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] TIFF2024539967000032.tif56152

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 they contribute to the onset of the disease 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 has been observed that the production of collagen-specific antibodies is decreased in CCR6-deficient mice compared with wild-type mice, and joint inflammation is also reduced (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 ). It has been shown that secukinumab, an IL-17A inhibitor, is effective for 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 is associated with disease activity. Furthermore, in 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 dynamics of germinal center (GC) formation and B cell responses, and CCR6 is considered to be a marker for memory B cell precursors 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 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 circulating blood of patients with pSS 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. 2015 / July 10;363(1):60-70.doi:10.1016 / j.canlet.2015.04.005.). Similar to NSCLC, hepatocellular carcinoma patients with elevated CCL20 expression had lower overall survival and recurrence-free survival. The same authors describe that CCL20 expression was significantly correlated with tumor size, tumor number, vascular invasion, tumor differentiation, and tumor recurrence (J Gastrointest Surg. 2012 / April;16(4):828-36.doi:10.1007 / s11605-011-1775-4.).

[0024] In addition to the correlation of CCR6 or CCL20 alone with disease progression, there are descriptions in the literature of the correlation between CCR6 / CCL20 co-expression and disease progression. In fact, overexpression of both CCL20 and CCR6 has been detected in higher-grade glioma tissues than in lower-grade tissues, and increases with the elevation of tumor grade defined by the World Health Organization (WHO). In particular, glioma patients with CCR6 / CCL20 co-expression had the shortest overall survival (Med Oncol. December 2012;29(5):3491-7. doi:10.1007 / s12032-012-0314-9.).

[0025] Furthermore, CCR6 and / or CCL20 expression correlates with enhanced chemoresistance and is associated with metastasis. In fact, expression of CCL20 may increase chemoresistance in breast cancer cells (PLoS Biol. July 2018;16(7):e2005869. doi:10.1371 / journal.pbio.2005869.). Rubie et al. reported that significant upregulation of CCL20 / CCR6 was observed (via RT-PCR) in human samples of colorectal liver metastasis (CRLM) and hepatocellular carcinoma (HOC). Furthermore, CCL20 is significantly overexpressed in colorectal liver metastases compared with primary HCC, indicating the involvement of the CCL20 / CCR6 ligand-receptor pair in the carcinogenesis and progression of hepatic malignancies (World J Gastroenterol. November 7, 2006;12(41):6627-33. doi:10.3748 / wjg.v12.i41.6627.).

[0026] 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 found 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 higher in tumor tissue compared to adjacent normal tissue. It was significantly higher in (Cancer Res Treat. April 2015; 47(2):306-12. doi:10.4143 / crt.2014.015.). CCR6 expression has been detected in common cancer cell lines, and indeed, according to Mays and collaborators, RT-PCR gene analysis of salivary adenoid cystic carcinoma (SACC-83) cells revealed that CCR6 was expressed along with other CC chemokine receptors (Anticancer Res. August 2016; 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.).

[0027] Similar to CCR6, it has been reported in the literature that the ligand CCL20 is expressed in multiple 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 patients with NSCLC, which was also verified at the protein level using immunohistochemical staining (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 pancreatic tissue 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.).

[0028] In addition to the expression of CCR6 or CCL20 alone, co-expression of both CCR6 and CCL20 has been reported in the literature for samples from cancer patients and cancer cell lines. It has been 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): 1200-8. 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 involving 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 to healthy tissues, and the expression of CCR6 and CCL20 in hepatocellular carcinoma cell lines (L02, Li- / -, Huh-7, SN U-387, Hep3B) (Oncol Rep. September 2019; 42(3): 1075-1089. doi: 10.3892 / or. 2019.7221.). According to Nandi et al., both CCL20 and CCR6 are expressed in human colorectal cancer (IHC protein staining). In NSCLC samples, significantly higher expression of both CCR6 and CCL20 was found (protein and mRNA) (Oncol Lett. December 2017; 14(6): 8183-8189. doi: 10.3892 / ol. 2017.7253). Using in situ hybridization, both mRNA portions of CCL20 and CCR6 were strongly expressed in all pancreatic cancer samples analyzed. In contrast, CCL20 and CCR6 expression was low in healthy pancreases (Int J Cancer. May 1999 17;81(4):650-7.doi:10.1002 / (sici)1097-0215(19990517)81:4<650::aid-ijc23>3.0.co;2-#.). Jin and collaborators investigated the expression of CCR6 and CCL20 in glioblastoma using publicly available datasets. The authors compared CCL20 and CCR6 mRNA levels between normal brain and glioblastoma tissue using the GEO dataset, GSE2223. Again, the expression levels of CCR6 and CCL20 were significantly higher in glioblastoma tissue than in normal brain tissue (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 endometrial adenocarcinoma cultured tissue and cell lines compared to 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 system is thought to play a role in breast cancer, cholangiocarcinoma, and thyroid cancer.This is because the expression of CCR6 / CCL20 gene and / or protein has been reported in patient-derived breast cancer cells (Mol Carcinog. July 2016; 55(7):1175-86. doi: 10.1002 / mc.22360.), in HuCCT1 and TFK-1 cholangiocarcinoma cell lines () (Win et al., PMID 32194362) (EXCLI J. 2020; 19:154-166. doi: 10.17179 / excli2019-1893.) and in 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, either alone or in combination, is considered useful for the treatment or prevention of cancers in which expression and / or evidence of CCR6 / CCL20 axis activity has been reported, or cancers in which CCR6+ regulatory T cells have been identified in the tumor microenvironment. [Summary of the Invention]

[0029] 1) One aspect of the present invention relates to a compound of formula (I):

[0030] [Chemical Formula] (wherein, - R 1 is C 1-3 -alkyl (especially methyl); R 2 is C 1-4 -alkyl (especially methyl); R 3 is 2,2,2-trifluoro-ethyl; -L- is -- optionally substituted with one hydroxy * -C≡C-C 0-2 -alkylene- ** (in particular, -C≡C- or -C≡C-C(CH3)(OH)-) (the asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) are R 4This indicates the connection point to ); or, -- Oxadiazole-diyl (especially 1,2,4-oxadiazole-diyl; particularly

[0031] [ka] (1 asterisk( * ) indicates a bond site to the pyridinyl ring, and two asterisks ( ** ) is R 4 This indicates the connection point to [the specified location]. It represents; and, R 4 teeth, C 3-7 -Cycloalkyl (especially cyclohexyl); -- A saturated 5- to 8-membered bridge or spironicyclic hydrocarbon ring system in which one ring carbon atom (especially in the spironicyclic hydrocarbon ring system) is optionally replaced by a nitrogen atom (in particular, such bridge or spironicyclic hydrocarbon ring system represents bicyclo[2.2.2]octane-1-yl, bicyclo[1.1.1]pentan-1-yl, or 2-azaspiro[3.3]heptane-6-yl); or, -- Six-membered heteroaryl compounds having one or two (especially two) ring nitrogen atoms (especially pyrimidinyl; particularly pyrimidine-4-yl); It represents; R 4 These are independently unsubstituted or have one hydroxyl, hydroxy-C 1-3 -Alkyl (especially hydroxymethyl), carbamoyl, C 1-3 -Alkyl-carbonyl-amino (especially acetyl-amino or ethyl-carbonyl-amino) or C 1-3 Substituted with alkyl-carbonyl (especially acetyl); [In particular, base-LR 4These are 5-(4-hydroxy-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-3-yl, 3-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-5-yl, 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo [2.2.2]Octane-1-yl)-1,2,4-Oxadiazole-3-yl, 5-(3-Acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-Oxadiazole-3-yl, 5-(2-Acetamide-2-azaspiro[3.3]heptan-6-yl)-1,2,4-Oxadiazole-3-yl, 5-(4-Acetamide-cyclohexyl)-1,2,4-Oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-Oxadiazole-3-yl or 5-(4-Carbamoyl-bicyclo[2.2.2]Octane-1-yl)-1,2,4- It represents oxadiazole-3-yl. ]; or, - R 1 is C 1-3 - Represents alkyl (especially methyl); R 2 is C 1-4 - Represents alkyl (especially methyl); R 3 isopropyl; and, -LR 4These are 2-(4-hydroxy-cyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole- Represents 3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; or, - R 1 is C 1-3 - Represents alkyl (especially methyl); R 2 is C 1-4 - Represents alkyl (especially methyl); R 3 represents 2,2,2-trifluoroethyl; and, -LR 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazole-5-yl.

[0032] The definitions set forth herein apply uniformly to compounds of formula (I) as defined in any one of embodiments 1) to 9), 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.

[0033] The term "amino," whether used alone or in combination with other terms, refers to the group -NH2.

[0034] The term "carbonyl," whether used alone or in combination with other terms, refers to the group -C(=O)-.

[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 1-4 -Alkyl groups have 1 to 4 carbon atoms. 1-4 -Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and isobutyl. Substituent R 2 C used for 1-4 -A preferred example of alkyl is methyl. Substituent R 1 C used for 1-3 A preferred example of alkyl is methyl.

