CCR6 receptor modulators

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 pharma- ceutically acceptable salts thereof and their use as CCR6 receptor modulators in the treatment or prevention of various diseases, conditions or disorders ameliorated by modulation of said receptor. The invention further relates to related aspects such as pharmaceutical compositions comprising one or more compounds of formula (I) and methods for preparing said compounds. [Background technology]

[0002] Chemokine receptors comprise a family of G protein-coupled receptors (GPCRs) that recognize and bind peptidergic chemokine ligands. The primary function of chemokine receptors and their ligands is to trigger 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 activation of integrin molecules on the surface of immune cells, allowing for strong adhesion to activated endothelium and facilitating migration from the blood into inflamed 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 expressed primarily on effector CD4+ T helper cells, but also on B cells, CD8+ cytotoxic T cells, regulatory T cells (Tregs), immature dendritic cells (DCs), and type 3 innate lymphoid cells (ILC3s) (Cua DJ, Nat Rev Immunol. 2010 Jul;10(7):479-89. doi:10.1038 / nri2800). CCR6 binds to the chemokine CCL20 (Chemokine (CC motif) ligand 20) (Greaves DR, J Exp Med. 1997 Sep 15;186(6):837-44. doi:10.1084 / jem.186.6.837.).CCL20 is also called macrophage inflammatory protein 3a (MIP-3a), liver and activation-regulated chemokine (LARC) or Exodus-1 (Schutyser E, Cytokine Growth Factor Rev. 2003 Oct;14(5):409-26. doi:10.1016 / s1359-6101 (03)00049-2). CCR6 / CCL20 interaction defines humoral responses in the intestinal mucosa and is required for lymphocyte homeostasis in the small intestinal mucosa (Cook DN, Immunity. 2000 May;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, and CCL20 expressed in Peyer's patches guides CCR6+lgA+ B cells to the mucosa, where secretory IgA is released into the intestinal lumen (Lin YL, Front Immunol, 2017;8:805.doi:10.3389 / fimmu.2017.00805; Reboldi A, Science. 2016 May 13;352(6287):aaf4822.doi:10.1126 / science.aaf4822). Under inflammatory conditions, expression of CCL20 is increased in both endothelial and epithelial cells (Harper EG, J Invest Dermatol. 2009 Sep;129(9):2175-83. doi:10.1038 / jid.2009.65; PLoS One. 2015;10(11):e0141710. doi:10.1371 / journal.pone.0141710) and. In tissue fibroblasts (Hattori T, Mediators Inflamm. 2015;2015:436067. doi:10.1155 / 2015 / 436067), it is strongly upregulated by proinflammatory cytokines including IL-17A, TNFa, and IL-1b. Expression of interleukin (IL)-17A is restricted to cells expressing the transcription factor RORgt (Cell. 2006 Sep 22;126(6):1121-33. doi:10.1016 / j.cell.2006.07.035). Expression of IL-17A has been shown to segregate with expression of CCR6 on human T cells (Singh SP, J Immunol. 2008 Jan 1;180(1):214-21. doi:10.4049 / jimmunol.180.1.214; Nat Immunol. 2007 Jun;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. 2014 Mar 15;192(6):2564-75. doi:10.4049 / jimmunol.1302190), thus explaining the co-expression of IL-17A and CCR6 in RORgt+ cell types.

[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 to target 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 cyclobutenediones for use in the treatment of chemokine / CCR6-related diseases. WO2019 / 136370 teaches a method for treating certain types of psoriasis. WO2019 / 147862 proposes azetidine derivatives that may be used as chemokine modulators. WO2021219849 relates to certain CCR6 receptor modulators.

[0004] Furthermore, WO1999 / 43664 discloses certain pyrrolidinones with 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. 2019 Jun 15;29(12):1463-1470.doi:10.1016 / j.bmcl.2019.04.021) relate to modulators of the RORyt receptor that may be used to treat 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 enhancers. US3458635 teaches certain pyrrolidines that may be used to treat depression. GB1304650 discloses antispasmodic pyrrolidines. US3479370, US3 Nos. 489769, 3499002, 3542807 and 3651085 relate to certain pyrrolidines having analgesic / sedative activity.

[0005] The CCR6 modulating agents of the present invention, alone or in combination, are believed to be useful in treating or preventing the following diseases or disorders: Rheumatoid arthritis (RA) causes chronic inflammation of the joints, and chemokines control the infiltration of the inflamed synovium 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. 2007 Nov. 26;204(12):2803-12.doi:10.1084 / jem.20071397; Matsui T, Clin Exp Immunol. 2001 Jul;125(1):155-61.doi:10.1046 / j.1365-2249.2001.01542.x). In patients with RA, CCR6+ Th cells have been found in the inflamed synovium, and in patients with early RA, an increased proportion of peripheral blood CCR6+ Th cells has been found (van Hamburg JP, Arthritis Rheum. 2011 January;63(1):73-83. doi:10.1002 / art.30093; Leipe J Arthritis Rheum. 2010 October;62(10):2876-85. doi:10.1002 / art.27622; Nistala K, Arthritis Rheum. 2008 March;58(3):875-87. doi:10.1002 / art.23291). CCL20 production is known to be upregulated in synovium explants or fibroblast-like synoviocytes from RA patients following stimulation with TNF-α, IL-1b 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 RA synovium and contribute to pathogenesis by antigen presentation, autoantibody production, and / or inflammatory cytokine production. Furthermore, Rituximab is an effective treatment for RA (Cohen SB, Arthritis Rheum. 2006 Sep;54(9):2793-806.doi:10.1002 / art.22025), supporting the role of CCR6+ B cells in the pathogenesis of RA. In addition, CCR6-deficient mice have impaired lgG1-dependent memory B cell responses (J Immunol. 2015 Jan 15;194(2):505-13.doi:10.4049 / jimmunol.1401553). Preclinical rodent models have shown that the severity of joint inflammation in a collagen-induced arthritis (CIA) model is less in CCR6-deficient mice. The production of collagen-specific antibodies was observed to be reduced in CCR6-deficient mice compared to wild-type mice, and joint inflammation was also reduced (J Cell Mol Med. 2018 Nov;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. 2007 Nov 26;204(12):2803-12.doi:10.1084 / jem.20071397).

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

[0007] Psoriasis is a common autoimmune skin disease. The role of Th17-associated cytokines has been clinically validated, confirming their role in psoriatic inflammation (Paul C, J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1082-90.doi:10.1111 / jdv.12751). It has also been shown that an IL-17R blocking antibody (brodalumab, AMG 827) reduces clinical symptoms of psoriasis and decreases the expression of CCL20 in skin biopsies of psoriasis patients (Papp KA, N Engl J Med. 2012 Mar 29;366(13):1181-9.doi:10.1056 / NEJMoa1109017). Also, an IL-23 neutralizing antibody (guselkumab) was shown to be effective in reducing psoriatic inflammation (Reich K, Lancet. 2019 Sep 7;394(10201):831-839.doi:10.1016 / S0140-6736(19)31773-8). CCR6-deficient mice did not develop psoriasiform skin lesions after intradermal injection of IL-23 (Hedrick MN, J Clin Invest. 2009 Aug;119(8):2317-29.doi:10.1172 / jci37378). Small molecule CCR6 antagonists have also been shown to be effective in Aldara and IL-36a-injected mouse psoriasis models (Campbell JJ, J Immunol. 2019 Mar 15;202(6):1687-1692. doi:10.4049 / jimmunol.1801519; Campbell (Yu S, J Invest Dermatol. 2019 Feb;139(2):485-488.doi:10.1016 / j.jid.2018.07.036) Furthermore, CCR6-deficient mice were shown to be protected from imiquimod-induced ear swelling (Yu S, J Invest Dermatol. 2019 Feb;139(2):485-488.doi:10.1016 / j.jid.2018.07.036).

[0008] Anti-CCR6 neutralizing antibodies also showed efficacy against Aldara-induced ear swelling in mice (Robert R, JCI Insight. 2017 Aug 3;2(15):e94821. Published online Aug 3, 2017 doi:10.1172 / jci.insight.94821). An engineered disulfide-linked CCL20 dimer that binds CCR6 but inhibits T cell migration was 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). Thus, these data indicate that a positive feedback loop consisting of epidermal and dermal CCL20 production, robust recruitment of CCR6+ T cells to inflamed psoriatic skin, their activation by IL-23, and their expression of IL-17A and IL-22 drives a pathogenic Th17 response in psoriatic skin lesions. Thus, inhibition of CCR6 is recognized as a potential therapeutic tool for treating psoriasis (Hedrick MN, Expert Opin Ther Targets. 2010 Sep;14(9):911-22. doi:10.1517 / 14728222.2010.504716; Mabuchi T, J Dermatol Sci. 2012 Jan; 65(1):4-11.doi:10.1016 / j.jdermsci.2011.11.007). Expression of CCR6 has been shown to be upregulated in the synovium of patients with psoriatic arthritis (PsA) (Dolcino M, PLoS One. 2015 Jun 18;10(6):e0128262.doi:10.1371 / journal.pone.0128262). IL-17A and GM-CSF expressing CD4+ T cells isolated from synovial fluid of PsA patients also expressed CCR6 (Al-Mossawi et al., Nat Commun. 2017 Nov 15;8(1):1510.doi:10.1038 / s41467-017-01771-2). CCL20 has been shown to be significantly upregulated in the synovial fluid of PsA patients (Melis L, Ann Rheum Dis. 2010 March;69(3):618-23. doi:10.1136 / ard.2009.107649).

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

[0010] CCR6 and CCL20 are significantly elevated in active Crohn's disease (CD) and ulcerative colitis (UC) (Skovdahl et al., PLoS One. 2015 Nov 4;10(11):e0141710.doi:10.1371 / journal.pone.0141710). Elevated enterocyte CCL20 production has been proposed to play an important role in lymphocyte recruitment to the colonic epithelium in irritable bowel syndrome (IBD) (Kwon JH, Gut. 2002 Dec;51(6):818-26.doi:10.1136 / gut.51.6.818). Expression of CCL20 and CCR6 also correlates with histological severity in resected rectum from UC patients. CCL20 expression in chronic UC is higher than that in acute UC after pathological examination (Uchida K, Gastroenterol Res Pract.2015;2015:856532.doi:10.1155 / 2015 / 856532). Compared with healthy controls, the expression of CCL20 was significantly upregulated in PBMCs of UC patients. UC groups treated with sulfasalazine and GC showed a decrease in CCL20 expression in PBMCs, which was accompanied by 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 Dec;11(12):1070-9. doi:10.1097 / 01.mib.0000187576.26043.ac). Deficiency of CCR6 caused reduced intestinal pathology in mice treated with dextran sodium sulfate (DSS) to induce chronic inflammation (Varona R, Eur J Immunol. 2003 Oct;33(10):2937-46. doi:10.1002 / eji.200324347).

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

[0012] CCR6 expression has been described on T cells isolated from the cerebrospinal fluid of patients with multiple sclerosis (MS) (van Langelaar J, Brain, 2018 May 1;141(5):1334-1349. doi:10.1093 / brain / awy069 ). CCR6 expression was also found 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 polymorphisms were shown to be associated with MS patient cohorts (El Sharkav et al., Gene. 2019 Feb 15;685:164-169.doi:10.1016 / j.gene.2018.11.006). Preclinical data showed that CCR6 is important for the pathogenesis of EAE (Reboldi A, Nat Immunol. 2009 May;10(5):514-23.doi:10.1038 / ni.1716). This finding was confirmed by later studies, i.e., CCR6-deficient mice were shown to be resistant to disease induction and to have a reduced peak severity. In the same study, vaccination with hCCL20 generated an anti-mouse CCL20 response in host mice, which was sufficient to reduce the clinical score (Abraham M, Clin Immunol. 2017 Oct;183:316-324.doi:10.1016 / j.clim.2017.09.018). However, there are conflicting data on the role of CCR6 in EAE pathogenesis (J Neuroimmunol. 2009 Aug 18;213(1-2):91-9.doi:10.1016 / j.jneuroim.2009.05.011). The severity and histopathology of EAE was significantly reduced after injection of anti-CCL20 at the first clinical symptoms (Kohler RE, J Immunol. 2003 Jun 15;170(12):6298-306. doi:10.4049 / jimmunol.170.12.6298). Anti-CCR6 neutralizing antibodies were shown to reduce the severity of EAE in mice (Robert R, JCI Insight. 2017 Aug 3;2(15):e94821. Published online Aug 3, 2017. doi:10.1172 / jci.insight.94821).IL-6 and IL-17 increase expression of CCL20 in mouse astrocytes (Meares GP, Glia. 2012 May;60(5)771-81. doi:10.1002 / glia.22307).

