples from adult T-cell leukemia / lymphoma (ATLL), CCR6 transcripts were detected, and further CCR6 was identified at the protein level by flow cytometry analysis (Leuk Lymphoma. 2006 / October;47(10):2163-73.doi:10.1080 / 10428190600775599.). In patient-derived prostate cancer samples, CCR6 gene expression (mRNA) was significantly higher in tumor tissue compared to adjacent normal tissue (Cancer Res Treat. 2015 / April;47(2):306-12.doi:10.4143 / crt.2014.015.). CCR CCR6 expression has been detected in common cancer cell lines, and indeed, according to Mays and collaborators, RT-PCR gene analysis revealed that CCR6 was expressed along with other CC chemokine receptors in salivary adenoid cystic carcinoma (SACC-83) cells (Anticancer Res. 2016 August;36(8):4013-8). According to Moeller et al., U266 CCR6 was also expressed in multiple myeloma (MM) cell lines including 1970, U-266, 1984, U-1958, Karpas 707, LP-1, 28 L-363, HL407E, and HL407L.3 (Leukemia. January 2003; 17(1):203-10. doi:10.1038 / sj.leu.2402717.).

[0026] Similar to CCR6, it has been reported in the literature that the ligand CCL20 is expressed in numerous tumor samples and tumor cell lines. For example, Zhang and co-workers demonstrated using RT-PCR that CCL20 expression is higher in tumor samples than in adjacent tissue samples from NSCLC patients, which was also verified at the protein level using immunohistochemical analysis (Biomed Pharmacother. February 2015;69:242-8. doi: 10.1016 / j.biopha.2014.12.008.). Gene expression analysis of cholangiocarcinoma samples and corresponding normal tissues revealed that CCL20 is one of the most significantly overexpressed genes in malignant tissues compared with healthy tissues (EXCLI J. 2020;19:154-166. doi: 10.17179 / excli2019-1893.). CCL20 expression has also been reported in human samples of multiple myeloma (MM) (Cancer Res. August 15, 2008;68(16):6840-50. doi: 10.1158 / 0008-5472.CAN-08-0402.). Furthermore, according to Rubies et al., CCL20 mRNA and protein are significantly upregulated (8-fold) in pancreatic cancer compared with equivalent normal pancreas with weak CCL20 expression (J Transl Med. May 2010;8:45. doi: 10.1186 / 1479-5876-8-45.). CCL20 is also expressed in oral squamous cell carcinoma (IHC staining), and Lee et al. reported that its expression is enhanced in human CCR6+ regulatory T cells with excellent suppressive activity (J Immunol. July 15, 2017;199(2):467-476. doi: 10.4049 / jimmunol.1601815.).

[0027] In addition to the expression of CCR6 or CCL20 alone, the co-expression of both CCR6 and CCL20 has been reported in the literature for samples from cancer patients and cancer cell lines. It is described that both genes are expressed in samples from patients with adult T-cell leukemia / lymphoma (by microarray and IHC protein staining) (Int J Oncol. September 2014; 45(3): 1200-1208. doi: 10.3892 / ijo.2014.2524.) and in CTCL. In the latter, CCL20 and CCR6 were detected at the mRNA and protein levels (Clin Cancer Res. December 15, 2011; 17(24): 7529-7538. doi: 10.1158 / 1078-0432.CCR-11-1192.). Transcriptome analysis (Nanostring) of hepatocellular carcinoma samples revealed the expression of CCR6 and CCL20. Furthermore, a chemotactic gradient between non-tumor and tumor tissues has been reported, suggesting a recruitment process of T regulatory cells, tumor-associated macrophages and natural killer cells involved in the CCR6 / CCL20 axis (Proc Natl Acad Sci U S A. July 18, 2017; 114(29): E5900-E5909. doi: 10.1073 / pnas.1706559114.). Similarly, Guo and co-workers reported the upregulation of CCR6 and CCL20 in hepatocellular carcinoma lesions compared with healthy tissues, and the expression of CCR6 and CCL20 in hepatocellular carcinoma cell lines (L02, Li- / -, Huh-7, SNU-387, Hep3B) (Oncol Rep. September 2019; 42(3): 1075-1089. doi: 10.3892 / or.2019.7221.). Nandi et al According to the report, both CCL20 and CCR6 are expressed in human colorectal cancer (IHC protein staining). In NSCLC samples, it was found that the expression of both CCR6 and CCL20 was significantly increased (at protein and mRNA levels) (Oncol Lett. December 2017;14(6):8183-8189. doi:10.3892 / ol.2017.7253). Using in situ hybridization, both CCL20 and CCR6 mRNA sequences were strongly expressed in all analyzed pancreatic cancer samples. In contrast, the expression of CCL20 and CCR6 was low in healthy pancreas (Int J Cancer. May 17, 1999;81(4):650-7. doi:10.1002 / (sici)1097-0215(19990517)81:4<650::aid-ijc23>3.0.co;2-#). Jin et al. investigated the expression of CCR6 and CCL20 in glioblastoma using publicly available datasets. The authors compared mRNA levels of CCL20 and CCR6 between normal brain and glioblastoma tissues using the GEO dataset GSE2223. Again, the expression levels of CCR6 and CCL20 were significantly higher in glioblastoma tissues than in normal brain tissues (Oncogene. June 2018;37(23):3070-3087. doi:10.1038 / s41388-018-0182-7). In addition, Wallace et al. observed that the expression of CCL20 and its receptor CCR6 was higher in endometrioid adenocarcinoma cultured tissues and cell lines compared with non-malignant endometrium (mRNA, RT-PCR) (Mol Cell Endocrinol. January 1, 2011;331(1):129-35. doi:10.1016 / j.mce.2010.08.018). The CCL20 / CCR6 axis is considered to play a role in breast cancer, cholangiocarcinoma and thyroid cancer.This is because the expression of CCR6 / CCL20 genes and / or proteins has been reported in patient-derived breast cancer cells (Mol Carcinog. July 2016; 55(7): 1175-186. doi: 10.1002 / mc.22360.), HuCCT1 and TFK-1 cholangiocarcinoma cell lines () (Win et al., PMID 32194362) (EXCLI J. 2020; 19: 154-166. doi: 10.17179 / excli2019-1893.), and thyroid cancer cell lines such as TPC-1, BCPAP, FTC-133 and SW1736 (Tumour Biol. April 2016; 37(4): 5569-75. doi: 10.1007 / s13277-015-4418-7.). Furthermore, the CCR6 modulator of the present invention, alone or in combination, is considered useful for the treatment or prevention of cancers for which expression and / or evidence of CCR6 / CCL20 axis activity have been reported, or cancers in which CCR6+ regulatory T cells have been identified in the tumor microenvironment. [Summary of the Invention]

[0028] 1) One aspect of the present invention relates to a compound of formula (I):

[0029] [Chemical Formula] (wherein, Q represents N, CH or C-R (R represents halogen or C 1-3 -alkyl); R 1 represents - C 1-3 -alkyl (especially methyl); ; R 2 represents - hydrogen; - C 1-4 -alkyl (especially methyl or isopropyl); - hydroxy-C 1-3 -alkyl (especially 2-hydroxyethyl); - C 1-3 -fluoroalkyl (especially C1-fluoroalkyl; especially 2,2-difluoroethyl); or - C 3-5 -Cycloalkyl; It represents; R 3a teeth, - Halogens (especially bromine); - C 1-5 -Alkyl (especially ethyl, n-propyl, isopropyl, tert-butyl; particularly isopropyl); - C 1-3 -Fluoroalkyl (especially 2,2,2-trifluoroethyl); - C 1-3 -Fluoroalkoxy (especially C1-fluoroalkoxy; particularly trifluoromethoxy); - C 3-5 -Cycloalkyl (especially cyclopropyl); or, - 1-(C 1-3 -Fluoroalkyl)-C 3-5 -Cycloalkyl (especially 1-(C1-fluoroalkyl)-C 3-5 -Cycloalkyl; particularly 1-trifluoromethyl-cyclopropyl); It represents; R 3b teeth, - Hydrogen; or, - Halogen; It represents; R 4 teeth, - C 1-4 - Alkyl, unsubstituted; substituted with one substituent, wherein the substituent is hydroxyl or C 1-3 - Select from alkyl-amino (especially methyl-amino) or substituted by two substituents, where the first substituent represents hydroxyl and the second substituent represents C1-fluoroalkyl (especially trifluoromethyl), C 1-4 -alkyl[especially, fortunately C 1-4 -Alkyl represents 1-hydroxy-1-methyl-ethyl, 1-methyl-1-(methyl-amino)-ethyl, or 1-hydroxy-1-trifluoromethyl-ethyl. ]; or, - -L-Cy( -- -L- represents a direct bond (i.e., Cy is directly bonded to the triazolyl ring mentioned above) or -CH2- (especially a direct bond); -- Cy optionally has one ring heteroatom selected from nitrogen or oxygen. 3-7 - Represents a cycloalkyl group (in particular, such Cy represents cyclobutyl, cyclohexyl, tetrahydropyran-4-yl, or piperidinyl; in particular, cyclobutyl, cyclohexyl, tetrahydropyran-4-yl, or piperidin-4-yl), and Cy is independently unsubstituted; or --- 1 piece ---- Hydroxy; ---- Oxo; ---- C 1-4 -alkyl; ---- -C(=O)R A (R A C 1-3 -Alkyl (especially methyl) or hydroxy-C 1-3 - Represents alkyl. ); or, ---- C 1-3 -alkyl-carbonyl-amino; Replaced by; or, --- Substituted by two substituents, the first substituent representing oxo and the second substituent representing C 1-3 - Represents alkyl; or is substituted with two substituents, where the first substituent represents hydroxyl and the second substituent is C 1-3 - Represents alkyl-carbonyl; -- Alternatively, Cy represents a saturated 5-8 membered bridged bicyclic hydrocarbon ring system (in particular, such a ring system represents bicyclo[1.1.1]pentan-1-yl or bicyclo[2.2.2]octane-1-yl), and Cy is independently substituted with one substituent (in particular at the tertiary carbon atom of the ring system), and the substituent is --- Hydroxy-C 1-3 -alkyl (especially hydroxymethyl); or, --- -C(=O)R B (R B teeth, ---- Hydroxy; ---- -NRN1 R N2 (R N1 and R N2 These are, independently, hydrogen or C 1-3 - Represents alkyl; or R N1 and R N2 They, together with the nitrogen atom to which they bond, form pyrrolidinyl. ); or, ---- C 1-3 -alkoxy (especially methoxy); This represents... Selected from; -- Or, Cy represents a 5 or 6-membered heteroaryl (especially a 6-membered heteroaryl) having one or two (especially one) ring heteroatoms (especially nitrogen) independently selected from nitrogen or oxygen (in particular, Cy represents pyridinyl; in particular pyridine-3-yl). [In particular, such -L-Cy groups represent tetrahydropyran-4-yl, 4-hydroxy-tetrahydropyran-4-yl, 1-hydroxy-cyclobutyl-methyl, 4-hydroxy-cyclohexyl, pyridine-3-yl, 4-methoxycarbonyl-bicyclo[2.2.2]octan-1-yl, 4-carboxy-bicyclo[2.2.2]octan-1-yl, 3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl, or N-acetyl-piperidine-4-yl.] Represents; and R 5 teeth, - C 1-4 -Alkyl (especially methyl, ethyl, isopropyl, or tert-butyl); - Hydroxy-C 1-3 -Alkyl (especially 2-hydroxyethyl); - C 1-3 -alkoxy-C 1-3 -alkyl; - C 3-7 -Cycloalkyl (especially cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); - C 1-3 -Fluoroalkyl (especially 2,2-difluoropropyl); - C 1-3-alkyl-carbonyl; or, - C 1-3 -alkyl-carbonyl-amino-C 1-3 -alkyl; Does it represent; Or, R 4 and R 5 Together with the triazolyl ring to which they are attached, they form 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-yl or 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl.

[0030] The definitions set forth herein apply uniformly to compounds of formula (I) as defined in any one of embodiments 1) to 13), and shall apply throughout this specification and claims with necessary modifications unless a broader or narrower definition is provided by a specific definition. Naturally, a definition or preferred definition of a term may independently (and together with) define and replace any or all of the terms defined herein or each term in a preferred definition. Unless otherwise expressly defined in any embodiment or claim, groups as defined herein are unsubstituted.

[0031] The term "halogen," whether used alone or in combination, refers to fluorine, chlorine, bromine, or iodine; in particular, it means fluorine, chlorine, or bromine. 3b A preferred example for this is fluorine.

[0032] The term "oxy," whether used alone or in combination with other terms, refers to the group -O-.

[0033] The term "oxo," whether used alone or in combination with other terms, refers to the base = O.

[0034] The term "amino," whether used alone or in combination with other terms, refers to the group -NH2.

[0035] The term "alkyl," whether used alone or in combination, refers to a linear or branched saturated hydrocarbon chain group having 1 to 6 carbon atoms. x-y The term "alkyl" (where x and y are integers) refers to the previously defined alkyl group having x to y carbon atoms. x-y -When an alkyl group is used in combination with another substituent, this term means that the substituent is C x-y - This means bonding to the rest of the molecule via an alkyl group. For example, C 1-6 -Alkyl groups have 1 to 6 carbon atoms. 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and isobutyl.

[0036] The term "hydroxyalkyl (or hydroxy-alkyl)," whether used alone or in combination, refers to the previously defined alkyl group in which one hydrogen atom is replaced by a hydroxyl group. x-y The term "-alkyl" (where x and y are integers) refers to the previously defined hydroxyalkyl group, whether used alone or in combination, in which the alkyl group has x to y carbon atoms. For example, hydroxy-C 1-3 - Alkyl groups are 1~ It is a hydroxyalkyl group having three carbon atoms, as defined earlier. 1-3 Examples of alkyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-1-methylethyl, and 1-methyl-2-hydroxyethyl.

[0037] The term "fluoroalkyl," whether used alone or in combination, refers to the previously defined alkyl group in which one or more (and possibly all) hydrogen atoms are replaced by fluorine.x-y The term "-fluoroalkyl" (where x and y are integers) refers to the previously defined fluoroalkyl group having x to y carbon atoms. For example, C 1-3 -Fluoroalkyl groups have 1 to 3 carbon atoms and 1 to 7 hydrogen atoms are replaced by fluorine. 1-3 -Examples of fluoroalkyl groups are trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. 1-3 - Preferred examples of fluoroalkyl groups are C1-fluoroalkyl groups having one carbon atom and one to three hydrogen atoms replaced by fluorine. Examples of such C1-fluoroalkyl groups are mono-, di-, and tri-fluoromethyl groups; trifluoromethyl in particular.

[0038] The term "cycloalkyl," whether used alone or in combination, refers to a saturated monocyclic hydrocarbon ring having 3 to 7 carbon atoms (preferably 3 to 6 carbon atoms). x-y The term "cycloalkyl" (where x and y are integers) refers to a saturated monocyclic hydrocarbon ring having x to y carbon atoms. For example, C 3-6 -Cycloalkyl groups have 3 to 6 carbon atoms. 3-5 - Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, and cyclopentyl. 3-7 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The above cycloalkyl groups are either unsubstituted or substituted as explicitly defined.

[0039] "C which optionally has one ring heteroatom" 3-7 The term "cycloalkyl," whether used alone or in combination, refers to a carbon ring atom that is replaced by a heteroatom selected from oxygen, nitrogen, or sulfur (particularly oxygen or nitrogen), or is replaced as explicitly defined, as previously defined C 3-7- Represents a cycloalkyl group. A C group optionally having one ring heteroatom selected from nitrogen or oxygen. 3-7 -Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azilidinyl, oxylanil, azetidinyl, oxetanil, pyrrolidinyl, tetrahydrofuranil, piperidinyl, and tetrahydropyranil; in particular pyrrolidinyl, tetrahydrofuranil, tetrahydropyranil, and piperidinyl; especially tetrahydropyranil and piperidinyl. The above groups are either unsubstituted or substituted as explicitly defined.

[0040] "C 1-3 -Fluoroalkyl-C 3-5 The term "cycloalkyl," whether used alone or in combination, refers to a single hydrogen atom that is a C as defined above. 1-3 -The previously defined C is replaced with a fluoroalkyl (especially C1-fluoroalkyl). 3-5 - This refers to a cycloalkyl group. In particular, the C 1-3 -Fluoroalkyl is the C that is added to the rest of the molecule. 3-5 -The group is bonded at the cycloalkyl bond site. Examples of such groups are 1-trifluoromethyl-cyclopropyl, 1-trifluoromethyl-cyclobutyl, and 1-trifluoromethyl-cyclopentyl.

[0041] The term "alkyl-carbonyl," whether used alone or in combination, means an alkyl group as defined herein, in which one hydrogen atom is replaced by the group -C(=O)-. x-y -alkyl-carbonyl (x and y are each one The term (which is a number) refers to the previously defined alkyl-carbonyl group, where the alkyl group has x to y carbon atoms, whether used alone or in combination. For example, C 1-3The -alkyl-carbonyl group is an alkyl-carbonyl group as defined above having 1 to 3 carbon atoms. Examples of such groups are acetyl, ethyl-carbonyl, propyl-carbonyl and isopropyl-carbonyl.