[0036] "-C x-y The term "-alkylene-", whether used alone or in combination, refers to the previously defined alkyl group having x to y carbon atoms and bonded bivalently. In particular, the bond site of any bivalently bonded alkyl group is in a 1,1-diyl configuration. 0-y -Alkylene- group When used in combination with substituents, this term means that the substituent is directly bonded to the rest of the molecule (i.e., the -C0-alkyl- group represents a direct bond that causes the substituent to bond to the rest of the molecule), or that it is -C 1-y -This means that the molecule is bonded to the rest of the molecule via an alkylene group. -C 1-y -Examples of alkylene groups include methylene, ethylene, and ethane-1,1-diyl -C 1-2 It is an alkylene group. The group -C≡CC 0-2 Examples of alkylenes include -C≡C-, -C≡C-CH2-, -C≡C-CH2-CH2-, and -C≡C-CH(CH3)-; in particular, -C≡C- and -C≡C-CH(CH3)-. The group -C≡CC 0-2 When it is stated that -alkylene- is substituted with one hydroxyl group, the substitution is -C 1-2 It is understood that this is only possible if an alkylene is present. Such a -C≡CC substituted with a single substituent. 0-2 Examples of alkylene groups include -C≡C-CH(OH)-, -C≡C-CH(OH)-CH2-, -C≡C-CH2-CH(OH)-, -C≡C-CH(CH2OH)-, and -C≡CC(CH3)(OH)-; in particular, -C≡CC(CH3)(OH)-. * -C≡CC 0-2 -Alkilen- ** The single asterisk in the term " * ) indicates the bond site to the pyridinyl ring shown in formula (I), and the two asterisks ( ** ) is R 4 This indicates the connection point to [the specified location].

[0037] The terms "amino-carbonyl" or "carbamoyl," whether used alone or in combination, refer to the group NH2-C(=O)-.

[0038] "C 1-3The term "alkyl-carbonyl," whether used alone or in combination, refers to the previously defined alkyl group in which one hydrogen atom is replaced by a carbonyl group.

[0039] "C 1-3 The term "alkyl-carbonyl-amino," whether used alone or in combination, refers to a single hydrogen atom that is a C atom as defined above. 1-3 - This refers to an amino group that has been replaced with an alkyl-carbonyl group.

[0040] 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. 1-3 -An alkyl group is a hydroxyalkyl group defined earlier, having 1 to 3 carbon atoms. Hydroxy-C 1-3 Examples of alkyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, and 1-hydroxy-1-methylethyl.

[0041] 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 3-7 -Cycloalkyl groups have 3 to 7 carbon atoms. 3-7- Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; in particular, cyclohexyl. The above groups are either unsubstituted or substituted as explicitly defined.

[0042] The term "six-membered heteroaryl," whether used alone or in combination, refers to a six-membered monocyclic aromatic ring having one or two (especially two) ring nitrogen atoms. It has a taste. Examples include pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; in particular pyrimidinyl. The above heteroaryl groups are either unsubstituted or substituted as explicitly defined.

[0043] The term "saturated 5- to 8-membered bridged or spironicyclic hydrocarbon ring system" refers to two hydrocarbon rings sharing one or two carbon atoms, where the total number of carbon atoms in both rings is an integer between 5 and 8. More specifically, - The term "saturated 5- to 8-membered bridged bicyclic hydrocarbon ring system" refers to compounds described by the term "bicyclo[xyz]alkyl, where the total number of carbon atoms is an integer between 5 and 8, and each of "x", "y", and "z" is greater than 0" [i.e., the sum of "x", "y", and "z" is between 3 and 6; the integers "x", "y", and "z" independently indicate the number of carbon atoms in each of the three bridges bonded to two tertiary carbon atoms in descending order (x>y>z)]. Examples of such 5- to 8-membered bridged bicyclic hydrocarbon ring systems include bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.1]heptanyl, and bicyclo[3.2.1]octanyl; in particular, bicyclo[2.2.2]octan-1-yl and bicyclo[1.1.1]pentan-1-yl; - The term saturated 5- to 8-membered spirodicyclic hydrocarbon ring system means a compound described by the term “spiro[xy]alkyl,” where the total number of carbon atoms is an integer between 5 and 8; [where the integers “x” and “y” represent the number of carbon atoms in each of the two carbon rings bonded to one tertiary carbon atom]. For example, the following combinations of [xy] are possible: [2.2], [2.3], [3.3], [3.4], and [3.5]. Examples of such 5- to 8-membered spirodicyclic hydrocarbon ring systems are spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl; in particular, spiro[3.3]heptanyl.

[0044] The dotted lines represent the bonding points of the listed groups to the rest of the molecule. For example, the following groups

[0045] [ka] This represents 1,2,4-oxadiazole-diyl.

[0046] Further aspects of the present invention are described below: 2) One aspect is, - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 This represents 2,2,2-trifluoroethyl; -L- is, -- Optionally substituted with one hydroxyl group * -C≡CC 0-2 -Alkilen- ** (In particular, -C≡C- or -C≡CC(CH3)(OH)-)(asterisk( * ) indicates a bond site to the pyridinyl ring, and two asterisks ( ** ) is R 4 This indicates the connection point to ); or, - oxadiazole-diyl (particularly 1,2,4-oxadiazole-diyl; especially

[0047]

Chemical Formula

[0048] 3) A further embodiment provides that - R 1 is C 1-3 -alkyl (especially methyl); R 2 is C 1-4 -alkyl (especially methyl); R 3 This represents 2,2,2-trifluoroethyl; -L- is, -- Optionally substituted with one hydroxyl group * -C≡CC 0-2 -Alkilen- ** (In particular, -C≡C- or -C≡CC(CH3)(OH)-)(asterisk( * ) indicates a bond site to the pyridinyl ring, and two asterisks ( ** ) is R 4 This indicates the connection point to [the specified location]. It represents; and, R 4 but, -- C substituted with one substituent 3-7 -Cycloalkyl (especially cyclohexyl), wherein the substituent is hydroxy, carbamoyl, or C 1-3 -Selected from alkyl-carbonyl-amino (especially acetyl-amino or ethyl-carbonyl-amino), C 3-7 -Cycloalkyl (especially cyclohexyl); -- Or, an unsubstituted six-membered heteroaryl (especially pyrimidinyl; especially pyrimidine-4-yl) having one or two (especially two) ring nitrogen atoms; Does it represent; - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 This represents 2,2,2-trifluoroethyl; -L- is, -- Oxadiazole-diyl (especially 1,2,4-oxadiazole-diyl; particularly

[0049] [ka] (1 asterisk( * ) indicates a bond site to the pyridinyl ring, and two asterisks ( ** ) is R4 This indicates the connection point to [the specified location]. It represents; and, R 4 but, -- C substituted with one substituent 3-7 -Cycloalkyl (especially cyclohexyl), wherein the substituent is hydroxy, carbamoyl, or C 1-3 -Selected from alkyl-carbonyl-amino (especially acetyl-amino or ethyl-carbonyl-amino), C 3-7 -Cycloalkyl (especially cyclohexyl); -- Or, a saturated 5- to 8-membered bridge or spironicyclic hydrocarbon ring system in which one ring carbon atom (especially in the spironicyclic hydrocarbon ring system) is optionally replaced by a nitrogen atom (in particular, such bridge or spironicyclic hydrocarbon ring system represents bicyclo[2.2.2]octane-1-yl, bicyclo[1.1.1]pentan-1-yl, or 2-azaspiro[3.3]heptan-6-yl), wherein the 5- to 8-membered bridge or spironicyclic hydrocarbon ring system independently comprises one hydroxyl,hydroxy-C 1-3 -Alkyl (especially hydroxymethyl), carbamoyl, C 1-3 -Alkyl-carbonyl-amino (especially acetyl-amino) or C 1-3 Saturated 5- to 8-membered bridged or spirodicyclic hydrocarbon ring systems substituted with alkylcarbonyl (especially acetyl); Does it represent; - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 isopropyl; and, -LR 4However, 2-(4-hydroxy-cyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole- Represents 3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; or, - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 represents 2,2,2-trifluoroethyl; and, -LR 4 This represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazole-5-yl; This relates to compounds according to Embodiment 1).

[0050] 4) Further aspects include: - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 This represents 2,2,2-trifluoroethyl; -L- is, -- Optionally substituted with one hydroxyl group * -C≡CC 0-2-Alkilen- ** (In particular, -C≡C- or -C≡CC(CH3)(OH)-)(asterisk( * ) indicates a bond site to the pyridinyl ring, and two asterisks ( ** ) is R 4 This indicates the connection point to [the specified location]. It represents; and, R 4 but, -- C substituted with one substituent 3-7 -Cycloalkyl (especially cyclohexyl), wherein the substituent is hydroxyl. 3-7 -Cycloalkyl (especially cyclohexyl); or, -- Unsubstituted six-membered heteroaryl compounds having one or two (especially two) ring nitrogen atoms (especially pyrimidinyl; particularly pyrimidine-4-yl); Does it represent; - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 This represents 2,2,2-trifluoroethyl; -L- is, -- Oxadiazole-diyl (especially 1,2,4-oxadiazole-diyl; particularly

[0051] [ka] (1 asterisk( * ) indicates a bond site to the pyridinyl ring, and two asterisks ( ** ) is R 4 This indicates the connection point to [the specified location]. It represents; and, R 4 but, -- C substituted with one substituent 3-7 -Cycloalkyl (especially cyclohexyl), wherein the substituent is hydroxy, carbamoyl, or C 1-3-Selected from alkyl-carbonyl-amino (especially acetyl-amino or ethyl-carbonyl-amino), C 3-7 -Cycloalkyl (especially cyclohexyl); -- Or, a saturated 5- to 8-membered bridge or spironicyclic hydrocarbon ring system in which one ring carbon atom (especially in the spironicyclic hydrocarbon ring system) is optionally replaced by a nitrogen atom (in particular, such bridge or spironicyclic hydrocarbon ring system represents bicyclo[2.2.2]octane-1-yl, bicyclo[1.1.1]pentan-1-yl, or 2-azaspiro[3.3]heptan-6-yl), wherein the 5- to 8-membered bridge or spironicyclic hydrocarbon ring system independently comprises one hydroxyl,hydroxy-C 1-3 -Alkyl (especially hydroxymethyl), carbamoyl, C 1-3 -Alkyl-carbonyl-amino (especially acetyl-amino) or C 1-3 Saturated 5- to 8-membered bridged or spirodicyclic hydrocarbon ring systems substituted with alkylcarbonyl (especially acetyl); Does it represent; - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 isopropyl; and, -LR 4However, 2-(4-hydroxy-cyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole- Represents 3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; or, - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 represents 2,2,2-trifluoroethyl; and, -LR 4 This represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazole-5-yl; This relates to compounds according to Embodiment 1).

