The present invention relates to novel compounds of Formula (I), or pharmaceutically acceptable salts thereof, and their use as CCR6 receptor modulators in the prevention or treatment of various diseases, conditions or disorders ameliorated by modulating said receptor. Furthermore, the present invention concerns related aspects such as pharmaceutical compositions containing one or more compounds of Formula (I) and processes for the preparation of said compounds.

Chemokine receptors comprise a family G-protein coupled receptors (GPCRs) that recognize and bind to peptide chemokine ligands. The predominant functions of chemokine receptors and their ligands are to induce leukocyte trafficking to-and-from lymphoid organs and tissues in the steady state, as well as in the context of an infection or inflammation. Additionally, chemokine signaling events can induce the activation of integrin molecules on the surface of immune cells, allowing firm adhesion to activated endothelium, facilitating migration from blood into inflamed tissue (Montresor A, Frontiers in Imm., 2012; Meissner A, Blood, 2003). Chemokine receptor 6 (CCR6, aliases BN-1 , C-C CKR-6, CD196, CKRL3, CMKBR6, DCR2, DRY6, GPR29, GPRCY4, STRL22) is a GPCR mainly expressed on effector CD4+ T helper cells, but is also present on B cells, CD8+ cytotoxic T cells, regulatory T cells (Treg), immature dendritic cells (DC) and type 3 innate lymphoid cells (ILC3) (Cua DJ, Nat Rev Immunol. 2010 Jul; 10(7):479-89. doi: 10.1038/nri2800). CCR6 binds to the chemokine CCL20 (chemokine (C-C 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 interactions dictate the humoral response in the intestinal mucosa and are required for lymphocyte homeostasis in the mucosa of the small intestine (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 production of IgA in the intestine, where CCL20 expressed in Peyer's patches guides CCR6+lgA+ B cells to the mucosa and secretory IgA can be released into the gut 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 highly upregulated by proinflammatory cytokines including IL-17A, TNFa and IL-1 b 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 tissue fibroblasts (Hattori T, Mediators Inflamm. 2015; 2015:436067. doi: 10.1155/2015/436067). Interleukin (IL)-17A expression 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). I L-17A expression has been shown to segregate with CCR6 expression 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 was also 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 clarifying the co-expression of IL-17A and CCR6 in RORgt+ cell types.

Certain disclosures in the prior art may be regarded as relating to modulation of CCR6. For instance, Tawaraishia et al. (Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 18, 2018, Pages 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 treating CCR6-mediated diseases such as autoimmune diseases, inflammation, psoriasis, multiple sclerosis or cancer. WC2014/075580 describes the use of aurintricarboxylic acid for targeting chemokine receptors. WC2015/084842 teaches certain sulfonamides which may be used in treating CCR6 related diseases. WC2017/087607, WC2010/131145, WO2013/061004, WC2013/061005, WC2019/036374 and WC2020/058869 provide certain cyclobutendiones for use in the treatment of chemokine/CCR6 related diseases. WC2019/136370 teaches a method of treating a certain type of psoriasis. WC2019/147862 proposes azetidine derivatives which may be used as chemokine modulators. WO2021219849 discloses azetidinyl-methanol derivatives as CCR6 receptor modulators.

Further, WO1999/43664 discloses certain pyrrolidinones with anti-inflammatory and analgesic properties. In W02019/105915 certain heterocyclic compounds are provided which may be used as MAGL inhibitors. WO2015/057626, US2015/0105366, WO2014/062658, W02015/057205 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 which may be used in treating rheumatoid arthritis or psoriasis. W003/022808 proposes certain azetidine derivatives for use as pesticides. W02008/103426 and W02007/022351 disclose certain quaternary ammonium compounds useful as muscarinic receptor antagonists. W02006/136830 teaches certain heteroaryl-alkylamines as protein kinase inhibitors. WO91/13359 proposes heterocyclic cholinergic enhancers. US3458635 teaches certain pyrrolidines which may be used for treating depression. GB 1304650 discloses spasmolytic pyrrolidines. US3479370, US3489769, US3499002, US 3542807 and US3651085 relate to certain pyrrolidines with analgesic/tranquilizing activity.

The present CCR6 modulators may be useful, alone, or in combination in the prevention or treatment of the following diseases or disorders: Rheumatoid arthritis (RA) causes chronic inflammation of the joints and chemokines regulate infiltration of the inflamed synovium by inflammatory cells. RA is characterized by the increased release of CCL20 and the 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 increased proportions of peripheral blood CCR6+ Th cells have been found in patients with early RA (van Hamburg JP, Arthritis Rheum. 2011 Jan; 63(1)73-83. doi: 10.1002/art.30093; Leipe J Arthritis Rheum. 2010 Oct; 62(10):2876-85. doi: 10.1002/art.27622; Nistala K, Arthritis Rheum. 2008 Mar; 58(3):875-87. doi: 10.1002/art.23291). The production of CCL20 is known to be up-regulated in synovium explants or fibroblast-like synoviocytes from RA patients after stimulation of TNF-a, IL-1 b and IL-17 (Matsui T, Clin Exp Immunol. 2001 Jul; 125(1): 155-61. doi: 10.1046/j.1365-2249.2001.01542.x; J Immunol. 2001 Nov 15; 167(10):6015-20. doi: 10.4049/jimmunol.167.10.6015; Chevrel G, Ann Rheum Dis. 2002 Aug; 61 (8)730-3. doi: 10.1136/ard.61.8.730). CCR6+ B cells in RA synovium have been reported, contributing to pathogenesis by antigen presentation, autoantibody production and/or inflammatory cytokine production. Furthermore, Rituximab is an efficacious therapy for RA (Cohen SB, Arthritis Rheum. 2006 Sep; 54(9):2793-806. doi: 10.1002/art.22025), supporting a role for CCR6+ B cells in RA pathogenesis. Additionally, 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 showed that CCR6-deficient mice developed a less severe joint inflammation in the collagen-induced arthritis (CIA) model. Reduced production of collagen-specific antibodies in CCR6-deficient mice were observed compared to WT mice, and arthritic 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).

CCR6+ Th17 are increased in peripheral blood in ankylosing spondylitis patients (Shen H, Arthritis Rheum. 2009 Jun; 60(6): 1647-56. doi: 10.1002/art.24568). Circulating interleukin-17-secreting interleukin-23 receptor-positive y/5 T cells were also 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, in was shown to be efficacious in ankylosing spondylitis (AS) (Baeten D, N Engl J Med. 2015 Dec 24; 373(26):2534-48. doi: 10.1056/NEJMoal 505066). CD32B expression on memory B cells in AS was increased and was associated with disease activity. Furthermore, CCR6 ⁺ cytotoxic T-cells and CD32B ⁺ memory B-cells were highly enriched within the synovial compartment of AS patients (Sueur A, Clin Exp Rheumatol. 2019 Nov 20; PMID: 31820725).

Psoriasis is a commonly occurring autoimmune skin disease. The role of Th17-associated cytokines has been clinically validated and their role in psoriatic inflammation confirmed (Paul C, J Eur Acad Dermatol Venereol. 2015 Jun; 29(6): 1082-90. doi: 10.1111/jdv.12751). An IL-17R-blocking antibody (brodalumab, AMG 827) were shown to reduce clinical manifestations of psoriasis and also to reduce CCL20 expression in skin biopsies from psoriasis patients (Papp KA, N Engl J Med. 2012 Mar 29; 366(13):1181-9. doi: 10.1056/NEJMoal 109017). Also, an IL-23 neutralizing antibody (guselkumab) was shown to be efficacious 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 failed to develop psoriasiform skin lesions following intradermal IL-23 injections (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 efficacious in the Aldara and IL-36a- injection mouse psoriasis models (Campbell JJ, J Immunol. 2019 Mar 15; 202 (6): 1687- 1692. doi: 10.4049/jimmunol.1801519; Campbell JJ, J Immunol. 2017 Nov 1 ; 199(9):3129-3136. doi: 10.4049/jimmunol.1700826). Furthermore, CCR6-deficient mice have been 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.2O18.07.036).

Anti-CCR6 neutralizing antibodies have also shown efficacy in Aldara induced ear swelling in mice (Robert R, JCI Insight. 2017 Aug 3; 2(15): e94821. Published online 2017 Aug 3. doi: 10.1172/jci.insight.94821). An engineered disulfide-linked CCL20 dimer, which 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 U S A. 2017 Nov 21 ; 114(47): 12460- 12465. doi: 10.1073/pnas.1704958114). Collectively, these data show that a positive feedback consisting of epidermal and dermal production of CCL20, potent recruitment of CCR6+ T cells or into inflamed psoriatic skin, their activation by IL-23 and their expression of IL-17A and IL-22, drives a pathogenic Th 17 response in psoriatic skin lesions. Inhibition of CCR6 has therefore been recognized as a potential therapeutic pathway to treat 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). CCR6 expression was shown to be upregulated in synovial membranes of psoriatic arthritis (PsA) patients (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 was shown to be highly upregulated in synovial fluid retrieved from PsA patients (Melis L, Ann Rheum Dis. 2010 Mar;69(3):618-23. doi: 10.1136/ard.2009.107649).

Additional inflammatory skin disorders including rosacea have been shown to have highly elevated levels of CCL20 in inflamed skin (Buhl T, JID, 2015).

CCR6 and CCL20 are highly 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). Increased enterocyte CCL20 production has been proposed to play an important role in lymphocyte recruitment to the colonic epithelium in irritable bowel disease (IBD) (Kwon JH, Gut. 2002 Dec; 51 (6):818-26. doi: 10.1136/gut.51 .6.818). CCL20 and CCR6 expression are also correlated with histological severity in rectum resected 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). Expression of CCL20 was significantly up-regulated in the PBMCs of patients with UC compared with those of normal healthy controls. UC groups treated with sulfasalazine and GC showed decreases of CCL20 expression in PBMCs, accompanied by ameliorated disease. TNFo or IL-1 p-induced CCL20 secretion was strongly reduced by sulfasalazine and/or GC treatment of human intestinal epithelial cell lines (Lee H J, 2 Inflamm Bowel Dis. 2005 Dec; 11 (12): 1070-9. doi: 10.1097/01. mib.0000187576.26O43.ac). CCR6 deficiency resulted in reduced intestinal pathology in mice treated with dextran sodium sulfate (DSS) to induce colonic inflammation (Varona R, Eur J Immunol. 2003 Oct; 33(10): 2937-46. doi: 10.1002/ej i.200324347). Th17 cells expressing CCR6 were shown to be important effectors mediating dry eye disease (DED), an inflammatory state at the ocular surface, potentially resulting in corneal perforation. Antibody-mediated neutralization of CCL20 in a DED mouse model reduced Th 17 recruitment into the ocular surface, resulting in improved clinical readouts (Dohlman TH, Invest Ophthalmol Vis Sci. 2013 Jun 12; 54(6):4081 -91 . doi: 10.1167/iovs.12-11216). Inhibition of the CCR6/CCL20 axis was therefore proposed as a therapeutic mechanism to treat DED.

CCR6 expression has been described on T cells isolated from the cerebrospinal fluid of multiple sclerosis (MS) patients (van Langelaar J, Brain, 2018 May 1 ; 141 (5): 1334-1349. doi: 10.1093/brain/awy069). CCR6 expression was also shown 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 have been 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 has shown that CCR6 is important for development of EAE (Reboldi A, Nat Immunol. 2009 May; 10(5):514-23. doi: 10.1038/ni.1716). This finding was confirmed in later study, showing that CCR6-deficient mice were resistant to disease induction with reduced peak severity. In the same study, vaccination with hCCL20 produced an anti-mouse CCL20 response in the host mice, which was sufficient to reduce clinical scores (Abraham M, Clin Immunol. 2017 Oct; 183:316-324. doi: 10.1016/j. dim.2017.09.018). However, conflicting data exists concerning the role for CCR6 in EAE development (J Neuroimmunol. 2009 Aug 18; 213(1-2):91-9. doi: 10.1016/j.jneuroim.2009.05.011). EAE severity and histopathology were significantly reduced after injection of anti- CCL20 upon first clinical manifestations (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 2017 Aug 3. doi: 10.1172/jci.insight.94821). IL-6 and IL-17 increase the expression of CCL20 from murine astrocytes (Meares GP, Glia. 2012 May; 60(5)771-81. doi: 10.1002/glia.22307).

CCR6 and CCL20 are proposed to influence kinetics of germinal center (GC) formation and B cell responses and CCR6 is considered a marker memory B cell precursors 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). Expression of CCR6 on naive, pre-GC, GC/plasma cell and memory B cells in peripheral B cells of systemic lupus erythematosus (SLE) patients 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 were shown to be increased in anti-DNA+ SLE patients, which correlated with disease severity and erythrocyte sedimentation rate (Zhong W, PeerJ. 2018; 6:e4294. doi: 10.7717/peerj .4294). Increased CCR6 expression in the salivary glands of patients with primary Sjogren's syndrome (pSS) was demonstrated [Scand J Immunol. 2020 Mar;91 (3):e12852. doi: 10.1111/sji.12852], A trend towards increased CCL20 mRNA expression was also observed. Significant reductions in CCR6+ Th cells (both CCR9- and CCR9+) in the circulation of patients with pSS as compared with healthy controls (HCs) were demonstrated [Scand J Immunol. 2020 Mar;91 (3):e12852. doi: 10.1111/sji.12852],

In an animal model of autoimmune hepatitis (AIH), administering anti-TNF-o suppressed hepatic CCL20 expression. Mice receiving anti-CCL20 showed reduced AIH. Furthermore, TNFo stimulation enhanced CCL20 expression in hepatocytes. These findings suggest that TNFo is essential in the induction of AIH through upregulation of hepatic CCL20 expression, which recruits CCR6+ T cells which drive pathology (Clin Immunol. 2013 Jan; 146(1): 15-25. doi: 10.1016/j.clim.2012.10.008).

The present CCR6 modulators may be useful, alone, or in combination in the prevention or treatment of autoimmune diseases or disorders including Posterior uveitis, allergic conjunctivitis, allergic disease in the gastrointestinal tract, type I diabetes and endometriosis (Medicina (Kaunas). 2018 Nov 16; 54(5). doi: 10.3390/medicina54050088). CCR6 modulators may also be useful, alone or in combination, to treat diseases of the ocular surface in which elevated levels of IL-17A have been recorded, including meibomian gland dysfunction; GVHD, graft-versus host disease; autoimmune keratitis, filamentary keratitis, dry eye syndrome with rheumatic arthritis; dry eye syndrome without systemic disease; Stevens-Johnson syndrome. (J Korean Med Sci. 2011 Jul;26(7):938-44. doi: 10.3346/jkms.2011.26.7.938).

The present CCR6 modulators may be useful, alone, or in combination in the prevention or treatment of malignant diseases. Modulation of the CCR6/CCL20 axis using siRNA, shRNA, CCR6 knock-out animals, CCL20 ligand treatment or antibodies has been shown to alter tumor growth and metastatic processes in experimental disease models as single agents, or in combination with immunotherapy (such as especially PD1 and/or PDL1 blockade) for the prevention I prophylaxis or treatment of cancers.

The therapeutic potential of modulating this axis for the treatment of malignancies has been described in tumor mouse models using small interfering RNA (siRNA) or small hairpin RNA (shRNA)-mediated silencing of CCR6 or CCL20. Specifically, in a mouse model of cutaneous T cell lymphoma (My-La cells), Abe et al. reported that the administration of a CCR6-targeted siRNA prolonged survival of animals when compared with control animals (Oncotarget. 2017 Jan 31; 8(5)7572-7585. doi: 10.18632/oncotarget.13810.). Using another approach, Ito and colleagues demonstrated that mice, injected with T lymphoma cells (My-La) harboring 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 co-workers demonstrated that, the average volume and weight of tumor nodules in mice injected subcutaneously with a set of colorectal cancer cell lines was decreased when CCR6 was silenced in the cancer cells by means of shRNA (PMID Biochim Biophys Acta Mol Basis Dis. 2018 Feb; 1864(2): 387-397. doi: 10.1016/j.bbadis.2O17.10.033.). In glioblastoma xenograft models using patient-derived glioblastoma cell lines, mice injected with cells harboring a shRNA construct silencing CCR6 expression survived longer than those injected with control cells. In addition, histology and immunohistochemistry revealed that tumors formed by glioma cells with CCR6-targeting shRNA were much smaller, and tumor vessel formation was significantly lower versus control tumors. Collectively, these data further support the notion that CCR6 signaling enhances the oncogenic potential of malignancies including lymphoma, colorectal tumors and glioblastoma (Oncogene. 2018 Jun; 37(23): 3070-3087. doi: 10.1038/s41388-018-0182-7.). Specifically, the implication of the CCR6/CCL20 axis in tumorigenesis using CCR6 knock-out animals was reported in the literature. In the CMT93 mouse model of colorectal cancer (ORC), the infiltration of T regulatory cells was completely prevented in tumors of mice deficient in CCR6 in comparison to wildtype animals. The reported data further suggest that the homing and trafficking of tumor-infiltrating T regulatory cells to the tumor mass 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 and colleagues, in a mouse model of spontaneous intestinal tumorigenesis [APCMIN/+ mice, heterozygous for a mutation in the adenomatous polyposis coll (APC) gene], mice deficient in CCR6 had a lower occurrence of spontaneous intestinal tumorigenesis (PLoS One. 2014; 9(5):e97566. doi: 10.1371/journal.pone.0097566.).

The potential role of the CCR6/CCL20 axis in tumorigenesis was also demonstrated by administrating the recombinant CCL20 chemokine. Specifically, in a mouse model of colorectal cancer (CMT93 cells), Liu and colleagues showed that tumor size was significantly increased in mice treated with recombinant mouse CCL20 compared with PBS controls, suggesting a critical role for CCL20 in colorectal cancer growth and development (PLoS One. 2011 Apr 29; 6(4):e19495. doi: 10.1371/journal. pone.0019495.).

Specifically, using neutralizing CCL20 antibodies, the potential role of the CCR6/CCL20 axis in tumor promotion was demonstrated in the literature using mouse models. Ikeda and co-workers used a specific cutaneous T cell lymphoma (CTCL) mouse model in which animals succumb to metastasis of CTCL cells into multiple organs. However, administration of a neutralizing CCL20 antibody significantly prolonged the survival of the xenografted mice (Oncotarget. 2016 Mar 22; 7(12): 13563-74. doi: 10.18632/oncotarget.6916.). Lee and co-workers described in a mouse model of metastatic breast cancer (MDA-MB-231 cells were injected into the left cardiac ventricles of nude mice) that the administration of an anti-CCL20 antibody prevented the development of bone metastasis, one of the major site of breast cancer metastasis 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 a significant decrease of T regulatory cell recruitment into the tumor when mice were injected with anti-CCL20 monoclinal antibody in comparison 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 hepatocarcinoma (Hepa1-6 cells), blockade of CCL20 activity in immunocompetent mice using an anti-CCL20 antibody, attenuated tumor incidence, restrained tumor growth and distal metastasis. Moreover, the authors reported that in this mouse model, tumor angiogenesis was significantly inhibited upon CCL20 neutralization. (He at al., PMID 28560063 - Am J Cancer Res. 2017; 7(5):1151-1163.). Using the same mouse model, the administration of the anti-CCL20 neutralizing antibody remarkably reduced the infiltration of T regulatory cells into the tumor, especially CCR6 positive T regulatory cells, and significantly decreased tumor growth. Antitumor efficacy was further enhanced when the mice were co-treated with an anti-PDL-1 antibody. Collectively these data sets suggest that CCL20 blockade could abrogate anti-PD-L1 resistance in a mouse model of hepatocarcinoma by inhibiting T regulatory recruitment to the tumor (Hepatology. 2019 Jul; 70(1): 198-214. doi: 10.1002/hep.30593.).

Specifically, the potential role of the CCR6/CCL20 axis in tumor metastasis was described in the literature. Dellacasagrande and colleagues reported that, in a mouse model of plasmacytoma, tumor cells that disseminated to the liver overexpressed functional CCR6 in comparison with tumor cells of the primary tumor (from s.c. injection of mouse plasmacytoma (MOPC315)). The same authors found that CCR6 was overexpressed in small liver metastases of colon, thyroid and ovarian carcinomas compared with normal liver (Scand J Immunol. 2003 Jun; 57(6):534-44. doi : 10.1046/j .1365-3083.2003.01263.x.).

Furthermore, the present CCR6 modulators may be useful, alone, or in combination in the prevention or treatment of cancers where the expression of CCR6 and/or CCL20 correlates with disease progression and resistance to standard treatment care. Specifically, the correlation of CCR6 expression with disease progression was described in the literature for numerous cancer indications. For example, in renal cell carcinoma CCR6 expression is associated with a lower 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 upregulated CCR6 predicts poor survival, shorter disease- free survival (PLoS One. 2014; 9(6):e101137. doi: 10.1371/journal. pone.0101137.), and poorer 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 was also associated with a worse prognosis (Cancer Lett. 2020 Mar 1; 472:59- 69. doi: 10.1016/j. can let.2019.12.024.). CCR6 expression was associated with rectal cancer aggressiveness, indeed, high-level expression of CCR6 protein was more common in non-responders to radiotherapy than in responders (Cancer Res Treat. 2018 Oct; 50(4): 1203-1213. doi: 10.4143/crt.2O17.538.). The expression level of CCR6 in prostate cancer was associated with clinical and pathologic 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 was associated with shorter disease-free survival and conferred a disease stage-independent 5-fold increased risk for disease recurrence (PLoS One. 2011 ; 6(9):e24856. doi: 10.1371/journal. pone.0024856.). Hepatocarcinoma patients with increased infiltrated CCR6 positive immune cells in tumor tissues showed a poorer prognosis (Am J Cancer Res. 2017; 7(5): 1151-1163.).

Analogous to CCR6, expression of its ligand CCL20 has been reported to correlate with poorer disease outcome for several indications. Specifically, in breast cancer, elevated CCL20 expression significantly correlated with lower overall free survival, lower percent metastasis free survival (Sci Rep. 2017 Aug 29; 7(1):9610. doi: 10.1038/s41598-017- 09040-4.), with higher histological grade, higher KI67 index, and axillary lymph node metastases. Moreover, breast tumor CCL20 expression positively correlated with expression of FOXP3, a marker of T regulatory cells. Patients with axillary lymph node metastases, and concomitant elevation in CCL20 expression and FOXP3-positive T regulatory cells, had the worst overall survival. (Medicine (Baltimore). 2019 Dec; 98(50):e18403. doi: 10.1097/MD.0000000000018403.). In NSCLC higher expression of CCL20 was associated with a lower overall survival (Biomed Pharmacother. 2015 Feb; 69:242-8. doi: 10.1016/j.biopha.2014.12.008.)(Cancer Lett. 2015 Jul 10; 363(1):60-70. doi: 10.1016/j.canlet.2015.04.005.). Analogous to NSCLC, hepatocellular carcinoma patients with high CCL20 expression had poorer overall survival and poorer recurrence-free survival. The same authors described that CCL20 expression was significantly associated with tumor size, tumor number, vascular invasion, tumor differentiation and tumor recurrence (J Gastrointest Surg. 2012 Apr; 16(4):828-36. doi: 10.1007/s11605-011-1775-4.). In addition to CCR6 or CCL20 alone, correlation of CCR6/CCL20 co-expression with disease progression is stated in literature. Indeed, overexpression of both, CCL20 and CCR6, was detected in high-grade glioma tissues as compared to low-grade tissues and increased with ascending tumor World Health Organization (WHO) grades. Particularly 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.).

Besides, CCR6 and/or CCL20 expression correlates with enhance chemotherapeutic resistance and is associated with metastasis. Indeed, CCL20 expression can increase the chemotherapeutic resistance of breast cancer cells (PLoS Biol. 2018 Jul; 16(7):e2005869. doi: 10.1371/journal.pbio.2005869.). Rubie and colleagues describe that in colorectal liver metastases (CRLM) and in human samples of hepatocellular carcinoma (HOC), significant up-regulation of CCL20/CCR6 was detected (RT-PCR). Moreover, CCL20 was significantly overexpression in colorectal liver metastases as compared to the primary HOC, indicating an 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.).

The present CCR6 modulators may be useful, alone, or in combination in the prevention or treatment of diseases or disorders where CCR6 and/or CCL20 are expressed or overexpressed in patient samples or cancer cell lines. Specifically, the chemokine receptor CCR6 is described to be expressed in several cancer types or cancer cell lines in the literature. Lu and coworkers describe that CCR6 expression was higher in laryngeal cancer tissues compared with their normal controls. The authors reported that CCR6 was also expressed in commonly used laryngeal cancer cells such as TU212, M4E, M2E and Hep-2 (Biomed Pharmacother. 2017 Jan; 85:486-492 doi: 10.1016/j.biopha.2016.11.055.). Based on gene expression data from malignant melanoma, among the biological networks reported CCR6 gene was described and characterized as a valuable factor involved in immune responses and tumor progression (PLoS One. 2018; 13(1 ):e0190447. doi: 10.1371/journal. pone.0190447.) Whole exome sequencing in 21 MALT lymphomas of the salivary gland and thyroid revealed that CCR6 was expressed (Haematologica. 2018 Aug; 103(8): 1329-1336. doi: 10.3324/haematol.2018.191601.). In samples of adult human T-cell leukemia I lymphoma (ATLL) transcripts of CCR6 were detected, and CCR6 was further found at the protein level using flow cytometric analysis (Leuk Lymphoma. 2006 Oct; 47(10):2163-73. doi: 10.1080/10428190600775599.). In patient- derived prostate cancer samples the gene expression of CCR6 (mRNA) was significantly higher in tumor tissue as compared to adjacent normal tissue (Cancer Res Treat. 2015 Apr; 47(2):306-12. doi: 10.4143/crt.2014.015.). CCR6 expression was detected in commonly used cancer cell lines, indeed, according to Mays and co-workers, in salivary adenoid cystic carcinoma cells SACC-83, among other CC chemokine receptors, CCR6 was expressed using RT-PCR gene analysis (Anticancer Res. 2016 Aug; 36 (8): 4013-8.). According to Moller and colleagues, in multiple myeloma (MM) cell lines including U266 1970, U-266 1984, U-1958, Karpas 707, LP-1 ,28 L-363, HL407E and HL407L.3, CCR6 was also expressed (Leukemia. 2003 Jan; 17(1):203-10. doi: 10.1038/sj. leu.2402717.).

Analogous to CCR6, the ligand CCL20 was reported to be expressed in multiple tumor samples and tumor cell lines in the literature. For example, Zhang and co-workers demonstrated that in samples from NSCLC patients, using RT-PCR, CCL20 showed higher expression in tumor samples than in samples of adjacent tissue, this was also verified at the protein level using immunohistochemistry (Biomed Pharmacother. 2015 Feb; 69:242-8. doi: 10.1016/j.biopha.2014.12.008.). Gene expression analysis of cholangiocarcinoma samples and corresponding normal tissue revealed CCL20 to be one of the genes most significantly over-expressed in malignant vs healthy tissue (EXCLI J. 2020; 19:154-166. doi: 10.17179/excli2019-1893.). CCL20 expression was also reported in multiple myeloma (MM) human samples (Cancer Res. 2008 Aug 15; 68(16):6840-50. doi: 10.1158/0008-5472. CAN-08-0402.). Besides, according to Rubies et al., CCL20 mRNA and protein was significantly up-regulated in pancreatic carcinoma (8-fold) as compared to matched normal pancreas in which CCL20 was weakly expressed (J Transl Med. 2010 May 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 expression is enriched in human CCR6+ regulatory T cells with superior suppressive activity (J Immunol. 2017 Jul 15; 199 (2): 467-476. doi: 10.4049/jimmunol.1601815.).

In addition to CCR6 or CCL20 alone, the co-expression of both CCR6 and CCL20 is reported for samples of cancer patients and cancer cells lines in literature. Both genes have been described to be expressed in adult T-cell leukemia/lymphoma patient samples (Microarray and IHC protein staining) (Int J Oncol. 2014 Sep; 45(3):1200-8. doi: 10.3892/ijo.2014.2524.) and in CTCL. In the latter, CCL20 and CCR6 were detected at the mRNA and protein levels (Clin Cancer Res. 2011 Dec 15; 17(24)7529-38. doi: 10.1158/1078-0432. CCR-11-1192.). Transcriptomic analysis (nanostring) of samples of hepatocellular carcinoma revealed CCR6 and CCL20 expression. Moreover, a chemotactic gradient between non-tumor and tumor tissues was reported and a recruitment process of T regulatory cells, tumor associated macrophages and natural killer cells involving the CCR6/CCL20 axis suggested (Proc Natl Acad Sci U S A. 2017 Jul 18; 114(29): E5900-E5909. doi: 10.1073/pnas.1706559114.). Similarly, Guo and co-workers reported CCR6 and CCL20 upregulation in hepatocarcinoma lesions compared to healthy tissue as well as CCR6 and CCL20 expression in hepatocarcinoma cell lines (L02, Li-/, Huh-7, SNU-387, Hep3B) (Oncol Rep. 2019 Sep; 42(3): 1075-1089. doi: 10.3892/or.2019.7221 .). In human colorectal cancer, both CCL20 and CCR6 are expressed according to Nandi et al. (IHC protein staining). Both, CCR6 and CCL20, were found to be highly expressed in samples of NSCLC (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 moieties were strongly expressed in all pancreatic cancer samples analysed. In contrast, in healthy pancreas CCL20 and CCR6 expression was low (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 co-workers examined CCR6 and CCL20 expression in glioblastoma using publicly available datasets. The authors used the GEO dataset GSE2223 to compare the mRNA levels of CCL20 and CCR6, between normal brain and glioblastoma tissues. Again, CCR6 and CCL20 expression levels 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 and colleagues observed that in endometrial adenocarcinoma explants and cell lines, expression of CCL20 and its receptor CCR6 were higher 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.). CCL20/CCR6 axis may play a role in breast cancer, cholangiocarcinoma, and thyroid cancer since expression of CCR6/CCL20 genes and/or proteins was reported in patient derived breast cancer cells (Mol Carcinog. 2016 Jul; 55(7): 1175-86. doi: 10.1002/mc.22360.), in HuCCTI and TFK-1 cholangiocarcinoma cell lines () (Win et al., PMID 32194362 ) (EXCLI J. 2020; 19:154-166. doi: 10.17179/excli2019-1893.) and thyroid cancer cell lines such as TPC-1 , BCPAP, FTC-133, and SW1736 (Tumour Biol. 2016 Apr; 37 (4): 5569-75. doi: 10.1007/s 13277- 015-4418-7.). Furthermore, the present CCR6 modulators may be useful, alone, or in combination in the prevention or treatment of cancers where the expression and/or evidence of CCR6/CCL20 axis activity has been reported, or where CCR6+ regulatory T cells have been identified inside the tumor microenvironment.

1) A first aspect of the present invention relates to compounds of Formula (I) wherein m represents the integer 1 or 2 (especially 1); n represents the integer 0 or 1 (i.e. when n represents 0, R ⁴ is absent); p represents the integer 0 or 1 (i.e. when p represents 0, R ⁵ is absent);

R ¹ represents

• Ci-3-alkyl (especially methyl);

• cyano; • halogen (especially fluorine); • amino; or • amino-carbonyl; R ² represents • hydrogen; • C _1-4 -alkyl (especially methyl, ethyl, or isopropyl); • hydroxy-C _1-3 -alkyl (especially 2-hydroxyethyl); • C _1-3 -fluoroalkyl (especially 2,2-difluoroethyl or 2-fluoroethyl); • C _3-6 -cycloalkyl (especially cyclopropyl); or • oxetanyl (especially oxetan-3-yl); R ³ represents • halogen (especially chlorine); • C _1-4 -alkyl (especially methyl, ethyl, n-propyl, or isopropyl; in particular isopropyl); • C _1-3 -fluoroalkyl (especially difluoromethyl or trifluoromethyl); • C _3-6 -cycloalkyl (especially cyclopropyl); • C _1-3 -alkyl-amino (especially methyl-amino); or • –OR ^OB1 , wherein R ^OB1 represents ^ C _1-3 -alkyl (especially n-propyl); ^ C _1-3 -fluoroalkyl (notably C ₁ -fluoroalkyl; especially difluoromethyl or trifluoromethyl); ^ phenyl; or ^ C _3-6 -cycloalkyl (especially cyclobutyl); [in particular the grou represents 4-chloro-phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 4-(n-propyl)- phenyl, 4-isopropyl-ph ethyl-phenyl, 4-trifluoromethyl-phenyl, 4-cyclopropyl-phenyl, 4-(methyl-amino)- phenyl, 4-(n-propoxy)-phenyl, 4-difluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 4-phenoxy-phenyl, or 4- cyclobutoxy-phenyl]; R ⁴ represents • halogen (especially chlorine, fluorine, or bromine); • cyano; • C _1-3 -alkyl (especially methyl); • hydroxy-C _1-4 -alkyl (especially hydroxy-methyl or 4-hydroxy-butyl); • C _3-6 -cycloalkyl optionally conta (notably cyclopropyl or tetrahydrofuranyl; especially cyclopropyl or tetrahydrofuran-3-yl); • C _1-3 -alkoxy-CH ₂ -C _2-3 -alkenyl (notably 3-methoxy-prop-1-en-1-yl; especially (Z)-3-methoxy-prop-1-en-1-yl); • C _1-3 -alkylthio (especially methylthio); • C _1-3 -alkoxy-C _1-4 -alkyl (especially methoxy-methyl or 3-methoxy-propyl); • N,N-di-C _1-3 -alkyl-amino-carbonyl-oxy-C _1-3 -alkyl (especially N,N-diethyl-amino-carbonyl-oxy-methyl); • C _1-3 -alkoxy-C _1-3 -alkoxy-(CH ₂ ) _0-2 - (especially 2-methoxy-ethoxy-methyl); • C _1-3 -alkyl-carbonyl (especially acetyl); • C _1-4 -alkoxy-carbonyl (especially tert-butoxy-carbonyl); • phenyl optionally mono-substituted with halogen (especially 3-chloro-phenyl); • phenyl-S(=O) ₂ -NH-C _1-3 -alkyl (especially phenyl-S(=O) ₂ -NH-methyl); • piperidin-4-yl optionally containing one ring carbon-carbon double bond; wherein said piperidin-4-yl is N- substituted with C _1-4 -alkoxy-carbonyl (especially tert-butoxy-carbonyl) [in particular such piperidin-4-yl represents N-(tert-butoxy-carbonyl)-piperidin-4-yl or 1-(tert-butoxy-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]; • C _1-3 -alkoxyphenyl-C _1-3 -alkyl-carbonyl-amino-C _1-3 -alkyl (especially 3-methoxyphenyl-methyl-carbonyl-amino- methyl); • –NR ^N1 R ^N2 wherein ^ R ^N1 represents C _1-3 -alkyl (especially methyl); and ^ R ^N2 represents hydroxy-C _1-3 -alkyl (especially 2-hydroxyethyl); ^ or R ^N1 and R ^N2 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated heterocyclic ring containing one or two ring nitrogen heteroatoms (especially such heterocyclic ring represents pyrrolidinyl, piperidinyl, or piperazinyl); wherein said heterocyclic ring independently is unsubstituted or mono-substituted with hydroxy, hydroxy-C _1-3 -alkyl (especially 1- methyl-1-hydroxy-ethyl), C _3-6 -cycloalkyl-carbonyl (especially cyclopentyl-carbonyl), or C _1-3 -alkoxy-C _{1- 3} -alkoxy-carbonyl (especially 2-methoxy-ethoxy-carbonyl); [in particular such –NR ^N1 R ^N2 represents N-methyl-N-(2-hydroxyethyl)-amino, pyrrolidinyl, 3-hydroxy- pyrrolidinyl, 3-(1-methyl-1-hydroxy-ethyl)-pyrrolidin-1-yl, piperidinyl, 4-(2-methoxy-ethoxy-carbonyl)-piperazin- 1-yl, or 4-(cyclopentyl-carbonyl)-piperazin-1-yl]; • –OR ^OA1 , wherein R ^OA1 represents ^ C _1-3 -alkyl (especially methyl, ethyl, or isopropyl); ^ phenyl; ^ pyridinyl (especially pyridin-3-yl); ^ C _3-6 -cycloalkyl-C _1-3 -alkyl (especially cyclopropyl-methyl); ^ hydroxy-C _2-5 -alkyl (es l-butyl); or ^ tetrahydropyranyl (especially tetrahydropyran-4-yl); • –L ¹ –HET, wherein –L ¹ – represents a direct bond (i.e. HET is directly attached to the phenyl ring) or –CH ₂ – (especially –L ¹ – represents a direct bond); and HET represents a 5-membered heteroaryl containing one to four ring heteroatoms independently selected from nitrogen or oxygen (notably isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, imidazolyl, pyrazolyl, furanyl, or tetrazolyl; especially isoxazol-5-yl, oxazol-2-yl, 1,2,3- triazol-2-yl, 1,2,4-triazol-1-yl, imidazol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol- 5-yl, 1,3,4-oxadiazol-2-yl, furan-2-yl, or 2H-tetrazol-5-yl); or HET represents a 6-membered heteroaryl containing one or two nitrogen ring atoms (notably said 6-membered heteroaryl represents pyridinyl; especially pyridin-3-yl); wherein said HET (i.e. said 5- or 6-membered heteroaryl) independently is unsubstituted or mono- substituted (especially at position 3 with respect to the point of attachment of HET to the phenyl ring); wherein the substituent is selected from ^ hydroxy; ^ C _1-3 -fluoroalkyl (notably C ₁ -fluoroalkyl; especially trifluoromethyl); ^ C _1-4 -alkyl which is unsubstituted (especially methyl) or mono-substituted with ^ hydroxy; ^ C _1-3 -alkyl-carbonyl-oxy (especially acetoxy); ^ C _3-5 -cycloalkoxy (especially cyclobutoxy); ^ C _1-4 -alkoxy (especially methoxy or tert-butoxy); ^ C _1-3 -alkyl-sulfonyl (especially methyl-sulfonyl); ^ C _1-3 -fluoroalkoxy (especially 2,2,2-trifluoroethoxy); or ^ –NR ^N3 R ^N4 wherein ^ R ^N3 represents hydrogen or C _1-3 -alkyl (especially methyl); and ^ R ^N4 represents hydroxy-C _1-3 -alkyl-carbonyl (especially hydroxy-methyl-carbonyl) or C _1-3 -alkyl-carbonyl (especially acetyl); [in particular such mono-substituted C _1-4 -alkyl represents acetoxy-methyl, hydroxy-methyl, 1-hydroxy- 1-methyl-ethyl, 2-hydroxy-2-methyl-propyl, 2-hydroxy-1,1-dimethyl-ethyl, methyl-sulfonyl-methyl, 2- methyl-2-(acetyl-amino)-propyl, 2-methoxy-1,1-dimethyl-ethyl, 2,2,2-trifluoroethoxy-methyl, tert- butoxy-methyl, N-methyl-N-(hydroxy-methyl-carbonyl)-amino-methyl, 2-(N-methyl-N-acetyl-amino)- 2-methyl-propyl, or cyclobutoxy-methyl]; ^ –OR ^OA2 , wherein R ^OA2 represents ^ C _1-3 -alkyl (especially ethyl); ^ hydroxy-C _2-3 -alkyl (especially 1-methyl-1-hydroxy-ethyl); ^ C _1-3 -alkoxy-C _1-3 -alkyl (especially 2-methoxy-ethyl); or ^ C _1-3 -fluoroal oroethoxy); [in particular such –OR ^OA2 represents ethoxy, 1-methyl-1-hydroxy-ethoxy, 2,2,2-trifluoroethoxy, or 2- methoxy-ethoxy]; ^ –C(=O)NR ^N5 R ^N6 wherein ^ R ^N5 represents hydrogen or C _1-3 -alkyl (especially methyl); and ^ R ^N6 represents ^ C _1-3 -alkoxy-C _1-3 -alkyl (especially 2-methoxy-1,1-dimethylethyl); ^ C _3-6 -cycloalkyl-C _1-3 -alkyl (cyclohexyl-methyl); ^ phenyl, or 6-membered heteroaryl containing one or two ring nitrogen atoms; wherein said phenyl or heteroaryl independently is attached to the nitrogen atom of the –C(=O)NR ^N5 R ^N6 group via direct bond or via C _1-2 -alkylene (notably -CH ₂ - or -CH ₂ -CH ₂ -; especially -CH ₂ -); wherein said phenyl or heteroaryl independently is unsubstituted or mono-substituted with C _1-3 -alkoxy (especially methoxy) [notably such phenyl or 6-membered heteroaryl represents methoxy-phenyl, pyridinyl- methyl, or pyrazinyl-methyl; especially 2-methoxyphenyl, pyridin-4-yl-methyl, or pyrazin-2-yl-methyl]; ^ or R ^N5 and R ^N6 , together with the nitrogen atom to which they are attached, form pyrrolidinyl or morpholinyl; wherein said pyrrolidinyl or morpholinyl independently are mono- or di- substituted, wherein the substituents are independently selected from C _1-3 -alkyl (especially methyl), or hydroxy-C _1-3 -alkyl (especially 1-hydroxy-1-methyl-ethyl); [in particular such –C(=O)NR ^N5 R ^N6 represents N-(2-methoxy-1,1-dimethylethyl)-amino-carbonyl, 2,6-dimethyl-morpholin-4-yl-carbonyl, 3-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl-carbonyl, phenyl-amino-carbonyl, 2-methoxyphenyl-amino-carbonyl, 3-isopropoxyphenyl-amino-carbonyl, 4-methoxyphenyl-amino-carbonyl, pyridin-4-yl-methyl-amino-carbonyl, or pyrazin-2-yl-methyl- amino-carbonyl]; ^ –NR ^N7 R ^N8 , wherein ^ R ^N7 represents C _1-3 -alkyl (especially methyl); and ^ R ^N8 represents C _1-3 -alkoxy-C _1-3 -alkyl (especially 2-methoxy-ethyl); ^ –L ² –Cy ² , wherein ^ –L ² – represents ^ a direct bond (i.e. Cy ² is directly attached to HET); ^ C _1-2 -alkylene (especially -CH ₂ - or -CH ₂ -CH ₂ -) independently unsubstituted or mono-substituted with hydroxy (especially -CH(OH)-); or ^ C ₁ -CH ₂ -O-), wherein the oxygen atom is directly attached to Cy ² ; and ^ Cy ² represents a C _3-6 -cycloalkyl optionally containing one or two ring heteroatoms independently selected from nitrogen or oxygen (notably such Cy ² represents cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl, azetidinyl, morpholinyl, tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl; especially cyclopropyl, cyclobutyl, cyclohexyl, oxetan-3-yl, azetidin-3-yl, piperidin-4-yl, morpholin-4-yl, tetrahydropyran-4-yl, tetrahydrofuran-3-yl); wherein said Cy ² is unsubstituted; mono-substituted with hydroxy, halogen (especially fluorine), C _1-3 -alkyl (especially methyl), C _1-3 -alkoxy (especially methoxy), C _1-3 -alkyl-carbonyl (especially acetyl), hydroxy-C _1-3 -alkyl-carbonyl (especially hydroxymethyl-carbonyl), N-(C _1-3 -alkyl-carbonyl)-N- C _1-3 -alkyl-carbonylamino (especially N-acetyl-N-methyl-carbonylamino), or C _1-3 -alkyl- carbonylamino (especially acetyl-amino); or di-substituted, wherein the substituents independently are selected from C _1-3 -alkyl (especially methyl), hydroxy, or C _1-3 -alkyl- carbonyl (especially acetyl); ^ or Cy ² represents a saturated 5- to 7-membered bridged bicyclic hydrocarbon ring system optionally containing one or two ring heteroatoms independently selected from oxygen or nitrogen (especially such ring system represents bicyclo[1.1.1]pentan-1-yl, 6-oxa-3-aza- bicyclo[3.1.1]heptan-3-yl, or 7-oxabicyclo[2.2.1]heptan-2-yl); wherein said ring system independently is unsubstituted or mono-substituted with hydroxy-C _1-3 -alkyl (especially hydroxy-methyl); ^ or Cy ² represents a 5-membered heteroaryl containing one or two ring heteroatoms independently selected from nitrogen or oxygen (notably isoxazolyl or pyrazolyl; especially isoxazol-3-yl, 1H-pyrazol-1-yl, or 1H-pyrazol-4-yl), wherein said 5-membered heteroaryl is unsubstituted or mono-substituted with C _1-3 -alkyl (especially methyl) or hydroxy; ^ or Cy ² represents phenyl which is unsubstituted or mono-substituted with C _1-3 -alkoxy (especially methoxy); [in particular such –L ² –Cy ² group represents 1-(acetyl-amino)-cyclopropyl, 1-(N-acetyl-N-methyl- amino)-cyclopropyl, N-acetyl-azetidin-3-yl-methyl, 3-hydroxy-cyclobutyl, 1-hydroxy-cyclobutyl- methyl, 1-cyclohexyl-1-hydroxy-methyl, 1-methoxy-cyclobutyl, 4-hydroxy-cyclohexyl, 3-hydroxy- oxetan-3-yl, morpholin-4-yl, morpholin-4-yl-methyl, 2,6-dimethyl-morpholin-4-yl, tetrahydropyran-4- yl, 4-fluoro-tetrahydropyran-4-yl, 4-methyl-tetrahydropyran-4-yl, 4-hydroxy-tetrahydropyran-4-yl, 4- hydroxy-tetrahydropyran-4-yl-methyl, 3-hydroxy-tetrahydrofuran-3-yl, 3-hydroxymethyl- bicyclo[1.1.1]pentan-1-yl, 6-oxa-3-aza-bicyclo[3.1.1]heptan-3-yl, 7-oxabicyclo[2.2.1]heptan-2-yl, 5- methyl-isoxazol-3-yl, 2-(3-hydroxy-isoxazol-5-yl)-ethyl, 2-(3-methyl-pyrazol-1-yl)-ethyl, (1-methyl- pyrazol-4-yl)-oxy-methyl, 3-methoxy-phenyl, phenyl-oxy-methyl, 2-phenyl-ethyl, N-acetyl-piperidin-4- yl, N-acetyl-4-hydroxy-piperidin-4-yl, N-acetyl-4-hydroxy-piperidin-4-yl-methyl, or N-(hydroxymethyl- carbonyl)-piperidin-4-yl];

[in particular such -L ¹ -HET represents 5-(1 -hydroxy-1 -methyl-ethyl)-pyridin-3-yl, pyrazol-1-yl, 3-methyl-pyrazol-1- yl, 1-methyl-pyrazol-3-yl, imidazol-1-yl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,3-triazol-2-yl, 5-methyl-furan-2-yl, 2-methyl-2H- tetr azol -5-yl, 5-hydroxy-1 ,2,4-oxadiazol-3-yl, 5-methyl-1 ,2,4-oxadiazol-3-yl, 5-methyl-1 ,3,4-oxadiazol-2-yl, 3- methyl-isoxazol-5-yl, 5-methyl-oxazol-2-yl, 4-methyl-oxazol-2-yl, 3-methyl-1 ,2,4-triazol-1-yl, 5-hydroxymethyl- 1 ,2,4-oxadiazol-3-yl, 3-ethoxy-1 ,2,4-oxadiazol-5-yl, 5-(1 -hydroxy-1 -methyl-ethyl)-1 , 2, 4-oxadiazol-3-yl, 3- trifluoromethyl-1,2,4-oxadiazol-5-yl, 5-(1-(acetyl-amino)-cyclopropyl)-1,2,4-oxadiazol-3-yl, 5-(3-hydroxy- cyclobutyl)-1,2,4-oxadiazol-3-yl, 5-((1-hydroxy-cyclobutyl)-methyl)-1 ,2,4-oxadiazol-3-yl, 3-(3-hydroxy-oxetan-3-yl)-

1.2.4-oxadi azol-5-y I, 5-(2-hy d roxy-2-methy l-propy l)-1 , 2,4-oxadiazol-3-y I, 3-(2-hy d roxy-2-methy l-propyl)- 1 ,2,4- oxadiazol-5-yl, 3-(2-hydroxy-1 , 1-dimethyl-ethyl)-1 ,2,4-oxadiazol-5-yl, 5-(methyl-sulfonyl-methyl)-1 ,2,4-oxadiazol- 3-yl, 3-(2-methoxy-ethoxy)-1 ,2,4-oxadiazol-5-yl, 5-(acetyl-oxy-methyl)-1,2,4-oxadiazol-3-yl, 5-(2-methoxy-1, 1- dimethy l-ethy I)- 1 ,2,4-oxadi azol-3-yl , 3-(tert-butoxy-methy I)- 1 ,2,4-oxadi azol-5-yl, 5-(N-methyl-N-(2-methoxy-ethyl)- amino)-1 , 2, 4-oxadiazol-3-y I, 5- (4-fl uoro-tetrahydropy ran-4-y I)- 1 ,2,4-oxadiazol-3-y I, 5-(tetrahy d ropy ran-4-y l)-1 ,2,4- oxadi azol-3-y I, 3-(4-methyl-tetrahy d ropy ran-4-y I )- 1 ,2, 4-oxadi azol-5-yl , 3-(tetrahy d ropy ran-4-y I)- 1 , 2, 4-oxadi azol -5- yl, 5-(1-methoxy-cyclobutyl)-1 ,2,4-oxadiazol-3-yl, 3-(cyclobutoxy-methyl)-1,2,4-oxadiazol-5-yl, 3-(3-hydroxy- tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl, 4-(tetrahydropyran-4-yl)-oxazol-2-yl, 3-(tetrahydropyran-4-yl)-isoxazol- 5-yl, 2-phenyl-oxazol-5-yl, 3-(5-methyl-isoxazol-3-yl)-1 ,2,4-oxadiazol-5-yl, 3-(2-(3-methyl-pyrazol-1-yl)-ethyl)-

1.2.4-oxadiazol-5-yl, 3-((1-methyl-pyrazol-4-yl)-oxy-methyl)-1,2,4-oxadiazol-5-yl, 3-(morpholin-4-yl)-1,2,4- oxadi azol-5-y I, 3-(morphol i n-4-y l-methy I)- 1 , 2,4-oxadiazol-5-y I, 3-(2, 6-di methy l-morphol in-4-y I)- 1 , 2,4-oxad i azol-5- yl, 3-(4-hydroxy-cyclohexyl)-1 ,2,4-oxadi azol-5-y I, 3-(4-hy d roxy-tetrahy d ropy ran-4-y I)- 1 ,2, 4-oxadi azol-5-y 1 , 3-(4- hydroxy-tetrahydropyran-4-yl-methyl)-1 ,2,4-oxadiazol-5-yl, 3-(N-methyl-N-(hydroxy-methyl-carbonyl)-amino- methy l)-1 , 2, 4-oxadiazol-5-y I, 5-(3-hyd roxy methy l-bicyclo [1 .1.1 ]pentan-1 -yl)-1 ,2, 4-oxadiazol-3-y I, 3-(6-oxa-3-aza- bicyclo[3.1.1]heptan-3-yl)-1 ,2,4-oxadiazol-5-yl, 3-(7-oxabicyclo[2.2.1]heptan-2-yl)-1 ,2,4-oxadiazol-5-yl, 5-(2- methyl-2-(acetyl-amino)-propyl)-1 ,2,4-oxadiazol-3-yl, 3-(3-methoxy-phenyl)-1,2,4-oxadiazol-5-yl, 5-(1-cyclohexyl- 1-hydroxy-methyl)-1,2,4-oxadiazol-3-yl, 3-(phenyl-oxy-methyl)-1 ,2,4-oxadiazol-5-yl, 3-(2-phenyl-ethyl)-1 ,2,4- oxadiazol-5-yl, 5-(1-(N-acetyl-N-methyl-amino)-cyclopropyl)-1,2,4-oxadiazol- 3-yl, 3-(N-acetyl-azetidin-3-yl- methy l)-1 , 2, 4-oxadiazol-5-y I, 5-(2-(3-hy d roxy-isoxazol-5-y I )-ethy I)- 1 , 2, 4-oxadiazol-3-y I, 5-(2-(N-methyl-N-acetyl- amino)-2-methyl-propyl)-1 ,2,4-oxadiazol-3-yl, 3-(N-(2-methoxy-1,1-dimethylethyl)-amino-carbonyl)-1,2,4- oxadiazol-5-yl, 3-(phenyl-amino-carbonyl)-1,2,4-oxadiazol-5-yl, 5-(N-acetyl-piperidin-4-yl)-1 ,2,4-oxadiazol-3-yl, 3- (pyridin-4-yl-methyl-amino-carbonyl)-1 ,2,4-oxadiazol-5-yl, 3-(pyrazin-2-yl-methyl-amino-carbonyl)-1 ,2,4- oxadiazol-5-yl, 5-(N-acetyl-4-hydroxy-piperidin-4-yl)-1 ,2,4-oxadiazol-3-yl, 3-(N-acetyl-4-hydroxy-piperidin-4-yl- methyl)-1 ,2,4-oxadiazol-5-yl, 3-(2,6-dimethyl-morpholin-4-yl-carbonyl)-1,2,4-oxadiazol-5-y l, 3-(N-(hydroxymethyl- carbonyl)-piperidin-4-yl)-1,2,4-oxad droxy-1-methyl-ethyl)-pyrrolidin-1-yl-carbonyl)-1,2,4- oxadiazol-5-yl, 3-(2-methoxyphenyl-amino-carbonyl)-1,2,4-oxadiazol-5-yl, 3-(4-methoxyphenyl-amino-carbonyl)- 1,2,4-oxadiazol-5-yl, or 3-(3-isopropoxyphenyl-amino-carbonyl)-1,2,4-oxadiazol-5-yl]; • –L ³ –R ^T , wherein ^ –L ³ – represents -C≡C-CH(OH)- or -C≡C-C(CH ₃ )(OH)-, wherein the carbon atom bearing the hydroxy group is attached to R ^T ; and ^ R ^T represents ^ hydrogen; ^ phenyl; or ^ 5- or 6-membered heteroaryl containing one or two (especially two) ring nitrogen atom(s) (notably pyrazolyl or pyrimidinyl; especially 1H-pyrazol-3-yl or pyrimidin-4-yl), wherein said 5- or 6-membered heteroaryl is independently unsubstituted, or mono- or di-substituted (notably mono- or di-substituted) with C _1-3 -alkyl (especially methyl); [in particular such –L ³ -R ^T represents 3-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-but-1-yn-1-yl, 4-hydroxy-but- 1-yn-1-yl, 3-hydroxy-3-phenyl-prop-1-yn-1-yl, 3-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-but-1-yn-1-yl, 3- hydroxy-3-(1,5-dimethyl-1H-pyrazol-3-yl)-but-1-yn-1-yl, or 3-hydroxy-3-(6-methyl-pyrimidin-4-yl)-but-1- yn-1-yl]; or • –L ⁴ –Cy ⁴ , wherein ^ –L ⁴ – represents -CH ₂ -CH ₂ -CH(OH)- or -CH ₂ -CH ₂ -C(CH ₃ )(OH)-; wherein the carbon atom bearing the hydroxy group is attached to Cy ⁴ ; ^ Cy ⁴ represents phenyl or pyrazolyl (especially pyrazol-3-yl); wherein said phenyl or pyrazolyl independently is mono-substituted with hydroxy or C _1-3 -alkyl (especially methyl); [in particular such –L ⁴ –Cy ⁴ represents 3-hydroxy-3-phenyl-propyl or 3-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)- butyl]; R ⁵ represents halogen (especially fluoro) or C _1-3 -alkoxy (especially methoxy or ethoxy); or R ⁴ together with R ⁵ form saturated or aromatic 5- or 6-membered heterocyclic ring fused to the phenyl; said heterocyclic ring containing one or two heteroatoms independently selected from oxygen or nitrogen (especially such groups wherein a 5- or 6-membered heterocyclic ring fused to the phenyl are benzooxazolyl, benzo[1,3]dioxolyl, 2,3- dihydrobenzofuranyl, or 2,3-dihydro-benzo[1,4]dioxinyl; wherein it is understood that said groups are attached to the rest of the molecule at the phenyl ring, especially in position 5 or 6 of said groups); wherein said heterocyclic ring is unsubstituted; or mono-substituted with C _1-3 -alkyl (especially methyl); or di-substituted with fluoro [in particular such 5- or 6-membered heterocyclic ring together with the phenyl to which it is fused represents 2-methyl- benzooxazol-6-yl, benzooxazol-5-yl, 2,2-difluoro-benzo[1 ,3]dioxol-5-yl, 2,3-dihydrobenzofuran-5-yl, or 2,3-dihydro- benzo[1,4]dioxin-6-yl].