[0042] The term "alkyl-carbonyl-amino", whether used alone or in combination, means an amino group as defined above, in which one hydrogen atom is replaced by an alkyl-carbonyl group as defined above. "C x-y -alkyl-carbonyl-amino" (wherein x and y are each an integer), whether used alone or in combination, means a C x-y -alkyl-carbonyl-amino group as defined above, wherein the alkyl group has x to y carbon atoms. C 1-3 -alkyl-carbonyl-amino group is an alkyl-carbonyl group as defined above having 1 to 3 carbon atoms. Examples of such C 1-3 -alkyl-carbonyl-amino groups are acetyl-amino, ethyl-carbonyl-amino, propyl-carbonyl-amino, isopropyl-carbonyl-amino; in particular acetyl.

[0043] The term "alkoxy", whether used alone or in combination, means an alkyl group as defined above in which one hydrogen atom is replaced by -O-, that is, the alkyl-O- group. "C x-y -alkoxy" (wherein x and y are each an integer), whether used alone or in combination, means an alkoxy group as defined above, wherein the alkoxy group has x to y carbon atoms. For example, C 1-3 -alkoxy group is an alkoxy group as defined herein having 1 to 3 carbon atoms. C 1-3 Examples of -alkoxy groups are methoxy, ethoxy, n-propoxy or isopropoxy; in particular methoxy.

[0044] The term "fluoroalkoxy," whether used alone or in combination, refers to the previously defined alkoxy group in which one or more (and possibly all) hydrogen atoms are replaced by fluorine. x-y The term "-fluoroalkoxy" (where x and y are integers) refers to the previously defined fluoroalkoxy group having x to y carbon atoms. For example, C 1-3 -Fluoroalkoxy groups have 1 to 3 carbon atoms and 1 to 7 hydrogen atoms are replaced by fluorine. 1-3 Examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0045] The term "5- or 6-membered heteroaryl" means, whether used alone or in combination, a 5- or 6-membered monocyclic aromatic ring having 1 to 4 ring heteroatoms (preferably 1 to 3 ring heteroatoms) each independently selected from oxygen, nitrogen, and sulfur. Examples of 5-membered groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl. Examples of 6-membered heteroaryl groups are pyridinyl, pyrimidinyl, pyridadinyl, or pyrazinyl. Preferred examples of such 5- or 6-membered heteroaryl groups are pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridadinyl, or pyrazinyl. The above heteroaryl groups are unsubstituted or substituted as explicitly defined.

[0046] The term "saturated 5-8 membered bridged bicyclic hydrocarbon ring system," whether used alone or in combination, refers to two hydrocarbon rings sharing two carbon atoms. It means a hydrocarbon ring wherein the total number of carbon atoms in both rings is an integer of 5 to 8. More specifically, the term refers to "bicyclo[x.y.z]alkyl, wherein the total number of carbon atoms is an integer of 5 to 8, and each of "x", "y" and "z" is greater than 0 bicyclo[x.y.z]alkyl" [that is, the sum of "x", "y" and "z" is 3 to 6; "x", "y" and "z", which are integers, independently represent the number of carbon atoms in each of the three bridges bonded to two tertiary carbon atoms in descending order (x>y>z).] means a compound described by the term. Examples of such 5 to 8 membered bridged bicyclic hydrocarbon ring systems are bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl and bicyclo[2.2.2]octanyl. The above ring systems are unsubstituted or substituted as explicitly defined.

[0047] In the present patent application, a bond drawn as a dotted line indicates the point of attachment of the stated group to the remainder of the molecule. For example, the following group

[0048] [[Chemical formula drawing]] represents 1-R 2 -3-R 1 -azetidin-3-yl.

[0049] Further aspects of the invention are described below: 2) One aspect is that, Q represents CH; R 1 is, - C 1-3 -alkyl (especially methyl); represents; R 2 is, - hydrogen; - C 1-4 -alkyl (especially methyl or isopropyl); - hydroxy-C 1-3 -alkyl (especially 2-hydroxyethyl); or, - C1-3 -Fluoroalkyl (especially C1-fluoroalkyl; particularly 2,2-difluoroethyl); It represents; R 3a but, - Halogens (especially bromine); - C 1-5 -Alkyl (especially ethyl, n-propyl, isopropyl, tert-butyl; particularly isopropyl); - C 1-3 -Fluoroalkyl (especially 2,2,2-trifluoroethyl); - C 1-3 -Fluoroalkoxy (especially C1-fluoroalkoxy; particularly trifluoromethoxy); - C 3-5 -Cycloalkyl (especially cyclopropyl); or, - 1-(C 1-3 -Fluoroalkyl)-C 3-5 -Cycloalkyl (especially 1-(C1-fluoroalkyl)-C 3-5 -Cycloalkyl; particularly 1-trifluoromethyl-cyclopropyl); It represents; R 3b but - Hydrogen; It represents; R 4 but, - C 1-4 -Alkyl, substituted with one substituent, wherein the substituent is hydroxyl or C 1-3 -Selected from alkyl-amino (especially methyl-amino); or substituted with two substituents, where the first substituent represents hydroxyl and the second substituent represents C1-fluoroalkyl (especially trifluoromethyl), C 1-4 -alkyl; [In particular, such C 1-4 -Alkyl represents 1-hydroxy-1-methyl-ethyl, 1-methyl-1-(methyl-amino)-ethyl, or 1-hydroxy-1-trifluoromethyl-ethyl. ]; or, - -L-Cy( -- -L- represents a direct bond (i.e., Cy is directly bonded to the triazolyl ring mentioned above) or -CH2- (especially a direct bond); -- Cy is a C atom that optionally has one ring heteroatom selected from nitrogen or oxygen. 3-7 - Represents a cycloalkyl group (in particular, such Cy represents cyclobutyl, cyclohexyl, tetrahydropyran-4-yl, or piperidinyl; in particular, cyclobutyl, cyclohexyl, tetrahydropyran-4-yl, or piperidin-4-yl), and Cy is independently unsubstituted; or --- 1 piece ---- Hydroxy; or, ---- -C(=O)R A (R A is C 1-3 - Represents alkyl (especially methyl). Replaced by; -- Alternatively, Cy represents a saturated 5-8 membered bridged bicyclic hydrocarbon ring system (in particular, such a ring system represents bicyclo[1.1.1]pentan-1-yl or bicyclo[2.2.2]octane-1-yl), and Cy is independently substituted with one substituent (in particular at the tertiary carbon atom of the ring system), and the substituent is --- Hydroxy-C 1-3 -alkyl (especially hydroxymethyl); or, --- -C(=O)R B (R B teeth, ---- Hydroxy; or, ---- C 1-3 -alkoxy (especially methoxy); This represents... Selected from; -- Alternatively, Cy represents a six-membered heteroaryl compound having one ring nitrogen atom (in particular, Cy represents pyridinyl; especially pyridine-3-yl). [In particular, such -L-Cy groups represent tetrahydropyran-4-yl, 4-hydroxy-tetrahydropyran-4-yl, 1-hydroxy-cyclobutyl-methyl, 4-hydroxy-cyclohexyl, pyridine-3-yl, 4-methoxycarbonyl-bicyclo[2.2.2]octan-1-yl, 4-carboxy-bicyclo[2.2.2]octan-1-yl, 3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl, or N-acetyl-piperidine-4-yl.] It represents; R 5 but, - C 1-4 -Alkyl (especially methyl, ethyl, isopropyl, or tert-butyl); - Hydroxy-C 1-3 -Alkyl (especially 2-hydroxyethyl); - C 3-7 -Cycloalkyl (especially cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); or, - C 1-3 -Fluoroalkyl (especially 2,2-difluoropropyl); Represents; This relates to compounds according to Embodiment 1).

[0050] 3) Further embodiments relate to compounds according to embodiment 1), wherein Q represents CH.

[0051] 4) Further aspects include R 3b This relates to a compound according to embodiment 1), wherein represents hydrogen.

[0052] 5) Further aspects include R 2 but, - C 1-4 -Alkyl (especially methyl or isopropyl); or, - Hydroxy-C 1-3 -Alkyl (especially 2-hydroxyethyl); This relates to a compound that follows any one of embodiments 1) to 4) that represents the given characteristics.

[0053] 6) Further aspects include R 2C 1-4 This relates to compounds according to embodiment 5) that represent alkyl (especially methyl).

[0054] 7) Further aspects include: R 3a but, - C 1-5 -Alkyl (especially ethyl, n-propyl, isopropyl, or tert-butyl); or, - C 1-3 -Fluoroalkyl (especially 2,2,2-trifluoroethyl); This relates to a compound that conforms to any one of embodiments 1) to 6) that represents the given characteristics.

[0055] 8) Further aspects include R 3a C 1-5 This relates to compounds according to embodiment 7) that represent alkyl (particularly isopropyl).

[0056] 9) Further aspects include: R 4 but, - C 1-4 -alkyl, substituted with one hydroxyl group; or substituted with two substituents, where the first substituent represents hydroxyl and the second substituent represents C1-fluoroalkyl (especially trifluoromethyl), C 1-4 -alkyl; or, - -L-Cy( -- -L- indicates a direct bond (i.e., Cy is directly bonded to the triazolyl ring mentioned above). -- Cy is a C atom that optionally has one ring heteroatom selected from nitrogen or oxygen. 3-7 - Represents a cycloalkyl group (in particular, such Cy represents cyclohexyl, tetrahydropyranyl, or piperidinyl; especially, cyclohexyl, tetrahydropyran-4-yl, or piperidin-4-yl), where Cy is independently unsubstituted; or, --- 1 piece ---- Hydroxy; or, ---- -C(=O)R A (R A is C 1-3- Represents alkyl (especially methyl). Replaced by; -- Or, Cy represents bicyclo[1.1.1]pentan-1-yl or bicyclo[2.2.2]octan-1-yl, and Cy is independently substituted with one substituent (particularly at the tertiary carbon atom of the ring system), and the substituent is --- Hydroxy-C 1-3 -alkyl (especially hydroxymethyl); or, --- -C(=O)R B (R B teeth, ---- Hydroxy; or, ---- C 1-3 -alkoxy (especially methoxy); This represents... Selected from; -- Alternatively, Cy represents a six-membered heteroaryl compound having one ring nitrogen atom (in particular, Cy represents pyridinyl; especially pyridine-3-yl). This relates to a compound that conforms to any one of embodiments 1) to 8).

[0057] 10) Further aspects include: R 4 but, - -L-Cy( -- -L- indicates a direct bond (i.e., Cy is directly bonded to the triazolyl ring mentioned above). -- Cy represents cyclohexyl, tetrahydropyran-4-yl, or piperidinyl (especially cyclohexyl, tetrahydropyran-4-yl, or piperidin-4-yl), and Cy is independently unsubstituted; or --- 1 piece ---- Hydroxy; or, ---- -C(=O)R A (R A is C 1-3 - Represents alkyl (especially methyl). Replaced by; -- Or, Cy represents bicyclo[1.1.1]pentan-1-yl or bicyclo[2.2.2]octan-1-yl, and Cy is independently substituted with one substituent (particularly at the tertiary carbon atom of the ring system), and the substituent is --- Hydroxy-C 1-3 -alkyl (especially hydroxymethyl); or, --- -C(=O)R B (R B teeth, ---- Hydroxy; or, ---- C 1-3 -alkoxy (especially methoxy); This represents... Selected from; -- Alternatively, Cy represents pyridinyl (especially pyridine-3-yl). This relates to compounds that conform to the representation; aspect 9).

[0058] 11) Further aspects include R 5 but, - C 1-4 -Alkyl (especially methyl, ethyl, isopropyl, or tert-butyl); or, - C 3-7 -Cycloalkyl (especially cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); The present invention relates to a compound according to any one of embodiments 1) to 10) that preferably represents isopropyl or cyclopropyl.

[0059] 12) One embodiment relates to a compound according to any one of embodiments 1) to 11), wherein at least one, particularly two, or especially all of the following features a), b) and / or c) are present: a) group

[0060] [ka] This represents 3-methylazetidine-3-yl, 1,3-dimethylazetidine-3-yl, 1-isopropyl-3-methylazetidine-3-yl, 1-(2-hydroxyethyl)-3-methylazetidine-3-yl, or 1-(2,2-difluoroethyl)-3-methylazetidine-3-yl; b) basis

[0061] [ka] This represents 4-bromophenyl, 4-ethylphenyl, 4-(n-propyl)phenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-cyclopropylphenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-trifluoromethoxyphenyl, or 4-(1-trifluoromethyl-cyclopropyl)phenyl; c) base

[0062] [ka] However, 5-(1-cyclopropyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(4-hydroxy-cyclohexyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl (especially trans-5-(1-cyclopropyl-5-(4-hydroxy-cyclohexyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl), 5-(1-cyclopropyl-5-(1-hydroxy-1-tri Fluoromethyl-ethyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(4-methoxycarbonyl-bicyclo[2.2.2]octan-1-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(1-methyl-1-methylamino-ethyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(1-hydroxy-cyclobutyl-methyl) -1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(4-carboxy-bicyclo[2.2.2]octan-1-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclohexyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-methyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl , 5-(1-(2-hydroxyethyl)-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-ethyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-isopropyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopentyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole (1-(1-(2,2-difluoropropyl)-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, (1-(2,2-difluoropropyl)-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, (1-cyclobutyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, (1-cyclopropyl-5-( Pyridine-3-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(1-hydroxy-1-methyl-ethyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-isopropyl-5-(1-hydroxy-1-methyl-ethyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl)-1H -1,2,4-triazol-3-yl)-pyridine-3-yl, 5-(1-isopropyl-5-(3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl)-1H-1,2,4-triazol-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(4-hydroxy-tetrahydropyran-4-yl)-1H-1,2,4-triazol-3-yl)-pyridine-3-yl, 5-(1-isopropyl-5-(4-hydroxy-tetrahydropyran-4-yl)-1H-1,2 This represents ,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(N-acetyl-piperidine-4-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-isopropyl-5-(N-acetyl-piperidine-4-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, or 5-(1-cyclopropyl-5-(1-hydroxy-1-methyl-ethyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl).

[0063] 13) Further embodiments relate to compounds according to any one of embodiments 1) to 12), wherein the chiral carbon atom supporting the hydroxyl group has the absolute configuration shown in formula (II):

[0064] [ka]

[0065] 14) Another embodiment relates to a compound according to embodiment 1), selected from the following compounds: (R)-(4-bromophenyl)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3 -yl-(1,3-dimethylazetidine-3-yl)methanol; (R)-(4-tert-butylphenyl)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-[4-(1-trifluoromethylcyclopropyl)-phenyl]-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-trifluoromethoxyphenyl)-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-[4-(2,2,2-trifluoroethyl)-phenyl]-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-ethylphenyl)-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-propylphenyl)-methanol; trans-4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-cyclohexanol; (R)-2-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-1,1,1-trifluoro-propane-2-ol; 4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester; (R)-{5-[1-cyclopropyl-5-(1-methyl-1-methylaminoethyl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; 1-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-ylmethyl)cyclobutanol; 4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-bicyclo[2.2.2]octane-1-carboxylic acid; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-cyclohexyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl) )-{5-[1-methyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}methanol; 2-[3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-5-(tetrahydropyran-4-yl)-[1,2,4]triazole-1-yl]ethanol; (R)-(1,3-dimethylazetidine-3-yl)-{5-[1-ethyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-3-yl}-(4-isopropylphenyl)-methanol; (R)-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-{5-[1-isopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}methanol; (R)-{5-[1-cyclopentyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-tert-butyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-(2,2-difluoropropyl)-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-cyclobutyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-[5-(1-cyclopropyl-5-pyridine-3-yl-1H-[1,2,4]triazole-3-yl)-pyridine-3-yl]-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-(4-cyclopropylphenyl)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-methanol; 2-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-propane-2-ol; 2-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-propane-2-ol; (R)-{5-[1-cyclopropyl-5-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-(1,3-dimethylazetidine-3-yl)-{5-[5-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-1-isopropyl-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(4-isopropyl-phenyl)-methanol; 4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-tetrahydropyran-4-ol; 4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl Lu-2H-[1,2,4]triazol-3-yl)-tetrahydropyran-4-ol; 1-[4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-piperidine-1-yl]-ethanone; 1-[4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-piperidine-1-yl]-ethanone; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1-isopropyl-3-methylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-[1-(2,2-difluoroethyl)-3-methylazetidine-3-yl]-(4-isopropylphenyl)-methanol; 2-{3-[(R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-yl}ethanol; or, 2-(2-cyclopropyl-5-{5-[(R)-hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidine-3-yl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-propan-2-ol.

[0066] 15) Another embodiment relates to a compound according to embodiment 1), selected from the following compounds: (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(3-fluoro-4-isopropyl-phenyl)-methanol; 4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]-2-fluoropyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-trans-cyclohexanol; 4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]-2-methylpyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-trans-cyclohexanol; (R)-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-[5-(1-isopropyl-5-propyl-1H-[1,2,4]triazole-3-yl)-pyridine-3-yl]methanol; 4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-1-methyl-piperidine-2-one; N-[4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-trans-cyclohexyl]acetamide; 1-[4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-piperidine-1-yl]-2-hydroxy-ethanone; 4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-4-methylpiperidine-2-one; 4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-piperidine-2-one; 1-[4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-4-hydroxy-piperidine-1-yl]-ethanone; (R)-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-{5-[1-(2-methoxyethyl)-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}methanol; (R)-(1-cyclopropyl-3-methylazetidine-3-yl)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-3-yl}-(4-isopropylphenyl)-methanol; N-{2-[3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-5-(tetrahydropyran-4-yl)-[1,2,4]triazole-1-yl]-ethyl}acetamide; or, (R)-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-{6-[1-isopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridazin-4-yl}methanol.