[0052] 5) Further aspects include: - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 This represents 2,2,2-trifluoroethyl; -L- is, -- Optionally substituted with one hydroxyl group * -C≡CC 0-2-Alkilen- ** (Especially -C≡C- or -C≡CC(CH3)(OH)-; in particular -C≡C-)(asterisk( * ) indicates a bond site to the pyridinyl ring, and two asterisks ( ** ) is R 4 This indicates the connection point to [the specified location]. It represents; and, -- R 4 However, C substituted with one substituent 3-7 -Cycloalkyl (especially cycloalkyl) C(xyl) and the above substituent is hydroxyl 3-7 -Cycloalkyl (especially cyclohexyl); Does it represent; - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 This represents 2,2,2-trifluoroethyl; -L- is, -- Oxadiazole-diyl (especially 1,2,4-oxadiazole-diyl; particularly

[0053] [ka] (1 asterisk( * ) indicates a bond site to the pyridinyl ring, and two asterisks ( ** ) is R 4 This indicates the connection point to [the specified location]. It represents; and, R 4 but, -- C substituted with one substituent 3-7 -Cycloalkyl (especially cyclohexyl), wherein the substituent is hydroxy, carbamoyl, or C 1-3 -Selected from alkyl-carbonyl-amino (especially acetyl-amino or ethyl-carbonyl-amino), C 3-7 -Cycloalkyl (especially cyclohexyl) [especially, C3-7 -When cycloalkyl represents cyclohexyl, the substituent is attached at the 4-position. -- Or, a saturated 5-8 membered bridged bicyclic hydrocarbon ring system (in particular, such saturated 5-8 membered bridged bicyclic hydrocarbon ring system represents bicyclo[2.2.2]octane-1-yl or bicyclo[1.1.1]pentan-1-yl), wherein the saturated 5-8 membered bridged bicyclic hydrocarbon ring system independently comprises one hydroxyl,hydroxy-C 1-3 -Alkyl (especially hydroxymethyl), carbamoyl or C 1-3 -Saturated 5- to 8-membered bridged bicyclic hydrocarbon ring systems substituted with alkyl-carbonyl-amino (especially acetyl-amino) molecules [in particular, the substituents are bonded to tertiary carbon atoms in the 5- to 8-membered bridged bicyclic hydrocarbon ring system.]; -- Or, a saturated 5- to 8-membered spirodicyclic hydrocarbon ring system in which one ring carbon atom is replaced by a nitrogen atom (in particular, such a saturated 5- to 8-membered spirodicyclic hydrocarbon ring system is 2-azaspiro[3.3]heptan-6-yl); the saturated 5- to 8-membered spirodicyclic hydrocarbon ring system is one C 1-3 -Saturated 5- to 8-membered spironicyclic hydrocarbon ring systems substituted with alkyl-carbonyl (especially acetyl) [in particular, the substituent is bonded to the nitrogen atom]; Does it represent; - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 isopropyl; and, -LR 4However, 2-(4-hydroxy-cyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-aceta Represents mido-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; or, - R 1 C 1-3 - Represents alkyl (especially methyl); R 2 C 1-4 - Represents alkyl (especially methyl); R 3 represents 2,2,2-trifluoroethyl; and, -LR 4 However, this represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazole-5-yl; This relates to compounds according to Embodiment 1).

[0054] 6) Further aspects include R 1 The present invention relates to compounds that follow any one of embodiments 1) to 5) where methyl is represented.

[0055] 7) Further aspects include R 2 The present invention relates to compounds that follow any one of embodiments 1) to 6) where methyl is represented.

[0056] 8) Further aspects include: - R 1 represents methyl; R 2 represents methyl; R 3 represents 2,2,2-trifluoroethyl; and, -LR 4 However, 5-(4-hydroxy-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-3-yl, 3-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-5-yl, 2-(4-hydroxy-cyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2] ox Represents tan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; - R 1 represents methyl; R 2 represents methyl; R 3 isopropyl; and, -LR 4However, 2-(4-hydroxy-cyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole- Represents 3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; or, - R 1 represents methyl; R 2 represents methyl; R 3 represents 2,2,2-trifluoroethyl; and, -LR 4 This represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazole-5-yl; This relates to compounds according to Embodiment 1).

[0057] 9) Further embodiments relate to compounds according to any one of embodiments 1) to 8), wherein the chiral carbon atom supporting the hydroxyl group has the absolute configuration shown in formula (II):

[0058] [ka] 10) Another embodiment relates to a compound according to embodiment 1), selected from the following compounds: trans-4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]cyclohexanol; cis-4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]-cyclohexanol;(R)-(1,3-dimethylazetidine-3-yl)-{5-[5-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-[1,2,4]oxadiazole-3-yl]-pyridine-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol; N-[3-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[1.1.1]penta-1-yl]acetamide; 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octan-1-ol; 2-[5-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-3-yl]-2-methyl-propan-1-ol; 1-[6-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-2-azaspiro[3.3]hepta-2-yl]-etanone; trans-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]-propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]-propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]acetamide; trans-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]acetamide; (R)-(1,3-dimethylazetidine-3-yl)-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-[1,2,4]oxadiazole-5-yl]-pyridine-3-yl}-[4-(2,2,2-trifluoroethyl)-phenyl]-methanol; (R)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-pyrimidine-4-ylbuta-3-in-2-ol; (S)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-pyrimidine-4-ylbuta-3-in-2-ol; trans-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-ylethynyl}cyclohexanol; cis-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-ylethynyl}cyclohexanol; 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide; cis-4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexanecarboxylic acid amide; or, trans-4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexanecarboxylic acid amide.

[0059] 11) Another embodiment relates to a compound according to embodiment 1), selected from the following compounds: trans-4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]cyclohexanol; (R)-(1,3-dimethylazetidine-3-yl)-{5-[5-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-[1,2,4]oxadiazole-3-yl]-pyridine-3-yl}-[4-(2,2,2-trifluoroethyl)-phenyl]-methanol; N-[3-(3-{5-[(R)-(1,3-dimethyl-azetidine-3-yl)-Hyd Roxy-(4-isopropylphenyl)-methyl]-pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[1.1.1]penta-1-yl]-acetamide; 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octan-1-ol; 2-[5-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-3-yl]-2-methyl-propan-1-ol; 1-[6-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-2-azaspiro[3.3]hepta-2-yl]-etanone; trans-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]-propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]acetamide; trans-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]acetamide; (R)-(1,3-dimethylazetidine-3-yl)-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-[1,2,4]oxadiazole-5-yl]-pyridine-3-yl}-[4-(2,2,2-trifluoroethyl)-phenyl]-methanol; (R)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-pyrimidine-4-ylbuta-3-in-2-ol; (S)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-pyrimidine-4-ylbuta-3-in-2-ol; trans-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-ylethynyl}cyclohexanol; cis-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-ylethynyl}cyclohexanol; 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide; or, 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexanecarboxylic acid amide.

[0060] 12) Another embodiment relates to a compound according to embodiment 1), selected from the following compounds: 4-[3-(5-{(R)-(1,3-dimethyl-azetidine-3-yl)-hydroxy -[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]-bicyclo[2.2.2]octane-1-carboxylic acid amide; or, N-{4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]-trans-cyclohexyl}acetamide.

[0061] The present invention relates to compounds of formula (I) as defined in aspect 1), or such compounds further limited by any one of the features of aspects 2) to 9) 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.

[0062] 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.

[0063] 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.

[0064] Any reference to a compound of formula (I) according to aspects 1) to 12) shall, depending on the context, also be understood to refer to a salt of such a compound (especially a pharmaceutically acceptable salt).

[0065] 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.

[0066] Compounds of formula (I) may include compounds having one or more chiral centers, such as one or more chiral carbon atoms, and they may exist in (R)- and (S)- configurations. Compounds of formula (I) may further include compounds having one or more double bonds, and they may exist in Z- and E- configurations, and / or compounds having substituents in the ring system, and they may exist in cis and trans configurations relative to each other. Thus, compounds of formula (I) are mixtures of stereoisomers. They may exist as substances, or preferably in a form enriched with stereoisomers, particularly as essentially pure stereoisomers. Mixtures of stereoisomers may be separated by methods known to those skilled in the art.

[0067] 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). The same applies to compounds described as cis- or trans-stereoisomers, with the necessary modifications.

[0068] 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).

[0069] 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.

[0070] The absolute stereochemical configuration of the compounds of formula (I) disclosed previously or hereafter and / or intermediates in the synthesis of compounds of formula (I) may be determined by methods commonly used in the art, such as obtaining a single crystal of the compound / intermediate and performing X-ray diffraction analysis thereon, similar to the methods applied to the compounds / intermediates disclosed in PCT / EP2021 / 061401.

[0071] Compounds of formula (I) according to embodiments 1) to 12) 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).

[0072] 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.

[0073] 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, then the variable number is It means the integer 1, 2, 3, or 4.

[0074] 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.

[0075] 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.

[0076] 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 juvenile rheumatoid arthritis; polyarticular rheumatoid arthritis; enteropathic arthritis; juvenile Reiter syndrome; ankylosing spondylitis; juvenile ankylosing spondylitis; SEA syndrome; reactive arthritis (reactive arthropathy); psoriatic arthritis; juvenile enteropathic arthritis; polymyalgia rheumatica; enteropathic spondylitis It may be defined as an inflammatory / autoimmune disease, condition, or disorder, encompassing 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; intratraperotoneal abscesses; intra-abdominal abscesses; and / or secondary osteoarthritis from inflammatory diseases.