[0013] It has been proposed that CCR6 and CCL20 influence the dynamics of germinal center (GC) formation and B cell responses, and CCR6 is considered to be a marker memory B cell precursor in both mouse and human germinal centers (Suan D, Immunity. 2017 Dec 19;47(6):1142-1153.e4.doi:10.1016 / j.immuni.2017.11.022). In peripheral B cells of systemic lupus erythematosus (SLE) patients, the expression of CCR6 on naive, pre-GC, GC / plasma cells, and memory B cells was increased (Lee AYS, Clin Rheumatol. 2017 Jun;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, Peer J. 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. 2020 Mar;91(3):e12852.doi:10.1111 / sji.12852]. A trend towards increased CCL20 mRNA expression was also observed. A significant decrease in CCR6+ Th cells (both CCR9- and CCR9+) in the circulation of patients with pSS when compared to healthy controls (HC) has been shown [Scand J Immunol. 2020 Mar;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 reduced AIH. TNFα stimulation enhanced CCL20 expression in hepatocytes. These findings suggest that TNFα is essential for the induction of AIH through upregulation of hepatic CCL20 expression, which recruits CCR6+ T cells and drives pathogenesis (Clin Immunol. 2013 Jan;146(1):15-25. doi:10.1016 / j.clim.2012.10.008).

[0016] The CCR6 modulators of the present invention, alone or in combination, are believed to be useful for the treatment or prevention of autoimmune diseases or disorders including posterior uveitis, allergic conjunctivitis, allergic diseases in the gastrointestinal tract, type I diabetes and endometriosis (Medicina (Kaunas). 2018 Nov. 16; 54(5). doi:10.3390 / medicina54050088). CCR6 modulators, alone or in combination, may also be useful in treating ocular surface diseases in which elevated IL-17A levels have been documented, including meibomian gland dysfunction; GVHD, graft-versus-host disease; dry eye syndrome associated with autoimmune keratitis, filamentous keratitis, and 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 modulating agents of the present invention, alone or in combination, are believed to be useful 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 metastatic processes in experimental disease models, either as single agents or in combination with immunotherapy (especially PD1 and / or PDL1 blockade) for the prevention or treatment of cancer.

[0018] The therapeutic potential of modulating this system for the treatment of malignancies 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-targeting siRNA extended the survival of the animals when compared to control animals (Oncotarget. 2017 Jan 31;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) carrying a CCR6-silencing siRNA construct survived significantly longer than mice injected with control cells (Blood. 2014 Mar 6;123(10):1499-511. doi:10.1182 / blood-2013-09-527739.). Zhu and coworkers showed that silencing CCR6 in cancer cells with shRNA reduced the average 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. 2018 Feb;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 carrying shRNA constructs silencing CCR6 expression survived longer than those injected with control cells. In addition, histology and immunohistochemistry revealed that tumors formed by glioma cells carrying CCR6-targeting shRNA were much smaller and had significantly reduced tumor angiogenesis compared to control tumors. Thus, these data further support the notion that CCR6 signaling enhances the oncogenic potential of malignant tumors, including lymphomas, colorectal tumors, and glioblastomas (Oncogene. 2018 Jun;37(23):3070-3087. doi:10.1038 / s41388-018-0182-7.). Specifically, using CCR6 knockout animals, The involvement of the CCR6 / CCL20 system in tumorigenesis has been reported in the literature. In the CMT93 mouse model of colorectal cancer (CRC), infiltration of T regulatory cells was completely inhibited in tumors from mice lacking CCR6 compared to wild-type animals. The reported data further suggest that homing and trafficking of tumor-infiltrating T regulatory cells to tumor masses is dependent on the chemokine receptor CCR6 in vivo (PLoS One, 2011 Apr. 29;6(4):e19495.doi:10.1371 / journal.pone.0019495.). According to Nandi et al., in a mouse model of spontaneous intestinal tumorigenesis [APCMIN / + mice, heterozygous for a mutation in the adenomatous polyposis coli (APC) gene], mice lacking CCR6 had reduced development 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 was also 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 for CCL20 in the growth and development of colorectal cancer (PLoS One. 2011 Apr 29;6(4):e19495. doi:10.1371 / journal.pone.0019495.).

[0020] Specifically, using neutralizing CCL20 antibodies, a potential role for the CCR6 / CCL20 axis in tumor promotion has been demonstrated in the literature using mouse models. Ikeda and coworkers used a specific cutaneous T-cell lymphoma (CTCL) mouse model. 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. 2016 Mar 22;7(12):13563-74. doi:10.18632 / oncotarget.6916.). Lee and coworkers described that in a mouse model of metastatic breast cancer (MDA-MB-231 cells were injected into the left ventricle of nude mice), administration of anti-CCL20 antibodies prevented the development of bone metastases, one of the main metastatic sites of breast cancer in human disease (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 when mice were injected with anti-CCL20 monoclonal antibodies, the recruitment of T regulatory cells into the tumors was significantly reduced 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 immunocompetent mice using anti-CCL20 antibodies reduced tumor initiation and inhibited tumor growth and distant metastasis. Furthermore, the authors reported that neutralization of CCL20 in this mouse model was accompanied by significant inhibition of tumor angiogenesis (He et al., PMID 28560063-Am J Cancer Res.2017;7(5):1151-1163.). Using the same mouse model, administration of anti-CCL20 neutralizing antibodies significantly reduced the infiltration of T regulatory cells, especially CCR6-positive T regulatory cells, into tumors and significantly reduced tumor growth. Co-treatment of mice with anti-PDL-1 antibodies further enhanced the antitumor activity.Together, 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, a potential role for 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 neoplasms, tumor cells seeded in the liver overexpressed functional CCR6 compared to tumor cells of the primary tumor (by sc injection of mouse plasma cell neoplasm (MOPC315)). The same authors found that CCR6 was overexpressed in small liver metastases of colon, thyroid and ovarian cancer compared to normal liver (Scand J Immunol. 2003 June;57(6):534-44. doi:10.1046 / j.1365-3083.2003.01263.x.).

[0022] Furthermore, the CCR6 modulators of the present invention, alone or in combination, are believed to be useful for treating or preventing cancers in which expression of CCR6 and / or CCL20 correlates with disease progression and resistance to standard treatment. In particular, the correlation of CCR6 expression with 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). 2019 Dec. 30; 12(1). doi:10.3390 / cancersl 2010089.). In colorectal cancer, tumor expression of CCR6 positively correlates with metastasis, and upregulation of CCR6 predicts poor survival, short disease-free survival (PLoS One. 2014;9(6):e101137. doi:10.1371 / journal.pone.0101137.) and poor 5-year overall survival (Biochim Biophys Acta Mol Basis Dis. 2018 Feb;1864(2):387-397. doi:10.1016 / j.bbadis.2017.10.033.). In ovarian cancer, high CCR6 mRNA expression also correlates with poor prognosis (Cancer Lett. 2020 Mar 1;472:59-69. doi:10.1016 / j.canlet.2019.12.024.). CCR6 expression correlates with the aggressiveness of rectal cancer, and indeed high levels of CCR6 protein expression are more prevalent in non-responders than in responders to radiation therapy (Cancer Res Treat. 2018 Oct;50(4):1203-1213.doi:10.4143 / crt.2017.538.). CCR6 expression levels in prostate cancer correlated with clinical and pathological features of more advanced and aggressive disease (J Cancer Res Clin Oncol. 2008 Nov;134(11):1181-9.doi:10.1007 / s00432-008-0403-5.). In non-small cell lung cancer (NSCLC), high CCR6 expression correlates with shorter disease-free survival and increases the risk of disease recurrence five-fold, independent of stage (PLoS One. 2011;6(9):e24856. doi:10.1371 / journal.pone.0024856.).Patients with hepatocellular carcinoma 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, expression of its ligand CCL20 has been reported to correlate with poor disease outcome 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 Aug 29;7(1):9610.doi:10.1038 / s41598-017-09040-4.), higher histological grade, higher KI67 index, and axillary lymph node metastasis. Furthermore, CCL20 expression in breast tumors was positively correlated with expression of FOXP3, a marker of T regulatory cells. Patients with axillary lymph node metastasis and concomitant elevation of CCL20 expression and FOXP3-positive T regulatory cells had the lowest overall survival (Medicine (Baltimore). 2019 Dec;98(50):e18403.doi:10.1097 / MD.0000000000018403.). In NSCLC, elevated expression of CCL20 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 poor overall and recurrence-free survival. The same authors noted that CCL20 expression 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 CCR6 or CCL20 alone, the correlation of CCR6 / CCL20 co-expression with disease progression has been described in the literature. Indeed, overexpression of both CCL20 and CCR6 has been detected in higher grade glioma tissues than in lower grade tissues and increased with increasing World Health Organization (WHO) tumor grade. Notably, glioma patients with CCL20 / CCR6 co-expression had the shortest overall survival (Med Oncol. 2012 Dec;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. Indeed, CCL20 expression can increase chemoresistance of breast cancer cells (PLoS Biol. 2018 July;16(7):e2005869.doi:10.1371 / journal.pbio.2005869.). Rubie et al. describe that a significant upregulation of CCL20 / CCR6 was observed (RT-PCR) in human samples of colorectal liver metastases (CRLM) and hepatocellular carcinoma (HOC). Furthermore, CCL20 is significantly overexpressed in colorectal cancer liver metastases compared to primary HCC, indicating the involvement of the CCL20 / CCR6 ligand-receptor pair in the carcinogenesis and progression of hepatic malignancies (World J Gastroenterol. 2006 Nov 7;12(41):6627-33. doi:10.3748 / wjg.v12.i41.6627.).

[0026] The CCR6 modulators of the present invention, alone or in combination, are believed to be useful in treating or preventing diseases or disorders in which CCR6 and / or CCL20 are expressed or overexpressed in patient samples or cancer cell lines. In particular, the expression of the chemokine receptor CCR6 in several types of cancer or cancer cell lines has been described in the literature. Lu and coworkers have described that CCR6 expression is higher in laryngeal cancer tissues than in their normal controls. The authors reported that CCR6 is also expressed in common laryngeal cancer cells such as TU212, M4E, M2E and Hep-2 (Biomed Pharmacother. 2017 January;85:486-492 doi:10.1016 / j.biopha.2016.11.055.). Based on gene expression data in malignant melanoma, together 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 analysis of 21 MALT lymphomas of the salivary gland and thyroid revealed that CCR6 was expressed (Haematologica. 2018 August;103(8):1329-1336. doi:10.3324 / haematol.2018.191601.). In adult T-cell leukemia / lymphoma (ATLL) samples, CCR6 transcripts were detected, and furthermore, 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 significantly higher in tumor tissues than in adjacent normal tissues. (Cancer Res Treat. 2015 Apr;47(2):306-12. doi:10.4143 / crt.2014.015.) CCR6 expression has been detected in a wide variety of cancer cell lines, and in fact, Mays and coworkers reported that salivary adenoid cystic carcinoma cells SACC-83 expressed CCR6, along with other CC chemokine receptors, by RT-PCR gene analysis (Anticancer Res. 2016 Aug;36(8):4013-8.) According to Moeller et al., U266 CCR6 was also expressed in multiple myeloma (MM) cell lines including U-1970, U-266 1984, U-1958, Karpas 707, LP-1, 28 L-363, HL407E and HL407L.3 (Leukemia. 2003 January;17(1):203-10. doi:10.1038 / sj.leu.2402717.).

[0027] Similar to CCR6, the ligand CCL20 has been reported in the literature to be expressed in a number of tumor samples and tumor cell lines. For example, Zhang and coworkers showed that in samples from NSCLC patients, CCL20 expression was higher in tumor samples than in samples from adjacent tissues using RT-PCR, which was also verified at the protein level using immunohistochemistry (Biomed Pharmacother. 2015 February;69:242-8.doi:10.1016 / j.biopha.2014.12.008.). Gene expression analysis of cholangiocarcinoma samples and corresponding normal tissues revealed that CCL20 was one of the most significantly overexpressed genes in malignant tissues versus healthy tissues (EXCLI J. 2020;19:154-166.doi:10.17179 / excli2019-1893.). CCL20 expression was also reported in human samples of multiple myeloma (MM) (Cancer Res. 2008 Aug 15;68(16):6840-50. doi:10.1158 / 0008-5472.CAN-08-0402.). Furthermore, Rubies et al. reported that CCL20 mRNA and protein are significantly upregulated (8-fold) in pancreatic cancer compared to comparable normal pancreas, where CCL20 expression is weak (J Transl Med. 2010 May 15;68(16):6840-50. doi:10.1158 / 0008-5472.CAN-08-0402.). 10;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. 2017 July 15;199(2):467-476. doi:10.4049 / jimmunol.1601815.).