Definitions provided herein are intended to apply uniformly to the compounds of Formula (I) as defined in any one of embodiments 1) to 24), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.

If not explicitly defined otherwise in the respective embodiment or claim, groups defined herein are unsubstituted.

The term "halogen”, used alone or in combination, means fluorine, chlorine, bromine, or iodine; notably fluorine, chlorine, or bromine.

The term "cyano", used alone or in combination, refers to a group -CN.

The term "oxy", used alone or in combination, refers to a group -O-.

The term "sulfonyl” , used alone or in combination, refers to the group -S(=O)-.

The integer “m” as defined herein refers to the number of the -CH2- groups in the ring of Formula (I). Preferred “m” is 1 , corresponding to an azetidine ring.

The integer “n” as defined herein refers to the number of substituents R ⁴ in the phenyl ring of Formula (I). When “n” represents the integer 0, R ⁴ is absent. When “n” represents the integer 1, only one substituent R ⁴ is present; notably, attached in any one of positions 3 or 4 of said phenyl ring with regard to the point of attachment of said phenyl ring to the rest of the molecule. Preferably R ⁴ is attached in position 3.

The integer “p” as defined herein refers to the number of substituents R ⁵ in the phenyl ring of Formula (I). When “p” represents the integer 0, R ⁵ is absent. When “p” represents the integer 1, only one substituent R ⁵ is present; notably, R ⁵ may be attached in any one of positions 2, 3, or 4 of said phenyl ring with regard to the point of attachment of said phenyl ring to the rest of the molecule.

For avoidance of doubt and provided that both R ⁴ and R ⁵ are present, it is understood that when R ⁴ is attached in any one of positions 3 or 4 in the phenyl ring of Formula (I) with regard to the point of attachment of said phenyl ring to the rest of the molecule, the substituent R ⁵ may be attached in any one of the remaining positions of the phenyl ring; especially R ⁵ is attached in position 2.

The term "amino-carbonyl”, used alone or in combination, refers to a carbamoyl group NH2-C(=O)-.

The term "amino-carbonyl-oxy”, used alone or in combination, refers to the group NH2-C(=O)-O-, wherein mono- or disubstitution to the amino group may be further defined. For example, N-(Ci-3-alkyl)-amino-carbonyl-oxy- means that the amino group of said amino-carbonyl-oxy group is substituted with a Ci-3-alkyl group, said Ci-3-alkyl group being defined herein. An example of N-(C _1-3 -alkyl)-am propyl)-amino-carbonyl-oxy. A further example of a di-substituted amino group with ethyl is N,N-diethyl-amino-carbonyl-oxy-methyl. The term “alkyl”, used alone or in combination, refers to a saturated straight or branched hydrocarbon chain group containing one to six carbon atoms. The term “C _x-y -alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. In case a C _x-y -alkyl group is used in combination with another substituent, the term means that said substituent is linked through a C _x-y -alkyl group to the rest of the molecule. For example, a C _{1- 6} -alkyl group contains from one to six carbon atoms. Examples of C _1-4 -alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and isobutyl. A preferred example of a C _1-3 -alkyl as used for the substituent R ⁴ is methyl. The term “mono-substituted C _1-4 -alkyl” as used for the substituent of HET refers to a mono-substituted methyl, mono- substituted ethyl, or mono-substituted n-propyl. A most preferred example of C _1-4 -alkyl for R ³ is isopropyl. The term “-(CH ₂ ) _0-2 -”, used alone or in combination, refers to bivalently bound alkyl group as defined herein containing 0 to 2 carbon atoms. Said group comprises the following alternatives: -(CH ₂ ) ₀ -, -(CH ₂ ) ₁ -, and -(CH ₂ ) ₂ -, wherein -(CH ₂ ) ₀ - refers to the absence of a -CH ₂ - group, i.e. it represents a single bond between the two entities represented as attached to -(CH ₂ ) ₀ -); -(CH ₂ ) ₁ - refers to the group -CH ₂ -; and -(CH ₂ ) ₂ - refers to the groups -CH ₂ -CH ₂ - and -CH(CH ₃ )- (preferably -(CH ₂ ) ₂ - refers to the group -CH ₂ -CH ₂ -). The term “C _1-2 -alkylene”, used alone or in combination, refers to bivalently bound alkyl group as defined before containing 1 or 2 carbon atoms. Examples of C _1-2 -alkylene groups are the groups -CH ₂ -, -CH ₂ -CH ₂ -, and -CH(CH ₃ )- (preferably -CH ₂ - or -CH ₂ -CH ₂ -). The term “C _1-2 -alkylene-oxy”, used alone or in combination, refers to an C _1-2 -alkylene-O- group, wherein the C _1-2 - alkylene group is as defined herein. Examples of C _1-2 -alkylene-oxy groups are -CH ₂ -O-, -CH ₂ -CH ₂ -O-, and -CH(CH ₃ )- O- (preferably the groups -CH ₂ -O- and -CH ₂ -CH ₂ -O-). The term “alkenyl”, used alone or in combination, refers to a straight or branched chain hydrocarbon group containing one to six (especially one to four) carbon atoms wherein said hydrocarbon group contains at least one carbon-carbon double bond. The term “C _x-y -alkenyl” (x and y each being an integer), refers to an alkenyl group as defined before, containing x to y carbon atoms. For example, a C _2-3 -alkenyl group contains two or three carbon atoms. Examples of a C _2-3 -alkenyl group are vinyl and allyl group. The term “amino-alkyl”, used alone or in combination, refers to an alkyl group as defined before, wherein one hydrogen atom has been replaced by an amino group. The term “amino-C _x-y -alkyl” (x and y each being an integer), used alone or in combination, refers to an amino-alkyl group as defined before wherein the alkyl group contains x to y carbon atoms. For example, amino-C _1-3 -alkyl is an amino-alkyl group containing from one to three carbon atoms. Examples of such amino-C _1-3 -alkyl groups are amino-methyl, 1-amino-ethyl, 2-amino-ethyl and 2-amino-2,2-dimethyl-ethyl. The term “hydroxyalkyl” (or hydroxy-alkyl), used alone or in combination, refers to an alkyl group as defined before, wherein one hydrogen atom has been replaced by a hydroxy group. The term “hydroxy-C _x-y -alkyl” (x and y each being an integer), used alone or in combination, refers to a hydroxyalkyl group as defined before wherein the alkyl group contains x to y carbon atoms. For exam oup is a hydroxyalkyl group as defined before which contains from one to four carbon atoms. A hydroxy-C _2-5 -alkyl is a hydroxyalkyl group as defined before which contains from two to five carbon atoms. A hydroxy-C _2-3 -alkyl is a hydroxyalkyl group as defined before which contains from two to three carbon atoms. In the context of the present invention, preferred hydroxy-C _2-5 -alkyl groups are groups of the formula HO-C _1-4 -alkylene-CH ₂ -, wherein C _1-4 -alkylene refers to bivalently bound alkyl group as defined before containing 1 or 4 carbon atoms; preferred hydroxy-C _2-3 -alkyl groups are groups of the formula HO-C _1-2 -alkylene-CH ₂ -, wherein C _{1- 2} -alkylene refers to bivalently bound alkyl group as defined before. The term "fluoroalkyl”, used alone or in combination, refers to an alkyl group as defined before in which one or more (and possibly all) hydrogen atoms have been replaced by fluorine. The term “C _x-y -fluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example, a C _1-3 -fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Examples of C _1-3 -fluoroalkyl groups are trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. A preferred example of C _1-3 -fluoroalkyl group is a C ₁ -fluoroalkyl group containing one carbon atom in which one to three hydrogen atoms have been replaced with fluorine. Examples of such C ₁ -fluoroalkyl group are mono-, di-, and tri- fluoromethyl; especially trifluoromethyl. The term "cycloalkyl", used alone or in combination, refers to a saturated monocyclic hydrocarbon ring containing three to seven carbon atoms (preferably three to six carbon atoms). The term "C _x-y -cycloalkyl" (x and y each being an integer), refers to a saturated monocyclic hydrocarbon ring containing x to y carbon atoms. For example, a C _3-6 -cycloalkyl group contains from three to six carbon atoms. Examples of C _3-6 -cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkoxy”, used alone or in combination, refers to a cycloalkyl group as defined before, wherein one hydrogen atom has been replaced by -O-.The term “C _x-y -cycloalkoxy” (x and y each being an integer), used alone or in combination, refers to a cycloalkoxy group as defined before, wherein the cycloalkoxy group contains x to y carbon atoms. For example, a C _3-5 -cycloalkoxy group is a cycloalkoxy group as defined before which contains from three to five carbon atoms. Examples of C _3-5 -cycloalkoxy groups are cyclopropoxy, cyclobutoxy, or cyclopentoxy. The term “alkyl-carbonyl”, used alone or in combination, refers to an alkyl group as defined herein, wherein one hydrogen atom has been replaced by the group -C(=O)-. The term “C _x-y -alkyl-carbonyl” (x and y each being an integer), used alone or in combination, refers to an alkyl-carbonyl group as defined before, wherein the alkyl group contains x to y carbon atoms. For example, a C _1-3 -alkyl-carbonyl group is an alkyl-carbonyl group as defined before which contains from one to three carbon atoms. The term “(hydroxy-alkyl)-carbonyl”, used alone or in combination, refers to a hydroxy-alkyl group as defined herein, wherein one hydrogen atom of the alkyl has been replaced by the group -C(=O)-. The term “(hydroxy-C _x-y -alkyl)- carbonyl” (x and y each being an integer), used alone or in combination, refers to (hydroxy-alkyl)-carbonyl group as defined before, wherein the alkyl grou toms. For example, a (hydroxy-C _1-3 -alkyl)-carbonyl group is an (hydroxy-alkyl)-carbonyl group as defined before which contains from one to three carbon atoms. The term “alkoxy”, used alone or in combination, refers to an alkyl group as defined before, wherein one hydrogen atom has been replaced by -O-, i.e. to the group alkyl-O-.The term “C _x-y -alkoxy” (x and y each being an integer), used alone or in combination, refers to an alkoxy group as defined before, wherein the alkoxy group contains x to y carbon atoms. For example, a C _1-3 -alkoxy group is an alkoxy group as defined herein which contains from one to three carbon atoms. Examples of C _1-3 -alkoxy groups are methoxy, ethoxy, n-propoxy, or isopropoxy; notably methoxy. The term “C _x-y -alkoxy-carbonyl” refers to the group C _x-y -alkoxy-(C=O)-. The term “C _x-y -alkoxy-C _x-y -alkyl” refers to an C _x-y -alkyl group as defined before, wherein one hydrogen atom is replaced by C _x-y -alkoxy group as defined before. Examples of a C _1-3 -alkoxy-C _1-3 -alkyl group are methoxy-methyl, 1-methoxy- ethyl, 2-methoxy-ethyl, 1-methoxy-propyl, 2-methoxy-propyl, 3-methoxy-propyl, ethoxy-methyl, 1-ethoxy-ethyl, 2- ethoxy-ethyl, 1-ethoxy-propyl, 2-ethoxy-propyl, 3-ethoxy-propyl, or 2-methoxy-1,1-dimethylethyl. The term "fluoroalkoxy”, used alone or in combination, refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “C _x-y -fluoroalkoxy” (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example, a C _1-3 -fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced by fluorine. Examples of C _1-3 -fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. The term "heteroaryl", used alone or in combination, refers to a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to four heteroatoms (notably containing one to three heteroatoms), each independently selected from oxygen, nitrogen, or sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl. The above-mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined. The term "5- or 6-membered heteroaryl", used alone or in combination, refers to a 5- to 6-membered monocyclic aromatic ring containing one to four ring heteroatoms (preferably one to three ring heteroatoms), each independently selected from oxygen, nitrogen, and sulfur. Examples of 5-membered groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl. In the case of HET as defined in the current application, the more preferred examples of 5- or 6-membered heteroaryl rings are 5-membered heteroaryl rings; especially HET represents 1,2,4-oxadiazol-5-yl or 1,2,4- oxadiazol-3-yl. Examples of 6-membered heteroaryl groups are pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. The above-mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined.

In the context of unsubstituted/mono-substituted HET being 5- or 6-membered heteroaryl groups, especially the 5- membered heteroaryl groups are preferred, wherein it is understood that a substitution in position 3 in said 5-membered heteroaryl groups with respect to the point of attachment to the rest of the molecule (e.g. point of attachment of HET to the phenyl ring) means that the substituent in position 3 and the point of attachment to the phenyl are in a relative 1 ,3- arrangement. Examples of such 5-membered heteroaryl groups HET which are unsubstituted or mono-substituted in position 3 are selected from a group consisting of wherein one asterisk (*) denotes the attachment point to the substituent, if present; and two asterisks (**) denote the attachment point to the phenyl depicted in Formula (I). Preferred are

The term "5- or 6-membered heterocyclic ring”, used alone or in combination, refers to mono carbocyclic ring containing five to six carbon atoms, wherein one or more carbon atoms (as explicitly defined) are replaced with heteroatoms each independently selected from oxygen or nitrogen (as explicitly defined); wherein said ring optionally contains one or more ring double bonds. The term "saturated 5- or 6-membered heterocyclic ring” refers to a 5- or 6-membered heterocyclic ring as defined above which has no ring double bonds. Examples of "saturated or aromatic 5- or 6-membered heterocyclic ring fused to phenyl”, as used herein, wherein said heterocyclic ring contains one or two heteroatoms independently selected from oxygen or nitrogen are the following groups: doubt, when a substituent is referred to as "5- or 6-membered heterocyclic ring fused to phenyl” the point of attachment of said substituent to the rest of the molecule is in the phenyl ring of the substituent, especially position 5 or 6. For avoidance of doubt, when the term "saturated 5- or 6-membered heterocyclic ring fused to phenyl ring” is used, the delocalized carbon-carbon bonds of the phenyl ring are regarded as belonging to said phenyl ring and not to the saturated 5- or 6-membered heterocyclic ring.

The term "saturated 5- to 7-membered bridged bicyclic hydrocarbon ring system”, used alone or in combination, refers to two hydrocarbon rings which have two carbon atoms in common, wherein the total number of carbon atoms in both rings is an integer from 5 to 7. More particularly, said term refers to compounds described by the term “bicy clo [x.y . z]alky I, wherein the total number of carbon atoms is an integer from 5 to 7, and each one of “x”, “y” and “z” is larger than 0 [i.e. the sum of “x”, “y” and “z” is from 3 to 5; and the integers “x”, “y” and “z” independently indicate the number of carbon atoms in each of the three bridges linked to the two tertiary carbon atoms in descending order (x>y>z)]. Examples for such 5- to 7-membered bridged bicyclic hydrocarbon ring system are bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl bicyclo[3.1 .1]heptanyl, or bicyclo[2.2.1]heptanyl.

When a linker of the type -L ^x - (x being an integer such as 1, 2, 3, 4) represents a direct bond, said direct bond is a direct covalent bond.

A bond drawn as a dotted line shows the point of attachment of the radical drawn to the rest of the molecule. For example, the radical drawn below represents 1-R ² -3-R ¹ -azetidine-3-yl or 1 -R ² -3-R ¹ -pyrrolidin-3-yl group.

Further embodiments of the invention are presented hereinafter:

2) Another embodiment relates to compounds according to embodiment 1), wherein m represents the integer 1.

3) Another embodiment relates to compounds according to any one of embodiments 1) or 2), wherein R ¹ represents Ci-3-alkyl (especially methyl), halogen (especially fluorine), or amino.

4) Another embodiment relates to compounds according to any one of embodiments 1) or 2), wherein R ¹ represents Ci-3-alkyl (especially methyl).

5) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein R ² represents Ci. 4-alkyl (especially methyl, ethyl, or isopropyl), Ca-e-cycloalkyl (especially cyclopropyl), or oxetanyl (especially oxetan-3- yi).

6) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein R ² represents Cis-alkyl (especially methyl, ethyl, or isopropyl) [in particular, R ² represents methyl],

7) Another embodiment relates to compounds according to embodiment 1), wherein the radical represents 3-methyl-azetidine-3-yl, 1 ,3-dimethyl-azetidine-3-yl, 1-ethyl-3-methyl-azetidine-3-yl, 1- isopropyl-3-methyl-azetidine-3-yl, 1-cyclopropyl-3-methyl-azetidine-3-yl, 1-(2-fluoroethyl)-3-fluoro-azetidine-3-yl, 1- methyl-3-amino-azetidine-3-yl, 1-methyl-3-cyano-azetidine-3-yl, 1-cyclopropyl-3-fluoro-azetidine-3-yl, 1-methyl-3- methyl-pyrrolidin-3-yl, 1-(oxetan-3-yl)-3-methyl-azetidine-3-yl, 1-(2-hydroxyethyl)-3-methyl-azetidine-3-yl, 1-(2,2- difluoroethyl)-3-methyl-azetidine-3-yl, or 1-(amino-carbonyl)-3-methyl-azetidine-3-yl (notably 1 ,3-dimethyl-azetidine-3- yl, 1-ethyl-3-methyl-azetidine-3-yl, 1-isopropyl-3-methyl-azetidine-3-yl, 1-cyclopropyl-3-methyl-azetidine-3-yl, 1-(2- fluoroethyl)-3-fluoro-azetidine-3-yl, 1 -methyl-3-amino-azetidine-3-yl, 1 -cyclopropyl-3-fluoro-azetidine-3-yl, or 1-(oxetan-

3-yl)-3-methyl-azetidine-3-yl; especially 1 ,3-dimethyl-azetidine-3-yl, 1-ethyl-3-methyl-azetidine-3-yl, 1-isopropyl-3- methyl-azetidine-3-yl, 1-cyclopropyl-3-methyl-azetidine-3-yl, or 1-cyclopropyl-3-fluoro-azetidine-3-yl; in particular 1 ,3- dimethyl-azetidine-3-yl.

8) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein R ³ represents

• Ci-4-alkyl (especially methyl, ethyl, n-propyl, or isopropyl; in particular isopropyl);

• Ci-3-fluoroalkyl (especially difluoromethyl or trifluoromethyl);

• C3-6-cycloalky I (especially cyclopropyl); or

• -OR ^OB1 , wherein R ^0B1 represents Ci-3-alkyl (especially n-propyl); Ci-3-fluoroalkyl (notably Ci-fluoroalkyl; especially difluoromethyl or trifluoromethyl).

9) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein R ³ represents Ci.

4-alkyl (especially methyl, ethyl, n-propyl, or isopropyl; in particular isopropyl), or -OR ^OB1 , wherein R ^0B1 represents C1-3- fluoroalkyl (notably Ci-fluoroalkyl; especially difluoromethyl or trifluoromethyl).

10) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein R ³ represents Ci-4-alkyl (especially methyl, ethyl, n-propyl, or isopropyl; in particular R ³ represents isopropyl).

11) Another embodiment relates to compounds according to according to any one of embodiments 1) to 7), wherein the radical represents 4-chloro-phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 4-(n-propyl)-phenyl, 4-isopropyl- phenyl, 4-difluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 4-cyclopropyl-phenyl, 4-(methyl-amino)-phenyl, 4-(n- propoxy)-phenyl, 4-difluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 4-phenoxy-phenyl, or 4-cyclobutoxy-phenyl; notably 4-isopropyl-phenyl, 4-ethyl-phenyl, 4-trifluoromethoxy-phenyl, or 4-difluoromethyl-phenyl; especially 4- isopropyl-phenyl. 12) Another embodiment relates to compounds according to any one of embodiments 1) to 11), wherein n represents the integer 1.

13) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein the radical attached in position 3 (mefa-position) with respect to the point of attachment of the phenyl ring to the rest of molecule; and R ⁵ (if present) is attached in any one of the remaining positions of said phenyl ring); or

• attached in position 4 (para-position) with respect to the point of attachment of the phenyl ring to the rest of molecule; and R ⁵ (if present) is attached in any one of the remaining positions of said phenyl ring).

14) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein the radical attached in position 3 (mefa-position) with respect to the point of attachment of the phenyl ring to the rest of molecule; and R ⁵ (if present) is attached in any one of the remaining positions of said phenyl ring). 15) Another embodiment relates to compounds according to any one of embodiments 1) to 14), wherein p represents the integer 1.

16) Another embodiment relates to compounds according to any one of embodiments 1) to 15), wherein R ⁵ represents halogen (especially fluoro). 17) Another embodiment relates to com e of embodiments 14) to 16), wherein R ⁵ is attached in any one of positions 2, 4, or 6 with respect to the point of attachment of the phenyl ring to the rest of molecule [especially wherein R ⁴ is attached in position 3 (meta-position) of said phenyl ring according to any one of embodiments 14) to 16)]. 18) Another embodiment relates to compounds according to any one of embodiments 1) to 14), wherein p represents the integer 0 (i.e. R ⁵ is absent). 19) Another embodiment relates to compounds according to any one of embodiments 1) to 18), wherein R ⁴ represents • halogen (especially chlorine, fluorine, or bromine); • cyano; • C _1-3 -alkyl (especially methyl); • hydroxy-C _1-4 -alkyl (especially hydroxy-methyl or 4-hydroxy-butyl); • C _3-6 -cycloalkyl optionally containing one oxygen ring atom (notably cyclopropyl or tetrahydrofuranyl; especially cyclopropyl or tetrahydrofuran-3-yl); • C _1-3 -alkoxy-CH ₂ -C _2-3 -alkenyl (notably 3-methoxy-prop-1-en-1-yl; especially (Z)-3-methoxy-prop-1-en-1-yl); • C _1-3 -alkylthio (especially methylthio); • C _1-3 -alkoxy-C _1-4 -alkyl (especially methoxy-methyl or 3-methoxy-propyl); • N,N-di-C _1-3 -alkyl-amino-carbonyl-oxy-C _1-3 -alkyl (especially N,N-diethyl-amino-carbonyl-oxy-methyl); • C _1-3 -alkoxy-C _1-3 -alkoxy-(CH ₂ ) _0-2 - (especially 2-methoxy-ethoxy-methyl); • C _1-3 -alkyl-carbonyl (especially acetyl); • C _1-4 -alkoxy-carbonyl (especially tert-butoxy-carbonyl); • –NR ^N1 R ^N2 wherein ^ R ^N1 represents C _1-3 -alkyl (especially methyl); and ^ R ^N2 represents hydroxy-C _1-3 -alkyl (especially 2-hydroxyethyl); ^ or R ^N1 and R ^N2 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated heterocyclic ring containing one or two ring nitrogen heteroatoms (especially such heterocyclic ring represents pyrrolidinyl, piperidinyl, or piperazinyl); wherein said heterocyclic ring independently is unsubstituted or mono-substituted with hydroxy, hydroxy-C _1-3 -alkyl (especially 1- methyl-1-hydroxy-ethyl), C _3-6 -cycloalkyl-carbonyl (especially cyclopentyl-carbonyl), or C _1-3 -alkoxy-C _{1- 3} -alkoxy-carbonyl (especially 2-methoxy-ethoxy-carbonyl); • –OR ^OA1 , wherein R ^OA1 represents ^ C _1-3 -alkyl (especially methyl, ethyl, or isopropyl); ^ phenyl; ^ pyridinyl (especially pyridin-3-yl); ^ C _3-6 -cycloalkyl-C _1-3 -a methyl); ^ hydroxy-C _2-5 -alkyl (especially 3-hydroxy-3-methyl-butyl); or ^ tetrahydropyranyl (especially tetrahydropyran-4-yl); • –L ¹ –HET, wherein –L ¹ – represents a direct bond (i.e. HET is directly attached to the phenyl ring) or –CH ₂ – (especially –L ¹ – represents a direct bond); and HET represents a 5-membered heteroaryl containing one to four ring heteroatoms independently selected from nitrogen or oxygen (notably isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, imidazolyl, pyrazolyl, furanyl, or tetrazolyl; especially isoxazol-5-yl, oxazol-2-yl, 1,2,3- triazol-2-yl, 1,2,4-triazol-1-yl, imidazol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol- 5-yl, 1,3,4-oxadiazol-2-yl, furan-2-yl, or 2H-tetrazol-5-yl); or HET represents a 6-membered heteroaryl containing one or two nitrogen ring atoms (notably said 6-membered heteroaryl represents pyridinyl; especially pyridin-3-yl); wherein said HET (i.e. said 5- or 6-membered heteroaryl) independently is unsubstituted or mono- substituted (especially at position 3 with respect to the point of attachment of HET to the phenyl ring); wherein the substituent is selected from ^ C _1-3 -fluoroalkyl (notably C ₁ -fluoroalkyl; especially trifluoromethyl); ^ C _1-4 -alkyl which is unsubstituted (especially methyl) or mono-substituted with ^ hydroxy; ^ C _1-3 -alkyl-carbonyl-oxy (especially acetoxy); ^ C _3-5 -cycloalkoxy (especially cyclobutoxy); ^ C _1-4 -alkoxy (especially methoxy or tert-butoxy); ^ C _1-3 -alkyl-sulfonyl (especially methyl-sulfonyl); ^ C _1-3 -fluoroalkoxy (especially 2,2,2-trifluoroethoxy); or ^ –NR ^N3 R ^N4 wherein ^ R ^N3 represents hydrogen or C _1-3 -alkyl (especially methyl); and ^ R ^N4 represents hydroxy-C _1-3 -alkyl-carbonyl (especially hydroxy-methyl-carbonyl) or C _1-3 -alkyl-carbonyl (especially acetyl); ^ –OR ^OA2 , wherein R ^OA2 represents ^ C _1-3 -alkyl (especially ethyl); ^ hydroxy-C _2-3 -alkyl (especially 1-methyl-1-hydroxy-ethyl); ^ C _1-3 -alkoxy-C _1-3 -alkyl (especially 2-methoxy-ethyl); or ^ C _1-3 -fluoroalkoxy (especially 2,2,2-trifluoroethoxy); ^ –C(=O)NR ^N5 R ^N6 wherein ^ R ^N5 represents hydrogen or C _1-3 -alkyl (especially methyl); and ^ R ^N6 represents ^ C _1-3 -alkoxy-C _1-3 -alkyl (especially 2-methoxy-1,1-dimethylethyl); ^ C _3- hexyl-methyl); ^ phenyl, or 6-membered heteroaryl containing one or two ring nitrogen atoms; wherein said phenyl or heteroaryl independently is attached to the nitrogen atom of the –C(=O)NR ^N5 R ^N6 group via direct bond or via C _1-2 -alkylene (notably -CH ₂ - or -CH ₂ -CH ₂ -; especially -CH ₂ -); wherein said phenyl or heteroaryl independently is unsubstituted or mono-substituted with C _1-3 -alkoxy (especially methoxy) [notably such phenyl or 6-membered heteroaryl represents methoxy-phenyl, pyridinyl- methyl, or pyrazinyl-methyl; especially 2-methoxyphenyl, pyridin-4-yl-methyl, or pyrazin-2-yl-methyl]; ^ or R ^N5 and R ^N6 , together with the nitrogen atom to which they are attached, form pyrrolidinyl or morpholinyl; wherein said pyrrolidinyl or morpholinyl independently are mono- or di- substituted, wherein the substituents are independently selected from C _1-3 -alkyl (especially methyl), or hydroxy-C _1-3 -alkyl (especially 1-hydroxy-1-methyl-ethyl); ^ –L ² –Cy ² , wherein ^ –L ² – represents ^ direct bond (i.e. Cy ² is directly attached to the 5-membered heteroaryl); ^ C _1-2 -alkylene (especially -CH ₂ - or -CH ₂ -CH ₂ -) independently unsubstituted or mono-substituted with hydroxy (especially -CH(OH)-); or ^ C _1-2 -alkylene-oxy (especially -CH ₂ -O-), wherein the oxygen atom is directly attached to Cy ² ; and ^ Cy ² represents a C _3-6 -cycloalkyl optionally containing one or two ring heteroatoms independently selected from nitrogen or oxygen (notably such Cy ² represents cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl, azetidinyl, morpholinyl, tetrahydrofuranyl, piperidinyl, or tetrahydropyranyl; especially cyclopropyl, cyclobutyl, cyclohexyl, oxetan-3-yl, azetidin-3-yl, piperidin-4-yl, morpholin-4-yl, tetrahydropyran-4-yl, tetrahydrofuran-3-yl); wherein said Cy ² is unsubstituted; mono-substituted with hydroxy, halogen (especially fluorine), C _1-3 -alkyl (especially methyl), C _1-3 -alkoxy (especially methoxy), C _1-3 -alkyl-carbonyl (especially acetyl), hydroxy-C _1-3 -alkyl-carbonyl (especially hydroxymethyl-carbonyl), N-(C _1-3 -alkyl-carbonyl)-N- C _1-3 -alkyl-carbonylamino (especially N-acetyl-N-methyl-carbonylamino), or C _1-3 -alkyl- carbonylamino (especially acetyl-amino); or di-substituted, wherein the substituents independently are selected from C _1-3 -alkyl (especially methyl), hydroxy, or C _1-3 -alkyl- carbonyl (especially acetyl); ^ or Cy ² represents a saturated 5- to 7-membered bridged bicyclic hydrocarbon ring system optionally containing one or two ring heteroatoms independently selected from oxygen or nitrogen (es epresents bicyclo[1.1.1]pentylan-1-yl, 6-oxa-3-aza- bicyclo[3.1.1]heptan-3-yl, or 7-oxabicyclo[2.2.1]heptan-2-yl); wherein said ring system independently is unsubstituted or mono-substituted with hydroxy-C _1-3 -alkyl (especially hydroxy-methyl); ^ or Cy ² represents a 5-membered heteroaryl containing one or two ring heteroatoms independently selected from nitrogen or oxygen (notably isoxazolyl or pyrazolyl; especially isoxazol-3-yl, 1H-pyrazol-1-yl, or 1H-pyrazol-4-yl), wherein said 5-membered heteroaryl is unsubstituted or mono-substituted with C _1-3 -alkyl (especially methyl) or hydroxy; ^ or Cy ² represents phenyl which is unsubstituted or mono-substituted with C _1-3 -alkoxy (especially methoxy); • –L ³ –R ^T , wherein ^ –L ³ – represents -C≡C-CH(OH)- or -C≡C-C(CH ₃ )(OH)-, wherein the carbon atom bearing the hydroxy group is attached to R ^T ; and ^ R ^T represents ^ hydrogen; ^ phenyl; or ^ 5- or 6-membered heteroaryl containing one or two (especially two) ring nitrogen atom(s) (notably pyrazolyl or pyrimidinyl; especially 1H-pyrazol-3-yl or pyrimidin-4-yl), wherein said 5- or 6-membered heteroaryl is independently unsubstituted, or mono- or di-substituted (notably mono- or di-substituted) with C _1-3 -alkyl (especially methyl); or • –L ⁴ –Cy ⁴ , wherein ^ –L ⁴ – represents -CH ₂ -CH ₂ -CH(OH)- or -CH ₂ -CH ₂ -C(CH ₃ )(OH)-; wherein the carbon atom bearing the hydroxy group is attached to Cy ⁴ ); ^ Cy ⁴ represents phenyl or pyrazolyl (especially pyrazol-3-yl); wherein said phenyl or pyrazolyl independently is mono-substituted with hydroxy or C _1-3 -alkyl (especially methyl). 20) Another embodiment relates to compounds according to any one of embodiments 1) to 19), wherein R ⁴ represents –L ¹ –HET, wherein –L ¹ – represents a direct bond (i.e. HET is directly attached to the phenyl ring) or –CH ₂ – (especially –L ¹ – represents a direct bond); and HET represents a 5-membered heteroaryl selected from isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, imidazolyl, pyrazolyl, furanyl, or tetrazolyl (especially isoxazol-5-yl, oxazol-2-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, imidazol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4- oxadiazol-2-yl, furan-2-yl, or 2H-tetrazol-5-yl); wherein said HET is unsubstituted or mono-substituted; wherein the substituent is as defined in any one of embodiments 1) or 19). 21) Another embodiment relates to compounds according to any one of embodiments 1) to 19), wherein R ⁴ represents –L ¹ –HET, wherein –L ¹ – represents a direct bond (i.e. HET is directly attached to the phenyl ring) or –CH ₂ – (especially –L ¹ – represents a direct bond); and HE especially 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5- yl); wherein said HET is unsubstituted or mono-substituted; wherein the substituent is as defined in any one of embodiments 1) or 19). 22) Another embodiment relates to compounds according to any one of embodiments 1) to 19), wherein R ⁴ represents • –L ³ –R ^T , wherein ^ –L ³ – represents -C≡C-CH(OH)- or -C≡C-C(CH ₃ )(OH)-, wherein the carbon atom bearing the hydroxy group is attached to R ^T ; and ^ R ^T represents ^ phenyl; or ^ 5- or 6-membered heteroaryl containing one or two (especially two) ring nitrogen atom(s) (notably pyrazolyl or pyrimidinyl; especially 1H-pyrazol-3-yl or pyrimidin-4-yl), wherein said 5- or 6-membered heteroaryl is independently unsubstituted, or mono- or di-substituted (notably mono- or di-substituted) with C _1-3 -alkyl (especially methyl); 23) Another embodiment relates to compounds according to any one of embodiments 1) to 22), wherein at least one, especially two and in particular all of the following characteristics a), b) and/or c) below are present: a) the radical represents e-3-yl, 1,3-dimethyl-azetidine-3-yl, 1-ethyl-3-methyl-azetidine-3-yl, 1-isopropyl-3-methyl- azetidine-3-yl, 1-cyclopropyl-3-methyl-azetidine-3-yl, 1-(2-fluoroethyl)-3-fluoro-azetidine-3-yl, 1-methyl-3- amino-azetidine-3-yl, 1-methyl-3-cyano-azetidine-3-yl, 1-cyclopropyl-3-fluoro-azetidine-3-yl, 1-methyl-3- methyl-pyrrolidin-3-yl, 1-(oxetan-3-yl)-3-methyl-azetidine-3-yl, 1-(2-hydroxyethyl)-3-methyl-azetidine-3-yl, 1- (2,2-difluoroethyl)-3-methyl-azetidine-3-yl, or 1-(amino-carbonyl)-3-methyl-azetidine-3-yl; b) the radical represents 4-methyl-phenyl, 4-ethyl-phenyl, 4-(n-propyl)-phenyl, 4-isopropyl-phenyl, 4-difluoromethyl- phenyl, 4-trifluoromethyl-phenyl, 4-cyclopropyl-phenyl, 4-(methyl-amino)-phenyl, 4-(n-propoxy)-phenyl, 4- difluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 4-phenoxy-phenyl, or 4-cyclobutoxy-phenyl; c) the radical phenyl, 3-(5-(1 -hydroxy-1 -methyl-ethyl)-pyridin-3-yl)-phenyl, 3-(pyrazol-1-yl)-phenyl, 3-(pyrazol-1-yl- methyl)-phenyl, 3-(3-methyl-pyrazol-1-yl)-phenyl, 3-(1-methyl-pyrazol-3-yl)-phenyl, 3-(imidazol-1-yl)- phenyl, 3-(imidazol-1-yl-methyl)-phenyl, 3-(1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(1 ,2,3-triazol-2-yl)-phenyl, 3-(5-methyl-furan-2-yl)-phenyl, 3-(2-methyl-2H-tetrazol-5-yl)-phenyl, 3-(5-hydroxy-1 ,2,4-oxadiazol-3- yl)-phenyl, 3-(5-methyl-1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(5-methyl-1,3,4-oxadiazol-2-yl)-phenyl, 3-(3- methyl-isoxazol-5-yl)-phenyl, 3-(5-methyl-oxazol-2-yl)-phenyl, 3-(4-methyl-oxazol-2-yl)-phenyl, 3-(3- methyl-1 ,2,4-triazol-1-yl)-phenyl, 3-(3-ethoxy-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(5-(1-hydroxy-1-methyl- ethyl)-1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(3-trifluoromethyl-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(5-(1-(acetyl- amino)-cyclopropyl)-1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(5-(3-hydroxy-cyclobutyl)-1 ,2,4-oxadiazol-3-yl)- phenyl, 3-(5-((1-hydroxy-cyclobutyl)-methyl)-1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(3-(3-hydroxy-oxetan-3- yl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(5-(2-hy d roxy-2-methy I -propy l)-1 ,2, 4-oxadi azol-3-y l)-pheny 1 , 3-(3- (2-hydroxy-2-methyl-propyl)-1,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(2-hydroxy-1 ,1-dimethyl-ethyl)-1 ,2,4- oxadiazol-5-yl)-phenyl, 3-(5-(methyl-sulfonyl-methyl)-1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(3-(2-methoxy- ethoxy)-1 , 2, 4-oxadiazol-5-y l)-pheny I, 3-(5-(acetyl-oxy-methyl)-1 ,2, 4-oxadi azol-3-y l)-pheny 1 , 3-(5-(2- methoxy-1 ,1-dimethyl-ethyl)-1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(3-(tert-butoxy-methyl)-1 ,2,4-oxadiazol- 5-yl)-phenyl, 3-(5-(N-methyl-N-(2-methoxy-ethyl)-amino)-1,2,4-oxadiazol-3- yl)-phenyl, 3-(5-(4-fluoro- tetrahydropyran-4-yl)-1,2,4-oxadiazol-3-yl)-phenyl, 3-(5-(tetrahydropyran-4-yl)-1 ,2,4-oxadiazol-3-yl)- phenyl, 3-(3-(4-methyl-tetrahydropyran-4-yl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(tetrahydropyran-4- yl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(5-(1-methoxy-cyclobutyl)-1,2,4-oxadiazol-3-yl)-phenyl, 3-(3- (cyclobutoxy-methyl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(3-hydroxy-tetrahydrofuran-3-yl)-1,2,4- oxadiazol-5-yl)-phenyl, 3-(4-(tetrahydropyran-4-yl)-oxazol-2-yl)-phenyl, 3-(3-(tetrahydropyran-4-yl)- isoxazol-5-yl)-phenyl, 3-(2-phenyl-oxazol-5-yl)-phenyl, 3-(3-(5-methyl-isoxazol-3-yl)-1,2,4-oxadiazol- 5-yl)-phenyl, 3-(3-(2-(3-methyl-pyrazol-1-yl)-ethyl)-1,2,4-oxadiazol-5-yl) -phenyl, 3-(3-((1-methyl- pyrazol-4-yl)-oxy-methyl)-1,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(morpholin-4-yl)-1 ,2,4-oxadiazol-5-yl)- phenyl, 3-(3-(morpholin-4-yl-methyl)-1,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(2,6-dimethyl-morpholin-4- yl)-1 ,2, 4-oxadi azol-5-y l)-phenyl , 3-(3-(4-hydroxy-cyclohexyl)-1 , 2, 4-oxadiazol-5-y l)-pheny I, 3-(3-(4- hydroxy-tetrahydropyran-4-yl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(4-hydroxy-tetrahydropyran-4-yl- methyl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(N-methyl-N-(hydroxy-methyl-carbonyl)-amino-methyl)- 1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(5-(3-hydroxymethyl-bicyclo[1.1 ,1]pentan-1-yl)-1 ,2,4-oxadiazol-3-yl)- phenyl, 3-(3-(6-oxa-3-aza-bicyclo[3.1.1]heptan-3-yl)-1,2,4-oxadiazol -5-yl)-phenyl, 3-(3-(7- oxabicyclo[2.2.1]heptan-2-yl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(5-(2-methyl-2-(acetyl-amino)-propyl)-

1.2.4-oxadiazol-3-yl)-phenyl, 3-(3-(3-methoxy-phenyl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(5-(1- cyclohexyl-1-hydroxy-methyl)-1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(3-(phenyl-oxy-methyl)-1,2,4- oxadiazol-5-yl)-phenyl, 3-(3-(2-phenyl-ethyl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(5-(1-(N-acetyl-N- methyl-amino)-cyclopropyl)-1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(3-(N-acetyl-azetidin-3-yl-methyl)-1 ,2,4- oxadiazol-5-yl)-phenyl, 3-(5-(2-(3-hydroxy-isoxazol-5-yl)-ethyl)-1 ,2,4-oxadiazol-3-yl)-phenyl, 3-(5-(2- (N-methyl-N-acetyl-amino)-2-methyl-propyl)-1,2,4-oxadiazol-3 -yl)-phenyl, 3-(3-(N-(2-methoxy-1,1- dimethylethyl)-amino-carbonyl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(phenyl-amino-carbonyl)-1,2,4- oxadiazol-5-yl)-phenyl, 3-(5-(N-acetyl-piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-phenyl, 3-(3-(pyridin-4-yl- methyl-amino-carbonyl)-1,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(pyrazin-2-yl-methyl-amino-carbonyl)-

1.2.4-oxadi azol-5-y I )-pheny I, 3-(5- (N-acety l-4-hy droxy-pi perid i n-4-y l)-1 , 2, 4-oxadiazol-3-y l)-pheny 1, 3- (3-(N-acetyl-4-hydroxy-piperidin-4-yl-methyl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(2,6-dimethyl- morpholin-4-yl-carbonyl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(N-(hydroxymethyl-carbonyl)-piperidin-4- yl)-1 ,2,4-oxadiazol-5-yl)-phenyl, 3-(3-(3-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl-carbonyl) -1 ,2,4- oxadiazol-5-yl)-phenyl, 3-(3-(2-methoxyphenyl-amino-carbonyl)-1,2,4-oxadiazol-5-yl)- phenyl, 3-(3- (4-methoxyphenyl-amino-carbonyl)-1,2,4-oxadiazol-5-yl)-pheny l, 3-(3-(3-isopropoxyphenyl-amino- carbonyl)-1,2,4-oxadiazol-5-yl)-phenyl, 3-chloro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 3-bromo- phenyl, 3-methyl-phenyl, 3-cyano-phenyl, 3-methylthio-phenyl, 3-(hydroxy-methyl)-phenyl, 3-(4- hydroxy-butyl)-phenyl, 3-cyclopropyl-phenyl, 3-(tetrahydrofuran-3-yl)-phenyl, 3-acetyl-phenyl, 3-(tert- butoxy-carbonyl)-phenyl, 3-(methoxy-methyl)-phenyl, 3-(cyclopropyl-methyl)-phenyl, 3-(pyrrolidin-1- yl)-phenyl, 3-(4-hydroxy-but-1-yn-1-yl)-phenyl, 3-(3-methoxy-prop-1-en-1-yl)-phenyl, 3-(3-methoxy- propyl)-phenyl, 3-(N-methyl-N-(2-hydroxyethyl)-amino)-phenyl, 3-(2-methoxy-ethoxy-methyl)-phenyl, 3-(3-hydroxy-pyrrolidinyl)-phenyl, 3-(3-(1-methyl-1-hydroxy-ethyl)-pyrrolidin-1-yl)-phenyl, 3- piperidinyl-phenyl, 3-(4-(2-methoxy-ethoxy-carbonyl)-piperazin-1-yl)-phenyl, 3-(4-(cyclopentyl- carbonyl)-piperazin-1-yl)-phenyl, 3-(phenyl-sulfonamido-methyl)-phenyl, 3-(N-(tert-butoxy-carbonyl)- piperidin-4-yl)-phenyl, 3-(1-(tert-butoxy-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)- phenyl, 3-(3- methoxyphenyl-methyl-carbonyl-amino-methyl)-phenyl, 3-(3-hydroxy-3-(1-methyl-1 H-pyrazol-3-yl)- but-1-yn-1-yl)-phenyl, 3-(3-(4-hydroxy-but-1-yn-1-yl)-phenyl)-phenyl, 3-(3-hydroxy-3-phenyl-prop-1- yn-1-yl)-phenyl, 3-(3-hydroxy-3-(1-methyl-1 H-pyrazol-3-yl)-but-1-yn-1-yl)-phenyl, 3-(3-hydroxy-3- (1,5-dimethyl-1 H-pyrazol-3-yl)-but-1-yn-1-yl)-phenyl, 3-(3-hydroxy-3-(6-methyl-pyrimidin-4-yl)-but-1- yn-1-yl)-phenyl, 3-(3-hydroxy-3-phenyl-propyl)-phenyl, 3-(3-hydroxy-3-(1-methyl-1 H-pyrazol-3-yl)- butyl)-phenyl, 3-(3-hydroxy-3-methyl-butoxy)-phenyl, or 3-(tetrahydropyran-4-yl-oxy)-phenyl; or 4-phenoxy-phenyl, 4-cyano-phenyl, 4-fluoro-phenyl, 4-(tetrahydropyran-4-yl-oxy)-phenyl, 4- isopropoxy-phenyl, 4-(pyridin-3-yl-oxy)-phenyl, 4-methyl-phenyl, 4-chloro-phenyl, 4-methylthio- phenyl, 4-(N,N-diethyl-amino-carbonyl-oxy-methyl)-phenyl, or 4-(3-(2-(3-methyl-pyrazol-1-yl)-ethyl)- 1 ,2,4-oxadiazol-5-yl)-phenyl; or 3-chloro-4-fluoro-phenyl, 2-fluoro-3-methoxy-phenyl, 2-fluoro-4-ethoxy-phenyl, 3-methoxy-4-fluoro- phenyl, 3, 5-di methoxy-phenyl, 2-f I uoro-3-(5-(tetrahy dropy ran-4-yl)- 1 ,2, 4-oxadi azol-3-y l)-pheny I, 2- fluoro-5-(5-(tetrahydropyran-4-yl)-1,2,4-oxadiazol-3-yl)-phe nyl, or 3-(3-methyl-1 ,2,4-oxadiazol-5-yl)-

4-ethoxy-phenyl; or 3-(2-methyl-benzooxazol-6-yl)-phenyl, 3-(benzooxazol-5-yl)-phenyl, 3-(2, 2-dif I uoro-benzo [1 , 3] d ioxol-

5-y l)-phenyl , 3-(2, 3-di hydrobenzofuran-5-yl)-pheny I, or 3-(2, 3-d i hydro-benzo [1 , 4]dioxin-6-yl)-pheny I .