[0077] 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; colorectal adenoma; colorectal adenocarcinoma; colorectal cancer liver metastasis; hereditary non-polypoid colorectal cancer; esophageal cancer; gastric cancer; advanced gastric cancer; gallbladder cancer; bile duct cancer ;hepatocellular carcinoma;pancreatic cancer including pancreatic adenocarcinoma or ductal adenocarcinoma;pancreatic endocrine tumors;gastrointestinal cancer including 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;oligogliomas;ependymal tumors;anaplastic astrocytoma;pilocytic astrocytoma;craniopharyngioma;spinal cord tumors;brainstem gliomas;atypical teratomas / rhabdomyosarcomas of the central nervous system;medulloblastoma;germ cell tumors of the central nervous system;craniopharyngioma;ependymoma;neuroblastoma;head and neck cancers such as sensory neuroblastoma;cervical cancer 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 Waldenstrom 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 Sarcoma; malignant fibrous histiocytoma of bone; chordoma; sarcoma including soft tissue sarcoma; myeloma;Multiple myeloma; labial cancer; laryngeal cancer; hypopharyngeal carcinoma; tongue cancer; salivary gland carcinoma; cervix carcinoma; uterine cancer; endometrium carcinoma; choriocarcinoma; testicular cancer; urinary carcinoma; bronchial cancer; basal cell tumor; teratoma; retinoblastoma; choroidal melanoma; seminomas; chondrosarcoma; myasarcoma; 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.

[0078] 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; spinal cord disease) Arthritis; 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 (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).

[0079] 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 may be selected; 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).

[0080] When used for the prevention or treatment of cancer, such use is limited to the compounds of formula (I) of the present invention or the compounds of formula (I) disclosed in WO2021219849 (e.g., 2-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl} This includes the use of (S)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-(6-methylpyrimidine-4-yl)-buta-3-in-2-ol; or pharmaceutically acceptable salts thereof) as monotherapy and in combination with (especially in combination with targeted therapy) one or more chemotherapeutic agents and / or radiotherapy and / or targeted therapy.

[0081] The term "radiotherapy" (or "radiation therapy" or "radiation oncology") refers to the prevention of cancer. This refers to the medical use of ionizing radiation in adjunctive therapy and / or treatment; it includes external and internal radiation therapy.

[0082] 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. The compounds of formula (I) of the present invention or the compounds of formula (I) disclosed in WO2021219849 (e.g., 2-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4] Examples of targeted therapies particularly well suited to combination with (xadiazole-5-yl)-piperidine-1-yl]-ethanone; or (S)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-(6-methylpyrimidine-4-yl)-buta-3-in-2-ol; or pharmaceutically acceptable salts thereof) include immunotherapies, especially those targeting programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1.

[0083] 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.

[0084] A compound of formula (I) of the present invention or a compound of formula (I) disclosed in WO2021219849 (e.g., 2-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-piperidine-1-yl]-ethanone; or (S)-4-{5-[ When used in combination with (R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-(6-methylpyrimidine-4-yl)-buta-3-in-2-ol; or its pharmaceutically acceptable salts), 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, icotinib, lapatinib, panitumumab, zalutumumab, nimotuzumab, matuzumab, and cetuximab) and 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-) Anti-PD1 antibodies such as 011), AMP-514 / MEDI0680, PDR001, SHR-1210; REGN2810, BGBA317, PF-06801591, 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, A Tezolizumab (MPDL3280A, RG7446), avelumab (MSB0010718C), durvalumab (MEDI4736); anti-PDL2 antibody (e.g., AMP224); anti-CTLA-4 antibody (e.g., ipilimumab, tremilmumab); anti-lymphocyte activator gene 3 (LAG-3) antibody (e.g., Relatlimab (BMS-986016), IMP701, IMP731, MK-4280, ImmuFact) IMP321); anti-T cell immunoglobulin mucin-3 (TIM-3) antibodies (e.g., MBG453, TSR-022); anti-Ig and T cell immune receptor (TIGIT) antibodies with 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 Tumor-specific antigens such as mimetic proteins and T-cell surface markers Molecules that bind to them (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.

[0085] A compound of formula (I) of the present invention or a compound of formula (I) disclosed in WO2021219849 (e.g., 2-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1, When used in combination with (2,4)oxadiazole-5-yl)-piperidine-1-yl]-ethanone; or (S)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-(6-methylpyrimidine-4-yl)-buta-3-in-2-ol; or a pharmaceutically acceptable salt thereof), an immune checkpoint inhibitor, and in particular those targeting the PD-1 receptor or its ligand PD-L1, is preferred.

[0086] 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.

[0087] As used herein, the terms “cytotoxic chemotherapeutic agent” or “chemotherapeutic agent” mean an active antineoplastic agent that induces apoptosis or cell necrosis.

[0088] The compounds of formula (I) of the present invention or the compounds of formula (I) disclosed in WO2021219849 (e.g., 2-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-yl) When used in combination with (S)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-(6-methylpyrimidine-4-yl)-buta-3-in-2-ol; or its pharmaceutically acceptable salts), 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-based drugs (e.g., cisplatin, carboplatin, or oxaliplatin);3) Antimetabolites (e.g., 5-fluorouracil, floxuridine, pentostatin, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, or pemetrexed);4) Antitumor antibiotics (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C, or mitoxantrone);5) Mitosis 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). Appropriate treatments include cytotoxic agents, such as biological response modifiers, growth inhibitors, antihormonal therapeutic agents, leucovorin, tegafur, and hematopoietic growth factors.

[0089] The compounds of formula (I) of the present invention or the compounds of formula (I) disclosed in WO2021219849 (e.g., 2-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-yl) When used in combination with (S)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-(6-methylpyrimidine-4-yl)-buta-3-in-2-ol; or a pharmaceutically acceptable salt thereof), the preferred cytotoxic chemotherapeutic agent is the alkylating agent (in particular, fotemustine (fo These include temustine, cyclophosphamide, ifosfamide, carmustine, dacarbazine, and their prodrugs, particularly 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] The meaning of the term "prevention" may be understood as "prophylaxis".

[0094] Preparation of Compounds of Formula (I) A further aspect of the present invention is a process for the preparation of a compound of formula (I). Compounds according to formula (I) of the present invention may be prepared from commercially available or known starting materials according to the methods described in the experimental section; by analogous methods; or may be prepared by appropriate modification of the general synthetic routes disclosed in PCT / EP2021 / 061401. The resulting compound may be converted into a salt, in particular a pharmaceutically acceptable salt thereof, by methods known per se.

[0095] Experiment section Abbreviations (used in this section and the preceding portions of the specification): Ac Acetyl anal For analytical use anh Anhydrous aq. Aqueous Boc tert.-Butyloxycarbonyl CC Column chromatography CDI 1,1'-Carbonyldiimidazole DEA Diethylamine DCM Dichloromethane DMF N,N-Dimethylformamide EA Ethyl acetate Et Ethyl eq Equivalent FLIPR Fluorescent imaging plate reader Fluo-8-AM Acetyloxymethyl 2-[N-[2-(acetyloxymethoxy)-2-oxoethyl]-4-[3-(acetyloxymethoxy)-6-oxoxanthen-9-yl]-2-[2-[2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]anilino]acetate g Gram HEK Human embryonic kidney Hex Hexyl h hour Hep Heptane HPLC High Performance Liquid Chromatography HV High Vacuum LC-MS Liquid Chromatography-Mass Spectrometry M Molar Concentration [mol / L] Me Methyl mg Milligram min Minute mL Milliliter nBu n-Butyl org Organic prep Preparative iPr Isopropyl PyBOP (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate rpm Revolutions per Minute RT Room Temperature rxn Reaction sat Saturated SFC Supercritical Fluid Chromatography soln Solution t Time T3P® Propane Phosphonic Anhydride tBu tert-Butyl TEA Triethylamine t R Retention Time THF Tetrahydrofuran

[0096] I. Chemistry The following examples illustrate the preparation of biologically active compounds of the present invention, but do not limit the scope of the present invention in any way.

[0097] General: All temperatures are given in degrees Celsius (°C). Unless otherwise stated, reactions are carried out under an argon atmosphere at RT, in a round-bottom flask equipped with a magnetic stir bar or a sealable tube.

[0098] Qualitative analysis methods used: LC-MS retention times were 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):

[0099] [Table 1] The retention time for chiral HPLC / SFC was obtained using the following elution conditions: I) Chiral HPLC (A): A CHIRALPAK AD-H, 5 μm, 4.6 x 250 mm column was used, temperature-controlled at 25°C. Two elution solvents were used: Solvent A = Hep; Solvent B = EtOH. The elution flow rate was 0.8 mL / min, and the proportion of isocratic solvent was 80% (A) / 20% (B).

[0100] II) Chiral SFC (B): 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 = MeOH. The elution flow rate was 4 mL / min, and the proportion of non-gradient solvents was 90% (A) / 10% (B).

[0101] III) Chiral SFC(C): A CHIRALPAK AD-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 = EtOH. The eluate flow rate was 4 mL / min, and the proportion of non-gradient solvents was 80% (A) / 20% (B).

[0102] IV) Chiral SFC(D): A CHIRALPAK IC, 5 μm, 4.6×250 mm column temperature-controlled at 40°C was used. The two types of elution solvents were as follows: Solvent A = CO₂; Solvent B = iPrOH + 0.1% DEA. The flow rate of the eluate was 4 mL / min, and the proportion of isocratic solvent was 85% (A) / 15% (B).