[0067] In accordance with the dependencies of the different embodiments 1) to 13) disclosed earlier, the following embodiments are possible, intended, and are specifically disclosed herein as individual forms: 2+1、3+1、4+1、5+1、5+2+1、5+3+1、5+4+1、6+5+1、6+5+2+1、6+5+3+1、6+5+4+1、7+1、7+2+1、7+3+1、7+4+1、7+5+1、7+5+2+1、7+5+3+1、7+5+4+1、7+6+5+1、7+6+5+2+1、7+6+5+3+1、7+6+5+4+1、8+7+1、8+7+2+1、8+7+3+1、8+7+4+1、8+7+5+1、8+7+5+2+1、8+7+5+3+1、8+7+5+4+1、8+7+6+5+1、8+7+6+5+2+1、8+7+6+5+3+1、8+7+6+5+4+1、9+1、9+2+1、9+3+1、9+4+1、9+5+1、9+5+2+1、9+5+3+1、9+5+4+1、9+6+5+1、9+6+5+2+1、9+6+5+3+1、9+6+5+4+1、9+7+1、9+7+2+1、9+7+3+1、9+7+4+1、9+7+5+1、9+7+5+2+1、9+7+5+3+1、9+7+5+4+1、9+7+6+5+1、9+7+6+5+2+1、9+7+6+5+3+1、9+7+6+5+4+1、9+8+7+1、9+8+7+2+1、9+8+7+3+1、9+8+7+4+1、9+8+7+5+1、9+8+7+5+2+1、9+8+7+5+3+1、9+8+7+5+4+1、9+8+7+6+5+1、9+8+7+6+5+2+1、9+8+7+6+5+3+1、9+8+7+6+5+4+1、10+9+1、10+9+2+1、10+9+3+1、10+9+4+1、10+9+5+1、10+9+5+2+1、10+9+5+3+1、10+9+ 5+4+1、10+9+6+5+1、10+9+6+5+2+1、10+9+6+5+3+1、10+9+6+5+4+1、10+9+7+1、10+9+7+2+1、10+9+7+3+1、10+9+7+4+1、10+9+7+5+1、10+9+7+5+2+1、10+9+7+5+3+1、10+9+7+5+4+1、10+9+7+6+5+1、10+9+7+6+5+2+1、10+9+7+6+5+3+1、10+9+7+6+5+4+1、10+9+8+7+1、10+9+8+7+2+1、10+9+8+7+3+1、10+9+8+7+4+1、10+9+8+7+5+1、10+9+8+7+5+2+1、10+9+8+7+5+3+1、10+9+8+7+5+4+1、10+9+8+7+6+5+1、10+9+8+7+6+5+2+1、10+9+8+7+6+5+3+1、10+9+8+7+6+5+4+1、11+1、11+2+1、11+3+1、11+4+1、11+5+1、11+5+2+1、11+5+3+1、11+5+4+1、11+6+5+1、11+6+5+2+1、11+6+5+3+1、11+6+5+4+1、11+7+1、11+7+2+1、11+7+3+1、11+7+4+1、11+7+5+1、11+7+5+2+1、11+7+5+3+1、11+7+5+4+1、11+7+6+5+1、11+7+6+5+2+1、11+7+6+5+3+1、11+7+6+5+4+1、11+8+7+1、11+8+7+2+1、11+8+7+3+1、11+8+7+4+1、11+8+7+5+1、11+8+7+5+2+1、11+8+7+5+3+1、11+8+7+5+4+1、11+8+7+6+5+1、11+8+7+6+5+2+1、11+8+7+6+5+3+1、11+8+7+6+5+4+1、11+9+1、11+9+2+1、11+9+3+1、11+9+4+1、11+9+5+1、11+9+5+2+1、11+9+5+3+1、11+9+5+4+1、11+9+6+5+1、11+9+6+5+2+1、11+9+6+5+3+1、11+9+6+5+4+1、11+9+7+1、11+9+7+2+1、11+9+7+3+1、11+9+7+4+1、11+9+7+5+1、11+9+7+5+2+1、11+9+7+5+3+1、11+9+7+5+4+1、11+9+7+6+5+1、11+9+7+6+5+2+1、11+9+7+6+5+3+1、11+9+7+6+5+4+1、11+9+8+7+1、11+9+8+7+2+1、11+9+8+7+3+1、11+9+8+7+4+1、11+9+8+7+5+1、11+9+8+7+5+2+1、11+9+8+7+5+3+1、11+9+8+7+5+4+1、11+9+8+7+6+5+1、11+9+8+7+6+5+2+1、11+9+8+7+6+5+3+1、11+9+8+7+6+5+4+1、 11+10+9+1、11+10+9+2+1、11+10+9+3+1、11+10+9+4+1、11+10+9+5+1、11+10+9+5+2+1、11+10+9+5+3+1、11+10+9+5+4+1、11+10+9+6+5+1、11+10+9+6+5+2+1、11+10+9+6+5+3+1、11+10+9+6+5+4+1、11+10+9+7+1、11+10+9+7+2+1、11+10+9+7+3+1、11+10+9+7+4+1、11+10+9+7+5+1、11+10+9+7+5+2+1、11+10+9+7+5+3+1、11+10+9+7+5+4+1、11+10+9+7+6+5+1、11+10+9+7+6+5+2+1、11+10+9+7+6+5+3+1、11+10+9+7+6+5+4+1、11+10+9+8+7+1、11+10+9+8+7+2+1、11+10+9+8+7+3+1、11+10+9+8+7+4+1、11+10+9+8+7+5+1、11+10+9+8+7+5+2+1、11+10+9+8+7+5+3+1、11+10+9+8+7+5+4+1、11+10+9+8+7+6+5+1、11+10+9+8+7+6+5+2+1、11+10+9+8+7+6+5+3+1、11+10+9+8+7+6+5+4+1、12+1、13+1、13+2+1、13+3+1、13+4+1、13+5+1、13+5+2+1、13+5+3+1、13+5+4+1、13+6+5+1、13+6+5+2+1、13+6+5+3+1、13+6+5+4+1、13+7+1、13+7+2+1、13+7+3+1、13+7+4+1、13+7+5+1、13+7+5+2+1、13+7+5+3+1、13+7+5+4+1、13+7+6+5+1、13+7+6+5+2+1、13+7+6+5+3+1、13+7+6+5+4+1、13+8+7+1、13+8+7+2+1、13+8+7+3+1、13+8+7+4+1、13+8+7+5+1、13+8+7+5+2+1、13+8+7+5+3+1、13+8+7+5+4+1、13+8+7+6+5+1、13+8+7+6+5+2+1、13+8+7+6+5+3+1、13+8+7+6+5+4+1、13+9+1、13+9+2+1、13+9+3+1、13+9+4+1、13+9+5+1、13+9+5+2+1、13+9+5+3+1、13+9+5+4+1、13+9+6+5+1、13+9+6+5+2+1、13+9+6+5+3+1、13+9+6+5+4+1、13+9+7+1、13+9+7+2+1、13+9+7+3+1、13+9+7+4+1、13+9+7+5+1、13+9+7+5+2+1、13+9+7+5+3+1、13+9+7+5+4+1、13+9+7+6+5+1、13+9+7+6+5+2+1、13+9+7+6+5+3+1、13+9+7+6+5+4+1、13+9+8+7+1、13+9+8+7+2+1、13+9+8+7+3+1、13+9+8+7+4+1、13+9+8+7+5+1、13+9+8+7+5+2+1、13+9+8+7+5+3+1、13+9+8+7+5+4+1、13+9+8+7+6+5+1、13+9+8+7+6+5+2+1、13+9+8+7+6+5+3+1、13+9+8+7+6+5+4+1、13+10+9+1、13+10+9+2+1、13+10+9+3+1、13+10+9+4+1、13+10+9+5+1、13+10+9+5+2+1、13+10+9+5+3+1、13+10+9+5+4+1、13+10+9+6+5+1、13+10+9+6+5+2+1、13+10+9+6+5+3+1、13+10+9+6+5+4+1、13+10+9+7+1、13+10+9+7+2+1、13+10+9+7+3+1、13+10+9+7+4+1、13+10+9+7+5+1、13+10+9+7+5+2+1、13+10+9+7+5+3+1、13+10+9+7+5+4+1、13+10+9+7+6+5+1、13+10+9+7+6+5+2+1、13+10+9+7+6+5+3+1、13+10+9+7+6+5+4+1、13+10+9+8+7+1、13+10+9+8+7+2+1、13+10+9+8+7+3+1、13+10+9+8+7+4+1、13+10+9+8+7+5+1、13+10+9+8+7+5+2+1、13+10+9+8+7+5+3+1、13+10+9+8+7+5+4+1、13+10+9+8+7+6+5+1、13+10+9+8+7+6+5+2+1、13+10+9+8+7+6+5+3+1、13+10+9+8+7+6+5+4+1、 13+11+1、13+11+2+1、13+11+3+1、13+11+4+1、13+11+5+1、13+11+5+2+1、13+11+5+3+1、13+11+5+4+1、13+11+6+5+1、13+11+6+5+2+1、13+11+6+5+3+1、13+11+6+5+4+1、13+11+7+1、13+11+7+2+1、13+11+7+3+1、13+11+7+4+1、13+11+7+5+1、13+11+7+5+2+1、13+11+7+5+3+1、13+11+7+5+4+1、13+11+7+6+5+1、13+11+7+6+5+2+1、13+11+7+6+5+3+1、13+11+7+6+5+4+1、13+11+8+7+1、13+11+8+7+2+1、13+11+8+7+3+1、13+11+8+7+4+1、13+11+8+7+5+1、13+11+8+7+5+2+1、13+11+8+7+5+3+1、13+11+8+7+5+4+1、13+11+8+7+6+5+1、13+11+8+7+6+5+2+1、13+11+8+7+6+5+3+1、13+11+8+7+6+5+4+1、13+11+9+1、13+11+9+2+1、13+11+9+3+1、13+11+9+4+1、13+11+9+5+1、13+11+9+5+2+1、13+11+9+5+3+1、13+11+9+5+4+1、13+11+9+6+5+1、13+11+9+6+5+2+1、13+11+9+6+5+3+1、13+11+9+6+5+4+1、13+11+9+7+1、13+11+9+7+2+1、13+11+9+7+3+1、13+11+9+7+4+1、13+11+9+7+5+1、13+11+9+7+5+2+1、13+11+9+7+5+3+1、13+11+9+7+5+4+1、13+11+9+7+6+5+1、13+11+9+7+6+5+2+1、13 +11+9+7+6+5+3+1, 13+11+9+7+6+5+4+1, 13+11+9+8+7+1, 13+11+9+8+7+2+1, 13+11+9+8+7+3+1, 13+11+9+8+7+4+1, 13+11+9+8+7+5+1, 13+11+9+8+7+5+2+1, 13+11+9+8+7+5+3+1, 13+11+9+8+7+5+4+1, 13+11+9+8+7+6+5+1, 13+11+9+8+7+6+5+2+1, 13+11+9+8+7+6+5+3+1, 13+11 +9+8+7+6+5+4+1, 13+11+10+9+1, 13+11+10+9+2+1, 13+11+10+9+3+1, 13+11+10+9+4+1, 13+11+10+9+5+1, 13+11+10+9+5+2+1, 13+11+10+9+5+3+1, 13+11+10+9+5+4+1, 13+11+10+9+6+5+1, 13+11+10+9+6+5+2+1, 13+11+10+9+6+5+3+1, 13+11+10+9+6+5+4+1, 13+11+10+9+7+1, 13 +11+10+9+7+2+1, 13+11+10+9+7+3+1, 13+11+10+9+7+4+1, 13+11+10+9+7+5+1, 13+11+10+9+7+5+2+1, 13+11+10+9+7+5+3+1, 13+11+10+9+7+5+4+1, 13+11+10+9+7+6+5+1, 13+11+10+9+7+6+5+2+1, 13+11+10+9+7+6+5+3+1, 13+11+10+9+7+6+5+4+1, 13+11+10+9+8+7+1, 13+11+10 +9+8+7+2+1, 13+11+10+9+8+7+3+1, 13+11+10+9+8+7+4+1, 13+11+10+9+8+7+5+1, 13+11+10+9+8+7+5+2+1, 13+11+10+9+8+7+5+3+1, 13+11+10+9+8+7+5+4+1, 13+11+10+9+8+7+6+5+1, 13+11+10+9+8+7+6+5+2+1, 13+11+10+9+8+7+6+5+3+1, 13+11+10+9+8+7+6+5+4+1 or 13+12+1.

[0068] In the list above, the numbers represent the corresponding aspects, and the "+" indicates a dependency relationship from other aspects. The various aspects are separated individually by commas. In other words, for example, "6+5+2+1" means aspect 6) which is dependent on aspect 5) which is dependent on aspect 2) which is dependent on aspect 1), that is equivalent to the compound of formula (I) that follows aspect 1) which is further limited by all the features of aspects 2), 5), and 6).

[0069] The present invention relates to compounds of formula (I) as defined in aspect 1), or such compounds further limited by any one feature of aspects 2) to 13) according to their respective dependencies; pharmaceutically acceptable salts thereof; and the use of such compounds as pharmaceuticals, in particular as pharmaceuticals in the treatment of diseases or disorders involving the CCR6 receptor as described below.

[0070] The present invention also relates to isotope-labeled, particularly 2 This also includes the H (deuterium)-labeled compound of formula (I), which is identical to the compound of formula (I), except that one or more atoms are replaced by atoms having the same atomic number but with atomic weights different from those commonly found in nature. 2 Compounds of formula (I) and salts thereof labeled with H (deuterium) are included in the scope of the present invention. 2 Substitution with H (deuterium) increases metabolic stability, which can lead to, for example, a longer in vivo half-life, a reduction in the required dose, or reduced inhibition of cytochrome P450 enzymes, thus improving the safety profile. In one embodiment of the present invention, the compounds of formula (I) are either unlabeled or labeled only by one or more deuterium atoms. In a secondary embodiment, the compounds of formula (I) are not isotopically labeled at all. Isotopically labeled compounds of formula (I) may be prepared in the same manner as described below, except that appropriate reagents or suitable isotopes of the starting materials are used.

[0071] When the plural form is used for compounds, salts, pharmaceutical compositions, diseases, etc., it is intended to also refer to a singular compound, salt, pharmaceutical composition, disease, etc.

[0072] Any reference to a compound of formula (I) according to aspects 1) to 15) shall, depending on the context, also be understood to refer to a salt of such compound (especially a pharmaceutically acceptable salt).

[0073] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the target compound while exhibiting minimal undesirable toxic effects. Such salts include inorganic or organic acid and / or base addition salts, depending on the presence of basic and / or acidic groups in the target compound. For reference, see, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use," P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystals," Johan Wouters and Luc. See Quere (Eds.), RSC Publishing, 2012.

[0074] The definitions set forth herein apply uniformly to compounds of formula (I) as defined in any one of embodiments 1) to 13), and shall apply throughout this specification and claims with necessary modifications unless a broader or narrower definition is provided by a specific definition. Naturally, a definition or preferred definition of a term may independently (and together with) define and replace any or all of the terms defined herein or each term in a preferred definition.

[0075] Compounds of formula (I) may include compounds having one or more chiral centers, such as one or more chiral carbon atoms, which may exist in (R)- and (S)- configurations. Compounds of formula (I) may further include compounds having one or more double bonds, which may exist in Z- and E- configurations, and / or compounds having substituents in the ring system, which may exist in cis and trans configurations relative to each other. Accordingly, compounds of formula (I) may exist as a mixture of stereoisomers, or preferably in a stereoisomer-enriched form, particularly as essentially pure stereoisomers. Mixtures of stereoisomers may be separated by methods known to those skilled in the art.

[0076] When a particular compound (or comprehensive structure) is described as an (R)- or (S)-enantiomer, such description is understood to mean each compound (or comprehensive structure) in an enriched, particularly essentially pure, enantiomer form. Similarly, when a particular chiral center of a compound is described as being in an (R)- or (S)- configuration, or in a particular relative configuration, such description is understood to mean the compound in an enriched, particularly essentially pure form with respect to each configuration of the chiral center. Similarly, cis or trans descriptions are understood to mean each stereoisomer in an enriched, particularly essentially pure form. Similarly, when a particular compound (or comprehensive structure) is described as a Z or E stereoisomer (or when a particular double bond in a compound is described as being in a Z or E configuration), such description is understood to mean each compound (or comprehensive structure) in an enriched, particularly essentially pure stereoisomer form (or the compound in an enriched, particularly essentially pure form with respect to each configuration of the double bond).

[0077] When the term "enriched" is used in relation to stereoisomers, in the context of this invention, it is understood to mean that each stereoisomer exists in a ratio of at least 70:30, and more particularly at least 90:10, with respect to each other stereoisomer / the total of each other stereoisomers (i.e., with a purity of at least 70% by weight, and more particularly at least 90% by weight).

[0078] When the term "essentially pure" is used in relation to stereoisomers, in the context of this invention, it is understood to mean that each stereoisomer exists in a purity of at least 95 percent by weight, and in particular at least 99 percent by weight, relative to each other stereoisomer / each other stereoisomer as a whole.