24) Another embodiment relates to compounds according to embodiment 14), which are also compounds of Formula (II) (i.e. the asymmetric carbon atom to which phenyl ring A and phenyl ring B are attached has the absolute configuration depicted in Formula (II))

Formula (II).

Based on the dependencies of the different embodiments 1) to 24) as disclosed hereinabove, the following embodiments are thus possible and intended, and herewith specifically disclosed in individualized form:

2+1, 4+1, 4+2+1, 6+1, 6+2+1, 6+4+1, 6+4+2+1, 8+1, 8+2+1, 8+4+1, 8+4+2+1, 8+6+1, 8+6+2+1, 8+6+4+1, 8+6+4+2+1, 14+1, 14+2+1, 14+4+1, 14+4+2+1, 14+6+1, 14+6+2+1, 14+6+4+1, 14+6+4+2+1, 14+8+1, 14+8+2+1, 14+8+4+1, 14+8+4+2+1, 14+8+6+1, 14+8+6+2+1, 14+8+6+4+1, 14+8+6+4+2+1, 15+1, 15+2+1, 15+4+1, 15+4+2+1, 15+6+1, 15+6+2+1, 15+6+4+1, 15+6+4+2+1, 15+8+1, 15+8+2+1, 15+8+4+1, 15+8+4+2+1, 15+8+6+1, 15+8+6+2+1, 15+8+6+4+1, 15+8+6+4+2+1, 15+14+1, 15+14+2+1, 15+14+4+1, 15+14+4+2+1, 15+14+6+1, 15+14+6+2+1, 15+14+6+4+1, 15+14+6+4+2+1, 15+14+8+1, 15+14+8+2+1, 15+14+8+4+1, 15+14+8+4+2+1, 15+14+8+6+1, 15+14+8+6+2+1, 15+14+8+6+4+1, 15+14+8+6+4+2+1, 18+1, 18+2+1, 18+4+1, 18+4+2+1, 18+6+1, 18+6+2+1, 18+6+4+1, 18+6+4+2+1, 18+8+1, 18+8+2+1, 18+8+4+1, 18+8+4+2+1, 18+8+6+1, 18+8+6+2+1, 18+8+6+4+1, 18+8+6+4+2+1, 18+14+1, 18+14+2+1, 18+14+4+1, 18+14+4+2+1, 18+14+6+1, 18+14+6+2+1, 18+14+6+4+1, 18+14+6+4+2+1, 18+14+8+1, 18+14+8+2+1, 18+14+8+4+1, 18+14+8+4+2+1, 18+14+8+6+1, 18+14+8+6+2+1, 18+14+8+6+4+1, 18+14+8+6+4+2+1, 18+15+1, 18+15+2+1, 18+15+4+1, 18+15+4+2+1, 18+15+6+1, 18+15+6+2+1, 18+15+6+4+1, 18+15+6+4+2+1, 18+15+8+1, 18+15+8+2+1, 18+15+8+4+1, 18+15+8+4+2+1, 18+15+8+6+1, 18+15+8+6+2+1, 18+15+8+6+4+1, 18+15+8+6+4+2+1, 18+15+14+1, 18+15+14+2+1, 18+15+14+4+1, 18+15+14+4+2+1, 18+15+14+6+1, 18+15+14+6+2+1, 18+15+14+6+4+1, 18+15+14+6+4+2+1, 18+15+14+8+1, 18+15+14+8+2+1, 18+15+14+8+4+1, 18+15+14+8+4+2+1, 18+15+14+8+6+1, 18+15+14+8+6+2+1,

18+15+14+8+6+4+1, 18+15+14+8+6+4+2+1, 20+1, 20+2+1, 20+4+1, 20+4+2+1, 20+6+1, 20+6+2+1, 20+6+4+1, 20+6+4+2+1, 20+8+1, 20+8+2+1, 20+8+4+1, 20+8+4+2+1, 20+8+6+1, 20+8+6+2+1, 20+8+6+4+1, 20+8+6+4+2+1, 20+14+1, 20+14+2+1, 20+14+4+1, 20+14+4+2+1, 20+14+6+1, 20+14+6+2+1, 20+14+6+4+1, 20+14+6+4+2+1, 20+14+8+1, 20+14+8+2+1, 20+14+8+4+1, 20+14+8+4+2+1, 20+14+8+6+1, 20+14+8+6+2+1, 20+14+8+6+4+1, 20+14+8+6+4+2+1, 20+15+1, 20+15+2+1, 20+15+4+1, 20+15+4+2+1, 20+15+6+1, 20+15+6+2+1, 20+15+6+4+1, 20+15+6+4+2+1, 20+15+8+1, 20+15+8+2+1, 20+15+8+4+1, 20+15+8+4+2+1, 20+15+8+6+1, 20+15+8+6+2+1, 20+15+8+6+4+1, 20+15+8+6+4+2+1, 20+15+14+1, 20+15+14+2+1, 20+15+14+4+1, 20+15+14+4+2+1, 20+15+14+6+1, 20+15+14+6+2+1, 20+15+14+6+4+1, 20+15+14+6+4+2+1, 20+15+14+8+1, 20+15+14+8+2+1, 20+15+14+8+4+1, 20+15+14+8+4+2+1, 20+15+14+8+6+1, 20+15+14+8+6+2+1, 20+15+14+8+6+4+1,

20+15+14+8+6+4+2+1, 20+18+1, 20+18+2+1, 20+18+4+1, 20+18+4+2+1, 20+18+6+1, 20+18+6+2+1, 20+18+6+4+1, 20+18+6+4+2+1, 20+18+8+1, 20+18+8+2+1, 20+18+8+4+1, 20+18+8+4+2+1, 20+18+8+6+1, 20+18+8+6+2+1, 20+18+8+6+4+1, 20+18+8+6+4+2+1, 20+18+14+1, 20+18+14+2+1, 20+18+14+4+1, 20+18+14+4+2+1, 20+18+14+6+1, 20+18+14+6+2+1, 20+18+14+6+4+1, 20+18+14+6+4+2+1, 20+18+14+8+1, 20+18+14+8+2+1, 20+18+14+8+4+1, 20+18+14+8+4+2+1, 20+18+14+8+6+1, 20+18+14+8+6+2+1, 20+18+14+8+6+4+1,

20+18+14+8+6+4+2+1, 20+18+15+1, 20+18+15+2+1, 20+18+15+4+1, 20+18+15+4+2+1, 20+18+15+6+1, 20+18+15+6+2+1, 20+18+15+6+4+1, 20+18+15+6+4+2+1, 20+18+15+8+1, 20+18+15+8+2+1, 20+18+15+8^+1, 20+18+15+8+4+2+1, 20+18+15+8+6+1, 20+18+15+8+6+2+1, 20+18+15+8+6+4+1, 20+18+15+8+6+4+2+1, 20+18+15+14+1, 20+18+15+14+2+1, 20+18+15+14+4+1, 20+18+15+14+4+2+1, 20+18+15+14+6+1,

20+18+15+14+6+2+1, 20+18+15+14+6+4+1, 20+18+15+14+6+4+2+1, 20+18+15+14+8+1, 20+18+15+14+8+2+1, 20+18+15+14+8+4+1, 20+18+15+14+8+4+2+1, 20+18+15+14+8+6+1, 20+18+15+14+8+6+2+1,

20+18+15+14+8+6+4+1, 20+18+15+14+8+6+4+2+1, 21+1, 21+2+1, 21+4+1, 21+4+2+1, 21+6+1, 21+6+2+1, 21 +6+4+1, 21+6+4+2+1, 21+8+1, 21+8+2+1, 21+8+4+1, 21+8+4+2+1, 21+8+6+1, 21+8+6+2+1, 21+8+6+4+1, 21+8+6+4+2+1, 21+14+1, 21+14+2+1, 21+14+4+1, 21+14+4+2+1, 21+14+6+1, 21+14+6+2+1, 21+14+6^+1, 21+14+6+4+2+1, 21+14+8+1, 21+14+8+2+1, 21+14+8+4+1, 21+14+8+4+2+1, 21+14+8+6+1, 21+14+8+6+2+1, 21+14+8+6+4+1, 21+14+8+6+4+2+1, 21+15+1, 21+15+2+1, 21+15+4+1, 21+15+4+2+1, 21+15+6+1, 21+15+6+2+1, 21+15+6+4+1, 21+15+6+4+2+1, 21+15+8+1, 21+15+8+2+1, 21+15+8+4+1, 21+15+8+4+2+1, 21+15+8+6+1, 21+15+8+6+2+1, 21+15+8+6+4+1, 21+15+8+6+4+2+1, 21+15+14+1, 21+15+14+2+1, 21+15+14+4+1, 21+15+14+4+2+1, 21+15+14+6+1, 21+15+14+6+2+1, 21+15+14+6+4+1, 21+15+14+6+4+2+1, 21+15+14+8+1, 21+15+14+8+2+1, 21+15+14+8+4+1, 21+15+14+8+4+2+1, 21+15+14+8+6+1, 21+15+14+8+6+2+1,

21+15+14+8+6+4+1, 21+15+14+8+6+4+2+1, 21+18+1, 21+18+2+1, 21+18+4+1, 21+18+4+2+1, 21+18+6+1, 21+18+6+2+1, 21+18+6+4+1, 21+18+6+4+2+1, 21+18+8+1, 21+18+8+2+1, 21+18+8+4+1, 21+18+8+4+2+1, 21+18+8+6+1, 21+18+8+6+2+1, 21+18+8+6+4+1, 21+18+8+6+4+2+1, 21+18+14+1, 21+18+14+2+1, 21+18+14+4+1, 21+18+14+4+2+1, 21+18+14+6+1, 21+18+14+6+2+1, 21+18+14+6+4+1, 21+18+14+6+4+2+1, 21+18+14+8+1, 21+18+14+8+2+1, 21+18+14+8+4+1, 21+18+14+8+4+2+1, 21+18+14+8+6+1, 21+18+14+8+6+2+1,

21+18+14+8+6+4+1, 21+18+14+8+6+4+2+1, 21+18+15+1, 21+18+15+2+1, 21+18+15+4+1, 21+18+15+4+2+1, 21+18+15+6+1, 21+18+15+6+2+1, 21+18+15+6+4+1, 21+18+15+6+4+2+1, 21+18+15+8+1, 21+18+15+8+2+1, 21+18+15+8+4+1, 21+18+15+8+4+2+1, 21+18+15+8+6+1, 21+18+15+8+6+2+1, 21+18+15+8+6+4+1,

21+18+15+8+6+4+2+1, 21+18+15+14+1, 21+18+15+14+2+1, 21+18+15+14+4+1, 21+18+15+14+4+2+1, 21+18+15+14+6+1, 21+18+15+14+6+2+1, 21+18+15+14+6+4+1, 21+18+15+14+6+4+2+1, 21+18+15+14+8+1, 21+18+15+14+8+2+1, 21+18+15+14+8+4+1, 21+18+15+14+8+4+2+1, 21+18+15+14+8+6+1,

21+18+15+14+8+6+2+1, 21+18+15+14+8+6+4+1, 21+18+15+14+8+6+4+2+1, 21+20+1, 21+20+2+1, 21+20+4+1, 21+20+4+2+1, 21+20+6+1, 21+20+6+2+1, 21+20+6+4+1, 21+20+6+4+2+1, 21+20+8+1, 21+20+8+2+1, 21+20+8+4+1, 21+20+8+4+2+1, 21+20+8+6+1, 21+20+8+6+2+1, 21+20+8+6+4+1, 21+20+8+6+4+2+1, 21+20+14+1, 21+20+14+2+1, 21+20+14+4+1, 21+20+14+4+2+1, 21+20+14+6+1, 21+20+14+6+2+1, 21+20+14+6+4+1, 21+20+14+6+4+2+1, 21+20+14+8+1, 21+20+14+8+2+1, 21+20+14+8+4+1, 21+20+14+8+4+2+1, 21+20+14+8+6+1, 21+20+14+8+6+2+1, 21+20+14+8+6+4+1, 21+20+14+8+6+4+2+1, 21+20+15+1, 21+20+15+2+1, 21+20+15+4+1, 21+20+15+4+2+1, 21+20+15+6+1, 21+20+15+6+2+1, 21+20+15+6+4+1, 21+20+15+6+4+2+1, 21+20+15+8+1, 21+20+15+8+2+1, 21+20+15+8+4+1, 21+20+15+8+4+2+1, 21+20+15+8+6+1, 21+20+15+8+6+2+1,

21+20+15+8+6+4+1, 21+20+15+8+6+4+2+1, 21+20+15+14+1, 21+20+15+14+2+1, 21+20+15+14+4+1,

21+20+15+14+4+2+1, 21+20+15+14+6+1, 21+20+15+14+6+2+1, 21+20+15+14+6+4+1, 21+20+15+14+6+4+2+1, 21+20+15+14+8+1, 21+20+15+14+8+2+1, 21+20+15+14+8+4+1, 21+20+15+14+8+4+2+1, 21+20+15+14+8+6+1, 21+20+15+14+8+6+2+1, 21+20+15+14+8+6+4+1, 21+20+15+14+8+6+4+2+1, 21+20+18+1, 21+20+18+2+1, 21+20+18+4+1, 21+20+18+4+2+1, 21+20+18+6+1, 21+20+18+6+2+1, 21+20+18+6+4+1, 21+20+18+6+4+2+1, 21+20+18+8+1, 21+20+18+8+2+1, 21+20+18+8+4+1, 21+20+18+8+4+2+1, 21+20+18+8+6+1, 21+20+18+8+6+2+1, 21+20+18+8+6+4+1, 21+20+18+8+6+4+2+1, 21+20+18+14+1, 21+20+18+14+2+1, 21+20+18+14+4+1,

21+20+18+14+4+2+1, 21+20+18+14+6+1, 21+20+18+14+6+2+1, 21+20+18+14+6+4+1, 21+20+18+14+6+4+2+1, 21+20+18+14+8+1, 21+20+18+14+8+2+1, 21+20+18+14+8+4+1, 21+20+18+14+8+4+2+1, 21+20+18+14+8+6+1, 21+20+18+14+8+6+2+1, 21+20+18+14+8+6+4+1, 21+20+18+14+8+6+4+2+1, 21+20+18+15+1, 21+20+18+15+2+1, 21+20+18+15+4+1, 21+20+18+15+4+2+1, 21+20+18+15+6+1, 21+20+18+15+6+2+1, 21+20+18+15+6+4+1, 21+20+18+15+6+4+2+1, 21+20+18+15+8+1, 21+20+18+15+8+2+1, 21+20+18+15+8+4+1, 21+20+18+15+8+4+2+1, 21+20+18+15+8+6+1, 21+20+18+15+8+6+2+1, 21+20+18+15+8+6^+1, 21+20+18+15+8+6+4+2+1,

21+20+18+15+14+1, 21+20+18+15+14+2+1, 21+20+18+15+14+4+1, 21+20+18+15+14+4+2+1, 21+20+18+15+14+6+1 , 21 +20+18+15+14+6+2+1 , 21 +20+18+15+14+6+4+1 , 21+20+18+15+14+6+4+2+1 ,

21+20+18+15+14+8+1 , 21 +20+18+15+14+8+2+1 , 21 +20+18+15+14+8+4+1 , 21+20+18+15+14+8+4+2+1 ,

21+20+18+15+14+8+6+1 , 21 +20+18+15+14+8+6+2+1, 21 +20+18+15+14+8+6+4+1 , 21 +20+18+15+14+8+6+4+2+1 ,

24+14+1, 24+14+2+1 , 24+14+4+1 , 24+14+4+2+1 , 24+14+6+1 , 24+14+6+2+1 , 24+14+6+4+1 , 24+14+6+4+2+1 ,

24+14+8+1 , 24+14+8+2+1, 24+14+8+4+1 , 24+14+8+4+2+1 , 24+14+8+6+1 , 24+14+8+6+2+1 , 24+14+8+6+4+1 , or 24+14+8+6+4+2+1.

In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, “6+4+2+1” for example refers to embodiment 6) depending on embodiment 4), depending on embodiment 2), depending on embodiment 1), i.e. embodiment “6+4+2+1 ” corresponds to the compounds of Formula (I) according to embodiment 1) further limited by all the features of the embodiments 2), 4), and 6).

The invention relates to compounds of the Formula (I) as defined in embodiment 1), or to such compounds further limited by the characteristics of any one of embodiments 2) to 24), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of diseases or disorders where CCR6 receptors are involved as described hereinbelow.

25) Another embodiment relates to a compound according to embodiment 1), which is: (1,3-Dimethyl-azetidin-3-yl)-(2-fluoro-phenyl)-(4-trifluorom ethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-(4-ethoxy-2-fluoro-phenyl)-(4-t rifluoromethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-(2-fluoro-3-methoxy-phenyl)-(4- trifluoromethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-(3-fluoro-phenyl)-(4-trifluorom ethoxy-phenyl)-methanol;

(3-Bromo-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluorometho xy-phenyl)-methyl]-benzonitrile; (3-Cyclopropyl-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-trifl uoromethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-[3-(1-methyl-1 H-pyrazol-3-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol ; (1,3-Dimethyl-azetidin-3-yl)-(3-methylsulfanyl-phenyl)-(4-tr ifluoromethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-(3-piperidin-1-yl-phenyl)-(4-tr ifluoromethoxy-phenyl)-methanol;

(1,3-Dimethyl-azetidin-3-yl)-(4-isopropoxy-phenyl)-(4-tri fluoromethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-[4-(pyridin-3-yloxy)-phenyl]-(4 -trifluoromethoxy-phenyl)-methanol;

4-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluorometho xy-phenyl)-methyl]-benzonitrile; (1,3-Dimethyl-azetidin-3-yl)-p-tolyl-(4-trifluoromethoxy-phe nyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-(4-fluoro-phenyl)-(4-trifluorom ethoxy-phenyl)-methanol;

(4-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol; (1,3-Dimethyl-azetidin-3-yl)-(4-methylsulfanyl-phenyl)-(4-tr ifluoromethoxy-phenyl)-methanol; (2,3-Dihydro-benzofuran-5-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(2,2-Difluoro-benzo[1 ,3]dioxol-5-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(1 ,3-Dimethyl-azetidin-3-yl)-(4-fluoro-3-methoxy-phenyl)-(4-tr ifluoromethoxy-phenyl)-methanol;

(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(1 ,3-Dimethyl-azetidin-3-yl)-m-tolyl-(4-trifluoromethoxy-pheny l)-methanol;

(S)-(3-Chloro-4-fluoro-phenyl)-(1,3-dimethyl-azetidin-3-y l)-(4-trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-trifluorome thoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-[1 ,2,4]triazol-1-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-metha nol;

(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-pyrazol-1-yl)-phenyl ]-(4-trifluoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-[3-(4-methyl-oxazol-2-yl)-phenyl] -(4-trifluoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-(3-hydroxymethyl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol;

(3,5-Dimethoxy-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-1-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-pyrrolidin-3-ol;

2-((S)-1-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-pyrrolidin-3-yl)- propan-2-ol;

2-({3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-methyl-amino)-ethanol;

1-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-ethanone;

(1 ,3-Dimethyl-azetidin-3-yl)-(3-imidazol-1-yl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-(3-[1 ,2,3]triazol-2-yl-phenyl)-(4-trifluoromethoxy-phenyl)-methan ol;

(1 ,3-Dimethyl-azetidin-3-yl)-(3-pyrazol-1-yl-phenyl)-(4-triflu oromethoxy-phenyl)-methanol;

(3'-Chloro-biphenyl-3-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-furan-2-yl)-phenyl]- (4-trifluoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-[3-((E)-3-methoxy-propenyl)-pheny l]-(4-trifluoromethoxy-phenyl)-methanol;

4-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester;

[3-(2,5-Dihydro-furan-3-yl)-phenyl]-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

4-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-piperidine-1 -carboxylic acid tertbutyl ester;

(1 _J 3-Dimethyl-azetidin-3-yl)-[3-(tetrahydro-furan-3-yl)-p henyl]-(4-trifluoromethoxy-phenyl)-methanol;

(1 S)-3-(3-((1 ,3-dimethylazetidin-3-yl)(hydroxy)(4-(trifluoromethoxy)pheny l)methyl)phenyl)-1-phenylprop-2-yn-1-ol;

4-{3-[(1 _J 3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-phenyl}-but-3-yn-1-ol;

(1 R)-3-(3-((1 _J 3-dimethylazetidin-3-yl)(hydroxy)(4-(trifluoromethoxy) phenyl)methyl)phenyl)-1-phenylpropan-1-ol;

4-{3-[(1 _J 3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-phenyl}-butan-1-ol;

(1 _J 3-Dimethyl-azetidin-3-yl)-[3-(2-phenyl-oxazol-5-yl)-ph enyl]-(4-trifluoromethoxy-phenyl)-methanol; (1 ,3-Dimethyl-azetidin-3-yl)-[3-(2-methyl-2H-tetrazol-5-yl)-ph enyl]-(4-trifluoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-{3-[5-(2,2,2-trifluoro-ethoxy)-py ridin-3-yl]-phenyl}-(4-trifluoromethoxy-phenyl)-methanol;

Diethyl-carbamic acid 4-[(1 , 3-d i methyl -azetidi n-3-y I )-hydroxy- (4-trifl uoromethoxy-phenyl)-methyl]-benzy I ester;

(1 ,3-Dimethyl-azetidin-3-yl)-(4-{3-[2-(3-methyl-pyrazol-1-yl)- ethyl]-[1 ,2,4]oxadiazol-5-yl}-phenyl)-(4-trifluoromethoxy- phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-[3-(3 -trifluoromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-phenethyl-[1,2,4]oxadiazol- 5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-[1,3,4]oxadiazol-2-y l)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol;

5-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3-carboxylic acid benzyl-methyl-amide;

(1 ,3-Dimethyl-azetidin-3-yl)-(3-imidazol-1-ylmethyl-phenyl)-(4 -trifluoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-(3-pyrazol-1-ylmethyl-phenyl)-(4- trifluoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-(3-methoxymethyl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-[3-(2-methoxy-ethoxymethyl)-pheny l]-(4-trifluoromethoxy-phenyl)-methanol;

5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3- carboxylic acid (pyrazin-2-ylmethyl)-amide;

5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3- carboxylic acid (2-methoxy-1 , 1-dimethyl-ethyl)-amide;

5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3- carboxylic acid (pyridin-4-ylmethyl)-amide;

5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3- carboxylic acid cyclohexylmethyl-amide;

(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazol-3-yl)-[(S)- 3-(1 -hydroxy-1 -methyl-ethyl)-pyrrolidin-1-yl]-methanone;

(5-(3-((S)-(1 ,3-dimethylazetidin-3-yl)(hydroxy)(4-(trifluoromethoxy)pheny l)methyl)phenyl)-1 ,2,4-oxadiazol-3- yl)((2RS,6SR)-2,6-dimethylmorpholino)methanone;

5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3- carboxylic acid (3-isopropoxy-phenyl)-amide;

5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3- carboxylic acid (5-methyl-isoxazol-3-ylmethyl)-amide;

5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3- carboxylic acid (4-methoxy-phenyl)-amide;

5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3- carboxylic acid (2-methoxy-phenyl)-amide; 5-{3-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hy henyl)-methyl]-phenyl}-[1,2,4]oxadiazole-3- carboxylic acid phenylamide; (S)-(1,3-Dimethyl-azetidin-3-yl)-[3-(3-phenoxymethyl-[1,2,4] oxadiazol-5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)- methanol; (S)-(1,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-oxazol-2-yl)-p henyl]-(4-trifluoromethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-[3-(tetrahydro-pyran-4-yloxy)-p henyl]-(4-trifluoromethoxy-phenyl)-methanol; 4-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluorometho xy-phenyl)-methyl]-phenoxy}-2-methyl-butan-2-ol; (S)-(3-Chloro-phenyl)-(3-methyl-1-oxetan-3-yl-azetidin-3-yl) -(4-trifluoromethoxy-phenyl)-methanol; (S)-(3-Chloro-phenyl)-(1-ethyl-3-methyl-azetidin-3-yl)-(4-tr ifluoromethoxy-phenyl)-methanol; (S)-(3-Chloro-phenyl)-(1-isopropyl-3-methyl-azetidin-3-yl)-( 4-trifluoromethoxy-phenyl)-methanol; (S)-(3-Chloro-phenyl)-(1-cyclopropyl-3-methyl-azetidin-3-yl) -(4-trifluoromethoxy-phenyl)-methanol; (S)-(3-Chloro-phenyl)-[1-(2-fluoro-ethyl)-3-methyl-azetidin- 3-yl]-(4-trifluoromethoxy-phenyl)-methanol; (S)-(3-Chloro-phenyl)-[1-(2,2-difluoro-ethyl)-3-methyl-azeti din-3-yl]-(4-trifluoromethoxy-phenyl)-methanol; 2-{3-[(S)-(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phen yl)-methyl]-3-methyl-azetidin-1-yl}-ethanol; (1,3-Dimethyl-azetidin-3-yl)-bis-(4-phenoxy-phenyl)-methanol ; (S)-(1,3-Dimethyl-azetidin-3-yl)-(3-{3-[2-(3-methyl-pyrazol- 1-yl)-ethyl]-[1,2,4]oxadiazol-5-yl}-phenyl)-(4-trifluorometh yl- phenyl)-methanol; (S)-[3-(3-Cyclobutoxymethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-( 1,3-dimethyl-azetidin-3-yl)-(4-ethyl-phenyl)-methanol; 1-(5-{3-[(S)-(4-Cyclopropyl-phenyl)-(1,3-dimethyl-azetidin-3 -yl)-hydroxy-methyl]-phenyl}-[1,2,4]oxadiazol-3-yl)-2- methyl-propan-2-ol; (S)-(1,3-Dimethyl-azetidin-3-yl)-(3-pyrrolidin-1-yl-phenyl)- (4-trifluoromethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-(4-methylamino-phenyl)-(3-pyrro lidin-1-yl-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-[4-ethoxy-3-(3-methyl-[1,2,4]ox adiazol-5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol; (S)-(3-Chloro-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-triflu oromethoxy-phenyl)-methanol; (3-Cyclopropylmethoxy-phenyl)-(1,3-dimethyl-azetidin-3-yl)-( 4-trifluoromethoxy-phenyl)-methanol; Benzooxazol-5-yl-(1,3-dimethyl-azetidin-3-yl)-(4-trifluorome thoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-(2-methyl-benzooxazol-6-yl)-(4- trifluoromethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-[4-(tetrahydro-pyran-4-yloxy)-p henyl]-(4-trifluoromethoxy-phenyl)-methanol; (1,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-[1,2,4]oxadiazol-3 -yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol; (3-Fluoro-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-trif luoromethoxy-phenyl)-methanol; (3-Chloro-phenyl)-(3-fluoro-1-methyl-azetidin-3-yl)-(4-trifl uoromethoxy-phenyl)-methanol; 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-1-methyl-azetidine-3-carboxylic acid amide; 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-1-methyl-azetidine-3-carbonitrile; (3-chlorophenyl)(4-(difluoromethyl)phenyl)(1,3-dimethylazeti din-3-yl)methanol; (3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-propyl-phenyl)-methanol;

(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-propoxy-phenyl)-methanol;

(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-methanol;

(4-Chloro-phenyl)-(3-chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-methanol;

(3-Chloro-phenyl)-(4-cyclobutoxy-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-methanol;

(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-p-tolyl-methanol;

(4-Difluoromethoxy-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-phenyl-methano l;

(1 ,3-Dimethyl-azetidin-3-yl)-{2-fluoro-3-[5-(tetrahydro-pyran- 4-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(4-isopropyl-phenyl)- methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-{2-fluoro-5-[5-(tetrahydro-pyran- 4-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(4-isopropyl- phenyl)-methanol;

2-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-pyridin-3-yl)-propan-2-ol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(tetra hydro-pyran-4-yl)-isoxazol-5-yl]-phenyl}-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-[3-(3-methyl -isoxazol-5-yl)-phenyl]-methanol;

(1 _J 3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-( 1-methoxy-cyclobutyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methano l;

(1 ,3-Dimethyl-azetidin-3-yl)-{3-[5-(4-fluoro-tetrahydro-pyran- 4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-(4-isopropyl-phenyl)- methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-(2-met hoxy-1 , 1-dimethyl-ethyl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}- methanol;

5-[2-(3-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)-ethyl]- isoxazol-3-ol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-(tetra hydro-pyran-4-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}- methano;

(S)-{3-[5-((R)-Cyclohexyl-hydroxy-methyl)-[1,2,4]oxadiazo l-3-yl]-phenyl}-(1 ,3-dimethyl-azetidin-3-yl)-(4-isopropyl- phenyl)-methanol; trans-4-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)- cyclohexanol;

1-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)-2-methyl- propan-2-ol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-[3-(5-methan esulfonylmethyl-[1 ,2,4]oxadiazol-3-yl)-phenyl]- methanol;

2-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1,2,4]oxadiazol-5-yl)-propan-2- ol; trans-3-(3-{3-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-i sopropyl-phenyl)-methyl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)- cyclobutanol;

(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(4-met hyl-tetrahydro-pyran-4-yl)-[1,2,4]oxadiazol-5-yl]-phenyl}- methanol;

3-(5-(3-((1 ,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl) phenyl)-1 ,2,4-oxadiazol-3-yl)tetrahydrofuran-3- ol;

(S)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1-methyl-1 H-pyrazol-3-yl)- but-3-yn-2-ol;

(S)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1-methyl-1 H-pyrazol-3-yl)- butan-2-ol;

(R)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1-methyl-1 H-pyrazol-3-yl)- but-3-yn-2-ol;

(S)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1 ,5-dimethyl-l H-pyrazol-3- yl)-but-3-yn-2-ol;

(R)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1 ,5-dimethyl-l H-pyrazol-3- yl)-but-3-yn-2-ol;

(R)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(6-methyl-pyrimidin-4-yl)-but- 3-yn-2-ol;

(S)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(6-methyl-pyrimidin-4-yl)-but-

3-yn-2-ol;

4-{3-[(S)-(1 _J 3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl) -methyl]-phenyl}-piperazine-1 -carboxylic acid 2- methoxy-ethyl ester;

Cyclopentyl-(4-{3-[(S)-(1 _J 3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl) -methyl]-phenyl}-piperazin-1-yl)- methanone;

N-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-benzyl}-benzenesulfonamide;

N-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-benzyl}-2-(3-methoxy-phenyl)-acetamide;

(S)-(1 _J 3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-[3-(3-m orpholin-4-ylmethyl-[1 _J 2,4]oxadiazol-5-yl)-phenyl]- methanol;

(S)-(1 _J 3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-( 2,2,2-trifluoro-ethoxymethyl)-[1,2 _J 4]oxadiazol-5-yl]-phenyl}- methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(3-met hoxy-phenyl)-[1 ,2,4]oxadiazol-5-yl]-phenyl}-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[(1 S,2S,4R)-3-(7-oxa-bicyclo[2.2.1]hept-2-yl)-[1 ,2,4]oxadiazol-

5-yl]-phenyl}-methanol; (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(5-met hyl-isoxazol-3-yl)-[1 ,2,4]oxadiazol-5-yl]-phenyl}- methanol;

(S)-(1 ,3-Dimethylazetidin-3-yl)(4-isopropylphenyl)(3-(3-(((1-methy l-1 H-pyrazol-4-yl)oxy)methyl)-1,2,4-oxadiazol-5- yl)phenyl)methanol;

2-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1,2,4]oxadiazol-3-yl)-2-methyl- propan-1 -ol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(tetra hydro-pyran-4-yl)-[1 ,2,4]oxadiazol-5-yl]-phenyl}- methanol;

(S)-[3-(3-tert-Butoxymethyl-[1 ,2,4]oxadiazol-5-yl)-phenyl]-(1 ,3-dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[4-(tetra hydro-pyran-4-yl)-oxazol-2-yl]-phenyl}-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-ethoxy-[1,2,4]oxadiazol-5-y l)-phenyl]-(4-isopropyl-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-[3-(3-morpho lin-4-yl-[1 ,2,4]oxadiazol-5-yl)-phenyl]-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-(3-{3-[(2-me thoxy-ethyl)-methyl-amino]-[1 ,2,4]oxadiazol-5-yl}- phenyl)-methanol;

(1 S)-(3-(3-(6-oxa-3-azabicyclo[3.1.1 ]heptan-3-y I)- 1 , 2, 4-oxad i azol-5-y l)phenyl)(1 , 3-di methy I azetidin-3-y I) (4- isopropylphenyl)methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-{3-[3-((2R,6R)-2,6-dimethyl-morph olin-4-yl)-[1 ,2,4]oxadiazol-5-yl]-phenyl}-(4-isopropyl- phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(2-met hoxy-ethoxy)-[1,2,4]oxadiazol-5-yl]-phenyl}-methanol;

(3-Amino-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-tr ifluoromethoxy-phenyl)-methanol;

(1 ,3-Dimethyl-azetidin-3-yl)-phenyl-(4-trifluoromethoxy-phenyl )-methanol;

(3-Chloro-phenyl)-(1 ,3-dimethyl-pyrrolidin-3-yl)-(4-trifluoromethoxy-phenyl)-met hanol;

(1 ,3-Dimethyl-pyrrolidin-3-yl)-(4-phenoxy-phenyl)-(4-trifluoro methoxy-phenyl)-methanol;

1-[4-(3-{3-[(S)-(3-Fluoro-1-methyl-azetidin-3-yl)-hydroxy -(4-isopropyl-phenyl)-methyl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)- piperidin-1-yl]-ethanone;

2-(3-{3-[(S)-(1-Cyclopropyl-3-fluoro-azetidin-3-yl)-hydro xy-(4-isopropyl-phenyl)-methyl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)- propan-2-ol;

1-[4-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)- piperidin-1-yl]-ethanone;

1-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1,2,4]oxadiazol-5-ylmethyl)- cyclobutanol;

N-[1-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)- cyclopropyl]-N-methyl-acetamide; N-[1-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)- cyclopropyl]-acetamide;

N-[2-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)-1 ,1- dimethyl-ethyl]-acetamide;

Acetic acid 3-{3-[(S)-(1 ,3-dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5- yl methyl ester;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-{3-[5-(3-hydroxymethyl-bicyclo[1 .1 ,1]pent-1-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(4- isopropyl-phenyl)-methanol;

N-[2-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)-1 ,1- dimethyl-ethyl]-N-methyl-acetamide;

N-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-ylmethyl)-2- hydroxy-N-methyl-acetamide;

1-[4-(3-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)-4- hydroxy-piperidin-1-yl]-ethanone;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-(3-[1 ,2,4]oxadiazol-3-yl-phenyl)-methanol;

(S)-3-(3-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropy lphenyl)methyl)phenyl)-1 ,2,4-oxadiazol-5(4H)-one;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-hydroxymethyl-[1 ,2,4]oxadiazol-3-yl)-phenyl]-(4-isopropyl-phenyl)-methanol;

1-[4-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-3-yl)- piperidin-1-yl]-2-hydroxy-ethanone;

3-(5-{3-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isop ropyl-phenyl)-methyl]-phenyl}-[1,2,4]oxadiazol-3-yl)-oxetan- 3- ol;

1-[4-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-3-ylmethyl)-

4-hydroxy-piperidin-1-yl]-ethanone;

4-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-3-yl)- tetrahydro-pyran-4-ol;

4-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1,2,4]oxadiazol-3-ylmethyl)- tetrahydro-pyran-4-ol;

1-[3-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-3-ylmethyl)- azetidin-1-yl]-ethanone; or

3-[(S)-Hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidin-3- yl)-methyl]-benzoic acid tert-butyl ester.

26) Another embodiment relates to a compound according to embodiment 1), which is:

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(2-fluoro-phenyl)-(4-trifluoromet hoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-ethoxy-2-fluoro-phenyl)-(4-tri fluoromethoxy-phenyl)-methanol; (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(2-fluoro-3-methoxy-phenyl)-(4-tr ifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-fluoro-phenyl)-(4-trifluoromet hoxy-phenyl)-methanol;

(S)-(3-Bromo-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-benzonitrile;

(S)-(3-Cyclopropyl-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-(1,3-Dimethyl-azetidin-3-yl)-[3-(1-methyl-1 H-pyrazol-3-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol ;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-methylsulfanyl-phenyl)-(4-trif luoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-piperidin-1-yl-phenyl)-(4-trif luoromethoxy-phenyl)-methanol;

(S)-(1,3-Dimethyl-azetidin-3-yl)-(4-isopropoxy-phenyl)-(4 -trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[4-(pyridin-3-yloxy)-phenyl]-(4-t rifluoromethoxy-phenyl)-methanol;

(S)-4-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-benzonitrile;

(S)-(1,3-Dimethyl-azetidin-3-yl)-p-tolyl-(4-trifluorometh oxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-fluoro-phenyl)-(4-trifluoromet hoxy-phenyl)-methanol;

(S)-(4-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-methylsulfanyl-phenyl)-(4-trif luoromethoxy-phenyl)-methanol;

(S)-(2,3-Dihydro-benzofuran-5-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-(2,2-Difluoro-benzo[1 ,3]dioxol-5-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-fluoro-3-methoxy-phenyl)-(4-tr ifluoromethoxy-phenyl)-methanol;

(S)-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-m-tolyl-(4-trifluoromethoxy-pheny l)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-[1 ,2,4]triazol-1-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-(1,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-pyrazol-1-y l)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(4-methyl-oxazol-2-yl)-phenyl] -(4-trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-hydroxymethyl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol;

(S)-(3,5-Dimethoxy-phenyl)-(1,3-dimethyl-azetidin-3-yl)-( 4-trifluoromethoxy-phenyl)-methanol;

(S)-2-({3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-triflu oromethoxy-phenyl)-methyl]-phenyl}-methyl-amino)-ethanol;

(S)-2-({3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-triflu oromethoxy-phenyl)-methyl]-phenyl}-methyl-amino)-ethanol 1-

(S)-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoro methoxy-phenyl)-methyl]-phenyl}-ethanone;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-imidazol-1-yl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol;

(S)-(1,3-Dimethyl-azetidin-3-yl)-(3-[1 ,2,3]triazol-2-yl-phenyl)-(4-trifluoromethoxy-phenyl)-methan ol;

(S)-(1,3-Dimethyl-azetidin-3-yl)-(3-pyrazol-1-yl-phenyl)- (4-trifluoromethoxy-phenyl)-methanol;

(S)-(3'-Chloro-biphenyl-3-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-(1,3-Dimethyl-azetidin-3-yl)-[3-((E)-3-methoxy-propen yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol; (S)-4-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester;

(S)-[3-(2,5-Dihydro-furan-3-yl)-phenyl]-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-4-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(tetrahydro-furan-3-yl)-phenyl ]-(4-trifluoromethoxy-phenyl)-methanol;

(S)-4-{3-[(1 _J 3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-phenyl}-but-3-yn-1-ol;

(1R)-3-(3-((S)-(1 _J 3-dimethylazetidin-3-yl)(hydroxy)(4-(trifluoromethoxy) phenyl)methyl)phenyl)-1-phenylpropan-1-ol;

(S)-4-{3-[(1 _J 3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-phenyl}-butan-1-ol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(2-phenyl-oxazol-5-yl)-phenyl] -(4-trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(2-methyl-2H-tetrazol-5-yl)-ph enyl]-(4-trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-{3-[5-(2 _J 2,2-trifluoro-ethoxy)-pyridin-3-yl]-phenyl}-(4-trifluo romethoxy-phenyl)- methanol;

(S)-Diethyl-carbamic acid 4-[(1 , 3-di methy l-azetidin-3-y l)-hydroxy-(4-trifl uoromethoxy-pheny l)-methy l]-benzy I ester;

(S)-(1 _J 3-Dimethyl-azetidin-3-yl)-(4-{3-[2-(3-methyl-pyrazol-1 -yl)-ethyl]-[1 ,2,4]oxadiazol-5-yl}-phenyl)-(4- trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-[3-(3 -trifluoromethyl-[1 ,2,4]oxadiazol-5-yl)-phenyl]- methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-phenethyl-[1 ,2,4]oxadiazol-5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-met hanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-[1 ,3,4]oxadiazol-2-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-met hanol;

(S)-5-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole-3- carboxylic acid benzyl-methyl-amide;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-imidazol-1-ylmethyl-phenyl)-(4 -trifluoromethoxy-phenyl)-methanol;

(S)-(1,3-Dimethyl-azetidin-3-yl)-(3-pyrazol-1-ylmethyl-ph enyl)-(4-trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-methoxymethyl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol;

(S)-(1,3-Dimethyl-azetidin-3-yl)-[3-(2-methoxy-ethoxymeth yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(tetrahydro-pyran-4-yloxy)-phe nyl]-(4-trifluoromethoxy-phenyl)-methanol;

(S)-4-{3-[(1 _J 3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-phenoxy}-2-methyl-butan-2-ol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-bis-(4-phenoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-methylamino-phenyl)-(3-pyrroli din-1-yl-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[4-ethoxy-3-(3-methyl-[1 ,2,4]oxadiazol-5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)- methanol;

(S)-(3-Cyclopropylmethoxy-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(S)-Benzooxazol-5-yl-(1,3-dimethyl-azetidin-3-yl)-(4-trif luoromethoxy-phenyl)-methanol; (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(2-methyl-benzooxazol-6-yl)-(4-tr ifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[4-(tetrahydro-pyran-4-yloxy)-phe nyl]-(4-trifluoromethoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-[1 ,2,4]oxadiazol-3-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-met hanol;

(S)-(3-Fluoro-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)- (4-trifluoromethoxy-phenyl)-methanol;

(S)-(3-Chloro-phenyl)-(3-fluoro-1-methyl-azetidin-3-yl)-( 4-trifluoromethoxy-phenyl)-methanol;

(S)-3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phen yl)-methyl]-1-methyl-azetidine-3-carboxylic acid amide;

(S)-3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phen yl)-methyl]-1-methyl-azetidine-3-carbonitrile;

(S)-(3-chlorophenyl)(4-(difluoromethyl)phenyl)(1,3-dimeth ylazetidin-3-yl)methanol;

(S)-(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-propyl-phenyl)-methanol;

(S)-(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-propoxy-phenyl)-methanol;

(S)-(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-methanol;

(S)-(4-Chloro-phenyl)-(3-chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-methanol;

(S)-(3-Chloro-phenyl)-(4-cyclobutoxy-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-methanol;

(S)-(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-p-tolyl-methanol;

(S)-(4-Difluoromethoxy-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-phenyl-methano l;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-{2-fluoro-3-[5-(tetrahydro-pyran- 4-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(4-isopropyl- phenyl)-methanol;

(S)-(1 _J 3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-[3-(3-m ethyl-isoxazol-5-yl)-phenyl]-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-(1-met hoxy-cyclobutyl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}- methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-{3-[5-(4-fluoro-tetrahydro-pyran- 4-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(4-isopropyl- phenyl)-methanol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-(2-met hoxy-1 ,1-dimethyl-ethyl)-[1 ,2,4]oxadiazol-3-yl]- phenylj-methanol;

(S)-5-[2-(3-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)-ethyl]- isoxazol-3-ol;

(S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(4-met hyl-tetrahydro-pyran-4-yl)-[1 ,2,4]oxadiazol-5-yl]- phenylj-methanol;

(S)-3-(5-(3-((1 ,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl) phenyl)-1 ,2,4-oxadiazol-3- yl)tetrahydrofuran-3-ol;

(S)-N-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-benzyl}-benzenesulfonamide;

(S)-N-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-benzyl}-2-(3-methoxy-phenyl)-acetamide;

(S)-(3-Amino-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)-( 4-trifluoromethoxy-phenyl)-methanol; (S)-(1 _J 3-Dimethyl-azetidin-3-yl)-phenyl-(4-trifluoromethoxy-p henyl)-methanol;

(S)-(3-Chloro-phenyl)-(1 ,3-dimethyl-pyrrolidin-3-yl)-(4-trifluoromethoxy-phenyl)-met hanol;

(S)-(1 ,3-Dimethyl-pyrrolidin-3-yl)-(4-phenoxy-phenyl)-(4-trifluoro methoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(2-fluoro-phenyl)-(4-trifluoromet hoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-ethoxy-2-fluoro-phenyl)-(4-tri fluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(2-fluoro-3-methoxy-phenyl)-(4-tr ifluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-fluoro-phenyl)-(4-trifluoromet hoxy-phenyl)-methanol;

(R)-(3-Bromo-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(R)-3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-benzonitrile;

(R)-(3-Cyclopropyl-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(1-methyl-1 H-pyrazol-3-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol ;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-methylsulfanyl-phenyl)-(4-trif luoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-piperidin-1-yl-phenyl)-(4-trif luoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropoxy-phenyl)-(4-trifluor omethoxy-phenyl)-methanol;

(R)-(1,3-Dimethyl-azetidin-3-yl)-[4-(pyridin-3-yloxy)-phe nyl]-(4-trifluoromethoxy-phenyl)-methanol;

(R)-4-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-benzonitrile;

(R)-(1,3-Dimethyl-azetidin-3-yl)-p-tolyl-(4-trifluorometh oxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-fluoro-phenyl)-(4-trifluoromet hoxy-phenyl)-methanol;

(R)-(4-Chloro-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-tri fluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-methylsulfanyl-phenyl)-(4-trif luoromethoxy-phenyl)-methanol;

(R)-(2,3-Dihydro-benzofuran-5-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(R)-(2,2-Difluoro-benzo[1 ,3]dioxol-5-yl)-(1,3-dimethyl-azetidin-3-yl)-(4-trifluoromet hoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-fluoro-3-methoxy-phenyl)-(4-tr ifluoromethoxy-phenyl)-methanol;

(R)-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(R)-(1 _J 3-Dimethyl-azetidin-3-yl)-m-tolyl-(4-trifluoromethoxy- phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-[1 ,2,4]triazol-1-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-metha nol;

(R)-(1,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-pyrazol-1-y l)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(4-methyl-oxazol-2-yl)-phenyl] -(4-trifluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-hydroxymethyl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol;

(R)-(3,5-Dimethoxy-phenyl)-(1,3-dimethyl-azetidin-3-yl)-( 4-trifluoromethoxy-phenyl)-methanol;

(R)-2-({3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-methyl-amino)-ethanol;

(R)-2-({3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-methyl-amino)-ethanol 1-

(R)-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoro methoxy-phenyl)-methyl]-phenyl}-ethanone;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-imidazol-1-yl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol; (R)-(1,3-Dimethyl-azetidin-3-yl)-(3-[1 ,2,3]triazol-2-yl-phenyl)-(4-trifluoromethoxy-phenyl)-methan ol;

(R)-(1,3-Dimethyl-azetidin-3-yl)-(3-pyrazol-1-yl-phenyl)- (4-trifluoromethoxy-phenyl)-methanol;

(R)-(3'-Chloro-biphenyl-3-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(R)-(1,3-Dimethyl-azetidin-3-yl)-[3-((E)-3-methoxy-propen yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol;

(R)-4-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluo romethoxy-phenyl)-methyl]-phenyl}-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester;

(R)-[3-(2,5-Dihydro-furan-3-yl)-phenyl]-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(R)-4-{3-[(1 _J 3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester;

(R)-(1 _J 3-Dimethyl-azetidin-3-yl)-[3-(tetrahydro-furan-3-yl)-p henyl]-(4-trifluoromethoxy-phenyl)-methanol;

(R)-4-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluo romethoxy-phenyl)-methyl]-phenyl}-but-3-yn-1-ol;

(1R)-3-(3-((R)-(1 _J 3-dimethylazetidin-3-yl)(hydroxy)(4-(trifluoromethoxy) phenyl)methyl)phenyl)-1-phenylpropan-1-ol;

(R)-4-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluo romethoxy-phenyl)-methyl]-phenyl}-butan-1-ol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(2-phenyl-oxazol-5-yl)-phenyl] -(4-trifluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(2-methyl-2H-tetrazol-5-yl)-ph enyl]-(4-trifluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-{3-[5-(2 _J 2,2-trifluoro-ethoxy)-pyridin-3-yl]-phenyl}-(4-trifluo romethoxy-phenyl)- methanol;

(R)-Diethyl-carbamic acid 4-[(1 , 3-di methy l-azetidin-3-y l)-hydroxy-(4-trifl uoromethoxy-pheny l)-methy l]-benzy I ester;

(R)-(1 _J 3-Dimethyl-azetidin-3-yl)-(4-{3-[2-(3-methyl-pyrazol-1 -yl)-ethyl]-[1 ,2,4]oxadiazol-5-yl}-phenyl)-(4- trifluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-[3-(3 -trifluoromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]- methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-phenethyl-[1 ,2,4]oxadiazol-5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-met hanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-[1 ,3,4]oxadiazol-2-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-met hanol;

(R)-5-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluo romethoxy-phenyl)-methyl]-phenyl}-[1,2,4]oxadiazole-3- carboxylic acid benzyl-methyl-amide;

(R)-(1 _J 3-Dimethyl-azetidin-3-yl)-(3-imidazol-1-ylmethyl-pheny l)-(4-trifluoromethoxy-phenyl)-methanol;

(R)-(1 _J 3-Dimethyl-azetidin-3-yl)-(3-pyrazol-1-ylmethyl-phenyl )-(4-trifluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-methoxymethyl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol;

(R)-(1,3-Dimethyl-azetidin-3-yl)-[3-(2-methoxy-ethoxymeth yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol;

(R)-(1 _J 3-Dimethyl-azetidin-3-yl)-[3-(tetrahydro-pyran-4-yloxy )-phenyl]-(4-trifluoromethoxy-phenyl)-methanol;

(R)-4-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluo romethoxy-phenyl)-methyl]-phenoxy}-2-methyl-butan-2-ol;

(R)-(1,3-Dimethyl-azetidin-3-yl)-bis-(4-phenoxy-phenyl)-m ethanol;

(R)-(1 _J 3-Dimethyl-azetidin-3-yl)-(4-methylamino-phenyl)-(3-py rrolidin-1-yl-phenyl)-methanol; (R)-(1 ,3-Dimethyl-azetidin-3-yl)-[4-ethoxy-3-(3-methyl-[1 ,2,4]oxadiazol-5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)- methanol;

(R)-(3-Cyclopropylmethoxy-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol;

(R)-Benzooxazol-5-yl-(1,3-dimethyl-azetidin-3-yl)-(4-trif luoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(2-methyl-benzooxazol-6-yl)-(4-tr ifluoromethoxy-phenyl)-methanol;

(R)-(1,3-Dimethyl-azetidin-3-yl)-[4-(tetrahydro-pyran-4-y loxy)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-[1 ,2,4]oxadiazol-3-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-met hanol;

(R)-(3-Fluoro-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)- (4-trifluoromethoxy-phenyl)-methanol;

(R)-(3-Chloro-phenyl)-(3-fluoro-1-methyl-azetidin-3-yl)-( 4-trifluoromethoxy-phenyl)-methanol;

(R)-3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phen yl)-methyl]-1-methyl-azetidine-3-carboxylic acid amide;

(R)-3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phen yl)-methyl]-1-methyl-azetidine-3-carbonitrile;

(R)-(3-chlorophenyl)(4-(difluoromethyl)phenyl)(1 ,3-dimethylazetidin-3-yl)methanol;

(R)-(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-propyl-phenyl)-methanol;

(R)-(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-propoxy-phenyl)-methanol;

(R)-(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-methanol;

(R)-(4-Chloro-phenyl)-(3-chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-methanol;

(R)-(3-Chloro-phenyl)-(4-cyclobutoxy-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-methanol;

(R)-(3-Chloro-phenyl)-(1,3-dimethyl-azetidin-3-yl)-p-toly l-methanol;

(R)-(4-Difluoromethoxy-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-phenyl-methano l;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-{2-fluoro-3-[5-(tetrahydro-pyran- 4-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(4-isopropyl- phenyl)-methanol;

(R)-(1,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-[3- (3-methyl-isoxazol-5-yl)-phenyl]-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-(1-met hoxy-cyclobutyl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}- methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-{3-[5-(4-fluoro-tetrahydro-pyran- 4-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(4-isopropyl- phenyl)-methanol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-(2-met hoxy-1 ,1-dimethyl-ethyl)-[1 ,2,4]oxadiazol-3-yl]- phenylj-methanol;

(R)-5-[2-(3-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-5-yl)-ethyl]- isoxazol-3-ol;

(R)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(4-met hyl-tetrahydro-pyran-4-yl)-[1 ,2,4]oxadiazol-5-yl]- phenylj-methanol; (R)-3-(5-(3-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropy lphenyl)methyl)phenyl)-1,2,4-oxadiazol-3- yl)tetrahydrofuran-3-ol;

(R)-N-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isoprop yl-phenyl)-methyl]-benzyl}-benzenesulfonamide;

(R)-N-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-benzyl}-2-(3-methoxy-phenyl)-acetamide;

(R)-(3-Amino-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)-( 4-trifluoromethoxy-phenyl)-methanol;

(R)-(1,3-Dimethyl-azetidin-3-yl)-phenyl-(4-trifluorometho xy-phenyl)-methanol;

(R)-(3-Chloro-phenyl)-(1 ,3-dimethyl-pyrrolidin-3-yl)-(4-trifluoromethoxy-phenyl)-met hanol; or (R)-(1 ,3-Dimethyl-pyrrolidin-3-yl)-(4-phenoxy-phenyl)-(4-trifluoro methoxy-phenyl)-methanol.