[0103] V) Chiral SFC (E): A CHIRALPAK IB, 5 μm, 4.6×250 mm column temperature-controlled at 40°C was used. The two types of elution solvents were as follows: Solvent A = CO₂; Solvent B = MeOH + 0.1% DEA. The flow rate of the eluate was 4 mL / min, and the proportion of isocratic solvent was 75% (A) / 25% (B).

[0104] Purification method used: Preparative LC-MS method used: Purification by preparative LC-MS was carried out using the conditions described below.

[0105] I) Prep LC-MS (I): An X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two types of elution solvents were as follows: Solvent A = water + 0.5% formic acid; Solvent B = MeCN. The flow rate of the eluate was 75 mL / min, and the characteristics of the mixing ratio of the elution mixture as a function of time t from the start of elution are summarized in the table below (a linear gradient is used between two consecutive time points):

[0106] 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):

[0107] [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):

[0108] [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):

[0109] [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):

[0110] [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):

[0111] [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):

[0112] [Table 8] VIII) Prep LC-MS (VIII): 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):

[0113] [Table 9] IX) Prep LC-MS(IX): 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):

[0114] [Table 10] X) Prep LC-MS(X) An X-Bridge column (Waters C18, 10 μm OBD, 50 x 150 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):

[0115] [Table 11] XI) Prep LC-MS(XI) 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):

[0116] [Table 12] Preparative chiral SFC and HPLC methods used: Purification by preparative chiral SFC and HPLC was performed under the conditions described below.

[0117] I) Prep chiral HPLC (I): A ChiralPak AD-H (5 μm, 30 x 250 mm) column was used, temperature-controlled at 25°C. The elution solvent was Hep / EtOH 80 / 20, flowed at a rate of 34 mL / min.

[0118] II) Prep Chiral SFC (II): 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.

[0119] III) Prep Chiral SFC (III): A ChiralPak AD-H column (5 μm, 30 x 250 mm) was used, temperature-controlled at 40°C. The elution solvent was CO2 / EtOH 80 / 20, flowed at a flow rate of 160 mL / min.

[0120] IV) Prep Chiral SFC (IV): A ChiralPak IC column (5 μm, 30 x 250 mm) was used, temperature-controlled at 40°C. The elution solvent was CO2 / (iPrOH + 0.1% DEA) 85 / 15, flowed at a flow rate of 160 mL / min.

[0121] V) Prep Chiral SFC (V): A ChiralPak IB column (5 μm, 30 x 250 mm) was used, temperature-controlled at 40°C. The elution solvent was CO2 / MeOH 75 / 25, flowed at a flow rate of 160 mL / min.

[0122] Preparation of the intermediate for formula A2 A2.1 3-(methoxy-methyl-carbamoyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a suspension of 1-Boc-3-methylazetidine-3-carboxylic acid (20 g) and N,O-dimethylhydroxylamine hydrochloride (9.72 g) in DCM (270 mL), DIPEA (54 mL) and T3P® (50% in DCM, 55.5 mL) were sequentially added dropwise while maintaining the temperature at RT in a water bath. The resulting solution was stirred at RT for 1 hour and quenched with semi-saturated aq. NaHCO3. The aqueous phase was further extracted with DCM, and the organic phase was combined, dried over MgSO4, and concentrated under vacuum. The residue was dried under HV to obtain the title compound as a grayish-white solid (22.4 g). LC-MS(A):t R =0.79min;[M+H]+:259.13.

[0123] Production of intermediates for formula A4 A4.1: 3-methyl-3-[4-(2,2,2-trifluoroethyl)-benzoyl]azetidine-1-carboxylic acid tert-butyl ester 1-Bromo-4-(2,2,2-trifluoroethyl)benzene (1.36g) To a solution cooled to -78°C in Et2O (12 mL), tBuLi (1.6 M in pentane, 5.17 mL) was added dropwise under argon while maintaining the internal temperature below -70°C. The resulting mixture was stirred at -78°C for 5 min, and a solution of Weinrebamide A2.1 (1.2 g) in anh THF (12 mL) was added dropwise while maintaining the internal temperature below -70°C. The reaction mixture was stirred for 15 min, quenched with water, and extracted with EA. The organic phases were combined, washed with brine, dried over MgSO4, and evaporated to dryness. The resulting crude material was purified by CC using Biotage® pre-filled cartridge Sfaer Silica D and eluted with Hep / EA to obtain the title compound as a white powder (1.445 g). LC-MS(A):t R =1.05min;[M+H]+:358.07.

[0124] A4.2: 3-(4-isopropyl-benzoyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a solution of 1-bromo-4-isopropylbenzene (10.4 g) in anh THF (100 mL) cooled to -78°C, nBuLi (2.5 M in hexane, 21.2 mL) was added dropwise under argon while maintaining the internal temperature below -70°C. The resulting mixture was stirred at -78°C for 20 min. A solution of Weinrebamide A2.1 (10 g) in anhydrous THF (50 mL) 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 resulting crude material was purified by CC using Biotage® pre-filled cartridge Sfaer Silica D and eluted with Hep / EA to obtain the title compound as a yellow resin (11.7 g). LC-MS(A):t R =1.09min;[M+H]+:318.31.

[0125] Preparation of intermediates for formula A6 To a solution of the ketone of formula A4 (1 eq) and 5-bromonicotinonitrile (1.1-1.3 eq) in anh THF (2.5-5.5 mL / mmol) cooled to -78°C, HexLi (2.3 M in hexane, 1.3-1.4 eq) was added dropwise under argon, while maintaining the internal temperature below -70°C (except for the intermediate of formula A6.1 in which HexLi was replaced with nBuLi in 2.5 M hexane). 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 purified by elution with Hep / EA using Biotage® pre-filled cartridges Sfaer KP-Amino D and / or Sfaer Silica D. If necessary, further purification by prep.LC-MS was performed using the conditions listed in the table below.

[0126] The intermediate of formula A6.1 was obtained as the enantiomer that first eluted the title compound by subsequent purification by prep chiral HPLC(I) (chiral HPLC(A): t R (=6.76 min).

[0127] The intermediate of formula A6.2 was purified by subsequent prep-chiral SFC(II) HPLC, yielding the title compound as the second eluted enantiomer (chiral HPLC(B): t R (=2.21 min).

[0128] [Table 13] Preparation of intermediates for formula A7 TEA (2 eq) was added dropwise to a solution of the intermediate of formula A6 (1 eq) and hydroxylamine hydrochloride (1.5 eq) in DMSO (5.4 mL / mmol). The reaction mixture was stirred in RT for 4.5 to 18 hours and fractionated between EA and water. The organic phase was washed with water and brine, dried over MgSO4, and evaporated to dryness to obtain the crude title compound.

[0129] [Table 14] Preparation of intermediates for formula A8 A8.1: To a solution of 3-hydroxymethyl-bicyclo[1.1.1]pentane-1-carboxylic acid (300 mg) in EtOH (4.6 mL), water (1 mL) and aq. NaOH (10.8 M, 1.3 mL) were added. The reaction mixture was heated to 75 °C and stirred for 1 h 30. After cooling to RT, it was acidified with aq. HCl (1 M) and extracted with EA. The organic phases were combined, dried over MgSO4, and evaporated to dryness to obtain the crude title compound as a white solid (268 mg). 1 H NMR (500MHz, DMSO) δ: 12.24 (s, 1H), 4.54 (t, J=5.6Hz, 1H), 3.37 (d, J=5.5Hz, 2H), 1.77-1.84 (m, 6H).

[0130] A8.2: Trans-4-propionylaminocyclohexanecarboxylic acid A8.2.1: Trans-4-amino-cyclohexanecarboxylic acid methyl ester Methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (500 mg) was treated with a solution of HCl in dioxane (4 M, 5 mL). This solution was stirred in RT for 30 min, and the solvent was evaporated to obtain the desired product as a white solid (380 mg). LC-MS(A):t R =0.34min;[M+H] + :158.15.

[0131] A8.2.2: Trans-4-propionylaminocyclohexanecarboxylic acid methyl ester To a suspension of the intermediate of formula A8.2.1 (190 mg) in THF (2 mL), propionic anhydride (0.14 mL) and TEA (0.41 mL) were added, and the mixture was stirred at 60°C for 2 hours. The solvent was evaporated, and the residue was purified by prep LC-MS(X) to obtain the desired product as a white solid (85 mg). LC-MS(A):t R=0.62min;[M+H] + :214.26.

[0132] A8.2.3 Trans-4-propionylaminocyclohexanecarboxylic acid Lithium hydroxide monohydrate (31 mg) was added to a suspension of the intermediate of formula A8.2.2 (84 mg) in MeOH (3.5 mL), and the mixture was stirred at 65°C for 2.5 hours. After adding another 15 mg of lithium hydroxide monohydrate, the mixture was stirred at 65°C for 16 hours. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified by prep LC-MS(VI) to obtain the desired product as a white powder (66 mg). LC-MS(A):t R =0.49min;[M+H] + :200.31.

[0133] A8.3 3-Acetamido bicyclo[1.1.1]pentane-1-carboxylic acid To a suspension of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate (200 mg) in THF (2 mL), anhydrous acetate (0.12 mL) and TEA (0.47 mL) were added. The reaction mixture was heated to 60 °C and stirred for 1 hour. The reaction mixture was diluted with MeCN and water, and directly purified by prep LC-MS(X+VI) to obtain the desired product as a white solid. It was obtained as a whole (119 mg). Hydrolysis of the methyl ester is thought to have occurred during purification by prep LC-MS under basic conditions (X). LC-MS (A): t R =0.38min;[M+H] + :169.99.

[0134] Preparation of intermediates for formula A9 Step A: A mixture of the intermediate of formula A7 (1 eq), the carboxylic acid of formula A8 (1.5 eq), PyBOP (1.5-3 eq), and TEA (3 eq) in DMF (7.5-8 mL / mmol) was heated to 80°C and stirred for 20 hours. The reaction mixture was cooled to RT and filtered. The filtrate was directly purified by prep LC-MS using the conditions described in the table below to obtain the title compound.