[0079] Compounds of formula (I) according to embodiments 1) to 15) and pharmaceutically acceptable salts thereof can be used as pharmaceuticals, for example, in the form of pharmaceutical compositions for enteral administration (particularly orally) or parenteral administration (including topical application or inhalation).

[0080] The manufacture of the pharmaceutical composition may be carried out by methods well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]), by combining the compound of formula (I) described above or a pharmaceutically acceptable salt thereof, optionally with other therapeutically beneficial substances, with a suitable non-toxic, inert, therapeutically compatible solid or liquid carrier material and, if necessary, a conventional pharmaceutical adjuvant, to form a pharmaceutical dosage.

[0081] Whenever the word "between" is used to describe a range of numbers, the endpoints of the indicated range are explicitly included within that range. For example, if the temperature range is described as being between 40°C and 80°C, it means that the endpoints, 40°C and 80°C, are included within that range; or, if a variable number is defined as an integer between 1 and 4, it means that the variable number is the integer 1, 2, 3, or 4.

[0082] In relation to temperature, the term "approximately" (or "around") placed before a numerical value "X" when not used in this application means, in this application, between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X. In the case of temperature, the term "approximately" placed before a temperature "Y" means, in this application, between Y-10°C and Y+10°C, preferably between Y-5°C and Y+5°C.

[0083] The compounds of formula (I) defined above are useful for the prevention or treatment of various diseases, conditions, or disorders that are improved by the modulation of the CCR6 receptor. Such diseases, conditions, or disorders involving the CCR6 receptor may be defined as inflammatory and / or autoimmune diseases, conditions, or disorders, as well as cancer.

[0084] The compound of formula (I) defined above is useful for the prevention or treatment of various diseases, conditions, or disorders that are improved by the modulation of the CCR6 receptor. Diseases, conditions, or disorders involving the CCR6 receptor include: rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; psoriasis; psoriatic arthritis; inflammatory skin disorders such as rosacea; Crohn's disease; ulcerative colitis; inflammatory bowel disease; irritable bowel syndrome; dry eye diseases; multiple sclerosis; systemic lupus erythematosus; Sjögren's syndrome; autoimmune hepatitis; primary sclerosing cholangitis; posterior uveitis; allergic conjunctivitis; allergic diseases of the gastrointestinal tract; type 1 diabetes and endometriosis; diseases of the ocular surface with elevated IL-17A levels, such as meibomian gland dysfunction; GVHD; graft-versus-host disease; autoimmune keratitis; filamentous keratitis; dry eye syndrome associated with rheumatoid arthritis; dry eye syndrome without systemic disease; Stevens-Johnson syndrome; psoriasis vulgaris, guttate psoriasis, inverse psoriasis. Psoriasis (including pustular psoriasis and erythrodermic psoriasis); autoimmune keratitis; filamentous keratitis; autoimmune uveitis; allergic conjunctivitis; asthma; allergic diseases of the gastrointestinal tract; T1D; endometriosis; meibomian gland dysfunction; graft-versus-host disease; juvenile arthritis; juvenile rheumatoid arthritis; systemic rheumatoid arthritis; oligoarticular rheumatoid arthritis; oligoarticular rheumatoid arthritis It may be defined as an inflammatory / autoimmune disease, condition, or disorder encompassing juvenile rheumatoid arthritis; polyarticular rheumatoid arthritis; enteroarthritis; juvenile Reiter syndrome; ankylosing spondylitis; SEA syndrome; reactive arthritis; psoriatic arthritis; juvenile enteroarthritis; polymyalgia rheumatica; enteropathic spondylitis; juvenile idiopathic arthritis (JIA); juvenile psoriatic arthritis; juvenile rheumatoid arthritis; systemic juvenile rheumatoid arthritis; acute pancreatitis; chronic pancreatitis; giant cell arteritis; arteriosclerosis; bone erosion; intraperitoneal abscesses; intraperitoneal abscesses; and / or secondary osteoarthritis from inflammatory diseases.

[0085] Furthermore, diseases, conditions, or disorders that can be improved by regulating the CCR6 receptor include skin cancers such as melanoma (superficial spreading, nodular, lentigo malignant, and acral lentiginous melanoma); advanced melanoma; metastatic melanoma; Merkel cell carcinoma; Kaposi's sarcoma; basal cell carcinoma; squamous cell carcinoma; and precancerous skin lesions such as actinic keratosis; small cell lung cancer and non-small cell lung cancer (SCLC, NSCLC) including squamous and non-squamous NSCLC; lung cancer including pleuroblastoma and tracheobronchial tumors; and bladder cancer (urinary bladder cancer). bladder cancer; urothelial cell carcinoma; mesothelioma; clear cell RCC; papillary RCC; chromophobe RCC; non-clear cell RCC; unclassifiable RCC; metastatic renal cell carcinoma; Renal cancer, including renal cell carcinoma (RCC); colorectal cancer; metastatic colorectal cancer; familial polyposis polyposis (FAP); rectal cancer; Carcinoma; colorectal adenoma; colorectal adenocarcinoma; liver metastasis of colorectal cancer; hereditary non-polypoid colorectal cancer; esophageal cancer; gastric cancer; advanced gastric cancer; gallbladder cancer; bile duct cancer; hepatocellular carcinoma; pancreatic cancer such as pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma; pancreatic endocrine tumors; gastrointestinal cancers including these; endometrial cancer; ovarian cancer; prostate cancer including castration-resistant prostate cancer; brain tumors including brain metastases, malignant glioma, glioblastoma multiforme, medulloblastoma, meningioma, and astrocytoma; peripheral neuroectodermal tumors; oligoastrocytic tumors; oligodendroglioma; ependymal tumors; anaplastic astrocytoma Astrocytoma; pilocytic astrocytoma; craniopharyngioma; spinal cord tumor; brainstem glioma; atypical teratomas / rhabdomyosarcomas of the central nervous system; medulloblastoma; germ cell tumors of the central nervous system; craniopharyngioma; ependymoma; neuroblastoma; sensory neuroblastoma and other head and neck cancers; cervical cancer; advanced cervical cancer; normal-like, basal-like, claudin-low, HER2-positive, luminal-A, luminal-B and triple-negative breast carcinoma; pregnancy breast cancer and male breast cancer; breast cancer encompassing these; oral tumors; nasopharyngeal tumors; cardiac tumors; thoracic cancer Cancer; Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma; primary intraocular B-cell lymphoma; diffuse large B-cell lymphoma; mediastinal large B-cell lymphoma; mucosal-associated lymphoid tissue (MALT) lymphoma; gastric MALT lymphoma; cutaneous T-cell lymphoma; primary lymphoma of the central nervous system; Sézary syndrome and Waldenstroem macroglobulinemia; and other lymphomas; acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphoblastic leukemia; chronic myeloid leukemia; hairy cell leukemia; chronic myeloid leukemia; adult T-cell leukemia; and other leukemias; carcinoma; adenocarcinoma;Thyroid cancer, including papillary thyroid carcinoma and medullary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma; bone cancers such as osteosarcoma; high-grade osteosarcoma; rhabdomyosarcoma; Ewing's sarcoma; malignant fibrous histiocytoma of bone; chordoma; sarcomas, including soft tissue sarcoma; myeloma; multiple myeloma; labial cancer; laryngeal cancer; hypopharyngeal cancer; tongue cancer; salivary gland cancer; Land carcinoma; Cervical carcinoma; Endometrium carcinoma; Choriocarcinoma; Testicular carcinoma; Urinary carcinoma; Bronchial carcinoma; Basal cell tumor; Teratoma; Retinoblastoma; Choroidal melanoma; Seminomas; Chondrosarcoma; Myosarcoma; Liposarcoma; Fibrosarcoma; Plasma cell tumor; Hepatocellular carcinoma; Advanced liver cancer; Gastrointestinal stromal tumor; Neuroendocrine tumor; Bile duct cancer; Appendiceal cancer; Gastrointestinal carcinoid tumor; Carcinoid tumor; Pancreatic islet tumor; Small intestine cancer; Stomach cancer pheochromocytoma; pituitary tumor; penile cancer; renal pelvic and ureteral cancer; testicular cancer; urethral cancer; Wilms tumor; extracranial germ cell tumor; extragonadal germ cell tumor; cancer); laryngeal cancer; papillomatosis cancer; lip and oral cavity cancer; metastatic squamous cell carcinoma of the neck; mouth cancer; nasopharyngeal cancer; oropharyngeal cancer; neoplasm); myelodysplastic syndrome; myeloproliferative disease; midline carcinoma It may be defined as encompassing cancers such as tract carcinoma; virus-induced tumors; and / or diseases involving CCR6 and / or CCL20-mediated metastasis, chemotaxis, cell adhesion, transendothelial migration, cell proliferation, and / or survival.

[0086] In particular, the diseases, conditions, or disorders that are improved by modulation of the CCR6 receptor are selected from the following: - Inflammatory / autoimmune diseases, conditions or disorders (e.g., rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; psoriasis; psoriatic arthritis; inflammatory skin disorders, e.g., rosacea; Crohn's disease; ulcerative colitis; irritable bowel syndrome; inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjögren's syndrome; autoimmune hepatitis; primary sclerosing cholangitis; psoriasis including plaque psoriasis, guttate psoriasis, reverse psoriasis, pustular psoriasis, and erythrodermic psoriasis; autoimmune keratitis; filamentous keratitis; autoimmune uveitis; allergic conjunctivitis; asthma; allergic diseases of the gastrointestinal tract; type 1 diabetes mellitus (T1D); endometriosis; meibomian gland dysfunction; and / or graft-versus-host disease); and / or - Cancer (e.g., lymphoma including T-cell lymphoma and primary mediastinal large B-cell lymphoma; brain cancer including glioma and glioblastoma; breast cancer including triple-negative breast cancer; colorectal cancer; hepatocellular carcinoma; renal cell carcinoma; lung cancer including non-small cell lung cancer and small cell lung cancer; gastric cancer; melanoma including Merkel cell carcinoma, cutaneous squamous cell carcinoma and malignant melanoma; bladder cancer; head and neck cancer including squamous cell carcinoma of the head and neck; Hodgkin lymphoma; cervical cancer; endometrial cancer; colon cancer; gastrointestinal stromal tumor; pancreatic cancer; prostatic cancer; leukemia including acute myeloid leukemia; ovarian cancer; esophageal cancer) Carcinomas; mesothelioma; neuroblastoma; sarcomas, e.g., high-grade osteosarcoma; astrocytoma; myeloma; urothelial carcinoma, including locally advanced and metastatic urothelial carcinoma; MSI-H or dMMR cancer; rectal cancer; laryngeal cancer; salivary gland cancer; multiple myeloma; bile duct cancer; oral squamous cell carcinoma; thyroid cancer; and / or esophagogastric junction cancer).

[0087] In particular, the diseases, conditions, or disorders that are improved by modulation of the CCR6 receptor are selected from the following: - Inflammatory / autoimmune diseases, conditions, or disorders (e.g., psoriasis; psoriatic arthritis; rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; inflammatory skin disorders, e.g., rosacea; Crohn's disease; ulcerative colitis; irritable bowel syndrome; inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjögren's syndrome; autoimmune hepatitis; and / or primary sclerosing cholangitis). In particular, Such diseases, conditions, or disorders are psoriasis, psoriatic arthritis, or inflammatory bowel disease; in particular, A1) psoriasis or psoriatic arthritis; or A2) inflammatory bowel disease; and / or - Cancer (e.g., lymphoma (e.g., T-cell lymphoma); brain cancer (e.g., glioma or glioblastoma); breast cancer; colorectal cancer; hepatocarcinoma; renal cell carcinoma; lung cancer; and / or gastric cancer).

[0088] When used for the prevention or treatment of cancer, such use includes the use of the compound of formula (I) as a monotherapy agent and in combination with one or more chemotherapeutic agents and / or radiotherapy and / or targeted therapies (in particular, in combination with targeted therapy).

[0089] The term “radiotherapy” (or “radiation therapy” or “radiation oncology”) means the medical use of ionizing radiation in the prevention (adjuvant therapy) and / or treatment of cancer; it encompasses external and internal radiation therapy.

[0090] The term "targeted therapy" refers to the prevention (adjuvant therapy) and / or treatment of cancer using one or more antineoplastic agents, such as small molecules or antibodies, that act on specific types of cancer cells or stromal cells. Some types of targeted therapy block the action of certain enzymes, proteins, or other molecules involved in the proliferation and spread of cancer cells. Other types of targeted therapy help the immune system kill cancer cells (immunotherapy); or inhibit angiogenesis, the growth and formation of new blood vessels within tumors; or directly deliver toxic substances to kill cancer cells. An example of a targeted therapy particularly well suited to be combined with the compound of formula (I) is immunotherapy, especially immunotherapy targeting programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1.

[0091] Immunotherapy further means (i) agonists of stimulating receptors (including co-stimuli), or (ii) antagonists of inhibitory signals (including co-inhibition) to T cells, both of which cause amplification of antigen-specific T cell responses (often called immune checkpoint regulators). Some of the stimulating and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulating or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-HI (PD-LI), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is a group of TNF family molecules that bind to members of the same TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-IBBL, CD137(4-IBB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI / TLIA, TRAMP / DR3, EDAR, EDAI, XEDAR, EDA2, TNFRI, Lymphotoxin a / TNFp, TNFR2, TNFa, LTPR, and Lymphotoxin a This includes 1p2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0092] When used in combination with the compound of formula (I), the term "targeted therapy" specifically refers to the following drugs: a) Epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (e.g., gefitinib, erlotinib, afatinib) Afatinib, Icotinib, Lapatinib, Panitumumab, Zalutumumab, Nimotuzumab, Matuzumab, and Cetuximab, as well as trastuzumab (HERCEPTIN); b) RAS / RAF / MEK pathway inhibitors (e.g., vemurafenib, sorafenib, dabrafenib, GDC-0879, PLX-4720, LGX818, RG7304, trametinib (GSK1120212), cobimetinib (GDC-0973 / XL518), binimetinib (MEK162, ARRY-162), selumetinib (AZD6244)); c) Janus kinase (JAK) inhibitors (e.g., ruxolitinib, itacitinib, momerotinib); d) Aromatase inhibitors (e.g., exemestane, letrozole, anastrozole, vorozole, formestane, fadrozole); e) Signal transduction inhibitors (STIs). Signal transduction inhibitors are drugs that induce apoptosis by selectively inhibiting one or more important steps in the signaling pathways of normal cancer cells. Suitable STIs include: (i) bcr / abl kinase inhibitors (e.g., STI 571 (GLEEVEC®), dasatinib); (ii) Epidermal growth factor (EGF) receptor inhibitors (e.g., kinase inhibitors (IRESSA®, SSI-774) and antibodies (Imclone:C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)] and Abgenix:ABX-EGF)); (iii) (iv) Inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (2000))); (v) Cell cycle kinase inhibitors (e.g., flavopiridol and UCN-01 (see, for example, Sausville, Curr. Med. Chem. Anti-Cane. Agents, 3:47-56 (2003))); and (vi) Phosphatidylinositol kinase inhibitors (e.g., LY294002 (see, for example, Vlahos et al., J See Biol. Chem., 269:5241-5248 (1994). )) are examples, but are not limited to these; f) Angiogenesis inhibitors, especially VEGF signaling inhibitors (e.g., bevacizumab (Avastin), ramucirumab, sorafenib, or axitinib); g) Immune checkpoint inhibitors (e.g., pembrolizumab (lambrolizumab, MK-3475), nivolumab, pidilizumab (CT-011), AMP-514 / MEDI0680, PDR001, SHR-1210; REGN2810, BGBA317, PF-0680) Anti-PD1 antibodies such as 1591, MGA-012, TSR042, JS-001, BCD100, IBI-308, BI-754091; PD-1 targeting fusion proteins (e.g., AMP-224); small molecule anti-PD1 agents (e.g., compounds disclosed in WO2015 / 033299, WO2015 / 044900 and WO2015 / 034820); anti-PD1L antibodies (e.g., BMS-936559) , atezolizumab (MPDL3280A, RG7446), avelumab (MSB0010718C), durvalumab (MEDI4736); anti-PDL2 antibodies (e.g., AMP224); anti-CTLA-4 antibodies (e.g., ipilimumab, tremilmumab); anti-lymphocyte activator gene 3 (LAG-3) antibodies (e.g., Relatlimab (BMS-986016), IMP701, IMP731, MK-4280, ImmuFact IMP321); anti-T cell immunoglobulins Mucin-3 (TIM-3) antibodies (e.g., MBG453, TSR-022); T-cell immune receptor (TIGIT) antibodies with anti-Ig and ITIM domains (e.g., RG6058 (anti-TIGIT, MTIG7192A)); anti-killer cell immunoglobulin-like receptors (KIRs) (e.g., lirilumab (IPH2102 / BMS-986015)); galectin antagonists (e.g., galectin-1, galectin-9); BTLA; h) Vaccine therapy approaches (e.g., dendritic cell vaccine therapy, DNA, peptide or protein vaccine therapy (e.g., using gp100 peptide or MAGE-A3 peptide), and recombinant viruses); i) Reintroduction of patient-derived or allogenic (non-self) cancer cells genetically modified to secrete immunomodulatory factors such as granulocyte-monocyte colony-stimulating factor (GMCSF) gene-transfected tumor cell vaccine (GVAX), Fms-associated tyrosine kinase 3 (Flt-3) ligand gene-transfected tumor cell vaccine (FVAX), or Toll-like receptor-enhanced GM-CSF tumor-based vaccine (TEGVAX); j) T cell-based adoptive immunotherapy using chimeric antigen receptor (CAR) modified T cells (e.g., CTL019); k) Cytokine or immunocytokine-based therapies (e.g., interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 6, interleukin 10, interleukin 15, TGF-β); l) Toll-like receptor (TLR) agonists (e.g., resiquimod, imiquimod, motolimod, glucopyranosyllipid A, CpG oligodeoxynucleotide); m) Thalidomide analogs (e.g., lenalidomide, pomalidomide); n) Activators of T cell costimulatory receptors (e.g., anti-CD137 / 4-1BB antibodies (e.g., BMS-663513 / urelumab, Utomilumab (PF-05082566)); anti-OX40 / CD134 (tumor necrosis factor receptor superfamily, member 4) (e.g., RG7888 (MOXR0916), 9B12; MEDI6469, GSK3174998, MEDI6383, MEDI0562), anti-OX40-ligand / CD252; anti-glucocorticoid-induced TNFR family receptors) Linked genes (GITR) (e.g., TRX518, MEDI1873, MK-4166, BMS-986156, BMS-986153), anti-CD40 (TNF receptor superfamily member 5) antibodies (e.g., Dacetuzumab (SGN-40), HCD122, CP-870, 893, RG7876, ADC-1013, APX005M, SEA-CD40); anti-CD40-ligand antibodies (e.g., BG9588); anti-CD27 antibodies (e.g., Varlilumab); anti-CD28 antibodies; anti-ICOS antibodies); o) Bispecific antibodies or antibody fragments, antibody-mimicking proteins (antibody Molecules that bind to tumor-specific antigens such as mimetic proteins and T-cell surface markers (e.g., designed ankyrin repeat proteins (DARPINS), bispecific T-cell engagers (BITE, e.g., AMG103, AMG330)); p) Antibodies or small molecular weight inhibitors targeting the colony-stimulating factor-1 receptor (CSF-1R) (e.g., Emactuzumab (RG7155), Cabiralizumab (FPA-008), PLX3397); q) Drugs that target immune cell checkpoints on natural killer cells (e.g., antibodies against killer cell immunoglobulin-like receptors (KIRs) (e.g., Lirilumab (IPH2102 / BMS-986015)); r) Drugs that target adenosine receptors or ectonucleotidases CD39 and CD73, which convert adenosine triphosphate (ATP) to adenosine (e.g., MEDI9447 (anti-CD73 antibody), PBF-509; CPI-444 (adenosine A2a receptor antagonist)); s) Antagonists for chemokine receptors such as CCR2 or CCR4; t) (For example, using an anti-CD25 monoclonal antibody (e.g., daclizumab), or ex vivo anti-CD25 bead depletion (ex vivo) (Anti-CD25 bead depletion) depletes or inhibits T regulatory cells, or restores or prevents T cell anergy or exhaustion, complement factors (v) A regulator of system v agents.