The present invention also includes isotopically labelled, especially ² H (deuterium) labelled compounds of Formula (I), which compounds are identical to the compounds of Formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially ² H (deuterium) labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope ² H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of Formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases, and the like, this is intended to also mean a single compound, salt, pharmaceutical composition, disease or the like.

Any reference to compounds of Formula (I) according to embodiments 1) to 26) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit 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 Quere (Eds.), RSC Publishing, 2012.

The compounds of Formula (I) may encompass compounds with one or more asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in (R)- as well as (S)-configuration. The compounds of Formula (I) may further encompass compounds with one or more double bonds which are allowed to be present in Z- as well as E- configuration and/or compounds with substituents at a ring system which are allowed to be present, relative to each other, in cis- as well as trans-configuration. The compounds of Formula (I) may thus be present as mixtures of stereoisomers or preferably in stereoisomerically enriched form, especially as essentially pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art. In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, cis- or trans-designations are to be understood as referring to the respective stereoisomer in enriched, especially essentially pure, form. Likewise, in case a particular compound (or generic structure) is designated as Z- or E-stereoisomer (or in case a specific double bond in a compound is designated as being in Z- or E-configuration), such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, stereoisomeric form (or to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of the double bond).

The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer I the entirety of the respective other stereoisomers.

The term "essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer I the entirety of the respective other stereoisomers. The compounds of Formula (I) according to embodiments 1) to 26) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).

The production of the pharmaceutical compositions can be effected in a manner which will be familiar 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 bringing the described compounds of Formula (I), or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

Whenever the word "between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1 , 2, 3, or 4. Unless used regarding temperatures, the term "about” (or alternatively the term "around”) placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term "about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C. For avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.

The compounds of Formula (I) as defined hereinabove are useful for the prevention or treatment of various diseases, conditions or disorders ameliorated by modulating CCR6 receptors. Such diseases, conditions, or disorders, where CCR6 receptors are involved may be defined as inflammatory and/or autoimmune diseases, conditions, or disorders; and cancer.

The compounds of Formula (I) as defined hereinabove are useful for the prevention or treatment of of various diseases, conditions, or disorders, ameliorated by modulating CCR6 receptors. Such diseases, conditions, or disorders, where CCR6 receptors are involved may be defined as inflammatory/autoimmune diseases, conditions, or disorders, including rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; psoriasis; psoriatic arthritis; inflammatory skin disorders such as rosacea; Crohn's disease; ulcerative colitis; inflammatory bowel disease; irritable bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjogren's disease; autoimmune hepatitis; Primary Sclerosing Cholangitis; Posterior uveitis; allergic conjunctivitis; allergic disease in the gastrointestinal tract; type I diabetes and endometriosis; diseases of the ocular surface in which elevated levels of IL-17A have been recorded such as meibomian gland dysfunction; GVHD; graft-versus host disease; autoimmune keratitis; filamentary keratitis; dry eye syndrome with rheumatic arthritis; dry eye syndrome without systemic disease; Stevens-Johnson syndrome; psoriasis including plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis; autoimmune keratitis; filamentary keratitis; autoimmune uveitis; allergic conjunctivitis; asthma; allergic disease of the gastrointestinal tract; T1 D; endometriosis; meibomian gland dysfunction; graft-versus host disease; juvenile arthritis; juvenile rheumatoid arthritis; systemic onset rheumatoid arthritis; pauciarticular rheumatoid arthritis; pauciarticular 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; juvenile idiopathic arthritis (JIA); juvenile psoriatic arthritis; juvenile rheumatoid arthritis; systemic onset juvenile rheumatoid arthritis; acute pancreatitis; chronic pancreatitis; giant cell arteritis; atherosclerosis; bone erosion; intraperotoneal abscesses; intraperitoneal abscesses; and/or secondary osteoarthritis from inflammatory diseases.

Further, such diseases, conditions, or disorders, ameliorated by modulating CCR6 receptors may be defined as including cancer such as skin cancer e.g. melanoma (superficial spreading, nodular, lentigo maligna and acral lentiginous melanoma); advanced melanoma; metastatic melanoma; Merkel cell carcinoma; Kaposi sarcoma; basal cell carcinoma; squamous cell carcinoma; and pre-cancerous skin lesions such as actinic keratosis; lung cancer including small cell lung cancer and non-small (SCLC, NSCLC) such as squamous and non-squamous NSCLC; pleuropulmonary blastoma and tracheobronchial tumors; bladder cancer including urinary bladder cancer; urothelial cell carcinoma; mesothelioma; renal carcinomas including renal cell carcinoma (RCC) such as clear cell RCC; papillary RCC; chromophobe RCC; non-clear cell RCC; unclassified RCC; metastatic renal cell carcinoma; metastatic renal clear cell carcinoma; renal parenchymal carcinoma; gastro-intestinal cancers including colorectal cancer; metastatic colorectal cancer; familial adenomatous polyposis (FAP); rectum carcinoma; colon carcinoma; colorectal adenoma; colorectal adenocarcinoma; colorectal cancer liver metastases; hereditary non-polyposis colorectal cancer; esophageal cancer; gastric cancer; advanced gastric cancer; gallbladder cancer; cholangiocarcinoma; hepatocellular carcinoma; pancreatic cancer such as pancreatic adenocarcinoma or pancreatic ductal (adeno)carcinoma; pancreatic neuroendocrine tumors; endometrial cancer; ovarian cancer; prostate cancer including castrate-resistant prostate cancer; brain tumors including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas, astrocytoma; peripheral neuroectodermal tumors; oligoastrocytic tumors; oligodendrogliomas; ependymal tumors; anaplastic astrocytoma; pilocytic astrocytoma; craniopharyngioma; spinal cord tumors; brain stem glioma; central nervous system atypical teratoid/rhabdoid tumor; medulloblastoma; central nervous system germ cell tumors; craniopharyngioma; ependymoma; neuroblastoma; head and neck cancer such as 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 tumors; nasopharyngeal tumors; heart tumors; thoracic cancer; lymphomas such as Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma; primary intra-ocular 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 Waldenstrom macroglobulinemia; leukemia such as acute lymphoblastic leukemia; acute myeloid leukemia ; chronic lymphocytic leukemia; chronic myelogenous leukemia; hairy cell leukemia; chronic myeloid leukemia; adult T-cell leukemia; carcinomas; adenocarcinomas; thyroid carcinoma including papillary thyroid carcinoma and medullary thyroid carcinoma choriocarcinoma; sarcomas including Ewing's sarcoma; bone cancer such as osteosarcoma; high-grade osteosarcoma; rhabdomyosarcoma; Ewing sarcoma; malignant fibrous histiocytoma of the bone; chordoma; soft tissue sarcoma; myeloma; multiple myelomas; labial carcinoma; larynx carcinoma; hypopharynx carcinoma; tongue carcinoma; salivary gland carcinoma; cervix carcinoma; uterine corpus carcinoma; endometrium carcinoma; chorion carcinoma; testis carcinoma; urinary carcinoma; bronchial carcinoma; basalioma; teratoma; retinoblastoma; choroid melanoma; seminoma; chondrosarcoma; myosarcoma; liposarcoma; fibrosarcoma; plasmacytoma; hepatocarcinoma; advanced liver cancer; gastrointestinal stromal tumors; neuroendocrine tumors; bile duct cancer; appendix cancer; gastrointestinal carcinoid tumor; carcinoid tumor; islet cell tumor; small intestine cancer; stomach cancer; adrenocortical carcinoma; parathyroid cancer; paraganglioma; pheochromocytoma; pituitary tumor; penile cancer; renal pelvis and ureter cancer; testicular cancer; urethral cancer; Wilms tumor; extracranial germ cell tumor; extragonadal germ cell tumor; fallopian tube cancer; gestational trophoblastic tumor; primary peritoneal cancer; vaginal cancer; vulvar cancer; hypopharyngeal cancer; laryngeal cancer; papillomatosis cancer; lip and oral cavity cancer; metastatic squamous neck cancer; mouth cancer; nasopharyngeal cancer; oropharyngeal cancer; paranasal sinus and nasal cavity and paranasal sinus cancer; parathyroid cancer; pharyngeal cancer; throat cancer; chronic myeloproliferative neoplasm; Langerhans cell histiocytosis; plasma cell neoplasm; myelodysplastic syndromes; myeloproliferative neoplasm; midline tract carcinoma; vi rally induced tumors; and/or diseases involving CCR6 and/or CCL20 mediated metastasis, chemotaxis, cell adhesion, trans-endothelial migration, cell proliferation and/or survival.

Notably, such diseases, conditions, or disorders, ameliorated by modulating CCR6 receptors are selected from

• inflammatory/autoimmune diseases, conditions, or disorders, such as rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; psoriasis; psoriatic arthritis; inflammatory skin disorders e.g. rosacea; Crohn's disease; ulcerative colitis; irritable bowel disease; inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjogren's disease; autoimmune hepatitis; Primary Sclerosing Cholangitis; psoriasis including plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis; autoimmune keratitis; filamentary keratitis; autoimmune uveitis; allergic conjunctivitis; asthma; allergic disease of the gastrointestinal tract; type 1 diabetes (T1 D); endometriosis; meibomian gland dysfunction; and/or graft-versus host disease; and/or

• cancer such as lymphoma including T cell lymphoma and primary mediastinal B-cell lymphoma; brain cancer including glioma and glioblastoma; breast cancer including triple negative breast cancer; colorectal cancer; hepatocarcinoma; 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 carcinoma; Hodgkin's lymphoma; cervical cancer; endometrial cancer; colon cancer; gastrointestinal stromal tumors; pancreatic cancer; prostatic cancer; leukemia including acute myeloid leukemia; ovarian cancer; oesophageal carcinomas; mesothelioma; neuroblastoma; sarcoma e.g. high-grade osteosarcoma; astrocytoma; myeloma; urothelial cancer including locally advanced and metastatic urothelial cancer; MSI-H or dMMR cancer; rectal cancer; laryngeal cancer; salivary adenocarcinoma; multiple myeloma; cholangiocarcinoma; oral squamous cell carcinoma; thyroid cancer; and/or esophagogastric junction cancer.

Especially, such diseases, conditions, or disorders, ameliorated by modulating CCR6 receptors are selected from

• inflammatory/autoimmune diseases, conditions, or disorders, such as psoriasis; psoriatic arthritis; rheumatoid arthritis; ankylosing spondylitis; spondyloarthritis; inflammatory skin disorders e.g. rosacea; Crohn's disease; ulcerative colitis; irritable bowel disease; inflammatory bowel disease; dry eye disease; multiple sclerosis; systemic lupus erythematosus; Sjogren's disease; autoimmune hepatitis; and/or Primary Sclerosing Cholangitis; In particular, such diseases, conditions, or disorders, are psoriasis, psoriatic arthritis, or inflammatory bowel disease; and especially may be selected from A1) psoriasis (preferred) or psoriatic arthritis; or A2) inflammatory bowel disease; and/or

• cancer such as lymphoma (e.g. T cell lymphoma); brain cancer (e.g. glioma or glioblastoma); breast cancer; colorectal cancer; hepatocarci nomas; renal cell carcinoma; lung cancer; and/or gastric cancer.

When used for the prevention I prophylaxis or treatment of a cancer, such use includes use of the present compounds as single therapeutic agents and their use in combination with one or more chemotherapy agents and I or radiotherapy and I or targeted therapy (especially in combination with targeted therapy).

The terms "radiotherapy" or "radiation therapy" or "radiation oncology", refer to the medical use of ionizing radiation in the prevention I prophylaxis (adjuvant therapy) and I or treatment of cancer; including external and internal radiotherapy. The term "targeted therapy" refers to the prevention I prophylaxis (adjuvant therapy) and I or treatment of cancer with one or more anti-neoplastic agents such as small molecules or antibodies which 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 (immunotherapies); or inhibit angiogenesis, the growth and formation of new blood vessels in the tumor; or deliver toxic substances directly to cancer cells and kill them. An example of a targeted therapy which is in particular suitable to be combined with the compounds of the present invention is immunotherapy, especially immunotherapy targeting the progammed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1.

Immunotherapy further refers to (I) an agonist of a stimulatory (including a co-stimulatory) receptor or (II) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators). Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7- 1 , B7-2, B7-HI (PD-LI), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-IBBL, CD137 (4-IBB), TRAIL/Apo2- L, TRAI LR1/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 1 p2, FAS, FASL, RELT, DR6, TROY, NGFR.

When used in combination with the present compounds, the term "targeted therapy" especially refers to agents such as: a) Epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (for example Gefitinib, Erlotinib, Afatinib, Icotinib, Lapatinib, Panitumumab, Zalutumumab, Nimotuzumab, Matuzumab and Cetuximab) as well as trastuzumab (HERCEPTIN); b) RAS/RAF/MEK pathway inhibitors (for example 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 ( for example Ruxolitinib, Itacitinib, Momelotinib); d) Aromatase inhibitors (for example Exemestane, Letrozole, Anastrozole, Vorozole, Formestane, Fadrozole); e) signal transduction inhibitors (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to apoptosis. Suitable STis include but are not limited to: (i) bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC®), Dasatinib; (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, 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 such as famesyl transferase inhibitors (FTI) such as, for example, L-744,832 (Kohl et al., Nat. Med., 1 (8):792-797 (1995)); (iv) inhibitors of Akt family kinases or the Akt pathway, such as, for example, rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (2000)); (v) cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-01 (see, for example, Sausville, Curr. Med. Chem. Anti-Cane. Agents, 3:47-56 (2003)); and (vi) phosphatidyl inositol kinase inhibitors such as, for example, LY294002 (see, for example, Vlahos et al., J Biol. Chem., 269:5241-5248 (1994)). f) Angiogenesis inhibitors, especially VEGF signalling inhibitors such as Bevacuzimab (Avastin), Ramucirumab, Sorafenib or Axitinib; g) Immune Checkpoint inhibitors (for example: anti-PD1 antibodies such as Pembrolizumab (Lambrolizumab, MK- 3475), Nivolumab, Pidilizumab (CT-011), AMP-514/MEDI0680, PDR001 , SHR-1210; REGN2810, BGBA317, PF- 06801591 , MGA-012, TSR042, JS-001 , BCD100, IBI-308, BI-754091; fusion proteins targeting PD-1 such as AMP-224; small molecule anti-PD1 agents such as for example compounds disclosed in WC2015/033299, WC2015/044900 and WC2015/034820; anti-PD1 L antibodies, such as BMS-936559, atezolizumab (MPDL3280A, RG7446), avelumab (MSB0010718C), durvalumab (MEDI4736); anti-PDL2 antibodies, such as AMP224; anti-CTLA-4 antibodies, such as ipilimumab, tremelimumab; anti-Lymphocyte-activation gene 3 (LAG-3) antibodies, such as Relatlimab (BMS-986016), IMP701 , IMP731 , MK-4280, ImmuFact IMP321; anti T cell immunoglobulin mucin-3 (TIM-3) antibodies, such as MBG453, TSR-022; anti T cell immunoreceptor with Ig and ITIM domains (TIGIT) antibodies, such as RG6058 (anti- TIGIT, MTIG7192A); anti- Killer-cell immunoglobulin-like receptors (KIR) for example Lirilumab (IPH2102/BMS- 986015), antagonists of Galectins (such as Galectin-1, Galectin-9), BTLA; h) Vaccination approaches (for example dendritic cell vaccination, DNA, peptide or protein vaccination (for example with gp100 peptide or MAGE-A3 peptide) as well as recombinant viruses; i)Re-introduction of patient derived or allogenic (non-self) cancer cells genetically modified to secrete immunomodulatory factors such as granulocyte monocyte colony stimulating factor (GMCSF) gene-transfected tumor cell vaccine (GVAX) 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 immunotherapies, including chimeric antigen receptor (CAR) engineered T-cells (for example CTL019); k) Cytokine or immunocytokine based therapy (for example Interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 6, interleukin 10, interleukin 15, TGF-p); l) Toll-like receptor (TLR) agonists (for example resiquimod, imiquimod, motolimod, glucopyranosyl lipid A, CpG oligodesoxynucleotides); m) Thalidomide analogues (for example Lenalidomide, Pomalidomide); n) Activators of T-cell co-stimulatory receptors (for example anti-CD137/4-1 BB antibodies, such as BMS-663513 (urelumab), Utomilumab (PF-05082566); anti-CX40/CD134 (Tumor necrosis factor receptor superfamily, member 4) (such as RG7888 (MCXR0916), 9B12; MEDI6469, GSK3174998, MEDI6383, MEDI0562), anti CX40-Ligand/CD252; anti-glucocorticoid-induced TNFR family related gene (GITR) (such as TRX518, MEDI1873, MK-4166, BMS-986156, BMS-986153), anti-CD40 (TNF receptor superfamily member 5) antibodies (such as Dacetuzumab (SGN-40), HCD122, CP-870,893, RG7876, ADC-1013, APX005M, SEA-CD40); anti-CD40-Ligand antibodies (such as BG9588); anti-CD27 antibodies such as Varlilumab; anti-CD28 antibodies; anti-ICOS antibodies; o) Molecules binding a tumor specific antigen as well as a T-cell surface marker such as bispecific antibodies or antibody fragments, antibody mimetic proteins such as designed ankyrin repeat proteins (DARPINS), bispecific T-cell engager (BITE, for example AMG103, AMG330); p) Antibodies or small molecular weight inhibitors targeting colony-stimulating factor-1 receptor (CSF-1R) (for example Emactuzumab (RG7155), Cabiralizumab (FPA-008), PLX3397); q) Agents targeting immune cell check points on natural killer cells such as antibodies against Killer-cell immunoglobulin-like receptors (KIR) for example Lirilumab (IPH2102/BMS-986015); r) Agents targeting the Adenosine receptors or the ectonucleases CD39 and CD73 that convert adenosin triphosphate (ATP) to Adenosine, such as MEDI9447 (anti-CD73 antibody), PBF-509; CPI-444 (Adenosine A2a receptor antagonist); s) antagonists to chemokine receptors including CCR2 or CCR4; t) modulators of the complement system v) agents that deplete or inhibit T regulatory cells (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion) or reverse/prevent T cell anergy or exhaustion.

When used in combination with the present compounds, immune checkpoint inhibitors, and especially those targeting the PD-1 receptor or its ligand PD-L1 , are preferred. The term "chemotherapy" refers to the treatment of cancer with one or more cytotoxic anti-neoplastic agents ("cytotoxic chemotherapy agents"). Chemotherapy is often used in conjunction with other cancer treatments, such as radiation therapy or surgery. The term especially refers to conventional chemotherapeutic agents which act by killing cells that divide rapidly, one of the main properties of most cancer cells. Chemotherapy may use one drug at a time (single-agent chemotherapy) or several drugs at once (combination chemotherapy or polychemotherapy). Chemotherapy using drugs that convert to cytotoxic activity only upon light exposure is called photochemotherapy or photodynamic therapy.

The term "cytotoxic chemotherapy agent” or "chemotherapy agent” as used herein refers to an active anti-neoplastic agent inducing apoptosis or necrotic cell death.

When used in combination with the compounds of the present invention, the term especially refers to conventional cytotoxic chemotherapy agents such as: 1) alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, procarbazine, dacarbazine, temozolomide, pipobroman, triethylene-melamine, triethylenethiophosphoramine, thiotepa or altretamine; in particular temozolomide); 2) platinum drugs (for example cisplatin, carboplatin or oxaliplatin); 3) antimetabolite drugs (for example 5-fluorouracil, floxuridine, pentostatine, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine or pemetrexed); 4) anti-tumor antibiotics (for example daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or mitoxantrone); 5) mitotic inhibitors (for example paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or estramustine); or 6) topoisomerase inhibitors (for example 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.

When used in combination with the compounds of the present invention, preferred cytotoxic chemotherapy agents are the above-mentioned alkylating agents (notably fotemustine, cyclophosphamide, ifosfamide, carmustine, dacarbazine and prodrugs thereof such as especially temozolomide or pharmaceutically acceptable salts of these compounds; in particular temozolomide); mitotic inhibitors (notably paclitaxel, docetaxel, ixabepilone; or pharmaceutically acceptable salts of these compounds; in particular paclitaxel); platinum drugs (notably cisplatin, oxaliplatin and carboplatin); as well etoposide and gemcitabine.

For avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, conditions or disorders, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.

The present invention also relates to a method for the prevention or treatment of diseases, conditions or disorders, mentioned hereinabove and/or hereinbelow comprising administering to a subject in need of such prevention or treatment a pharmaceutically active amount of a compound as described hereinabove or/and hereinbelow either alone or in combination with other pharmacologically active compounds and/or therapies. In a preferred embodiment of the invention, the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.

The meaning of the term "prevention” may also be understood as "prophylaxis”.

Preparation of compounds of Formula (I)

A further aspect of the invention is a process for the preparation of compounds of Formula (I). Compounds according to Formula (I) of the present invention can be prepared from commercially available or well-known starting materials according to the methods described in the experimental part; by analogous methods; or according to the general sequence of reactions outlined below. The terms "m”, "n”, "R ¹ ”, "R ² ”, "R ³ ”, "R ⁴ ”, and "R ⁵ ”, as used hereinbelow, are as defined for the compounds of Formula (I) unless specifically defined otherwise. The meaning of R, R’, R”, R’”, R ^a , R ^b , R ^c , as used hereinbelow, can be deduced from the corresponding definitions in Formula (I) or is explicitly/implicitly defined in the text. The radical "A” as used hereinbelow refers to the phenyl ring bearing substituents (R ⁴ ) _n and (R ⁵ ) _p , that is, the phenyl ring labeled A in Formula (I). The radical “B” as used hereinbelow refers to the phenyl ring bearing substituent R ³ , that is, the phenyl ring labeled B in Formula (I). Other abbreviations used herein are explicitly defined or are as defined in the experimental section. The use of protecting groups is well known in the art (see for example "Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known perse. General preparation routes:

Compounds of Formula (I) can be prepared starting from an intermediate of Formula (A1), which is reacted with N,O- dimethylhydroxylamine hydrochloride under standard conditions (e.g. HATU, DIPEA, DMF) to give the Weinreb amide derivative of Formula (A2) (Scheme A). The ketone derivative of Formula (A4) can be produced upon reaction of the Weinreb amide derivative of formula (A2) with a compound of Formula (A3) wherein X is bromine, in presence of n- butyl lithium in THF at a temperature around -78°C, or with the corresponding Grignard reagent of Formula (A3') which is either commercially available or can be prepared starting with the corresponding bromine reagent of Formula (A3) and Mg metal or through iPrMgCl-LiCI-mediated halogen-metal exchange. The compounds of Formula (A4) can be further reacted similarly with a compound of Formula (A5) wherein X is a halogen atom, preferably bromine or iodine, to provide the tertiary alcohol intermediate of Formula (A6). A chiral separation by HPLC over a chiral stationary phase can be performed at this stage to yield enantiomerical ly pure intermediates of Formula (A6). Cleavage of the protecting group (PG) under standard conditions such as treatment with HCI in dioxane in the case of a Boc protecting group, can provide the free NH derivative of Formula (A7). A reductive amination step can be performed with an aldehyde of Formula (A8) or a ketone of Formula (A9) under standard conditions such as using NaBH(OAc)3 or NaBHaCN as reductive agent, in presence of a base such as DIPEA or TEA, or in presence of an acid such as acetic acid, in a solvent such as DCM, MeOH, THF or dioxane, and at a temperature around RT to provide compounds of Formula (I). As alternative to the two-step procedures (deprotection, reductive amination), the Boc protecting group can be directly reduced to the methylazetidine by using a reducing agent such as lithium aluminium hydride in a solvent such as THF heated at reflux. For the compounds of Formula (I) wherein R ² is cyclopropyl, specific conditions were used that are described in the experimental part (Example 79). In addition, the intermediate of Formula (A7) can be coupled to a reactant of Formula (A10) wherein X is iodine, bromine or triflate, in presence of a base such as TEA, DIPEA or CS2CO3, in a solvent such as MeOH, THF or DMF, and stirring at a temperature from 0°C to 70°C.

Alternatively, the compounds of Formula (I) can be prepared following the route described in Scheme B. The protecting group in intermediate (A4) can be removed and the free NH of the resulting intermediate (B1) can be reacted with a reagent of Formula (A8), (A9) or (A10), as previously described. The resulting intermediate of Formula (B2) can be reacted with a compound of Formula (A5) wherein X is a halogen atom, preferably bromine, using conditions described in Scheme A to provide compounds of Formula (I). A chiral separation by HPLC over a chiral stationary phase can be performed at this stage to yield enantiomerical ly pure compounds of Formula (I).

Alternatively, the compounds of Formula (I) can be prepared using the same synthetic strategies as those described in Schemes A and B, with the difference of performing the addition of the compound of Formula (A5) prior to the addition of the compound of Formula (A3) or (A3') in the synthetic sequence (Scheme C), and using the same conditions as those reported previously.

A compound of Formula (I) or an intermediate of Formula (A6) containing a cyano group in ring A can be transformed into a hydroxy-amidine derivative of Formula (D1) by reaction with hydroxylamine hydrochloride in a solvent such as EtOH and water, in presence of a base such as K2CO3, and at a temperature between 80°C and 100°C (Scheme D). The intermediate of Formula (D1) can be further reacted with a carboxylic acid of Formula (D2) to form an oxadiazole- containing derivative of Formula (I) in one step if R is R ² , using a coupling agent such as PyBOP, EDC combined with HOBt, T3P, or GDI, in presence of a base such as DIPEA or K3PO4, in a solvent such as dioxane or DMF, and heating at a temperature between 80°C and 110°C; or in three steps if R is a protecting group as described above.

The intermediate of Formula (A6) wherein R is Boc can be reduced to the corresponding amine of Formula (D3) with concomitant conversion of the Boc group a methyl group using LiAl H4 as reducing agent in a solvent such as THF at a temperature around reflux. The final step can be a sulfonamidation type reaction using a sulfonylchloride derivative of Formula (D4), or an amide coupling type reaction using an acid derivative of formula (D5) and a coupling agent such as HATU, in both cases in presence of a base like DIPEA, in a solvent like DMF at a temperature around RT, to give the desired compounds of Formula (I).

The cyano-containing intermediate (A6) can be further transformed into the isoxazole derivative of Formula (I) via condensation of the reagent of Formula (D7) and hydroxylamine with the corresponding methyl ketone of Formula (D6), as described in Example 113.

The intermediates of Formula (E1) (see Scheme E) wherein R is a protecting group, or wherein R is R ² , can be prepared starting from the appropriate compound of Formula (A5) wherein A contains a protected aldehyde function such as a diethylacetal moiety in meta position to the halogen atom X, following the route described in Scheme A for the synthesis of intermediates of Formula (A6), or compounds of Formula (I), respectively. After deprotection of the protecting group (e.g. diethylacetal moiety), the aldehyde of Formula (E1) can be oxidized to the corresponding carboxylic acid of Formula (E3) using KMnC>4 as oxidant, in dioxane/water as a solvent, and at a temperature around RT, or using AgNOa as oxidant with aq. NaOH as base in a mixture of EtOH/FhO, and at a temperature around RT. Alternatively, the intermediate of Formula (E3) can be obtained by the cleavage of the tert-butyl ester of the intermediate of Formula (E2), using standard conditions such as HCI in dioxane at a temperature around RT. The intermediate of Formula (E3) can be transformed into the intermediate of Formula (E5) wherein R' is an alkyl group, preferably ethyl, by reaction with a hydroxyamidine derivative of Formula (E4) using conditions described in Scheme (D). The ester derivative of Formula (E5) can be saponified into an acid derivative of Formula (E6), which can be further reacted with a symmetrical or asymmetrical amine of Formula (E7) yielding compounds of Formula (E8) if R is a protecting group, or of Formula (I) if R is R ² , and using HOBt/EDC or T3P as coupling agent, in presence of a base such as DIPEA, in a solvent such as DCM or CH3CN, and at a temperature around RT. In addition, the carboxylic acid derivative of Formula (E3) can be cyclized to a 1 ,2,4-oxadiazole derivative of Formula (E10) with a hydroxyamidine derivative of Formula (E9) if R is a protecting group, or of Formula (I) if R is R ² . Hydroxyamidine derivatives of Formula (E9), if not commercially available, can be prepared using the same protocol as described in Scheme (D) starting from the corresponding cyano derivative.

Moreover, the carboxylic acid derivative of Formula (E3) can be cyclized to a 1 ,3,4-oxadiazole derivative of Formula (E12) if R is a protecting group, or of Formula (I) if R is R ² , with a hydrazide reagent of Formula (E11), using HOBT/EDC as coupling agent, DIPEA as a base and in dioxane at a temperature around RT, followed by treatment with the Burgess reagent (ethyl N-(triethylammoniosulfonyl)carbamate) at 110°C under microwave conditions in a solvent like THF.

It will be understood by one skilled in the art that the steps described in Scheme (E) can be performed with the protected azetidine ring (m=1) prior to the introduction of the R ² group, or with the azetidine ring substituted with the R ² group, and following the two-step protocol from the intermediate (A6) described in Scheme (A) to yield compounds of Formula (I).

Scheme E

The intermediates of Formula (F1) wherein R is a protecting group, or the compounds of Formula (I) wherein R is R ² (see Scheme F) can be prepared following the route described in Scheme C using the appropriate derivative of Formula (A6). The intermediates of Formula (F2) (R = PG) or compounds of Formula (I) (R = R ² ) can be prepared by reacting an intermediate of Formula (F1) with an NH-containing reactant of Formula (E7) being an amine, a lactam or an NH- containing heterocycle, using standard conditions for a Buchwald type reaction, using a palladium catalyst such as Pd2(dba)3 , in presence of a ligand such as Bl NAP, or RuPhos Pd G3 in presence of a base such as NaOtBu, CS2CO3, NEts, and heating in dioxane at a temperature around 100-115°C. Alternative conditions for this transformation can be using a copper catalyst such as Cu in a solvent such as DMF, and heating at a temperature around 100°C.

Furthermore, an intermediate of Formula (F1) (R = PG) or a compound of Formula (I) (R = R ² ) can be reacted with a boronic acid (R’” = H) or boronate ester reagent (R’” = pinacol) of Formula (F3) (R” = alkenyl or aryl/heteroaryl) using standard conditions for a Suzuki type reaction, using a palladium catalyst such as Pd(dppf)2Cl2, Pd(PPhs)4 or PdCI ₂ (PPh ₃ )2, in presence of a base such as Na2CO3, K2CO3 or K3PO4, in a solvent such as MeCN/water, DME/water or dioxane/water mixture, and heating at a temperature around 80-100°C, to provide an intermediate of Formula (F4) (R = PG), or a compound of Formula (I) (R = R ² ).

An intermediate of Formula (F1) (R = PG) or a compound of Formula (I) (R = R ² ) can be converted to a boronic acid derivative of Formula (F8), which can further react in a Suzuki-type reaction with a bromoaryl reagent of Formula (F9) to yield an intermediate of Formula (F10) (R = PG) or a compound of Formula (I) (R = R ² ).

In addition, an intermediate of Formula (F1) (R = PG) or a compound of Formula (I) (R = R ² ) can be reacted with an alkyne-containing reagent of Formula (F6), using standard conditions for a Sonogashira type reaction, using a palladium catalyst such as Pd(PPhs)4 or Pd(OAc)2, optionally combined with a copper catalyst such as Cui, optionally in presence of a ligand such as PPhs, in presence of a base such as piperidine or K3PO4, in a solvent such as THF or DMSO/toluene mixture, and heating at a temperature between 60°C and 80°C, to provide an intermediate of Formula (F7) (R = PG) or a compound of Formula (I) (R = R ² ).

The resulting alkene and alkyne-containing compounds of Formula (I) or (F4) and (F7) can be further transformed by hydrogenation of the alkene or alkyne functionality into a linear alkane chain as in Formula (F5) (R’ = e.g. methoxymethyl) or into cyclic alkane derivatives (e.g. Example 42) from cyclic alkenes using Pd/C (50% water) in EtOH or MeOH and under a hydrogen atmosphere.

It will be understood by one skilled in the art that the steps described in Scheme (F) can be performed with the protected azetidine ring (m=1) prior to the introduction of the R ² group, or with the azetidine ring substituted with the R ² group, and following the two-step protocol from the intermediate (A6) described in Scheme (A) to yield compounds of Formula (I).

Scheme F

An acid derivative of Formula (E3) can be reacted with an aminoalcohol derivative of Formula (G1) using EDC as coupling agent, 4-methylmorpholine as a base in presence of sodium chloride in DMF at a temperature of around 50°C to provide an intermediate of Formula (G2) (Scheme G). Further oxidation of the primary alcohol residue using Dess- Martin periodinane in DCM can provide the aldehyde of Formula (G3), which can be reacted by ring closure to the 4- substituted oxazole of Formula (G7) if R is PG or (I) if R is R ² , in presence of iodine, PPha, and N Eta as a base in DCM at RT. An alternative oxazole synthesis can be performed using gold-catalyzed cyclization of propargyl amide (see Example 73). Condensation followed by cyclization of compounds of Formula (G2) with N-hydroxyguanidine sulfate in presence of EDC/HOBT and a base like DIPEA in dioxane gives the amino-oxadiazole derivative of Formula (G4), which can be converted in a Sandmeyer type reaction using HNO2 and HCI to the corresponding chloro-oxadiazole derivative of Formula (G5). Aromatic nucleophilic substitution with a sodium alcoholate of Formula (G6) in a solvent such as EtOH or THF at a temperature between RT and 80°C, or with an amine of Formula (E7) in EtOH, optionally in presence of a base such as DIPEA, and heating at around 80°C in a microwave oven, can provide the desired intermediates of Formula (G8) and (G9), respectively, if R is PG, or compounds of Formula (I) if R is R ² . It will be understood by one skilled in the art that the steps described in Scheme (G) can be performed with the protected azetidine ring (m=1) prior to the introduction of the R ² group, or with the azetidine ring substituted with the R ² group, and following the two-step protocol from the intermediate (A6) described in Scheme (A) to yield compounds of Formula (I).

Scheme G

An intermediate of Formula (E1) can be submitted to a Wittig-Horner type reaction with a phosphonate derivative of Formula (H2), using K2CO3 as a base, in EtOH at a temperature around reflux to provide an intermediate of Formula (H1), which can be further converted into an isoxazole derivative of Formula (H6) (R = PG) or (I) (R = R ² ) using hydroxylamine and DIPEA in EtOH at elevated temperatures (around 90°C). Reduction of the aldehyde derivative of Formula (E1) to the corresponding alcohol of Formula (H3) (R = PG) or (I) (R = R ² ) using UAIH4 in THF at -78°C can give access to carbamate derivatives of Formula (H7) (R = PG) or (I) (R = R ² ) by treatment with acyl chloride reagents of Formula (H5) or to benzylic halide intermediates of Formula (H4), preferentially bromides, by treatment with PPha and tetrabromomethane in DCM. Substitution of the benzylic halides with deprotonated alcohols of Formula (H6) or amines of Formula (E7) can provide intermediates of Formula (H8) or (H9) (R = PG), respectively, or compounds of Formula (I) (R = R ² ).

It will be understood by one skilled in the art that the steps described in Scheme (G) can be performed with the protected azetidine ring (m=1) prior to the introduction of the R ² group, or with the azetidine ring substituted with the R ² group, and following the two-step protocol from the intermediate (A6) described in Scheme (A) to yield compounds of Formula (I).

Scheme H

Intermediates of Formula (11) wherein PG is methyl or benzyl, prepared according to the route described in Scheme A, can be transformed into intermediates of Formula (I2), using BBra in DCM at RT, or hydrogen over palladium/charcoal (Scheme I). Such intermediates of Formula (I2) can be transformed into compounds of Formula (I) by performing a Mitsunobu type reaction with a hydroxy-containing derivative of Formula (G6), using conditions such as cyanomethyltributylphosphorane in toluene and heating at a temperature around 80-95 °C.

Scheme I

Compounds bearing two substituents in phenyl ring A of Formula (I), i.e. compounds where both n and p represent the integer 1 (especially such compounds, wherein R ⁴ is attached in position 3 (mefa-position) with respect to the point of attachment of the phenyl ring A to the rest of molecule; and R ⁵ is attached in any one of the remaining positions of said phenyl ring; in particular in position 2 with respect to the point of attachment of the phenyl ring A to the rest of molecule), can be prepared according to the procedures described in Schemes A to I with the corresponding minor adaptations in order to account for the presence of a second substituent R ⁵ in the phenyl ring A. For example, the compounds of Examples 109/110 can be prepared following Schemes A and D, the compound of Example 21 according to Scheme B; and the compounds of Example 89 following Scheme C and D.

Compounds bearing R ⁴ in position 4 (para-position) with respect to the point of attachment of the phenyl ring A to the rest of molecule can be prepared according to procedures described in Schemes A to I. For example, the compound of Example 2 can be prepared following Scheme A, the compound of Example 51 can be prepared following Schemes A and H, and the compound of Example 52 can be prepared following Schemes A and E.

Reactants of Formula (A3), (A3’), (A5), (A8), (A9), (A10), (D2), (D4), (D5), (D7), (E4), (E7), (E11), (F3), (F6), (F9), (G1), (G6), (H2), and (H5), are either commercially available or can be synthesized according to published protocols.

Whenever the compounds of Formula (I) are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase. Enantiomeric separation may be performed at the stage of intermediate (A6) or with compounds of Formula (I). Depending on the purification conditions, intermediates and compounds of Formula (I) may be isolated as free bases or as salts such as formate salts, or hydrochloride salts. Methods known to one skilled in the art may be applied to isolate free forms if applicable. Experimental section Abbreviations (as used herein and in the description above): Ac acetyl aq. aqueous Boc tert.-butyloxycarbonyl BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl BSA Bovine serum albumin BuLi butyllithium CC column chromatography on silica gel CDI 1,1'-carbonyldiimidazole conc. concentrated CV column volume dba dibenzylideneacetone DCM dichloromethane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA N-ethyldiisopropylamine DME Dimethoxyethane DMEM Dulbecco’s modified eagle media DMA N,N-Dimethylacetamide DMAP 4-(Dimethylamino)pyridine DMF dimethylformamide DMSO dimethylsulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EA ethyl acetate EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et ethyl FCS fetal calf serum FLIPR Fluorescent imaging plate reader Fluo-8-AM acetyloxymethyl 2-[N-[2-(acetyloxymethoxy)-2-oxoethyl]-4-[3-(acetyloxymethox y)-6-oxoxanthen-9- yl]-2-[2-[2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]pheno xy]ethoxy]anilino]acetate Fmoc fluorenylmethoxycarbonyl g gram h hour(s) HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium HEK Human embryonic ki Hep heptanes HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HexLi hexyllithium HOBt hydroxybenzotriazole HV high vacuum HPLC high performance liquid chromatography iPr isopropyl IT internal temperature L liter(s) µL microliter(s) LC liquid chromatography M molarity [mol L ^-1 ] MeCN acetonitrile Me methyl min minute(s) mL milliliter(s) MS mass spectrometry MW microwave NMR nuclear magnetic resonance spectroscopy org. organic Pd/C palladium on carbon Ph phenyl PG protecting group Prep preparative PTFE polytetrafluorethylen PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate RT room temperature RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl sat. saturated t tert tBME tert-butyl methyl ether T3P propylphosphonic anhydride TEA triethylamine TFA trifluoroacetic acid

THF tetrahydrofuran t _R retention time

I. Chemistry

The following Examples illustrate the preparation of biologically active compounds of the invention but do not at all limit the scope thereof.

General: All temperatures are stated in degrees Celsius (°C). Unless otherwise indicated, the reactions take place at RT under an argon atmosphere and are run in a flame dried (for water-sensitive reactions) round-bottomed flask or sealable tube equipped with a magnetic stir bar.

Characterization methods used:

The LC-MS retention times have been obtained using the following elution conditions:

I) LC-MS (A):

Zorbax RRHD SB-Aq, 1 ,8pim, 2.1x50mm column thermostated at 40°C. The two elution solvents were as follows: solvent A= water + 0.04%TFA; solvent B = MeCN. The eluent flow rate was 0.8mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):

II) LC-MS (B):

Waters BEH C18, 2.5um, 2.1x50mm column thermostated at 40°C. The two elution solvents were as follows: solvent A= water + 0.04% TFA; solvent B = MeCN. The eluent flow rate was 4.5mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):

The chiral HPLC/SFC retention times have been obtained using the following elution conditions:

I) Chiral HPLC (A): CHIRALPAK AD-H, 5pm, 4.6x250mm column thermostated at 25°C was used. The two elution solvents were as follows: solvent A= Hep+0.05% DEA; solvent B = EtOH+0.05% DEA. The eluent flow rate was 0.8mL/min, the duration of the run was 10min and the isocratic solvent proportion was 80% (A) 1 20% (B).

II) Chiral SFC (B):

CHIRALPAK AD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = EtOH+O.1 % DEA. The eluent flow rate was 4mL/min, the duration of the run was 4min and the isocratic solvent proportion was 90% (A) 1 10% (B).

III) Chiral SFC (C):

CHIRALCEL OZ-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = MeOH. The eluent flow rate was 4mL/min, the duration of the run was 4min and the isocratic solvent proportion was 82% (A) 1 18% (B).

IV) Chiral SFC (D):

CHIRALPAK AD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = EtOH. The eluent flow rate was 4mL/min, the duration of the run was 5min and the isocratic solvent proportion was 90% (A) 1 10% (B).

V) Chiral SFC (E):

CHIRALCEL OD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = EtOH + 0.1% DEA. The eluent flow rate was 4mL/min, the duration of the run was 5min and the isocratic solvent proportion was 75% (A) 1 25% (B).

VI) Chiral SFC (F):

CHIRALPAK AD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = EtOH + 0.1% DEA. The eluent flow rate was 4mL/min, the duration of the run was 10min and the isocratic solvent proportion was 80% (A) 1 20% (B).

VII) Chiral SFC (G):

CHIRALCEL OD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = EtOH + 0.1% DEA. The eluent flow rate was 4mL/min, the duration of the run was 5min and the isocratic solvent proportion was 80% (A) 1 20% (B).

VIII) Chiral SFC (H):

CHIRALPAK IG, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = MeOH. The eluent flow rate was 4mL/min, the duration of the run was 5min and the isocratic solvent proportion was 80% (A) 1 20% (B).

IX) Chiral SFC (I): CHIRALPAK AD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = EtOH. The eluent flow rate was 4mL/min, the duration of the run was 3.5min and the isocratic solvent proportion was 85% (A) 1 15% (B).

X) Chiral SFC (J):

CHIRALCEL OZ-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = ACN 1 2-Propanol (50/50). The eluent flow rate was 4mL/min, the duration of the run was 5min and the isocratic solvent proportion was 65% (A) 1 35% (B).

XI) Chiral SFC (K):

CHIRALPAK AD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = EtOH. The eluent flow rate was 4mL/min, the duration of the run was 3.5min and the isocratic solvent proportion was 80% (A) 1 20% (B).

XII) Chiral SFC (L):

CHIRALCEL OD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = EtOH. The eluent flow rate was 4mL/min, the duration of the run was 2.5min and the isocratic solvent proportion was 80% (A) 1 20% (B).

XIII) Chiral SFC (M):

CHIRALPAK IH, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = Hep/EtOH (1 :1). The eluent flow rate was 4mL/min, the duration of the run was 3min and the isocratic solvent proportion was 85% (A) 1 15% (B).

XIV) Chiral HPLC (N):

CHIRALPAK AY-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= Hep; solvent B = 2-Propanol. The eluent flow rate was 1 mL/min, the duration of the run was 15min and the isocratic solvent proportion was 80% (A) 1 20% (B).

XV) Chiral HPLC (O):

A ChiralCel OD-H column (5pm, 4.6x250mm) thermostated at 40°C was used. The two elution solvents were as follows: solvent A= ACN; solvent B = EtCH+0.1%DEA. The eluent flow rate was 4mL/min, the duration of the run was 5min and the isocratic solvent proportion was used. The elution solvent was 50% (A) 1 50% (B).

XVII) Chiral SFC (P):

CHIRALPAK AD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = EtOH. The eluent flow rate was 4mL/min, the duration of the run was 5min and the isocratic solvent proportion was 50% (A) 1 50% (B).

XVIII) Chiral SFC (Q): CHIRALCEL OD-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = MeCN/EtOH 1 :1. The eluent flow rate was 4mL/min, the duration of the run was 5min and the isocratic solvent proportion was 85% (A) 1 15% (B).

XIX) Chiral SFC (C):

CHIRALCEL OZ-H, 5pm, 4.6x250mm column thermostated at 40°C was used. The two elution solvents were as follows: solvent A= CO2; solvent B = MeOH. The eluent flow rate was 4mL/min, the duration of the run was 4min and the isocratic solvent proportion was 82% (A) 1 18% (B).

Preparative LC-MS methods used:

The purifications by preparative LC-MS have been performed using the conditions described hereafter.

I) Prep LC-MS (I):

An Agilent column (Zorbax SB-Aq, 5pm OBD, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

II) Prep LC-MS (II):

X-Bridge column (Waters C18, 10pm OBD, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% NH4OH (25%); solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

III) Prep LC-MS (III):

An Agilent column (Zorbax SB-Aq, 5pm OBD, 30x75mm) was used. The two elution solvents were as follows: solvent

A = water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

IV) Prep LC-MS (IV):

A X-Bridge column (Waters C18, 10pim OBD, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% NH4OH (25%); solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

V) Prep LC-MS (V):

X-Bridge column (Waters C18, 10pim OBD, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% NH4OH (25%); solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

VI) Prep LC-MS (VI):

A Zorbax column (SB-AQ, 7pim OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = MeCN; solvent B = water + 0.5% Formic acid. The characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

VII) Prep LC-MS (VII):

A X-Bridge column (Waters C18, 10pm OBD, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% NH4OH (25%); solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

VIII) Prep LC-MS (VIII):

An Agilent column (Zorbax SB-Aq, 5pim OBD, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

IX) Prep LC-MS (IX): A Zorbax column (SB-AQ, 7pim OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = MeCN; solvent B = water + 0.5% formic acid. The characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

X) Prep LC-MS (X):

A X-Bridge column (Waters C18, 10pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = MeCN; solvent B = water + 0.5% NH4OH (25%). The eluent flow rate and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XI) Prep LC-MS (XI):

A X-Bridge column (Waters C18, 10pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% NH4OH (25%); solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XII) Prep LC-MS (XII):

A X-Bridge column (Waters C18, 10pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% NH4OH (25%); solvent B = MeCN. The characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XIII) Prep LC-MS (XIII): A Zorbax column (SB-AQ, 7pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XIV) Prep LC-MS (XIV):

X-Bridge column (Waters C18, 10pm OBD, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XV) Prep LC-MS (XV):

A Zorbax column (SB-AQ, 7pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XVI) Prep LC-MS (XVI): X-Bridge column (Waters C18, 10pm OBD, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XVII) Prep LC-MS (XVII):

A X-Bridge column (Waters C18, 10pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% NH4OH (25%); solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XVIII) Prep LC-MS (XVIII):

An Agilent column (Zorbax SB-Aq, 5pm OBD, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XIX) Prep LC-MS (XIX):

A X-Bridge column (Waters C18, 10pm OBD, 50x150mm) was used. The two elution solvents were as follows solvent A = water + 0.5% Formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XX) Prep LC-MS (XX):

A X-Bridge column (Waters C18, 10pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XXI) Prep LC-MS (XXI):

A Zorbax SB-Aq column (Agilent, 5pm, 30x75mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XXII) Prep LC-MS (XXII): A Zorbax column (SB-AQ, 7pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XXIII) Prep LC-MS (XXIII):

A X-Bridge column (Waters C18, 10pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% NH4OH (25%); solvent B = MeCN. The eluent flow rate and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XXIV) Prep LC-MS (XXIV):

A Zorbax column (SB-AQ, 7pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = Water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate was 75mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XXV) Prep LC-MS (XXV): A X-Bridge column (Waters C18, 10pm OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% NH4OH (25%); solvent B = MeCN. The eluent flow rate and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points): XXVI) Prep LC-MS (XXVI):

A Zorbax column (SB-AQ, 7pim OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The eluent flow rate and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

XXVII) Prep LC-MS (XXVII):

A Zorbax column (SB-AQ, 7pim OBD, 50x150mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid; solvent B = MeCN. The characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):

Preparative chiral SFC and HPLC methods used:

The purifications by preparative chiral SFC and HPLC have been performed using the conditions described hereafter.