[0028] In addition to CCR6 or CCL20 alone, co-expression of both CCR6 and CCL20 has been reported in the literature for cancer patient samples and cancer cell lines. Expression of both genes has been described in samples from adult T-cell leukemia / lymphoma patients (Microarray and IHC protein staining) (Int J Oncol. 2014 Sep;45(3):1200-8.doi:10.3892 / ijo.2014.2524.) and in CTCL, where CCL20 and CCR6 were detected at the mRNA and protein levels (Clin Cancer Res. 2011 Dec 15;17(24)7529-38.doi:10.1158 / 1078-0432.CCR-11-1192.). Transcriptome analysis (nanostring) of hepatocellular carcinoma samples revealed expression of CCR6 and CCL20. Furthermore, a chemotactic gradient between non-tumor and tumor tissues has been reported, suggesting a recruitment step of T regulatory cells, tumor-associated macrophages and natural killer cells involving the CCR6 / CCL20 axis (Proc Natl Acad Sci US A. 2017 Jul 18;114(29):E5900-E5909.doi:10.1073 / pnas.1706559114.). Similarly, Guo and coworkers reported upregulation of CCR6 and CCL20 in hepatocellular carcinoma lesions compared to healthy tissues and expression of CCR6 and CCL20 in hepatocellular carcinoma cell lines (L02, Li- / , Huh-7, SN U-387, Hep3B) (Oncol Rep. 2019 Sep;42(3):1075-1089.doi:10.3892 / or.2019.7221.). According to Nandi et al., in human colorectal cancer, both CCL20 and CCR6 are expressed (IHC protein staining). In NSCLC samples, the expression of both CCR6 and CCL20 was found to be significantly higher (protein and mRNA) (Oncol Lett. 2017 Dec;14(6):8183-8189.doi:10.3892 / ol.2017.7253). Using in situ hybridization, both CCL20 and CCR6 mRNA portions were strongly expressed in all pancreatic cancer samples analyzed. In contrast, expression of CCL20 and CCR6 was low in healthy pancreas (Int J Cancer. 1999 May 17;81(4):650-7. doi:10.1002 / (sici)1097-0215(19990517)81:4<650::aid-ijc23>3.0.co;2-#.). Jin and coworkers 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 tissues using the GEO dataset, GSE2223. Again, expression levels of CCR6 and CCL20 were significantly higher in glioblastoma tissues than in normal brain tissues (Oncogene. 2018 Jun;37(23):3070-3087. doi:10.1038 / s41388-018-0182-7.). In addition, Wallace et al. observed higher expression of CCL20 and its receptor CCR6 in endometrial adenocarcinoma cultures and cell lines compared to non-malignant endometrium (mRNA, RT-PCR) (Mol Cell Endocrinol. 2011 Jan 1;331(1):129-35. doi:10.1016 / j.mce.2010.08.018.). The CCL20 / CCR6 axis may play a role in breast, cholangiocarcinoma, and thyroid cancer.This is because expression of the CCR6 / CCL20 gene and / or protein has been reported in patient-derived breast cancer cells (Mol Carcinog. 2016 July;55(7):1175-86. doi:10.1002 / mc.22360.), HuCCT1 and TFK-1 cholangiocarcinoma cell lines (Win et al., PMID 32194362) (EXCLI J. 2020;19:154-166. doi:10.17179 / excli2019-1893.) and in thyroid cancer cell lines such as TPC-1, BCPAP, FTC-133 and SW1736 (Tumour Biol. 2016 April;37(4):5569-75. doi:10.1007 / s13277-015-4418-7.). Furthermore, the CCR6 modulating agents of the present invention, alone or in combination, are believed to be useful in the treatment or prevention of cancers in which expression and / or evidence of CCR6 / CCL20 axis activity has been reported or in which CCR6+ regulatory T cells have been identified within the tumor microenvironment. Summary of the Invention

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

[0030] [ka] (In the formula, - R 1 is C 1-3 - alkyl (especially methyl); R 2 is C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; -L- is --Optionally substituted with one hydroxy * -C≡CC 0-2 -Alkylene- ** (Especially, -C≡C- or -C≡CC(CH3)(OH)-) (asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R 4; or -- oxadiazole-diyl (especially 1,2,4-oxadiazole-diyl; especially

[0031] [ka] (One asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R 4 Indicates the attachment point to . )); and R 4 teeth, -- C 3-7 - cycloalkyl (especially cyclohexyl); a saturated 5- to 8-membered bridged or spiro-bicyclic hydrocarbon ring system, in which (especially in said spiro-bicyclic hydrocarbon ring system) one ring carbon atom is optionally replaced by a nitrogen atom (in particular such bridged or spiro-bicyclic hydrocarbon ring systems represent bicyclo[2.2.2]octan-1-yl, bicyclo[1.1.1]pentan-1-yl or 2-azaspiro[3.3]heptan-6-yl); or -- 6-membered heteroaryl having 1 or 2 (especially 2) ring nitrogen atoms (especially pyrimidinyl; especially pyrimidin-4-yl); represents; R 4 is independently unsubstituted or contains one hydroxy, hydroxy-C 1-3 -Alkyl (especially hydroxy-methyl), carbamoyl, C 1-3 -Alkyl-carbonyl-amino (especially acetyl-amino or ethyl-carbonyl-amino) or C 1-3 -substituted by alkyl-carbonyl (especially acetyl); [Especially, the group -LR 4are 5-(4-hydroxy-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 3-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-5-yl, 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo [2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4- represents oxadiazol-3-yl; or - R 1 is C 1-3 - alkyl (especially methyl); R 2 is C 1-4 - alkyl (especially methyl); R 3 represents isopropyl; and -LR 4are 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol- 3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or - R 1 is C 1-3 - alkyl (especially methyl); R 2 is C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; and -LR 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl.

[0032] The definitions described herein are uniformly applied to the compounds of formula (I) defined in any one of the embodiments 1) to 9), and apply mutatis mutandis throughout the present specification and claims, unless a broader or narrower definition is given by a special definition. Of course, the definition or preferred definition of a term may independently (and together) define and replace each term in any or all other terms defined herein or in any preferred definition. Unless otherwise expressly defined in each embodiment or claim, the groups defined herein are unsubstituted.

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

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

[0035] The term "alkyl", used alone or in combination, means a straight or branched saturated hydrocarbon chain radical having 1 to 6 carbon atoms. x-y The term "-alkyl" (x and y are each integers) refers to an alkyl group as defined above having x to y carbon atoms. x-y When the -alkyl group is used in combination with another substituent, the term also applies when that substituent is C x-y - means that the group is attached to the rest of the molecule through 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. 2 About C used 1-4 A preferred example of -alkyl is methyl. 1 About C used 1-3 A preferred example of -alkyl is methyl.

[0036] "-C x-y The term "-alkylene-", used alone or in combination, refers to a bivalently bound alkyl group, as defined above, having from x to y carbon atoms. In particular, the points of attachment of any bivalently bound alkyl group are in a 1,1-diyl configuration. 0-y -Alkylene- group is different When used in combination with a substituent, this term refers to whether the substituent is directly attached to the remainder of the molecule (i.e., the -C0-alkyl- group represents a direct bond attaching the substituent to the remainder of the molecule) or whether it is a -C 1-y -C means to be attached to the remainder of the molecule via an alkylene group. 1-y Examples of -alkylene- groups include methylene, ethylene and ethane-1,1-diyl. 1-2 -alkylene- group. The group -C≡CC 0-2 Examples of -alkylene- are -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 -alkylene- is described as being substituted by one hydroxy, the substitution is also represented by -C 1-2 It is understood that -alkylene- is only possible when -C≡CC is substituted by one substituent. 0-2 Examples of -alkylene-groups are -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 -Alkylene- ** An asterisk ( * ) indicates the point of attachment to the pyridinyl ring shown in formula (I), and two asterisks ( ** ) is R 4 The attachment points to the

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

[0038] "C 1-3The term "-alkyl-carbonyl", used alone or in combination, refers to an alkyl group as defined above in which one hydrogen atom has been replaced with a carbonyl group.

[0039] "C 1-3 The term "-alkyl-carbonyl-amino", whether used alone or in combination, means any group in which one hydrogen atom is bonded to a C-alkyl-carbonyl-amino group as defined above. 1-3 -alkyl-carbonyl group.

[0040] The term "hydroxyalkyl" (or hydroxy-alkyl), used alone or in combination, means an alkyl group as defined above in which one hydrogen atom has been replaced with a hydroxy group. x-y The term "hydroxy-alkyl" (x and y are each integers), used alone or in combination, refers to a hydroxyalkyl group as defined above, wherein the alkyl group has x to y carbon atoms. 1-3 -alkyl group is a hydroxyalkyl group as defined above having 1 to 3 carbon atoms. 1-3 Examples of -alkyl groups are hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, 1-hydroxy-propyl, 2-hydroxy-propyl, 3-hydroxy-propyl and 1-hydroxy-1-methyl-ethyl.

[0041] The term "cycloalkyl", used alone or in combination, means a saturated monocyclic hydrocarbon ring having 3 to 7 carbon atoms, preferably 3 to 6 carbon atoms. x-y The term "cycloalkyl" (x and y are each 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. 3-7Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; in particular cyclohexyl. The above groups are unsubstituted or substituted as expressly defined.

[0042] The term "6-membered heteroaryl", whether used alone or in combination, refers to a 6-membered monocyclic aromatic ring having one or two (particularly two) ring nitrogen atoms. Examples are pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; especially pyrimidinyl. The above heteroaryl groups are unsubstituted or substituted as expressly defined.

[0043] The term "saturated 5-8 membered bridged or spiro bicyclic hydrocarbon ring system" means two hydrocarbon rings sharing one or two carbon atoms, the total number of carbon atoms in both rings being an integer between 5 and 8. More specifically, The term saturated 5-8 membered bridged bicyclic hydrocarbon ring system means a compound 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 represent the number of carbon atoms in each of the three bridges connecting the two tertiary carbon atoms, in descending order (x>y>z)). Examples of such 5-8 membered bridged bicyclic hydrocarbon ring systems are 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 5-8 membered spiro bicyclic hydrocarbon ring system means compounds described by the term "spiro[xy]alkyl", in which the total number of carbon atoms is an integer between 5 and 8; [the integers "x" and "y" represent the number of carbon atoms in each of the two carbocyclic rings attached 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 5-8 membered spiro bicyclic 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] Bonds drawn as dotted lines indicate the point of attachment of the depicted group to the remainder of the molecule. For example, the groups

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

[0046] Further aspects of the invention are described below: 2) In one aspect, - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; -L-, --Optionally substituted with one hydroxy * -C≡CC 0-2 -Alkylene- ** (Especially, -C≡C- or -C≡CC(CH3)(OH)-) (asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R 4 indicates the point of attachment to -- oxadiazole-diyl (especially 1,2,4-oxadiazole-diyl; especially

[0047] [ka] (One asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R 4 Indicates the attachment point to . )); and R 4 but, -- C substituted with one substituent 3-7 -cycloalkyl (especially cyclohexyl) where the substituents are hydroxy, carbamoyl or C 1-3 -alkyl-carbonyl-amino (in particular acetyl-amino or ethyl-carbonyl-amino), 3-7 - cycloalkyl (especially cyclohexyl); - saturated 5- to 8-membered bridged or spiro-bicyclic hydrocarbon ring systems, in which (particularly in the spiro-bicyclic hydrocarbon ring systems) one ring carbon atom is optionally replaced by a nitrogen atom (in particular such bridged or spiro-bicyclic hydrocarbon ring systems represent bicyclo[2.2.2]octan-1-yl, bicyclo[1.1.1]pentan-1-yl or 2-azaspiro[3.3]heptan-6-yl), and which 5- to 8-membered bridged or spiro-bicyclic hydrocarbon ring systems independently contain one hydroxy, hydroxy-C 1-3 -Alkyl (especially hydroxy-methyl), carbamoyl, C 1-3 -Alkyl-carbonyl-amino (especially acetyl-amino) or C 1-3 - a saturated 5-8 membered bridged or spiro bicyclic hydrocarbon ring system substituted by alkyl-carbonyl (especially acetyl); or unsubstituted 6-membered heteroaryl having 1 or 2 (especially 2) ring nitrogen atoms (especially pyrimidinyl; especially pyrimidin-4-yl); represents; - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents isopropyl; and -LR 4 However, 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol- 3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; and -LR 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl; It relates to compounds according to embodiment 1).