[0093] When used in combination with a compound of formula (I), immune checkpoint inhibitors, and in particular those targeting the PD-1 receptor or its ligand PD-L1, are preferred.

[0094] The term "chemotherapy" refers to the treatment of cancer with one or more cytotoxic antineoplastic agents ("cytotoxic chemotherapeutic agents"). Chemotherapy is often used in combination with other cancer treatments such as radiation therapy or surgery. This term specifically refers to conventional chemotherapeutic agents that work by killing rapidly dividing cells (which is one of the main characteristics of most cancer cells). Chemotherapy may involve the use of one drug at a time (monotherapy) or several drugs at a time (combination chemotherapy or multi-drug chemotherapy). Chemotherapy using drugs that become cytotoxic only upon exposure to light is called photochemotherapy or photodynamic therapy.

[0095] As used herein, the terms “cytotoxic chemotherapeutic agent” or “chemotherapeutic agent” mean an active antineoplastic agent that induces apoptosis or cell necrosis.

[0096] When used in combination with compounds of formula (I), this term specifically refers to conventional cytotoxic chemotherapeutic agents such as those listed below: 1) Alkylating agents (including, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes) (e.g., uracil mustard, mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, procarbazine, dacarbazine, temozolomide, pipobroman, triethylene-melamine, triethylenethiophosphoramine, thiotepa, or altretamine; especially temozolomide; 2) Platinum preparations (e.g., cisplatin, carboplatin, or oxaliplatin);3) Antimetabolites (e.g., 5-fluorouracil, floxuridine, pentostatin, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine) 4) Antitumor antibiotics (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C, or mitoxantrone); 5) Mitotic inhibitors (e.g., paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, or estramustine); or 6) Topoisomerase inhibitors (e.g., etoposide, teniposide, topotecan, irinotecan, diflomotecan, or elomotecan) are also appropriate. Other suitable options include cytotoxic agents, such as biological response modifiers, growth inhibitors, antihormonal therapeutic agents, leucovorin, tegafur, and hematopoietic growth factors.

[0097] When used in combination with the compounds of formula (I), preferred cytotoxic chemotherapeutic agents include the alkylating agents (especially fotemustine, cyclophosphamide, ifosfamide, carmustine, dacarbazine, and their prodrugs, especially temozolomide; or pharmaceutically acceptable salts of these compounds; especially temozolomide); mitotic inhibitors (especially paclitaxel, docetaxel, ixabepyrone; or pharmaceutically acceptable salts of these compounds; especially paclitaxel); platinum-based drugs (especially cisplatin, oxaliplatin, and carboplatin); and etoposide and gemcitabine.

[0098] To avoid any doubt, if a compound is described as useful for the prevention or treatment of a disease, condition, or disorder, then such a compound is also suitable for use in the manufacture of a medicine for the prevention or treatment of said disease.

[0099] The present invention also relates to a method for the prevention or treatment of diseases, conditions, or disorders mentioned above and / or below, comprising administering to a subject a pharmaceutically effective amount of one of the compounds described above and / or below, either alone or in combination with other pharmacologically effective compounds and / or treatments.

[0100] In a preferred embodiment of the present invention, the dosage of the compound of formula (I) is between 1 mg and 1000 mg / day, particularly between 5 mg and 500 mg / day, and even more particularly between 25 mg and 400 mg / day, and especially between 50 mg and 200 mg / day.

[0101] The term "prevention" may be understood as meaning "prophylaxis."

[0102] Preparation of the compound of formula (I) A further aspect of the present invention is a method for producing compounds of formula (I). Compounds according to formula (I) of the present invention can be produced from commercially available or well-known starting materials by the method described in the experimental section; by a similar method; or by the general reaction sequence outlined below. The term "R" used below 1 "R 2 "R 3a "R 3b "R 4 "R 5 The terms " and "Q" can be derived from the corresponding definitions in formula (I), or from the present The terms are explicitly and implicitly defined in the subscript. The term "R" is defined in the following scheme. To avoid ambiguity, the meaning of this term may differ from the meaning of the term "R" used to indicate a substituent of Q in formula (I). Other abbreviations used herein are explicitly defined in the Experimental section, or as defined. The use of protecting groups is well known in the art (see, for example, "Protective Groups in Organic Synthesis," TW Greene, PGMWuts, Wiley-Interscience, 1999). For this purpose, we assume that such protecting groups have been introduced as necessary. The resulting compounds may be converted to salts, in particular pharmaceutically acceptable salts thereof, by methods known by themselves.

[0103] Typical manufacturing route: The compound of formula (I) can be prepared using the intermediate of formula (A1) (PG represents an amine protecting group such as Boc) as a starting material, and reacted with N,O-dimethylhydroxylamine hydrochloride under standard conditions (e.g., T3P®, DIPEA, DCM, RT) to obtain the weinreb amide derivative of formula (A2) (Scheme A). In the presence of n-butyllithium, in THF at a temperature of around -78°C, the compound of formula (A3), where X is a halide such as bromine, is reacted to produce the ketone derivative of formula (A4). This can then be further reacted with the bromo derivative of formula (A5) using n-hexyllithium in THF at a temperature of around -78°C to give the tertiary alcohol intermediate of formula (A6). At this stage, chiral separation can be performed by HPLC or SFC in a chiral stationary phase to obtain the pure intermediate of formula (A6) as an enantiomer. In the case of the Boc protecting group, the NH derivative of formula (A7) can be obtained by cleaving the protecting group under standard conditions such as treatment with HCl in dioxane at a temperature near RT, and the substituent R 4 and R 5 Depending on the circumstances, this can be the final embodiment of formula (I). Under standard conditions such as using NaBH(OAc)3 or NaBH3CN as a reducing agent, a reductive amination step can be carried out using the amine of formula (A7) and the aldehyde of formula (A8) or the ketone of formula (A9) in a solvent such as DCM, MeOH, THF, or dioxane or a mixture thereof, in the presence of a base such as DIPEA or TEA, or an acid such as acetic acid, at a temperature near RT, to obtain the compound of formula (I). Alternatively, the intermediate of formula (A7) can be alkylated with the reactant of formula (A10), where X is iodine or bromine, by stirring in a solvent such as MeOH, THF, or DMF, in the presence of a base such as TEA, DIPEA, or Cs2CO3, at a temperature of 0°C to 70°C, to give the compound of formula (I). Furthermore, R 2 Compounds of formula (I), in which the parent molecule is cyclopropyl, can be produced by coupling (1-ethoxycyclopropoxy)trimethylsilane with NaBH3CN in MeOH in the presence of AcOH at a temperature near RT.

[0104] [ka] Alternatively, the compound of formula (I) can be prepared according to the procedure described in scheme B, and a solution of the ketone of formula (A4) and the bromocyanopyridine of formula (B6), where Q is CH, CMe, CF, or CCl, in a solvent such as THF can be treated with n-hexyllithium at a temperature of around -78°C. The resulting intermediate of formula (B1) may be converted to the amidoxime of formula (B2) by treatment with hydroxylamine in a solvent such as DMSO or EtOH at a temperature of around RT in the presence of a base such as DIPEA or K2CO3. The amidoxime of formula (B2) may exist in two tautomers, and the substituent of the 6-membered heteroaryl represents -C(NH2)=N-OH or -C(=NH)-NH-OH. The amidoxime of formula (B2) can be converted to the amidine of formula (B3) in a stepwise procedure involving acetylation with acetic anhydride in acetic acid, followed by hydrogenation (in the presence of Pd / C). The formation of the triazole ring in the compound of formula (A6) or (I) may be carried out by a two-step one-pot procedure. The amidine of formula (B3) can be coupled to the carboxylic acid of formula (B4) under standard amide coupling conditions (HATU, DIPEA, DMF), and then ring formation is carried out using the hydrazine of formula (B5) at a high temperature of around 80°C. Deprotection and N-alkylation of the azetidine ring according to the procedure described in Scheme A can be carried out at this step or earlier.

[0105] [ka] R 3a However, C 1-5 Alkyl, C 1-3 Fluoroalkyl or C 3-5 Another method for obtaining a compound of formula (I) or an intermediate of formula (A6) representing a cycloalkyl group is: 3a represents bromine, R 3ba bromophenyl compound of formula (I) in which represents hydrogen or the intermediate of formula (A6) is involved (Scheme C). Under Suzuki conditions (Pd catalyst and a base in toluene / water), BX represents BF₃K, Bpin or B(OH)₂, and R 3a is C 1-5 alkyl, C 1-3 fluoroalkyl or C 3-5 can be coupled with a boron species of formula (C1) representing cycloalkyl, wherein in both cases R 3a is C 1-5 alkyl, C 1-3 fluoroalkyl or C 3-5 represents cycloalkyl, R 3b represents hydrogen, to produce a compound of formula (I) or an intermediate of formula (A6).

[0106]

Chemical Formula

[0107]

Chemical Formula

[0108] Whenever a compound of formula (I) is obtained as a mixture of enantiomers, the enantiomers can be separated by methods known to those skilled in the art: for example, by formation and separation of diastereomeric salts, or by using HPLC on a chiral stationary phase. Enantiomer separation may be performed on the compound of formula (I) or at an earlier stage.

[0109] Depending on the purification conditions, the intermediate and the compound of formula (I) may be isolated as a free base or as a salt such as formate or hydrochloride. Depending on the circumstances, the free form may be isolated by methods known to those skilled in the art.

[0110] Experiment section Abbreviations (used in this section and the preceding parts of the specification): Acetyl for anal analysis anh anhydrous AQ water-based Boc tert.-butyloxycarbonyl Bu n-butyl BSA (Bovine Serum Albumin) cataCXium(registered trademark) A Pd G3 Mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)] Palladium(II) CC Column Chromatography CV column volume DBA Dibenzylideneacetone DCM Dichloromethane DEA (Diethylamine) DIPEA N,N-diisopropylethylamine DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) dppf 1,1'-bis(diphenylphosphin)ferrocene EA ethyl acetate Et ethyl FLIPR (Fluorescence Imaging Plate Reader) Fluo-8-AM Acetyloxymethyl 2-[N-[2-(acetyloxymethoxy)-2-oxoethyl]-4-[3-(acetyloxymethoxy)-6-oxoxanthene-9-yl]-2-[2-[2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]anilino]acetate eq equivalent g gram HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HEK Human Embryonic Kidney Hex n-hexyl h hour Hep heptane iPr isopropyl HPLC High Performance Liquid Chromatography LC-MS Liquid Chromatography-Mass Spectrometry [M] Molecular weight M Molar concentration [mol / L -1 Me methyl mg milligram min minute mL milliliter org organic Pd / C palladium on carbon PG protecting group pin pinacol prep preparative RT room temperature rxn reaction sat saturated SFC Supercritical Fluid Chromatography soln solution t time T3P® propane phosphonic acid anhydride TEA triethylamine t R retention time THF tetrahydrofuran

[0111] I. Chemistry The following examples illustrate the preparation of the biologically active compounds of the present invention, but do not limit the scope thereof in any way.

[0112] ​General: All temperatures are given in degrees Celsius (°C). Unless otherwise specified, reactions are carried out at RT under an argon atmosphere in flame-dried (for moisture-sensitive reactions) round-bottomed sluices or sealable tubes equipped with a magnetic stirring rod.

[0113] Qualitative analysis methods used: The retention time obtained by LC-MS was obtained using the following elution conditions: I) LC-MS(A): A Zorbax RRHD SB-Aq, 1.8 μm, 2.1 x 50 mm column was temperature-controlled at 40°C. Two elution solvents were used: Solvent A = Water + 0.04% TFA; Solvent B = MeCN. The elution flow rate was 0.8 mL / min. The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0114] [Table 1] The retention time for chiral HPLC / SFC was obtained using the following elution conditions: I) Chiral SFC(A): A CHIRALCEL OD-H, 5 μm, 4.6 x 250 mm column, temperature-controlled at 40°C, was used. Two elution solvents were used: Solvent A = CO2; Solvent B = MeOH. The elution flow rate was 4 mL / min, and the proportion of isocratic solvent was 90% (A) / 10% (B).

[0115] II) Chiral SFC (B): A CHIRALPAK ID, 5 μm, 4.6 x 250 mm column was used, temperature-controlled at 40°C. Two elution solvents were used: Solvent A = CO2; Solvent B = MeCN / EtOH / DEA 50 / 50 / 0.1. The eluate flow rate was 4 mL / min, and the proportion of non-gradient solvents was 65% (A) / 35% (B).

[0116] III) Chiral SFC(C): A Chiralcel OD-D, 5 μm, 4.6 x 250 mm column was used, temperature-controlled at 40°C. Two elution solvents were used: Solvent A = CO2; Solvent B = MeCN / EtOH / 1 / 1. The eluate flow rate was 4 mL / min, and the proportion of non-gradient solvents was 70% (A) / 30% (B).

[0117] IV) Chiral SFC(D): A ChiralCel OD-H, 5 μm, 4.6 x 250 mm column was used, temperature-controlled at 40°C. Two elution solvents were used: Solvent A = CO2; Solvent B = MeCN / EtOH / DEA 50 / 50 / 0.1. The eluate flow rate was 4 mL / min, and the proportion of non-gradient solvents was 65% (A) / 35% (B).

[0118] V) Chiral SFC(E): A ChiralCel OD-H, 5 μm, 4.6 x 250 mm column was used, temperature-controlled at 40°C. The two elution solvents were as follows: Solvent A = CO2; Solvent B = MeCN / EtOH / DEA 50 / 50 / 0.1. The elution flow rate was 4 mL / min. The proportion of the non-gradient solvent was 75% (A) / 25% (B).

[0119] VI) Chiral SFC(F): A ChiralPak ID, 5 μm, 4.6 x 250 mm column was used, temperature-controlled at 40°C. Two elution solvents were used: Solvent A = CO2; Solvent B = MeCN / EtOH / DEA 50 / 50 / 0.1. The eluate flow rate was 4 mL / min, and the proportion of non-gradient solvents was 65% (A) / 35% (B).

[0120] VII) Chiral SFC(G): A CHIRALCEL OJ-H, 5 μm, 4.6 x 250 mm column was used, temperature-controlled at 40°C. Two elution solvents were used: Solvent A = CO2; Solvent B = MeOH. The elution flow rate was 4 mL / min, and the proportion of non-gradient solvents was 95% (A) / 5% (B).

[0121] VIII) Chiral SFC (H): A CHIRALPAK IH, 5 μm, 4.6 x 250 mm column was used, temperature-controlled at 40°C. Two elution solvents were used: Solvent A = CO2; Solvent B = MeCN + EtOH 1 / 1. The elution flow rate was 4 mL / min, the elution (run) time was 5 min, and the proportion of non-gradient solvent was 85% (A) / 15% (B).