I) Prep chiral HPLC (I):

A ChiralPak AD-H column (5pm, 20x250mm) was used. The elution solvent was Hep/EtOH+O.1 % DEA 80/20, the run lasted for 7min and at a flow rate of 16mL/min.

II) Prep chiral SFC (II):

A ChiralPak AD-H column (5pm, 30x250mm) thermostated at 40°C was used. The elution solvent was CC2/EtCH+0.1 %DEA 90/10, the run lasted for 7min and at a flow rate of 160mL/min.

III) Prep chiral SFC (III):

A ChiralPak AD-H (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CO2/EtOH 70/30, run for 4min and at a flow rate of 160mL/min. IV) Prep chiral SFC (IV):

A ChiralPak AD-H column (5pm, 30x250mm) thermostated at 40°C was used. The elution solvent was CC^/EtOH 90/10, the run lasted for 4.9min and at a flow rate of 160mL/min.

V) Prep chiral SFC (V):

A ChiralPak OD-H (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CC2/EtCH+0.1 %DEA 75/25, run for 4min and at a flow rate of 160mL/min.

VI) Prep chiral SFC (VI):

A ChiralPak AD-H (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CC2/EtCH+0.1 %DEA 80/20, run for 3min and at a flow rate of 160mL/min.

VII) Prep chiral SFC (VII):

A ChiralPak OD-H (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CC2/EtCH+0.1 %DEA 80/20, run for 5.5min and at a flow rate of 160mL/min.

VIII) Prep chiral SFC (VIII):

A ChiralPak IG (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CO2/MeOH 80/20, run for 5min and at a flow rate of 160mL/min.

IX) Prep chiral SFC (IX):

A ChiralPak AD-H (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CO2/EtOH 85/15, run for 5.5min and at a flow rate of 160mL/min.

X) Prep chiral SFC (X):

A ChiralPak OZ-H (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CC2/50%ACN- 50%2-Propanol 65/35, run for 5min and at a flow rate of 160mL/min.

XI) Prep chiral SFC (XI):

A ChiralPak AD-H (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CO2/EtOH 80/20, run for 4.3min and at a flow rate of 160mL/min.

XII) Prep chiral SFC (XII):

A ChiralCel OD-H (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CO2/EtOH 80/20, run for 3.5min and at a flow rate of 160mL/min.

XIII) Prep chiral SFC (XIII):

A ChiralPak IH (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CO2/(Hep/EtOH 1 :1) 85/15, run for 3.5min and at a flow rate of 160mL/min.

XIV) Prep chiral HPLC (XIV):

A ChiralPak AY-H (5pm, 30x250mm) column thermostated at 40°C was used. The elution solvent was Hep/2-Propanol 80/20, run for 12.5min and at a flow rate of 38mL/min. XV) Prep chiral HPLC (XV): A ChiralCel OD-H column (5µm, 30x250mm) was used. The elution solvent was ACN/EtOH+0.1% DEA 50/50, the run lasted for 6min and at a flow rate of 160mL/min. XVI) Prep chiral SFC (XVI): A ChiralPak AD-H (5µm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CO ₂ /EtOH 50/50, run for 2.5min and at a flow rate of 160mL/min. XVII) Prep chiral SFC (XVII): A ChiralPak OD-H (5µm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CO ₂ /(MeCN/EtOH 1:1) 85/15, run for 6.5min and at a flow rate of 160mL/min. XVIII) Prep chiral SFC (XVIII): A ChiralPak OZ-H (5µm, 30x250mm) column thermostated at 40°C was used. The elution solvent was CO ₂ /MeOH (82/18), run for 5min and at a flow rate of 160mL/min. Preparation of Intermediate Examples of formula (A2), (A4), (A7), (B2), (C3), (D1), (D2), (D3), (E1), (E3), (E6), (E9), (F2), (F6), (F8), (H4), (I2) Example A2: 3-(Methoxy-methyl-carbamoyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a pale yellow solution of 1-Boc-3-methylazetidine-3-carboxylic acid (20g) in DCM (500mL) were added N,O- dimethylhydroxylamine hydrochloride (8.97g) and DIPEA (54mL). The mixture was then cooled at 0°C and T3P (50% w/w in EA, 68mL) was slowly added. The resulting pale-yellow solution was stirred 18h at RT and quenched with aq. sat. NaHCO ₃ solution. The org. layer was washed with citric acid (10%) and water. The combined org. layers were dried (MgSO ₄ ), filtered off and concentrated in vacuo to afford 24.1g of the title compound as yellowish resin which was used without further purification. LC-MS (A): t _R = 0.78min; [M+H] ⁺ : 259.32. Example A4.1: 3-Methyl-3-(4-trifluoromethoxy-benzoyl)-azetidine-1-carboxyl ic acid tert-butyl ester To a solution of 1-bromo-4-(trifluoromethoxy)benzene (12.2mL) in anhydrous THF (150mL) under argon cooled down to -78°C was added n-BuLi (2.5M in hexanes, 29.7mL) dropwise over 45min so that the IT did not rise above -70°C. The resulting mixture was stirred at -78°C for 20min. A solution of Example A2 (16g) in anhydrous THF (50mL) was added dropwise keeping the IT below -70°C. The resulting dark yellow solution was allowed to warm up to RT and was stirred overnight. The reaction mixture was quenched with water and extracted with DCM. The org. layers were washed with brine, dried (MgSO ₄ ), filtered off and concentrated in vacuo. The resulting crude material was purified by CC (Biotage, SNAP 340g, solvent A: Hep; solvent B: EA; gradient in %B: 10 over 2CV, 10 to 30 over 3CV, 30 over 2CV) to afford 18g of the title compound as yellow foam. LC-MS (A): t _R = 1.07min; [M+H-CH ₃ ] ⁺ : 345.11. Example A4.2: 3-(4-Isopropyl-benzoyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized starting from Example A2 (10g) and 1-bromo-4-isopropylbenzene (7.94mL), and following the procedure described in Example A4.1, and purified by CC (Biotage, SNAP 340g, solvent A: Hep; solvent B: EA; gradient in %B: 10 over 5CV, 1 11.73g of the title compound as a yellow resin. LC- MS (A): t _R = 1.09min; [M+H] ⁺ : 318.31. Example A7.1: (S)-(3-Chloro-phenyl)-(3-methyl-azetidin-3-yl)-(4-trifluorom ethoxy-phenyl)-methanol A7.1.1. 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-3-methyl-azetidine-1-carboxylic acid tert- butyl ester To a solution of Example A4.1 (3.2g) in THF (50mL) under argon and cooled at -10°C was added dropwise 3- chlorophenylmagnesium bromide (0.5M in THF, 55.6mL). The reaction mixture was stirred 3h at -10°C, quenched with water and extracted with EA (2x). The combined org. layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude material was purified by CC (Biotage, SNAP 100g, solvent A: Hep; solvent B: EA; gradient in %B 0 over 3CV, 0 to 10 over 3CV, 10 over 2CV, 10 to 20 over 3CV, 20 over 2CV) and by Prep LC-MS (X) to afford 2.32g of a white solid. LC-MS (A): t _R = 1.16min; [M+H] ⁺ : 472.13. A7.1.23-[(S)-(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-p henyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert- butyl ester Example A7.1.1 (2.32g) was purified by Prep chiral SFC (IV) to afford 1.066g of the title compound as pure enantiomer. Chiral SFC (D): t _R = 1.842min. A7.1.3 (S)-(3-Chloro-phenyl)-(3-methyl-azetidin-3-yl)-(4-trifluorom ethoxy-phenyl)-methanol A solution of Example A7.1.2 (1.05g) in HCl in dioxane (4M, 20mL) was stirred 45min at RT, concentrated in vacuo and the residue was diluted in EA, the org. layer was washed (2x) with sat. NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford 920mg of the desired product as a yellowish foam. LC-MS (A): t _R = 0.79min; [M+H] ⁺ : 372.09. Example A7.2: 3-[(S)-(3-Fluoro-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl) -methyl]-benzonitrile A7.2.13-Fluoro-3-(methoxy-methyl-carbamoyl)-azetidine-1-carb oxylic acid tert-butyl ester To a solution of 3-fluoro-1,3-azetidinedicarboxylic acid tert-butyl ester (2.00g) in DCM (65mL) was added N,O- dimethylhydroxylamine hydrochloride (940mg), DIPEA (5.6mL) and T3P (50wt% in EA, 7.1mL). The mixture was stirred at RT for 60min, quenched by the addition of aq. sat. NaHCO ₃ and extracted with DCM (3x). The combined org. layers were washed with aq. citric acid (10%) and water, passed through a phase separator, then concentrated in vacuo to give the crude product as a colorless oil (2.40g), which was used in the next step without further purification. LC-MS (A): t _R = 0.83min; [M+H-CH ₃ ] ⁺ : 248.20. A7.2.23-Fluoro-3-(4-isopropyl-benzoyl)-azetidine-1-carboxyli c acid tert-butyl ester To a solution of 1-bromo-4-isopropylbenzene (1.9mL) in THF (21mL) at -78°C was added dropwise a solution of HexLi (2.3 M in hexanes, 5.2mL) during 15min. The solution was stirred at -78°C for 30min before a solution of Example A7.2.1 (2.40g) in THF (7mL) was added during 15min. The resulting solution was stirred at -78°C for 70min. The cooling bath was removed, the reaction mixture was quenched with aq. NaHCO ₃ , warmed to RT, and extracted with EA (2x). The combined org. layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude as a dark yellow oil, which was purified Sep 80g SiO ₂ , gradient Hep/EA 100:0 to 85:15 over 30min at 60mL/min) to give 2.7g of the desired product as a white solid. LC-MS (A): t _R = 1.13min; [M+H-CH ₃ ] ⁺ : 307.16. A7.2.3 3-[(S)-(3-Cyano-phenyl)-hydroxy-(4-isopropyl-phenyl)-methyl] -3-fluoro-azetidine-1-carboxylic acid tert-butyl ester To a solution of 3-bromobenzonitrile (2.11g) in THF (22mL) was added at -78°C a solution of HexLi (2.3M in hexanes, 5.5mL) during 15-20min. After stirring at -78°C for 15min, a solution of Example A7.2.2 in THF (7.5mL) was added dropwise for 15-20min. The mixture was stirred at -78°C for 2h, after which the cooling bath was removed, the reaction quenched with aq. NH ₄ Cl and the aq. layer extracted with EA (3x). The combined org. layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude product as a yellow oil. The residue was further purified by CC (CombiFlash, RediSep 120g SiO ₂ , gradient Hep/EA 100:0 to 70:30 over 30min at 85mL/min) to give a white solid (1.50g) and then subjected to Prep LC-MS (XV) to give the desired product as a racemic mixture (1.40g). The individual enantiomers were separated by Prep chiral SFC (XVII) to give the desired enantiomer as the second eluting compound (white solid, 600mg). LC-MS (A): t _R = 1.14min; [M+H] ⁺ : 425.25. Chiral SFC (Q): t _R = 2.11min. A7.2.43-[(S)-(3-Fluoro-azetidin-3-yl)-hydroxy-(4-isopropyl-p henyl)-methyl]-benzonitrile A7.2.3 (602mg) was treated with a solution of HCl in dioxane (4 M, 3.5mL). The solution was stirred at RT for 1.5h. The solvent was removed in vacuo and the resulting white solid was used in the next steps without further purification (540mg). LC-MS (A): t _R = 0.74min; [M+H] ⁺ : 325.19. Example B2: (1,3-Dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-met hanone B2.1 (3-Methyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-methano ne A solution of Example A4.1 (8g) in EA (40mL) was treated with HCl in dioxane (4M, 56mL) and stirred for 1h30 at RT. Water and EA were added, the phases were separated, and the org. phase was washed with water. The aq. layers were combined, basified until pH 11 with 20% aq. NaOH (60mL) and extracted with EA (3x). The combined org. phases were dried (MgSO ₄ ), filtered off, concentrated in vacuo and dried under HV to afford 5g of the crude product as a yellow oil. LC-MS (A): t _R = 0.63min; [M+H] ⁺ : 260.16. B2.2 (1,3-Dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-met hanone To a solution of Example B2.1 (5g) in DCM (350mL) placed at 0°C were added formaldehyde (solution 37% w/w in water, 5.03mL), followed by NaBH(OAc) ₃ (6.46g). The reaction mixture was stirred at 0°C for 1h. The mixture was quenched with sat. NaHCO ₃ , the phases were separated and the org. one was washed once with water, dried (MgSO ₄ ), concentrated in vacuo and dried under HV to afford 5.12g of the title product as a yellow oil, which was used without further purification. LC-MS (A): t _R = 0.65min; [M+H] ⁺ : 274.03. Example C3.1: (3-chloro-phenyl)-(1,3-dimethyl-azetidin-3-yl)-methanone C3.1.13-(3-Chloro-benzoyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized (10.57g), 1-bromo-3-chlorobenzene (10.3g), and following the procedure described in Example A4.1 and purified by CC (Biotage, SNAP 340g, solvent A: Hep; solvent B: EA; gradient in %B: 10 over 2CV, 10 to 30 over 2CV, 30 over 3CV) to afford 12.1g of the title compound as a yellow oil. LC-MS (A): t _R = 1.03min; [M+H] ⁺ : 310.12. C3.1.2 (3-Chloro-phenyl)-(3-methyl-azetidin-3-yl)-methanone To a solution of Example C3.1.1 (800mg) in DCM (8mL) was added TFA (2mL) at RT and the reaction mixture was stirred 1h at RT. The reaction mixture was evaporated, dried under HV, the residue was taken up in DCM and washed with aq. sat. NaHCO ₃ . The aq layer was re-extracted with DCM (1x). The combined org. phases were dried (MgSO ₄ ), filtered off, concentrated in vacuo and dried under HV to afford 455mg of the title compound as a yellow foam. LC-MS (A): t _R = 0.54min; [M+H] ⁺ : 210.12 C3.1.3 (3-chlorophenyl)(1,3-dimethylazetidin-3-yl)methanone To a solution of Example C3.1.2 (438mg) in MeOH (20mL) were added formaldehyde (37% w/w in water, 0.933mL), acetic acid (2mL) and NaBH(OAc) ₃ (913mg). The resulting light-yellow suspension was stirred at RT, evaporated, the residue was diluted in water, basified with aq. sat. NaHCO ₃ and extracted with EA (3x). The combined org. layers were dried (MgSO ₄ ), filtered off, concentrated in vacuo and purified by CC (Biotage, SNAP 25g, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in %B: 25 over 1CV, 25 to 50 over 2CV, 50 over 3CV) to afford 288mg of the title compound as yellow oil. LC-MS (A): t _R = 0.57min; [M+H] ⁺ : 224.26. Example C3.2: (1,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-methanone C3.2.13-Methyl-3-(4-phenoxy-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized starting from Example A2 (2g) and 4-bromodiphenyl ether (1.78mL), and following the procedure described in Example A4.1 and purified by CC (Biotage, SNAP 100g, solvent A: Hep; solvent B: EA; gradient in %B: 10 over 2CV, 10 to 20 over 1CV, 20 over 1CV, 20 to 30 over 1CV, 30 over 2CV) to afford 2.47g of the title compound as light yellow resin. LC-MS (A): t _R = 1.11min; [M+H] ⁺ : 368.17. C3.2.2 (3-Methyl-azetidin-3-yl)-(4-phenoxy-phenyl)-methanone A solution of Example C3.2.1 (2.42mg) was treated with HCl in dioxane (4M, 20mL) and was stirred 1h at RT. The reaction mixture was concentrated in vacuo and dried under HV to afford 2.05g of the title compound as a light-yellow foam. LC-MS (A): t _R = 0.69min; [M+H] ⁺ : 268.31. C3.2.3 (1,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-methanone The title compound was synthesized starting from Example C3.2.2 (2g), and following the procedure described in Example C3.1, step 3, and purified by CC (Biotage, SNAP 50g, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in %B: 25 over 2CV, 25 to 50 over 3CV, 50 over 2CV) to afford 1.62g of the title compound as yellow oil. LC-MS (A): t _R = 0.71min; [M+H] ⁺ : 282.27. Example D1.1: (Z)-3-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylpheny l)methyl)-N'-hydroxybenzimidamide D1.1.13-[(3-Cyano-phenyl)-hydroxy-(4 3-methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized starting from Example A4.2 (4.8g) and 3-bromobenzonitrile (3.6g), and following the procedure described in Example A7.2, step 3, whereby the reaction the reaction mixture was quenched with water and extracted with DCM. The crude was purified (2x) by CC (Biotage, SNAP 330g, solvent A: Hep, solvent B: EA; gradient in %B: 0 over 1min, 0 to 10 over 5min, 10 over 3min, 10 to 30 over 22min, 30 over 5min, 30 to 100 over 10min) to afford 5.41g of the title product as a white foam. LC-MS (A): t _R = 1.11min; [M+H] ⁺ : 421.29. D1.1.23-[Hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidin-3-y l)-methyl]-benzonitrile A solution of Example D1.1.1 (3.41g), was treated with HCl in dioxane (4M, 21mL) and was stirred 1h at RT. The reaction mixture was concentrated in vacuo and dried under HV to afford 3.26g of the title compound as a white foam. LC-MS (A): t _R = 0.75min; [M+H] ⁺ : 321.25. D1.1.33-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-p henyl)-methyl]-benzonitrile The title compound was synthesized starting from Example D1.1.2 (3.26g) and following the procedure described in Example B2, step 2. The crude material was purified by Prep LC-MS (III) to afford 2.06g of the title compound as a white solid. LC-MS (A): t _R = 0.78min; [M+H] ⁺ : 335.22. D1.1.4. (Z)-3-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylpheny l)methyl)-N'-hydroxybenzimidamide To a solution of Example D1.1.3 (2.06g) in EtOH (30mL) and water (3.4mL) was added hydroxylamine hydrochloride (1.3g) and K ₂ CO ₃ (1.7g). The reaction mixture was heated at 90°C for 3h. Again, K ₂ CO ₃ (426mg) and hydroxylamine hydrochloride (216mg) were added and the reaction mixture was stirred at 90°C for 4h30, cooled down to RT and filtered off, the salts washed with EtOH. The filtrate was concentrated in vacuo, then triturated in EA, concentrated again and dried under HV to afford 2.73g of the title product as a white foam. LC-MS (A): t _R = 0.55min; [M+H] ⁺ : 368.28. Example D1.2: (S,Z)-3-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphe nyl)methyl)-N'-hydroxybenzimidamide D1.2.1 3-[(S)-(3-Cyano-phenyl)-hydroxy-(4-isopropyl-phenyl)-methyl] -3-methyl-azetidine-1-carboxylic acid tert-butyl ester D1.1.1 (4.93g) was purified by Prep chiral SFC (VIII) to afford 2.49g of the pure enantiomer as a white foam. Chiral SFC (H): t _R = 1.6min. D1.2.23-[(S)-Hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidin -3-yl)-methyl]-benzonitrile D1.2.1 (2.29g) was treated with HCl in dioxane (4M, 15mL) and the solution was stirred 1h at RT, concentrated in vacuo and dried under HV to afford 2.3g of the title compound as a white foam. LC-MS (A): t _R = 0.75min; [M+H] ⁺ : 321.18. D1.2.33-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isoprop yl-phenyl)-methyl]-benzonitrile The title compound was synthesized starting from Example D1.2.2 (2.3g) and following the procedure described in Example B2, step 2. The crude material was purified by Prep LC-MS (XII) to afford 1.12g of the title compound as a beige solid. LC-MS (A): t _R = 0.77min; [M+H] ⁺ : 335.38.

D1.2.4 (S,Z)-3-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphe nyl)methyl)-N'-hydroxybenzimidamide

The title compound was synthesized starting from Example D1.2.3 (1.12g) and following the procedure described in Example D1.1 , step 4, to afford 1.38g of the title product as a light-yellow foam. LC-MS (A): t _R = 0.55min; [M+H] ⁺ : 368.25.

Example D2.1 : 4-Acetoxy-1 -acetyl-piperidine-4-carboxylic acid

D2.1.1 4-Hydroxy-piperidine-4-carboxylic acid

1-Boc-4-hydroxy-4-piperidinecarboxylic acid (124mg) was treated with a solution of HCI in dioxane (4 M, 1.25mL) and was stirred at RT for 2.5h. The solvent was evaporated and the product was obtained as a white solid (87mg). LC-MS (A): t _R = 0.16min; [M+H] ⁺ : 146.09.

D2.1.2 4-Acetoxy-1-acetyl-piperidine-4-carboxylic acid

To a suspension of Example D2.1.1 (87mg) and DMAP (59mg) in THF (0.5mL) were added acetic anhydride (0.05mL) and TEA (0.2mL). The reaction mixture was heated to 60°C and stirred for 1 ,5h. The reaction was cooled to RT, treated with aq. HCI (1 M) and extracted (6x) with EA/MeOH (9:1). The combined org. layers were dried (MgSO4), filtered, concentrated in vacuo and dried under HV to give 87mg of the desired product as a white solid. ¹ H-NMR (500 MHz, DMSO) 5 = 12.50 (br s, 1 H), 4.16-4.08 (m, 1 H), 3.73-3.63 (m, 1 H), 3.29-3.21 (m, 1 H), 2.92-2.82 (m, 1 H), 2.08 (s, 3H), 2.03-1.90 (m, 3H), 2.01 (s, 3H), 1.80-1.72 (m, 1 H) ppm. LC-MS (A): t _R = 0.47min; [M+H] ⁺ : 230.19.

Example D2.2 to Example D2.5 were synthesized from the corresponding amino acids through acetylation according to the procedure described for Example D2.1 , step 2. LC-MS (A) retention times given in minutes:

1 H-NMR of Example D2.3 (500 MHz, DMSO) 5 = 12.34 (br s, 1 H), 8.36 (s, 1 H), 1.78 (s, 3H), 1.32-1.27 (m, 2H), 0.95- 0.91 (m, 2H).

Example D2.6: [(2-Hydroxy-acetyl)-methyl-amino]-acetic acid

To a solution of glycyl-sarcosine (200mg) in aq. HCI (1 M, 2.8mL) was added a solution of sodium nitrite (572mg) in water (1.4mL) at 0°C. After stirring at 0°C for 1h, the reaction was allowed to warm to RT and stirred for another 16h. The mixture was extracted (5x) with DCM/MeOH (9: 1). The aq. layer was purified by Prep LC-MS (XXIV) to give 96mg of the desired product as a white solid. LC-MS (A): t _R = 0.21 min; [M+H] ⁺ : 148.12. Example D2.7: 3-Hydroxymethyl-bicyclo[1 .1 .1]pentane-1-carboxylic acid

To a solution of 3- (hy d roxy methyl)bicy clo [ 1.1 .1]pentane-1 -carbonitrile (300mg) in EtOH (4.6mL) was added water (1 mL) and aq. NaOH (10.8 M, 1.3mL). The reaction was heated to 75°C and stirred for 1.5h. After cooling to RT, the pH of the mixture was lowered to 2-3 by addition of aq. HCI (1 M), followed by extraction with EA (4x). The combined org. layers were dried (MgSC^), filtered and concentrated in vacuo to give 268mg of the desired product as a white solid. ¹ H-NMR (500 MHz, DMSO) 5 = 12.24 (s, 1 H), 4.54 (t, J = 5.6 Hz, 1 H), 3.37 (d, J = 5.5 Hz, 2H), 1.81 (s, 6H) ppm. Example D3: (3-Aminomethyl-phenyl)-(1 , 3-di methy l-azetid i n-3-y l)-(4-isopropy l-pheny l)-methanol

To a hot solution of LIAIH4 (2M in THF, 2.14mL) in THF (2.8mL) (IT= 68°C) was added dropwise a solution of Example D1 .1 .1 (300mg) in THF (2.3mL). The reaction mixture was stirred 1 h at 68°C, cooled down to 0°C, quenched with water (0.17mL), aq. NaOH (15% w/w, 0.17mL) and with water (0.51 mL) again. EA was added and the reaction was warmed to RT and stirred 20min. The white precipitate was filtered off and washed with water and EA (3x). The phases of the filtrate were separated and the aq. one was re-extracted with EA. The combined org. phases were dried (MgSO4), filtered and concentrated in vacuo to afford 225.7mg of the title crude product as a yellow foam. LC-MS (A): IR = 0.56min; [M+H] ⁺ : 339.25.

Example E1.1 : 3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-benzaldehyde

To a solution of Example B2 (2.5g) in THF (30mL) cooled at 0°C was added dropwise 3-(benzaldehyde diethylacetal)magnesium bromide solution (1 M in THF, 22mL), while maintaining an IT below 7°C. The reaction mixture was stirred 2h at 0°C, quenched with water and extracted with EA. The combined org. layers were dried (MgSC>4), filtered off and concentrated in vacuo. The resulting yellow oil was dissolved in DCM (10mL) and treated with formic acid (2.1 mL). The reaction mixture was stirred 20min at RT and concentrated in vacuo. The residue was purified by CC (Biotage, SNAP 100g, solvent A: DCM; solvent B: 4:1 DCM/MeOH; gradient in %B: 0 over 3CV, 0 to 15 over 1CV, 15 over 2.5CV, 15 to 30 over 1CV, 30 over 2.5CV, 30 to 45 over 1CV, 45 over 2.5CV, 45 to 100 over 8CV, 100 over 2.6CV) to afford 2.1g of the title product as a white foam. LC-MS (A): IR = 0.75min; [M+H] ⁺ : 380.20.

Example E1.2: 4-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-benzaldehyde

The title compound was synthesized starting from Example B2 (2.5g) and 4-(benzaldehyde diethylacetal)magnesium bromide (1 M in THF, 30mL), following the procedure described in Example E1.1 and purified by CC (Biotage, SNAP 100g, solvent A: DCM; solvent B: 8/2 DCM/MeOH; gradient in %B: 0 over 3CV, 0 to 15 over 1CV, 15 over 2.5CV, 15 to 30 over 1CV, 30 over 2.5CV, 30 to 45 over 1CV, 45 over 2.5CV, 45 to 100 over 8CV, 100 over 2.6CV) to afford 2.36g of the desired compound as a light yellow foam. LC-MS (A): t _R = 0.73min; [M+H] ⁺ : 380.16.

Example E1.3: 3-[(3-Formyl-phenyl)-hydroxy-(4-isopropyl-phenyl)-methyl]-3- methyl-azetidine-1-carboxylic acid tertbutyl ester

In a previously heated flask, Example A4.2 (9.4g) and 3-bromobenzaldehyde diethyl acetal (7.37mL) were dissolved in THF (90mL) and cooled at -35°C. n-BuLi (2.5M in hexanes, 13.5mL) was added dropwise while maintaining the IT below -25°C. The reaction mixture was stirred 5min at RT, quenched with 1 M NaHCOa and extracted with DCM (3x). The combined org. layers were dried (M trated in vacuo. The residue was dissolved in DCM and treated with formic acid (10.5mL). The mixture was stirred 20min at RT and concentrated in vacuo. The crude was purified (2x) by CC (Biotage, SNAP 100g, solvent A: Hep, solvent B: EA; gradient in %B: 0 over 3CV, 0 to 40 over 12CV, 40 over 2CV) and by Prep LC-MS (XXII) to afford 5.9g of the title product as a white foam. LC-MS (A): t _R = 1.1min; [M+H] ⁺ : 424.38. Example E3.1: 3-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phe nyl)-methyl]-benzoic acid E3.1.1 3-[(S)-(3-tert-Butoxycarbonyl-phenyl)-hydroxy-(4-isopropyl-p henyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester A solution of Example A4.2 (6.00g) and t-butyl-3-bromobenzoate (6.58g) in THF (125mL) was cooled to -78°C. Thereto was added dropwise a solution of HexLi (2.3M in hexanes, 9.9mL) over 15min. The reaction was stirred at -78°C for 1h. The mixture was allowed to warm to RT and was quenched with water and extracted with DCM (3x). The combined org. layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The yellow oil was purified by CC (CombiFlash, RediSep 330g SiO ₂ , gradient Hep/EA: 100:0 to 95:5 over 2CV, 95:5 over 2CV, 95:5 to 90:10 over 2CV, 90:10 over 2CV, 90:10 to 70:30 over 5CV, 70:30 over 3CV, 200mL/min) to give a white foam. It was further purified by Prep LC-MS (XXVI) to give the desired product as a white foam (6.09g). The racemate was separated by Prep chiral SFC (XVIII) giving the desired product as the second eluting isomer (2.65g). LC-MS (A): t _R = 1.24min; [M+H] ⁺ : 496.35. Chiral SFC (C): t _R = 2.46min. E3.1.23-[(S)-Hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidin -3-yl)-methyl]-benzoic acid tert-butyl ester To a solution of Example E3.1.1 (2.45g) in EA (100mL) was added a solution of HCl in dioxane (4 M, 6.3mL). The mixture was stirred at RT for 7 days, whereby preferential Boc deprotection was observed compared to double deprotection of the Boc and t-butyl ester. The solvent was evaporated and the residue was purified by Prep LC-MS (XXVII) to give 1.4g of the desired product as a white foam. LC-MS (A): t _R = 0.86min; [M+H] ⁺ : 396.42. E3.1.33-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isoprop yl-phenyl)-methyl]-benzoic acid tert-butyl ester To a solution of Example E3.1.2 (1.40g) in dioxane (16mL) were added TEA (1.33mL), a solution of formaldehyde in water (37wt%, 0.83mL) and NaBH(OAc) ₃ (1.06g). The reaction mixture was stirred at RT for 16h. More TEA (1.33mL), formaldehyde solution (0.83mL) and NaBH(OAc) ₃ (1.06g) were added and the mixture was stirred for another 2h. Sat. aq. NaHCO ₃ was added, and the mixture was extracted with EA (3x). The combined org. layers were dried (MgSO ₄ ), filtered, concentrated in vacuo and dried at HV to give 1.4g of the desired product as a white foam. LC-MS (A): t _R = 0.88min; [M+H] ⁺ : 410.38. E3.1.43-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isoprop yl-phenyl)-methyl]-benzoic acid E3.1.3 (1.40g) was treated with a solution of HCl in dioxane (4 M, 18mL). The mixture was stirred at RT for 20h. Some more HCl in dioxane (4 M, 1mL) was added and the mixture was stirred for another 90min. The solvent was evaporated to give 1.56g of the title compound as a white foam. LC-MS (A): t _R = 0.68min; [M+H] ⁺ : 354.00. Example E3.2: Sodium 4-[(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-benzoate To a solution of Example E1.2 (500mg ded a solution of NaOH (96.2mg) in water (4.8mL). The solution was cooled at 0°C and KMnO ₄ (271mg) was added. The reaction mixture was stirred 1h at 0°C and KMnO ₄ (570mg) was added again and the reaction mixture was stirred 20min at 0°C, filtered and the filtrate was concentrated in vacuo. The residue was suspended in MeCN and water, then filtered off and the filtrate was lyophilized to afford 600mg of the title compound. LC-MS (A): t _R = 0.71min; [M+H] ⁺ : 396.18. Example E3.3: Sodium 3-[(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-benzoate The title compound was synthesized starting from Example E1.1 (1.5g), and following the procedure described in Example E3.2, to afford 1.1g of the title compound as a white solid. LC-MS (A): t _R = 0.71min; [M+H] ⁺ : 396.20. Example E3.4: 3-[(S)-(3-Carboxy-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl )-methyl]-3-methyl-azetidine-1- carboxylic acid tert-butyl ester E3.4.1 3-[(3-Formyl-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-3-methyl-azetidine-1-carboxylic acid tert- butyl ester To a solution of Example A4.1 (9.97g) in THF (300mL) was added at 0°C 3-(benzaldehyde diethylacetal)magnesium bromide (1M in THF, 55mL). The reaction mixture was stirred at 0°C and was allowed to warm at RT overnight, quenched with aq. HCl (1M, 100mL) and the mixture was stirred 10min. It was extracted with EA and the org. layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by CC (Biotage, SNAP 100g, solvent A: Hep; solvent B: EA; gradient in %B 0 over 3CV, 0 to 40 over 12CV) and by Prep LC-MS (IX) to afford 1.8g of the title compound. LC-MS (A): t _R = 1.08min; [M+H] ⁺ : 466.03. E3.4.2 (S)-3-[(3-Formyl-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl) -methyl]-3-methyl-azetidine-1-carboxylic acid tert- butyl ester E3.4.1 (1.8g) was purified by Prep chiral SFC (IV) to afford 750mg of the title compound as pure enantiomer. Chiral SFC (D): t _R = 1.523min. E3.4.3 3-[(S)-(3-Carboxy-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl )-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a solution of Example E3.4.2 (1.1g) in EtOH (50mL) and water (25mL) was added aq. NaOH (1M, 25.7mL) and silver nitrate (1g). The reaction mixture was stirred 1h at RT, filtered off and ethanol was removed in vacuo. The resulting mixture was acidified to pH 3 by adding aq. citric acid, extracted with DCM and the org. layer was dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford 1.25g of a white foam. LC-MS (B): t _R = 1.09min; [M+H] ⁺ : 481.94. Example E3.5: 3-[(3-Carboxy-phenyl)-hydroxy-(4-isopropyl-phenyl)-methyl]-3 -methyl-azetidine-1-carboxylic acid tert- butyl ester The title compound was synthesized starting from Example E1.3 (2.48g) and following the procedure described in Example E3.4, step 3 to afford 2.3g as a light-yellow foam. LC-MS (A): t _R = 1.02min; [M+H]+: 440.34. Example E3.6: 3-[(S)-(3-Carboxy-phenyl)-hydroxy-(4-isopropyl-phenyl)-methy l]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester E3.6.1 3-[(S)-(3-Formyl-phenyl)-hydro hyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester Example E1.3 (5.9g) was purified by Prep chiral SFC (IX) to afford 3g of the pure enantiomer as a white foam. Chiral SFC (I): t _R = 1.8min. E3.6.23-[(S)-(3-Carboxy-phenyl)-hydroxy-(4-isopropyl-phenyl) -methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized starting from Example E3.6.1 (305mg) and following the procedure described in Example E3.4, step 3 to afford 330mg of the title compound as a white solid. LC-MS (A): t _R = 1.03min; [M+H] ⁺ : 440.27. Example E6: 5-{3-[(S)-(1-tert-Butoxycarbonyl-3-methyl-azetidin-3-yl)-hyd roxy-(4-trifluoromethoxy-phenyl)-methyl]- phenyl}-[1,2,4]oxadiazole-3-carboxylic acid E6.1 5-{3-[(S)-(1-tert-Butoxycarbonyl-3-methyl-azetidin-3-yl)-hyd roxy-(4-trifluoromethoxy-phenyl)-methyl]-phenyl}- [1,2,4]oxadiazole-3-carboxylic acid ethyl ester A mixture of Example E3.4 (1.25g), ethyl 2-amino(hydroxyimino)acetate (389mg), HOBt (386mg), EDC·HCl (747mg) and DIPEA (0.89mL) in dioxane (3mL) was stirred 20h at RT. Ethyl 2-amino(hydroxyimino)acetate (206mg), HOBt (280mg) and EDC·HCl (446mg) were added again and the reaction mixture was stirred 2h at RT and 20h at 100°C. The reaction mixture was quenched with water and extracted with EA. The org. layer was washed with 10% citric acid, sat. NaHCO ₃ , dried (MgSO ₄ ), filtered and concentrated in vacuo to afford 1.3g of a white solid. LC-MS (B): t _R = 1.25min; [M+H] ⁺ : 578.05. E6.2 5-{3-[(S)-(1-tert-Butoxycarbonyl-3-methyl-azetidin-3-yl)-hyd roxy-(4-trifluoromethoxy-phenyl)-methyl]-phenyl}- [1,2,4]oxadiazole-3-carboxylic acid A solution of Example E6.1 (1.3g) in THF (18mL) was treated with LiOH·H ₂ O (378mg) and the reaction was stirred 2h at RT, acidified with citric acid until pH 3 and extracted with EA, the org. layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude material was purified by Prep LC-MS (VIII) to afford 1g of the desired product as a brownish foam. LC-MS (B): t _R = 1.10min; [M+H] ⁺ : 550.31. Example E9.1: (Z)-N',3-dihydroxy-3-methylbutanimidamide To a solution of 3-hydroxy-3-methylbutyronitrile in EtOH (2mL) were added K ₂ CO ₃ (680mg) and hydroxylamine hydrochloride (73.7µL). The reaction mixture was refluxed for 20h, cooled at RT, filtered and concentrated in vacuo to afford 165mg of the title product. LC-MS (A): t _R = 0.20min; [M+H ⁺ ]: 133.26. Example E9.2: (Z)-1-(2-((tert-butyldiphenylsilyl)oxy)acetyl)-N'-hydroxypip eridine-4-carboximidamide E9.2.1 (tert-Butyl-diphenyl-silanyloxy)-acetic acid To a solution of glycolic acid (2.00g), DMAP (318mg) and TEA (10.9mL) in THF (100mL) cooled at 0°C was added tert- butyl(chloro)diphenylsilane (7.6mL) dropwise. The suspension was allowed to warm to RT and was stirred for 16h. Aq. HCl (1 M) was added slowly until a pH of 1 was reached. The mixture was then extracted with Et ₂ O (3x). The combined org. layers were dried (MgSO ₄ ), filtered . The colorless oil was purified by CC (CombiFlash, RediSep 330g SiO ₂ , gradient of Hep/EA 100:0 to 70:30 over 25min, 200mL/min) to give 7.05g of the desired product as a colorless oil. ¹ H-NMR (500 MHz, DMSO) δ = 12.6 (br s, 1H), 7.67-7.63 (m, 4H), 7.50-7.41 (m, 6H), 4.19 (s, 2H), 1.02 (s, 9H) ppm. E9.2.21-[2-(tert-Butyl-diphenyl-silanyloxy)-acetyl]-piperidi ne-4-carbonitrile To a suspension of piperidine-4-carbonitrile hydrochloride (217mg), E9.2.1 (605mg) and HATU (900mg) in THF (4mL) was added DIPEA (0.76mL), and the mixture was stirred at RT for 1h. The reaction was diluted with EA, washed consecutively with aq. sat. NaHCO ₃ , aq. HCl (1M), water and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by CC (CombiFlash, RediSep 120g SiO ₂ , gradient Hep/EA 100:0 to 50:50 over 35min, 85mL/min) to give 261mg of the desired product as a colorless oil. LC-MS (A): t _R = 1.10min; [M+H] ⁺ : 407.21. E9.2.3 (Z)-1-(2-((tert-butyldiphenylsilyl)oxy)acetyl)-N'-hydroxypip eridine-4-carboximidamide The title compound was synthesized from Example E9.2.2 following the procedure described in Example D1.1, step 4. The product was obtained in 40% purity and was used in the next step without further purification. LC-MS (A): t _R = 0.84min; [M+H] ⁺ : 440.21. Example E9.3: (Z)-N'-hydroxy-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetimid amide E9.3.1 (4-Hydroxy-tetrahydro-pyran-4-yl)-MeCN At -78°C a solution of n-BuLi (2.5M in hexanes, 4.8mL) was added to THF (20mL). Thereto was slowly added MeCN (0.63mL). After stirring at -78°C for 10min a solution of tetrahydropyran-4-one (1.00g) in THF (3mL) was added slowly. The mixture was diluted with THF (5mL) and was then stirred at -78°C for 1.5h. The cooling bath was removed and the reaction was quenched with aq. sat. NH ₄ Cl. After addition of brine the mixture was extracted with EA (3x). The combined org. layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The resulting yellow oil was purified by CC (CombiFlash, RediSep 80g SiO ₂ , gradient Hep/EA 100:0 to 0:100 during 25min, 60mL/min) to give 1.02g of the desired product as a white solid. ¹ H-NMR (500 MHz, CDCl ₃ ) δ = 3.86-3.74 (m, 4H), 2.58 (s, 2H), 1.88-1.78 (m, 2H), 1.75-1.68 (m, 2H) ppm. E9.3.2. (Z)-N'-hydroxy-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetimid amide The title compound was synthesized from Example E9.3.1 (200mg) following the procedure described in Example D1.1, step 4. The product was obtained as a yellow oil (260mg) and used in the next step without further purification. LC-MS (A): t _R = 0.20min; [M+H] ⁺ : 175.33. Example E9.4: (Z)-2-(1-acetyl-4-hydroxypiperidin-4-yl)-N'-hydroxyacetimida mide E9.4.1 (1-Acetyl-4-hydroxy-piperidin-4-yl)-MeCN The product was synthesized from 1-acetyl-4-piperidone (0.87mL) following the procedure described for Example E9.3, step 1. The desired compound was purified by CC (CombiFlash, RediSep 24g SiO ₂ , gradient DCM/MeOH 100:0 to 90:10 over 35min, 35mL/min) and was isolated as a light-yellow oil (324mg). LC-MS (A): t _R = 0.37min; [M+H] ⁺ : 183.32. 9.4.2 (Z)-2-(1-acetyl-4-hydroxypiperidin-4-yl)-N'-hydroxyacetimida mide The title compound was synthesized from Example E9.4.1 (150mg) following the procedure described in Example D1 .1 , step 4. The product was obtained as a white sticky solid (209mg) in a purity of 60% and was used in the next step without further purification. LC-MS (A): t _R = 0.21 min; [M+H] ⁺ : 216.23.

Example E9.5: (Z)-2-(1-acetylazetidin-3-yl)-N'-hydroxyacetimidamide

E9.5. 1 (1-Acetyl-azetidin-3-yl)-MeCN

The product was obtained from azetidine-3-yl-MeCN (HCI salt, 484mg) following the procedure described for Example D2.1 , step 2. It was purified by Prep LC-MS (I) and isolated as a colorless oil (44mg). LC-MS (A): t _R = 0.36min; [M+H] ⁺ : 139.19.

E9.5.2 (Z) -2-( 1 -acetylazetidin-3-yl) -N'-hydroxyacetimidamide

The title compound was synthesized from Example E9.5.1 (34mg) following the procedure described in Example D1.1 , step 4. The product was obtained as a yellow sticky solid (56mg) in a purity of 50% and was used in the next step without further purification. LC-MS (A): t _R = 0.21 min; [M+H] ⁺ : 171.91.

Example E9.6 to Example 9.15 were synthesized starting from the appropriate nitrile derivative and following the procedure described in Example D1.1 , step 4. LC-MS data of Example E9.6 to Example 9.15 are listed in the table below. The LC-MS conditions used were LC-MS (A).

Example F2: 3-[(S)-Hydroxy-(4-isopropyl-phenyl)-(3-piperazin-1-yl-phenyl )-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

F2. 1 4-{3-[(S)-( 1 -tert-Butoxycarbonyl-3-methyl-azetidin-3-yl)-hydroxy-(4-isop ropyl-phenyl)-methyl]-phenyl}-piperazine- 1 -carboxylic acid benzyl ester

A mixture of Example 111.2 (600mg), benzyl piperazine-1 -carboxylate (0.244mL), NaOtBu (170mg), Pd2dba3 (57.9mg), and Bl NAP (118mg) in toluene (5.75mL) was heated 20h at 90°C. The mixture was filtered through a Celite pad, washed with EA, concentrated in vacuo and pu to afford (250mg) of the title product as a brownish solid. LC-MS (A): t _R = 1.21min; [M+H] ⁺ : 614.38. F2.2 3-[(S)-Hydroxy-(4-isopropyl-phenyl)-(3-piperazin-1-yl-phenyl )-methyl]-3-methyl-azetidine-1-carboxylic acid tert- butyl ester A mixture of Example F2.1 (250mg) and Pd/C (25mg) in MeOH (20mL) was stirred at RT under H ₂ atmosphere for 3h. The reaction mixture was filtered through a syringe filter, the filter was washed with MeOH and the filtrate was evaporated and dried under HV to afford 200mg of the title product as a yellow oil. LC-MS (A): t _R = 0.88min; [M+H] ⁺ : 480.32. Example F6.1: (S)-2-(1-Methyl-1H-pyrazol-3-yl)-but-3-yn-2-ol F6.1.12-(1-Methyl-1H-pyrazol-3-yl)-but-3-yn-2-ol A solution of trimethylsilylacetylene (0.62mL) in THF (7mL) was cooled at 0°C. Then, n-BuLi (2.5M in hexanes, 1.93mL) was added dropwise while maintaining the IT below 4°C. The solution was stirred 1h at 0°C and a solution of 3-acetyl- 1-methyl-1H-pyrazole (500mg) in THF (3mL). The resulting pale yellow solution was stirred at 0°C for 1h, allowed to warm to RT, quenched with aq. sat. NH ₄ Cl, diluted with water and extracted with DCM (3x). The combined org. layers were dried (MgSO ₄ ), filtered, concentrated in vacuo and dried under HV. The residue was dissolved in MeOH (10mL) and K ₂ CO ₃ (835mg) was added. The reaction mixture was stirred 30min at RT, filtered through a syringe filter and concentrated in vacuo. The crude was purified by Prep LC-MS (I) to afford 160mg of the title compound as a yellow resin. LC-MS (A): t _R = 0.43min; [M+H] ⁺ : 151.20. F6.1.2 (S)-2-(1-Methyl-1H-pyrazol-3-yl)-but-3-yn-2-ol Example F6.1.1 (160mg) was purified by Prep chiral SFC (XII) to afford 64mg of the pure enantiomer as a yellow oil. Chiral SFC (L): t _R = 1.17min. Example F6.2: (R)-2-(1-Methyl-1H-pyrazol-3-yl)-but-3-yn-2-ol Example F6.1.1 (160mg) was purified by Prep chiral SFC (XII) to afford 63.7mg of the pure enantiomer as a yellow oil. Chiral SFC (L): t _R = 1.67min. Example F6.3: (S)-2-(1,5-Dimethyl-1H-pyrazol-3-yl)-but-3-yn-2-ol F6.3.12-(1,5-Dimethyl-1H-pyrazol-3-yl)-but-3-yn-2-ol The title compound was synthesized starting from 1-(1,5-dimethyl-1H-pyrazol-3-yl)-ethanone (250mg) and following the procedure described in Example F6.1, step 1, then purified by CC (Biotage, SNAP 40g, solvent A: Hep, solvent B: EA; gradient in %B: 0 over 1min, 0 to 20 over 2.2min, 20 over 1.5min, 20 to 100 over 8.8min, 100 over 10min) to afford 172.2mg of the title product as a pale yellow solid. LC-MS (A): t _R = 0.48min; [M+H] ⁺ : 165.07. F6.3.2 (S)-2-(1,5-Dimethyl-1H-pyrazol-3-yl)-but-3-yn-2-ol Example F6.3.1 (167mg) was purified by Prep chiral SFC (XIII) to afford 63.9mg of the pure enantiomer as a white solid. Chiral SFC (M): t _R = 1.55min. Example F6.4: (R)-2-(1,5-Dimethyl-1H-pyrazol-3-yl)-but-3-yn-2-ol Example F6.3.1 (167mg) was purified b ford 70.9mg of the pure enantiomer as a white solid. Chiral SFC (M): t _R = 1.94min. Example F6.5: (R)-2-(6-Methyl-pyrimidin-4-yl)-but-3-yn-2-ol F6.5.12-(6-Methyl-pyrimidin-4-yl)-but-3-yn-2-ol The title compound was synthesized starting from 1-(6-methylpyrimidin-4-yl)ethenone (500mg) and following the procedure described in Example F6.1, step 1, then purified by Prep LC-MS (I) to afford 194.2mg of the title product as a pale brown solid. LC-MS (A): t _R = 0.47min; [M+H] ⁺ : 163.09. F6.5.2 (R)-2-(6-Methyl-pyrimidin-4-yl)-but-3-yn-2-ol Example F6.5.1 was purified by Prep chiral HPLC (XIV) to afford 79.7mg of the pure enantiomer as a white solid. Chiral HPLC (N): t _R = 7.00min. Example F6.6: (S)-2-(6-Methyl-pyrimidin-4-yl)-but-3-yn-2-ol Example F6.5.1 was purified by Prep chiral HPLC (XIV) to afford 83.3mg of the pure enantiomer as a white solid. Chiral HPLC (N): t _R = 8.9min. Example F8: (3-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-(trifluoromethoxy )phenyl)methyl)phenyl)boronic acid To a solution of Example 5 (500mg) in anhydrous THF (10mL) cooled down to -78°C was added dropwise n-BuLi (2.5M in hexanes, 1.02mL) while keeping the IT below -70°C. The resulting mixture was stirred 10min at -78°C and triisopropylborate (0.66mL) was added. The reaction mixture was stirred 1h30 at -78°C and n-BuLi (5mL) was added again followed by triisopropylborate (2mL). The mixture was stirred 30min at -78°C and quenched with water. Aq. HCl (1M) was added until pH 8 was reached, the aq. layer was extracted with EA (3x), the combined org. layers were dried (MgSO ₄ ), filtered off and concentrated in vacuo. The crude material was purified by Prep LC-MS (I) to afford 230mg of the title compound as a white solid. LC-MS (A): t _R = 0.70min; [M+H] ⁺ : 396.24. Example H4: (3-Bromomethyl-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-trifl uoromethoxy-phenyl)-methanol To a solution of Example 28 (150mg) in DCM (2mL) was added triphenylphosphine (208mg) and tetrabromomethane (91µL). The reaction mixture was stirred 3h at RT and purified by CC (Biotage, SNAP 10g, solvent A: DCM; solvent B: 8/2 DCM/MeOH; gradient in %B: 0 to 10 over 0.5CV, 10 over 3CV, 10 to 20 over 0.5CV, 20 over 3CV, 20 to 30 over 0.5CV, 30 over 3CV, 30 to 40 over 0.5CV, 40 over 3CV, 40 to 50 over 1CV, 50 over 6.2CV) to afford 80mg of the title compound as yellow foam. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 444.09. Example I2: 3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-phenol I2.13-[Hydroxy-(3-methoxy-phenyl)-(4-trifluoromethoxy-phenyl )-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester To a solution of Example A4.1 (680mg) in THF (20mL) and cooled at 0°C was added dropwise 3- methoxyphenylmagnesium bromide (1M in THF, 7.57mL). The reaction mixture was stirred 30min at RT, diluted with EA and the org. layer was washed with sat. NaHCO ₃ and brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by CC (Biotage, SNAP 25g, solvent A: Hep; solvent B: EA; gradient in %B 0 over 1CV, 0 to 10 over 0.5CV, 10 over 1.5CV, 10 to 20 V, 20 to 30 over 0.5CV, 30 over 2.1CV, 30 to 40 over 0.5CV, 40 over 2CV, 40 to 50 over 0.5CV) to afford 640mg of the title compound as a white foam. LC-MS (A): t _R = 1.12min; [M+H] ⁺ : 468.06. I2.2 (3-Methoxy-phenyl)-(3-methyl-azetidin-3-yl)-(4-trifluorometh oxy-phenyl)-methanol Example I2.1 (640mg) was treated with HCl in dioxane (4M, 7mL) and the reaction mixture was stirred 1h at RT, concentrated in vacuo to afford 580mg of the title product as a colorless oil. LC-MS (A): t _R = 0.76min; [M+H] ⁺ : 368.11. I2.3 (1,3-Dimethyl-azetidin-3-yl)-(3-methoxy-phenyl)-(4-trifluoro methoxy-phenyl)-methanol The title compound was synthesized starting from I2.2 (580mg) following the procedure described in Example 72, step 3 to afford 530mg of the title crude product as a white foam. LC-MS (A): t _R = 0.80min; [M+H] ⁺ : 382.12. I2.43-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluorometh oxy-phenyl)-methyl]-phenol To a solution of Example I2.3 (400mg) in DCM (5mL) was added dropwise boron tribromide (1M in DCM, 2.1mL). The reaction mixture was stirred 2h at RT, quenched with sat. NaHCO ₃ , extracted with DCM (3x) and the combined org. layers were dried (Na ₂ SO ₄ ), filtered, concentrated in vacuo and dried under HV to afford 320mg of the desired compound as a yellow foam. LC-MS (A): t _R = 0.71min; [M+H] ⁺ : 368.25. Preparation of Examples of Formula (I) Example 1: (1,3-Dimethyl-azetidin-3-yl)-(2-fluoro-phenyl)-(4-trifluorom ethoxy-phenyl)-methanol To a solution of 1-bromo-2-fluorobenzene (89µL) in THF (1mL) was added dropwise isopropylmagnesium chloride lithium chloride complex solution in THF (1.3M, 0.7mL) at RT. The reaction mixture was heated 1h at 60°C and Example B2 (100mg) was added. The reaction mixture was heated at 60°C for 15min, quenched with aq. sat. NH ₄ Cl, diluted with water and extracted 3x with DCM. The combined org. layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by Prep LC-MS (I) to afford 51mg of the title compound as a white solid. LC-MS (A): t _R = 0.72min; [M+H] ⁺ : 370.07. Example 2 to Example 22 were synthesized starting from Example B2 and the appropriate bromo derivative and following the procedure described in Example 1. LC-MS data and purification methods of Example 2 to Example 22 are listed in the table below. The LC-MS conditions used were LC-MS (A), except for Example 7 and Example 12 where the LC-MS (B) has been used. Example N° Name Purification t _R [M+H] ⁺

Example 23: (S)-(3-Chloro-4-fluoro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol

23.1 (3-Chloro-4-fluoro-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-t rifluoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example B2 (49mg) and 4-bromo-2-chloro-1 -fluorobenzene (57mg), following the procedure described in Example 1, except performing the reaction at RT. The crude was purified by Prep LC-MS (III) to afford 61 mg of the desired product. LC-MS (B): t _R = 0.87min; [M+H] ⁺ : 404.14.