[0048] 3) A further aspect is - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; -L-, --Optionally substituted with one hydroxy * -C≡CC 0-2 -Alkylene- ** (Especially, -C≡C- or -C≡CC(CH3)(OH)-) (asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R 4 ); and R 4 but, -- C substituted with one substituent 3-7 -cycloalkyl (especially cyclohexyl) where the substituents are hydroxy, carbamoyl or C 1-3 -alkyl-carbonyl-amino (in particular acetyl-amino or ethyl-carbonyl-amino), 3-7 - cycloalkyl (especially cyclohexyl); -- or unsubstituted 6-membered heteroaryl having 1 or 2 (especially 2) ring nitrogen atoms (especially pyrimidinyl; especially pyrimidin-4-yl); represents; - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; -L-, -- oxadiazole-diyl (especially 1,2,4-oxadiazole-diyl; especially

[0049] [ka] (One asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R4 Indicates the attachment point to . )); and R 4 but, -- C substituted with one substituent 3-7 -cycloalkyl (especially cyclohexyl) where the substituents are hydroxy, carbamoyl or C 1-3 -alkyl-carbonyl-amino (in particular acetyl-amino or ethyl-carbonyl-amino), 3-7 - cycloalkyl (especially cyclohexyl); or a saturated 5- to 8-membered bridged or spiro-bicyclic hydrocarbon ring system, in which (particularly in the spiro-bicyclic hydrocarbon ring system) one ring carbon atom is optionally replaced by a nitrogen atom (in particular such bridged or spiro-bicyclic hydrocarbon ring system represents bicyclo[2.2.2]octan-1-yl, bicyclo[1.1.1]pentan-1-yl or 2-azaspiro[3.3]heptan-6-yl), and the 5- to 8-membered bridged or spiro-bicyclic hydrocarbon ring system independently represents one hydroxy, hydroxy-C 1-3 -Alkyl (especially hydroxy-methyl), carbamoyl, C 1-3 -Alkyl-carbonyl-amino (especially acetyl-amino) or C 1-3 - saturated 5-8 membered bridged or spiro bicyclic hydrocarbon ring systems substituted by alkyl-carbonyl (especially acetyl); represents; - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents isopropyl; and -LR 4However, 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol- 3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; and -LR 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl; It relates to compounds according to embodiment 1).

[0050] 4) A further aspect is - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; -L-, --Optionally substituted with one hydroxy * -C≡CC 0-2-Alkylene- ** (Especially, -C≡C- or -C≡CC(CH3)(OH)-) (asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R 4 ); and R 4 but, -- C substituted with one substituent 3-7 -cycloalkyl (especially cyclohexyl), where the substituent is hydroxy. 3-7 -cycloalkyl (especially cyclohexyl); or unsubstituted 6-membered heteroaryl having 1 or 2 (especially 2) ring nitrogen atoms (especially pyrimidinyl; especially pyrimidin-4-yl); represents; - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; -L-, -- oxadiazole-diyl (especially 1,2,4-oxadiazole-diyl; especially

[0051] [ka] (One asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R 4 Indicates the attachment point to . )); and R 4 but, -- C substituted with one substituent 3-7 -cycloalkyl (especially cyclohexyl) where the substituents are hydroxy, carbamoyl or C 1-3-alkyl-carbonyl-amino (in particular acetyl-amino or ethyl-carbonyl-amino), 3-7 - cycloalkyl (especially cyclohexyl); or a saturated 5- to 8-membered bridged or spiro-bicyclic hydrocarbon ring system, in which (particularly in the spiro-bicyclic hydrocarbon ring system) one ring carbon atom is optionally replaced by a nitrogen atom (in particular such bridged or spiro-bicyclic hydrocarbon ring system represents bicyclo[2.2.2]octan-1-yl, bicyclo[1.1.1]pentan-1-yl or 2-azaspiro[3.3]heptan-6-yl), and the 5- to 8-membered bridged or spiro-bicyclic hydrocarbon ring system independently represents one hydroxy, hydroxy-C 1-3 -Alkyl (especially hydroxy-methyl), carbamoyl, C 1-3 -Alkyl-carbonyl-amino (especially acetyl-amino) or C 1-3 - saturated 5-8 membered bridged or spiro bicyclic hydrocarbon ring systems substituted by alkyl-carbonyl (especially acetyl); represents; - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents isopropyl; and -LR 4However, 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol- 3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; and -LR 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl; It relates to compounds according to embodiment 1).

[0052] 5) A further aspect is - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; -L-, --Optionally substituted with one hydroxy * -C≡CC 0-2-Alkylene- ** (particularly, -C≡C- or -C≡CC(CH3)(OH)-; especially -C≡C-) (asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R 4 ); and -- R 4 is substituted with one substituent 3-7 -Cycloalkyl (especially cyclohexyl) xyl), wherein the substituent is hydroxy. 3-7 - cycloalkyl (especially cyclohexyl); represents; - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; -L-, -- oxadiazole-diyl (especially 1,2,4-oxadiazole-diyl; especially

[0053] [ka] (One asterisk ( * ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ** ) is R 4 Indicates the attachment point to . )); and R 4 but, -- C substituted with one substituent 3-7 -cycloalkyl (especially cyclohexyl) where the substituents are hydroxy, carbamoyl or C 1-3 -alkyl-carbonyl-amino (in particular acetyl-amino or ethyl-carbonyl-amino), 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 a saturated 5-8 membered bridged bicyclic hydrocarbon ring system is bicyclo[2.2.2]octan-1-yl or bicyclo[1.1.1]pentan-1-yl), which may independently contain one hydroxy, hydroxy-C 1-3 -alkyl (especially hydroxy-methyl), carbamoyl or C 1-3 -a saturated 5-8 membered bridged bicyclic hydrocarbon ring system substituted with alkyl-carbonyl-amino (particularly acetyl-amino) (particularly, the above substituent is bonded to a tertiary carbon atom in the 5-8 membered bridged bicyclic hydrocarbon ring system); or a saturated 5-8 membered spiro bicyclic hydrocarbon ring system in which one ring carbon atom is replaced by a nitrogen atom (in particular, such a saturated 5-8 membered spiro bicyclic hydrocarbon ring system is 2-azaspiro[3.3]heptan-6-yl); 1-3 -alkyl-carbonyl (especially acetyl) substituted, in particular said substituents being attached to said nitrogen atom, saturated 5-8 membered spiro bicyclic hydrocarbon ring systems; represents; - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents isopropyl; and -LR 42-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or - R 1 C 1-3 - alkyl (especially methyl); R 2 C 1-4 - alkyl (especially methyl); R 3 represents 2,2,2-trifluoro-ethyl; and -LR 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl; It relates to compounds according to embodiment 1).

[0054] 6) A further aspect is R 1 represents methyl; relates to compounds according to any one of embodiments 1) to 5).

[0055] 7) A further aspect is R 2 represents methyl; relates to compounds according to any one of embodiments 1) to 6).

[0056] 8) A further aspect is - R 1 represents methyl; R 2 represents methyl; R 3 represents 2,2,2-trifluoro-ethyl; and -LR 4 However, 5-(4-hydroxy-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 3-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-5-yl, 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octyl)-1,2,4-oxadiazol-5-yl, 5-(4-hydroxy-bicyclo[2.2.2]octyl)-1,2,4-oxadiazol-3 ...5-yl, 5-(4-hydroxy-bicyclo[2 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; - R 1 represents methyl; R 2 represents methyl; R 3 represents isopropyl; and -LR 4However, 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol- 3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or - R 1 represents methyl; R 2 represents methyl; R 3 represents 2,2,2-trifluoro-ethyl; and -LR 4 represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl; It relates to compounds according to embodiment 1).

[0057] 9) A further embodiment relates to a compound according to any one of embodiments 1) to 8), in which the asymmetric carbon atom carrying the hydroxy group has the absolute configuration shown in formula (II):

[0058] [ka] 10) Another embodiment relates to a compound according to embodiment 1), which is selected from the following compounds: trans-4-[3-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-cyclohexanol; cis-4-[3-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-cyclohexanol;(R)-(1,3-dimethyl-azetidin-3-yl)-{5-[5-(3-hydroxymethyl-bicyclo[1.1.1]pent-1-yl)-[1,2,4]oxadiazol-3-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol; N-[3-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[1.1.1]pent-1-yl]-acetamide; 4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octan-1-ol; 2-[5-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-methyl-propan-1-ol; 1-[6-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-2-aza-spiro[3.3]hept-2-yl]-ethanone; trans-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide; trans-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide; (R)-(1,3-Dimethyl-azetidin-3-yl)-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]pent-1-yl)-[1,2,4]oxadiazol-5-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol; (R)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-pyrimidin-4-yl-but-3-yn-2-ol; (S)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-pyrimidin-4-yl-but-3-yn-2-ol; trans-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-ylethynyl}-cyclohexanol; cis-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-ylethynyl}-cyclohexanol; 4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide; cis-4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid amide; or trans-4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid amide.

[0059] 11) Another embodiment relates to a compound according to embodiment 1), which is selected from the following compounds: trans-4-[3-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-cyclohexanol; (R)-(1,3-Dimethyl-azetidin-3-yl)-{5-[5-(3-hydroxymethyl-bicyclo[1.1.1]pent-1-yl)-[1,2,4]oxadiazol-3-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol; N-[3-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydride {roxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[1.1.1]pent-1-yl]-acetamide; 4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octan-1-ol; 2-[5-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-methyl-propan-1-ol; 1-[6-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-2-aza-spiro[3.3]hept-2-yl]-ethanone; trans-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide; trans-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide; (R)-(1,3-Dimethyl-azetidin-3-yl)-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]pent-1-yl)-[1,2,4]oxadiazol-5-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol; (R)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-pyrimidin-4-yl-but-3-yn-2-ol; (S)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-pyrimidin-4-yl-but-3-yn-2-ol; trans-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-ylethynyl}-cyclohexanol; cis-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-ylethynyl}-cyclohexanol; 4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide; or 4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid amide.

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

[0061] The present invention relates to compounds of formula (I) as defined in embodiment 1), or such compounds further defined by the features of any one of embodiments 2) to 9), according to their respective subdivisions; pharma- ceutically acceptable salts thereof; and to the use of such compounds as medicaments, in particular as medicaments in the treatment of diseases or disorders involving the CCR6 receptor, as described below.

[0062] The present invention also relates to isotopically labeled, especially 2 H (deuterium) labeled compounds of formula (I) are also included, which are identical to compounds of formula (I) except that one or more atoms have been replaced by an atom having the same atomic number but a different atomic mass than that normally found in nature, respectively. Isotopically labeled compounds, particularly 2 H (deuterium) labeled compounds of formula (I) and salts thereof are within the scope of the present invention. 2 Substitution with H (deuterium) can increase metabolic stability, for example, prolonging in-vivo half-life, or reducing the required dose, or reducing inhibition of cytochrome P450 enzymes, for example, improving safety profile. In one embodiment of the present invention, the compounds of formula (I) are not isotopically labeled, or they are labeled only with one or more deuterium atoms. In a subembodiment, the compounds of formula (I) are not isotopically labeled at all. Isotopically labeled compounds of formula (I) may be prepared in a similar manner to the method described below, except that appropriate isotopic species of suitable reagents or starting materials are used.

[0063] When the plural forms are used for compounds, salts, pharmaceutical compositions, disorders, and the like, they are intended to refer to a singular compound, salt, pharmaceutical composition, disorder, and the like.

[0064] Any reference to compounds of formula (I) according to embodiments 1) to 12) will, where appropriate, be understood to also refer to the salts (especially the pharma- ceutically acceptable salts) of such compounds.

[0065] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological 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 subject 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 asymmetric centers, such as one or more asymmetric carbon atoms, which may exist in (R)- and (S)-configurations. Compounds of formula (I) may further include compounds having one or more double bonds, which may exist in Z- and E-configurations, and / or compounds having substituents on ring systems, which may exist in cis- and trans-configurations relative to each other. Thus, compounds of formula (I) may include mixtures of stereoisomers. The stereoisomers may be present in the form of a mixture of stereoisomers, or preferably in a stereoisomer-enriched form, in particular 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 generic structure) is described as being an (R)- or (S)-enantiomer, such description is understood to mean the respective compound (or generic structure) in enriched, particularly essentially pure, enantiomeric form. Similarly, when a particular asymmetric center of a compound is described as being in the (R)- or (S)-configuration or in a particular relative configuration, such description is understood to mean said compound in enriched, particularly essentially pure form with respect to each configuration of said asymmetric center. Similarly, a description of cis or trans is understood to mean the respective stereoisomer in enriched, particularly essentially pure form. Similarly, when a particular compound (or generic structure) is described as being a Z or E stereoisomer (or when a particular double bond in a compound is described as being in the Z or E configuration), such description is understood to mean the respective compound (or generic structure) in enriched, particularly essentially pure stereoisomeric form (or the compound in enriched, particularly essentially pure form with respect to each configuration of the double bond). The same applies mutatis mutandis to compounds described as being cis- or trans-stereoisomers.