[0135] Step B: The solutions of carboxylic acid (1.5 eq) and CDI (1.5 eq) of formula A8 in DMSO (4 mL / mmol A7) were stirred at RT for 30 minutes. The mixture was then transferred to the solution of the intermediate (1 eq) of formula A7 in DMSO (1.5 mL / mmol). The mixture was stirred at RT for another 30 minutes, then heated to 85°C and stirred for 8 hours. The reaction mixture was diluted with MeCN, filtered through a syringe filter, and purified directly by prep LC-MS (see the table below).

[0136] [Table 15]

[0137] [Table 16] Preparation of intermediates for formula A10 To a solution of the intermediate of formula A9 (1 eq) in dioxane (5-8 mL / mmol), HCl (4 M in dioxane, 8.9 eq) was added, and the reaction mixture was stirred at RT for 18 hours. If necessary to complete the reaction, additional amounts of HCl (4 M in dioxane) were added. The reaction mixture was evaporated to dryness to obtain the crude hydrochloride salt.

[0138] [Table 17] Preparation of the intermediate of formula B1 B1.1: 5-{(R)-(1-tert-butoxycarbonyl-3-methylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}nicotinic acid To a suspension of the intermediate of formula A6.1 (450 mg) in EtOH (5.75 mL), aq. NaOH (1 M, 5.75 mL) was added. The mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated under vacuum (to half volume), diluted with water, and treated with aq. citric acid (10%) to a pH of ~3. The mixture was extracted with EA (3 times), the organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum. The residue was suspended in EA and filtered. The filtrate was concentrated to dryness to obtain the desired product as a white solid (540 mg). LC-MS(A):t R =0.88min;[M+H] + :480.95.

[0139] Preparation of the intermediate for formula B2 B2.1: N',3-dihydroxy-2,2-dimethylpropanimidoamide To a solution of 3-hydroxy-2,2-dimethylpropanenitrile (200 mg) in EtOH (14 mL), hydroxylamine hydrochloride (425 mg) and K2CO3 (1.12 g) were added. The mixture was heated to 85°C and stirred for 21 hours. The reaction mixture was filtered and washed with EtOH. The filtrates were combined, concentrated under vacuum, suspended in n-heptane, and then concentrated again to obtain the title compound as a white, slightly viscous solid (280 mg). LC-MS(A):t R =0.20min;[M+H] + :133.37.

[0140] B2.2: N'-Hydroxy-3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-carboximidoamide (carboximidamide) To a solution of 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carbonitrile (250 mg) in EtOH (4.3 mL), hydroxylamine hydrochloride (325 mg) and K2CO3 (1.07 g) were added. The reaction mixture was heated to 80°C and stirred for 16 hours. After cooling to RT, the reaction mixture was filtered, concentrated, and dried under HV to obtain the desired product as a white, viscous foam (324 mg). LC-MS(A):t R=0.22min;[M+H] + :157.19.

[0141] Preparation of the intermediate for formula B3 B3.1: 3-{(R)-hydroxy-{5-[3-(2-hydroxy-1,1-dimethyl-ethyl)-[1,2,4]oxadiazole-5-yl]-pyridine-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a solution of the intermediate of formula B1.1 (50 mg) in DMF (1 mL), DIPEA (40 mg) and PyBOP (83 mg) were added. After stirring for 15 mins in RT, the solution of the intermediate of formula B2.1 (28 mg) in DMF (0.3 mL) and K3PO4 (90 mg) were added. The mixture was heated at 85°C for 16 hours. The reaction mixture was diluted with MeCN and purified directly by prep LC-MS(VI) to obtain the desired product as a white solid (34 mg). LC-MS(A):t R =1.01min;[M+H] + :577.14.

[0142] B3.2: 3-{(R)-hydroxy-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-[1,2,4]oxadiazole-5-yl]-pyridine-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a solution of intermediate B1.1 (50 mg) in DMF (1 mL), DIPEA (40 mg) and PyBOP (83 mg) were added. After stirring for 20 mins in RT, a solution of intermediate B2.2 (33 mg) in DMF (0.7 mL) and K3PO4 (90 mg) were added. The mixture was heated at 85°C for 16 hours. The reaction mixture was diluted with MeCN and purified directly by prep LC-MS(III)+(I) to obtain the desired product as a white solid (15 mg). LC-MS(A):t R =0.99min;[M+H] + :601.26.

[0143] Production of intermediates for formula B4 B4.1: 2-[5-(5-{(R)-hydroxy-(3-methylazetidine-3-yl)-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-3-yl]-2-methyl-propane-1-ol The intermediate of formula B3.1 (34 mg) was treated with a solution of HCl in dioxane (4 M, 1.0 mL). After stirring for 1 hour under RT, the reaction mixture was concentrated to dryness, and the desired product was obtained as a yellow foam (39 mg). LC-MS(A):t R =0.69min;[M+H] + :477.28.

[0144] B4.2: (R)-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-[1,2,4]oxadiazole-5-yl]-pyridine-3-yl}-(3-methyl-azetidine-3-yl)-[4-(2,2,2-trifluoroethyl)-phenyl]-methanol The intermediate of formula B3.2 (15 mg) was treated with a solution of HCl in dioxane (4 M, 0.3 mL). After stirring for 1 hour under RT, the reaction mixture was concentrated to dryness, and the desired product was obtained as a white solid (14 mg). LC-MS(A):t R =0.69min;[M+H] + :501.07.

[0145] Preparation of the intermediate of formula C1 C1.1: 3-[(R)-(5-bromopyridine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized using the intermediate of formula A4.2 and 3,5-dibromopyridine as starting materials, following the procedure described for the intermediate of formula A6. Subsequent chiral separation using prep chiral SFC(III) yielded the title compound as the first eluted enantiomer. LC-MS(A):t R =1.12min;[M+H]+ :475.09; Chiral SFC(C):t R = 1.41 min.

[0146] Preparation of the intermediate of formula C2 C2.1: (R)-(5-bromopyridine-3-yl)-(4-isopropylphenyl)-(3-methylazetidine-3-yl)-methanol The title compound was synthesized using the intermediate of formula C1.1 as the starting material, following the procedure described for intermediate A10. LC-MS(A):t R =0.74min;[M+H] + :375.02.

[0147] Preparation of intermediates for formula C3 C3.1: (R)-(5-bromopyridine-3-yl)-(1,3-dimethylazetidine-3-yl)-(4-isopropylphenyl)-methanol The title compound was synthesized using the intermediate of formula C2.1 as the starting material, following the procedure (Procedure A) described in Examples 1 to 9. LC-MS(A):t R =0.75min;[M+H] + :389.06.

[0148] Preparation of intermediates for formula C4 C4.1: (R)-or (S)-2-pyrimidine-4-ylbuta-3-in-2-ol C4.1.1: Pyrimidine-4-carboxylic acid methoxymethylamide To a suspension of pyrimidine-4-carboxylic acid (500 mg) in DCM (50 mL), N,O-dimethylhydroxylamine hydrochloride (413 mg), DIPEA (2.37 mL), and T3P® (50% in DCM, 1.93 mL) were sequentially added. The resulting solution was stirred in RT for 18 hours and quenched with sat.aq.NaHCO3. The aqueous phase was further extracted with DCM, the organic phase was combined, washed with brine, dried over MgSO4, and concentrated under vacuum. The resulting crude material was then placed in a Biotage® pre-filled cartridge. The title compound was purified by elution with DCM / MeOH using Silica D, and then purified by CC to obtain a colorless resin (500 mg). LC-MS(A):t R =0.41min;[M+H] + :168.08.

[0149] C4.1.2: 1-Pyrimidine-4-yl-ethanone To a solution of the intermediate of formula C4.1.1 (500 mg) in anh THF (7.5 mL) cooled to -78°C, MeMgBr (3 M in Et2O, 2 mL) was added dropwise under argon. The reaction mixture was stirred in RT for 15 min, quenched with semi-saturated aq.NH4Cl, and extracted with DCM. The organic phases were combined, dried over MgSO4, and evaporated to dryness. The resulting crude material was purified by CC using a Biotage® pre-filled cartridge Sfaer Silica D by elution with DCM / MeOH to obtain the title compound as a grayish-white solid (260 mg). LC-MS(A):t R =0.46min; 1 H NMR (400MHz, CDCl3) δ: 9.39 (s, 1H), 9.00 (d, J=4.6Hz, 1H), 7.92 (d, J=4.7Hz, 1H), 2.75 (s, 3H).

[0150] C4.1.3: (R)-or (S)-2-pyrimidine-4-ylbuta-3-in-2-ol To a solution of trimethylsilylacetylene (267 mg) cooled to 0°C in anh THF (3.5 mL), HexLi (2.3 M in hexane, 1.16 mL) was added dropwise under argon while maintaining the temperature below 5°C. The reaction mixture was stirred at 0°C for 1 hour, and the intermediate of formula C4.1.2 (260 mg) in anh THF (1.5 mL) was added dropwise at 0°C. The reaction mixture was stirred for 19.5 hours while slowly raising the temperature to RT. It was quenched by adding MeOH (5 mL), and K2CO3 (294 mg) was added. After stirring at RT for 30 minutes, the reaction mixture was filtered, diluted with MeOH and water, and purified by prep LC-MS(III). Subsequent chiral separation using prep chiral SFC(IV) yielded the title compound as the first eluting enantiomer. LC-MS(A):t R =0.44min;[M+H] + :149.14; Chiral SFC(D):t R = 1.42 min. The second enantiomer to elute had the following retention time: chiral SFC(D): t R = 1.81 min.