[0122] Purification method used: Preparative LC-MS method used: Purification by preparative LC-MS was performed under the conditions described below.

[0123] I) Prep LC-MS(I): A Zorbax column (SB-AQ, 7 μm OBD, 50 x 150 mm) was used. The two elution solvents were as follows: Solvent A = MeCN; Solvent B = Water + 0.5% Formic Acid (25%). The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0124] [Table 2] II) Prep LC-MS(II): An X-Bridge column (Waters C18, 10 μm OBD, 30 x 75 mm) was used. The two elution solvents were as follows: Solvent A = Water + 0.5% NH4OH (25%); Solvent B = MeCN. The elution flow rate was 75 mL / min. The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0125] [Table 3] III) Prep LC-MS (III) An X-Bridge column (Waters C18, 10 μm OBD, 30 x 75 mm) was used. The two elution solvents were as follows: Solvent A = Water + 0.5% NH4OH (25%); Solvent B = MeCN. The elution flow rate was 75 mL / min. The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0126] [Table 4] IV) Prep LC-MS(IV) An X-Bridge column (Waters C18, 10 μm OBD, 30 x 75 mm) was used. The two elution solvents were as follows: Solvent A = Water + 0.5% NH4OH (25%); Solvent B = MeCN. The elution flow rate was 75 mL / min. The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0127] [Table 5] V) Prep LC-MS(V): An Agilent column (Zorbax SB-Aq, 5 μm OBD, 30 x 75 mm) was used. The two elution solvents were as follows: Solvent A = water + 0.5% formic acid; Solvent B = MeCN. The elution flow rate was 75 mL / min. The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0128] [Table 6] VI) Prep LC-MS(VI): An Agilent column (Zorbax SB-Aq, 5 μm OBD, 30 x 75 mm) was used. The two elution solvents were as follows: Solvent A = water + 0.5% formic acid; Solvent B = MeCN. The elution flow rate was 75 mL / min. The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0129] [Table 7] VII) Prep LC-MS (VII): An Agilent column (Zorbax SB-Aq, 5 μm OBD, 30 x 75 mm) was used. The two elution solvents were as follows: Solvent A = water + 0.5% formic acid; Solvent B = MeCN. The elution flow rate was 75 mL / min. The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0130] [Table 8] VIII) Prep LC-MS (VIII): An Agilent column (Zorbax SB-Aq, 5 μm OBD, 30 x 75 mm) was used. The two elution solvents were as follows: Solvent A = water + 0.5% formic acid; Solvent B = MeCN. The elution flow rate was 75 mL / min. The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0131] [Table 9] IX) Prep LC-MS(IX): An X-Bridge column (Waters C18, 10 μm OBD, 30 x 75 mm) was used. The two elution solvents were as follows: Solvent A = Water + 0.5% Formic Acid; Solvent B = MeCN. The elution flow rate was 75 mL / min. The characteristics of the elution mixture's mixing ratio are summarized in the table below as a function of time t from the start of elution (a linear gradient is used between two consecutive time points):

[0132] [Table 10] X) Prep LC-MS(X): An X-Bridge column (Waters C18, 10 μm OBD, 30 x 75 mm) was used. The two elution solvents were as follows: Solvent A = water + 0.5% formic acid; Solvent B = MeCN. The elution flow rate was 75 mL / min, and the characteristics of the mixing ratio of the elution mixture are summarized in the table below as a function of time t from the start of elution (between two consecutive time points). (Uses a straight gradient):

[0133] [Table 11] Preparative chiral SFC and HPLC methods used: Purification by preparative chiral SFC and HPLC was performed under the conditions described below.

[0134] I) Prep Chiral SFC (I): A ChiralCel OD-H (5μm, 30x250mm) column was used, temperature-controlled at 40°C. The elution solvent was CO2 / MeOH 90 / 10, flowed at a rate of 160 mL / min.

[0135] II) Prep Chiral SFC (II): A ChiralPak ID (5 μm, 30 x 250 mm) column was used, temperature-controlled at 40°C. The elution solvent was CO2 / MeCN:EtOH:DEA 80:80:0.1 80 / 20, and the column was flowed at a flow rate of 160 mL / min.

[0136] III) Prep Chiral SFC (III): A ChiralCel OD-H (5μm, 30x250mm) column was used, temperature-controlled at 40°C. The elution solvent was CO2 / MeCN:EtOH 1:1 70 / 30, flowed at a flow rate of 160 mL / min.

[0137] IV) Prep Chiral SFC (IV): A ChiralCel OD-H (5 μm, 30 x 250 mm) column was used, temperature-controlled at 40°C. The elution solvent was CO2 / (MeCN:EtOH:DEA 50:50:0.1) 65 / 35, flowed at a flow rate of 160 mL / min.

[0138] V) Prep Chiral SFC (V): A ChiralCel OD-H (5μm, 30x250mm) column was used, temperature-controlled at 40°C. The elution solvent was CO2 / (MeCN:EtOH:DEA 50:50:0.1) 75 / 25, flowed at a flow rate of 160 mL / min.

[0139] VI) Prep Chiral SFC (VI): A ChiralPak ID (5μm, 30x250mm) column was used, temperature-controlled at 40°C. The elution solvent was CO2 / (MeCN:EtOH:DEA 50:50:0.1). The ratio was 65 / 35, and the mixture was flowed at a flow rate of 160 mL / min.

[0140] VII) Prep Chiral SFC (VII): A ChiralCel OJ-H (5μm, 30x250mm) column was used, temperature-controlled at 40°C. The elution solvent was CO2 / MeOH 95 / 5, flowed at a flow rate of 160 mL / min.

[0141] VIII) Prep Chiral SFC (VIII): A temperature-controlled (R,R)Whelk-O1 (5μm, 30x250mm) column was used at 40°C. The elution solvent was CO2 / (MeCN:EtOH:DEA 50:50:0.1) 60 / 40, and it was flowed at a flow rate of 160 mL / min.

[0142] IX) Prep Chiral SFC (IX): A ChiralPak IH (5μm, 30x250mm) column was used, temperature-controlled at 40°C. The elution solvent was CO2 / 50%MeCN-50%EtOH 85 / 15, and it was flowed at a flow rate of 160 mL / min for 6 minutes.

[0143] Preparation of the intermediate for formula A2 A2.1 3-(methoxy-methyl-carbamoyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a solution of 1-Boc-3-methylazetidinecarboxylic acid (20 g) in DCM (500 mL), N,O-dimethylhydroxylamine hydrochloride (8.97 g), DIPEA (54 mL), and 1.72 M T3P (registered trademark) (68 mL) in DCM were added to RT while cooling in a water bath. The resulting solution was stirred in RT for 2 h 30, and then quenched with aq.sat.NaHCO3. The phases were separated, and the organic layer was washed with citric acid (10%) and water. The aqueous layer was then re-extracted with 1x DCM. The combined organic layers were dried over MgSO4, filtered, concentrated under vacuum, and dried under HV to obtain 24.9 g of the title compound as a brown oil. LC-MS(A):t R =0.78min;[M+H] + :259.29.

[0144] Production of intermediates for formula A4 To a solution of bromide A3 (1.3 eq) in anhTHF (1.6-2.6 mL / mmol) cooled to -78°C, BuLi (2.5 M in hexane, 1.2 eq) was added dropwise under argon, while maintaining the internal temperature below -70°C (except for the preparation of intermediate A4.6, in which BuLi was replaced with HexLi). The resulting mixture was stirred at -78°C for 30 minutes. A solution of weinrebamide A2 (1 eq) in anhTHF (0.9-1.1 mL / mmol) was added dropwise, while maintaining the internal temperature below -70°C. The resulting solution was warmed to RT and stirred until the reaction was complete. The reaction mixture was quenched with water and extracted with DCM. The organic phases were combined, washed with brine, dried over MgSO4, and evaporated to dryness. The obtained crude material was eluted with Hep / EA using Biotage® pre-filled cartridges Sfaer Silica D or Snap KP-SIL, and then purified by CC.

[0145] [Table 12] Preparation of intermediates for formula A5 A5.1 3-Bromo-5-[1-Cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine DMF (40.2 mL) and DIPEA (4.61 mL) were added to 5-bromopyridine-3-carboxyimamide hydrochloride (2 g), tetrahydropyran-4-carboxylic acid (1387 mg), and HATU (3.36 g). This solution was stirred overnight in RT. Then cyclopropylhydrazine hydrochloride (1.38 g) and then AcOH (4.61 mL) were added, and the mixture was stirred at 80°C. The mixture was then diluted with EA and washed with aq.sat.NaHCO3, then water and brine. The organic phases were combined, dried over MgSO4, filtered, concentrated under vacuum, and purified by CC (Biotage®, 110 g sphere amino, A:Hep, B:EA; gradient (%B); 12-50 over 4.3 CV) to obtain 1.88 g of the title compound as a white solid. LC-MS(A):tR =0.89min;[M+H] + :350.94.

[0146] Preparation of intermediates for formula A6 To a solution of ketone A4 (1 eq) and bromide A5.1 (1.0-1.1 eq) cooled to -78°C in anhTHF (3.4-9 mL / mmol), HexLi (2.3 M in hexane, 1.05-1.3 eq) was added dropwise under argon, while maintaining the internal temperature below -70°C. The resulting solution was stirred below -70°C until the reaction was complete, quenched with water, and extracted with EA. The organic phases were combined, washed with brine, dried over MgSO4, and concentrated under vacuum. The resulting crude product was analyzed using Biotage® pre-filled cartridges Sfaer KP-Amino or Snap KP-SIL, and then Hep / EA( Purification was performed by elution with A6.1~A6.3) or DCM / MeOH (A6.15). If necessary, further purification by prep.LC-MS was performed using Method III. A6.16 was further purified by prep.chiral SFC(III) (chiral SFC(C):t R = 2.43 min (second isomer to elute). A6.25 was purified by prep.LC-MS method X.

[0147] [Table 13] DIPEA (4 eq.) was added to a mixture of intermediate B3.1 (1 eq.), carboxylic acid (1.2 eq.), molecular sieve (3A, 450 mg / mmol B3.1), and HATU (1.2 eq.) in DMF (4 mL / mmol B3.1). After stirring at RT for 2.5 hours, a pre-mixed solution of carboxylic acid (1.2 eq.) and HATU (1.2 eq.) in DMF (2 mL / mmol B3.1) was added, and the mixture was stirred for a further 1 hour until the formation of the intermediate was complete. Substituted hydrazine (1.5 eq.) and AcOH (10 eq.) were then added to the mixture. The reaction mixture was stirred at 85°C for 1 hour or until the transformation of the intermediate was complete. After cooling to RT, the mixture was diluted with EA, washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by prep.LC-MS using the conditions described in the table below.

[0148] [Table 14]

[0149] [Table 15]

[0150] [Table 16] DIPEA (4 eq.) was added to a mixture of the corresponding intermediate B3 (1 eq.), carboxylic acid (1.2 eq.), molecular sieve (3A, 450 mg / mmol B3.1), and HATU (1.2 eq.) in DMF (4 mL / mmol B3). After stirring at RT for 1 hour, if the conversion of the starting materials was incomplete, a pre-mixed solution of carboxylic acid (1.2 eq.) and HATU (1.2 eq.) in DMF (2 mL / mmol B3) was added, and the mixture was stirred for another hour until the formation of the intermediate was complete. Substituted hydrazine (1.5 eq.) and AcOH (10 eq.) were then added to the mixture. The reaction mixture was stirred at 85°C for 1 hour or until the conversion of the intermediate was complete. After cooling to RT, the mixture was diluted with EA, washed with sat.aq.NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by prep.LC-MS using the conditions described in the table below.

[0151] [Table 17] Preparation of intermediates for formula A7 To a solution of intermediate A6 (1 eq) in dioxane (4-5 mL / mmol), HCl (4 M, 8 eq in dioxane) was added. The reaction mixture was stirred in RT for 1-2 hours and evaporated to dryness to obtain the crude hydrochloride salt. The reaction mixtures of A7.28 and A7.29 were neutralized to pH 8-10 by adding aq.sat.NaHCO3 and 1N NaOH, respectively, without evaporation to dryness, and then extracted with DCM. The combined organic layers were evaporated and dried in HV.

[0152] [Table 18]

[0153] [Table 19]

[0154] [Table 20] Preparation of the intermediate of formula B1 B1.1 3-[(R)-(5-cyanopyridine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester Intermediate A4.4 (10.0 g), 5-bromo-3-cyanopyridine (7.49 g), and THF (100 mL) were charged into a flask. The mixture was cooled to -78°C, and then a solution of HexLi in hexane (2.3 M, 17.8 mL) was added dropwise over 30 min. After stirring at -78°C for 1 hour, the cooling bath was removed, and the reaction mixture was quenched by adding sat.aq.NH4Cl. After warming to RT, the mixture was diluted with EA, washed sequentially with water and brine, dried over MgSO4, filtered, and concentrated under vacuum to obtain the crude substance as a brown oil. The residue was subjected to CC (CombiFlash, RediSep 330g SiO2, gradient 200mL / min, Hep / EA 9:1 to 5:5 over 30 min) to obtain a yellow amorphous solid, which was further purified by prep LC-MS(I), and then the enantiomer was separated by prep chiral SFC(I) to obtain 3.22 g of the desired product (grayish-white solid) as the second eluted enantiomer. LC-MS(A):t R =1.05min;[M+H] + :422.28. Chiral SFC(A):t R = 2.21 min.

[0155] B1.2 5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]nicotinonitrile B1.2.1 5-[(R)-hydroxy-(4-isopropylphenyl)-(3-methyl-azetidine-3-yl)-methyl]nicotinonitrile Intermediate B1.1 (0.5 g) was treated with HCl (4 M in dioxane, 8.9 mL). The reaction mixture was stirred in RT for 2 hours and evaporated to dryness to obtain the crude hydrochloride as a beige powder. LC-MS(A):t R =0.69min;[M+H] +:321.92.

[0156] B1.2.2 5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]nicotinonitrile To a solution of intermediate B1.2.1 (0.55 g) in anh dioxane (24 mL), DIPEA (1.1 mL), formaldehyde (37% solution of H2O, 0.15 mL), and NaBH(OAc)3 (741 mg) were added. The reaction mixture was stirred in RT for 15 min, quenched with NaOH (1 M), and extracted with EA. The organic phases were combined, dried over MgSO4, and concentrated under vacuum. The resulting crude product was eluted with EA / MeOH using a Biotage® pre-filled cartridge Sfaer KP-Amino D, and purified by CC to obtain the title compound as a yellow oil (0.34 g). LC-MS(A):t R =0.70min;[M+H] + :336.09.

[0157] B1.3 3-[(R)-(5-cyano-6-fluoropyridine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester Intermediate B1.3 was synthesized using intermediate A4.4 (2.00 g) and 5-bromo-2-fluoronicotinonitrile (1.73 g) according to the procedure described for B1.1. After workup, the crude product was subjected to CC (CombiFlash, RediSep 330 g SiO2, gradient nHept / siRNA 100 / 0 to 60 / 40), followed by prep LC-MS (Zorbax column SB-AQ, 7 μm OBD, 50 x 150 mm, gradient). The product was purified at 150 mL / min for 8 min by (0.5% formic acid in H2O) / MeCN (60 / 40 to 25 / 75) to obtain a racemic mixture (630 mg). Further purification by chiral SFC (Method I) yielded the product as a pure white solid (282 mg) as an enantiomer. LC-MS(A):t R =1.08min;[M+H]+ :440.32. Analytical chiral SFC(A): 1.99 min.

[0158] B1.4 3-[(R)-(5-cyano-6-methylpyridine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester Intermediate B1.4 was synthesized using intermediate A4.4 (2.00 g) and 5-bromo-2-methylnicotinonitrile (1.68 g) according to the procedure described for B1.3. After workup, the crude product was purified by CC (CombiFlash, RediSep 220 g SiO2, gradient nHept / siRNA 100 / 0 to 50 / 50), then by prep LC-MS (Zorbax column SB-AQ, 7 μm OBD, 50 x 150 mm, gradient 150 mL / min, (0.5% formic acid in H2O) / MeCN 60 / 40 to 30 / 70 for 8 min) to obtain the racemic product (1.73 g mg). Further purification by chiral SFC (Method VII) yielded the product as a pure white solid (619 mg) as an enantiomer. LC-MS(A):t R =1.07min;[M+H] + :436.34. Analytical chiral SFC(G): 1.82 min.

[0159] B1.5 3-[(R)-(6-cyanopyridazin-4-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester B1.5.1 3-[(6-chloropyridazin-4-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester The title compound (4.0 g, beige solid) was synthesized using intermediate A4.4 (10 g) and 5-bromo-3-chloropyridazine (7.1 g) as starting materials, following the procedure described in intermediate B1.1, but using toluene instead of THF as the solvent. The crude product was purified by CC (Biotage, SNAP 340 g, solvent A: Hep; solvent B: EA; gradient expressed in %B: 0 to 50). LC-MS(A): t R =1.06min;[M+H] + :432.08.

[0160] B1.5.2. 3-[(R)-(6-chloropyridazin-4-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester The title compound was obtained by chiral separation using Prep chiral SFC(IX) as described in Example B1.5.1. LC-MS(A):t R =1.05min;[M+H] + :432.22; Chiral SFC(H): 2.72 min.