[0068] The term "enriched", when used in connection with stereoisomers, is understood in the context of the present invention to mean that the respective stereoisomer is present relative to the respective other stereoisomer / total of the respective other stereoisomer in a ratio of at least 70:30, in particular at least 90:10 (i.e. in a purity of at least 70% by weight, in particular at least 90% by weight).

[0069] The term "essentially pure", when used in relation to stereoisomers, is understood in the context of the present invention to mean that each stereoisomer is present in a purity of at least 95 percent by weight, in particular at least 99 percent by weight, relative to each other stereoisomer / total of each other stereoisomer.

[0070] The absolute stereochemical configuration of the compounds of formula (I) disclosed above or below and / or of intermediates in the synthesis of the compounds of formula (I) may be determined by methods conventional in the art, such as by obtaining single crystals of said compounds / intermediates and subjecting them to X-ray diffraction analysis, e.g. similar to the methods applied to the compounds / intermediates disclosed in PCT / EP2021 / 061401.

[0071] The compounds of formula (I) according to embodiments 1) to 12) and their pharma- ceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical compositions for enteral (such as, in particular, oral) or parenteral (including topical application or inhalation) administration.

[0072] The preparation of pharmaceutical compositions can be carried out in a manner 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 above-mentioned compounds of formula (I) or pharma- ceutical acceptable salts thereof, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if necessary, with conventional pharmaceutical adjuvants, to form a pharmaceutical dosage form.

[0073] Whenever the word "between" is used to describe a range of numerical values, the endpoints of the stated range are expressly intended to be included in the range. For example: if a temperature range is described as being between 40°C and 80°C, the endpoints 40°C and 80°C are meant to be included in the range; or, if a variable is defined as an integer between 1 and 4, the variable It means the integers 1, 2, 3, or 4.

[0074] When not used in relation to temperature, the term "about" (or "around") preceding a numerical value "X" in this application means 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 "about" preceding a temperature "Y" in this application means between Y-10°C and Y+10°C, preferably between Y-5°C and Y+5°C.

[0075] The compounds of formula (I) as defined above are useful for the prevention or treatment of various diseases, conditions or disorders that are ameliorated by modulation of the CCR6 receptor. Such diseases, conditions or disorders in which the CCR6 receptor is involved may be defined as inflammatory and / or autoimmune diseases, conditions or disorders, and cancer.

[0076] The compounds of formula (I) as defined above are useful in the prevention or treatment of various diseases, conditions or disorders that are ameliorated by modulation of the CCR6 receptor. Such diseases, conditions or disorders in which the CCR6 receptor is involved 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 disease; multiple sclerosis; systemic lupus erythematosus; Sjogren's syndrome; autoimmune hepatitis; primary sclerosing cholangitis; posterior uveitis; allergic conjunctivitis; allergic diseases in the gastrointestinal tract; type I diabetes mellitus and endometriosis; diseases of the ocular surface where elevated levels of IL-17A have been documented, 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-onset rheumatoid arthritis;oligoarticular rheumatoid arthritis;oligoarticular juvenile rheumatoid arthritis;polyarticular rheumatoid arthritis;enteropathic arthritis;juvenile Reiter's syndrome;ankylosing spondylitis;juvenile ankylosing spondylitis;SEA syndrome;reactive arthritis (reactive arthropathy);psoriatic arthropathy;juvenile enteropathic arthritis;polymyalgia rheumatica;enteropathic spondylitis (enteropathic spondylitis); juvenile idiopathic arthritis (JIA); juvenile psoriatic arthritis; juvenile rheumatoid arthritis; systemic-onset juvenile rheumatoid arthritis; acute pancreatitis; chronic pancreatitis; giant cell arteritis; arteriosclerosis; bone erosion; intrapetrotoneal abscesses; intraperitoneal abscesses; and / or inflammatory / autoimmune diseases, conditions or disorders including osteoarthritis secondary to inflammatory diseases.

[0077] Further, such diseases, conditions or disorders that are ameliorated by modulation of the CCR6 receptor include skin cancer, e.g., melanoma (superficial spreading, nodular, lentigo maligna and acral lentigo 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 and non-small cell lung cancer (SCLC, NSCLC), such as squamous and non-squamous NSCLC; lung cancer, including pleuropulmonary blastoma and tracheobronchial tumors; 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, such as pancreatic adenocarcinoma or pancreatic 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, astrocytoma; peripheral neuroectodermal tumors; oligoastrocytic tumors; oligodendroglioma; ependymal tumors; anaplastic astrocytoma; pilocytic astrocytoma; craniopharyngioma; spinal tumors; brain stem glioma; central nervous system atypical teratoid / rhabdomyosarcoma-like tumors; medulloblastoma; central nervous system germ cell tumors; craniopharyngioma; ependymoma; head and neck cancer, such as neuroblastoma and esthesioneuroblastoma; cervical cancer advanced cervical cancer; breast cancer including normal-like, basal-like, claudin-low, HER2 positive, luminal-A, luminal-B and triple negative breast carcinoma; pregnancy breast cancer and male breast cancer; oral cavity tumors; nasopharyngeal tumors; cardiac tumors; thoracic cancer cancer);Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma;primary intraocular B-cell lymphoma;diffuse large B-cell lymphoma;primary mediastinal large B-cell lymphoma;mucosa-associated lymphoid tissue (MALT) lymphoma;gastric MALT lymphoma;cutaneous T-cell lymphoma;primary central nervous system lymphoma;Sezary syndrome and Waldenstroem macroglobulinemia;lymphomas such as;acute lymphocytic leukemia;acute myeloid leukemia;chronic lymphocytic leukemia;chronic myeloid leukemia;hairy cell leukemia;chronic myeloid leukemia;adult T-cell leukemia;leukemias such as;carcinoma;adenocarcinoma;thyroid cancer, including papillary and medullary thyroid carcinoma;choriocarcinoma;Ewing's sarcoma;bone cancer, including osteosarcoma;high-grade osteosarcoma;rhabdomyosarcoma;Ewing's sarcoma sarcoma);malignant fibrous histiocytoma of bone;chordoma;sarcomas including soft tissue sarcomas;myeloma;Multiple myeloma;Labia cancer;Laryngeal cancer;Hypopharynx carcinoma;Tongue cancer;Salivary gland carcinoma;Cervix carcinoma;Uterine cancer;Endometrium carcinoma;Chorion carcinoma;Testicular cancer;Urinary carcinoma;Bronchial cancer;Basal cell tumor;Teratoma;Retinoblastoma;Choroidal melanoma;Seminoma;Chondrosarcoma;Myosarcoma;Liposarcoma;Fibrosarcoma;Plasma cell neoplasm;Hepatocellular carcinoma;Advanced liver cancer;Gastrointestinal stromal tumor;Neuroendocrine tumor;Bile duct cancer;Appendix cancer;Gastrointestinal carcinoid tumor;Carcinoid tumor;Pancreatic islet tumor;Small intestine cancer;Gastric 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 and / or diseases involving CCR6 and / or CCL20 mediated metastasis, chemotaxis, cell adhesion, transendothelial migration, cell proliferation and / or survival.

[0078] In particular, such diseases, conditions or disorders ameliorated 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 injury) arthritis; psoriasis; psoriatic arthritis; inflammatory skin disorders, such as rosacea; Crohn's disease; ulcerative colitis; irritable bowel syndrome; inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjogren's syndrome; autoimmune hepatitis; primary sclerosing cholangitis; psoriasis, including plaque psoriasis, guttate psoriasis, inverse 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 head and neck cancer; Hodgkin's lymphoma; cervical cancer; endometrial cancer; colon cancer; gastrointestinal stromal tumor; pancreatic cancer; prostatic cancer; leukemia, including acute myeloid leukemia; ovarian cancer; oesophageal cancer carcinomas); mesothelioma; neuroblastoma; sarcoma, such as 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, such diseases, conditions or disorders ameliorated by modulation of the CCR6 receptor are selected from the following: - an inflammatory / autoimmune disease, condition or disorder (e.g. psoriasis; psoriatic arthritis; rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; inflammatory skin disorders such as rosacea; Crohn's disease; ulcerative colitis; irritable bowel syndrome; inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjogren's syndrome; autoimmune hepatitis; and / or primary sclerosing cholangitis). In particular, such a disease, condition or disorder is psoriasis, psoriatic arthritis or inflammatory bowel disease; and may in particular be selected from A1) psoriasis or psoriatic arthritis; or A2) inflammatory bowel disease; and / or - cancer (e.g. lymphoma (e.g. T-cell lymphoma); brain cancer (e.g. glioma or glioblastoma); breast cancer; colorectal cancer; hepatocarcinomas; renal cell carcinoma; lung cancer; and / or gastric cancer.

[0080] When used for the prevention or treatment of cancer, such use may be achieved by administering to a patient 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl} -[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-ethanone; or (S)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-(6-methyl-pyrimidin-4-yl)-but-3-yn-2-ol; or a pharma- ceutically acceptable salt thereof) as monotherapy, as well as in combination with one or more chemotherapeutic agents and / or radiotherapy and / or targeted therapy, in particular in combination with targeted therapy.

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

[0082] The term "targeted therapy" refers to the prevention (adjuvant therapy) and / or treatment of cancer with one or more anti-neoplastic agents, such as small molecules or antibodies, that act on specific types of cancer cells or stromal cells. Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells (immunotherapy); or inhibit angiogenesis, the growth and formation of new blood vessels within tumors; or deliver toxic substances directly to cancer cells to kill them. 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl]-propan-2-ol; An example of a targeted therapy that is particularly suitable for combination with (S)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-(6-methyl-pyrimidin-4-yl)-but-3-yn-2-ol; or a pharma- ceutically acceptable salt thereof) is immunotherapy, in particular immunotherapy targeting the programmed death receptor 1 (PD-1 receptor) or its ligand PD-L1.

[0083] Immunotherapy further refers to (i) agonists of stimulatory (including costimulatory) receptors or (ii) antagonists of inhibitory (including costimulatory) signals to T cells, both of which lead to the amplification of antigen-specific T cell responses (often called immune checkpoint regulators). Some of the stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory 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 the TNF family of molecules that bind to the cognate TNF receptor family members: 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, Lymphotoxin a These include 1p2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0084] The compound of formula (I) of the present invention or the compound of formula (I) disclosed in WO2021219849 (e.g., 2-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-ethanone; or (S)-4-{5-[ When used in combination with (R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-(6-methyl-pyrimidin-4-yl)-but-3-yn-2-ol; or a pharma- ceutically acceptable salt thereof), the term "targeted therapy" refers in particular to agents such as: 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, Momelotinib); d) Aromatase inhibitors (e.g., Exemestane, Letrozole, Anastrozole, Vorozole, Formestane, Fadrozole); e) Signal Transduction Inhibitors (STIs). "Signal Transduction Inhibitors" are agents that induce apoptosis by selectively inhibiting one or more critical steps in a signal pathway in the normal functioning of cancer cells. Suitable STi's 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) her-2 / neu receptor inhibitors (e.g., farnesyltransferase inhibitors (FTIs) (e.g., L-744,832 (Kohl et al., Nat. Med., 1(8):792-797 (1995))); (iv) inhibitors of the Akt family kinases or Akt pathway (e.g., rapamycin (see, e.g., Sekulic et al., Cancer Res., 60:3504-3513 (2000))); (v) cell cycle kinase inhibitors (e.g., flavopiridol and UCN-01 (see, e.g., Sausville, Curr. Med. Chem. Anti-Cane. Agents, 3:47-56 (2003))); and (vi) phosphatidylinositol kinase inhibitors (e.g., LY294002 (see, e.g., Vlahos et al., J. Med. 1999, 11:111-112 (2003))). Biol. Chem., 269:5241-5248 (1994).)) f) Angiogenesis inhibitors, in particular VEGF signaling inhibitors (e.g. Bevacuzimab (Avastin), Ramucirumab, Sorafenib or Axitinib); g) Immune checkpoint inhibitors (e.g., Pembrolizumab (Lambrolizumab, MK-3475), Nivolumab, Pidilizumab (CT- anti-PD1 antibodies such as REGN2810, BGBA317, PF-06801591, MGA-012, TSR042, JS-001, BCD100, IBI-308, BI-754091; fusion proteins targeting PD-1 (e.g., AMP-224); small molecule anti-PD1 agents (e.g., compounds disclosed in WO2015 / 033299, WO2015 / 044900, and WO2015 / 034820); anti-PD1L antibodies (e.g., BMS-936559, atezolizumab (MPDL3280A, RG7446), avelumab (MSB0010718C), durvalumab (MEDI4736); anti-PDL2 antibodies (e.g., AMP224); anti-CTLA-4 antibodies (e.g., ipilimumab, tremilmumab); anti-lymphocyte activation gene 3 (LAG-3) antibodies (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 immunoreceptor (TIGIT) antibodies with ITIM domains (e.g., RG6058 (anti-TIGIT, MTIG7192A)); anti-killer cell immunoglobulin-like receptors (KIR) (e.g., Lirilumab (IPH2102 / BMS-986015)), galectin antagonists (e.g., Galectin-1, Galectin-9), BTLA; h) Vaccine therapy approaches (e.g. dendritic cell vaccination, DNA, peptide or protein vaccination (e.g. using gp100 peptides or MAGE-A3 peptides) as well as recombinant viruses; i) Reintroduction of patient-derived or allogenic (non-autologous) cancer cells genetically modified to secrete immune modulators such as Granulocyte-Monocyte Colony-Stimulating Factor (GMCSF) gene-transfected tumor cell vaccine (GVAX) or Fms-related 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, such as chimeric antigen receptor (CAR) modified T cells (e.g., CTL019); k) cytokine or immunocytokine-based therapy (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, glucopyranosyl lipid A, CpG oligodeoxynucleotides); m) Thalidomide analogues (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 receptor associated gene (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 mimetic proteins Tumor-specific antigens such as inflammatory bowel disease (IMD) and T-cell surface markers molecules that bind to (e.g., designed ankyrin repeat proteins (DARPINS), bispecific T cell engagers (BITEs, e.g., AMG103, AMG330); p) antibodies or small molecule inhibitors targeting the colony-stimulating factor-1 receptor (CSF-1R) (e.g., Emactuzumab (RG7155), Cabiralizumab (FPA-008), PLX3397); q) Agents 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) Agents that target adenosine receptors or the ectonucleotidases CD39 and CD73 that convert adenosine triphosphate (ATP) to adenosine (e.g., MEDI9447 (anti-CD73 antibody), PBF-509; CPI-444 (adenosine A2a receptor antagonist); s) antagonists to chemokine receptors such as CCR2 or CCR4; t) (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or ex vivo anti-CD25 bead depletion depleting or inhibiting T regulatory cells (by anti-CD25 bead depletion) or reversing or preventing T cell anergy or exhaustion; system v) agents).