[0151] Manufacturing of the Examples To a solution of intermediate (1 eq) of formula A10 or B4 in anh-dioxane (18-25 mL / mmol), DIPEA (2-3 eqs), formaldehyde (37% solution in H2O, 1.5-3.5 eqs), and NaBH(OAc)3 (1.5-2.6 eqs) were added. The reaction mixture was stirred at RT for 15 min to 18 h, quenched with aq. 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 described in the table below.

[0152] The compound from Example 8 was further purified with prep chiral SFC(V) to obtain a single cis or trans isomer. The compound from Example 8 was the second isomer to elute (chiral SFC(E):t R It was isolated at t = 2.23 min). The first isomer to elute was t at 1.84 min. R It had a value.

[0153] [Table 18] A mixture of the intermediate of formula C3.1 (1 eq), the alkyne of formula C4 (1.3 eq), CuI (0.025 eq), tetrakis(triphenylphosphine)palladium (0) (0.1-0.4 eq), and pyrrolidine (3.5-5 eq) in anh THF (9.7-15.6 mL / mmol) was flushed with argon, heated at 80°C, and stirred for 30 min to 1.5 h. The reaction mixture was cooled to RT, diluted with MeOH and water, filtered, and purified by prep LC-MS under the conditions shown in the table below. 4-ethynylcyclohexane-1-ol is commercially available and received as a 3:7 mixture of cis / trans isomers. After cross-coupling, the cis / trans isomers could be separated by prep LC-MS.

[0154] [Table 19] Preparation of Example 13: 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide 13.1: 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester To a suspension of the intermediate of formula A10.3 (350 mg) in dioxane (3.5 mL), DIPEA (0.17 mL), aq. formaldehyde (37 wt.%, 0.13 mL), and NaBH(OAc)3 (163 mg) were added. The yellow suspension was stirred at RT for 30 min. The mixture was then treated with aq. NaHCO3 and extracted twice with EA. The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to obtain a yellow oil, which was purified by prep LC-MS(IV) to obtain the desired product as a white powder (230 mg). LC-MS(A):t R =0.89min;[M+H] + :545.15.

[0155] 13.2: 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid To a solution of the intermediate of formula A13.1 (230 mg) in MeOH (5 mL), LiOH.H2O (35 mg) was added, and the mixture was stirred at 65°C for 2 hours. To complete the conversion, LiOH.H2O was added two more times (30 mg and 15 mg respectively), and the mixture was stirred further at 65°C for 5 hours and 1 hour, respectively. After cooling to RT, the mixture was filtered, and the solvent was evaporated. The residue was purified by prep LC-MS(VI) to obtain the desired product as a white powder (166 mg). LC-MS(A):t R =0.80min;[M+H] + :531.28.

[0156] 13.3: 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide DIPEA (20 mg) was added to a solution of the intermediate of formula 13.2 (25 mg) and HATU (17 mg) in DMF (1 mL). After stirring at RT for 5 minutes, a solution of ammonium chloride (2.8 mg) in DMF (1 mL) was added, and the reaction mixture was stirred at RT for 1 hour. The mixture was diluted with MeCN and water, and purified directly by prep LC-MS(III) to obtain the desired product as a white powder (7.5 mg). LC-MS(A):t R =0.74m in;[M+H] + :530.11.

[0157] Preparation of Example 14: 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexanecarboxylic acid amide 14.1: trans-4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexanecarboxylic acid methyl ester To a suspension of the intermediate of formula A10.9 (45 mg) in dioxane (0.5 mL), DIPEA (21 mg), aq. formaldehyde (37 wt.%, 24 mg) and NaBH(OAc)3 (27 mg) were added. The yellow suspension was stirred at RT for 30 min. The mixture was then treated with aq. NaHCO3 and extracted twice with EA. The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to obtain a yellow oil, which was purified by prep LC-MS(XI) to obtain the desired product as a white powder (28 mg). LC-MS(A):t R =0.84min;[M+H] + :519.29.

[0158] 14.2: 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexanecarboxylic acid LiOH·H2O (4.5 mg) was added to a suspension of the intermediate of formula 14.1 (28 mg) in MeOH (0.5 mL). The mixture was stirred at RT for 16 hours. Lithium hydroxide monohydrate (4.5 mg) was further added, and the mixture was stirred at 85°C for 4 hours. The reaction mixture was filtered, the solvent evaporated, and the crude product was purified by prep LC-MS(VI) to obtain the desired product as a white powder (21 mg). Due to partial isomerization, a mixture of cis and trans isomers was obtained. LC-MS(A):t R =0.76min;[M+H] + :505.33.

[0159] 14.3: 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexanecarboxylic acid amide DIPEA (17 mg) was added to a solution of the intermediate of formula 14.2 (21 mg) and HATU (15 mg) in DMF (1 mL). After stirring at RT for 5 minutes, a solution of ammonium chloride (2.5 mg) in DMF (1 mL) was added, and the reaction mixture was stirred at RT for 1 hour. The mixture was diluted with MeCN and water, and purified directly by prep LC-MS(III) to obtain the desired product as a white powder (10 mg). LC-MS(A):t R =0.72min;[M+H] + :504.36.

[0160] Preparation of Example 15: 4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]-bicyclo[2.2.2]octane-1-carboxylic acid amide 15.1: 5-{(R)-hydroxy-(3-methylazetidine-3-yl)-[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}nicotinonitrile as an HCl salt The title compound was synthesized using the intermediate of formula A6.1 as the starting material, following the procedure described for the intermediate of formula B4.1. LC-MS(A):t R =0.67min;[M+H] + :361.99.

[0161] 15.2: 5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy -[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}nicotinonitrile The title compound was synthesized using the intermediate of formula 15.1 as the starting material, following the procedure described for the intermediate of formula 14.1. LC-MS(A):t R =0.68min;[M+H] + :376.04.

[0162] 15.3: 5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}-N-hydroxy-nicotinamidine The title compound was synthesized using the intermediate of formula 15.2 as the starting material, following the procedure described for the intermediate of formula A7. LC-MS(A):t R =0.52min;[M+H] + :409.06.

[0163] 15.4: 4-Carbamoyl-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester The title compound was synthesized using 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid as the starting material, following the procedure described for the intermediate of formula 14.3. LC-MS(A):t R =0.59min;[M+H] + :212.13.

[0164] 15.5: 4-Carbamoyl-bicyclo[2.2.2]octane-1-carboxylic acid as a lithium salt To a solution of intermediate 15.4 (175 mg) in THF (2.4 mL), MeOH (0.8 mL), and water (0.8 mL), LiOH·H2O (105 mg) was added, and the reaction mixture was stirred at 50°C for 1 hour. The crude product was obtained as a white powder (238 mg) by evaporation to dryness. LC-MS(A):t R =0.43min;[M+H] + :198.18.

[0165] 15.6: 4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]-bicyclo[2.2.2]octane-1-carboxylic acid amide To a solution of intermediate 15.3 (30 mg) in DMF (1.4 mL), intermediate 15.5 (21 mg), DIPEA (40 mg), and HATU (48 mg) were added. After stirring for 40 mins in RT, the reaction mixture was heated overnight at 60°C. The reaction mixture was diluted with SiO2 and washed with 1 M NaOH. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by prep LC-MS(III) to obtain the desired product as a white solid (18 mg). LC-MS(A):t R =0.72min;[M+H] + :570.12.

[0166] Preparation of Example 16: N-{4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]-trans-cyclohexyl}acetamide 16.1: {4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]-cyclohexyl}carbamate tert-butyl ester The title compound was synthesized using Boc-trans-4-aminocyclohexanecarboxylic acid and intermediate 15.3 as starting materials, following the procedure described for the intermediate of formula 15.6. LC-MS(A):t R =0.86min;[M+H] + :616.16.

[0167] 16.2: (R)-{5-[5-(trans-4-amino-cyclohexyl)-[1, 2,4]Oxadiazole-3-yl]-pyridine-3-yl}-(1,3-dimethylazetidine-3-yl)-[4-(2,2,2-trifluoroethyl)-phenyl]-methanol The title compound was synthesized using the intermediate of formula A16.1 as the starting material, following the procedure described for the intermediate of formula B4.1. LC-MS(A):t R =0.58min;[M+H] + :516.09.

[0168] 16.3: N-{4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]-trans-cyclohexyl}acetamide To a solution of intermediate 16.2 (12 mg) and triethylamine (13 μL) in CH2Cl2, acetyl chloride (6 μL) was added at 0°C. The reaction mixture was stirred at 0°C for 30 min and then at rt for 1 hour. The reaction mixture was diluted with CH2Cl2, the organic phase was washed with sat.aq.NaHCO3, and the mixture was concentrated under vacuum. The crude product was dissolved in MeOH, K2CO3 (37 mg) was added, and the mixture was stirred overnight at rt. The organic phase was washed with sat.aq.NaHCO3 and brine, dried over MgSO4, and concentrated under vacuum to obtain the title compound as a yellowish solid (9 mg). LC-MS(A):t R =0.73min;[M+H] + :558.09.

[0169] 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 the same compound. 50 If the value was calculated several times, the average value is shown. The data is shown in the table below.