[0161] B1.5.3 3-[(R)-(6-cyanopyridazin-4-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester A suspension of intermediate B1.5.2 (140 mg), zinc powder (75 mg), zinc cyanide (62 mg), Pd2(dba)3 (21 mg), and dppf (103 mg) in DMF (1.5 mL) was heated under reflux for 1 h45. The reaction mixture was cooled to RT and diluted with H2O and DCM. The layers were separated, and the aqueous phase was extracted with DCM (3x). The combined organic layers were dried over MgSO4 and concentrated under vacuum. Purification by prep LC-MS(VII) yielded 49 mg of the desired product as a beige solid. LC-MS(A):t R =1.03min;[M+H] + :423.24.

[0162] B1.6 3-{(R)-(5-cyanopyridine-3-yl)-hydroxy-[4-(1-trifluoromethyl-cyclopropyl)-phenyl]-methyl}-3-methyl-azetidine-1-carboxylic acid tert-butyl ester Intermediate A4.3 (800 mg), 5-bromo-3-cyanopyridine (424 mg), and THF (53 mL) were charged into a flask. The mixture was cooled to -78°C, and then a solution of BuLi in hexane (2.5 M, 1.24 mL) was added dropwise over 15 minutes. After stirring at -78°C for 30 minutes, the cooling bath was removed, and the reaction mixture was quenched by adding water. The mixture was extracted with EA, the combined organic layers were washed with brine, and dried over MgSO4. The mixture was filtered and concentrated under vacuum to obtain the crude substance as a brown oil. The residue was subjected to CC (Biotage 50g SiO2, gradient Hep / EA 12% to 100%) to obtain a yellow foam, which was further purified by prep LC-MS(VIII), and the enantiomer was separated by prep chiral SFC(I) to obtain 0.15g of the desired product as the second elutenable enantiomer. LC-MS(A):t R =1.06min;[M+H] + :488.05. Chiral SFC(A):t R = 1.78 min.

[0163] B1.7 5-{(R)-(1,3-dimethyl-azetidine-3-yl)-hydroxy-[4-(1-trifluoromethyl-cyclopropyl)-phenyl]-methyl}nicotinonitrile The title compound was synthesized using intermediate B1.6 (134 mg) as the starting material, following the two-step procedure described for intermediate B1.2. The crude product was isolated as a white foam (74 mg). LC-MS(A):t R =0.73min;[M+H] + :401.97.

[0164] Preparation of the intermediate for formula B2 B2.1 3-[(R)-hydroxy-[5-(N-hydroxycarbamimidoyl)-pyridine-3-yl]-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester (or its tautomer form tert-butyl (R,Z)-3-(hydroxy(5-(N'-hydroxycarbamimidoyl)pyridine-3-yl)(4-isopropylphenyl)methyl)-3-methylazetidine-1-carboxylate) To a solution of intermediate B1.1 (1.00 g) and hydroxylamine hydrochloride (247 mg) in DMSO (5 mL), DIPEA (0.81 mL) was added dropwise. The reaction mixture was stirred at RT for 3 hours. After complete conversion, it was slowly (10 min) transferred to a flask cooled in an ice bath containing water. The resulting white suspension was stirred at RT for 30 min. The mixture was filtered, the residue was washed three times with water, and dried overnight under HV, then under vacuum at 45°C. A white solid (1.09 g) was obtained. LC-MS(A):t R =0.81min;[M+H] + :455.31.

[0165] B2.2 5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]-N-hydroxy-nicotinamidine A suspension of intermediate B1.2 (372 mg), hydroxylamine hydrochloride (234 mg), and K2CO3 (613 mg) in EtOH (8.1 mL) was stirred for 5 hours in RT. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude title compound as a white powder (497 mg). LC-MS(A):t R =0.54min;[M+H] + :369.04.

[0166] B2.3 3-[(R)-[6-fluoro-5-(N-hydroxycarbamimidoyl)-pyridine-3-yl]-hydroxy-(4-isopropylphenyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was prepared using intermediate B1.3 (279 mg), hydroxylamine hydrochloride (66 mg), and DIPEA (0.22 mL) according to the procedure described for B2.1. The crude product was purified by prep LC-MS(V) to obtain the desired product as a bright yellow solid (61 mg). LC-MS(A):t R =0.87min;[M+H] + :473.30.

[0167] B2.4 3-[(R)-hydroxy-[5-(N-hydroxycarbamimidoyl)-6-methylpyridine-3-yl]-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester The title compound was divided into intermediate B1.4 (619 mg) and hydroxylamine hydrochloride (148 mg). The product was prepared using ) and DIPEA (0.49 mL) according to the procedure described for B2.1. Hydroxylamine and DIPEA were added several more times to accelerate the completion of the conversion. The crude product was purified by prep LC-MS(VI) to obtain the desired product as a white solid (207 mg). LC-MS(A):t R =0.78min;[M+H] + :469.38.

[0168] B2.5 3-[(R)-hydroxy-[6-(N-hydroxycarbamimidoyl)-pyridazin-4-yl]-(4-isopropylphenyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester A suspension of intermediate B1.5 (49 mg), hydroxylamine hydrochloride (24.4 mg), and K2CO3 (64 mg) in EtOH (0.84 mL) was stirred for 20 hours in RT. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude title compound as a brownish solid (63 mg). LC-MS(A):t R =0.92min;[M+H] + :456.28.

[0169] B2.6 5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(1-trifluoromethyl-cyclopropyl)-phenyl]-methyl}-N-hydroxy-nicotinamidine The title compound was synthesized using intermediate B1.7 (72 mg) as the starting material, following the procedure described for intermediate B2.2. The crude product was isolated as a white foam (74 mg). LC-MS(A):t R =0.57min;[M+H] + :435.18.

[0170] Preparation of the intermediate for formula B3 B3.1 3-[(R)-(5-carbamimidoylpyridine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester To a solution of intermediate B2.1 (400 mg) in AcOH (15 mL), acetic anhydride (0.11 mL) was added. This solution was stirred in RT for 45 min. Palladium-activated carbon (10%, hydrated (50%), 20 mg) was added, and the mixture was hydrogenated in RT for 1 h 15 min. The reaction mixture was filtered through Celite, the residue was washed with AcOH, and the combined filtrate was concentrated under vacuum to obtain the crude substance as a colorless amorphous solid. The crude substance was further purified by prep LC-MS(V) to obtain the title compound as a white solid (265 mg). LC-MS(A):t R =0.78min;[M+H] + :439.29.

[0171] B3.2 5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]nicotinamidine The title compound was synthesized using intermediate B2.2 (497 mg) as the starting material, except that the acetylation step was performed at RT for 2 hours and the hydrogenation step at RT for 18 hours. The crude product was isolated as a yellow foam (216 mg). LC-MS(A):t R =0.50min;[M+H] + :353.04.

[0172] B3.3 3-[(R)-(5-carbamimidoyl-6-fluoropyridine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized from intermediate B2.3 (57 mg) following the procedure described for B3.1 (acetylation 1 h, hydrogenation 2 h). The crude product was purified by prep LC-MS(V) to obtain the desired product as a white solid (45 mg). LC-MS(A):t R =0.82min;[M+H] + :457.36.

[0173] B3.4 3-[(R)-(5-carbamimidoyl-6-methylpyridine-3-yl) -Hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized from intermediate B2.4 (80 mg) according to the procedure described for B3.1 (acetylation 30 min, hydrogenation 1.5 h), and the desired product was obtained as a white foam (75 mg). The crude product was used in the next step without further purification. LC-MS(A):t R =0.78min;[M+H] + :453.38.

[0174] B3.5 3-[(R)-(6-carbamimidoyl-pyridazin-4-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized from intermediate B2.5 (52 mg) according to the procedure described for B3.1 (acetylation 17 h, hydrogenation 23 h). After the reaction was complete, the reaction mixture was filtered, and the filtrate was basicized to pH 12 by adding 1N NaOH and extracted by DCM (3x). The combined organic layers were dried over MgSO4 and concentrated under vacuum to obtain the desired product as a yellowish solid (75 mg). The crude product was used in the next step without further purification. LC-MS(A):t R =0.79min;[M+H] + :440.28.

[0175] B3.6 5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(1-trifluoromethyl-cyclopropyl)-phenyl]-methyl}nicotinamidine The title compound was synthesized using intermediate B2.6 (70 mg) as the starting material, following the synthetic procedure described for intermediate B3.1. LC-MS(A):t R =0.53min;[M+H] + :419.23.

[0176] Production of intermediates for formula B4 B4.1 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylic acid To a solution of 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carbonitrile (150 mg) in EtOH (2.3 mL), water (0.5 mL) and aq. NaOH (10.8 M, 0.65 mL) were added. The reaction mixture was stirred at 75 °C for 2 hours. After cooling to RT, the mixture was acidified with aq. HCl (6.8 M, ~1 mL) (pH 2-3). The mixture was extracted four times with EA, the organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to obtain the title compound as a white solid (180 mg). 1 H-NMR (500MHz, DMSO) δ=12.2(brs, 1H), 4.54(t, J=5.6Hz, 1H), 3.37(d, J=5.4Hz, 2H), 1.81(s, 6H)ppm.

[0177] Manufacturing of Examples 1-4 and 38 To a solution of intermediate A7 (1 eq) in anh dioxane (18.3 mL / mmol), DIPEA (3 eq), formaldehyde (37% solution in H2O, 1.5 eq), and NaBH(OAc)3 (2.6 eq) were added. The reaction mixture was stirred in RT for 15 min to 1 hour, quenched with NaOH (1 M), and extracted with EA. The organic phases were combined, dried over MgSO4, and concentrated under vacuum. The resulting crude product was purified by prep LC-MS using the conditions shown in the table below, and then by prep chiral SFC as shown in the table below. The pure enantiomer was purified by anal chiral SFC (method and retention time expressed in minutes (t R The chiral(s) are listed in the table below.) and analLC-MS (Method A, retention time expressed in minutes (t R The LC-MS and observed masses are shown in the table below.

[0178] [Table 21] Manufacturing of Examples 5-7 Example 1 (1 eq), organoborane (2 eq), cataCXium® A Pd G3 (0.1 eq), and Cs2CO3 (3 eq) were mixed in a mixture of toluene (5 mL / mmol) and water (0.5 mL / mmol). The mixture was flashed with argon, heated at 100°C in a sealed vial, and stirred for 18 hours. The reaction mixture was diluted with EA and washed with NaOH (1 M) and brine. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by prep LC-MS using the method shown in the table below.

[0179] [Table 22] Manufacturing of Examples 8-12 A mixture of intermediate B3.2 (1 eq), carboxylic acid (1.5 eq), and HATU (1.1 eq) in DMF (5 mL / mmol) was mixed with DIPEA (4 eq). After stirring at RT for 1 to 1.5 hours, cyclopropylhydrazine hydrochloride (1.5 eq) and AcOH (10 eq) were added at RT until the formation of the intermediate was complete. The reaction mixture was stirred at 80°C for 20 min to 18 hours. After cooling to RT, the mixture was diluted with EA, washed with 1 M aq. NaOH and brine, dried over MgSO4, and concentrated under vacuum. The crude product was purified by prep.LC-MS using the conditions described in the table below.

[0180] [Table 23] Preparation of Example 13: 4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-bicyclo[2.2.2]octane-1-carboxylic acid To the solution of Example 10 (1 eq) in MeOH (8.6 mL / mmol), LiOH·H2O (1.5 eq) and H2O (4.3 mL / mmol) were added. The reaction mixture was stirred in RT for 18 hours, concentrated under vacuum, and fractionated between EA and a semi-saturated NH4Cl aqueous solution. The organic phase was washed with brine, dried over MgSO4, and concentrated under vacuum to obtain the title compound as a yellowish oily residue. LC-MS(A):t R =0.76min;[M+H] + :570.16.

[0181] Manufacturing of Examples 14-33, 39, 40, 48 and 51 To a solution of intermediate A7 (1 eq.) in dioxane (10 mL / mmol), TEA (2 eq.) or AcOH (1.5 eq.; for Example 48), aq. formaldehyde (37 wt.%, 2 eq.) and NaBH(OAc)3 (1.5 eq.) were added. The mixture was stirred overnight in RT to completely convert the starting materials. The reaction mixture was filtered, concentrated under vacuum, and then purified by prep LC-MS to obtain the desired compound. The prep LC-MS method is described in the table below. Example 39 was further purified by chiral SFC(VIII) to separate the product from the unreacted starting materials.

[0182] [Table 24]

[0183] [Table 25]

[0184] [Table 26] Preparation of Example 34: (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1-isopropyl-3-methylazetidine-3-yl)-(4-isopropyl-phenyl)-methanol To a solution of intermediate A7.4 (30 mg) in MeOH (1 mL), AcOH (100 μL), and acetone (44.4 μL), NaB(OAc)3H (44 mg) was added by RT. The resulting suspension was stirred by RT for 3 hours and 30 minutes, then quenched with water, diluted with MeOH, and purified by prep LC-MS(III) to obtain 7 mg of the title compound as a white powder. LC-MS(A):t R =0.77min;[M+H] + :530.20.

[0185] Manufacturing of Examples 35-37 and 49 Example 35: (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-[1-(2,2-difluoroethyl)-3-methylazetidine-3-yl]-(4-isopropylphenyl)-methanol To a solution of intermediate A7.4 (30 mg) in MeOH (1 mL), TEA (36.4 μL) and then 1,1-difluoro-2-iodoethane (39 μL) were added by RT. This solution was shaken at 65°C for 10¹ hours, then cooled, diluted with MeOH and water, and purified by prep LC-MS(III) to obtain 6 mg of the title compound as a grayish-white powder. LC-MS(A):t R =0.76min;[M+H] + :552.10.

[0186] Example 36: 2-{3-[(R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-yl}ethanol The title compound was stirred for 70 hours with 2-iodoethanol (17.5 μL) as shown in Example The compound was synthesized according to the procedure described in section 35, and purified by prep LC-MS(IV) to obtain 3 mg of the title compound as a white powder. LC-MS(A):t R =0.71min;[M+H] + :532.10.

[0187] Example 37: 2-(2-cyclopropyl-5-{5-[(R)-hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidine-3-yl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-propane-2-ol Intermediate A7.17 was designated as Example 37. The procedure and characteristics are described in Section A7. LC-MS(A):t R =0.69min;[M+H] + :462.36.

[0188] Example 49: (R)-(1-cyclopropyl-3-methylazetidine-3-yl)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(4-isopropylphenyl)-methanol To a solution of intermediate A7.4 (24 mg) in MeOH (1 mL), AcOH (5.6 μL), and (1-ethoxycyclopropoxy)trimethylsilane (30 μL), NaBH3CN (30 μL) was added at 65°C. The reaction mixture was stirred for 6 hours and 30 minutes, then filtered through a syringe filter, diluted with water, and directly purified by prep LC-MS(IV) to obtain 8 mg of the title compound as a white powder. LC-MS(A):t R =0.77min;[M+H] + :528.36.

[0189] Manufacturing of Examples 41-47 DIPEA (4 eq) was added to a mixture of intermediate B3.2 (1 eq), carboxylic acid (1.5 eq), and HATU (1.1 eq) in DMF (5 mL / mmol). The mixture was stirred at 40–45°C for 15–60 minutes, and, if necessary, overnight in RT until the intermediate was completely formed. Isopropylhydrazine hydrochloride (1.5 eq) and AcOH (10 eq) were then added in RT. The reaction mixture was stirred at 80°C for 10–45 minutes. After cooling to RT, the mixture was diluted with EA, washed with 1 M aq. NaOH and brine, dried over MgSO4, and concentrated under vacuum. The crude product was optionally purified by biotage chromatography, followed by prep. LC-MS under the conditions described in the table below.

[0190] [Table 27] Preparation of Example 50: N-{2-[3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-5-(tetrahydropyran-4-yl)-[1,2,4]triazole-1-yl]-ethyl}acetamide 50.1: {2-[3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-5-(tetrahydropyran-4-yl)-[1,2,4]triazole-1-yl]-ethyl}carbamate tert-butyl ester A mixture of intermediate B3.2 (175 mg), tetrahydropyran-4-carboxylic acid (79 mg), molecular sieve (3A, 50 mg), and HATU (234 mg) in DMF (3 mL) was mixed with DIPEA (0.34 mL). After stirring at RT for 60 min, tert-butyl-N-(2-hydrazinylethyl)carbamate hydrochloride (158 mg) and AcOH (0.284 mL) were added at RT. The reaction mixture was stirred at 85 °C for 60 min. After cooling to RT, the mixture was neutralized by adding sat.aq.NaHCO3 and extracted with EA. The combined organic layer was dried over MgSO4 and concentrated under vacuum. The crude product was purified by prep.LC-MS(III) to obtain the title compound as a white solid (0.14 g). . LC-MS(A):t R =0.76min;[M+H] + :605.41.

[0191] 50.2: (R)-{5-[1-(2-amino-ethyl)-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol 50.1 mg (140 mg) of intermediate was mixed with 4 M HCl (5 mL) in dioxane, and the colorless solution was stirred in RT for 30 min. The reaction mixture was adjusted to pH 7-8 by adding sat.aq. NaHCO3 and diluted with H2O. The aqueous phase was extracted with EA (5x). The organic phases were combined, dried over MgSO4, and concentrated under vacuum. The aqueous phase was then basicized to pH 10 by adding 1 M NaOH and extracted with DCM. The organic phases were combined, dried over MgSO4, and concentrated under vacuum. Both crude products were combined and dried overnight under HV to obtain the title compound (107 mg) as a yellowish foam. LC-MS(A):t R =0.55min;[M+H] + :505.40.