[0085] 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl]-propan-2-ol; 2,4]oxadiazol-5-yl)-piperidin-1-yl]-ethanone; or (S)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-(6-methyl-pyrimidin-4-yl)-but-3-yn-2-ol; or a pharma- ceutically acceptable salt thereof), immune checkpoint inhibitors and, in particular, those targeting the PD-1 receptor or its ligand PD-L1 are preferred.

[0086] The term "chemotherapy" refers to the treatment of cancer with one or more cytotoxic anti-neoplastic agents ("cytotoxic chemotherapeutic agents"). Chemotherapy is often combined with other cancer treatments such as radiation therapy or surgery. The term specifically refers to traditional chemotherapy agents that act by killing rapidly dividing cells, which is one of the main characteristics of most cancer cells. Chemotherapy may use one drug at a time (single-agent chemotherapy) or several drugs at a time (combination or polychemotherapy). Chemotherapy that uses drugs that are converted to cytotoxic activity only by exposure to light is called photochemotherapy or photodynamic therapy.

[0087] The term "cytotoxic chemotherapeutic agent" or "chemotherapeutic agent" as used herein means an active anti-neoplastic agent that induces apoptosis or necrosis of cells.

[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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl]-propan-2-ol; or (S)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-(6-methyl-pyrimidin-4-yl)-but-3-yn-2-ol; or a pharma-ceutically acceptable salt thereof), the term refers in particular to conventional cytotoxic chemotherapeutic agents such as: 1) alkylating agents, including but not limited to nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes (e.g., uracil mustard, mechlorethamine, chlorambucil, cyclophosphamide, ifosfamido, streptozocin, carmustine, lomustine, melphalan, busulfan, procarbazine, dacarbazine, temozolomide, pipobroman, triethylene-melamine, triethylenethiophosphoramine, thiotepa, or altretamine; especially temozolomide; 2) Platinum agents (e.g., cisplatin, carboplatin, or oxaliplatin); 3) Antimetabolites (e.g., 5-fluorouracil, floxuridine, pentostatine, 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) a mitotic inhibitor (e.g., paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, or estramustine); or 6) a topoisomerase inhibitor (e.g., etoposide, teniposide, topotecan, irinotecan, diflomotecan, or elomotecan). Also suitable are cytotoxic agents, such as biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-propan-2-ol; 1-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl]-propan-2-ol;

[0036] Preferred cytotoxic chemotherapeutic agents are the alkylating agents described above, particularly fotemustine (fotemustine), when used in combination with (S)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-(6-methyl-pyrimidin-4-yl)-but-3-yn-2-ol, or a pharma- ceutical acceptable salt thereof. or pharmaceutically acceptable salts of these compounds; especially temozolomide; mitotic inhibitors (especially paclitaxel, docetaxel, ixabepilone; or pharmaceutically acceptable salts of these compounds; especially paclitaxel); platinum agents (especially cisplatin, oxaliplatin and carboplatin); and etoposide and gemcitabine.

[0090] For the avoidance of any doubt, where a compound is described as being useful for the prevention or treatment of a disease, condition or disorder, such compound is likewise suitable for use in the manufacture of a medicament for the prevention or treatment of that disease.

[0091] The present invention also relates to a method for the prevention or treatment of the diseases, conditions or disorders mentioned above and / or below, which comprises administering to a subject a pharma- ceutical effective amount of a compound as described above and / or below, alone or in combination with other pharmacologically effective compounds and / or treatments.

[0092] In a preferred embodiment of the invention, the dosage of the compound of formula (I) is comprised between 1 mg and 1000 mg / day, in particular between 5 mg and 500 mg / day, further between 25 mg and 400 mg / day, especially between 50 mg and 200 mg / day.

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

[0094] Preparation of Compounds of Formula (I) A further aspect of the present invention is a method for preparing the compound of formula (I). The compound according to formula (I) of the present invention can be prepared from commercially available or known starting materials according to the methods described in the experimental section; by analogy; or by suitable modification of the general synthetic route disclosed in PCT / EP2021 / 061401. The obtained compound may be converted into a salt, in particular into its pharma- ceutically acceptable salt, by methods known per se.

[0095] Experimental section Abbreviations (used in this section and in the preceding parts of the specification): Ac Acetyl for anal analysis anh anhydrous aq. Water-based 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 grams HEK Human Embryonic Kidney Hex h time 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 mL Milliliters nBu n-Butyl org organic prep for preparative separation iPr Isopropyl PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate rpm revolutions per minute RT room temperature rxn reaction sat saturation 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 are not intended to limit its scope in any way.

[0097] General: All temperatures are given in degrees Celsius (° C.). Unless otherwise noted, reactions take place at RT under an argon atmosphere and are carried out in round-bottom flasks or sealable tubes equipped with magnetic stir bars.

[0098] Qualitative methods used: LC-MS retention times were obtained using the following elution conditions: I) LC-MS(A): Zorbax RRHD SB-Aq, 1.8 μm, 2.1×50 mm column, thermostated at 40° C. The two elution solvents were: Solvent A=water+0.04% TFA; Solvent B=MeCN. The eluent flow rate was 0.8 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0099] [Table 1] Chiral HPLC / SFC retention times were obtained using the following elution conditions: I) Chiral HPLC (A): A CHIRALPAK AD-H, 5 μm, 4.6×250 mm column was used, thermostated at 25° C. The two elution solvents were as follows: Solvent A=Hep; Solvent B=EtOH. The eluent flow rate was 0.8 mL / min, and the isocratic solvent ratio was 80% (A) / 20% (B).

[0100] II) Chiral SFC(B): A CHIRALCEL OD-H, 5 μm, 4.6×250 mm column was used, thermostated at 40° C. The two elution solvents were as follows: Solvent A=CO2; Solvent B=MeOH. The eluent flow rate was 4 mL / min, and the isocratic solvent ratio was 90% (A) / 10% (B).

[0101] III) Chiral SFC(C): A CHIRALPAK AD-H, 5 μm, 4.6×250 mm column was used, thermostated at 40° C. The two elution solvents were as follows: Solvent A=CO2; Solvent B=EtOH. The eluent flow rate was 4 mL / min, and the isocratic solvent ratio was 80% (A) / 20% (B).

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

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

[0104] Purification methods 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 elution solvents were as follows: Solvent A=water+0.5% formic acid; Solvent B=water+0.5% formic acid; = MeCN. The eluent flow rate 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 the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0106] [Table 2] II) Prep LC-MS(II): An X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% NH4OH (25%); Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0107] [Table 3] III) Prep LC-MS(III) An X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% NH4OH (25%); Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0108] [Table 4] IV) Prep LC-MS(IV) An X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% NH4OH (25%); Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0109] [Table 5] V) Prep LC-MS(V): An Agilent column (Zorbax SB-Aq, 5 μm OBD, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% formic acid; Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0110] [Table 6] VI) Prep LC-MS(VI): An Agilent column (Zorbax SB-Aq, 5 μm OBD, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% formic acid; Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0111] [Table 7] VII) Prep LC-MS(VII): An Agilent column (Zorbax SB-Aq, 5 μm OBD, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% formic acid; Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0112] [Table 8] VIII) Prep LC-MS(VIII): A Zorbax column (SB-Aq, 7 μm OBD, 50×150 mm) was used. The two elution solvents were: Solvent A=MeCN; Solvent B=water+0.5% formic acid (25%). The characteristics of the mixture proportions of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0113] [Table 9] IX) Prep LC-MS(IX): An Agilent column (Zorbax SB-Aq, 5 μm OBD, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% formic acid; Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0114] [Table 10] X) Prep LC-MS(X) An X-Bridge column (Waters C18, 10 μm OBD, 50×150 mm) was used. The two elution solvents were: Solvent A=water+0.5% NH4OH (25%); Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0115] [Table 11] XI) Prep LC-MS (XI) An X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% NH4OH (25%); Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the elution mixture as a function of the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0116] [Table 12] Preparative chiral SFC and HPLC methods used: Preparative chiral SFC and HPLC purification were carried out using the conditions described below.

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

[0118] II) Prep Chiral SFC (II): A ChiralCel OD-H (5 μm, 30×250 mm) column was used, thermostated at 40° C. The elution solvent was CO2 / MeOH 90 / 10, with a flow rate of 160 mL / min.

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

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

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

[0122] Preparation of intermediates of 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) was added dropwise successively DIPEA (54 mL) and T3P® (50% in DCM, 55.5 mL) while maintaining the temperature at RT with a water bath. The resulting solution was stirred at RT for 1 h and quenched with half-saturated aq. NaHCO3. The aqueous phase was further extracted with DCM and the organic phases were combined, dried over MgSO4 and concentrated under vacuum. The residue was dried under HV to give the title compound as an off-white solid (22.4 g). LC-MS (A):t R =0.79min;[M+H]+:259.13.

[0123] Preparation of intermediates of formula A4 A4.1: 3-Methyl-3-[4-(2,2,2-trifluoro-ethyl)-benzoyl]-azetidine-1-carboxylic acid tert-butyl ester 1-Bromo-4-(2,2,2-trifluoroethyl)benzene (1.36g) anh To a solution cooled to -78°C in Et2O (12 mL) was added dropwise tBuLi (1.6 M in pentane, 5.17 mL) under argon, keeping the internal temperature below -70°C. The resulting mixture was stirred at -78°C for 5 min and a solution of Weinreb amide A2.1 (1.2 g) in anh THF (12 mL) was added dropwise, keeping the internal temperature below -70°C. The reaction mixture was stirred for 15 min, quenched with water and extracted with EA. The combined organic phases were washed with brine, dried over MgSO4 and evaporated to dryness. The resulting crude material was purified by CC using a Biotage® pre-packed cartridge Sfaer Silica D, eluting with Hep / EA to give 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 under argon, nBuLi (2.5 M in hexanes, 21.2 mL) was added dropwise while maintaining the internal temperature below -70°C. The resulting mixture was stirred at -78°C for 20 min. A solution of Weinreb amide A2.1 (10 g) in anhydrous THF (50 mL) was added dropwise while maintaining the internal temperature below -70°C. The resulting solution was allowed to warm to RT and stirred until the reaction was complete. The reaction mixture was quenched with water and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4 and evaporated to dryness. The resulting crude material was purified by CC using a Biotage® pre-packed cartridge Sfaer Silica D eluting with Hep / EA to give 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 of formula A6 To a solution of 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 under argon, HexLi (2.3 M in hexane, 1.3-1.4 eq) was added dropwise while maintaining the internal temperature below -70°C (except for intermediate of formula A6.1 where HexLi was replaced by nBuLi, 2.5 M in 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 was purified using Biotage® pre-packed cartridges Sfaer KP-Amino D and / or Sfaer Silica D, eluting with Hep / EA. If necessary, further purification by prep. LC-MS was performed using the conditions listed in the table below.