23.2 (S)-(3-Chloro-4-fluoro-phenyl)-(1,3-dimethyl-azetidin-3-yl)- (4-trifluoromethoxy-phenyl)-methanol

Example 23.1 (57mg) was purified by Prep chiral HPLC (I) to afford 11.2mg of the title compound as pure enantiomer. Chiral HPLC (A): t _R = 4.59min.

Example 24: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-trifluorome thoxy-phenyl)-methanol

24.1 (1,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-trifluoro methoxy-phenyl)-methanol

The title compound was synthesized starting from Example B2 (98mg) and 4-bromodiphenyl ether (197mg), following the procedure described in Example 1, and was purified by Prep LC-MS (III) to afford 33.7mg of the desired product. LC-MS (A): t _R = 0.90min; [M+H] ⁺ : 444.12.

24.2 (S)-(1,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-tiifl uoromethoxy-phenyl)-methanol

Example 24.1 (31 mg) was purified by Prep chiral HPLC (I) to afford 10.4mg of the title compound as pure enantiomer. Chiral HPLC (A): t _R = 4.55min.

Example 25: (1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-[1 ,2,4]triazol-1-yl)-phenyl]-(4-trifluoromethoxy-phenyl)-metha nol

25. 1 (Z)-N'-(tosyloxy)acetimidamide

To a white suspension of 1-N-hydroxyacetamidine (1g) in THF (35mL) were added TEA (2.1mL) and p-toluenesulfonyl chloride (2.83g). The reaction mixture was stirred overnight at RT, filtered off and the filtrate was concentrated. The residue was dissolved in EA and wash e aq. layers were re-extracted with EA (2x) and the combined org. layers were dried (MgSO ₄ ), filtered off and concentrated in vacuo. Recrystallization from diisopropylether (10mL) gave 2.85g of the title product as pale rose crystals. LC-MS (A): t _R = 0.70min; [M+H] ⁺ : 229.07. 25.21-(3-Bromo-phenyl)-3-methyl-1H-[1,2,4]triazole To solution of 3-bromoaniline (1.82g) and Example 25.1 (2.81g) in THF (18mL) were added dropwise triethyl orthoformate (3.48mL) and ethanesulfonic acid (83.7µL). The solution was heated at 60°C for 20h30, cooled at RT and concentrated. The residue was diluted in DCM and aq. sat. K ₂ CO ₃ was added under stirring. Then, the mixture was diluted in water and extracted with DCM (2x). The combined org. layers were washed with brine, dried (MgSO ₄ ), filtered off and concentrated in vacuo. The crude was purified by CC (Biotage, SNAP 100g, solvent A: Hep; solvent B: EA; gradient in %B: 30 over 1CV, 30 to 50 over 2CV, 50 over 2CV, 50 to 70 over 2CV, 70 for 1CV) to afford 2.4g of the title compound as yellow solid. LC-MS (A): t _R = 0.82min; [M+H] ⁺ : 238.13. 25.3 (1,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-[1,2,4]triazol-1-y l)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol The title compound was synthesized starting from Example 25.2 (57mg) and Example B2 (50mg), following the procedure described in Example A4.1, and was purified by Prep LC-MS (V) to afford 9mg of the desired product as a white powder. LC-MS (A): t _R = 0.73min; [M+H] ⁺ : 433.07. Example 26: (1,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-pyrazol-1-yl)-phen yl]-(4-trifluoromethoxy-phenyl)-methanol 26.11-(3-Bromo-phenyl)-3-methyl-1H-pyrazole A sealed vial was charged with 3-butyn-2-one (150mg), 3-bromophenylhydrazine hydrochloride (477mg), MeOH (2mL) and conc. HCl (0.172mL). The reaction mixture was heated at 120°C under MW irradiation. MeOH was removed in vacuo and the residue was diluted in water and extracted 3x with DCM. The combined org. layers were dried (MgSO ₄ ), filtered off and evaporated in vacuo. The crude was purified by CC (Biotage, SNAP 10g, solvent A: Hep; solvent B: EA; gradient in %B: 0 over 2CV, 0 to 10 over 6CV, 10 over 2CV) to afford 156mg of the title compound as yellow oil. LC- MS (A): t _R = 0.95min; [M+H] ⁺ : 237.16. 26.2 (1,3-Dimethyl-azetidin-3-yl)-[3-(3-methyl-pyrazol-1-yl)-phen yl]-(4-trifluoromethoxy-phenyl)-methanol The title compound was synthesized starting from Example B2 and Example 26.1, following the procedure described in Example A4.1, and was purified by Prep LC-MS (V) and (III) to afford 3mg of the title compound as a white solid. LC- MS (A): t _R = 0.80min; [M+H] ⁺ : 432.22. Example 27: (1,3-Dimethyl-azetidin-3-yl)-[3-(4-methyl-oxazol-2-yl)-pheny l]-(4-trifluoromethoxy-phenyl)-methanol 27.12-(3-Bromo-phenyl)-4-methyl-oxazole A suspension of 3-bromobenzamide (1g) and chloroacetone (0.47mL) in toluene (5mL) was heated at 110°C for 94h. The reaction mixture was cooled at RT, diluted with EA and washed with water, aq. sat. NaHCO ₃ and brine. The aq. layers were re-extracted with EA (2x). The combined org. layers were dried (MgSO ₄ ), filtered off and concentrated in vacuo. The crude was purified by CC (Biotage, SNAP 50g, solvent A: Hep; solvent B: EA; gradient in %B: 5 over 3CV, 5 to 10 over 1CV, 10 over 2CV) to afford 516mg of the title compound as a yellow oil. LC-MS (A): t _R = 0.93min; [M+H] ⁺ : 238.03.

27.2 (1,3-Dimethyl-azetidin-3-yl)-[3-(4-methyl-oxazol-2-yl)-pheny l]-(4-tiifluoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example B2 and Example 27.1 , following the procedure described in Example A4.1 , and was purified by Prep LC-MS (V) to afford 11 mg of the title compound as a white solid. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 433.06.

Example 28: (1 ,3-Dimethyl-azetidin-3-yl)-(3-hydroxymethyl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol

A solution of Example E1.1 (1g) in THF (2.1mL) cooled at -78°C was treated with LIAIF (2.4M in THF, 2.5mL) and stirred 1 h30 at -78°C. The reaction mixture was quenched by adding water and extracted 3x with DCM. The combined org. layers were dried (MgSO4), filtered off, concentrated in vacuo and dried under HV to afford 700mg of the title product as a white foam. LC-MS (A): t _R = 0.68min; [M+H] ⁺ : 382.16.

Example 29: (3,5-Dimethoxy-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-trifl uoromethoxy-phenyl)-methanol

To a solution of 1-bromo-3,5-dimethoxybenzene (53.2mg) in dry THF (0.5mL) and cooled to -78°C was added dropwise n-BuLi (2.5M in hexanes, 88piL), while maintaining the IT below -70°C. The resulting solution was stirred 20min at - 78°C and a solution of Example B2 (50mg) in THF (0.5mL) was added dropwise at -78°C. The resulting yellow solution was stirred 1 h at -78°C, warmed up to RT, quenched with water and extracted with DCM (3x). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo. The crude was purified by Prep LC-MS (V) to afford 27mg of the desired compound as a white solid. LC-MS (A): t _R = 0.82min; [M+H] ⁺ : 412.24.

Example 30: (S)-1-{3-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-triflu oromethoxy-phenyl)-methyl]-phenyl}-pyrrolidin- 3-ol

30.1 (S)-(3-Bromo-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-trifluo romethoxy-phenyl)-methanol

Example 5 (1.55g) was purified by Prep chiral SFC (II) to afford the title compound as pure enantiomer (550mg). Chiral SFC (B): t _R = 1.675min.

30.2 (S)-1-{3-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-triflu oromethoxy-phenyl)-methyl]-phenyl}-pyirolidin-3-ol

A mixture of 30.1 (15mg), (S)-3-pyrrolidinol (5.8piL), RuPhos Pd G3 (1.53mg), NaOtBu (11.4mg) in dioxane (0.3mL) was heated at 100°C for 2 days. The reaction mixture was diluted with MeCN and water, filtered over a PTFE syringe filter and purified by Prep LC-MS (I) and (IV) to afford 4mg of the desired compound. LC-MS (A): t _R = 0.75min; [M+H] ⁺ : 437.30.

Example 31 : 2-((S)-1-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}- pyrrolidin-3-yl)-propan-2-ol

The title compound was synthesized starting from Example 30.1 (15mg) and (S)-2-(3-pyrrolidinyl)-2-propanol hydrochloride salt (12.2mg), following the procedure described in Example 30, step 2, and was purified by Prep LC-MS (V) to afford 8.4mg of the desired compound. LC-MS (A): t _R = 0.81 min; [M+H] ⁺ : 479.36. Example 32: 2-({3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-methyl-amino)- ethanol

The title compound was synthesized starting from Example 5 (20mg) and 2-(methylamino)ethanol (7.6piL), following the procedure described in Example 30, step 2, and was purified by Prep LC-MS (I) to afford 0.6mg of the desired compound as a white solid. LC-MS (A): tR = 0.62min; [M+H] ⁺ : 425.26.

Example 33: 1-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluorometho xy-phenyl)-methyl]-phenyl}-ethanone

A mixture of Example 5 (15mg), tributyl(1 -ethoxyvinyl)tin (133.4piL) and PdChfPPha)? (3.7mg) in DMF (1mL) was heated 15min at 160°C under MW irradiation. The mixture was cooled at RT and purified by Prep LC-MS (I) to afford 2.2mg of the title product. LC-MS (A): tR = 0.76min; [M+H] ⁺ : 394.25.

Example 34: (1 ,3-Dimethyl-azetidin-3-yl)-(3-imidazol-1-yl-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol

A mixture of Example 5 (30mg), imidazole (9.6mg), CS2CO3 (45.4mg), Pd2(dba)s (6.7mg) and 5-(di-tert-buty Iphosphino)- T,3',5'-triphenyl-TH-[1 ,4']bipyrazole (7.3mg) in dioxane (1.5mL) was heated overnight at 115°C. Pd2(dba)3 (6.7mg), 5- (di-tert-butylphosphino)-T,3',5'-triphenyl-TH-[1 ,4']bipyrazole (7.3mg) and imidazole (9.6mg) were added again and the reaction was heated for further 20h, cooled to RT and purified by Prep LC-MS (IV) to afford 0.4mg of the title product as a white solid. LC-MS (A): tR = 0.57min; [M+H] ⁺ : 417.84.

Example 35: (1 ,3-Dimethyl-azetidin-3-yl)-(3-[1 ,2,3]triazol-2-yl-phenyl)-(4-trifluoromethoxy-phenyl)-methan ol

The title compound was synthesized starting from Example 5 (25mg) and 2H-1,2,3-triazole (3.4|dL), following the procedure described in Example 34, and by adding a third time the catalyst, ligand and the triazole, then let stir for 20h. Purification by Prep LC-MS (V) to afford 1.8mg of the desired compound as a white solid. LC-MS (A): t _R = 0.79min; [M+H] ⁺ : 419.07.

Example 36: (1 ,3-Dimethyl-azetidin-3-yl)-(3-pyrazol-1-yl-phenyl)-(4-triflu oromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example 5 (25mg) and pyrazole (8.1 mg), following the procedure described in Example 35, and purified by Prep LC-MS (V) and (III) to afford 0.4mg of the desired compound as a white solid. LC-MS (A): t _R = 0.78min; [M+H] ⁺ : 417.86.

Example 37: (3'-Chloro-biphenyl-3-yl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol

A mixture of Example 5 (50.6mg), 3-chlorophenylboronic acid (36.7mg), Na2CO3 (32.4mg) and Pd(PPhs)4 (3mg) in DME (1 mL) and water (0.5mL) was refluxed for 3h. The reaction mixture was cooled at RT and DCM was added. The org. layer was washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by Prep LC-MS (III) to afford 13mg of the desired product. LC-MS (A): t _R = 1.01 min; [M+H] ⁺ : 462.09.

Example 38: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-furan-2-yl)-phenyl]- (4-trifluoromethoxy-phenyl)-methanol

38.1 (1,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-furan-2-yl)-phenyl ]-(4-trifluoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example 5 (50.6mg) and 5-methyl-2-furanboronic acid (29.6mg), following the procedure described in Example 37, and purified by Prep LC-MS (III) to afford 17.7mg of the desired compound. LC-MS (A): t _R = 0.95min; [M+H] ⁺ : 432.16. 38.2 (S)-(1,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-furan-2-yl)-ph enyl]-(4-trifluoromethoxy-phenyl)-methanol

Example 38.1 (15mg) was purified by Prep chiral HPLC (I) to afford 4.4mg of the title compound as pure enantiomer.

Chiral HPLC (A): t _R = 5.00min.

Example 39: (1 ,3-Dimethyl-azetidin-3-yl)-[3-((E)-3-methoxy-propenyl)-pheny l]-(4-trifluoromethoxy-phenyl)-methanol

A mixture of Example 5 (25mg), (E)-2-(3-methoxy-1-propen-1-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (26|dL), K3PO4 (37mg) and Pd(dppf)Cl2 CH2CI2 (9.5mg) in dioxane (0.4mL) and water (0.1 mL) was stirred overnight at 80°C, then purified by Prep LC-MS (III) to afford 1 mg of the desired compound. LC-MS (A): t _R = 0.84min; [M+H] ⁺ : 422.27.

Example 40: 4-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenyl}-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 5 (25mg) and N-Boc-1 ,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (35.9mg), following the procedure described in Example 39, and purified by Prep LC-MS (III) to afford 8.9mg of the desired compound. LC-MS (A): t _R = 0.95min; [M+H] ⁺ : 533.3.

Example 41 : [3-(2,5-D ihydro-furan-3-y l)-phenyl]- (1 , 3-d i methy l-azetid i n-3-y l)-(4-trif I uoromethoxy-pheny l)-methanol

The title compound was synthesized starting from Example 5 (25mg) and 2-(2,5-dihydrofuran-3-y l)-4, 4, 5,5-tetramethy I- 1 ,3,2-dioxaborolane (23.4mg), following the procedure described in Example 39, and purified by Prep LC-MS (III) to afford 10mg of the desired compound. LC-MS (A): t _R = 0.82min; [M+H] ⁺ : 420.23.

Example 42: 4-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluorometho xy-phenyl)-methyl]-phenyl}-piperidine-1- carboxylic acid tert-butyl ester

A mixture of Example 40 (3mg) and Pd/C (0.4mg) in EtOH (2mL) was stirred 1 h under H2 atmosphere. The mixture was filtered off, the filtrate was concentrated in vacuo, and purified by Prep LC-MS (III) to afford 1.9mg of the desired compound as a white solid. LC-MS (A): t _R = 0.94min; [M+H] ⁺ : 535.32.

Example 43: (1 ,3-Dimethyl-azetidin-3-yl)-[3-(tetrahydro-furan-3-yl)-phenyl ]-(4-trifluoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example 41 (3mg) following the procedure described in Example 42, and purified by Prep LC-MS (III) to afford 0.2mg of the desired compound as a white solid. LC-MS (A): t _R = 0.81 min; [M+H] ⁺ : 422.25.

Example 44: (1S)-3-(3-((1 ,3-dimethylazetidin-3-yl)(hydroxy)(4-(trifluoromethoxy)pheny l)methyl)phenyl)-1-phenylprop- 2-yn-1-ol

A mixture of Example 5 (40mg), (R)-1-phenyl-2-propyn-1-ol (18.2mg), K3PO4 (37mg), PPF13 (30.3mg) and Pd(OAc)2 (1.1 mg) in DMSO (0.84mL) and toluene (0.12mL) was stirred overnight at 80°C, then purified (2x) by Prep LC-MS (V) to afford 7.5mg of the desired compound as a light brown solid. LC-MS (A): t _R = 0.86min; [M+H] ⁺ : 482.01.

Example 45: 4-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluorometho xy-phenyl)-methyl]-phenyl}-but-3-yn-1-ol

The title compound was synthesized starting from Example 5 (40mg) and 3-butyn-1-ol (9.7mg), following the procedure described in Example 44, and purified by Prep LC-MS (IV) to afford 20.4mg of the desired compound as a light brown solid. LC-MS (A): t _R = 0.76min; [M+H] ⁺ : 420.24. Example 46: (1 R)-3-(3-((1 ,3-dimethylazetidin-3-yl)(hydroxy)(4-(trifluoromethoxy)pheny l)methyl)phenyl)-1- phenylpropan-1-ol

A mixture of Example 44 (5.7mg) and Actimet™ M (0.70mg, Raney-Nickel) in MeOH (2mL) was stirred 5h under H2 atmosphere. The mixture was filtered off, the filtrate was concentrated in vacuo and purified by Prep LC-MS (III) to afford 3.2mg of the desired compound as a white powder. LC-MS (A): tR = 0.86min; [M+H] ⁺ : 486.31 .

Example 47: 4-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluorometho xy-phenyl)-methyl]-phenyl}-butan-1-ol

The title compound was synthesized starting from Example 45 (5mg) following the procedure described in Example 46, and purified by Prep LC-MS (V) to afford 2.5mg of the desired compound as a white solid. LC-MS (A): tR = 0.79min; [M+H] ⁺ : 424.25.

Example 48: (1 ,3-Dimethyl-azetidin-3-yl)-[3-(2-phenyl-oxazol-5-yl)-phenyl] -(4-trifluoromethoxy-phenyl)-methanol

A mixture of Example F8 (15mg), 5-bromo-2-phenyloxazole (9.9mg), K2CO3 (23.3mg), PdCl2(PPh3)2 (1.1 mg) in 1 :1 MeCN/water (0.30mL) was heated overnight at 90°C, cooled at RT and purified by Prep LC-MS (II) to afford 8.7mg of the title compound as a white solid. LC-MS (A): tR = 0.91 min; [M+H] ⁺ : 495.29.

Example 49 and Example 50 were synthesized starting from Example F8 and the appropriate bromo derivative and following the procedure described in Example 48. LC-MS data and purification methods of Example 49 and Example 50 are listed in the table below. The LC-MS conditions used were LC-MS (A).

Example 51 : Diethyl-carbamic acid 4-[(1 ,3-dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-benzyl ester

51.1 (1,3-Dimethyl-azetidin-3-yl)-(4-hydroxymethyl-phenyl)-(4-tri fluoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example E1.2 (1.2g) following the procedure described in Example 28, to afford 900mg of a yellow oil. LC-MS (A): t _R = 0.70min; [M+H] ⁺ : 382.22.

51.2 Diethyl-carbamic acid 4-[(1,3-dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy- phenyl)-methyl]-benzyl ester

To a solution of Example 51.1 (20mg) in THF (1 mL) was added NaH (2.52mg). The mixture was stirred 10min at RT and diethylcarbamoyl chloride (8.53mg) was added. The reaction mixture was stirred 1 h at RT, diluted in water and MeCN, filtered over a PTFE syringe filter and purified by Prep LC-MS (II) to afford 8.8mg of the title compound. LC-MS (A): t _R = 0.87min; [M+H] ⁺ : 481.10.

Example 52: (1 ,3-Dimethyl-azetidin-3-yl)-(4-{3-[2-(3-methyl-pyrazol-1-yl)- ethyl]-[1 ,2,4]oxadiazol-5-yl}-phenyl)-(4- trifluoromethoxy-phenyl)-methanol

A mixture of Example E3.2 (12mg), HOBt (4.3mg), EDC' HCI (8.3mg) and DIPEA (10piL) in dioxane (3mL) was stirred 10min at RT and N'-hydroxy-3-(3-methyl-1 H-pyrazol-1 -yl)propanimidamide (4.84mg) was added. The reaction mixture was stirred 24h at RT, heated at 100°C for 20h, concentrated in vacuo and purified by Prep LC-MS (VII) to afford 1 ,3mg of the title compound as a white solid. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 528.22.

Example 53: (1 ,3-Dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-[3-(3 -trifluoromethyl-[1 ,2,4]oxadiazol-5-yl)- phenyl]-methanol

A mixture of Example E3.3 (30mg), 2,2,2-trifluoro-N'-hydroxyethanimidamide (13.6mg), HOBt (12.3mg), EDC'HCI (17.5mg) and DIPEA (15.6|dL) in dioxane (1 mL) was stirred 20h at RT. Pyridine (12.2piL) was then added and the reaction mixture was heated overnight at 100°C, filtered and purified by Prep LC-MS (III) to afford 8.7mg of the title compound. LC-MS (A): t _R = 0.95min; [M+H] ⁺ : 488.15.

Example 54: (1 , 3-D i methyl -azetidi n-3-y l)-[3-(3-phenethy l-[1 , 2, 4] oxad i azol -5-y l)-pheny l]-(4-trifl uoromethoxy-pheny I)- methanol

The title compound was synthesized starting from Example E3.3 (30mg) and N'-hydroxy-3-phenylpropanimidamide (17.4mg), following the procedure described in Example 53, and was purified by Prep LC-MS (VIII) to afford 6.6mg. LC- MS (A): t _R = 0.99min; [M+H] ⁺ : 524.28.

Example 55: (1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-[1,3,4]oxadiazol-2-y l)-phenyl]-(4-trifluoromethoxy-phenyl)- methanol

A mixture of Example E3.3 (40mg), HOBt (13mg), EDC' HCI (27.6mg) and DIPEA (33piL) in dioxane (3mL) was stirred 10min at RT. Acethydrazide (7.9mg) was added and the reaction mixture was stirred 24h at RT, filtered and purified by Prep LC-MS (IV) to afford 12mg of intermediate. It was dissolved in THF (1 mL) and methyl N- (triethylammoniosulfonyl)carbamate (Burgess reagent, 35.3mg) was added. The reaction mixture was heated 5min at 110°C under MW irradiation and purified by Prep LC-MS (III) to afford 1.4mg of the title compound as a white solid. LC- MS (A): t _R = 0.74min; [M+H] ⁺ : 433.90.

Example 56: 5-{3-[(1 , 3-D i methyl-azetid i n-3-y I )-hyd roxy-(4-trifl uoromethoxy-pheny l)-methyl]-phenyl}-[1 ,2,4]oxadiazole- 3-carboxylic acid benzyl-methyl-amide

56.1 5-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluorometho xy-phenyl)-methyl]-phenyl}-[1,2,4]oxadiazole-3- carboxylic acid ethyl ester

The title compound was synthesized starting from Example E3.3 (300mg) and ethyl 2-amino(hydroxyimino)acetate (108mg), following the procedure described in Example 53, except heating at 80°C instead of 100°C, and was purified by Prep LC-MS (III) to afford 98mg of a light yellow oil. LC-MS (A): t _R = 0.85min; [M+H] ⁺ : 492.16. 56.2 5-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-tiifluorometho xy-phenyl)-methyl]-phenyl}-[1,2,4]oxadiazole-3- carboxylic acid

A solution of Example 56.1 (98mg) in THF (2.5mL) was treated with a solution of LiOH H2O (33.5mg) in water (0.5mL). The reaction mixture was stirred 2h at RT, acidified to pH 4 by addition of aq. citric acid and lyophilised to afford a white solid. LC-MS (A): t _R = 0.70min; [M+H] ⁺ : 464.13.

56.3 5-{3-[(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-tiifluorometho xy-phenyl)-methyl]-phenyl}-[1,2,4]oxadiazole-3- carboxylic acid benzyl-methyl-amide

A mixture of Example 56.2 (10mg), N-benzylmethylamine (4.85mg), HOBt (3.24mg), EDO HCI (4.6mg) and DIPEA (4.11 piL) in DCM (1mL) was stirred overnight at RT, concentrated in vacuo, dissolved in MeCN and water, filtered and purified by Prep LC-MS (III) to afford 0.6mg of the title compound. LC-MS (A): t _R = 0.92min; [M+H] ⁺ : 567.29.

Example 57: (1 ,3-Dimethyl-azetidin-3-yl)-(3-imidazol-1-ylmethyl-phenyl)-(4 -trifluoromethoxy-phenyl)-methanol

To a solution of imidazole (6.13mg) in DMF (0.25mL) was added NaH (60% in mineral oil, 2.2mg). The mixture was stirred 10min at RT and a solution of Example H4 (8mg) in DMF (0.25mL) was added. The reaction mixture was stirred 20h at RT, dissolved in MeCN and water, filtered and purified by Prep LC-MS (I) to afford 1.8mg of the title compound. LC-MS (A): t _R = 0.58min; [M+H] ⁺ : 432.22.

Example 58 to Example 60 were synthesized starting from Example H4 and the appropriate amine or alcohol derivative and following the procedure described in Example 57. LC-MS data and purification methods of Example 57 to Example 60 are listed in the table below. The LC-MS conditions used were LC-MS (A).

Example 61 : 5-{3-[(S)-(1 , 3-D I methyl -azetidi n-3-y l)-hy d roxy- (4-trifl uoromethoxy-phenyl)-methyl]-pheny I }-

[1 ,2,4]oxadiazole-3-carboxylic acid (pyrazin-2-ylmethyl)-amide

61.1 3-[(S)-Hydroxy-(3-{3-[(pyrazin-2-ylmethyl)-carbamoyl]-[1,2,4 ]oxadiazol-5-yl}-phenyl)-(4-trifluoromethoxy-phenyl)- methyl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester A mixture of Example E6 (25mg), 2-(aminomethyl)pyrazine (5.9mg), T3P (50% in DCM, 200mg), DIPEA (15.4piL) in MeCN (1mL) was stirred overnight at RT, concentrated in vacuo, dissolved in MeCN and water, and purified by Prep LC-MS (IV) to afford 29.1 mg of the desired product. LC-MS (B): t _R = 1.10min; [M+H] ⁺ : 641.05.

61.2 5-{3-[(S)-Hydroxy-(3-methyl-azetidin-3-yl)-(4-trifluorometho xy-phenyl)-methyl]-phenyl}-[1,2,4]oxadiazole-3- carboxylic acid (pyrazin-2-ylmethyl)-amide

Example 61.1 (28.8mg) was treated with HCI in dioxane (4M, 0.34mL) and the reaction mixture was stirred 2h at RT, concentrated in vacuo and purified by Prep LC-MS (VII) to afford 24mg of the desired product. LC-MS (A): t _R = 0.76min; [M+H] ⁺ : 541.11.

61.3 5-{3-[(S)-( 1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-tiifluoromethoxy-phen yl)-methyl]-phenyl}-[ 1, 2,4]oxadiazole-3- carboxylic acid (pyrazin-2-ylmethyl)-amide

The title compound was synthesized starting from Example 61.2 (24mg) following the procedure described in Example B2, step 2, with direct purification of the reaction mixture by Prep LC-MS (III) to afford 2mg of the title product. LC-MS (A): t _R = 0.78min; [M+H] ⁺ : 555.32.

Example 62 to Example 71 were synthesized starting from Example E6 and the appropriate amine and following the 3-steps procedure described in Example 61. LC-MS conditions and data of Example 62 to Example 71 are listed in the table below. The purification method was Prep LC-MS (III).

Example 72: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-phenoxymethyl-[1,2,4]oxadia zol-5-yl)-phenyl]-(4-trifluoromethoxy- phenyl)-methanol

72. 7 3-[(S)-Hydroxy-[3-(3-phenoxymethyl-[1,2,4]oxadiazol-5-yl)-ph enyl]-(4-trifluoromethoxy-phenyl)-methyl]-3-methyl- azetidine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example E3.4 (20mg) and N'-hydroxy-2-phenoxyethanimidamide (9.7mg), following the procedure described in Example 52, without doing any purification. The reaction was directly used in the next step. LC-MS (A): t _R = 1.18min; [M+H] ⁺ : 612.30.

72.2 (S)-(3-Methyl-azetidin-3-yl)-[3-(3-phenoxymethyl-[1,2,4]oxad iazol-5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)- methanol

Example 72.1 (25.7mg) was treated with HCI in dioxane (4M, 0.11 mL) and the reaction mixture was stirred 1 h at RT, concentrated in vacuo and purified by Prep LC-MS (III) to afford 4.2mg of the desired product. LC-MS (A): t _R = 0.91 min; [M+H] ⁺ : 512.28.

72.3 (S)-(1,3-Dimethyl-azetidin-3-yl)-[3-(3-phenoxymethyl-[1,2,4] oxadiazol-5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)- methanol To a solution of Example 72.2 (4.2mg) in DCM (1mL) placed at 0°C were added TEA (12.5piL), Formaldehyde (37% w/w in water, 23.5piL), followed by NaBH(OAc)3 (33.4mg). The reaction mixture was stirred at RT for 15min of the reaction, concentrated in vacuo and purified by Prep LC-MS (III) to give 1.2mg of the title product. LC-MS (A): t _R = 0.93min; [M+H] ⁺ : 526.31.

Example 73: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-oxazol-2-yl)-phenyl] -(4-trifluoromethoxy-phenyl)-methanol

73.1 3-[(S)-Hydroxy-(3-prop-2-ynylcarbamoyl-phenyl)-(4-trifluorom ethoxy-phenyl)-methyl]-3-methyl-azetidine-1- carboxylic acid tert-butyl ester

A mixture of Example E3.4 (50mg), propargylamine (7.5piL), HOBt (16.8mg), EDO HCI (21.9mg) and DIPEA (39.1 piL) in DCM (5mL) was stirred 20h at RT. The reaction mixture was then concentrated in vacuo, diluted in water and extracted with DCM (3x). The org. layers were dried (Na2SO4), filtered, concentrated in vacuo and dried under HV to afford 50mg of the desired product as a yellow oil. LC-MS (A): t _R = 1.03min; [M+H] ⁺ : 519.25.

73.2 3-[(S)-Hydroxy-[3-(5-methyl-oxazol-2-yl)-phenyl]-(4-trifluor omethoxy-phenyl)-methyl]-3-methyl-azetidine-1- carboxylic acid tert-butyl ester

To a solution of Example 73.1 (50mg) in MeCN (2.5mL) was added gold(lll) chloride (1.5mg). The reaction mixture was heated 3h at 45°C, concentrated in vacuo, diluted in water and extracted with DCM (3x). The org. layers were dried (Na2SO4), filtered, concentrated in vacuo and dried under HV to afford 54mg of the desired product as an oil. LC-MS (A): t _R = 1.12min; [M+H] ⁺ : 519.25.

73.3. (S)-(3-Methyl-azetidin-3-yl)-[3-(5-methyl-oxazol-2-yl)-pheny l]-(4-trifluoromethoxy-phenyl)-methanol

A solution of Example 73.2 (54mg) in EA (1 mL) was treated with HCI in dioxane (4M, 0.25mL). The reaction mixture was stirred 2h at RT, concentrated in vacuo, triturated in diethylether and concentrated again to dryness to afford 35mg of the desired product. LC-MS (A): t _R = 0.82min; [M+H] ⁺ : 419.24.

73.4 (S)-(1,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-oxazol-2-yl)-p henyl]-(4-trifluoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example 73.3 (28.8mg) following the procedure described in Example B2, step 2, and was purified by Prep LC-MS (III) to afford 11 mg of the desired product as a white solid. LC-MS (A): t _R = 0.84min; [M+H] ⁺ : 433.12.

Example 74: (1 ,3-Dimethyl-azetidin-3-yl)-[3-(tetrahydro-pyran-4-yloxy)-phe nyl]-(4-trifluoromethoxy-phenyl)-methanol To a solution of Example I2 (18.4mg) and tetrahydro-4-pyranol (8.8piL) in toluene (0.5mL) was added (tributylphosphoranylidene)acetonitrile (1 M in toluene, 0.1 mL). The reaction mixture was heated 1 h at 100°C, concentrated in vacuo and purified by Prep LC-MS (IV) and (III) to afford 2.7mg of the desired product. LC-MS (B): t _R = 0.83min; [M+H] ⁺ : 452.23.

Example 75: 4-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-pheny l)-methyl]-phenoxy}-2-methyl-butan- 2-ol The title compound was synthesized starting from I2 (18.4mg) and 3-methyl-1 ,3-butanediol (9.9 L), following the procedure described in Example 74 and purified by Prep LC-MS (IV) and (III) to afford 0.2mg of the desired product. LC-MS (B): t _R = 0.81 min; [M+H] ⁺ : 454.24.

Example 76: (S)-(3-Chloro-phenyl)-(3-methyl-1-oxetan-3-yl-azetidin-3-yl) -(4-trifluoromethoxy-phenyl)-methanol

76.1 (3-Chloro-phenyl)-(3-methyl-azetidin-3-yl)-(4-tiifluorometho xy-phenyl)-methanol

To a solution of Example A7.1.1 (646mg) in EA (5mL) was added HCI in dioxane (4M, 7mL). The reaction mixture was stirred 2h at RT, concentrated in vacuo and the residue was diluted in diethylether, concentrated again in vacuo and dried under HV to afford 410mg of the title product as a yellow oil. LC-MS (A): t _R = 0.80min; [M+H] ⁺ : 372.21.

76.2. (3-Chloro-phenyl)-(3-methyl-1-oxetan-3-yl-azetidin-3-yl)-(4- trifluoromethoxy-phenyl)-methanol

To a solution of Example 76.1 (50mg) in DCM (0.39mL) was added TEA (34.1 piL), oxetan-3-one (9.1 mg) and 5min later NaBH(OAc)3 (115mg). The reaction mixture was stirred 1 h at RT, quenched with sat. NaHCOa and extracted with DCM. The org. layers were dried (NaaSO^, filtered, concentrated in vacuo and purified by Prep LC-MS (III) to afford 29mg of a white solid. LC-MS (A): t _R = 0.80min; [M+H] ⁺ : 428.15.

76.3 (S)-(3-Chloro-phenyl)-(3-methyl-1-oxetan-3-yl-azetidin-3-yl) -(4-trifluoromethoxy-phenyl)-methanol

Example 76.2 (29mg) was purified by Prep chiral SFC (VI) to afford 7.7mg of the title compound as pure enantiomer.

Chiral SFC (F): t _R = 6.423min.

Example 77 : (S)- (3-Chloro-pheny I )-(1 -ethy l-3-methy l-azeti d i n-3-y I )-(4-trifl uoromethoxy-pheny l)-methanol

The title compound was synthesized starting from Example A7.1 (50mg) and acetaldehyde (545.6piL), following the procedure described in Example C3.1 , step 3, and purified by Prep LC-MS (II) to afford 30mg of the desired product as an orange resin. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 400.17.

Example 78: (S)-(3-Chloro-phenyl)-(1-isopropyl-3-methyl-azetidin-3-yl)-( 4-trifluoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example A7.1 (50mg) and Acetone (59.3piL), following the procedure described in Example C3.1 , step 3, and purified by Prep LC-MS (II) to afford 18mg of the desired product as a colorless resin. LC-MS (A): t _R = 0.85min; [M+H] ⁺ : 414.22.

Example 79: (S)-(3-Chloro-phenyl)-(1-cyclopropyl-3-methyl-azetidin-3-yl) -(4-trifluoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example A7.1 (50mg) and (l-ethoxycyclopropoxy)trimethylsilane (0.273mL), following the procedure described in Example C3.1 , step 3, except using EtOH as solvent, heating the mixture 2h30 at 50°C, then added 2eq of AcOH and heating 4h30 at 75°C, and purified by Prep LC-MS (V) to afford 9mg of the desired product as a white solid. LC-MS (A): t _R = 0.85min; [M+H] ⁺ : 412.21.

Example 80: (S)-(3-Chloro-phenyl)-[1-(2-fluoro-ethyl)-3-methyl-azetidin- 3-yl]-(4-trifluoromethoxy-phenyl)-methanol

To a solution of Example A7.1 (50mg) in MeOH (1 mL) were added TEA (41 ,2piL) and 1-iodo-2-fluoroethane (51.8piL). The reaction mixture was refluxed overnight at RT, diluted in water, filtered through a PTFE syringe filter and purified by Prep LC-MS (V) to afford 20mg of a yellowish resin. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 417.92.

Example 81 : (S)-(3-Chloro-phenyl)-[1-(2,2-difluoro-ethyl)-3-methyl-azeti din-3-yl]-(4-trifluoromethoxy-phenyl)-methanol To a suspension of Example A7.1 (50mg) in THF (1mL) was added DIPEA (46piL). The mixture was cooled at 0°C and 2,2-difluoroethyl trifluoromethanesulfonate (27.4piL) was added. The reaction mixture was allowed to warm slowly at RT over 30min, diluted in water, filtered through a PTFE syringe filter and purified by Prep LC-MS (V) to afford 15mg of the title compound as a colorless resin. LC-MS (A): t _R = 0.84min; [M+H] ⁺ : 436.13.

Example 82: 2-{3-[(S)-(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phen yl)-methyl]-3-methyl-azetidin-1-yl}-ethanol

82.1 (S)-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-3-methyl-a zetidin-3-yl}-(3-chloro-phenyl)-(4-trifluoromethoxy- phenyl)-methanol

A mixture of Example A7.1 (100mg), (2-bromoethoxy)-tert-butyldimethylsilane (87.4piL) and Cs2CO3 (175mg) in DMF (2mL) was heated 30min at 70°C. The reaction mixture was diluted in water, filtered through a PTFE syringe filter and purified by Prep LC-MS (II) to afford 34mg of the title compound as a white solid. LC-MS (A): t _R = 1.03min; [M+H] ⁺ : 530.05.

82.2 2-{3-[(S)-(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phen yl)-methyl]-3-methyl-azetidin-1-yl}-ethanol

To a solution of Example 82.1 (34mg) in THF (2mL), cooled at 0°C, was added TBAF (1 M in THF, 0.192mL). The reaction mixture was stirred 1 h30 at RT, diluted with DCM, washed with sat. NaHCOa and water, and the org. layer was dried (Na2SO4), filtered, concentrated in vacuo, dissolved in MeOH and purified by Prep LC-MS (VIII). The white solid obtained (26mg) was dissolved in EA and washed with water (3x), dried (MgSO4), filtered, concentrated in vacuo and dried under HV to afford 11 mg of the desired product as a colorless resin. LC-MS (A): t _R = 0.79min; [M+H] ⁺ : 416.19. Example 83: (1 , 3-D I methy l-azeti di n-3-y l)-bis-(4-phenoxy-pheny l)-methanol

To a solution of Example C3.2 (50mg) in THF (1 mL) and cooled at -10°C was added dropwise 4- phenoxyphenylmagnesium bromide (0.5M in THF, 0.201 mL). The reaction mixture was stirred 17h at -10°C, quenched with water and extracted with DCM (2x). The combined org. layers were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by Prep LC-MS (V) to afford 19mg of a colorless resin. LC-MS (A): t _R = 0.91 min; [M+H] ⁺ : 452.21.

Example 84: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-{3-[2-(3-methyl-pyrazol-1-yl)- ethyl]-[1 ,2,4]oxadiazol-5-yl}-phenyl)-(4- trifluoromethyl-phenyl)-methanol

84. 1 3-Methyl-3-(4-trifluoromethyl-benzoyl)-azetidine-1-carboxyli c acid tert-butyl ester

The title compound was synthesized starting from Example A2 (5g) and 4-bromobenzotrifluoride (3.02mL), following the procedure described in Example A4.1, with extraction with DCM instead of EA and washing the org. layer with sat. NH4CI and sat. NaHCOa to afford 6.4g of the crude product as a yellow oil. LC-MS (B): t _R = 1.17min; [M+H] ⁺ : 344.22.

84.2. 3-[(3-Formyl-phenyl)-hydroxy-(4-trifluoromethyl-phenyl)-meth yl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 84.1 (2.16g) and 3-(benzaldehyde diethylacetal)magnesium bromide solution (1 M in THF, 14.5mL), following the procedure described in Example E1.1 , and was purified by CC (Biotage, SNAP 50g, solvent A: Hep; solvent B: EA; gradient in %B 0 over 3CV, 0 to 40 over 12CV, 40 over 2.1 CV) and by Prep LC-MS (XIII) to afford 600mg of the title product as a white solid. LC-MS (B): t _R = 1.15min; [M+H] ⁺ : 449.99.

84.33-[(S)-(3-Formyl-phenyl)-hydroxy-(4-trifluoromethyl-p henyl)-methyl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

Example 84.2 (600mg) was purified by Prep chiral SFC (IV) to afford 250mg of the title compound as pure enantiomer.

Chiral SFC (D): t _R = 1.66min.

84.4. 3-[ ( S) -( 3-Carboxy-phenyl) -hydroxy -( 4-trifluoromethyl-phenyl) -methyl]-3-methyl-azetidine- 1 -carboxylic acid tertbutyl ester

The title compound was synthesized starting from Example 84.3 (250mg) following the procedure described in Example E3.4, step 3, to afford 230mg of an off-white solid. LC-MS (A): t _R = 0.99min; [M+H] ⁺ : 465.95.

84.5. 3-[(S)-Hydroxy-(3-{3-[2-(3-methyl-pyrazol-1-yl)-ethyl]-[1,2, 4]oxadiazol-5-yl}-phenyl)-(4-trifluoromethyl-phenyl)- methyl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 84.4 (9.3mg) and N'-hydroxy-3-(3-methyl-1 H-pyrazol-1- yl)propanimidamide (3.4mg), following the procedure described in Example 52, and purified by Prep LC-MS (XIV) to afford 2.4mg of the title product. LC-MS (B): t _R = 1.19min; [M+H] ⁺ : 598.29.

84.6. (S)-(3-Methyl-azetidin-3-yl)-(3-{3-[2-(3-methyl-pyrazol-1-yl )-ethyl]-[1,2,4]oxadiazol-5-yl}-phenyl)-(4- trifluoromethyl-phenyl)-methanol

Example 84.5 (2.4mg) was treated with HCI in dioxane (4M, 0.2mL) and the reaction mixture was stirred 1 h at RT, then concentrated in vacuo. LC-MS (B): t _R = 0.81 min; [M+H] ⁺ : 497.98.

84.7 3-Dimethyl-azetidin-3-yl) -( 3-{3-[2-( 3-methyl-pyrazol- 1 -yl) -ethyl]-[ 1,2, 4]oxadiazol-5-yl}-phenyl) -( 4- trifluoromethyl-phenyl)-methanol

The title compound was synthesized starting from Example 84.6 (2.5mg) following the procedure described in Example 72, step 3, and purified by Prep LC-MS (III) to afford 2.2mg of the title product. LC-MS (B): t _R = 0.82min; [M+H] ⁺ : 512.25. Example 85: (S)-[3-(3-Cyclobutoxymethyl-[1 , 2, 4]oxad i azol-5-y l)-phenyl]- (1 , 3-d i methy l-azetid i n-3-y l)-(4-ethy I -pheny I)- methanol

85. 1 3-(4-Ethyl-benzoyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example A2 (5g) and 1-bromo-4-ethyl benzene (3.24mL), following the procedure described in Example A4.1 , with washing the org. layer with sat. NH4CI and sat. NaHCOa to afford 6.2g of the crude product as a yellow oil. LC-MS (B): t _R = 1 .18min; [M+H] ⁺ : 304.0.

85.23-[(4-Ethyl-phenyl)-(3-formyl-phenyl)-hydroxy-methyl] -3-methyl-azetidine-1-carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 85.1 (2g) and 3-(benzaldehyde diethylacetal) (1 M in THF, 15.2mL), following the procedure described in Example E1.1 , and purified by CC (Biotage, SNAP 50g, solvent A: Hep; solvent B: EA; gradient in %B 0 over 3CV, 0 to 40 over 12CV, 40 over 1 ,6CV) and by Prep LC-MS (XV) to afford 580mg of the title product as a white solid. LC-MS (B): t _R = 1.18min; [M+H] ⁺ : 410.34. 85.3 3-[(S)-(4-Ethyl-phenyl)-(3-formyl-phenyl)-hydroxy-methyl]-3- methyl-azetidine-1-carboxylic acid tert-butyl ester Example 85.2 (580mg) was purified by Prep chiral SFC (IX) to afford 260mg of the title compound as pure enantiomer. Chiral SFC (I): t _R = 2.06min.

85.4 3-[(S)-(3-Carboxy-phenyl)-(4-ethyl-phenyl)-hydroxy-methyl]-3 -methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized starting from Example 85.3 (228mg) following the procedure described in Example E3.4, step 3, to afford 210mg of the title compound as a white foam. LC-MS (A): t _R = 1. OOmin; [M+H] ⁺ : 426.31.

85.5 3-[(S)-[3-(3-Cyclobutoxymethyl-[1,2,4]oxadiazol-5-yl)-phenyl ]-(4-ethyl-phenyl)-hydroxy-methyl]-3-methyl- azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 85.4 (8.5mg) and 2-cyclobutoxy-N'-hydroxyethanimidamide (2.9mg), following the procedure described in Example 52, and purified by Prep LC-MS (XVI) to afford 2.7mg of the title product. LC-MS (B): t _R = 1.36min; [M+H] ⁺ : 534.34.

85.6. (S)-[3-(3-Cyclobutoxymethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-( 4-ethyl-phenyl)-(3-methyl-azetidin-3-yl)-methanol

Example 85.5 (2.7mg) was treated with HCI in dioxane (4M, 0.2mL) and the reaction mixture was stirred 1 h at RT and concentrated in vacuo. LC-MS (B): t _R = 0.92min; [M+H] ⁺ : 434.07.

85.7. (S)-[3-(3-Cyclobutoxymethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-( 1,3-dimethyl-azetidin-3-yl)-(4-ethyl-phenyl)-methanol The title compound was synthesized starting from Example 85.6 (2.17mg), and following the procedure described in Example 72, step 3, and purified by Prep LC-MS (III) to afford 2.2mg of the title product. LC-MS (B): t _R = 0.94min; [M+H] ⁺ : 448.30.