[0192] 50.3: N-{2-[3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-5-(tetrahydropyran-4-yl)-[1,2,4]triazole-1-yl]-ethyl}acetamide To a solution of 50.2 mg of intermediate in 0.5 mL of dioxane, 33 μL of DIPEA and then 9 μL of acetic anhydride were added, and the mixture was stirred in RT for 1 hour. The reaction mixture was evaporated to dryness, the residue was dissolved in MeOH, and treated with K2CO3. After stirring in RT for 2 hours, the reaction mixture was filtered, diluted with water and CH3CN, and directly purified by prep.LC-MS(IV) to obtain 24 mg of the desired product as a white solid. LC-MS(A):t R =0.63min;[M+H] + :547.35.

[0193] II. Biological Assays FLIPR Assay: The biological activity of the compound is tested using a fluorescence imaging plate reader (FLIPR: Molecular Devices) with modified HEK-293 cells expressing human CCR6 (GenBank: AY242126). Two days before the bioassay, frozen cells are seeded on a 384-well plate pre-coated with poly-L-lysine in DMEM medium supplemented with 10% FCS and 1% penicillin-streptomycin. On the day of the bioassay, the cell supernatant is discarded, and the cells are buffered with 20 mM Hepes at pH 6.75 for 30 minutes at room temperature in the dark, and stained with Fluo-8-AM (Focus Biomolecules) in Hanks Balanced Salt Solution (Gibco) supplemented with 0.05% BSA. The same buffer used for washing and compound dilution is also used in the assay buffer, except that it does not contain the dye. Wash the cells in a wash-station (Biotek) to remove excess dye, leaving 40 microliters of assay buffer. Incubate the cells in the dark at room temperature for 15 minutes, then add the compounds. Prepare a stock solution of the test compounds to a concentration of 10 mM with DMSO, serially dilute it with DMSO, and then transfer it to the assay buffer to the concentration required for the inhibition-dose-response curve. After incubation time of 45 minutes at room temperature in the assay buffer, transfer 10 microliters of each compound dilution from the compound plate to the plate containing the recombinant cells in a FLIPR instrument according to the manufacturer's instructions. After pre-incubating the cells and compounds in the dark at room temperature for 30 minutes, add 10 microliters of the agonist CCL20 (Peprotech) to a final concentration of 10 nM using the FLIPR instrument again. Monitor the changes in fluorescence before and after the addition of the test compounds and agonists. Export the emission peak values ​​exceeding the baseline level after CCL20 addition after baseline subtraction. Calculate the IC 50 The values ​​may vary depending on the assay procedure performed each day. This type of variation is known to those skilled in the art. IC for objects 50 If the value was calculated several times, the average value is shown. The data is shown in the table below.

[0194] Table 28

Claims

1. Compound of formula (I) or its pharmaceutically acceptable salt 【Chemistry 1】 (In the formula, Q is N, CH, or C-R (R is halogen or C １－３ - Represents alkyl. ) Represents; R １ teeth, - C １－３ - Alkyl; It represents; R ２ teeth, - Hydrogen; - C １－４ - Alkyl; - Hydroxy-C １－３ - Alkyl; - C １－３ - Fluoroalkyl; Or, - C ３－５ - Cycloalkyl; It represents; R ３ａ is - Halogen; - C １－５ - Alkyl; - C １－３ - Fluoroalkyl; - C １－３ - Fluoroalkoxy; - C ３－５ - Cycloalkyl; Or, - 1 - (C １－３ -Fluoroalkyl)-C ３－５ - Cycloalkyl; It represents; R ３ｂ teeth, - Hydrogen; Or, - Halogen; It represents; R ４ teeth, - C １－４ - Alkyl, unsubstituted; substituted with one substituent, wherein the substituent is hydroxyl and C １－３ -Selected from alkyl-amino; or substituted with two substituents, where the first substituent represents hydroxyl and the second substituent represents C １ - Represents fluoroalkyl, C １－４ - Alkyl; Or, - -L-Cy( -- -L- is a direct bond or -CH ２ - represents; -- Cy is a C atom that optionally contains one ring heteroatom selected from nitrogen and oxygen. ３－７ - Represents a cycloalkyl group, where Cy is independently unsubstituted or; Or, --- 1 piece ---- Hydroxy; ---- Oxo; ---- C １－４ - Alkyl; -----C(=O)R Ａ (R Ａ C １－３ -Alkyl or hydroxy-C １－３ - Represents alkyl. ); or, ---- C １－３ -Alkyl-carbonyl-amino; Replaced by; Or, --- Substituted by two substituents, the first substituent representing oxo and the second substituent representing C １－３ - Represents alkyl; or is substituted with two substituents, where the first substituent represents hydroxyl and the second substituent is C １－３ - Represents alkyl-carbonyl; -- Alternatively, Cy represents a saturated 5-8 membered bridged bicyclic hydrocarbon ring system, and Cy is independently substituted by one substituent, and the substituent is --- Hydroxy-C １－３ - Alkyl; and, --- -C(=O)R Ｂ (R Ｂ teeth, ---- Hydroxy; ---- NR Ｎ１ R Ｎ２ (R Ｎ１ and R Ｎ２ These are independently hydrogen or C １－３ - Represents alkyl; or R Ｎ１ and R Ｎ２ They form pyrrolidinyl with the nitrogen atom to which they bond. ); or, ---- C １－３ - Alkoxy; (This represents...) Selected from; -- Alternatively, Cy represents a 5- or 6-membered heteroaryl compound containing one or two ring heteroatoms independently selected from nitrogen and oxygen. Represents; and R ５ teeth, - C １－４ - Alkyl; - Hydroxy-C １－３ - Alkyl; - C １－３ -Alkoxy-C １－３ - Alkyl; - C ３－７ - Cycloalkyl; - C １－３ - Fluoroalkyl; - C １－３ -Alkyl-carbonyl; Or, - C １－３ -Alkyl-carbonyl-amino-C １－３ - Alkyl; Does it represent; Or, R ４ and R ５ These, together with the triazolyl ring to which they are attached, form 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-yl or 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl.

2. Q represents CH; R １ but, - C １－３ - Alkyl; It represents; R ２ but, - Hydrogen; - C １－４ - Alkyl; - Hydroxy-C １－３ - Alkyl; Or, - C １－３ - Fluoroalkyl; It represents; R ３ａ but, - Halogen; - C １－５ - Alkyl; - C １－３ - Fluoroalkyl; - C １－３ - Fluoroalkoxy; - C ３－５ - Cycloalkyl; Or, - 1 - (C １－３ -Fluoroalkyl)-C ３－５ - Cycloalkyl; It represents; R ３ｂ but, - Hydrogen; It represents; R ４ but, - C １－４ - Alkyl, substituted with one substituent, wherein the substituent is hydroxyl and C １－３ -Selected from alkyl-amino; or substituted with two substituents, where the first substituent represents hydroxyl and the second substituent represents C １ - Represents fluoroalkyl, C １－４ - Alkyl; Or, - -L-Cy( -- -L- is a direct bond or -CH ２ - represents; -- Cy is a C atom that optionally contains one ring heteroatom selected from nitrogen and oxygen. ３－７ - Represents a cycloalkyl group, where Cy is independently unsubstituted or; Or, --- 1 piece ---- Hydroxy; Or, -----C(=O)R Ａ (R Ａ is C １－３ - Represents alkyl. Replaced by; -- Alternatively, Cy represents a saturated 5-8 membered bridged bicyclic hydrocarbon ring system, and Cy is independently substituted by one substituent, and the substituent is --- Hydroxy-C １－３ - Alkyl; or, --- -C(=O)R Ｂ (R Ｂ teeth, ---- Hydroxy; Or, ---- C １－３ - Alkoxy; (This represents...) Selected from; -- Alternatively, Cy represents a six-membered heteroaryl compound containing one ring nitrogen atom. It represents; R ５ but, - C １－４ - Alkyl; - Hydroxy-C １－３ - Alkyl; - C ３－７ - Cycloalkyl; Or, - C １－３ - Fluoroalkyl; Represents; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ３ａ is C １－５ -alkyl or C １－３ -fluoroalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ２ However, C １－４ -Alkyl or hydroxy-C １－３ - A compound according to claim 1 or a pharmaceutically acceptable salt thereof, representing an alkyl group.

5. R ４ but, - C １－４ -alkyl, which is substituted by one hydroxy; or substituted by two substituents, wherein the first substituent represents hydroxy and the second substituent represents C １ -fluoroalkyl, C １－４ -alkyl; Or, - -L-Cy( -- -L- indicates a direct bond; -- Cy is a C atom that optionally contains one ring heteroatom selected from nitrogen and oxygen. ３－７ - Represents a cycloalkyl group, where Cy is independently unsubstituted or; Or, --- 1 piece ---- Hydroxy; Or, -----C(=O)R Ａ (R Ａ is C １－３ - Represents alkyl. Replaced by; -- Alternatively, Cy represents bicyclo[1.1.1]pentan-1-yl or bicyclo[2.2.2]octane-1-yl, and Cy is independently substituted with one substituent, the substituent being, --- Hydroxy-C １－３ - Alkyl; and, --- -C(=O)R Ｂ (R Ｂ teeth, ---- Hydroxy; Or, ---- C １－３ - Alkoxy; (This represents...) Selected from; -- Or, Cy represents pyridinyl. Represents; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. R ５ However, C １－４ - Alkyl or C ３－７ - A compound according to claim 1 or a pharmaceutically acceptable salt thereof, representing a cycloalkyl group.

7. a) Base 【Chemistry 2】 This represents 3-methylazetidine-3-yl, 1,3-dimethylazetidine-3-yl, 1-isopropyl-3-methylazetidine-3-yl, 1-(2-hydroxyethyl)-3-methylazetidine-3-yl, or 1-(2,2-difluoroethyl)-3-methylazetidine-3-yl; b) base 【Transformation 3】 This represents 4-bromophenyl, 4-ethylphenyl, 4-(n-propyl)phenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-cyclopropylphenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-trifluoromethoxyphenyl, or 4-(1-trifluoromethylcyclopropyl)phenyl; c) base 【Chemistry 4】 However, 5-(1-cyclopropyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(4-hydroxycyclohexyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(1-hydroxy-1-trifluoromethyl-ethyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(4-methoxycarbonyl-bicyclo[2.2.2 ]octan-1-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl,5-(1-cyclopropyl-5-(1-methyl-1-methylaminoethyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl,5-(1-cyclopropyl-5-(1-hydroxycyclobutyl-methyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl,5-(1-cyclopropyl-5-(4-carboxybicyclo[2.2.2]octan-1-yl)-1H-1,2,4-triazole (Lu-3-yl)-pyridine-3-yl, 5-(1-cyclohexyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-methyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-(2-hydroxyethyl)-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-ethyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole -3-yl)-pyridine-3-yl, 5-(1-isopropyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopentyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-tert-butyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-(2,2-difluoropropyl)-5-tetrahydropyran-4-yl-1H-1, 2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclobutyl-5-tetrahydropyran-4-yl-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(pyridine-3-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(1-hydroxy-1-methyl-ethyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-isopropyl-5-(1-hydroxy-1-methyl-ethyl) )-1H-1,2,4-triazole-3-yl)-pyridine-3-yl,5-(1-cyclopropyl-5-(3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl,5-(1-isopropyl-5-(3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl,5-(1-cyclopropyl-5-(4-hydroxytetrahydropyran-4-yl)-1H-1,2,Representing 4-triazole-3-yl)-pyridine-3-yl, 5-(1-isopropyl-5-(4-hydroxytetrahydropyran-4-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-cyclopropyl-5-(N-acetyl-piperidine-4-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl, 5-(1-isopropyl-5-(N-acetyl-piperidine-4-yl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl or 5-(1-cyclopropyl-5-(1-hydroxy-1-methyl-ethyl)-1H-1,2,4-triazole-3-yl)-pyridine-3-yl; the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. A chiral carbon atom supporting a hydroxyl group has the absolute configuration shown in formula (II); the compound according to claim 1 or a pharmaceutically acceptable salt thereof: 【Transformation 5】

9. (R)-(4-bromophenyl)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-methanol; (R)-(4-tert-butylphenyl)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-[4-(1-trifluoromethyl-cyclopropyl)-phenyl]-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-trifluoromethoxyphenyl)-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-[4-(2,2,2-trifluoroethyl)-phenyl]-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-ethylphenyl)-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-propylphenyl)-methanol; trans-4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-cyclohexanol; (R)-2-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-1,1,1-triflu Olopropan-2-ol; 4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester; (R)-{5-[1-cyclopropyl-5-(1-methyl-1-methylaminoethyl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; 1-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-ylmethyl)cyclobutanol; 4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-bicyclo[2.2.2]octane-1-carboxylic acid; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-cyclohexyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-{5-[1-methyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}methanol; 2-[3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-5-(tetrahydropyran-4-yl)-[1,2,4]triazole-1-yl]ethanol; (R)-(1,3-dimethylazetidine-3-yl)-{5-[1-ethyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(4-isopropylphenyl)-methanol; (R)-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-{5-[1-isopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-methanol; (R)-{5-[1-cyclopentyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-tert-butyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-(2,2-difluoropropyl)-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-cyclobutyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-[5-(1-cyclopropyl-5-pyridine-3-yl-1H-[1,2,4]triazole-3-yl)-pyridine-3-yl]-(1,3-dimethyl-azetidine-3-yl)-(4-isopropyl-phenyl)-methanol; (R)-(4-cyclopropyl-phenyl)-{5-[1-cyclopropyl-5-(teto (Lahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-methanol; 2-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-propan-2-ol; 2-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-propan-2-ol; (R)-{5-[1-cyclopropyl-5-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1,3-dimethyl-azetidine-3-yl)-(4-isopropyl-phenyl)-methanol; (R)-(1,3-dimethyl-azetidine-3-yl)-{5-[5-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-1-isopropyl-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(4-isopropyl-phenyl)-methanol; 4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-tetrahydropyran-4-ol; 4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-tetrahydropyran-4-ol; 1-[4-(2-cyclopropyl-5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-piperidine-1-yl]-ethanone; 1-[4-(5-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-isopropyl-2H-[1,2,4]triazole-3-yl)-piperidine-1-yl]-ethanone; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-(1-isopropyl-3-methylazetidine-3-yl)-(4-isopropylphenyl)-methanol; (R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-[1-(2,2-difluoroethyl)-3-methylazetidine-3-yl]-(4-isopropylphenyl)-methanol; 2-{3-[(R)-{5-[1-cyclopropyl-5-(tetrahydropyran-4-yl)-1H-[1,2,4]triazole-3-yl]-pyridine-3-yl}-hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-yl}ethanol; Or, 2-(2-cyclopropyl-5-{5-[(R)-hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidine-3-yl)-methyl]pyridine-3-yl}-2H-[1,2,4]triazole-3-yl)-propan-2-ol; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. A compound comprising any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier.

11. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

12. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of inflammatory / autoimmune diseases, conditions, or disorders.

13. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of cancer.

14. A drug for the prevention or treatment of inflammatory / autoimmune diseases, conditions or disorders; or cancer, comprising, as an active ingredient, a compound described in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

15. Rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; psoriasis; Psoriatic arthritis; Inflammatory skin disorders, such as rosacea; Crohn's disease; Ulcerative colitis; irritable bowel syndrome; A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for use according to claim 12 in the prevention or treatment of inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjögren's syndrome; autoimmune hepatitis; primary sclerosing cholangitis; psoriasis; psoriasis vulgaris; guttate psoriasis; reverse psoriasis; pustular psoriasis; erythrodermic psoriasis; autoimmune keratitis; filamentous keratitis; autoimmune uveitis; allergic conjunctivitis; asthma; allergic diseases of the gastrointestinal tract; type 1 diabetes mellitus (T1D); endometriosis; meibomian gland dysfunction; or graft-versus-host disease.

16. Lymphoma; T-cell lymphoma; primary mediastinal large B-cell lymphoma; brain cancer; glioma; glioblastoma; breast cancer; triple-negative breast cancer; colorectal cancer; hepatocellular carcinoma; renal cell carcinoma; lung cancer; non-small cell lung cancer; small cell lung cancer; gastric cancer; melanoma; Merkel cell carcinoma, cutaneous squamous cell carcinoma; malignant melanoma; bladder cancer; head and neck cancer; squamous cell head and neck cancer; Hodgkin lymphoma; cervical cancer; endometrial cancer; colorectal cancer; gastrointestinal stromal tumor; pancreatic cancer; prostate cancer; leukemia; acute bone marrow For use according to claim 13 in the prevention or treatment of leukemia; ovarian cancer; esophageal cancer; mesothelioma; neuroblastoma; sarcoma; high-grade osteosarcoma; astrocytoma; myeloma; urothelial carcinoma; locally advanced urothelial carcinoma; metastatic urothelial carcinoma; MSI-H or dMMR cancer; rectal cancer; laryngeal cancer; salivary gland cancer; multiple myeloma; bile duct cancer; oral squamous cell carcinoma; thyroid cancer; or esophagogastric junction cancer, the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

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