[0126] For the intermediate of formula A6.1, subsequent purification by prep chiral HPLC (I) afforded the title compound as the first eluting enantiomer (Chiral HPLC (A): t R =6.76min).

[0127] For the intermediate of formula A6.2, subsequent purification by prep chiral SFC (II) afforded the title compound as the second eluting enantiomer (chiral HPLC (B): t R =2.21 min).

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

[0129] [Table 14] Preparation of intermediates of formula A8 A8.1: 3-Hydroxymethyl-bicyclo[1.1.1]pentane-1-carboxylic acid To a solution of 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carbonitrile (300 mg) in EtOH (4.6 mL) was added water (1 mL) and aq.NaOH (10.8 M, 1.3 mL). The reaction mixture was heated to 75° C. and stirred for 1 h30. 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 give 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-propionylamino-cyclohexanecarboxylic 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). The solution was stirred at RT for 30 min, after which the solvent was evaporated to give 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-propionylamino-cyclohexanecarboxylic acid methyl ester To a suspension of the intermediate of formula A8.2.1 (190 mg) in THF (2 mL) was added propionic anhydride (0.14 mL) and TEA (0.41 mL) and the mixture was stirred at 60° C. for 2 h. The solvent was evaporated and the residue was purified by prep LC-MS (X) to give 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-propionylamino-cyclohexanecarboxylic acid To a suspension of intermediate of formula A8.2.2 (84 mg) in MeOH (3.5 mL) was added lithium hydroxide monohydrate (31 mg) and the mixture was stirred at 65° C. for 2.5 h. An additional amount of lithium hydroxide monohydrate (15 mg) was added and the mixture was stirred at 65° C. for 16 h. The reaction was filtered and concentrated in vacuo. The crude was purified by prep LC-MS (VI) to give 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) was added acetic anhydride (0.12 mL) and TEA (0.47 mL), and the reaction mixture was heated to 60° C. and stirred for 1 h. The reaction was diluted with MeCN and water and directly purified by prep LC-MS (X+VI) to give the desired product as a white solid. During purification by prep LC-MS under basic conditions (X), hydrolysis of the methyl ester appears to have occurred. LC-MS (A): t R =0.38min;[M+H] + :169.99.

[0134] Preparation of intermediates of formula A9 Step A: A mixture of intermediate of formula A7 (1 eq), 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 h. The reaction mixture was cooled to RT and filtered. The filtrate was directly purified by prep LC-MS using the conditions listed in the table below to give the title compound.

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

[0136] [Table 15]

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

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

[0139] Preparation of intermediates of formula B2 B2.1: N',3-Dihydroxy-2,2-dimethylpropanimidamide To a solution of 3-hydroxy-2,2-dimethylpropanenitrile (200 mg) in EtOH (14 mL) was added hydroxylamine hydrochloride (425 mg) and K2CO3 (1.12 g). The mixture was heated to 85° C. and stirred for 21 h. The reaction was filtered and washed with EtOH. The combined filtrate was concentrated in vacuo, suspended in n-heptane, and then concentrated again to give the title compound as a white slightly sticky 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]pentane-1-carboximidamide To a solution of 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carbonitrile (250 mg) in EtOH (4.3 mL) was added hydroxylamine hydrochloride (325 mg) and K2CO3 (1.07 g). The reaction was heated to 80 °C and stirred for 16 h. After cooling to RT, the reaction mixture was filtered, concentrated, and dried under HV to give the desired product as a white viscous foam (324 mg). LC-MS (A): R=0.22min;[M+H] + :157.19.

[0141] Preparation of intermediates of formula B3 B3.1: 3-{(R)-hydroxy-{5-[3-(2-hydroxy-1,1-dimethyl-ethyl)-[1,2,4]oxadiazol-5-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a solution of intermediate of formula B1.1 (50 mg) in DMF (1 mL) was added DIPEA (40 mg) and PyBOP (83 mg). After stirring at RT for 15 min, a solution of intermediate of formula B2.1 (28 mg) in DMF (0.3 mL) and K3PO4 (90 mg) was added. The mixture was heated at 85° C. for 16 h. The reaction mixture was diluted with MeCN and purified directly by prep LC-MS (VI) to give 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]pent-1-yl)-[1,2,4]oxadiazol-5-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a solution of intermediate of formula B1.1 (50 mg) in DMF (1 mL) was added DIPEA (40 mg) and PyBOP (83 mg). After stirring at RT for 20 min, a solution of intermediate of formula B2.2 (33 mg) in DMF (0.7 mL) and K3PO4 (90 mg) was added. The mixture was heated at 85° C. for 16 h. The reaction mixture was diluted with MeCN and purified directly by prep LC-MS (III)+(I) to give the desired product as a white solid (15 mg). LC-MS (A):t R =0.99min;[M+H] + :601.26.

[0143] Preparation of intermediates of formula B4 B4.1: 2-[5-(5-{(R)-hydroxy-(3-methyl-azetidin-3-yl)-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-methyl-propan-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 at RT for 1 h, the reaction was concentrated to dryness to give the desired product as a yellow foam (39 mg). LC-MS (A): R =0.69min;[M+H] + :477.28.

[0144] B4.2: (R)-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]pent-1-yl)-[1,2,4]oxadiazol-5-yl]-pyridin-3-yl}-(3-methyl-azetidin-3-yl)-[4-(2,2,2-trifluoro-ethyl)-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 at RT for 1 h, the reaction was concentrated to dryness to give the desired product as a white solid (14 mg). LC-MS (A): R =0.69min;[M+H] + :501.07.

[0145] Preparation of intermediates of formula C1 C1.1: 3-[(R)-(5-Bromo-pyridin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized starting from the intermediate of formula A4.2 and 3,5-dibromo-pyridine following the procedure described for the intermediate of formula A6. Subsequent chiral separation using a prep chiral SFC (III) afforded the title compound as the first eluting enantiomer. LC-MS (A): R =1.12min;[M+H]+ : 475.09; Chiral SFC (C): t R =1.41min.

[0146] Preparation of intermediates of formula C2 C2.1: (R)-(5-bromo-pyridin-3-yl)-(4-isopropyl-phenyl)-(3-methyl-azetidin-3-yl)-methanol The title compound was synthesized starting from the intermediate of formula C1.1 according to the procedure described for intermediate A10. LC-MS (A): R =0.74min;[M+H] + :375.02.

[0147] Preparation of intermediates of formula C3 C3.1: (R)-(5-Bromo-pyridin-3-yl)-(1,3-dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-methanol The title compound was synthesized starting from the intermediate of formula C2.1 according to the procedure described for Examples 1-9 (Procedure A). LC-MS (A): R =0.75min;[M+H] + :389.06.

[0148] Preparation of intermediates of formula C4 C4.1: (R)- or (S)-2-pyrimidin-4-yl-but-3-yn-2-ol C4.1.1: Pyrimidine-4-carboxylic acid methoxy-methyl-amide To a suspension of pyrimidine-4-carboxylic acid (500 mg) in DCM (50 mL) were successively added N,O-dimethylhydroxylamine hydrochloride (413 mg), DIPEA (2.37 mL) and T3P® (50% in DCM, 1.93 mL). The resulting solution was stirred at RT for 18 h and quenched with sat. aq. NaHCO3. The aqueous phase was further extracted with DCM and the combined organic phases were washed with brine, dried over MgSO4 and concentrated under vacuum. The resulting crude material was purified by elution with Biotage® pre-packed cartridges Sfaer Purification by CC on Silica D eluting with DCM / MeOH gave the title compound as a colourless resin (500 mg). LC-MS (A): R =0.41min;[M+H] + :168.08.

[0149] C4.1.2: 1-Pyrimidin-4-yl-ethanone To a solution of intermediate of formula C4.1.1 (500 mg) in anh THF (7.5 mL) cooled to -78 °C under argon was added MeMgBr (3 M in Et2O, 2 mL) dropwise. The reaction mixture was stirred at RT for 15 min, quenched with half-saturated aq. NH4Cl and extracted with DCM. The combined organic phases were dried over MgSO4 and evaporated to dryness. The resulting crude material was purified by CC using a Biotage® pre-packed cartridge Sfaer Silica D eluting with DCM / MeOH to give the title compound as an off-white solid (260 mg). LC-MS (A):t R = 0.46 min; 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-Pyrimidin-4-yl-but-3-yn-2-ol To a solution of trimethylsilylacetylene (267 mg) in anh THF (3.5 mL) cooled to 0° C. under argon, HexLi (2.3 M in hexane, 1.16 mL) was added dropwise while maintaining the temperature below 5° C. The reaction mixture was stirred at 0° C. for 1 h 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 h while the temperature was allowed to slowly reach RT. It was quenched by the addition of MeOH (5 mL) and K2CO3 (294 mg) was added. After stirring at RT for 30 min, the reaction mixture was filtered, diluted with MeOH and water, and purified by prep LC-MS (III). Subsequent chiral separation using a prep chiral SFC (IV) afforded 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 eluting enantiomer had the following retention time: Chiral SFC (D): t R =1.81min.

[0151] Preparation of the Examples To a solution of intermediate of formula A10 or B4 (1 eq) in anhydrous dioxane (18-25 mL / mmol) was added DIPEA (2-3 eq), formaldehyde (37% solution in H2O, 1.5-3.5 eq) and NaBH(OAc)3 (1.5-2.6 eq). The reaction mixture was stirred at RT for 15 min-18 h, quenched with aq. NaOH (1M) and extracted with EA. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product obtained was purified by prep LC-MS using the conditions listed in the table below.

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

[0153] [Table 18] Mixtures of intermediate of formula C3.1 (1 eq), 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) were flushed with argon, heated at 80 °C and stirred for 30 min-1.5 h. The reaction mixtures were cooled to RT, diluted with MeOH and water, filtered and purified by prep LC-MS using the conditions shown in the table below. 4-Ethynylcyclohexan-1-ol was 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide 13.1: 4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester To a suspension of intermediate of formula A10.3 (350 mg) in dioxane (3.5 mL) was added DIPEA (0.17 mL), aq. formaldehyde (37 wt.%, 0.13 mL) and NaBH(OAc)3 (163 mg). 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 in vacuo to give a yellow oil which was purified by prep LC-MS (IV) to give 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid To a solution of intermediate of formula A13.1 (230 mg) in MeOH (5 mL) was added LiOH.H2O (35 mg) and the mixture was stirred at 65 °C for 2 h. As needed to complete the conversion, two more portions of LiOH.H2O were added (30 and 15 mg, respectively) and further stirred at 65 °C for 5 h and 1 h, respectively. After cooling to RT, the mixture was filtered and the solvent was evaporated. The residue was purified by prep LC-MS (VI) to give 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide To a solution of intermediate of formula 13.2 (25 mg) and HATU (17 mg) in DMF (1 mL) was added DIPEA (20 mg). After stirring at RT for 5 min, a solution of ammonium chloride (2.8 mg) in DMF (1 mL) was added and the reaction was stirred at RT for 1 h. The mixture was diluted with MeCN and water and purified directly by prep LC-MS (III) to give 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid amide 14.1: trans-4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid methyl ester To a suspension of intermediate of formula A10.9 (45 mg) in dioxane (0.5 mL) was added DIPEA (21 mg), aq. formaldehyde (37 wt.%, 24 mg) and NaBH(OAc)3 (27 mg). 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 in vacuo to give a yellow oil which was purified by prep LC-MS (XI) to give 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid To a suspension of intermediate 14.1 (28 mg) in MeOH (0.5 mL) was added LiOH·HO (4.5 mg). The mixture was stirred at RT for 16 h. Lithium hydroxide monohydrate (4.5 mg) was further added and the mixture was stirred at 85 °C for 4 h. The reaction was filtered, the solvent was evaporated and the crude was purified by prep LC-MS (VI) to give 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-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid amide To a solution of intermediate of formula 14.2 (21 mg) and HATU (15 mg) in DMF (1 mL) was added DIPEA (17 mg). After stirring at RT for 5 min, a solution of ammonium chloride (2.5 mg) in DMF (1 mL) was added and the reaction was stirred at RT for 1 h. The mixture was diluted with MeCN and water and purified directly by prep LC-MS (III) to give 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-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-bicyclo[2.2.2]octane-1-carboxylic acid amide 15.1: 5-{(R)-hydroxy-(3-methyl-azetidin-3-yl)-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-nicotinonitrile as the HCl salt The title compound was synthesized starting from the intermediate of formula A6.1 according to the procedure described for the intermediate of formula B4.1. LC-MS (A): R =0.67min;[M+H] + :361.99.