Example 86: 1-(5-{3-[(S)-(4-Cyclopropyl-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-hydroxy-methyl]-phenyl}-

[1 ,2,4]oxadiazol-3-yl)-2-methyl-propan-2-ol

86. 1 3-(4-Cyclopropyl-benzoyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

In a previously heated flask, 1-bromo-4-cyclopropylbenzene (4.68mL) was dissolved in THF (67.5mL). The solution was cooled at -78°C and HexLi (2.3M in hexanes, 19.8mL) was added dropwise, keeping the IT below -70°C. The mixture was stirred 30min at -78°C and a solution of Example A2 (9g) in THF (22.5mL) was added dropwise, keeping the IT below -70°C. The reaction mixture was stirred 30min at -78°C, quenched with sat. NH4CI, extracted once with toluene and iPrOAc. The combined org. layers were washed with brine and water, then evaporated and placed under HV. The crude was purified by CC (Biotage, SNAP 340g, solvent A: Hep; solvent B: EA; gradient in %B 8 over 2.2CV, 24 over 3.8CV) to afford 7.86g of the title product. LC-MS (A): t _R = 1 ,06min; [M+H-CH3] ⁺ : 301 .17.

86.2 3-[(4-Cyclopropyl-phenyl)-(3-formyl-phenyl)-hydroxy-methyl]- 3-methyl-azetidine-1-carboxylic acid tert-butyl ester In a dry flask, Example 86.1 (7.86g) and lanthanum(lll) chloride bis(lithium chloride) complex (0.6M in THF, 38.2mL) were dissolved in THF (27mL). The mixture was stirred 1 h at RT. In a second dry flask, a solution of 3- bromobenzaldehyde diethyl acetal (9.82mL) in THF abs. (130mL) was cooled at -78°C and HexLi (2.3M in hexanes, 20mL) was added dropwise over 20min. After 30min of stirring, the previously prepared mixture was added over 30min to this one. The resulting mixture was stirred 45min at -78°C, quenched with sat. NH4CI, extracted with Et20 (3x) and EA. The combined org. layers were dried (MgSO4), filtered and evaporated. The crude was dissolved in DCM and treated with formic acid (8.65mL). The mixture was stirred 30min at RT and the solvent was evaporated. The residue was purified by CC (Biotage, SNAP 340g, solvent A: Hep; solvent B: EA; gradient in %B 17 over 6CV, 34% over 3.6CV) and by Prep LC-MS (XV) to afford 6.4g of the title product as a white powder. LC-MS (A): IR = 1.08min; [M+H] ⁺ : 422.12.

86.3 3-[(S)-(4-Cyclopropyl-phenyl)-(3-formyl-phenyl)-hydroxy-meth yl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

Example 86.2 (6.4g) was purified by Prep chiral SFC (X) to afford the title compound as pure enantiomer (3.16g). Chiral SFC (J): IR = 2.03min.

86.4 3-[(S)-(3-Carboxy-phenyl)-(4-cyclopropyl-phenyl)-hydroxy-met hyl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 86.3 (3.16g) following the procedure described in Example 3.4, step 3, to afford 3.28g of the title product. LC-MS (B): t _R = 1. OOmin; [M+H] ⁺ : 438.12.

86.5 3-((S)-(4-Cyclopropyl-phenyl)-hydroxy-{3-[3-(2-hydroxy-2-met hyl-propyl)-[1,2,4]oxadiazol-5-yl]-phenyl}-methyl)-3- methyl-azetidine-1 -carboxylic acid tert-butyl ester

A mixture of Example 86.4 (40mg), Example E9.1 (13.3mg), PyBOP (73.1mg), K3PO4 (77.6mg) and DIPEA (47|dL) in DMF (1 mL) was heated 16h at 80°C and all the reagents (except 86.4) were added a second time. The reaction mixture was further stirred at 80°C for 2 days, quenched with water and extracted with DCM, dried (MgSO4), filtered, concentrated in vacuo, dried under HV and directly used in the next step. LC-MS (A): t _R = 1.07min; [M+H] ⁺ : 534.23.

86.6 1-(5-{3-[(S)-(4~Cyclopropyl-phenyl)-hydroxy-(3-methyl-azetid in-3-yl)-methyl]-phenyl}-[1,2,4]oxadiazol-3-yl)-2- methyl-propan-2-ol

Example 86.5 (48.8mg) was treated with HCI in dioxane (4M, 1mL) and the reaction mixture was stirred 1 h at RT and concentrated in vacuo. LC-MS (A): t _R = 0.74min; [M+H] ⁺ : 434.53.

86.7 1-(5-{3-[(S)-(4-Cyclopropyl-phenyl)-(1,3-dimethyl-azetidin-3 -yl)-hydroxy-methyl]-phenyl}-[1,2,4]oxadiazol-3-yl)-2- methyl-propan-2-ol

The title compound was synthesized starting from Example 86.6 (36.9mg), and following the procedure described in Example 72, step 3, and purified by Prep LC-MS (I) and (IV) to afford 14.1 mg of the title product. LC-MS (A): t _R = 0.77min; [M+H] ⁺ : 448.19.

Example 87: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(3-pyrrolidin-1-yl-phenyl)-(4-tri fluoromethoxy-phenyl)-methanol

87. 1 3-(3-Bromo-benzoyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example A2 (5g) and 1,3-dibromobenzene (3.14mL), and following the procedure described in Example 29, and extracted with EA and washed the org. layers with sat NaHCOa, sat NH4CI and brine to afford 6.87g of the title product. LC-MS (A): t _R = 1.06min; [M+H] ⁺ : 353.82.

87.2 3-[(3-Bromo-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-meth yl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester The title compound was synthesized starting from Example 87.1 (1.17g) and 1-bromo-4-(trifluoromethoxy)benzene (0.598mL), and following the procedure described in Example 29, and purified by CC (Biotage, SNAP 25g, solvent: DCM; solvent B: 9:1 DCM/MeOH; gradient in %B 0 over 4CV, 0 to 1 over 1CV, 1 over 5CV, 1 to 2 over 1CV, 2 over 2CV, 2 to 10 over 1CV, 10 over 3.7CV) and by Prep LC-MS (XIII) to afford 126mg of the title product. LC-MS (A): t _R = 1.17min; [M+H] ⁺ : 516.12.

87.3 3-[(S)-(3-Bromo-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)- methyl]-3-methyl-azetidine- 1 -carboxylic acid tertbutyl ester

Example 87.2 (126mg) was purified by Prep chiral SFC (IX) to afford the title compound as pure enantiomer (47mg). Chiral SFC (I): t _R = 1.08min.

87.4 3-[(S)-Hydroxy-(3-pyrrolidin-1-yl-phenyl)-(4-trifluoromethox y-phenyl)-methyl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 87.3 (47mg) and pyrrolidine (15.4piL), and following the procedure described in Example 30, by adding a second time all the reagents and heating again overnight at 100°C, and purified by Prep LC-MS (VIII) to afford 13.7mg of the title product as a white powder. LC-MS (A): t _R = 1.14min; [M+H] ⁺ : 507.26.

87.5 (S)-(3-Methyl-azetidin-3-yl)-(3-pyrrolidin-1-yl-phenyl)-(4-t rifluoromethoxy-phenyl)-methanol

Example 87.4 (13.7mg) was treated with HCI in dioxane (4M, 1mL) and the reaction mixture was stirred 1 h at RT and concentrated in vacuo. LC-MS (B): t _R = 0.81 min; [M+H] ⁺ : 407.22.

87.6 (S)-(1,3-Dimethyl-azetidin-3-yl)-(3-pyrrolidin-1-yl-phenyl)- (4-trifluoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example 87.5 (11 mg), and following the procedure described in Example 72, step 3, and purified by Prep LC-MS (III) to afford 7.7mg of the title product as a white powder. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 421.23.

Example 88: (1 ,3-Dimethyl-azetidin-3-yl)-(4-methylamino-phenyl)-(3-pyrroli din-1-yl-phenyl)-methanol

88. 1 3-Methyl-3-(3-pyrrolidin-1-yl-benzoyl)-azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example A2 (200mg) and 1-(3-bromophenyl)pyrrolidine (235mg), and following the procedure described in Example 29, and purified by CC (Biotage, SNAP 40g, solvent: Hep; solvent B: EA; gradient in %B 0 over 1 min, 0 to 20 over 15min, 20 over 5min) to afford 186mg of the title product as a yellow solid. LC-MS (A): t _R = 1.08min; [M+H] ⁺ : 345.28.

82.2. 3-[(4-Bromo-phenyl)-hydroxy-(3-pyrrolidin-1-yl-phenyl)-methy l]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 88.1 (77mg) and 1 ,4-dibromobenzene (65mg), and following the procedure described in Example 29, and purified by CC (Biotage, SNAP 40g, solvent A: Hep; solvent B: EA; gradient in %B 0 over 1 min, 0 to 10 over 5min, 10 over 3min, 10 to 30 over 12min, 30 over 5min, 30 to 60 over 10min, 60 over 5min) to afford 62mg of the title product as a white glass. LC-MS (A): t _R = 1 ,09min; [M+H] ⁺ : 501 .23. 88.3 (4-Methylamino-phenyl)-(3-methyl-azetidin-3-yl)-(3-pyrrolidi n-1-yl-phenyl)-methanol

To a sealed vial charged with Example 88.2 (60mg), copper (1mg) and DMF (0.45mL) was added methylamine (40wt% in water, 52piL). The reaction mixture was heated 23h at 100°C, cooled at RT and concentrated in vacuo. The residue was dissolved in MeOH (0.45mL) and HCI in dioxane (4M, 0.39mL) was added dropwise. The reaction mixture was stirred 3h at RT and HCI in dioxane (4M, 0.39mL) was added again. The reaction mixture was stirred 1 h30 at RT and HCI in dioxane (4M, 0.20mL) was added again. The reaction mixture was stirred 1h at RT, concentrated in vacuo, dissolved in MeCN and water the purified by Prep LC-MS (XVII) to afford 8.9mg of the title product as a white solid. LC- MS (A): t _R = 0.49min; [M+H] ⁺ : 352.23.

88.4. ( 1, 3-Dimethyl-azetidin-3-yl)-(4-methylamino-phenyl)-(3-pyrrolid in-1-yl-phenyl)-methanol

The title compound was synthesized starting from Example 88.3 (8.9mg), and following the procedure described in Example B2, step 2, and stirring at RT for 1 h, then directly concentrated in vacuo and purified by Prep LC-MS (I) to afford 1 mg of the title product as a white solid. LC-MS (A): t _R = 0.52min; [M+H] ⁺ : 366.25.

Example 89: (1 , 3-D i methy l-azetid i n-3-y l)-[4-ethoxy-3-(3-methy I- [1 , 2, 4] oxad i azol-5-y l)-pheny I]- (4-trifl uoromethoxy- phenyl)-methanol

89. 1 5-Bromo-2-ethoxy-benzoic acid ethyl ester

To a solution of 5-bromosalicylic acid (500mg) in DMF (10mL) were added K2CO3 (716mg) and iodomethane (0.421 mL). The reaction mixture was heated overnight at 50°C, quenched with water, extracted with EA (3x), the combined org. layers were washed with brine, dried (MgSO4), filtered, concentrated in vacuo and dried under HV to afford 729mg of the desired product. LC-MS (A): t _R = 0.99min; [M+H] ⁺ : 273.11.

89.2 5-Bromo-2-ethoxy-benzoic acid

A solution of Example 89.1 (100mg) in THF (0.7mL) was treated with a solution of LiOH H2O (30.7mg) in water (0.7mL). The reaction mixture was stirred overnight at RT, the solvent concentrated. The material was directly used in the next step. LC-MS (A): t _R = 0.79min; [M+H] ⁺ : 245.04.

89.3. 5-(5-Bromo-2-ethoxy-phenyl)-3-methyl-[1, 2, 4]oxadiazole

To a solution of Example 89.2 (89.7mg) in DMF (2mL) were added N'-hydroxyacetimidamide (33.2mg), HOBt (54.4mg), DIPEA (0.125mL) and EDC'HCI (105mg). The reaction mixture was stirred 2 days at RT and all the reagents were added in the same amount again. The reaction mixture was heated 5h at 40°C and all the reagents were added in the same amount again. The reaction mixture was heated overnight at 40°C, then overnight at 90°C, extracted with DCM and citric acid (10%), the org. layers were washed with sat. NaHCOa, dried, concentrated in vacuo and purified by Prep LC-MS (VIII) to afford 26.5mg of the title product. LC-MS (A): t _R = 0.97min; [M+H] ⁺ : 283.14.

89.43-[4-Ethoxy-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoy l]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example A2 (18.5mg) and Example 89.3 (26.4mg), and following the procedure described in Example 29. The crude was purified by Prep LC-MS (VIII) to afford 0.8mg of the title product. LC-MS (A): t _R = 1.04min; [M+H] ⁺ : 402.05. 89.5 3-[[4-Ethoxy-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-hydr oxy-(4-trifluoromethoxy-phenyl)-methyl]-3-methyl- azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 89.4 (0.8mg) and 1-bromo-4-(trifluoromethoxy)benzene (0.3mL), and following the procedure described in Example A7.2, step 2, to afford 1.12mg of the title product without any purification. LC-MS (A): tR = 1 .12min; [M+H] ⁺ : 564.34.

89.6 [4-Ethoxy-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-(3-meth yl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)- methanol

Example 89.5 (1.12mg) was treated with HCI in dioxane (4M, 2mL) and the reaction mixture was stirred 3h at RT, concentrated in vacuo and dried under HV to afford 0.9mg of the title product. LC-MS (A): tR = 0.83min; [M+H] ⁺ : 464.26.

89.7 (1,3-Dimethyl-azetidin-3-yl)-[4-ethoxy-3-(3-methyl-[1,2,4]ox adiazol-5-yl)-phenyl]-(4-trifluoromethoxy-phenyl)- methanol

The title compound was synthesized starting from Example 89.6 (0.9mg), and following the procedure described in Example B2, step 2. Purification of the reaction mixture by Prep LC-MS (I) afforded 0.6mg of the title product as a white powder. LC-MS (A): t _R = 0.84min; [M+H] ⁺ : 478.27.

Example 90: (S)-(3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol

90.1 (S)-(3-Chloro-phenyl)-(3-methyl-azetidin-3-yl)-(4-trifluorom ethoxy-phenyl)-methanol

Example A7.1.2 (1 ,8g) was treated with HCI in dioxane (4M, 9.5mL) and the reaction mixture was stirred 22h at RT and concentrated in vacuo to afford 1.72g of the title product as a white foam. LC-MS (B): t = 0.84min; [M+H] ⁺ : 372.17.

90.2 (S)-(3-Chloro-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-triflu oromethoxy-phenyl)-methanol

Example 90.1 (203mg) was dissolved in EA and extracted with aq. sat. NaHCOa and brine. Afterwards the aq. layers were re-extracted with EA (3x) and the combined org. layers were dried (MgSO4), filtered, evaporated and dried under HV to afford 182mg of free amine. The free amine was dissolved in MeOH (5mL) and formaldehyde (37% in water, 0.364mL), AcOH (0.5mL) and NaBH(OAc)3 (214mg) were added at RT. The resulting light yellow suspension was stirred 30min at RT, concentrated in vacuo, diluted with water and some brine and extracted with EA (3x). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo. The crude was purified by Prep LC-MS (V) to afford 112mg of the title product as a white powder. LC-MS (A): t = 0.81 min; [M+H] ⁺ : 385.94. The absolute configuration of Example 90 was determined to be (S)- by single crystal X-ray diffraction.

Example 91 : (3-Cyclopropylmethoxy-phenyl)-(1 , 3-d i methy l-azetid i n-3-y l)-(4-trifluoromethoxy-pheny l)-methanol

91.1 3-[(3-Cyclopropylmethoxy-phenyl)-hydroxy-(4-trifluoromethoxy -phenyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

To a dry flask were added Mg (41 mg) and THF (0.3mL). Some drops of a solution of 1-bromo-3- (cyclopropylmethoxy)benzene (129mg) in THF (1 mL) were added followed by a crystal of iodine. The mixture was heated until gas formation was visible, then the rest of the solution was added and the mixture was heated 30min at 70°C. Afterwards, the mixture was cooled to RT and a solution of Example A4.1 (200mg) in THF (1 mL) was slowly added. The reaction mixture was stirred 5h at RT, quenched with aq. sat. NH4CI, diluted with water and extracted with DCM (3x). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to afford 185mg of the title product as an oil. LC-MS (A): t _R = 1.18min; [M+H] ⁺ : 508.27.

91.2 ( 3-Cyclopropylmethoxy-phenyl) -( 3-methyl-azetidin-3-yl) -( 4-trifluoromethoxy-phenyl) -methanol

Example 91.1 (180mg) was treated with HCI in dioxane (4M, 1.83mL) and the reaction mixture was stirred 1 h at RT, concentrated in vacuo, triturated in EtaO and the solvent was removed, the residue dried under HV to afford 157mg of the title product as a yellow oil. LC-MS (A): t _R = 0.84min; [M+H] ⁺ : 408.24.

91.3. (3-Cyclopropylmethoxy-phenyl)-( 1, 3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-methan ol

The title compound was synthesized starting from Example 91.2 (157mg), and following the procedure described in Example 72, step 3, and quenched with sat. NaHCOa and extracted with DCM, before it was purified by Prep LC-MS (III) to afford 55mg of the title product as a white solid. LC-MS (A): t _R = 0.86min; [M+H] ⁺ : 422.23.

Example 92: Benzooxazol-5-yl-(1 ,3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-metha nol

92. 1 3-[Benzooxazol-5-yl-hydroxy-(4-trifluoromethoxy-phenyl)-meth yl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

To a dry flask were added Example A4.1 (70mg), THF (1mL) and 5-bromobenzooxazole (39.8mg). The solution was cooled at -100°C (liquid nitrogen/EtaO mixture) and n-BuLi (2.5M in hexanes, 78piL) was added dropwise. The reaction mixture was allowed to slowly reach RT overnight, quenched with sat. NH4CI, diluted with water and extracted with DCM (3x). The combined org. layers were dried (MgSO4), filtered and evaporated. The crude was purified by CC (Biotage, SNAP 10g, solvent A: Hep, solvent B: EA; gradient in %B: 0 over 2CV, 0 to 10 over 4CV, 10 to 50 over 6CV, 50 over 2CV) to afford 15mg of the title product as a brown solid. LC-MS (A): t _R = 1 ,07min; [M+H] ⁺ : 479.26.

92.2 Benzooxazol-5-yl-(3-methyl-azetidin-3-yl)-(4-trifluoromethox y-phenyl)-methanol

To a solution of Example 92.1 (180mg) in DCM (0.2mL) was added TFA (40|dL). The reaction mixture was stirred 2h at RT, basified with sat. NaHCOa, extracted with DCM (3x), and the combined org. layers were dried (MgSO4), filtered, concentrated in vacuo and dried under HV to afford 12mg of the title product as a brown. LC-MS (A): t _R = 0.73min; [M+H] ⁺ : 379.21.

92.3 Benzooxazol-5-yl-( 1, 3-dimethyl-azetidin-3-yl)-(4-trifluoromethoxy-phenyl)-methan ol

To a brown solution of Example 92.2 (12mg) in THF (0.5mL) were added fomaldehyde (37% in water, 4.7piL), acetic acid (2.7pil) and NaBH(OAc)3 (10.4mg) at RT. The reaction mixture was stirred overnight at RT, quenched with water, diluted with MeOH and purified by Prep LC-MS (XIX) to afford 5mg of the title product as an off-white powder. LC-MS (A): t _R = 0.76min; [M+H] ⁺ : 393.31.

Example 93: (1 ,3-Dimethyl-azetidin-3-yl)-(2-methyl-benzooxazol-6-yl)-(4-tr ifluoromethoxy-phenyl)-methanol

93.1 3-[Hydroxy-(2-methyl-benzooxazol-6-yl)-(4-trifluoromethoxy-p henyl)-methyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester The title compound was synthesized starting from Example A4.1 (100mg) and 6-bromo-2-methyl-1 ,3-benzoxazole (60.2mg), and following the procedure described in Example 92, step 1, and purified by Prep LC-MS (V) to afford 30mg of the title product as a yellow solid. LC-MS (A): t _R = 1.12min; [M+H] ⁺ : 493.27.

93.2 (3-Methyl-azetidin-3-yl)-(2-methyl-benzooxazol-6-yl)-(4-trif luoromethoxy-phenyl)-methanol

Example 93.1 (30mg) was treated with HCI in dioxane (4M, 1 mL) and the reaction mixture was stirred 1 h30 at RT, concentrated in vacuo and dried under HV to afford 30mg of the title product as a yellow resin. LC-MS (A): t _R = 0.77min; [M+H] ⁺ : 393.29.

93.3 (1,3-Dimethyl-azetidin-3-yl)-(2-methyl-benzooxazol-6-yl)-(4- trifluoromethoxy-phenyl)-methanol

To a solution of Example 93.2 (30mg) in MeOH (1 ,5mL) were added a solution of formaldehyde (37wt% in water, 34mg), AcOH (0.15mL) and NaBH(OAc)3 (31 mg). The reaction mixture was stirred at RT for 19h. It was diluted with water and directly purified by Prep LC-MS (III) to afford 13mg of the title product as a yellow solid. LC-MS (A): t _R = 0.78min; [M+H] ⁺ : 407.31.

Example 94: (1 ,3-Dimethyl-azetidin-3-yl)-[4-(tetrahydro-pyran-4-yloxy)-phe nyl]-(4-trifluoromethoxy-phenyl)-methanol 94. 1 3-[Hydroxy-(4-methoxy-phenyl)-(4-trifluoromethoxy-phenyl)-me thyl]-3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

To a solution of Example A4.1 (2g) in THF (80mL) cooled at -10°C was added 4-methoxyphenylmagnesium bromide (1 M in THF, 22.2mL). The reaction mixture was stirred at -10°C for 20min, diluted with EA, washed with sat. NaHCOa, brine, dried (NaaSO^, filtered and concentrated in vacuo. The crude was purified by CC (Biotage, SNAP 50g, solvent A: Hep, solvent B: EA; gradient in %B: 0 over 1CV, 0 to 10 over 0.5CV, 10 over 1.5CV, 10 to 20 over 0.5CV, 20 over 2.1CV, 20 to 30 over 0.5CV, 30 over 2.1CV, 30 to 40 over 0.5CV, 40 over 3CV) to afford 1 ,8g of the title product as a white foam. LC-MS (A): t _R = 1.12min; [M+H] ⁺ : 468.11.

94.2 (4-Methoxy-phenyl)-(3-methyl-azetidin-3-yl)-(4-trifluorometh oxy-phenyl)-methanol

A solution of Example 94.1 (1.8g) in EA (10mL) was treated with HCI in dioxane (4M, 20mL) and the reaction mixture was stirred 20min at RT, concentrated in vacuo and dried under HV to afford 1.5g of the title product. LC-MS (A): t _R = 0.77min; [M+H] ⁺ : 368.25.

94.3 (1,3-Dimethyl-azetidin-3-yl)-(4-methoxy-phenyl)-(4-trifluoro methoxy-phenyl)-methanol

To a solution of Example 94.2 (1.5g) in DCM (32mL) were added TEA (0.52mL), formaldehyde (37% in water, 1.94mL) and 5min later NaBH(OAc)3 (439mg). The reaction mixture was stirred 15min at RT, quenched with sat. NaHCOs, extracted with DCM and the org. layer was washed with water, dried (Na2SO4), filtered, concentrated in vacuo and dried under HV to afford 900mg of the title product as a yellow oil. LC-MS (A): t _R = 0.77min; [M+H] ⁺ : 382.26.

94.4. 4-[( 1, 3-Dimethyl-azetidin-3-yl)-hydroxy-(4-trifluoromethoxy-phenyl )-methyl]-phenol

The title compound was synthesized starting from Example 94.3 (900mg), and following the procedure described in EExample I2, step 4, to afford 350mg of the title product as a solid. LC-MS (A): t _R = 0.69min; [M+H] ⁺ : 368.10.

94.5 (1,3-Dimethyl-azetidin-3-yl)-[4-(tetrahydro-pyran-4-yloxy)-p henyl]-(4-trifluoromethoxy-phenyl)-methanol To a solution of Example 94.4 (50mg) and tetrahydro-4-pyranol (13.2piL) in toluene (0.57mL) was added (tributylphosphoranylidene)acetonitrile (1 M in toluene, 0.27mL). The reaction mixture was heated 1 h at 95°C, concentrated in vacuo, diluted in water and extracted with DCM (3x) and the combined org. layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by Prep LC-MS (XX) and (V) to afford 3.9mg of the desired product as an off-white solid. LC-MS (B): IR = 0.82min; [M+H] ⁺ : 452.19.

Example 95: (1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-[1,2,4]oxadiazol-3-y l)-phenyl]-(4-trifluoromethoxy-phenyl)- methanol

95. 1 3-[(3-Cyano-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-meth yl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example A4.1 (300mg) and 3-bromobenzonitrile (200mg), and following the procedure described in Example A7.2, step 2, Purification by CC (Biotage, SNAP 80g, solvent A: Hep, solvent B: EA; gradient in %B: 0 over 1 min, 0 to 5 over 1 min, 5 over 8min, 5 to 100 over 25min, 100 over 5min) afforded 316mg of the title product as a white foam. LC-MS (A): IR = 1.09min; [M+H] ⁺ : 463.19.

95.2 3-[Hydroxy-[3-(N-hydroxycarbamimidoyl)-phenyl]-(4-trifluorom ethoxy-phenyl)-methyl]-3-methyl-azetidine-1- carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 95.1 (202mg), and following the procedure described in Example D1.1 , step 4, to afford 203.7mg of the crude material as a white foam. LC-MS (A): IR = 0.84min; [M+H] ⁺ : 496.22.

95.3 3-[Hydroxy-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-(4-tr ifluoromethoxy-phenyl)-methyl]-3-methyl-azetidine-1- carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 95.2 (102mg) and acetic acid (13piL), and following the procedure described in Example 52, with direct heating of the mixture 7h30 at 90°C and purified by Prep LC-MS (VI 11) to afford 55mg of the title product as a white solid. LC-MS (A): IR = 1.12min; [M+H] ⁺ : 520.21.

95.4. (3-Methyl-azetidin-3-yl)-[3-(5-methyl-[1,2,4]oxadiazol-3-yl) -phenyl]-(4-trifluoromethoxy-phenyl)-methanol

Example 95.3 (50.6mg) was treated with HCI in dioxane (4M, 0.25mL) and the reaction mixture was stirred 1 h at RT, concentrated in vacuo and dried under HV to afford 44mg of the title product. LC-MS (A): IR = 0.78min; [M+H] ⁺ : 420.16.

95.5 (1,3-Dimethyl-azetidin-3-yl)-[3-(5-methyl-[1,2,4]oxadiazol-3 -yl)-phenyl]-(4-trifluoromethoxy-phenyl)-methanol

To a solution of Example 95.4 (44mg) in MeOH (0.5mL) was added formaldehyde (37wt% in water, 8.7piL) followed by NaBH(OAc)3 (31 ,9mg). The mixture was stirred at 1 h at RT and all the reagents were added in the same amount again and the reaction mixture was further stirred 45min at RT, concentrated in vacuo and the residue was dissolved in MeCN/water, then purified by Prep LC-MS (I). The solid obtained was dissolved in EA (10mL) and the solution was washed with sat. NaHCOa (3x), dried (MgSO4), filtered and concentrated in vacuo. EtaO was added and the mixture was concentrated again then dried under HV to afforded 22.1 mg of the title product as a white solid. LC-MS (A): IR = 0.81 min; [M+H] ⁺ : 434.21. Example 96: (3-Fluoro-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-trif luoromethoxy-phenyl)-methanol

96. 1 3-Fluoro-3-(4-trifluoromethoxy-benzoyl)-azetidine-1-carboxyl ic acid tert-butyl ester

The title compound was synthesized starting from 4-(trifluoromethoxy)bromobenzene (0.592mL) and 3-fluoro-3- (methoxy(methyl)carbamoyl)azetidine-1 -carboxylate (788mg), and following the procedure described in Example 29. Purification by CC (Biotage, SNAP 50g, solvent A: Hep, solvent B: EA; gradient in %B: 21 over 25min) afforded 977.7mg of the title product as a white solid. LC-MS (A): t _R = 0.99min; [M+H] ⁺ : 363.94.

96.2 3-Fluoro-3-[hydroxy-(4-phenoxy-phenyl)-(4-trifluoromethoxy-p henyl)-methyl]-azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from 4-iododiphenyl ether (95mg) and Example 96.1 (114mg) following the procedure described in Example 91, step 1. Purification CC (Biotage, SNAP 10g, solvent A: Hep, solvent B: EA; gradient in %B: 10 over 2CV, 10 to 30 over 3CV, 30 over 2CV) afforded 98mg of the title product as a yellow resin. LC- MS (A): t _R = 1.19min; [M+H] ⁺ : 534.23.

96.3 (3-Fluoro-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-trifluorometh oxy-phenyl)-methanol

Example 96.2 (90mg) was treated with HCI in dioxane (4M, 1 mL) and the reaction mixture was stirred 1 h at RT, diluted with water and extracted with DCM, and the org. layer was dried (MgSO4), filtered, evaporated and dried under HV to afford 94mg of the title product as a pale yellow solid. LC-MS (A): t _R = 0.86min; [M+H] ⁺ : 433.92.

96.4 (3-Fluoro-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-trif luoromethoxy-phenyl)-methanol

The title compound was synthesized starting from Example 96.3 (89mg), and following the procedure described in Example 72, step 3, and quenched with sat. NaHCOa, extracted with DCM, dried (MgSO4), filtered, evaporated and dried under HV to afford 57mg of the title product as a white foam. LC-MS (A): t _R = 0.88min; [M+H] ⁺ : 448.19.

Example 97: (3-Chloro-phenyl)-(3-fluoro-1-methyl-azetidin-3-yl)-(4-trifl uoromethoxy-phenyl)-methanol

97. 1 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-3-fluoro-azetidine-1 -carboxylic acid tert-butyl ester

In a flask previously heated out in vacuo and backfilled with argon were added Example 96.1 (100mg) and THF (1mL). The solution was cooled at 0°C and 3-chlorophenylmagnesium bromide (0.5M in THF, 1.1 mL) was added. The yellow solution was warmed to RT and stirred overnight at RT, quenched with sat. NH4CI, diluted with water and extracted with DCM (3x). The combined org. layers were dried (MgSO4), filtered, evaporated and the crude material was purified by CC (Biotage, SNAP 10g, solvent A: Hep, solvent B: EA; gradient in %B: 10 over 3CV, 10 to 30 over 2CV, 30 over 2CV) to afford 96mg of the title product as a colorless resin. LC-MS (A): t _R = 1.16min; [M+H] ⁺ : 476.01.

97.2 ( 3-Chloro-phenyl) -( 3-fluoro-azetidin-3-yl) -( 4-trifluoromethoxy-phenyl)-methanol

Example 97.1 (90mg) was treated with HCI in dioxane (4M, 1 mL) and the reaction mixture was stirred 1 h at RT, basified with 1 M NaOH until pH 14 was reached, diluted with water and extracted with DCM (3x), and the combined org. layers were dried (MgSO4), filtered, evaporated and dried under HV to afford 47mg of the title product as a pale yellow resin. LC-MS (A): t _R = 0.78min; [M+H] ⁺ : 376.0. 97.3 ( 3-Chloro-phenyl) -( 3-fluoro- 1 -methyl-azetidin-3-yl)-( 4-trifluoromethoxy-phenyl) -methanol

To a solution of Example 97.2 (42mg) in DCM (1mL) was added formaldehyde (37wt% in water, 29.1 pL) followed by NaBH(OAc)3 (37.4mg). The reaction mixture was stirred 71 h at RT and NaBH(OAc)3 (37.4mg) was added again. The reaction mixture was stirred 2h at RT and formaldehyde (29.1 pi L) was added. The reaction mixture was stirred overnight at RT and heated 2h30 at 40°C, cooled down at RT, quenched with sat. NaHCOs and extracted with DCM (3x). The combined org. layers were dried (MgSO4), filtered, evaporated and the crude was purified by Prep LC-MS (V) to afford 8mg of the title product as a white solid. LC-MS (A): IR = 0.81 min; [M+H] ⁺ : 390.18.

Example 98: 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-1-methyl-azetidine-3-carboxylic acid amide

98. 1 3-Cyano-3-(methoxy-methyl-carbamoyl)-azetidine-1 -carboxylic acid tert-butyl ester

To a solution of HATU (998mg) and DIPEA (1 .11mL) in DMF (5mL) was added 1-Boc-3-cyanoazetidine-3-carboxylic acid (500mg). The reaction mixture was stirred 15min at RT and N,O-dimethylhydroxylamine hydrochloride (256mg) was added. The reaction mixture was stirred 40min at RT, diluted with IPrOAc and the org. layer was washed with water and sat. NH4CI, dried (Na2SO4), filtered, concentrated in vacuo and dried under HV. The crude was purified by CC (Biotage, SNAP 25g, solvent A: Hep, solvent B: EA; gradient in %B: 10 over 3CV, 10 to 30 over 4CV, 30 over 3CV) to afford 435mg of the title product as a colorless resin. LC-MS (A): IR = 0.84min; [M+H] ⁺ : 270.29.

98.2 3-Cyano-3-(4-trifluoromethoxy-benzoyl)-azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 98.1 (200mg) and 4-(trifluoromethoxy)phenylmagnesium bromide (0.5M in THF (0.85mL), and following the procedure described in Example E1.1 , and quenched with sat. NH4CI and purified by CC (Biotage, SNAP 25g, solvent A: Hep, solvent B: EA; gradient in %B: 0% over 2CV, 0 to 10% over 5CV, 10% over 7CV) to afford 220mg of the title product as a yellow solid. LC-MS (A): t _R = 1 ,08min; [M+H] ⁺ : 371 .21 .

98.3 3-Carbamoyl-3-(4-trifluoromethoxy-benzoyl)-azetidine-1-carbo xylic acid tert-butyl ester

A suspension of Example 98.2 (50mg), acetaldehyde oxime (16.6piL), palladium(ll) acetate (3mg) and triphenylphosphine (7.2mg) in EtOH/water (3: 1 , 0.4mL) was refluxed for 1 h45, cooled at RT, filtered over a celite plug, washed with 1 : 1 EtOH/DCM and the filtrate concentrated in vacuo. The residue was purified by CC (Biotage, SNAP 10g, solvent A: Hep, solvent B: EA; gradient in %B: 30% over 2CV, 30 to 50% over 3CV, 50% over 3CV) to afford 31 mg of the title product as a white solid. LC-MS (A): t _R = 0.95min; [M+H] ⁺ : 389.23.

98.4 3-Carbamoyl-3-[(3-chloro-phenyl)-hydroxy-(4-trifluoromethoxy -phenyl)-methyl]-azetidine-1 -carboxylic acid tertbutyl ester

The title compound was synthesized starting from Example 98.3 (30mg) and 3-chlorophenylmagnesium bromide (0.5M in THF, 0.65mL), and following the procedure described in Example E1.1 , at -10°C and adding 2eq of 3- chlorophenylmagnesium bromide after 25min and after 1 h30. After further stirring for 4h and work-up, the crude was purified by Prep LC-MS (XXI) to afford 10mg of the title product as a white solid. LC-MS (A): t _R = 1.05min; [M+H] ⁺ : 501.17. 98.5 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-azetidine-3-carboxylic acid amide

Example 98.4 (10mg) was treated with HCI in dioxane (4M, 0.5mL) and the reaction mixture was stirred 15min at RT, evaporated and dried under HV to afford 15mg of the title product as a colorless resin. LC-MS (A): t _R = 0.71 min; [M+H] ⁺ : 401.09.

98.63-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phen yl)-methyl]-1-methyl-azetidine-3-carboxylic acid amide

To a solution of Example 98.5 (15mg) in MeOH (0.35mL) were added formaldehyde (37wt% in water, 15.3piL), acetic acid (35piL) and NaBH(OAc)3 (16.2mg). The reaction mixture was stirred 1 h30 at RT and 6eq of formaldehyde and 2eq of NaBH(OAc)3 were added again. The mixture was further stirred 1 h30 at RT, quenched with sat. NaHCOs, stirred 10min and extracted with DCM (3x). The combined org. layers were dried (MgSC>4), filtered, concentrated in vacuo. The crude was purified by Prep LC-MS (VI II) to afford 5.5mg of the title product as a white solid. LC-MS (A): t _R = 0.72min; [M+H] ⁺ : 415.15.

Example 99: 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-1-methyl-azetidine-3-carbonitrile

99. 1 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-3-cyano-azetidine-1-carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 98.2 (50mg) and 3-chlorophenylmagnesium bromide (0.5M in THF, 76piL), and following the procedure described in Example E1.1 at -10°C for 7h. The crude was purified by Prep LC-MS (XXI) to afford 13mg of the title product as a white solid. LC-MS (A): t _R = 1.13min; [M+H] ⁺ : 483.09.

99.2 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-azetidine-3-carbonitrile

Example 99.1 (13mg) was treated with HCI in dioxane (4M, 67piL) and the reaction mixture was stirred 35min at RT, then HCI in dioxane (4M, 5eq) was added again and the reaction mixture was further stirred 1 h at RT, evaporated and dried under HV to afford 14mg of the title product as a yellowish resin. LC-MS (A): t _R = 0.78min; [M+H] ⁺ : 383.17.

99.3 3-[(3-Chloro-phenyl)-hydroxy-(4-trifluoromethoxy-phenyl)-met hyl]-1-methyl-azetidine-3-carbonitrile

The title compound was synthesized starting from Example 99.2 (14mg), and following the procedure described in Example C3.1 , step 3. Purification by Prep LC-MS (VI II) afforded 5.5mg of the title product as a colorless solid. LC-MS (A): t _R = 0.79min; [M+H] ⁺ : 397.19.

Example 100: (3-chlorophenyl)(4-(difluoromethyl)phenyl)(1,3-dimethylazeti din-3-yl)methanol

The title compound was synthesized starting from Example C3.1 (50mg) and 1-bromo-4-(difluoromethyl)benzene (62.7mg), and following the procedure described in Example A4.1. Purification by Prep LC-MS (IV) afforded 16mg of the title compound as a white powder. LC-MS (A): t _R = 0.76min; [M+H] ⁺ : 352.2.

Example 101 to Example 105 were synthesized starting from Example C3.1 , the appropriate bromo derivative and following the procedure described in Example 1. LC-MS data and purification methods of Example 101 to 105 are listed in the table below. The LC-MS conditions used were LC-MS (A).

Example 106: (3-Chloro-phenyl)-(1 ,3-dimethyl-azetidin-3-yl)-p-tolyl-methanol

To a solution of Example C3.1 (50mg) in THF (1mL) at RT was added dropwise p-tolylmagnesium bromide (0.5M in Et20, 0.894mL), while maintaining the IT below 30°C. The reaction mixture was stirred at RT and at 65°C for 92h. It was quenched with water and extracted with DCM (2x). The combined org. layers were dried (MgSCh) and concentrated in vacuo. The crude was purified by Prep LC-MS (II) to afford 22mg of the title compound as a white powder. LC-MS (A): t _R = 0.76min; [M+H] ⁺ : 316.22.

Example 107: (4-Difluoromethoxy-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-p henoxy-phenyl)-methanol

The title compound was synthesized starting from Example C3.2 (50mg) and 4-(difluoromethoxy)bromobenzene (89.9mg), and following the procedure described in Example 1 . Purification by Prep LC-MS (V) afforded 4mg of a white powder. LC-MS (A): t _R = 0.85min; [M+H] ⁺ :426.23.

Example 108 ( 1,3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-phenyl-methan ol

108.1 ( 1, 3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-phenyl-methanol

The title compound was synthesized starting from Example C3.2 (50mg) and phenylmagnesium bromide (0.355mL, 1 M in THF) and following the procedure described in Example 1 . Purification by Prep LC-MS (V) afforded 35mg of a white powder. LC-MS (A): t _R = 0.81 min; [M+H] ⁺ : 360.28.

108.2 ( 1, 3-Dimethyl-azetidin-3-yl)-(4-phenoxy-phenyl)-phenyl-methanol

Example 108.1 (26mg) was purified by Prep chiral SFC (V) to afford 13mg of the pure enantiomer as pale yellow solid.

Chiral SFC (E): t _R = 2.1 min. Example 109: (1 ,3-Dimethyl-azetidin-3-yl)-{2-fluoro-3-[5-(tetrahydro-pyran- 4-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(4- isopropyl-phenyl)-methanol

109. 1 3-[(3-Cyano-2-fluoro-phenyl)-hydroxy-(4-isopropyl-phenyl)-me thyl]-3-methyl-azetidine-1-carboxylic acid tertbutyl ester

In a previously heated flask, Example A4.2 (200mg) and 3-bromo-2-fluorobenzonitrile (174mg) were dissolved in THF (4mL). The solution was cooled at -78°C and HexLi (2.3M in hexanes, 0.356mL) was added dropwise, keeping the IT below -70°C. The mixture was stirred 30min at -78°C, quenched with sat. NH4CI, diluted with water and extracted with DCM (3x). The combined org. layers were dried (MgSCh), filtered and concentrated in vacuo. The crude was purified by CC (Biotage, SNAP 10g, solvent A: Hep; solvent B: EA; gradient in %B: 39 over 4CV, 53 over 2.8CV). A second purification by CC was performed (Biotage, SNAP 10g, solvent A: Hep; solvent B: EA; gradient in %B: 12 over 4CV, 12 to 100 over 10CV, 100 over 0.2CV) to afford 160.6mg of the title product. LC-MS (A): t _R = 1.12min; [M+H] ⁺ : 439.15.

109.2 tert-butyl (Z)-3-((2-fluoro-3-(N'-hydroxycarbamimidoyl)phenyl)(hydroxy) (4-isopropylphenyl)methyl)-3- methylazetidine-1 -carboxylate

A mixture of Example 109.1 (161 mg), hydroxylamine hydrochloride (77.1 mg) and K2CO3 (202mg) in EtOH (3mL) was heated 17h at 80°C, cooled down at RT, filtered and the filtrate concentrated in vacuo and dried under HV to afford 172.4mg of the title product. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 472.19.

109.3 3-[{2-Fluoro-3-[5-( tetrahydro-pyran-4-yl)-[1 , 2,4]oxadiazol-3-yl]-phenyl}-hydroxy-(4-isopropyl-phenyl)-met hyl]-3- methyl-azetidine-1 -carboxylic acid tert-butyl ester

A mixture of Example 109.2 (172.4mg), tetrahydro-2H-pyran-4-carboxylic acid (52.8mg), T3P (50% solution in DCM, 0.284mL) and DIPEA (0.224mL) in DMF (4mL) was stirred 18h at RT, then heated 1 h at 110°C, quenched with brine and extracted 3x with iPrOAc. The combined org. layers were dried (MgSO4), filtered, concentrated in vacuo and dried under HV to afford 207mg of the title product. LC-MS (A): t _R = 1 .16min; [M+H] ⁺ : 566.13.

109.4 {2-Fluoro-3-[5-(tetrahydro-pyran-4-yl)-[1,2,4]oxadiazol-3-yl ]-phenyl}-(4-isopropyl-phenyl)-(3-methyl-azetidin-3- y I) -methanol

Example 109.3 (207mg) was treated with HCI in dioxane (4M, 4mL) and the reaction mixture was stirred 30min at RT, concentrated in vacuo to afford 170mg of the title product. LC-MS (A): t _R = 0.81 min; [M+H] ⁺ : 465.86.

109.5 ( 1,3-Dimethyl-azetidin-3-yl)-{2-fluoro-3-[5-( tetrahydro-pyran-4-yl)-[ 1, 2, 4]oxadiazol-3-yl]-phenyl}-(4-isopropyl- phenyl)-methanol

The title compound was synthesized starting from Example 109.4 (170mg) and following the procedure described in Example 72, step 3, except doing the reaction in dioxane. Purification by Prep LC-MS (III) gave 47.5mg of the desired product. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 480.15.

Example 110: (R)-(1 ,3-Dimethyl-azetidin-3-yl)-{2-fluoro-5-[5-(tetrahydro-pyran- 4-yl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(4- isopropyl-phenyl)-methanol 110.1 ( 1,3-Dimethyl-azetidin-3-yl)-{2-fluoro-5-[5-( tetrahydro-pyran-4-yl)-[ 1, 2, 4]oxadiazol-3-yl]-phenyl}-(4-isopropyl- phenyl)-methanol

The title compound was synthesized starting from Example A4.2 (200mg) and 3-bromo-4-fluorobenzonitrile (174mg), and following the 5-steps procedure described in Example 109. Purification by Prep LC-MS (III) gave 49mg of the desired product. LC-MS (A): IR = 0.86min; [M+H] ⁺ : 480.14.

110.2 (R)-(1,3-Dimethyl-azetidin-3-yl)-{2-fluoro-5-[5-(tetrahydro- pyran-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-(4-isopropyl- phenyl)-methanol

Example 110.1 (49mg) was purified by Prep chiral HPLC (XV) to afford 15.6mg of the pure enantiomer. Chiral HPLC (O): IR = 3.5min.

Example 111 : 2-(5-{3-[(S)-(1 , 3-D i methy l-azeti d i n-3-y I )-hy d roxy-(4-isopropy l-pheny I )-methy I] -pheny l}-py ri d i n-3-y I)- propan-2-ol

111. 1 3-[(3-Bromo-phenyl)-hydroxy-(4-isopropyl-phenyl)-methyl]-3-m ethyl-azetidine-1 -carboxylic acid tert-butyl ester A solution of Example A4.2 (1.6g) and 1 ,3-dibromobenzene (1.59g) in THF (16.8mL) was cooled to -40°C. Then, HexLi (2.3M in hexanes, 2.63mL) was added dropwise while maintaining the IT below -35°C. The resulting orange solution was stirred 1 h at -40°C, warmed up to RT, quenched with aq. sat. NH4CI, diluted with water and extracted with DCM (3x). The combined org. layers were dried (MgSO4), filtered, concentrated in vacuo and purified by CC (Biotage, SNAP 220g, solvent A: Hep; solvent B: EA; gradient in %B: 0 over 1 min, 0 to 5 over 3min, 5 over 3min, 5 to 30 over 25min, 30 over 5min) and by Prep LC-MS (XVIII) to afford 1.5368g of the title product as a white foam. LC-MS (A): t _R = 1.18min; [M+H] ⁺ : 474.01.

111.2 3-[(S)-(3-Bromo-phenyl)-hydroxy-(4-isopropyl-phenyl)-methyl] -3-methyl-azetidine-1 -carboxylic acid tert-butyl ester

Example 111.1 (49mg) was purified by Prep chiral SFC (IX) to afford 734mg of the pure enantiomer as a white solid. Chiral SFC (I): t _R = 1.75min.

111.3 3-[(S)-Hydroxy-{3-[5-(1 -hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-phenyl}-(4-isopropyl-phenyl)-me thyl]-3-methyl- azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example 111.2 (50mg) and 2-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-3-yl)propan-2-ol (55.5mg), and following the procedure described in Example 37. Purification by Prep LC-MS (V) afforded 43.8mg of the desired product as a white solid. LC-MS (A): t _R = 0.92min; [M+H] ⁺ : 531.13.

111.4 (S)-2-(5-(3-(hydroxy(4-isopropylphenyl)(3-methylazetidin-3-y l)methyl)phenyl)pyridin-3-yl)propan-2-ol

Example 111.3 (43mg) was treated with HCI in dioxane (4M, 0.21 mL) and the reaction mixture was stirred 1 h at RT, concentrated in vacuo to afford 40mg of the title product. LC-MS (A): t _R = 0.63min; [M+H] ⁺ : 431.22.

111.52-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-pyridin-3-yl)-propan-2-ol The title compound was synthesized starting from Example 111.4 (40mg) and following the procedure described in Example 72, step 3, except doing the reaction in dioxane. Purification by Prep LC-MS (I) gave 20.4mg of the desired product as a white solid. LC-MS (A): t _R = 0.66min; [M+H] ⁺ : 445.25.

Example 112: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(tetra hydro-pyran-4-yl)-isoxazol-5-yl]- phenylj-methanol

772. 7 [2-Oxo-2-(tetrahydro-pyran-4-yl)-ethyl]-phosphonic acid dimethyl ester

To a solution of methyl tetrahydro-2H-pyran-4-carboxylate (0.28mL) and dimethyl methylphosphonate (0.253mL) in THF (3.1mL) cooled at -5°C was added dropwise lithium diisopropylamide solution (1 M in THF/hexanes, 4.2mL) while maintaining the IT below 0°C. The reaction mixture was stirred at 0°C for 15min and the pH was adjusted to 6 by careful addition of aq. HCI (2M, 4.1 mL). The reaction mixture was extracted with DCM and the org. layer was dried (MgSO4), filtered and concentrated in vacuo. The crude was purified by CC (Biotage, SNAP 40g, solvent A: EA, solvent B: 9:1 EA/MeOH; gradient in %B: O over 1 min, O to 10 over 3min, 10 over 3min, 10 to 100 over 25min, 100 over 5min) to afford 395.6mg of the desired product as a colorless oil. LC-MS (A): t _R = 0.46min; [M+H] ⁺ : 237.39.

112.2 3-((S)-Hydroxy-(4-isopropyl-phenyl)-{3-[(E)-3-oxo-3-(tetrahy dro-pyran-4-yl)-propenyl]-phenyl}-methyl)-3-methyl- azetidine-1 -carboxylic acid tert-butyl ester

To a sealed vial charged with Example E3.6.1 (200mg) and Example 112.1 (134mg) were added EtOH (1.5mL) and K2CO3 (157mg). The reaction mixture was heated at 90°C for 30min, cooled at RT, diluted with water and extracted with EA (3x). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo. The crude was purified by CC (Biotage, SNAP 40g, solvent A: Hep, solvent B: EA; gradient in %B: 0 over 1 min, 0 to 10 over 3min, 10 over 5min, 10 to 60 over 15min, 60 over 5min) to afford 221.8mg of the title product as a white solid. LC-MS (A): t _R = 1.15min; [M+H] ⁺ : 534.46.

112.3 3-((S)-Hydroxy-(4-isopropyl-phenyl)-{3-[3-(tetrahydro-pyran- 4-yl)-isoxazol-5-yl]-phenyl}-methyl)-3-methyl- azetidine-1 -carboxylic acid tert-butyl ester

To a sealed vial charged with Example 112.2 (91.2mg) and hydroxylamine hydrochloride (36mg) were added EtOH (3.4mL) and DIPEA (0.182mL). The resulting solution was heated at 90°C for 45h, concentrated in vacuo, dissolved in MeCN and DMF, then purified by Prep LC-MS (XVIII) to afford 33.2mg of the title product as a white solid. LC-MS (A): t _R = 1.18min; [M+H] ⁺ : 547.26.