[0170] Table 20

Claims

1. Compound of formula (I) or its pharmaceutically acceptable salt 【Chemistry 1】 (In the formula, - R １ is C １－３ - Represents alkyl; R ２ is C １－４ - Represents alkyl; R ３ represents 2,2,2-trifluoroethyl; -L- is, -- optionally substituted with 1 hydroxy ＊ -C≡C-C ０－２ -alkylene- ＊＊ (asterisk ( ＊ ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ＊＊ ) indicates the point of attachment to R ４ ); or, -- Oxadiazole-diyl; It represents; and, R ４ teeth, -- C ３－７ - Cycloalkyl; -- A saturated 5- to 8-membered bridged or spirodicyclic hydrocarbon ring system in which one ring carbon atom is optionally replaced by a nitrogen atom; Or, -- A six-membered heteroaryl having one or two ring nitrogen atoms; It represents; R ４ These are independently unsubstituted or have one hydroxyl,hydroxy-C molecule. １－３ - Alkyl, carbamoyl, C １－３ -Alkyl-carbonyl-amino or C １－３ Substituted with an alkyl-carbonyl group; Or, - R １ is C １－３ - Represents alkyl; R ２ is C １－４ - Represents alkyl; R ３ represents isopropyl; and, -L-R ４ These are 2-(4-hydroxycyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl, and 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole Represents ru-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; Or, - R １ is C １－３ - Represents alkyl; R ２ is C １－４ - Represents alkyl; R ３ represents 2,2,2-trifluoroethyl; and, -L-R ４ represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazole-5-yl.

2. - R １ C １－３ - Represents alkyl; R ２ C １－４ - Represents alkyl; R ３ represents 2,2,2-trifluoroethyl; -L- is, -- Optionally substituted with one hydroxyl group ＊ -C≡C-C ０－２ -Alkilen- ＊＊ (asterisk( ＊ ) indicates a bond site to the pyridinyl ring, and two asterisks ( ＊＊ ) is R ４ It indicates the connection point to; or, -- Oxadiazole-diyl; It represents; and, R ４ but, -- C substituted with one substituent ３－７ - A cycloalkyl group, wherein the substituents are hydroxy, carbamoyl and C １－３ -Selected from alkyl-carbonyl-amino, C ３－７ - Cycloalkyl; -- A saturated 5- to 8-membered bridge or spironicyclic hydrocarbon ring system in which one ring carbon atom is optionally replaced by a nitrogen atom, and the 5- to 8-membered bridge or spironicyclic hydrocarbon ring system independently contains one hydroxy,hydroxy-C １－３ - Alkyl, carbamoyl, C １－３ -Alkyl-carbonyl-amino or C １－３ Saturated 5- to 8-membered crosslinked or spirodicyclic hydrocarbon ring systems substituted with alkyl-carbonyl groups; Or, -- Unsubstituted six-membered heteroaryl compounds having one or two ring nitrogen atoms; To represent; or - R １ C １－３ - Represents alkyl; R ２ C １－４ - Represents alkyl; R ３ This represents isopropyl; and, -L-R ４ However, 2-(4-hydroxycyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carb (moyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octane-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl) )-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; Or, - R １ C １－３ - Represents alkyl; R ２ C １－４ - Represents alkyl; R ３ represents 2,2,2-trifluoroethyl; and, -L-R ４ This represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazole-5-yl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. - R １ C １－３ - Represents alkyl; R ２ C １－４ - Represents alkyl; R ３ represents 2,2,2-trifluoroethyl; -L- is, -- Optionally substituted with one hydroxyl group ＊ -C≡C-C ０－２ -Alkilen- ＊＊ (asterisk( ＊ ) indicates a bond site to the pyridinyl ring, and two asterisks ( ＊＊ ) is R ４ (Indicates the connection point to ); It represents; and, R ４ but, -- C substituted with one substituent ３－７ - A cycloalkyl group, wherein the substituent is hydroxyl, C ３－７ - Cycloalkyl; or, -- Unsubstituted six-membered heteroaryl compounds having one or two ring nitrogen atoms; To represent; or - R １ C １－３ - Represents alkyl; R ２ C １－４ - Represents alkyl; R ３ represents 2,2,2-trifluoroethyl; -L- is, -- Oxadiazole-diyl; It represents; and, R ４ but, -- C substituted with one substituent ３－７ - A cycloalkyl group, wherein the substituents are hydroxy, carbamoyl and C １－３ -Selected from alkyl-carbonyl-amino, C ３－７ - Cycloalkyl; or, -- A saturated 5- to 8-membered bridge or spironicyclic hydrocarbon ring system in which one ring carbon atom is optionally replaced by a nitrogen atom, and the 5- to 8-membered bridge or spironicyclic hydrocarbon ring system independently contains one hydroxy,hydroxy-C １－３ - Alkyl, carbamoyl, C １－３ -Alkyl-carbonyl-amino or C １－３ Saturated 5- to 8-membered crosslinked or spirodicyclic hydrocarbon ring systems substituted with alkyl-carbonyl groups; To represent; or - R １ C １－３ - Represents alkyl; R ２ C １－４ - Represents alkyl; R ３ represents isopropyl; and, -L-R ４ However, 2-(4-hydroxycyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carb (moyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octane-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl) )-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; Or, - R １ C １－３ - Represents alkyl; R ２ C １－４ - Represents alkyl; R ３ represents 2,2,2-trifluoroethyl; and, -L-R ４ represents 3-(2-hydroxy-1,1-dimethylethyl)-1,2,4-oxadiazol-5-yl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ is a methyl compound; the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R ２ is a methyl compound; the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. - R １ represents methyl; R ２ represents methyl; R ３ represents 2,2,2-trifluoroethyl; and, -L-R ４ However, 5-(4-hydroxycyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-3-yl, 3-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-5-yl, 2-(4-hydroxycyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octa Represents 1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; or - R １ represents methyl; R ２ represents methyl; R ３ This represents isopropyl; and, -L-R ４ However, 2-(4-hydroxycyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[ 1.1.1]pentan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl It represents either 1,2,4-oxadiazole-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; Or, - R １ represents methyl; R ２ represents methyl; R ３ represents 2,2,2-trifluoroethyl; and, -L-R ４ This represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazole-5-yl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. R １ represents methyl; R ２ represents methyl; R ３ isopropyl; and -L-R ４ However, 2-(4-hydroxycyclohexyl)-ethin-1-yl, 3-hydroxy-3-(pyrimidine-4-yl)-buta-1-in-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl, 5-(3-acetamide-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazole This represents ru-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazole-3-yl, 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazole-3-yl, or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazole-3-yl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. R １ represents methyl; R ２ represents methyl; R ３ isopropyl; and -L-R ４ This represents 5-(4-acetamide-cyclohexyl)-1,2,4-oxadiazole-3-yl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. 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: 【Chemistry 2】 (In formula (II), L, R1, R2, R3, and R4 are as defined in claim 1.)

10. The chiral carbon atom supporting the hydroxyl group has the absolute configuration shown in formula (III); Claim 8 The compounds listed or their pharmaceutically acceptable salts: 【Transformation 3】 (In formula (III), L, R1, R2, R3, and R4 are as defined in claim 8.)

11. trans-4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]cyclohexanol; cis-4-[3-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-5-yl]cyclohexanol; (R)-(1,3-dimethylazetidine-3-yl)-{5-[5-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-[1,2,4]oxadiazole-3-yl]-pyridine-3-yl}-[4-(2,2,2-trifluoroethyl)-phenyl]-methanol; N-[3-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[1.1.1]penta-1-yl]acetamide; 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octan-1-ol; 2-[5-(5-{(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-[4-(2,2,2-trifluoroethyl)-phenyl]-methyl}pyridine-3-yl)-[1,2,4]oxadiazole-3-yl]-2-methyl-propan-1-ol; 1-[6-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-2-azaspiro[3.3]hepta-2-yl]-ethanone; trans-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl) [Hydroxy-(4-isopropylphenyl)-methyl]-pyridine-3-yl]-[1,2,4]oxadiazole-5-yl)-cyclohexyl]-acetamide; trans-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]acetamide; (R)-(1,3-dimethylazetidine-3-yl)-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]penta-1-yl)-[1,2,4]oxadiazole-5-yl]-pyridine-3-yl}-[4-(2,2,2-trifluoroethyl)-phenyl]-methanol; (R)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-pyrimidine-4-ylbuta-3-in-2-ol; (S)-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-2-pyrimidine-4-ylbuta-3-in-2-ol; trans-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-ylethynyl}cyclohexanol; cis-4-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-ylethynyl}cyclohexanol; 4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide; cis-4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexanecarboxylic acid amide; Or, trans-4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexanecarboxylic acid amide; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. cis-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]acetamide; or, trans-N-[4-(3-{5-[(R)-(1,3-dimethylazetidine-3-yl)-hydroxy-(4-isopropylphenyl)-methyl]pyridine-3-yl}-[1,2,4]oxadiazole-5-yl)-cyclohexyl]acetamide; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, and at least one pharmaceutically acceptable carrier.

14. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

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

16. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer.

17. An agent for the prevention or treatment of cancer; or inflammatory and / or autoimmune diseases, conditions, or disorders, comprising as an active ingredient a compound described in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

18. Rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; psoriasis; Psoriatic arthritis; Inflammatory skin disorders, rosacea; Crohn's disease; Ulcerative colitis; irritable bowel syndrome; For use in the treatment or prevention of inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjögren's syndrome; autoimmune hepatitis; primary sclerosing cholangitis; 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; endometriosis; meibomian gland dysfunction; or graft-versus-host disease, the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

19. 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; Gastrointestinal stromal tumor; Pancreatic cancer; Prostate cancer; Leukemia; A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of acute myeloid leukemia; ovarian cancer; esophageal cancer; mesothelioma; neuroblastoma; sarcoma; high-grade osteosarcoma; astrocytoma; myeloma; urothelial carcinoma; 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; or esophagogastric junction cancer.

20. Psoriasis; psoriatic arthritis; rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; Inflammatory skin disorders; rosacea; Crohn's disease; Ulcerative colitis; irritable bowel syndrome; A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjögren's syndrome; autoimmune hepatitis; or primary sclerosing cholangitis.

21. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of lymphoma; T-cell lymphoma; brain cancer; glioma; glioblastoma; breast cancer; colorectal cancer; hepatocellular carcinoma; renal cell carcinoma; lung cancer; or gastric cancer.

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