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

[0162] 15.3: 5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-N-hydroxy-nicotinamidine The title compound was synthesized starting from the intermediate of formula 15.2 following the procedure described for the intermediate of formula A7. LC-MS (A): 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 starting from 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid according to the procedure described for the intermediate of formula 14.3. LC-MS (A): R =0.59min;[M+H] + :212.13.

[0164] 15.5: 4-Carbamoyl-bicyclo[2.2.2]octane-1-carboxylic acid as its 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) was added LiOH·H2O (105 mg) and the reaction mixture was stirred at 50 °C for 1 h. Evaporation to dryness gave the crude product as a white powder (238 mg). LC-MS (A): R =0.43min;[M+H] + :198.18.

[0165] 15.6: 4-[3-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-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) was added intermediate 15.5 (21 mg), DIPEA (40 mg) and HATU (48 mg). After stirring at RT for 40 min, the reaction mixture was heated at 60° C. overnight. The reaction mixture was diluted with EtOAc and washed with 1M NaOH. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by prep LC-MS (III) to give 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-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-trans-cyclohexyl}-acetamide 16.1: {4-[3-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-cyclohexyl}-carbamic acid tert-butyl ester The title compound was synthesized starting from Boc-trans-4-aminocyclohexanecarboxylic acid and intermediate 15.3 following the procedure described for the intermediate of formula 15.6. LC-MS (A): R =0.86min;[M+H] + :616.16.

[0167] 16.2: (R)-{5-[5-(trans-4-amino-cyclohexyl)-[1, 2,4]Oxadiazol-3-yl]-pyridin-3-yl}-(1,3-dimethyl-azetidin-3-yl)-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol The title compound was synthesized starting from the intermediate of formula A16.1 according to the procedure described for the intermediate of formula B4.1. LC-MS (A): R =0.58min;[M+H] + :516.09.

[0168] 16.3: N-{4-[3-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-trans-cyclohexyl}-acetamide To a solution of intermediate 16.2 (12 mg) and triethylamine (13 μL) in CH2Cl2 was added acetyl chloride (6 μL) at 0 °C and the reaction mixture was stirred at 0 °C for 30 min and at rt for 1 h. The reaction mixture was diluted with CH2Cl2 and the organic phase was washed with sat. aq. NaHCO3 and concentrated in vacuum. The crude was dissolved in MeOH, K2CO3 (37 mg) was added and the mixture was stirred at rt overnight. The organic phase was washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and concentrated in vacuum to give 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 bioactivity of the compounds is tested in a fluorescent imaging plate reader (FLIPR:Molecular Devices) using modified HEK-293 cells expressing human CCR6 (GenBank:AY242126). Two days before the bioassay, frozen cells are seeded on 384-well plates pre-coated with poly-L-lysine in DMEM medium supplemented with 10% FCS and 1% penicillin-streptomycin. On the day of the bioassay, cell supernatant is discarded and cells are stained with Fluo-8-AM (Focus Biomolecules) in Hanks Balanced Salt Solution (Gibco) buffered with 20 mM Hepes at pH 6.75 and supplemented with 0.05% BSA for 30 minutes in the dark at room temperature. The same buffer as above is also used for the washing and compound dilution steps, except that it does not contain dye (assay buffer). The cells are washed in a wash-station (Biotek) to remove excess dye, leaving a final volume of 40 microliters of assay buffer. The cells are incubated for 15 minutes at room temperature in the dark before the addition of the compounds. Stock solutions of the test compounds are prepared in DMSO at a concentration of 10 mM, serially diluted first in DMSO and then transferred to assay buffer to the concentrations required for the inhibition dose-response curves. After a 45 minute incubation period at room temperature in assay buffer, 10 microliters of each compound dilution are transferred from the compound plate to the plate containing the recombinant cells in the FLIPR instrument according to the manufacturer's instructions. The cells and compounds are pre-incubated for 30 minutes at room temperature in the dark before adding 10 microliters of the agonist CCL20 (Peprotech) to a final concentration of 10 nM, again using the FLIPR instrument. The change in fluorescence is monitored before and after the addition of the test compounds and agonists. The peak emission values ​​above the basal level after the addition of CCL20 are exported after baseline subtraction. The calculated IC 50 Values ​​may vary depending on the assay run on each day. This type of variation is known to those skilled in the art. IC 50 If values ​​were determined multiple times, the average value is shown. The data are shown in the table below.

[0170]

Table 20

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof 【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-trifluoro-ethyl; -L- is -- optionally substituted with one hydroxy ＊ -C≡C-C ０－２ -Alkylene- ＊＊ (asterisk( ＊ ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ＊＊ ) is R ４ indicates the point of attachment to -- oxadiazole-diyl; represents; and, R ４ teeth, -- C ３－７ -cycloalkyl; -- saturated 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring systems, in which one ring carbon atom is optionally replaced by a nitrogen atom; Or, -- 6-membered heteroaryl having 1 or 2 ring nitrogen atoms; represents; R ４ are independently unsubstituted or contain one hydroxy, hydroxy-C １－３ -Alkyl, carbamoyl, C １－３ -Alkyl-carbonyl-amino or C １－３ -substituted by alkyl-carbonyl; 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 are 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-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-trifluoro-ethyl; and, -L-R ４ represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl.

2. -R １ is C １－３ represents alkyl; R ２ is C １－４ represents alkyl; R ３ represents 2,2,2-trifluoro-ethyl; -L-, -- optionally substituted with one hydroxy ＊ -C≡C-C ０－２ -Alkylene- ＊＊ (asterisk( ＊ ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ＊＊ ) is R ４ indicates the point of attachment to -- oxadiazole-diyl; represents; and, R ４ but, -- C substituted by one substituent ３－７ -cycloalkyl, where the substituents are hydroxy, carbamoyl and C １－３ -alkyl-carbonyl-amino, C ３－７ -cycloalkyl; -- a saturated 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring system in which one ring carbon atom is optionally replaced by a nitrogen atom, said 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring system independently containing one hydroxy, hydroxy-C １－３ -Alkyl, carbamoyl, C １－３ -Alkyl-carbonyl-amino or C １－３ - saturated 5-8 membered bridged or spiro bicyclic hydrocarbon ring systems substituted by alkyl-carbonyl; Or, --unsubstituted 6-membered heteroaryl having 1 or 2 ring nitrogen atoms; represents; 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 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carba 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl )-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-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-trifluoro-ethyl; and, -L-R ４ represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. -R １ is C １－３ represents alkyl; R ２ is C １－４ represents alkyl; R ３ represents 2,2,2-trifluoro-ethyl; -L-, -- optionally substituted with one hydroxy ＊ -C≡C-C ０－２ -Alkylene- ＊＊ (asterisk( ＊ ) indicates the point of attachment to the pyridinyl ring, and two asterisks ( ＊＊ ) is R ４ ) indicates the point of attachment to represents; and, R ４ but, -- C substituted by one substituent ３－７ -cycloalkyl, wherein the substituent is hydroxy; ３－７ -cycloalkyl; or --unsubstituted 6-membered heteroaryl having 1 or 2 ring nitrogen atoms; represents; or -R １ is C １－３ represents alkyl; R ２ is C １－４ represents alkyl; R ３ represents 2,2,2-trifluoro-ethyl; -L-, -- oxadiazole-diyl; represents; and, R ４ but, -- C substituted by one substituent ３－７ -cycloalkyl, where the substituents are hydroxy, carbamoyl and C １－３ -alkyl-carbonyl-amino, C ３－７ -cycloalkyl; or -- a saturated 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring system in which one ring carbon atom is optionally replaced by a nitrogen atom, said 5- to 8-membered bridged or spiro bicyclic hydrocarbon ring system independently containing one hydroxy, hydroxy-C １－３ -Alkyl, carbamoyl, C １－３ -Alkyl-carbonyl-amino or C １－３ - saturated 5-8 membered bridged or spiro bicyclic hydrocarbon ring systems substituted by alkyl-carbonyl; represents; 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 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carba 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl )-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-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-trifluoro-ethyl; and, -L-R ４ represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: represents methyl.

5. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: represents methyl.

6. -R １ represents methyl; R ２ represents methyl; R ３ represents 2,2,2-trifluoro-ethyl; and, -L-R ４ 5-(4-hydroxy-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 3-(3-hydroxymethyl-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-5-yl, 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octadecyl)- 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; or -R １ represents methyl; R ２ represents methyl; R ３ represents isopropyl; and, -L-R ４ 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[ 1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; Or, -R １ represents methyl; R ２ represents methyl; R ３ represents 2,2,2-trifluoro-ethyl; and, -L-R ４ represents 3-(2-hydroxy-1,1-dimethyl-ethyl)-1,2,4-oxadiazol-5-yl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. R １ represents methyl; R ２ represents methyl; R ３ represents isopropyl; and -L-R ４ 2-(4-hydroxy-cyclohexyl)-ethyn-1-yl, 3-hydroxy-3-(pyrimidin-4-yl)-but-1-yn-1-yl, 5-(4-carbamoyl-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(3-acetamido-bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl, 5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-1,2,4-oxadiazol-3-yl, 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl, 5-(4-(ethyl-carbonyl-amino)-cyclohexyl)-1,2,4-oxadiazol-3-yl or 5-(4-carbamoyl-bicyclo[2.2.2]octan-1-yl)-1,2,4-oxadiazol-3-yl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. R １ represents methyl; R ２ represents methyl; R ３ represents isopropyl; and -L-R ４ represents 5-(4-acetamido-cyclohexyl)-1,2,4-oxadiazol-3-yl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. 2. The compound of claim 1, wherein the asymmetric carbon atom bearing the hydroxy group has the absolute configuration shown in formula (II): or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 (In formula (II), L, R 1 , R 2 , R 3 and R 4 are as defined in claim 1.) 10. The asymmetric carbon atom bearing the hydroxy group has the absolute configuration shown in formula (III); or a pharmaceutically acceptable salt thereof. 【Transformation 3】 (In formula (III), L, R 1 , R 2 , R 3 and R 4 are as defined in claim 8.)

11. trans-4-[3-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-cyclohexanol; cis-4-[3-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-cyclohexanol; (R)-(1,3-dimethyl-azetidin-3-yl)-{5-[5-(3-hydroxymethyl-bicyclo[1.1.1]pent-1-yl)-[1,2,4]oxadiazol-3-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol; N-[3-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[1.1.1]pent-1-yl]-acetamide; 4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octan-1-ol; 2-[5-(5-{(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methyl}-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-methyl-propan-1-ol; 1-[6-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-2-aza-spiro[3.3]hept-2-yl]-ethanone; trans-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-propionamide; cis-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl) -hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide; trans-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide; (R)-(1,3-dimethyl-azetidin-3-yl)-{5-[3-(3-hydroxymethyl-bicyclo[1.1.1]pent-1-yl)-[1,2,4]oxadiazol-5-yl]-pyridin-3-yl}-[4-(2,2,2-trifluoro-ethyl)-phenyl]-methanol; (R)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-pyrimidin-4-yl-but-3-yn-2-ol; (S)-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-2-pyrimidin-4-yl-but-3-yn-2-ol; trans-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-ylethynyl}-cyclohexanol; cis-4-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-ylethynyl}-cyclohexanol; 4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-bicyclo[2.2.2]octane-1-carboxylic acid amide; cis-4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid amide; Or, trans-4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexanecarboxylic acid amide; 2. The compound of claim 1, wherein:

12. cis-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide; or trans-N-[4-(3-{5-[(R)-(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-methyl]-pyridin-3-yl}-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-acetamide; 2. The compound of claim 1, wherein:

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

14. 13. 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 or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for use in the prevention or treatment of an inflammatory and / or autoimmune disease, condition or disorder.

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. A drug for the prevention or treatment of cancer; or inflammatory and / or autoimmune diseases, conditions, or disorders, comprising as an active ingredient a compound according to 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; 13. The compound of 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; Sjogren's syndrome; autoimmune hepatitis; primary sclerosing cholangitis; plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis; autoimmune keratitis; filamentous keratitis; autoimmune uveitis; allergic conjunctivitis; asthma; allergic diseases of the gastrointestinal tract; type 1 diabetes; endometriosis; meibomian gland dysfunction; or graft-versus-host disease.

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's lymphoma; cervical cancer; endometrial cancer; gastrointestinal stromal tumor; pancreatic cancer; prostate cancer; leukemia; 13. The compound of 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; 13. The compound of 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; Sjogren'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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