112.4 (S)-(4-lsopropyl-phenyl)-(3-methyl-azetidin-3-yl)-{3-[3-(tet rahydro-pyran-4-yl)-isoxazol-5-yl]-phenyl}-methanol Example 112.3 (30mg) was treated with HCI in dioxane (4M, 0.14mL) and the reaction mixture was stirred 1 h30 at RT and concentrated in vacuo to afford 26.5mg of the title product. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 447.40.

112.5 (S)-( 1, 3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(tetrah ydro-pyran-4-yl)-isoxazol-5-yl]-phenyl}- methanol

To a solution of Example 112.4 (26.5mg) in THF (0.3mL) were added formaldehyde (37wt% in water, 8.2piL), acetic acid (4.7piL) and NaBH(OAc)3 (18mg). The reaction mixture was stirred 1 h at RT and all the reagents were added in the same amount again. The reaction mixture was stirred 30min at RT, quenched with sat. NaHCOa and extracted with EA (3x). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo. The crude was purified by Prep LC-MS (III) to afford 9.2mg of the title product as a white solid. LC-MS (A): t _R = 0.86min; [M+H] ⁺ : 461.42.

Example 113: (1 , 3-D I methy I -azeti d I n-3-y I )- (4-isopropy l-pheny I )- [3-(3-methy l-isoxazol-5-y I )-pheny I] -meth anol

113.1 1 -{3-[Hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidin-3-yl)-m ethyl]-phenyl}-ethanone

To a solution of Example D1.1.1 (200mg) in EtaO (1.6mL) cooled at -78°C was added dropwise methyllithium (1.6M in EtaO, 1.34mL), while maintaining the IT below -70°C. The solution was allowed to slowly reach 0°C, stirred 2h at this temperature then quenched with careful addition of aq. HCI (2M, 1.5mL). The biphasic mixture was stirred 45min and the pH was adjusted to 10-11 by adding aq. NaOH (3M, 0.6mL). The aq. layer was extracted with EA (3x) and the combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to afford 154mg of the crude product as a yellow solid. LC-MS (A): t _R = 0.76min; [M+H] ⁺ : 338.24.

113.2 3-[(3-Acetyl-phenyl)-hydroxy-(4-isopropyl-phenyl)-methyl]-3- methyl-azetidine-1 -carboxylic acid tert-butyl ester To a suspension of Example 113.1 (154mg) and di-tert-butyl dicarbonate (64.6mg) in THF (1 ,2mL) was added dropwise TEA (68piL). The reaction mixture was stirred 3h at RT, concentrated in vacuo and the residue was purified (2x) by CC (Biotage, SNAP 24g, solvent A: DCM, solvent B: 9: 1 DCM/MeOH; gradient in %B: 0 over 1 min, 0 to 100 over 12min, 100 over 5min) to afford 59mg of the title product as a white foam. LC-MS (A): t _R = 1.12min; [M+H] ⁺ : 438.32.

113.33-{Hydroxy-(4-isopropyl-phenyl)-[3-(3-methyl-isoxazo l-5-yl)-phenyl]-methyl}-3-methyl-azetidine- 1 -carboxylic acid tert-butyl ester

A sealed vial was charged with Example 113.2 (56mg) and N,N-dimethylacetamide dimethyl acetal (0.13mL). The reaction mixture was heated at 90°C for 7h and N,N-dimethylacetamide dimethyl acetal (0.13mL) was added again. The reaction mixture was heated at 90°C for 8h, cooled at RT , diluted with water and extracted with EA (3x). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to afford 54.2mg of intermediate. It was dissolved in EtOH (2.5mL) and treated with hydroxylamine (50wt% in water, 12piL). The reaction mixture was heated at 95°C for 1 h, cooled at RT, concentrated in vacuo and the residue was purified by Prep LC-MS (XXI) to afford 13.9mg of the title product as a yellow solid. LC-MS (A): t _R = 1 ,04min; [M+H] ⁺ : 477.29.

113.4. (4-lsopropyl-phenyl)-(3-methyl-azetidin-3-yl)-[3-(3-methyl-i soxazol-5-yl)-phenyl]-methanol

Example 113.3 (13.9mg) was treated with HCI in dioxane (4M, 73piL) and the reaction mixture was stirred 1 h at RT and concentrated in vacuo. LC-MS (A): t _R = 0.81 min; [M+H] ⁺ : 377.27.

113.5 ( 1 ,3-Dimethyl-azetidin-3-yl) -( 4-isopropyl-phenyl) -[3-( 3-methyl-isoxazol-5-yl) -phenyl]-methanol

The title product was synthesized starting from Example 113.4 (12mg) and following the procedure described in Example B2, step 2. Purification by Prep LC-MS (V) afforded 5.8mg of the title product as a white glass. LC-MS (A): t _R = 0.84min; [M+H] ⁺ : 391.31.

Example 114: (1,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-(1-m ethoxy-cyclobutyl)-[1 ,2,4]oxadiazol-3-yl]- phenylj-methanol To a solution of 1-methoxycyclobutane-1 -carboxylic acid (13mg) in DMF (400|j L) was added GDI (17mg). The reaction mixture was stirred 1 h at RT and a solution of Example D1.1 (51.4mg) in DMF (400|ul_) was then added. The reaction mixture was stirred 1 h at RT, then heated at 105°C (IT maintained to 90°C) and stirred for 1.5h. The crude product was purified by Prep LC-MS (III) to afford 28mg of the title compound. LC-MS (A): IR = 0.90min; [M+H] ⁺ : 462.32.

Example 115 to Example 117 were synthesized starting from Example D1.1 and the appropriate carboxylic acid derivative and following the procedure described in Example 114. LC-MS data and purification methods of Example 115 to Example 117 are listed in the table below. The LC-MS conditions used were LC-MS (A).

Example 118: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-(tetra hydro-pyran-4-yl)-[1 ,2,4]oxadiazol-3-yl]- phenylj-methanol

118.1 ( 1,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5-( tetrahydro-pyran-4-yl)-[1 , 2, 4]oxadiazol-3-yl]-phenyl}- methanol

A sealed vial was charged with Example D1.1 (350mg), tetrahydropyran-4-carboxy lie acid (152mg) and HOBt (180mg). Dioxane (9.5mL) and DIPEA (0.49mL) were added followed by EDC' HCI (277mg). The reaction mixture was stirred 6h30 at 90°C, cooled down to RT and concentrated in vacuo. The residue was diluted in EA and extracted with aq. sat. NaHCOa. The two phases were separated and the aq. layer was extracted with EA (2x). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by Prep LC-MS (III) to afford 192mg of the compound as formic acid salt. It was partitioned between EA and aq. sat. NaHCOa. The two phases were separated and the aq. layer was extracted with EA (2x). The combined org. layers were dried (MgSO4), filtered off and concentrated in vacuo to afford 186mg of the product as a beige foam. LC-MS (A): IR = 0.84min; [M+H] ⁺ : 462.35.

118.2. (S)-(1,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[5- (tetrahydro-pyran-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}- methanol Example 118.1 (186mg) was purified by Prep chiral SFC (VI I). The yellow foam obtained was treated with HCI in dioxane (4M, 0.4mL) and concentrated in vacuo to give 102mg of the pure enantiomer as a yellow foam. Chiral SFC (G): t _R = 2.5min.

Example 119: (S)-{3-[5-((R)-Cyclohexyl-hydroxy-methyl)-[1 ,2,4]oxadiazol-3-yl]-phenyl}-(1 ,3-dimethyl-azetidin-3- yl)-(4-isopropyl-phenyl)-methanol

A sealed vial was charged with Example D1.2 (31 ,1 mg), R)-(-)-hexahydromandelic acid (11 , 1mg), PyBOP (50mg), K3PO4 (27.6mg), DMF (0.8mL) and DIPEA (17piL). The reaction mixture was stirred 16h at 80°C, cooled down to RT and purified by Prep LC-MS (III) to afford 14.6mg of the title compound. LC-MS (A): t _R = 0.91 min; [M+H] ⁺ : 490.26.

Example 120 to Example 124 were synthesized starting from Example D1.2 and the appropriate carboxylic acid derivative and following the procedure described in Example 119. LC-MS data and purification methods of Example 120 to Example 124 are listed in the table below. The LC-MS conditions used were LC-MS (A).

Example 125: (1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(4-met hyl-tetrahydro-pyran-4-yl)-

[1 ,2,4]oxadiazol-5-yl]-phenyl}-methanol 125. 1 (Z)-N'-hydroxy-4-methyltetrahydro-2H-pyran-4-carboximidamide

The title compound was synthesized starting from 4-methyltetrahydro-2H-pyran-4-carbonitrile (162mg) and following the procedure described in Example D1.1, step 4, to afford the corresponding hydroxyamidine. LC-MS (A): tR = 0.25min; [M+H] ⁺ : 159.26.

125.2 3-(Hydroxy-(4-isopropyl-phenyl)-{3-[3-(4-methyl-tetrahydro-p yran-4-yl)-[1,2,4]oxadiazol-5-yl]-phenyl}-methyl)-3- methyl-azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example E3.5 (40mg) and Example 125.1 (21.6mg), and following the procedure described in Example 52. The crude material was purified by Prep LC-MS (XVIII) to afford 21 mg of the title compound. LC-MS (A): tR = 1.19min; [M+H] ⁺ : 562.34.

125.3 (4-isopropylphenyl)(3-methylazetidin-3-yl)(3-(3-(4-methyltet rahydro-2H-pyran-4-yl)-1,2,4-oxadiazol-5- yl)phenyl)methanol

The title compound was synthesized starting from Example 125.2 and following the procedure described in Example 94, step 2. LC-MS (A): t _R = 0.86min; [M+H] ⁺ : 462.35.

125.4 ( 1, 3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(4-meth yl-tetrahydro-pyran-4-yl)-[ 1,2, 4]oxadiazol-5-yl]- phenyl}-methanol

The title compound was synthesized starting from Example 125.3 and following the procedure described in Example 72, step 3, and purified by Prep LC-MS (III) to afford 12.9mg of the title compound. LC-MS (A): t _R = 0.89min; [M+H] ⁺ : 476.35.

Example 126: 3-(5-(3-((1 ,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl) phenyl)-1,2,4-oxadiazol-3- yl)tetrahydrofuran-3-ol

126. 1 (Z)-N\3-dihydroxytetrahydrofuran-3-carboximidamide

The title compound was synthesized starting from 3-hydroxyoxolane-3-carbonitrile (146mg) and following the procedure described in Example D1.1, step 4, to afford the corresponding hydroxyamidine. LC-MS (A): t _R = 0.18min, [M+H] ⁺ : 147.26.

126.2 3-(5-(3-((1,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphe nyl)methyl)phenyl)-1,2,4-oxadiazol-3- yl) tetrahydrofuran-3-ol

The title compound was synthesized starting from Example E3.5 (40mg) and Example 126.1 (19.9mg), and following the 3 last steps of the procedure described in Example 125. Purification by Prep LC-MS (I) afforded 8mg of the title compound. LC-MS (A): t _R = 0.75min; [M+H] ⁺ : 464.34.

Example 127: (S)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1-methyl-1 H- pyrazol-3-yl)-but-3-yn-2-ol 727. 7 (S)-(3-Bromo-phenyl)-(4-isopropyl-phenyl)-(3-methyl-azetidin -3-yl)-methanol

Example 111.2 (532mg) was treated with HCI in dioxane (4M, 2.8mL) and the solution was stirred 1 h at RT, concentrated in vacuo and dried under HV to afford 503mg of the title compound as a white foam. LC-MS (A): t _R = 0.82min; [M+H] ⁺ : 374.08.

127.2. (S)-(3-Bromo-phenyl)-(1,3-dimethyl-azetidin-3-yl)-(4-isoprop yl-phenyl)-methanol

The title compound was synthesized starting from Example 127.1 and following the procedure described in Example C3.1 , step 3, then purified by Prep LC-MS (III) to afford 345mg of the title compound as a white foam. LC-MS (A): t _R = 0.85min; [M+H] ⁺ : 387.86.

127.3 (S) -4-{3-[ (S)-( 1, 3-Dimethyl-azetidin-3-yl) -hydroxy-( 4-isopropyl-phenyl) -methyl]-phenyl}-2-( 1 -methyl- 1 H-pyrazol- 3-yl)-but-3-yn-2-ol

A mixture of Example 127.2 (51.7mg), Example F6.1 (26mg), copper(l) iodide (0.6mg), tetrakis(triphenylphosphine)palladium (61.5mg), piperidine (65.7piL) in THF (2mL) was stirred at 80°C for 30min. The reaction mixture was allowed to cool down to RT, purified by Prep LC-MS (IV) and Prep LC-MS (I) to afford 18.5mg of the title compound as a white solid. LC-MS (A): t _R = 0.78min; [M+H] ⁺ : 458.27.

Example 128: (S)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1-methyl-1 H- pyrazol-3-yl)-butan-2-ol

A mixture of Example 127 (10.8mg) and Pd/C (2.3mg) in EtOH (0.82mL) was stirred at RT under H2 atmosphere for 2h. The reaction mixture was filtered through a syringe filter, the filter was washed with EtOH and the filtrate was evaporated and dried under HV to afford 9.8mg of the title product as a white solid. LC-MS (A): t _R = 0.76min; [M+H] ⁺ : 462.31 .

Example 129: (R)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1-methyl-1 H- pyrazol-3-yl)-but-3-yn-2-ol

The title compound was synthesized starting from Example 127.2 (47.8mg) and Example F6.2 (24mg), and following the procedure described in Example 127.3. Purification by Prep LC-MS (IV) and Prep LC-MS (I) afforded 14.2mg of the title compound as a white solid. LC-MS (A): t _R = 0.77min; [M+H] ⁺ : 458.27.

Example 130: (S)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1,5-dimethyl- 1 H-py razol-3-y l)-but-3-y n-2-ol

The title compound was synthesized starting from Example 127.2 (50mg) and Example F6.3 (31.7mg), and following the procedure described in Example 127.3. Purification by Prep LC-MS (I) and Prep LC-MS (VI I) afforded 12.2mg of the title compound as a white solid. LC-MS (A): t _R = 0.77min; [M+H] ⁺ : 472.28.

Example 131 : (R)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(1,5-dimethyl- 1 H-py razol-3-y l)-but-3-y n-2-ol

The title compound was synthesized starting from Example 127.2 (50mg) and Example F6.4 (31.7mg), and following the procedure described in Example 127.3. Purification by Prep LC-MS (I) and Prep LC-MS (VII) afforded 15.6mg of the title compound as a white solid. LC-MS (A): t _R = 0.77min; [M+H] ⁺ : 472.29. Example 132: (R)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(6-methyl- pyrimidin-4-yl)-but-3-yn-2-ol

The title compound was synthesized starting from Example 127.2 (50mg) and Example F6.5 (27.1 mg), and following the procedure described in Example 127.3. Purification by Prep LC-MS (IV) and Prep LC-MS (III) afforded 8.9mg of the title compound as a pale yellow solid. LC-MS (A): IR = 0.81 min; [M+H] ⁺ : 470.28.

Example 133: (S)-4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-2-(6-methyl- pyrimidin-4-yl)-but-3-yn-2-ol

The title compound was synthesized starting from Example 127.2 (50mg) and Example F6.6 (27.1 mg), and following the procedure described in Example 127. Purification by Prep LC-MS (IV) and Prep LC-MS (III) afforded 5.2mg of the title compound as a pale yellow solid. LC-MS (A): IR = 0.81 min; [M+H] ⁺ : 470.3.

Example 134: 4-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-piperazine-1- carboxylic acid 2-methoxy-ethyl ester

134. 1 4-{3-[(S)-( 1 -tert-Butoxycarbonyl-3-methyl-azetidin-3-yl)-hydroxy-(4-isop ropyl-phenyl)-methyl]-phenyl}- piperazine-1 -carboxylic acid 2-methoxy-ethyl ester

To a solution of Example F2 (20mg) and methoxyethyl chloroformate (5.78mg) in DCM (1 mL) was added DIPEA (15piL). The reaction mixture was stirred 2h at RT, concentrated in vacuo, and purified by Prep LC-MS (XXI) to afford 18.2mg of the title compound. LC-MS (A): IR = 1.11 min; [M+H] ⁺ : 582.35.

134.2 4-{3-[(S)-Hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidin-3- yl)-methyl]-phenyl}-piperazine-1 -carboxylic acid 2- methoxy-ethyl ester

Example 134.1 (10.5mg) was treated with HCI in dioxane (4M, 0.125mL) and the solution was stirred 2h at RT, concentrated in vacuo and dried under HV to afford 9.5mg of the title compound. LC-MS (B): IR = 0.79min; [M+H] ⁺ : 481.88.

134.3 4-{3-[(S)-(1,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl- phenyl)-methyl]-phenyl}-piperazine-1 -carboxylic acid 2-methoxy-ethyl ester

The title compound was synthesized starting from Example 134.2 (9.3mg) and following the procedure described in Example 72, step 3. Purification by Prep LC-MS (I) afforded 8mg of the title compound. LC-MS (B): IR = 0.81 min; [M+H] ⁺ : 496.12.

Example 135: Cyclopentyl-(4-{3-[(S)-(1,3-dimethyl-azetidin-3-yl)-hydroxy- (4-isopropyl-phenyl)-methyl]-phenyl}- piperazin- 1 -yl)-methanone

135.1 3-[(S)-[3-(4-Cyclopentanecarbonyl-piperazin-1-yl)-phenyl]-hy droxy-(4-isopropyl-phenyl)-methyl]-3-methyl- azetidine-1 -carboxylic acid tert-butyl ester

A mixture of Example F2 (20mg), cyclopentanecarboxylic acid (4.76mg), HATU (17.4mg) and DIPEA (15|dL) in DCM (0.5mL) was stirred overnight at RT, concentrated in vacuo and purified by Prep LC-MS (XVIII) to afford 21 ,4mg of the title compound. LC-MS (A): t _R = 1.16min; [M+H] ⁺ : 576.36. 135.2 Cyclopentyl-(4~{3-[(S)-hydroxy-(4-isopropyl-phenyl)-(3-methy l-azetidin-3-yl)-methyl]-phenyl}-piperazin-1-yl)- methanone

Example 135.1 (12.1 mg) was treated with HCI in dioxane (4M, 0.125mL) and the reaction mixture was stirred 2h at RT, concentrated in vacuo and dried under HV to afford 11 mg of the title compound. LC-MS (B): tR = 0.87min; [M+H] ⁺ : 476.16.

135.3 Cyclopentyl-(4-{3-[(S)-(1,3-dimethyl-azetidin-3-yl)-hydroxy- (4-isopropyl-phenyl)-methyl]-phenyl}-piperazin-1-yl)- methanone

The title compound was synthesized starting from Example 135.2 (10.8mg) and following the procedure described in Example 72, step 3. Purification by Prep LC-MS (I) afforded 10.7mg of the title compound. LC-MS (B): tR = 0.89min; [M+H] ⁺ : 490.16.

Example 136: N-{3-[(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-benzyl}-benzenesulfonamide

To a solution of Example D3 (67.8mg) in DMF (0.85mL) were added benzenesulfonyl chloride (24.1 pL) and DIPEA (58.3piL). The reaction mixture was stirred 2h30 at RT and purified by Prep LC-MS (III) to afford 27.9mg of the title compound as a white solid. LC-MS (A): tR = 0.86min; [M+H] ⁺ :479.29.

Example 137 : N-{3-[(1 , 3-D i methyl -azeti d i n-3-y I )-hyd roxy- (4-isopropy l-pheny l)-methy l]-benzy l}-2-(3-methoxy-pheny I)- acetamide

A mixture of Example D3 (50mg), 3-methoxy phenyl acetic acid (25.3mg), HATU (71.6mg) and DIPEA (65piL) in DMF (0.6mL) was stirred 2h30 at RT. Purification by Prep LC-MS (III) afforded 11 .1mg of the title compound as a white solid. LC-MS (A): t _R = 0.82min; [M+H] ⁺ :487.33.

Example 138: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-[3-(3-morpho lin-4-ylmethyl-[1 ,2,4]oxadiazol-5-yl)- phenyl]-methanol

138.1 3-{(S)-Hydroxy-(4-isopropyl-phenyl)-[3-(3-morpholin-4-ylmeth yl-[1,2,4]oxadiazol-5-yl)-phenyl]-methyl}-3-methyl- azetidine-1 -carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example E3.6 (150mg) and Example E9.6 (117mg), and following the procedure described in Example 52. Purification by Prep LC-MS (III) afforded 7mg of the title compound. LC-MS (A): t _R = 0.93min; [M+H] ⁺ : 563.38.

138.2 (S)-(4-isopropylphenyl)(3-methylazetidin-3-yl)(3-(3-(morphol inomethyl)-1,2,4-oxadiazol-5-yl)phenyl)methanol

The title compound was synthesized starting from Example 138.1 (7mg) and following the procedure described in Example 94, step 2, to afford 5mg of the desired product. LC-MS (A): t _R = 0.64min; [M+H] ⁺ : 463.16.

138.3 (S)-(1,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-[3-(3- morpholin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)-phenyl]- methanol The title compound was synthesized starting from Example 138.2 (5mg), and following the procedure described in Example 72, step 3, but using dioxane as solvent. The reaction mixture was purified by Prep LC-MS (I) to afford 1mg of the title compound as a white solid. LC-MS (A): t _R = 0.64min; [M+H] ⁺ : 477.29.

Example 139 to Example 146 were synthesized starting from Example E3.6 and the appropriate hydroxyamidine and following the 3-steps procedure described in Example 138. LC-MS data and purification methods of Example 139 to

Example 146 are listed in the table below. The LC-MS conditions used were LC-MS (A). Example 147: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[4-(tetra hydro-pyran-4-yl)-oxazol-2-yl]-phenyl}- methanol

7477 tert-butyl 3-( ( 1 S) -hydroxy ( 3-( ( 2-hydroxy- 1 -( tetrahydro-2H-pyran-4-yl)ethyl) carbamoyl)phenyl)(4- isopropylphenyl)methyl)-3-methylazetidine- 1 -carboxylate

A sealed vial was charged with Example E3.6 (100mg), 2-amino-2-(oxan-4-yl)ethan-1-ol hydrochloride (145mg), EDC' HCI (242mg) and NaCI (39.9mg). DMF (2.2mL) was added followed by 1-hydroxy-7-azabenzotriazole solution (0.6M in DMF, 0.57mL) and 4-methylmorpholine (0.31 mL). The reaction mixture was heated 30min at 50°C, cooled down to RT, filtered over a PTFE syringe filter and purified by Prep LC-MS (III) to afford 49.6mg of the title compound as a white solid. LC-MS (A): t _R = 0.98min; [M+H] ⁺ : 567.28.

147.2 tert-butyl 3-( ( 1 S) -hydroxy(4-isopropylphenyl) (3-(( 2-oxo- 1 -( tetrahydro-2H-pyran-4- yl)ethyl)carbamoyl)phenyl)methyl)-3-methylazetidine-1-carbox ylate

To a solution of Example 147.1 (21.4mg) in DCM (0.38mL) was added Dess-Martin periodinane (16.5mg). The reaction mixture was stirred 2h at RT and Dess-Martin periodinane (8.26mg) was again added. The reaction mixture was stirred 1 h at RT, quenched with aq. sat. NaHCOa and extracted with 4x DCM. The combined org. layers were filtered over a phase separator and concentrated in vacuo to afford the crude product as a white foam. LC-MS (A): t _R = 1.06min; [M+H] ⁺ : 565.24.

147.3 3-(( S)-Hydroxy-( 4-isopropyl-phenyl)-{3-[4-( tetrahydro-pyran-4-yl) -oxazol-2-yl]-phenyl}-methyl) -3-methyl- azetidine-1 -carboxylic acid tert-butyl ester

To a solution of iodine (19.2mg) in DCM (0.3mL) was added triphenylphosphine (polymer bound 3mmol/g, 25.1 mg). The mixture was stirred 5min at RT and TEA (21 piL) was added. The mixture was stirred 5min and a solution of Example 147.2 (21.3mg) in DCM (0.2mL) was added to the mixture. The dark reaction mixture was stirred at RT for 18h and concentrated in vacuo. MeCN and DMF were added and the mixture was filtered through a PTFE syringe filter and purified by Prep LC-MS (XVIII) to afford 7.8mg of the title compound as a light brown solid. LC-MS (A): t _R = 1.18min; [M+H] ⁺ : 547.10.

147.4 (S)-(4-isopropylphenyl)(3-methylazetidin-3-yl)(3-(4-(tetrahy dro-2H-pyran-4-yl)oxazol-2-yl)phenyl)methanol

Example 147.3 (7.8mg) was treated with HCI in dioxane (4M, 0.1 mL) and the reaction mixture was stirred 1 h at RT and concentrated in vacuo. LC-MS (A): t _R = 0.85min; [M+H] ⁺ : 447.28.

147.5 (S)-(1,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[4- (tetrahydro-pyran-4-yl)-oxazol-2-yl]-phenyl}-methanol

The title compound was synthesized starting from Example 147.4 (6.9mg), and following the procedure described in Example 72, step 3, and using dioxane as solvent. Purification by Prep LC-MS (III) afforded 3.5mg of the title compound as a white solid. LC-MS (A): t _R = 0.85min; [M+H] ⁺ : 461.28. Example 148: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(3-ethoxy-[1 ,2,4]oxadiazol-5-yl)-phenyl]-(4-isopropyl-phenyl)- methanol

148.1 3-[(S)-[3-(3-Amino-[1,2,4]oxadiazol-5-yl)-phenyl]-hydroxy-(4 -isopropyl-phenyl)-methyl]-3-methyl-azetidine-1- carboxylic acid tert-butyl ester

The title compound was synthesized starting from Example E3.6 (2g) and N-hydroxyguanidine sulfate (1.24g), and following the procedure described in Example 52. Purification by CC (Biotage, SNAP 50g, solvent A: DCM, solvent B: MeOH; gradient in %B: 1 over 4CV, 1 to 4.8 over 7.4CV) afforded 1 ,63g of the title compound. LC-MS (A): tR = 1 ,06min; [M+H] ⁺ : 479.3.

148.2 (S)-[3-(3-Chloro-[1,2,4]oxadiazol-5-yl)-phenyl]-(4-isopropyl -phenyl)-(3-methyl-azetidin-3-yl)-methanol

Example 148.1 (1.63g) was dissolved in HCI cone. (10mL) and the mixture was cooled down to 0°C. A solution of sodium nitrite (239mg) in water (1mL) was then added. It was allowed to warm to RT overnight, cooled again at 0°C, diluted with water and quenched with solid NaHCOa. The mixture was extracted with DCM (4x), the org. layers were filtered over a phase separator and concentrated in vacuo to afford 1.36g of the desired compound. LC-MS (A): tR = 0.85min; [M+H] ⁺ : 397.98.

148.3(S)-[3-(3-Chloro-[1,2,4]oxadiazol-5-yl)-phenyl]-(1,3 -dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-methanol

The title compound was synthesized starting from Example 149.2 (1.36g) and following the procedure described in Example B2, step 2, then purified by Prep LC-MS (II) to afford 47.7mg of the title compound. LC-MS (A): tR = 0.87min; [M+H] ⁺ : 412.17.

148.4 (S)-(1,3-Dimethyl-azetidin-3-yl)-[3-(3-ethoxy-[1,2,4]oxadiaz ol-5-yl)-phenyl]-(4-isopropyl-phenyl)-methanol

Example 148.3 (40mg) was treated with sodium ethoxide (80piL) in EtOH (1.7mL). The reaction mixture was stirred at 80°C overnight, then concentrated in vacuo. Purification by Prep LC-MS (III) and Prep LC-MS (II) afforded 9.5mg of the title compound. LC-MS (A): tR = 0.87min; [M+H] ⁺ : 422.30.

Example 149: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-[3-(3-morpho lin-4-yl-[1 ,2,4]oxadiazol-5-yl)-phenyl]- methanol

A mixture of Example 148.3 (40mg) and morpholine (172pL) in EtOH (2mL) was heated at 80°C under microwave irradiations for 18h. The reaction mixture was concentrated in vacuo and purified by Prep LC-MS (III) and Prep LC-MS (II) to afford 9.5mg of the title compound. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 463.07.

Example 150: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-(3-{3-[(2-me thoxy-ethyl)-methyl-amino]- [1 ,2,4]oxadiazol-5-yl}-phenyl)-methanol

The title compound was synthesized starting from Example 148.3 (40mg) and (2-methoxyethyl)methylamine (0.22mL) and following the procedure described in Example 149, then purified by Prep LC-MS (in) and Prep LC-MS (ii) to afford 9.9mg of the title compound. LC-MS (A): t _R = 0.85min; [M+H] ⁺ : 465.21. Example 151 : (1 S)-(3-(3-(6-oxa-3-azabicyclo[3.1 .1]heptan-3-yl)-1 ,2,4-oxadiazol-5-yl)phenyl)(1 ,3-dimethylazetidin-3- yl)(4-isopropylphenyl)methanol

A mixture of Example 148.3 (25mg), 6-Oxa-3-aza-bicyclo[3.1.1]heptane hydrochloride (165mg) and DIPEA (0.21 mL) in EtOH (0.5mL) was heated at 80°C under microwave irradiation for 8h. The reaction mixture was concentrated in vacuo and purified by Prep LC-MS (III) and Prep LC-MS (V) to afford 3.4mg of the title compound. LC-MS (A): IR = 0.81 min; [M+H] ⁺ : 475.22.

Example 152: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-{3-[3-((2R,6R)-2,6-dimethyl-morph olin-4-yl)-[1 ,2,4]oxadiazol-5-yl]- phenyl}-(4-isopropyl-phenyl)-methanol

A solution of 148.3 (25mg) in (2R,6R)-2,6-dimethylmorpholine (0.49mL) was heated at 80°C under microwave irradiations for 8h. The reaction mixture was concentrated in vacuo and purified by Prep LC-MS (III) and Prep LC-MS (II) to afford 4.3mg of the title compound. LC-MS (A): IR = 0.87min; [M+H] ⁺ : 491.24.

Example 153: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-{3-[3-(2-met hoxy-ethoxy)-[1 ,2,4]oxadiazol-5-yl]- phenylj-methanol

To a solution of 2-methoxy-ethanol (39piL) in THF (1 mL) was added NaH (19.4mg). The reaction mixture was stirred 30min at RT and a solution of Example 148.3 (40mg) in THF (1 mL) was added. The reaction mixture was stirred overnight at RT, quenched with aq. sat. NH4CI and extracted with DCM (3x). The org. layers were filtered over a phase separator, concentrated in vacuo and the residue was purified by Prep LC-MS (III) and Prep LC-MS (II) to afford 1.5mg of the title compound. LC-MS (A): IR = 0.83min; [M+H] ⁺ : 452.31.

Example 154 (3-Amino-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol

154. 1 3-(9H-Fluoren-9-ylmethoxycarbonylamino)-azetidine-1,3-dicarb oxylic acid mono-tert-butyl ester

To a solution of 3-amino-1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid, trifluoroacetic acid salt (100mg) in water (8mL), was added sodium carbonate (152mg) followed by a solution of Fmoc chloride (228mg) in dioxane (6mL) at RT. The resulting emulsion was stirred at RT for 3h before it was diluted with water and extracted with tBME (2x). The aq. layer was acidified with 1 M HCI and re-extracted with EA (3x). The combined org. layers were dried (MgSO4), filtrated off and concentrated in vacuo to afford 105mg of the title compound as yellowish resin. LC-MS (A): t _R = 0.94min; [M+H] ⁺ : 439.23.

154.2 3-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(methoxy-methyl-ca rbamoyl)-azetidine-1 -carboxylic acid tert-butyl ester

Example 154.1 (1.3g) was added to a solution of HATU (1.38mg) in DMF (15mL) and DIPEA (1.54mL). Then N,O- dimethylhydroxylamine hydrochloride (354mg) was added at RT and the resulting brown suspension was stirred at RT. After 2h the mixture was diluted with EA and extracted with water and NH4CI aq. sat. The aq. layer were re-extracted with EA 2x. The combined org. layer were dried (MgSO4) and concentrated in vacuo. Purification by CC (Biotage, 50g snap, A: Hep, B: EA; gradient (in %B): 30 for 3CV, 30 to 50 over 3CV, 50 for 5CV) afforded 750mg of the title compound as white solid. LC-MS (A): t _R = 1.02min; [M+H] ⁺ : 481.70.

154.3 3-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(4-trifluoromethox y-benzoyl)-azetidine-1 -carboxylic acid tert-butyl ester

To a solution of Example 154.2 (100mg) in THF (2mL) was added 4-(trifluoromethxy)phenylmagnesium bromide (0.5M in THF, 830 pi L) slowly at 0°C. The resulting solution was stirred at RT for 2h, subsequently quenched with water and extracted with DCM (3x). The combined org. layers were dried (MgSCh), concentrated in vacuo and purified by CC (Biotage, 10g snap, A: Hep, B: EA; gradient (in %B): 30 for 3CV, 30 to 50 over 3CV, 50 for 5CV) to afford 83mg of the title compound. LC-MS (A): t _R = 1.16min; [M+H] ⁺ : 583.15.

154.4 3-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-[hydroxy-(4-phenox y-phenyl)-(4-trifluoromethoxy-phenyl)-methyl]- azetidine-1 -carboxylic acid tert-butyl ester

To a solution of Example 154.3 (80mg) in THF (1.5mL) cooled to -10°C was added 4-phenoxyphenylmagnesium bromide (0.5M in THF, 963piL) dropwise. After 5h the mixture was quenched by addition of aq. sat. NH4CI, extracted with EA and washed with water. The aq. layer were re-extracted with EA (2x). The combined org. layers were dried (MgSO4), concentrated in vacuo and purified by CC (Biotage, 10g snap, A: Hep, B: EA; gradient (in %B): 0 for 2CV, 0 to 10 over 3CV, 10 to 20 over 2CV, 20 for 3CV) to afford 20mg of the title compound as white solid. LC-MS (A): t _R = 1.28min; [M+H] ⁺ : 753.16.

154.5 {3-[Hydroxy-(4-phenoxy-phenyl)-(4-trifluoromethoxy-phenyl)-m ethyl]-azetidin-3-yl}-carbamic acid 9H-fluoren-9- ylmethyl ester

A solution of Example 154.4 (20mg) in 4M HCI in dioxane (500piL) was stirred at RT for 1 h, then the mixture was evaporated and dried at HV to afford 18mg of the title compound. LC-MS (A): t _R = 1.03min; [M+H] ⁺ : 653.11.

154.6 {3-[Hydroxy-(4-phenoxy-phenyl)-(4-trifluoromethoxy-phenyl)-m ethyl]-1-methyl-azetidin-3-yl}-carbamic acid 9H- fluoren-9-ylmethyl ester

To a solution of Example 154.5 (315mg) in MeOH (5mL) were added formaldehyde 37% in water (306piL), AcOH (500 pi L) and NaBH(OAC)3 (300mg) at RT. The resulting suspension was stirred at RT for 4h. The mixture was quenched with water and concentrated in vacuo. The crude was basified with aq. sat. NaHCOa and extracted with EA (3x). The combined org. layers were dried (MgSO4), filtrated off and concentrated in vacuo to afford 270mg of the desired compound as beige foam. LC-MS (A): t _R = 1.04min; [M+H] ⁺ : 667.14.

154.7 (3-Amino-1-methyl-azetidin-3-yl)-(4-phenoxy-phenyl)-(4-trifl uoromethoxy-phenyl)-methanol

To a solution of Example 154.6 (50mg) in DCM (500piL) was added diethylamine (31 OpiL) at RT and stirred for 4h. The reaction mixture was concentrated in vacuo and purified by Prep LC-MS (IV). The reside was dissolved in DCM, acidified with HC1 1 M to pH=2 and extracted with DCM (2x). The aq. layer was basified with NaOH 2M to pH=12 and re-extracted with DCM (2x). The combined org. layers from the basic extraction were dried (MgSO4), filtrated off and concentrated in vacuo to afford 7mg of the tile compound as a colourless resin. LC-MS (A): t _R = 0.84min; [M+H] ⁺ : 445.17 Example 155 (1 ,3-Dimethyl-azetidin-3-yl)-phenyl-(4-trifluoromethoxy-phenyl )-methanol

155. 1 3-[Hydroxy-phenyl-(4-trifluoromethoxy-phenyl)-methyl]-3-meth yl-azetidine-1-carboxylic acid tert-butyl ester

The title compound was synthesized using Example A4.1 and phenylmagnesium bromide following the procedure described in Example E1.1 , omitting the purification and used directly in the next step. LC-MS (A): t _R = 1.01 min; [M+H] ⁺ : 438.15.

155.2 (1,3-Dimethyl-azetidin-3-yl)-phenyl-(4-trifluoromethoxy-phen yl)-methanol

A solution of Example 155.1 (65.6mg) in THF (954|dL) was added dropwise to a heated (68°C) suspension of LiAIFk (2.4M in THF, 250piL) and the mixture was stirred at 68°C for 35min, allowed to cool down to RT and quenched with MeOH. Then aq. sat. solution of Seignette's salt was added (1mL). The mixture was filtered, dried (MgSC>4), concentrated in vacuo and purified by Prep LC-MS (V) to give 28mg of a white solid. LC-MS (A): t _R = 0.73min; [M+H] ⁺ : 352.06.

Example 156 (3-Chloro-phenyl)-(1 ,3-dimethyl-pyrrolidin-3-yl)-(4-trifluoromethoxy-phenyl)-met hanol

156. 1 N-methoxy-N, 1,3-trimethylpyrrolidine-3-carboxamide

The title compound was synthesized following the procedure described in Example 154, step 2, using 1 ,3- dimethylpyrrolidine-3-carboxylic acid (1000mg) but purified by CC (Biotage, 100g snap, A: DCM, B: DCM/MeOH 8/2; gradient (in %B): 15 for 3CV, 15 to 30 over 2CV, 30 for 3CV, 30 to 50 over 2CV) to afford 880mg yellow resin. LC-MS (A): t _R = 0.35min; [M+H] ⁺ : 187.37.

156.2 (1, 3-Dimethyl-pyrrolidin-3-yl)-(4-trifluoromethoxy-phenyl)-meth anone

The title compound was synthesized following the procedure described in Example A4.1 using Example 156.1 (880mg) but purified by CC (Biotage, SNAP 50g, A: DCM, B: DCM/MeOH 8/2; gradient (in %B): 15 for 3CV, 15 to 30 over 4CV, 30 for 3CV) to afford 470mg of the desired product as an orange oil. LC-MS (A): t _R = 0.66min; [M+H] ⁺ : 288.17.

156.3 (3-Chloro-phenyl)-( 1, 3-dimethyl-pyrrolidin-3-yl)-(4-trifluoromethoxy-phenyl)-meth anol

To a solution of Example 156.2 (50mg) in THF (1 mL) was added 3-chlorophenylmagnesium bromide (0.5M in THF, 696piL) at 0°C and the mixture stirred overnight at RT. The reaction mixture was quenched with water, extracted with DCM (3x), dried (MgSO4), filtrated off, concentrated in vacuo. Purification by Prep LC-MS (V) afforded 13mg colorless resin. LC-MS (A): t _R = 0.83min; [M+H] ⁺ : 400.22.

Example 157 (1 ,3-Dimethyl-pyrrolidin-3-yl)-(4-phenoxy-phenyl)-(4-trifluoro methoxy-phenyl)-methanol

The title compound was synthesized following the procedure described in Example 156, step 3, using 4- phenoxyphenylmagnesiumbromide (0.5M in THF) to afford 26mg of the title compound as colourless resin. LC-MS (A): t _R = 0.89min; [M+H] ⁺ : 458.2.

Example 158: 1-[4-(3-{3-[(S)-(3-Fluoro-1-methyl-azetidin-3-yl)-hydroxy-(4 -isopropyl-phenyl)-methyl]-phenyl}- [1 ,2,4]oxadiazol-5-yl)-piperidin-1-yl]-ethanone

158.1 3-[(S)-(3-Fluoro-1-methyl-azetidin-3-yl)-hydroxy-(4-isopropy l-phenyl)-methyl]-benzonitrile To a suspension of Example A7.2 (180mg) in DCM (2.5mL) at 0°C was added aq. formaldehyde (37wt%, 0.11 mL) and after 5min of stirring NaBH(OAc)3 (163mg). After stirring at 0°C for 75min, more NaBH(OAc)3 (40mg) was added and the mixture was stirred for another 30min. The reaction mixture was purified by Prep HPLC (IV) to give 136mg of the desired product as a white solid. LC-MS (A): IR = 0.75min; [M+H] ⁺ : 339.22.

Example 158.2 (S,Z)-3-((3-fluoro-1-methylazetidin-3-yl)(hydroxy)(4-isoprop ylphenyl)methyl)-N'-hydroxybenzimidamide Example 158.1 (140mg) was treated according to the procedure described for Example D1.1 , step 4, to give the desired product as a grey solid (188mg). LC-MS (A): IR = 0.74min; [M+H] ⁺ : 372.22.

158.3. 1 -[4-(3-{3-[(S)-(3-Fluoro-1-methyl-azetidin-3-yl)-hydroxy-(4- isopropyl-phenyl)-methyl]-phenyl}-[ 1, 2,4]oxadiazol- 5-yl)-piperidin- 1 -yl]-ethanone

A mixture of Example 158.2 (93mg), 1 -acetylpiperidine-4-carboxylic acid (48mg), PyBOP (326mg) and K3PO4 (175mg) in DMF (1.5mL) was treated with DIPEA (0.11mL). The mixture was heated to 85°C and stirred for 18h. After cooling to RT, the reaction mixture was diluted with EA, washed with aq. NaHCOs and brine (2x), dried (Na2SO4), filtered and concentrated in vacuo to give a yellow oil. The residue was purified by Prep LC-MS (IV) to give 53mg of the title compound as a slightly yellow solid. LC-MS (A): IR = 0.79min; [M+H] ⁺ : 507.33.

Example 159: 2-(3-{3-[(S)-(1-Cyclopropyl-3-fluoro-azetidin-3-yl)-hydroxy- (4-isopropyl-phenyl)-methyl]-phenyl}- [1 ,2,4]oxadiazol-5-yl)-propan-2-ol

159. 1 3-[(S)-( 1 -Cyclopropyl-3-fluoro-azetidin-3-yl)-hydroxy-(4-isopropyl-ph enyl)-methyl]-benzonitrile

To a solution of Example A7.2 (50mg) in MeOH (5mL) was added (l-ethoxycyclopropoxy)trimethylsilane (0.59mL), acetic acid (0.11mL) and NaBHsCN (128mg). The suspension was heated to 65°C and stirred for 2h, then the temperature was reduced to 55°C and the mixture was heated for 15h. The reaction mixture was filtered, diluted with DCM and washed with aq. NaHCOs. The aq. phase was re-extracted with DCM/MeOH (9:1). The combined org. layers were passed through a phase separator and concentrated in vacuo. The resulting colorless oil was further purified by Prep LC-MS (V) to give 226mg of the desired product as a white solid. LC-MS (A): IR = 0.79min; [M+H] ⁺ : 365.22.

159.2 (S,Z)-3-((1-cyclopropyl-3-fluoroazetidin-3-yl)(hydroxy)(4-is opropylphenyl)methyl)-N'-hydroxybenzimidamide

Example 159.1 (217mg) was treated according to the procedure described for Example D1.1, step 4, to give 330mg of the desired product as a white solid. It was used in the next step without further purification. LC-MS (A): IR = 0.57min; [M+H] ⁺ : 398.25.

159.32-(3-{3-[(S)-(1-Cyclopropyl-3-fluoro-azetidin-3-yl)- hydroxy-(4-isopropyl-phenyl)-methyl]-phenyl}-[1,2,4]oxadiazo l- 5-yl)-propan-2-ol

Example 159.2 (69mg) was subjected to the reaction conditions described for Example 158, step 3, but using alphahydroxybutyric acid as the corresponding carboxylic acid. The reaction was heated 15h at 85°C and 5h at 90°C. The product was purified by Prep LC-MS (V) and Prep LC-MS (III) to give 4mg of the title compound as a white solid. LC- MS (A): t _R = 0.80min; [M+H] ⁺ : 466.08. Example 160 to Example 169 were synthesized from Example D1.2 according to the procedure described in Example 119 and using the corresponding carboxylic acids indicated in the table below (if not commercial). The Prep LC-MS purification methods as well as retention times and observed mass of the LC-MS (A) are also shown in the table.

Example 170: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-(4-isopropyl-phenyl)-(3-[1,2,4]ox adiazol-3-yl-phenyl)-methanol

To a solution of Example D1 .2 (50mg) in DMA (0.46mL) was added trimethyl orthoformate (0.14mL) and boron trifluoride diethyletherate (5mg). The mixture was heated to 50°C and stirred for 18h. More trimethyl orthoformate (0.14mL) and boron trifluoride diethyletherate (20mg) were added, the mixture was heated to 80°C and stirred for 3h. The mixture was cooled to RT, treated with TEA (0.04mL) and aq. sat. NaHCOa, then extracted (2x) with DCM/MeOH (9: 1). The combined org. layers were passed through a phase separator and concentrated in vacuo. The residue was purified by Prep LC-MS (V) and Prep LC-MS (I) to give the desired product as a white solid (6mg). LC-MS (A): t _R = 0.78min; [M+H] ⁺ : 378.21. Example 171 : (S)-3-(3-((1 ,3-dimethylazetidin-3-yl)(hydroxy)(4-isopropylphenyl)methyl) phenyl)-1,2,4-oxadiazol-5(4H)- one

To a solution of Example D1.2 (50mg) and DBU (0.05mL) in dioxane (0.84mL) was added GDI (33mg). The mixture was heated to 100°C and stirred for 1 h. The reaction was cooled to RT diluted with MeCN and directly purified by Prep LC-MS (XI) and Prep LC-MS (I) to give 23 mg of the desired product as a white solid. LC-MS (A): t _R = 0.71 min; [M+H] ⁺ : 394.22.

Example 172: (S)-(1 ,3-Dimethyl-azetidin-3-yl)-[3-(5-hydroxymethyl-[1 ,2,4]oxadiazol-3-yl)-phenyl]-(4-isopropyl-phenyl)- methanol To a solution of Example 165 (7mg) in MeOH (0.5mL) was added K2CO3 (11 mg). The reaction was stirred at RT for 1 h. The mixture was diluted with MeCN, filtered and directly purified by Prep LC-MS (VII) to give 5mg of the desired product as a white solid. LC-MS (A): t _R = 0.74min; [M+H] ⁺ : 408.25.

Example 173: 1-[4-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}- [1 ,2,4]oxadiazol-3-yl)-piperidin-1-yl]-2-hydroxy-ethanone

173.1 2-(teit-Butyl-diphenyl-silanyloxy)-1-[4-(5-{3-[(S)-(1,3-dime thyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)- methyl]-phenyl}-[ 1,2, 4]oxadiazol-3-yl)-piperidin-1-yl]-ethanone

A mixture of Example E3.1 (50mg), Example E9.2 (211 mg), PyBOP (207mg), K3PO4 (111 mg), DMF (0.64mL) and DIPEA (50mg) was heated to 80°C and stirred for 16h. After cooling to RT, the reaction mixture was diluted with MeCN and directly subjected to Prep LC-MS (XXI) and Prep LC-MS (XXI) to give the desired product as a white solid (11 mg) in 60% purity. LC-MS (A): t _R = 1.08min; [M+H] ⁺ : 757.07.

173.2.2 1-[4-(5-{3-[(S)-(1 ,3-Dimethyl-azetidin-3-yl)-hydroxy-(4-isopropyl-phenyl)-meth yl]-phenyl}-[1 ,2,4]oxadiazol-3-yl)- piperidin-1-yl]-2-hydroxy-ethanone

To a solution of Example 173.1 (11 mg) in THF (0.2mL) was added a solution of TBAF in THF (1.0 M, 5mg). The mixture was stirred at RT for 2h, diluted with MeCN and directly subjected to purification by Prep LC-MS (II) to give 2mg of the desired product as a white solid. LC-MS (A): t _R = 0.77min; [M+H] ⁺ : 519.27.

Example 174 to Example 178 were synthesized from Example E3.1 and the corresponding amidoximes, according to the procedure described for Example 173.1. The Prep LC-MS purification methods as well as retention times and observed mass of the LC-MS (A) are shown in the table below.

Example 179

3-[(S)-Hydroxy-(4-isopropyl-phenyl)-(3-methyl-azetidin-3- yl)-methyl]-benzoic acid tert-butyl ester

To a solution of Example E3.1.1 (2.45g) in EA (100mL) was added a solution of HCI in dioxane (4 M, 6.3mL). The mixture was stirred at RT for 7 days. The solvent was evaporated and the residue was purified by Prep LC-MS (XXVII) to give 1.4g of the desired product as a white foam. LC-MS (A): IR = 0.86min; [M+H] ⁺ : 396.42.

II. BIOLOGICAL ASSAYS

FLIPR assay: The bioactivity of compounds is tested in a fluorometric imaging plate reader (FLIPR: Molecular Devices) using engineered HEK-293 cells expressing the human CCR6 (GenBank: AY242126). Frozen cells are plated on Poly- L-Lysine precoated 384-well plates 2 days prior to bioassay in DMEM medium supplemented with 10% FCS and 1 % Penici II in-Streptomyci n. At the day of bioassay, cell supernatant is discarded and cells are dye loaded for 30minutes at room temperature in the dark with Fluo-8-AM (Focus Biomolecules) in Hanks Balanced Salt Solution (Gibco), buffered with 20mM Hepes at pH 6.75 and supplemented with 0.05 % BSA. This buffer, but lacking the dye, is also used for washing and compound dilution steps (assay buffer). Cells are washed free of excess dye with a wash-station (Biotek), leaving 40 microliter of assay buffer at the end. Cells were incubated for 15minutes at room temperature in the dark, before adding compounds. Stock solutions of test compounds are made up at a concentration of 10mM in DMSO, and serially diluted first in DMSO and then transferred in assay buffer to concentrations required for inhibition dose response curves. After a 45minute incubation period in assay buffer at room temperature, 10 microliters of each compound dilution are transferred from a compound plate to the plate containing the recombinant cells in the FLIPR instrument according to the manufacturer's instructions. After cells and compounds were preincubated for 30minutes at room temperature in the dark, 10 microliter agonist CCL20 (Peprotech) at a final concentration of 10 nM is added, again using the FLIPR instrument. Changes in fluorescence are monitored before and after addition of the test compounds and agonist. Emission peak values above base level after CCL20 addition are exported after base line subtraction. The calculated IC50 values may fluctuate depending on the daily assay performance. Fluctuations of this kind are known to those skilled in the art. In the case where I C50 values have been determined several times for the same compound, mean values are given. Data are shown in the table below.